US 20170172961A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172961 A1 HELLER et al. (43) Pub. Date: Jun. 22, 2017

(54) PHARMACEUTICAL SUSPENSIONS Publication Classification CONTAINING DRUG PARTICLES, DEVICES FOR THEIR ADMINISTRATION, AND (51) Int. Cl. METHODS OF THEIR USE A63L/98 (2006.01) A6IR 9/14 (2006.01) (71) Applicant: Synagile Corporation, Wilson, WY A69/06 (2006.01) A6II 47/8 (2006.01) (US) A6IR 9/00 (2006.01) (72) Inventors: Adam HELLER, Austin, TX (US); A69/10 (2006.01) Ephraim HELLER, Wilson, WY (US); A6II 47/12 (2006.01) Karl Göran WESTERBERG, San A6II 47/34 (2006.01) Giovanni d'Asso (IT): John A61, 7/00 (2006.01) SPIRIDIGLIOZZI, Boston, MA (US) A6II 47/02 (2006.01) (52) U.S. Cl. CPC ...... A61K 31/198 (2013.01); A61J 7/0076 (21) Appl. No.: 15/448,208 (2013.01); A61K 9/14 (2013.01); A61K 9/06 (2013.01); A61K 47/02 (2013.01); A61 K (22) Filed: Mar. 2, 2017 9/0053 (2013.01); A61K 9/10 (2013.01); A61 K 47/12 (2013.01); A61K 47/34 (2013.01); A61 K Related U.S. Application Data 47/183 (2013.01) (63) Continuation of application No. PCT/US2016/ (57) ABSTRACT 03.1308, filed on May 6, 2016. The invention features a pharmaceutical Suspension contain (60) Provisional application No. 62/292,072, filed on Feb. ing drug particles, a drug delivery device anchored in the 5, 2016, provisional application No. 62/157,806, filed mouth for continuously administering the pharmaceutical on May 6, 2015. Suspension, and methods of their use.

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US 2017/0172961 A1 Jun. 22, 2017

PHARMACEUTICAL SUSPENSIONS temporarily or permanently increase or decrease the drug CONTAINING DRUG PARTICLES, DEVICES delivery rate from the device. Intra-oral drug delivery FOR THEIR ADMINISTRATION, AND devices must also administer the drug into a Suitable location METHODS OF THEIR USE in the mouth, e.g., to a location where it can be immediately Swallowed or to a location where the drug does not accu FIELD OF THE INVENTION mulate in an unwanted manner. There is, therefore, a need for improved drug delivery devices that can operate com 0001. The invention features a pharmaceutical suspen sion containing drug particles, a drug delivery device fortably, safely, and reliably in the mouth over extended anchored in the mouth for continuously administering the periods of time. pharmaceutical Suspension, and methods of their use. 0005 Intra-oral pumps have previously been proposed in inconvenient formats, e.g., wherein the device can be BACKGROUND located within a replacement tooth. There is a need for improved intra-oral drug delivery devices that can conve 0002. This invention relates to devices and methods for niently be inserted and removed by the patient, without continuous or semi-continuous drug administration via the requiring the insertion or removal of a replacement tooth, oral route. It is an aim of this invention to solve several dental bridge, or denture. A problem with these and other problems related to drugs with short physiological half-lives pumps that reside in the mouth and that can continuously of drugs (e.g., shorter than 8 hours, 6 hours, 4 hours, 2 hours, deliver drug in the mouth, such as controlled release osmotic 1 hour, 30 min, 20 min or 10 min) and/or narrow therapeutic tablets and muco-adhesive drug delivery patches, can be that windows of drugs that are currently dosed multiple times per once drug delivery has begun it cannot be temporarily day: it is inconvenient to take a drug that must be dosed stopped. Temporarily stopping the drug delivery can be multiple times per day or at night, the drug's pharmacoki desirable so that drug is not wasted and, more importantly, netics and efficacy may be sub-optimal, and side effects may so that dispensed drug does not accumulate on the Surface of increase in frequency and/or severity. Continuous or semi the device while the device is removed from the mouth. continuous administration can be particularly beneficial for Such an unquantified accumulation of drug on the Surface of drugs with a short half-life (e.g., in the plasma), and/or short the device might lead to the undesired delivery of a bolus of persistence of the drug's physiological effect, and/or a an unknown quantity of drug to the patient when the device narrow therapeutic window, such as levodopa (LD), muscle is placed back into the mouth. Maintenance of accurate rate relaxants (e.g., baclofen for managing spasticity), anti-epi of drug delivery when the ambient atmospheric pressure leptics (e.g., Oxcarbazepine, topiramate, lamotrigine, gaba changes, e.g., during air-travel or at elevated locations, can pentin, carbamazepine, Valproic acid, levetiracetam, pre also be challenging. gabalin), parasympathomimetics (e.g., pyridostigmine) and sleep medications (e.g., Zaleplon). Continuous or semi 0006. The pumps of the invention can provide constant continuous infusion in the mouth can provide for lesser rate, continuous administration of drugs in the mouth, and in fluctuation in the concentration of a drug in an organ or fluid, Some embodiments can be temporarily stopped when the for example in the blood or plasma. Convenient, automatic devices are removed from the mouth. administration of a drug can also increase patient compli 0007 Most drugs intended for oral administration have ance with their drug regimen, particularly for patients who been formulated as Solids (e.g., pills, tablets), Solutions, or must take medications at night and for patients with demen Suspensions that are administered once or several times per tia. day. Such drugs are not formulated to meet the requirements 0003 Medical conditions managed by continuously of continuous or semi-continuous, constant-rate, intra-oral orally administered drugs include Parkinson's disease, spas administration. For example, many suspensions and solu ticity, muscular weakness, bacterial infections, cancer, pain, tions have been formulated in relatively large daily volumes organ transplantation, disordered sleep, epilepsy and sei that don’t fit in the mouth without interfering with its Zures, anxiety, mood disorders, post-traumatic stress disor functions, particularly with speech, and/or in formulations der, arrhythmia, hypertension, heart failure, dementia, aller that are physically or chemically unstable over the course of gies, and diabetic nephropathy. a day at body temperature; and pills and tablets have rarely 0004. A challenge with most drug delivery devices in the been formulated in units and dosage amounts appropriate for prior art can be that they are not designed for placement and dosing frequently throughout the day. operation in the mouth. Devices must be designed to be 0008 Large quantities of drug must be administered to Small, comfortable, and non-irritating, and to not interfere treat some diseases. For example, 1,000 mg of levodopa is with speech, Swallowing, drinking and/or eating. In the a typical daily dose administered to patients with advanced mouth saliva, food or drink may penetrate into the drug Parkinson's disease. In order to continuously administer reservoir and/or the pump, thereby potentially unpredictably Such large quantities of drug into the mouth in a fluid volume extracting and delivering the drug, reacting with the drug, or that will fit comfortably in the mouth (typically less than 5 clogging the delivery device. Pumps that have been Sug mL) for many hours, it is sometimes necessary to employ gested for operation in the mouth, Such as osmotic tablets concentrated, often viscous, fluid formulations of the drug. and mucoadhesive patches, often do not reliably provide Use of viscous fluids can provide the small volumes, high constant rate drug delivery for extended periods of time concentrations, uniform drug dispersion, storage stability, under the conditions in the mouth. Drinking of hot or cold and operational stability desired for the drugs and methods beverages may cause undesirable changes in drug delivery, of the invention. Consequently, it is often necessary to e.g., delivery of a drug bolus. Likewise, Sucking on the employ miniaturized pumps tailored to provide the pressures device may cause delivery of an unwanted bolus. Exposure required to pump the viscous fluids. The drug devices and to foods and liquids such as oils, alcohols, and acids may formulations of the invention address these unmet needs. US 2017/0172961 A1 Jun. 22, 2017

0009. As a specific example, Parkinson's disease (PD) is to about 30%, or from about 28% to about 30%) of one or characterized by the inability of the dopaminergic neurons in more water-immiscible compounds, (iii) from about 2% to the Substantia nigra to produce the neurotransmitter dop about 16% (w/w) (e.g., from about 2% to about 15%, from amine. PD impairs motor skills, cognitive processes, auto about 2% to about 13%, from about 2% to about 12%, from nomic functions, and sleep. Motor symptoms include about 2% to about 10%, from about 2% to about 8%, from tremor, rigidity, slow movement (bradykinesia), and loss of about 2% to about 6%, from about 2% to about 4%, from the ability to initiate movement (akinesia) (collectively, the about 4% to about 13%, from about 6% to about 13%, from “off” state). Non-motor symptoms of PD include dementia, about 8% to about 13%, from about 6% to about 10%, from dysphagia (difficulty Swallowing), slurred speech, orthos about 10% to about 13%, or from about 13% to about 16%) tatic hypotension, seborrheic dermatitis, urinary inconti water, and (iv) from about 1% to about 8% (w/w) (e.g., from nence, constipation, mood alterations, sexual dysfunction, about 1% to about 7%, from about 1% to about 5%, from and sleep issues (e.g., daytime somnolence, insomnia). about 1% to about 3%, from about 3% to about 8%, or from 0010. After more than 40 years of clinical use levodopa about 5% to about 8%) surfactant, wherein the pharmaceu (LD) therapy remains the most effective method for man tical composition is physically stable and Suitable for con aging PD and provides the greatest improvement in motor tinuous or frequent intermittent intra-oral delivery. In some function. Consequently, LD administration is the primary embodiments, the pharmaceutical composition includes a treatment for PD. LD is usually orally administered. The drug particle-containing emulsion. orally administered LD enters the blood and part of the LD 0014. In a second aspect, the invention features a phar in the blood crosses the blood brain barrier. It is metabolized, maceutical composition including a Suspension including (i) in part, in the brain to dopamine which temporarily dimin from about 35% to about 75% (w/w) (e.g., as described ishes the motor symptoms of PD. As the neurodegeneration herein) drug particles, (ii) from about 19% to about 30% underlying PD progresses, the patients require increasing (w/w) (e.g., as described herein) of one or more water doses of LD and the fluctuations of brain dopamine levels immiscible compounds, (iii) from about 2% to about 16% increase. When too much LD is transported to the brain, (w/w) (e.g., as described herein) water, and (iv) from about dyskinesia sets in (uncontrolled movements such as writh 1% to about 8% (w/w) surfactant, wherein the pharmaceu ing, twitching and shaking); when too little is transported, tical composition is physically stable and Suitable for con the patient re-enters the off state. Furthermore, as PD pro tinuous or frequent intermittent intra-oral delivery. In some gresses, the therapeutic window for oral formulations of LD embodiments, the pharmaceutical composition includes a narrows, and it becomes increasingly difficult to control PD drug particle-containing emulsion. In other embodiments, motor symptoms without inducing motor complications. In the pharmaceutical composition is macroscopically Substan addition, most PD patients develop response fluctuations to tially homogeneous. intermittent oral LD therapy, such as end of dose wearing 0015. In a third aspect, the invention features a pharma off, Sudden on/offs, delayed time to on, and response fail ceutical composition including a suspension including (i) an U.S. excess of one or more water-immiscible compounds over 0011. The devices, formulations and methods of the water, and (ii) from about 35% to about 75% (w/w) (e.g., as invention provide improved therapies for patients with PD. described herein) drug particles, wherein the pharmaceutical composition is physically stable (e.g., for 6 months, 8 SUMMARY OF THE INVENTION months, 10 months, 12 months, or more) at about 5° C. 0012. The present invention features a pharmaceutical and/or about 25°C. In some embodiments, the pharmaceu Suspension containing drug particles, a drug delivery device tical composition includes an emulsion (e.g., a drug particle for continuously administering the pharmaceutical Suspen containing emulsion). In other embodiments, the pharma sion to the oral cavity, and methods of using the same. ceutical composition is macroscopically Substantially 0013. In a first aspect, the invention features a pharma homogeneous. In some embodiments, the pharmaceutical ceutical composition including a suspension, the Suspension composition is suitable for continuous or frequent intermit including (i) from about 35% to about 75% (w/w) (e.g., from tent intra-oral delivery. about 35% to about 70%, from about 35% to about 65%, 0016. In any of the preceding aspects, the Suspension from about 35% to about 60%, from about 35% to about may be an extrudable, non-pourable emulsion. In some 55%, from about 35% to about 50%, from about 35% to embodiments, the Suspension is physically stable for about about 45%, from about 35% to about 40%, from about 40% 12 months at about 5° C. In other embodiments, the sus to about 45%, from about 40% to about 45%, from about pension is physically stable for about 12 months at about 25° 40% to about 50%, from about 40% to about 55%, from C. In certain embodiments, after 12 months (e.g., after 13 about 40% to about 60%, from about 40% to about 65%, months, after 14 months, after 15 months, or more) the from about 40% to about 65%, from about 40% to about suspension is physically stable for about 48 hours at about 70%, from about 40% to about 75%, from about 45% to 370 C. about 75%, from about 50% to about 75%, from about 55% 0017. In any of the preceding aspects, the pharmaceutical to about 75%, from about 60% to about 75%, from about composition may include a continuous hydrophilic phase. 65% to about 75%, from about 70% to about 75%, or from The continuous hydrophilic phase can provide for rapid about 50% to about 65%) drug particles including levodopa dispersion of Solid drug particle containing Suspensions in and/or carbidopa, or salts thereof, (ii) from about 19% to saliva and the well dispersed solid drug particles can dis about 30% (w/w) (e.g., from about 19% to about 28%, from Solve rapidly in Saliva. about 19% to about 26%, from about 19% to about 24%, 0018. In any of the preceding aspects, the concentration from about 19% to about 22%, from about 19% to about of drug in a pharmaceutical composition may be at least 1.75 21%, from about 21% to about 24%, from about 21% to M (e.g., more than 1.80 M, 1.85 M, 1.90 M, 1.95 M, 2.0 M, about 30%, from about 24% to about 30%, from about 26% 2.5M, 3.0 M, or even 3.5 M). In some embodiments, the US 2017/0172961 A1 Jun. 22, 2017 pharmaceutical composition includes from about 50% to the oil comprises a saturated fatty acid triglyceride or a about 70% (w/w) (e.g., from about 50% to about 65%, from mixture of saturated fatty acid triglycerides. In other about 50% to about 60%, from about 50% to about 55%, embodiments, the oil can be a medium-chain fatty acid from about 55% to about 70%, from about 60% to about triglyceride or a mixture of medium-chain fatty acid triglyc 70%, or from about 65% to about 70%) solid drug particles, erides. For example, the oil can be a Miglyol(R) or chemical wherein the concentration of drug in the pharmaceutical equivalent. In certain embodiments, the oil can be a canola composition is at least 3.0M (e.g., 3.1 M, 3.2 M, 3.5 M, or oil. In particular embodiments, the oil can be a coconut oil. more). In some embodiments, the oil can be a triglyceride or one or 0019. In some embodiments, the suspension of any of the more C-C fatty acids, such as a triglyceride of one or preceding aspects includes one or more water-immiscible more Cs-C fatty acids. For example, the oil can be a compounds that melts or softens below 45° C. (e.g., at 40° triglyceride of Cs-C fatty acids, Ca-Cs fatty acids, or C., 37°C., 35°C., or less). In some embodiments, the weight Co-C fatty acids, or a mixture thereof. In some embodi ratio of the one or more water-immiscible compounds to ments, at least 50% (w/w) of the one or more water water is greater than 1.0 (e.g., greater than 1.5, greater than immiscible compounds can be a triglyceride of one or more 2.0, greater than 3.0, or greater than 5.0). Cs-C fatty acids. In certain embodiments, the Suspension 0020. In some embodiments, the one or more water can include less than or equal to about 30% (w/w) (e.g., immiscible compounds of any of the preceding aspects about 29% (w/w), about 27% (w/w), or about 25% (w?w)) of includes an oil. In some embodiments, the Suspension the oil. In particular embodiments, the Suspension can includes a continuous hydrophilic phase including greater include greater than or equal to about 19% (w/w) (e.g., about than 50% (w/w) (e.g., 55%, 60%. 65%, 70%, or 75%) drug 21% (w/w), or about 23% (w/w)) of the oil. In certain particles. In certain embodiments, the Suspension includes embodiments, the suspension can include 20+2% (w/w) of an oil in water emulsion. In some embodiments, the Sus the oil. In typical embodiments, the Suspension can include pension is free of polymers of a molecular mass greater than 24+2% (w/w) of the oil. In some embodiments, the suspen 1,000 Daltons (e.g., greater than about 1,100 Daltons, sion can include 28+2% (w/w) of the oil. greater than about 1,200 Daltons, greater than about 1,500 0024. In any of the preceding aspects, the pharmaceutical Daltons, greater than about 1,700 Daltons, or greater than composition may include a Surfactant. A Surfactant of a about 2,000 Daltons). In some embodiments, the suspension pharmaceutical composition may be a non-ionic Surfactant. has a dynamic viscosity of at least 100 cp (e.g., greater than In some embodiments, the non-ionic Surfactant can include 500 cP, 1,000 cB, 5,000 cP, 10,000 cP 50,000 cP, or 100,000 a polyglycolized glyceride, a poloxamer, an alkyl saccha cP) at 37° C. ride, an ester saccharide, or a polysorbate Surfactant. In 0021. In any of the preceding aspects, the Suspension certain embodiments, the non-ionic Surfactant can include a may include greater than 50% (w/w) (e.g., greater than 55%, poloxamer. In other embodiments, the non-ionic Surfactant greater than 60%, greater than 65%, or greater than 70%) can include a polyglycolized glyceride Such as a polyethoxy drug particles. In some embodiments, the Dso of the drug lated castor oil. In particular embodiments, the non-ionic particles can be less than or equal to about 500 um, about Surfactant can include a polysorbate surfactant that can be 250 um, about 200 um, about 150 um, about 125 um, or Polysorbate 60. In some embodiments, the suspension can about 100 um. In some embodiments, the Dso of the drug include less than or equal to about 8% (w/w) (e.g., about 7% particles can be greater than or equal to about 1 um, about (w/w), about 6% (w/w), or about 5% (w?w)) of the surfac 3 um, about 5um, about 10 um, or about 25 um, or the Dso tant. In some embodiments, the Suspension can include of the drug particles can be less than or equal to 50 um Such greater than or equal to about 2% (w/w) (e.g., about 3% as less than or equal to 25 Jum. In typical embodiments, the (w/w) or about 4% (w/w)) of the surfactant. In certain Ds of the drug particles can be 25-24 Lum: 1-10 um; 11-20 embodiments, the suspension can include about 5+2% (w/w) um; 21-30 um; 31-40 um; or 41-50 um. In other embodi of the surfactant. ments, the Dso of the drug particles can be 75+25um; 51-75 0025. In some embodiments, a pharmaceutical composi um; or 76-100 um. In certain embodiments, the Ds of the tion of any of the preceding aspects can further include an drug particles can be 125+25um. In further embodiments, antioxidant such as Vitamin E, TPGS, ascorbylpalmitate, a the Ds of the drug particles can be 175+25 um. tocopherol, thioglycerol, thioglycolic acid, cysteine, 0022. In any of the preceding aspects, the Suspension N-acetyl cysteine, Vitamin A, propyl gallate, octyl gallate, may include less than or equal to about 16% (w/w), about butylhydroxyanisole, or butylhydroxytoluene. In some 13% (w/w), about 12% (w/w), about 11% (w/w), or about embodiments, the antioxidant can be oil soluble. In other 9% (w/w) water. In some embodiments, the Suspension can embodiments, the apparent pH of the Suspension of any of include greater than or equal to about 1% (w/w), about 2% the preceding aspects can be less than or equal to about 7.0, (w/w), or about 3% (w/w) water. In certain embodiments, about 5.0, or about 4.0, the apparent pH being the pH the Suspension can include 4t2% (W/w) water. In particular measured by inserting an aqueous Solution calibrated glass embodiments, the suspension can include 8+2% (w/w) walled pH electrode into the formulation at 23+3° C. In water. In other embodiments, the Suspension can include certain embodiments, the apparent pH can be greater than or 13+3% (w/w) water. equal to about 2.5. Such as greater than or equal to 3.0 or 3.5. 0023. In any of the preceding aspects, the one or more In some embodiments, the shelf life of the pharmaceutical water-immiscible compounds may include an oil selected composition can be 1 year or longer at 5+3°C. In particular from a saturated fatty acid triglyceride, an unsaturated fatty embodiments, the shelf life of the pharmaceutical compo acid triglyceride, a mixed saturated and unsaturated fatty sition can be 1 year or longer at 25+3° C. For example, the acid triglyceride, a medium-chain fatty acid triglyceride, apparent pH of the pharmaceutical composition can be less canola oil, coconut oil, palm oil, olive oil, soybean oil, than pH 5 and can remain less than pH 5 after 3 months sesame oil, corn oil, or mineral oil. In some embodiments, storage at about 25°C., can remain less than pH 4 after 3 US 2017/0172961 A1 Jun. 22, 2017

months storage at 25°C., or the apparent pH can equal or be stable and suitable for continuous or frequent intermittent less than pH 3 after 3 months storage at about 25°C. The intra-oral delivery. The pharmaceutical composition can pharmaceutical compositions can optionally include a bac include a paste or an emulsion. In particular embodiments, teriostatic or a fungistatic agent, such as benzoic acid or a the suspension can be physically stable for 12 months at 5° benzoate salt. In particular embodiments, the combined C., or can be physically stable for 12 months at 25°C., or concentrations of benzoic acid and benzoate salt in the after the 12 months the suspension can be physically stable pharmaceutical composition can be between 0.1 percent by for 48 hours at 37° C. The concentration of solid and/or weight and 1 percent by weight. The pharmaceutical com dissolved drug in the pharmaceutical composition can be positions can optionally include a transition metal ion com plexing agent or a salt thereof. Such as EDTA. In particular between about 50 mg/mL and about 1,000 mg/mL (e.g., embodiments, the combined concentrations of EDTA and its 50-500, 70+20, 150+60, or 350+150 mg/mL, 500+200 salt or salts can be between 0.05 weight % and 0.25 weight mg/mL, 700+200 mg/mL, 800+200 mg/mL). In particular %. The pharmaceutical compositions can optionally include embodiments the pharmaceutical composition can include a a Sulfur containing compound Such as cysteine and N-ace solid excipient. The density of the solid excipient can be at tylcysteine capable of reacting at 25+3° C. with dopaqui about 25°C. between about 1.2 g/mL and 3.5 g/mL such as none or with quinone formed by oxidation of carbidopa. between 1.2 g/mL and 1.8 g/mL. The concentration of solid 0026. In any of the preceding aspects, the Suspension of excipient in the pharmaceutical composition can be between the drug particles of a pharmaceutical composition may 200 mg/mL and 1,500 mg/mL, such as between 200 and 800 include levodopa or a levodopa prodrug, or carbidopa or a mg/mL, or between 400 and 800 mg/mL. In some embodi carbidopa prodrug, benserazide, or any mixture thereof. In ments, the excipient particles may not Substantially Swell in particular embodiments, the Suspension of the drug particles water and/or in the oil of the Suspension. In some embodi can include levodopa and/or carbidopa. In some embodi ments, the Dso of the excipient particles can be greater than ments that include carbidopa, the pharmaceutical composi or equal to about 1 um, about 3 um, about 5 um, about 10 tion can include less than about 2 Lug (e.g., less than 1.5 jug, um, or about 25um, or the Dso of the excipient particles can 1.2 Lig, 1.0 ug, 0.8 ug, or even less) of hydrazine per mg of be less than or equal to 50 Lum Such as less than or equal to the one or more drugs after 1 week storage under ambient air 25 Jum. In typical embodiments, the Ds of the excipient at about 60° C. In certain embodiments, the suspension of particles can be 25-24 lum: 1-10 um; 11-20 um; 21-30 um; the drug particles can include carbidopa and the pharma 31-40 um; or 41-50 um. In other embodiments, the Ds of ceutical composition can further include less than about 8 Jug the excipient particles can be 75+25 um; 51-75 um; or (e.g., 7 Lig, 6 Lig, 5 Lig. 4 Lig, 3 Jug, 2 Lig, or 1 Lig) of hydrazine 76-100 um. In certain embodiments, the Dso of the excipient particles can be 125+25 Lum. In further embodiments, the per mg of carbidopa after 6 or 12 months storage at 5+3° C. Ds of the excipient particles can be 175+25um. In some or at 253 C. embodiments, the Solid excipient can include cellulose or 0027. In other embodiments, the drug particles can cellulose derivatives that do not substantially swell in water include one or more allergens, allergen extracts, or allergen or in oils, amino acids (such as tyrosine, phenylalanine or derivatives. For example, the one or more allergens can be cysteine), titanium dioxide, calcium silicate, or calcium pollen, a part of a mite, or a component of the feline or phosphate. canine skin, or an extract or a conversion product thereof. 0028. In any of the preceding aspects, the Suspension 0031. In some embodiments, the drug in the pharmaceu may not cream or sediment when centrifuged for 1 hour at tical composition can include Baclofen, Tizanidine, Mido an acceleration of about 5,000 G or greater (e.g., about 7,000 drine, Metoclopramide, Captopril, Treprostinil, Bitolterol, G, about 9,000 G, about 10,000 G, or about 16,000 G) at Oxybutinin, Darifenacin, pyridostigmine or a pharmaceuti 25+3° C. In some embodiments, the pharmaceutical com cally acceptable salt thereof. In a typical embodiment, the position may not cream or sediment when stored for 12 pharmaceutical composition can have a viscosity greater months at 5+3° C. or 25+3°C. In some embodiments, after than 10,000 cP at 37° C. In one particular embodiment of the centrifugation or storage, the concentrations of drug in any of the pharmaceutical compositions described herein, the layer containing the top 20 volume 96 and the layer the drug is baclofen or a salt thereof, or the pharmaceutical containing the bottom 20 volume '% of the composition can composition includes baclofen or a salt thereof. In another differ by less than 10%. In particular embodiments, after the embodiment of any of the pharmaceutical compositions centrifugation or storage the concentrations of drug in the described herein, the drug is pyridostigmine or a salt thereof, layer containing the top 20 volume '% and the layer con or the pharmaceutical composition includes pyridostigmine taining the bottom 20 volume 96 of the composition can or a salt thereof. differ by less than 6% (e.g., 5%, 4%. 3%, 2%, 1%, or less). 0032. The invention also features a pharmaceutical com In any of these embodiments, after the centrifugation or position Suitable for continuous infusion in the mouth storage a pharmaceutical composition may exhibit no visible including: a solution, an oil-in-water emulsion, a water-in creaming or sedimentation. oil emulsion, or a solid particle including a Suspension of 0029. In any of the preceding aspects, the pharmaceutical between 20 mg/mL and 150 mg/mL (e.g., 40+20, 75+25, or composition may have Substantially no taste. 125+75 mg/mL) of a drug selected from Baclofen, Tizani 0030 The invention features a pharmaceutical composi dine, Midodrine, Metoclopramide, Captopril, Treprostinil, tion including a suspension including (i) from about 20% to Bitolterol, Oxybutinin, Darifenacin. The pharmaceutical about 80% (w/w) solid excipients; (ii) from about 5% to composition can further include a thickener. In certain 60% (w/w) drug particles, (iii) from 19% to 30% (w/w) of embodiments, the viscosity of the pharmaceutical composi one or more water-immiscible compounds, (iv) from 2% to tion can be greater than 100 cF, 1,000 cB, or 10,000 cF at 25% (w/w) water, and (v) from 1% to 10% (w/w) surfactant, about 37°C. In particular embodiments, the pharmaceutical wherein the pharmaceutical composition can be physically composition can further include a Surfactant. US 2017/0172961 A1 Jun. 22, 2017

0033. The invention further features an extrudable phar the diaphragm). The diaphragm can be folded, pleated, or maceutical composition Suitable for continuous infusion in scored. The device can be hermetically sealed except for one the mouth having a pH of from 3 to 10 (e.g., 5-2, 7-2, or or more orifices for drug filling or drug delivery. Optionally, 8-2) including a magnesium compound, a Zinc compound, the one or more orifices for drug filling or drug delivery can or an iron compound at a concentration between 60 mg/mL be hermetically or non-hermetically sealed. Optionally, the to 1,600 mg/mL (e.g., 100+40, 600+200, or 1,300+300 one or more orifices for drug filling or delivery are hermeti mg/mL). The pharmaceutical composition can further cally sealed. In particular embodiments, the propellant include a gelling agent or a thickener. In particular embodi chamber can be hermetically sealed and can include a ments, the viscosity of the pharmaceutical composition is hermetically sealed orifice for filling with propellant. In greater than 1,000 cF. 10,000 cB, or 100,000 cF at about 37° certain embodiments, the drug chamber can include two, C three, or more hermetically sealable or sealed orifices for 0034. In still other embodiments, the pharmaceutical filling with drug or for drug delivery. In still other embodi composition can include a magnesium compound and the ments, the rigid housing and the diaphragm can be joined by Mg" concentration in the pharmaceutical composition can a hermetically sealing weld. For example, the hermetically be greater than 200 mg/mL (e.g., 300+100, 500+150, or sealing weld can prevent the influx of air and water vapor or 750+200 mg/mL). the outflux of water vapor, drug or propellant, or prevent the 0035. The invention further features a pharmaceutical influx of air or oxygen, or prevent the influx or the outflux composition Suitable for continuous infusion in the mouth of helium. In particular embodiments, the rigid housing of including a solution, Suspension or gel including between the device can include a metal, a ceramic, or a composite of 0.1 mg/mL and 20 mg/mL of a drug selected from Tizani a polymer reinforced by fibers (e.g., carbon fibers, glass dine, Iloprost, Beraprost, Ciclesonide, Flunisolide, Budes fibers, or metal fibers). The rigid housing can include a onide, Beclomethasone, Mometasone, Vilanterol, material having at 25+3° C. a yield strength greater than 100 Levosalbutamol sulfate, Salbutamol, Salmeterol, Glycopy MPa, and/or having at 25+3° C. a tensile yield strength rronium bromide, Ipatropium bromide, Aclidinium bromide, greater than 100 MPa, and/or having at 25+3° C. a modulus Hexoprenaline sulfate, Pirbuterol, Fenoterol, Terbutaline, of elasticity greater than 30 GPa, and/or having at 25+3° C. Metaproterenol, Tolterodine tartarate. The pharmaceutical a Brinell hardness greater than 200 MPa, and/or having a composition can further include a gelling agent or a thick density greater than 2.5 g/cm at 25+3°C., e.g., greater than ener. In particular embodiments, the Viscosity of the phar 3.5 g/cm such as greater than 4.5 g/cm, or having a density maceutical composition can be greater than 100 cF, 1,000 cp. equal to or greater than 5.5 g/cm. The rigid housing can or 10,000 cF at about 37° C. In particular embodiments, the include a metal selected from the group titanium or iron or pharmaceutical composition can further include a surfactant. aluminum or molybdenum or tungsten or an alloy of tita 0036. The invention features a drug delivery device con nium or iron or aluminum or molybdenum or tungsten. In figured to be removably inserted in a patient’s mouth and for particular embodiments, the rigid housing can include tita continuous or semi-continuous intraoral administration of a nium or an alloy of titanium and a metallic diaphragm (that drug, the device including a propellant-driven pump includ can separate chambers within the housing) can be welded to ing a rigid housing, the rigid housing including a wall of a the rigid housing including titanium or an alloy of titanium. first chamber containing a drug-including fluid and a wall of In certain embodiments, the diaphragm can include silver or a second chamber containing a propellant. The device can an alloy of silver or it can optionally include tin or an alloy include a flexible and/or deformable propellant-imperme of tin. In some embodiments, the diaphragm can include tin able diaphragm separating the first chamber from the second or an alloy of tin, or silver or an alloy of silver. In one chamber. The diaphragm can include a wall of the first embodiment, neither the metal of the rigid housing nor the chamber and a wall of the second chamber. In particular metal of the metallic diaphragm can corrode visibly after 3 embodiments, the density of the propellant-impermeable months when the housing metal and the diaphragm metal are diaphragm can be greater than 2.0 g per cm at 25°C. The electrically contacted and are immersed in an air exposed 0.1 diaphragm can be metallic (e.g., tin or silver or aluminum or Mcitrate buffer solution of pH 4.0 at 23+3° C.; or neither the copper or an alloy of tin or of silver or of aluminum or of metal of the rigid housing nor the metal of the metallic copper). Optionally, the metallic diaphragm can comprise diaphragm can corrode visibly after 3 months when the silver or an alloy of silver, or tin or an alloy of tin. The housing metal and the diaphragm metal are electrically diaphragm can be shaped to Substantially conform to the contacted and are immersed in a Substantially de-oxygenated interior housing wall of the first chamber and/or the interior 0.1 M citrate buffer solution of pH 4.0 at 23+3° C. The housing wall of the second chamber. The diaphragm can be density of the corrosion current flowing between two elec between 10 um and 250 um thick, e.g., between 20 m and trically shorted electrodes of about equal area, one of the 125 um thick, such as between 25 um and 75 um thick. In metal of the rigid housing and the other of the metal of the particular embodiments, the thickness of the diaphragm can diaphragm, can be less than 2 LA cm, less than 0.5 LLA vary across the interior of the housing by less than +25%, or cm, or less than 0.1 LA cm after about 24 hour immer by less than +10%. In other embodiments, the diaphragm sion of the electrodes in a substantially de-oxygenated 0.1 M includes a rim that is thicker than the center of the dia citrate buffer solution of pH 4.0 at 23+3° C. phragm (e.g., the thickness of the rim can be at least 1.5 0037. In one particular embodiment, the shapes of the times greater than the thickness of the center of the dia interior housing wall of the first chamber and the interior phragm, the thickness of the rim can be between 1.5 times housing wall of the second chamber can be substantially and 2 times the thickness of the center of the diaphragm, the mirror images of each other excepting for grooves or ports thickness of the rim can be between 2 times and 3 times the for flow of drug-including fluid to the drug exit orifice. The thickness of the center of the diaphragm, or the thickness of first chamber can include one or more interior channels, the rim can be 3 times or more the thickness of the center of grooves, or tubes for flow of drug-including fluid to the drug US 2017/0172961 A1 Jun. 22, 2017

exit orifice. In one embodiment, at least one channel, 2.1 bar at 37°C., and (ii) the average rate of drug delivery groove, or tube is not blocked by the diaphragm after more can increase or decrease by less than +20% across the than 60 weight %, more than 75 weight %, more than 85 atmospheric pressure range between 0.782 bar and 1.013 weight%, or more than 95 weight% of the drug is depleted. bar. In other embodiments, (i) the propellant can have a In another embodiment, at least one channel, groove, or tube vapor pressure of greater than 3.2 bar at 37° C., and (ii) the is not blocked by the diaphragm when the diaphragm has average rate of drug delivery can increase or decrease by less been fully extended into the drug chamber and drug flow has than it 10% across the atmospheric pressure range between Substantially stopped. Optionally, a housing wall can include 0.782 bar and 1.013 bar. In certain embodiments, (i) the the at least one channel, groove, or tube. Optionally, an propellant can have a vapor pressure of greater than 4.7 bar insert can include the at least one channel, groove, or tube. at 37° C., and (ii) the average rate of drug delivery can In certain embodiments, the at least one channel, groove, or increase or decreases by less than to% across the atmo tube can include one or more flow restrictors that substan spheric pressure range between 0.782 bar and 1.013 bar. The tially control the rate of drug delivery. In certain embodi drug delivery device can include a reservoir containing any ments, the diaphragm can be shaped and sized so that it pharmaceutical composition described herein. contacts 0%-10%, 11%-20%, 21%-30%, 31%-40%, or 41%- 50% of the interior surface area of the drug chamber 0040. In another aspect, the invention features a drug (excluding the Surface area of the diaphragm itself) after delivery device configured to be removably inserted in a delivery of 85%, 90%, or 95% of the starting pharmaceutical patient's mouth and for continuous or semi-continuous composition in the drug chamber. In certain embodiments, intraoral administration of a drug, the device including: (i) the diaphragm can be shaped and sized so that it does not a fastener to removably secure the drug delivery device to a substantially block the flow of the pharmaceutical compo Surface of the patient's mouth; (ii) an electrical or mechani sition from the exit orifice after 85%, 90%, or 95% of the cal pump; and (iii) an oral liquid impermeable drug reservoir starting pharmaceutical composition in the drug chamber containing any of the pharmaceutical compositions of the has been delivered. invention, the volume of the drug reservoir being from 0.1 mL to 5 mL (e.g., from 0.1 mL to 4 mL, from 0.1 mL to 3 0038. In a related aspect, the invention features a method mL, from 0.1 mL to 2 mL, from 0.1 mL to 1 mL, from 0.1 of forming the diaphragm for a delivery device of the mL to 0.5 mL, from 0.1 mL to 0.25 mL, from 0.2 mL to 5 invention, the method including stamping, hot-stamping, mL, from 0.3 mL to 5 mL, from 0.5 mL to 5 mL, from 1 mL electroplating, electroless plating, or hydroforming. The to 5 mL, from 2 mL to 5 mL, from 4 mL to 5 mL, from 0.5 method can include welding the rigid housing and the mL to 1 mL, from 0.5 mL to 2 mL, from 1 mL to 2 mL, from diaphragm to form a hermetic Seal by, e.g., resistance welding, laser welding or electron beam welding. In par 2 mL to 3 mL). ticular embodiments, the method can also include preheating 0041. In a further aspect, the invention features a drug the housing and the diaphragm. The method can further delivery device configured to be removably inserted in a include annealing at a temperature between 400° C. and patient's mouth and for continuous or semi-continuous 700° C. for 15 minutes or more. intraoral administration of a drug, the device including: (i) 0039. In a related aspect, the invention features a drug a fastener to removably secure the drug delivery device to a delivery device configured to be removably inserted in a Surface of the patient's mouth; (ii) an electrical or mechani patient’s mouth and for continuous or semi-continuous cal pump; (iii) an oral liquid impermeable drug reservoir intraoral administration of a drug, the device including: a containing any of the pharmaceutical compositions of the first chamber containing a drug-including fluid; a second invention, the volume of the drug reservoir being from 0.1 chamber containing a propellant; and a flexible and/or mL to 5 mL (e.g., as described herein); and (iv) an automatic deformable diaphragm separating the first chamber from the stop? start. second chamber, wherein 75%-85%, 86%-95%, or >95% of 0042. In some embodiments, the drug delivery device can the drug-including fluid can be dispensed while the delivery be configured to be automatically stopped upon one or more rate can vary by less than +20%, 15%, +10%, or +5%, over of the following: (a) the drug delivery device, the pump, a period of at least 4, 8, 16, or 24 hours. The pump can and/or the oral liquid impermeable reservoir are removed include a liquid propellant, the liquid propellant having a from the mouth; (b) the drug delivery device, the pump, boiling point of less than 37° C. at sea level atmospheric and/or the oral liquid impermeable reservoir are discon pressure. In particular embodiments, the liquid propellant nected from the fastener; or (c) the oral liquid impermeable can be a hydrocarbon, a halocarbon, a hydrofluoralkane, an reservoir is disconnected from the pump. In particular ester, or an ether (e.g., the liquid propellant can be isopen embodiments, the drug delivery device can be configured to tane, trifluorochloromethane, dichlorofluoromethane, be automatically started upon one or more of the following: 1-fluorobutane, 2-fluorobutane, 1,2-difluoroethane, methyl (a) the drug delivery device, the pump, and/or the oral liquid ethyl ether, 2-butene, butane, 1-fluoropropane, 1-butene, impermeable reservoir are inserted into the mouth; (b) the 2-fluoropropane, 1,1-difluoroethane, cyclopropene, pro drug delivery device, the pump, and/or the oral liquid pane, propene, or diethyl ether). In certain embodiments, the impermeable reservoir are connected to the fastener; or (c) liquid propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- the oral liquid impermeable reservoir is connected to the heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, octa pump. In certain embodiments, the automatic stop? start is fluorocyclobutane or isopentane. The propellant can have a selected from: a pressure sensitive Switch, a clip, a fluidic vapor pressure of greater than 1.5 bar and less than 20 bar channel that kinks, a clutch, a sensor, or a cap. In some at 37°C., such as a vapor pressure of greater than 2.0 bar and embodiments, the drug delivery device can further include a less than 15 bar at 37°C., or a vapor pressure of greater than suction-induced flow limiter, a temperature-induced flow 3.0 bar and less than 10 bar at 37°C. In some embodiments, limiter, bite-resistant structural Supports, or a pressure-in (i) the propellant can have a vapor pressure of greater than variant mechanical pump. US 2017/0172961 A1 Jun. 22, 2017

0043. In yet another aspect, the invention features a drug lant. The rigid metal housing material can include titanium delivery device configured to be removably inserted in a or a titanium alloy. In particular embodiments, the pharma patient’s mouth and for continuous or semi-continuous ceutical composition and the propellant are separated by a intraoral administration of a drug, the device including: (i) flexible and/or deformable diaphragm comprising a metal. a fastener to removably secure the drug delivery device to a The flexible and/or deformable diaphragm can include tin or Surface of the patient’s mouth; (ii) a mechanical pump; (iii) silver. In other embodiments, the pump can be propellant an oral liquid impermeable drug reservoir containing any of driven and the temperature-induced flow limiter can include the pharmaceutical compositions of the invention, the Vol a propellant having a vapor pressure that increases by less ume of the drug reservoir being from 0.1 mL to 5 mL (e.g., than about 80% (e.g., 70%, 60%, 50%, 40%, 30%, 20%, or as described herein); and (iv) a suction-induced flow limiter. less) when the oral temperature is raised from about 37° C. 0044. In some embodiments, the suction-induced flow to about 55° C. for a period of about one minute. In some limiter includes pressurized surfaces that are in fluidic (gas embodiments, the drug delivery device further includes a and/or liquid) contact with the ambient atmosphere via one Suction-induced flow limiter, an automatic stop/start, bite or more ports or openings in the housing of the drug delivery resistant structural Supports, or a pressure-invariant device. In other embodiments, the suction-induced flow mechanical pump. limiter is selected from the group consisting of a deformable 0048. In yet another aspect, the invention features a drug channel, a deflectable diaphragm, a compliant accumulator, delivery device configured to be removably inserted in a an inline vacuum-relief valve, and a float valve. In certain patient's mouth and for continuous or semi-continuous embodiments, the suction-induced flow limiter can be con intraoral administration of a drug, the device including: (i) figured to prevent the delivery of a bolus greater than about a fastener to removably secure the drug delivery device to a 1% (e.g., 2%. 3%, 4%, 5%, or more) of the contents of a Surface of the patient's mouth; (ii) an electrical or mechani fresh drug reservoir, when the ambient pressure drops by cal pump; (iii) an oral liquid impermeable drug reservoir 0.14 bar for a period of one minute. In some embodiments, containing any of the pharmaceutical compositions of the the drug delivery device further includes an automatic invention, the volume of the drug reservoir being from 0.1 stop? start, a temperature-induced flow limiter, bite-resistant mL to 5 mL (e.g., as described herein); and (iv) bite-resistant structural Supports, or a pressure-invariant mechanical structural Supports. pump. 0049. In some embodiments, the bite-resistant structural 0045. In another aspect, the invention features a drug Supports are selected from: a housing that encapsulates the delivery device configured to be removably inserted in a entire drug reservoir and pump components; posts; ribs; or patient’s mouth and for continuous or semi-continuous a potting material. In particular embodiments, the drug intraoral administration of a drug, the device including: (i) delivery device further includes a suction-induced flow a fastener to removably secure the drug delivery device to a limiter, an automatic stop/start, a temperature-induced flow Surface of the patient's mouth; (ii) an electrical or mechani limiter, or a pressure-invariant mechanical pump. cal pump; (iii) an oral liquid impermeable drug reservoir 0050. In a further aspect, the invention features a drug containing any of the pharmaceutical compositions of the delivery device configured to be removably inserted in a invention, the volume of the drug reservoir being from 0.1 patient's mouth and for continuous or semi-continuous mL to 5 mL (e.g., as described herein); and (iv) a tempera intraoral administration of a drug, the device including: (i) ture-induced flow limiter. a fastener to removably secure the drug delivery device to a 0046. In some embodiments, the temperature-induced Surface of the patient’s mouth; (ii) a pressure-invariant flow limiter can include insulation with a material of low mechanical pump; and (iii) an oral liquid impermeable drug thermal conductivity proximate the drug reservoir and/or the reservoir containing any of the pharmaceutical compositions pump. In certain embodiments, the temperature-induced of the invention, the volume of the drug reservoir being from flow limiter can include an elastomer whose force in a fresh 0.1 mL to 5 mL (e.g., as described herein). reservoir increases by less than 30% when the oral tempera 0051. In some embodiments, the pressure-invariant ture is raised from about 37° C. to about 55° C. for a period mechanical pump includes pressurized surfaces that are in of one minute. In some embodiments, the pump can include fluidic (gas and/or liquid) contact with the ambient atmo a spring and the temperature-induced flow limiter can sphere, optionally via one or more ports or openings in the include a spring configured to produce a force in a fresh housing of the drug delivery device. In certain embodiments, reservoir that increases by less than 30% (e.g., 25%, 20%, the pressure-invariant mechanical pump is configured to 15%, or less) when the oral temperature is raised from about maintain an internal pressure of greater than or equal to 37° C. to about 55° C. for a period of one minute. In about 2 bar, about 3 bar, about 4 bar, about 6 bar, or about particular embodiments, the temperature-induced flow lim 8 bar. In some embodiments, the pressure-invariant iter can include a spring including a 300 series stainless mechanical pump is configured Such that the average rate of steel, titanium, Inconel, or austenitic Nitinol. In certain drug delivery increases by less than about 20% (e.g., 15%, embodiments, the pump can be gas-driven. It can comprise 10%. 5%, 2% or less) when the atmospheric pressure an actuator actuated by the temperature decrease upon decreases from about 0.898 bar to about 0.782 or from 1.013 removal from the mouth, i.e., a temperature change actuated bar to 0.898 bar; and/or decreases by less than about 20% flow limiter. Its liquefied or compressed gas can have a (e.g., less than 15%, 10%, 5%, 2%) when the atmospheric volume of less than about 40% (e.g., 35%, 30%, 25%, 20%, pressure increases from about 0.782 bar to about 0.898 bar; 10% or less) of the volume of the pharmaceutical compo and/or such that the average rate of drug delivery decreases sition in a fresh reservoir at 37° C. and about 1.013 bar. by less than about 20% (e.g., 15%, 10%, 5%, 2% or less) 0047. In some embodiments of any of the above drug when the atmospheric pressure increases from about 0.898 delivery devices, the device includes a rigid metal housing bar to about 1.013 bar. In particular embodiments, the drug containing the pharmaceutical composition and the propel delivery device further includes a suction-induced flow US 2017/0172961 A1 Jun. 22, 2017

limiter, an automatic stop/start, a temperature-induced flow than 30%, 25%, 20% or 10%) of the volume of the phar limiter, or bite-resistant structural Supports. maceutical composition. In some embodiments, a gas-driven 0052. In another aspect, the invention features a drug pump includes a gas generator. delivery device configured to be removably inserted in a 0056. In any of the preceding aspects, a drug delivery patient’s mouth and for continuous or semi-continuous device may include a mechanical pump that is a propellant intraoral administration of a drug, the device including: (i) driven pump. In some embodiments, the pump includes a a fastener to removably secure the drug delivery device to a liquid propellant, the liquid propellant having a boiling point Surface of the patient's mouth; (ii) a mechanical pump; and of less than 37°C. (e.g., less than or equal to 35°C., 33°C., (iii) an oral liquid impermeable drug reservoir containing 30° C., or 25° C.) at sea level atmospheric pressure. In any of the pharmaceutical compositions of the invention, the certain embodiments, the liquid propellant is a hydrocarbon, volume of the drug reservoir being from 0.1 mL to 5 mL a halocarbon, a hydrofluoralkane, an ester, or an ether. For (e.g., as described herein). example, the liquid propellant can be selected from the 0053. In some embodiments, the mechanical pump is group consisting of isopentane, trifluorochloromethane, pressure-invariant. In certain embodiments, the mechanical dichlorofluoromethane, 1-fluorobutane, 2-fluorobutane, 1,2- pump is driven by a spring, an elastomer, a compressed gas, difluoroethane, methyl ethyl ether, 2-butene, butane, 1-fluo or a propellant. In some embodiments, the oral liquid ropropane, 1-butene, 2-fluoropropane, 1,1-difluoroethane, impermeable reservoir includes one or more of metal res cyclopropene, propane, propene, or diethyl ether. In particu ervoirs, plastic reservoirs, elastomeric reservoirs, metallic lar embodiments, the liquid propellant is 1,1,1,2-tetrafluo barrier layers, valves, squeegees, baffles, rotating augers, roethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3- rotating drums, propellants, pneumatic pumps, diaphragm hexafluoropropane, octafluorocyclobutane, or isopentane. In pumps, hydrophobic materials, and hydrophobic fluids. In certain embodiments, the liquid propellant is isopentane, particular embodiments, the drug delivery device can be trifluorochloromethane, dichlorofluoromethane, or 1,1,1,2- configured Such that 4 hours after inserting a drug delivery tetrafluoroethane. In some embodiments, the liquid propel device including a fresh reservoir in a patient’s mouth and lant has a vapor pressure of greater than 1.5 bar (e.g., 2.0 bar, initiating the administration, less than 5%. 3%, or 1% by 2.5 bar, 3 bar, or greater) and less than 20 bar (e.g., 15 bar, weight of an originally contained pharmaceutical composi 12 bar, 10 bar, 9 bar, 8 bar, 7.0 bar, 6.0 bar, or less) at about tion in the reservoir includes an oral liquid. In certain 37°C. In other embodiments, (i) the liquid propellant has a embodiments, the oral liquid impermeable drug reservoir vapor pressure of greater than 2.1 bar (e.g., greater than 2.2 includes a fluidic channel in a spiral configuration. In some bar, 2.5 bar, or 3.0 bar) at 37° C., and (ii) the average rate embodiments, the drug delivery device further includes a of drug delivery increases or decreases by less than +20% Suction-induced flow limiter, an automatic stop/start, a tem across the atmospheric pressure range between about 0.782 perature-induced flow limiter, a pressure-invariant mechani bar and about 1.013 bar. In particular embodiments, (i) the cal pump, or bite-resistant structural Supports. liquid propellant has a vapor pressure of greater than 3.2 bar 0054 Certain drug delivery devices of the invention may (e.g., greater than 3.3 bar, 3.4 bar, or 3.5 bar) at 37°C., and feature an electrical pump. In some embodiments, an elec (ii) the average rate of drug delivery increases or decreases trical pump is a piezoelectric pump or an electroosmotic by less than it 10% across the atmospheric pressure range pump. In particular embodiments, the electrical pump is a between about 0.782 bar and about 1.013 bar. In further piezoelectric pump that is configured to operate at a fre embodiments, (i) the propellant has a vapor pressure of quency of less than about 20,000 Hz (e.g., 15,000 Hz, greater than 4.7 bar (e.g., 4.8 bar, 5.0 bar, or greater) at 37° 10,000 Hz, 5,000 Hz, or less). In certain embodiments, the C., and (ii) the average rate of drug delivery increases or electrical pump includes a motor. decreases by less than to% across the atmospheric pressure 0055 Any of the drug delivery devices of the preceding range between about 0.782 bar and about 1.013 bar. aspects may include a mechanical pump. In some embodi 0057. In any of the preceding aspects of the invention, a ments, the mechanical pump is an elastomeric drug pump. In drug delivery device may include two or more drug pumps. particular embodiments, the elastomeric drug pump includes A drug delivery device may also include two or more drug an elastomeric balloon, an elastomeric band, or a com reservoirs. pressed elastomer. In other embodiments, the mechanical 0058. In any of the preceding aspects of the invention, a pump is a spring-driven pump. In particular embodiments, drug reservoir may be substantially impermeable to oxygen the spring-driven pump includes a constant force spring. In gas. In certain embodiments, the drug reservoir includes a certain embodiments, the spring-driven pump includes a pharmaceutical composition comprising greater than 33% spring that retracts upon relaxation. In some embodiments, (e.g., greater than 35%, greater than 37%, greater than 39%. the spring-driven pump includes two coaxial compression greater than 40%, greater than 50%, greater than 60%, or springs wherein, upon compression, a first spring with a first more) of the total volume of the drug reservoir and pump. In diameter is wholly or partially nested within a second spring Some embodiments, the total Volume of the one or more drug with a second, larger diameter. In other embodiments, the reservoirs and the one or more drug pumps is less than 5 mL mechanical pump is a negative pressure pump, a pneumatic (e.g., less than 4 mL, less than 3 mL, less than 2 mL, or less pump, or a gas-driven pump. In certain embodiments, the than 1 mL). mechanical pump is a gas-driven pump including a gas in a 0059. In some embodiments, the drug reservoir of a drug first compartment and drug in a second compartment, the gas delivery device of the invention is a Syringe assembly providing a pressure exceeding about 1 bar. In some embodi including a plunger and a barrel, the plunger being in ments, the gas-driven pump includes a compressed gas slidable arrangement with the barrel. In certain embodi cartridge. In particular embodiments, the gas-driven pump ments, the Syringe assembly further includes a seal (e.g., an includes a compressed or liquefied gas, the Volume of the O-ring) fitted over the plunger, the seal being in contact with compressed or liquefied gas being less than 35% (e.g., less the barrel. In some embodiments, the barrel, plunger, and/or US 2017/0172961 A1 Jun. 22, 2017

seal is not wetted by water and/or oil. In particular embodi pharmaceutical composition. In some embodiments, the ments, the barrel, plunger, and/or seal is non-wettable by a fastener includes a pump or a power source. pharmaceutical composition of the invention. In some 0062. In particular embodiments, the drug delivery embodiments, a barrel, plunger, and/or seal is formed from device includes one or more drug metal wall including or coated with a fluoropolymer or fluoroelastomer. In certain reservoirs and one or more pumps, wherein the drug reser embodiments, a barrel, plunger, and/or seal is coated with a voirs or the pumps are configured to administer the phar lubricant. The solubility of the lubricant in the one or more maceutical composition onto the buccal or Sublingual water-immiscible compounds of the pharmaceutical compo mucosa of the patient. The drug delivery device can include sition may be less than 3% (w/w) (e.g., less than 2% (w/w) a tube, channel, or orifice having a distal end positioned or less than 1% (w/w)) at, for example, 25° C. In some proximal to the buccal or Sublingual mucosa within a Zone embodiments, the lubricant can be a halogenated oil or bounded in part by a water vapor and gas permeable grease. Such as a perfluorinated polymer, a chlorofluorinated membrane that is saliva-repelling. polymer, or a fluorinated polyether. In certain embodiments, 0063. In some embodiments, the drug reservoir of a drug the lubricant can be a halogenated oil or grease having an delivery device of the invention is in fluid communication average molecular mass equal to or greater than about 1,000 with a tube, channel, or orifice of less than 4 cm (e.g., less Daltons (e.g., greater than about 1,100 Daltons, greater than than 3 cm, less than 2 cm, less than 1 cm, less than 0.5 cm, about 1,200 Daltons, greater than about 1,500 Daltons, or less than 0.2 cm) in length and the dynamic viscosity of greater than about 1,700 Daltons, or greater than about 2,000 the pharmaceutical composition can be greater than about Daltons). In some embodiments, the drug reservoir of a drug 1,000 cp (e.g., greater than about 5,000 cp, greater than delivery device can be a syringe barrel and the drug delivery about 10,000 cF. greater than about 50,000 cF, or greater device can further include a deformable and/or mobile plug than about 100,000 cp), and the device is configured to separating two compartments of the Syringe barrel. In certain administer drug via the tube, channel, or orifice. In certain embodiments, the deformable and/or mobile plug includes a embodiments, the tube, channel, or orifice has a minimum perfluorinated, fluorinated, or chlorofluorinated oil or internal diameter of greater than about 0.2 mm, e.g., greater grease. Such a drug delivery device may further include a than about 0.3 mm, greater than about 0.4 mm, greater than propellant in one of the compartments and the pharmaceu about 0.5 mm, greater than about 0.6 mm, greater than about tical composition in the other of the compartments. 0.7 mm, greater than about 1 mm, greater than about 2 mm, greater than about 3 mm, greater than about 4 mm, greater 0060 A drug delivery device of the invention may than about 5 mm, or greater than about 6 mm. In certain removably secure to one or more teeth of the patient. In embodiments, the internal diameter is greater than about 0.1 some embodiments, the fastener that removably secures the mm and less than 1 mm, 0.8 mm, 0.6 mm, 0.5 mm, 0.4 mm, drug delivery device to one or more teeth includes a band, 0.3 mm or 0.2 mm. Preferred minimum internal diameters a bracket, a clasp, a splint, or a retainer. For example, the are 0.1-2 mm (0.1-0.7 mm, 0.2-0.5 mm, 0.5-0.75 mm. fastener may include a transparent retainer or a partial 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferred retainer attachable to fewer than 5 teeth. lengths are 0.25-5 cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 0061. A drug delivery device of the invention may cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 include one or more drug reservoirs and one or more pumps cm). configured to be worn in the buccal vestibule, on the lingual 0064. In some embodiments, a drug delivery device of side of the teeth, or simultaneously in the buccal vestibule the invention further includes a flow restrictor (e.g., a flared and on the lingual side of the teeth. In some embodiments, flow restrictor). The flow restrictor can have an internal one or more drug reservoirs and one or more pumps are diameter Smaller than 1 mm and larger than 0.05 mm and a configured bilaterally. In certain embodiments, the one or length between 0.5 cm and 10 cm. In particular embodi more drug reservoirs and/or pumps are configured to admin ments, the flow restrictor can have an internal diameter ister the pharmaceutical composition into the mouth of the smaller than 0.7 mm and larger than 0.2 mm. Preferred patient on the lingual side of the teeth. A fluidic channel from minimum internal diameters are 0.1-2 mm (0.1-0.7 mm, the buccal side to the lingual side of the patient’s teeth may 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or be included for dispensing the pharmaceutical composition. 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as In one particular embodiment of any of the above drug 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 delivery devices, the device includes one or more drug cm, 2-3 cm, 3-4 cm, or 4-5 cm). The flow restrictor can be reservoirs and one or more pumps, wherein the drug reser made of a plastic, such as an engineering plastic. In par voirs or the pumps are configured to administer the phar ticular embodiments, the engineering plastic includes a maceutical composition onto the buccal or Sublingual polyamide or a polyester, or a polycarbonate, or a mucosa of the patient. For example, the drug delivery device polyetheretherketone, or a polyetherketone, or a polyimide, can include a tube, channel, or orifice having a distal end or a polyoxymethylene, or a polyphenylene Sulfide, or a positioned proximal to the buccal or Sublingual mucosa polyphenylene oxide, or a polysulphone, or polytetrafluo within a Zone bounded in part by a water vapor and gas roethylene, or polyvinylidene difluoride, or ultra-high-mo permeable membrane that is saliva-repelling. In some lecular-weight polyethylene, or a strong elastomer. embodiments, the drug delivery device can include a fluidic 0065. In certain embodiments, the flow restrictor controls channel in the fastener through which the pharmaceutical the flow of the pharmaceutical composition. In some composition is administered into the mouth of the patient. In embodiments, the length of the flow restrictor sets the certain embodiments, the device may include a leak-free administration rate of the pharmaceutical composition. In fluidic connector for direct or indirect fluidic connection of particular embodiments, the flow restrictor may be adjusted the fastener to the one or more drug reservoirs, and/or a flow by a physician or the patient to set the rate of flow. In certain restrictor in the fastener for controlling the flow of the embodiments, a drug delivery device can include a tapered US 2017/0172961 A1 Jun. 22, 2017

flow path for the drug with a taper less than or equal to about per hour after the drug delivery device is immersed for five 60 degrees, about 45 degrees, or about 30 degrees. Option minutes in a stirred physiological saline solution at 37° C. ally, the device can include one or more flow-controlling including any one of the following conditions: (a) pH of noZZles, channels or tubes which can be plastic, e.g. made of about 2.5; (b) pH of about 9.0; (c) 5% by weight olive oil; or including an engineering plastic. The optionally plastic and (d) 5% by weight ethanol. noZZles, channels or tubes can have an internal diameter less 0067. The invention also features a method of treating than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm and they can be Parkinson's disease (including patients with scores of 4 and shorter than 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. 5 on the Hoehn and Yahr scale) including administering a Preferred minimum internal diameters are 0.1-2 mm (0.1-0.7 pharmaceutical composition of the invention to a patient mm, 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as using a drug delivery device of the invention. 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 0068. In another aspect, the invention features a method cm, 2-3 cm, 3-4 cm, or 4-5 cm). of administering a pharmaceutical composition to a patient, 0066. Any of the drug delivery devices of the invention the method including removably attaching a drug delivery may be configured to deliver an average hourly rate of device of the invention to an intraoral surface of the patient. volume of from about 0.015 mL/hour to about 1.25 mL/hour In certain embodiments, the method further includes detach (e.g., from about 0.015 mL/hour to about 1.20 mL/hour, ing the device from the intraoral Surface and/or administer from about 0.015 mL/hour to about 1.15 mL/hour, from ing drug to the patient for a delivery period of not less than about 0.015 mL/hour to about 1.10 mL/hour, from about about 4 hours and not more than about 7 days. In some 0.015 mL/hour to about 1.05 mL/hour, from about 0.015 embodiments, the drug delivery device includes a drug mL/hour to about 1.00 mL/hour, from about 0.015 mL/hour reservoir including a Volume of a drug, and the method to about 0.90 mL/hour, from about 0.015 mL/hour to about further includes oral administration at a rate in the range of 0.80 mL/hour, from about 0.015 mL/hour to about 0.70 from 15 uL per hour to about 1.25 mL per hour (e.g., as mL/hour, from about 0.015 mL/hour to about 0.60 mL/hour, described herein) during the delivery period. In particular from about 0.015 mL/hour to about 0.50 mL/hour, from embodiments, the fluctuation index of the drug is less than about 0.015 mL/hour to about 0.25 mL/hour, from about or equal to 2.0, 1.5, 1.0, 0.75, 0.50, 0.25, or 0.15 during the 0.015 mL/hour to about 0.10 mL/hour, from about 0.015 delivery period. In some embodiments, the drug delivery mL/hour to about 0.05 mL/hour, from about 0.015 mL/hour device can include a drug reservoir including a pharmaceu to about 0.025 mL/hour, from about 0.015 mL/hour to about tical composition including a drug and the drug is admin 0.020 mL/hour, from about 0.020 mL/hour to about 1.25 istered to the patient at an average rate of not less than 0.01 mL/hour, from about 0.025 mL/hour to about 1.25 mL/hour, mg per hour and not more than 125 mg per hour (e.g., from from about 0.050 mL/hour to about 1.25 mL/hour, from about 0.01 mg/hour to about 125 mg/hour, from about 0.05 about 0.075 mL/hour to about 1.25 mL/hour, from about mg/hour to about 125 mg/hour, from about 0.10 mg/hour to 0.10 mL/hour to about 1.25 mL/hour, from about 0.20 about 125 mg/hour, from about 0.50 mg/hour to about 125 mL/hour to about 1.25 mL/hour, from about 0.50 mL/hour mg/hour, from about 1.0 mg/hour to about 125 mg/hour to about 1.25 mL/hour, from about 0.75 mL/hour to about from about 5.0 mg/hour to about 125 mg/hour, from about 1.25 mL/hour, from about 1.00 mL/hour to about 1.25 10 mg/hour to about 125 mg/hour, from about 25 mg/hour mL/hour, from about 1.10 mL/hour to about 1.25 mL/hour, to about 125 mg/hour, from about 50 mg/hour to about 125 from about 1.15 mL/hour to about 1.25 mL/hour, from about mg/hour, from about 100 mg/hour to about 125 mg/hour, 0.25 mL/hour to about 0.50 mL/hour, from about 0.5 from about 0.01 mg/hour to about 100 mg/hour, from about mL/hour to about 0.75 mL/hour, or from about 0.75 mL/hour 0.01 mg/hour to about 50 mg/hour, from about 0.01 mg/hour to about 1.0 mL/hour) over a period of from about 4 hours to about 25 mg/hour, from about 0.01 mg/hour to about 10 to about 168 hours (e.g., from about 4 hours to about 120 mg/hour, from about 0.01 mg/hour to about 5.0 mg/hour, hours, from about 4 hours to about 100 hours, from about 4 from about 0.01 mg/hour to about 1.0 mg/hour, from about hours to about 80 hours, from about 4 hours to about 72 0.01 mg/hour to about 0.5 mg/hour, from about 0.01 hours, from about 4 hours to about 60 hours, from about 4 mg/hour to about 0.25 mg/hour, from about 0.01 mg/hour to hours to about 48 hours, from about 4 hours to about 36 about 0.1 mg/hour, from about 0.01 mg/hour to about 0.05 hours, from about 4 hours to about 24 hours, from about 4 mg/hour, or from about 1 mg/hour to about 10 mg/hour, hours to about 12 hours from about 4 hours to about 8 hours, from about 10 mg/hour to about 100 mg/hour). In some from about 4 hours to about 6 hours, from about 6 hours to embodiments, the pharmaceutical composition can be about 168 hours, from about 8 hours to about 168 hours, administered to the patient at least once every 60 minutes, at from about 12 hours to about 168 hours, from about 24 hours least once every 30 minutes, or at least once every 15 to about 168 hours, from about 36 hours to about 168 hours, minutes. In other embodiments, the pharmaceutical compo from about 48 hours to about 168 hours, from about 60 hours sition is administered to the patient continuously. In certain to about 168 hours, or from about 72 hours to about 168 embodiments, the pharmaceutical composition can be hours) at about 37° C. and a constant pressure of about 1.013 administered to the patient over a delivery period of about 8 bar, wherein the average hourly rate varies by less than or more hours (e.g., more than 10, 12, 14, 16, 18, 20, or 24 +20% or +10% per hour over a period of 4 or more hours hours). (e.g., 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 0069. In certain embodiments, a method of administering hours, 36 hours, 48 hours, 60 hours, 72 hours, 168 hours, or a pharmaceutical composition of the invention further more). In some embodiments, the drug delivery device can includes treating a disease in the patient, wherein the disease include oral fluid contacting Surfaces that are compatible is spasticity, muscle weakness, mucositis, allergy, immune with the oral fluids, such that the average rate of delivery of disease, anesthesia, bacterial infections, cancer, pain, organ the drug increases or decreases by less than +20% or +10% transplantation, disordered sleep, epilepsy and seizures, US 2017/0172961 A1 Jun. 22, 2017 anxiety, mood disorders, post-traumatic stress disorder, acid, alginic acid, or salts thereof. Alternatively, it can be an arrhythmia, hypertension, heart failure, or diabetic neph undissolved viscosity increasing thickening agent. In par ropathy. ticular embodiments, the thickening agent is a cellulose, 0070. In one particular embodiment of any of the above Such as a non-Swelling cellulose derivative; or a cellulose methods, the method further includes treating a disease in derivative, or an undissolved polymer selected from car the patient, wherein the disease is multiple Sclerosis, cere boxymethyl cellulose, hyaluronic acid, polyacrylic acid, bral palsy, spasticity, neurogenic orthostatic hypotension, polymethacrylic acid, alginic acid, or salts thereof, or a solid Wilson's disease, cystinuria, rheumatoid arthritis, Alzheim amino acid, like tyrosine or phenylalanine. er's disease, myasthenia gravis, Type-1 Gaucher disease, 0076. In any of the methods of the invention, the method Type C Niemann-Pick disease, eosinophilic gastroenteritis, may further include treating Parkinson's disease (including chronic mastocytosis, ulcerative colitis, gastro-oesophageal patients with scores of 4 and 5 on the Hoehn and Yahr scale), reflux, gastroenteritis, hyperemesis gravidarum, glioblas wherein the pharmaceutical composition includes levodopa toma multiformae, anaplastic astrocytoma, pulmonary or a levodopa prodrug. hypertension, coronary heart disease congestive heart fail 0077. The invention also features a method for treating ure, angina, Type 2 diabetes, COPD, asthma, irritable bowel Parkinson's disease in a patient (including patients with syndrome, overactive bladder, and urinary urge inconti scores of 4 and 5 on the Hoehn and Yahr scale), the method nence. In one particular embodiment, the method includes including: (a) inserting a drug delivery device of the inven treating myasthenia gravis and the pharmaceutical compo tion into the patient’s mouth, the device having a drug sition includes pyridostigmine, or a pharmaceutically reservoir including levodopa or a levodopa prodrug; (b) acceptable salt thereof. administering into the patient's mouth the levodopa or a 0071. In one particular embodiment, the pharmaceutical levodopa prodrug for a period of at least 4, 6, or 8 hours composition includes one or more drugs selected from (e.g., as described herein) at an hourly rate in the range of methylphenidate, prostaglandins, prostacyclin, treprostinil, 30 mg/hour to 150 mg/hour (e.g., as described herein, such beraprost, nimodipine, and testosterone. In still other as 50 mg/hour to 125 mg/hour). Such that a circulating embodiments, the pharmaceutical composition includes a plasma levodopa concentration greater than 1,200 ng/mL mucoadhesive polymer. The pharmaceutical composition (e.g., greater than 1,400 ng/mL, 1,500 ng/mL, 1,600 ng/mL, can further include a permeation enhancer. In particular 1,800 ng/mL, 2,000 ng/mL, or 2.200 ng, mL) and less than embodiments of any of the above methods, the pharmaceu 2,500 ng/mL (e.g., less than 2,200 ng/mL, 2,000 ng/mL, tical composition can include drug dissolved in an aqueous 1,800 ng/mL, 1,600 ng/mL, or 1,400 ng/mL) is continuously Solution. The aqueous solution can optionally further maintained for a period of at least 4, 6, or 8 hours (e.g., as include glycerol, ethanol, propylene glycol, polyethylene described herein) during the administration; and (c) remov glycol (PEO, PEG) or DMSO. In still other embodiments, ing the drug delivery device from the mouth. the pharmaceutical composition further includes a thicken 0078. In another aspect, the invention features a method ing agent (e.g., a Sugar, a Sugar alcohol, or a polymer, Such for treating Parkinson's disease in a patient (including as cellulose or a cellulose derivative). In particular embodi patients with scores of 4 and 5 on the Hoehn and Yahr scale), ments, the thickening agent is selected from carboxymethyl the method including: (a) inserting a drug delivery device cellulose, microcrystalline cellulose, hyaluronic acid, poly including a pharmaceutical composition of the invention acrylic acid, polymethacrylic acid, alginic acid, or salts into the patient’s mouth, the pharmaceutical composition thereof. In still other embodiments, the thickening agent is including levodopa or levodopa prodrug; (b) administering selected from Sucrose, glucose, fructose, Sorbitol, and man into the patient's mouth the levodopa or levodopa prodrug nitol. for a period of at least 4, 6, or 8 hours (e.g., as described 0072. In any of the methods of the invention, the phar herein) at an hourly rate in the range of 30 mg/hour to 150 maceutical composition may include one or more of meth mg/hour (e.g., as described herein, such as 50 mg/hour to ylphenidate, prostaglandins, prostacyclin, treprostinil, 125 mg/hour). Such that a circulating plasma levodopa beraprost, nimodipine, and testosterone. concentration greater than 1,200 ng/mL (e.g., as described 0073. In any of the preceding embodiments of the above herein) and less than 2,500 ng/mL (e.g., as described herein) compositions and methods, the pharmaceutical composition is continuously maintained for a period of at least 4, 6, or 8 may include a mucoadhesive polymer and, optionally, a hours (e.g., as described herein) during the administration; permeation enhancer (e.g., to aid transport across the Sub and (c) removing the drug delivery device from the mouth. lingual or buccal mucosa). 0079. In a method for treating Parkinson's disease in a 0074. In any of the preceding embodiments of the above patient (including patients with scores of 4 and 5 on the compositions and methods, the pharmaceutical composition Hoehn and Yahr scale), the fluctuation index of levodopa may include drug dissolved in an aqueous solution. The may be less than or equal to 2.0, 1.5, 1.0, 0.75, 0.50, 0.25, aqueous Solution can further include glycerol, ethanol, pro or 0.15 for a period of at least 4 hours (e.g., at least 6 hours, pylene glycol, polyethylene glycol (PEO, PEG) or DMSO at least 8 hours, or longer) during the administration. In (e.g., from 0.5% (w/w) to 20% (w/w)). Some embodiments, during administration the circulating 0075. In any of the preceding embodiments of the above levodopa plasma concentration varies by less than +/-20% compositions and methods, the pharmaceutical composition or +/-10% from its mean for a period of at least 1 hour (e.g., may further include a viscosity-increasing agent (e.g., a 2 hours, 3 hours, 4 hours, or more hours). dissolved Sugar or Sugar alcohol Such as one selected from 0080. In a further aspect, the invention features a method Sucrose, glucose, fructose, Sorbitol, and mannitol, or a for treating Parkinson's disease in a patient (including dissolved polymer, or water-swollen polymer, or a gel patients with scores of 4 and 5 on the Hoehn and Yahr scale), forming polymer, such one selected from carboxymethyl the method including continuous or semi-continuous admin cellulose, hyaluronic acid, polyacrylic acid, polymethacrylic istration of a pharmaceutical composition of the invention US 2017/0172961 A1 Jun. 22, 2017 into the patient at a rate of 10 mg/hour to 200 mg/hour (e.g., prodrug semi-continuously at a frequency of at least once as described herein, such as 30 mg/hour to 150 mg/hour or every 30 minutes. In certain embodiments, the Suspension or 50 mg/hour to 125 mg/hour) for a period of about 4 hours to solid is administered to the subject for a period of at least 8 about 168 hours (e.g., as described herein). hours at an hourly rate in the range of 10-125 mg/hour. Such 0081. In some embodiments of methods of treating Par that a circulating plasma levodopa concentration greater kinson's disease, the patient has a motor or non-motor than 1,200 ng/mL and less than 2,500 ng/mL is continuously complication of Parkinson's disease such as a complication maintained for a period of at least 8 hours during the including tremor, akinesia, bradykinesia, dyskinesia, dysto administration. nia, cognitive impairment, or disordered sleep. In particular I0086. In one particular embodiment, the subject can have embodiments, the method of treating Parkinson's disease delayed gastric emptying or retarded gastrointestinal transit, includes treating a motor or non-motor complication of e.g., induced by LD-derived dopamine, the dopamine being Parkinson's disease. formed by decarboxylation of LD (e.g., in the mesentery of 0082. The invention also features a method of treating the gastrointestinal tract). Parkinson's disease (including patients with scores of 4 and I0087. In still other embodiments, the drug reservoir 5 on the Hoehn and Yahr scale) in a patient including includes a composition including a Suspension that is a drug administering a pharmaceutical composition of the inven particle-containing emulsion including (i) from 35% to 70% tion to a patient using the methods described herein. (w/w) drug particles including levodopa and/or carbidopa, 0083. In a further aspect, the invention features a method or salts thereof, (ii) from 19% to 30% (w/w) of one or more of preparing a pharmaceutical composition including from water-immiscible compounds, (iii) from 2% to 16% (w/w) about 35% (w/w) to about 70% (w/w) of a drug including water, and (iv) from 1% to 8% (w/w) surfactant. The levodopa and/or carbidopa; the pharmaceutical composition Suspension can include a continuous hydrophilic phase including a surfactant, an oil, and water, the pharmaceutical including greater than 50% (w/w) drug particles. Optionally, composition, when at 37° C., including solid particles of the drug delivery device includes an automatic stop/start, a drug; the drug having a partition coefficient in favor of suction-induced flow limiter, a temperature-induced flow water, the Surfactant being present in an amount Sufficient to limiter, and/or bite-resistant structural Supports. render the composition physically stable; and the method I0088. In a related aspect, the invention features a method including contacting an aqueous solution including the Sur for treating spasticity in a Subject, the method including: (a) factant and water with solid particles of the drug, to produce inserting a drug delivery device into the Subject's mouth, the a mixture of solid particles in aqueous solution. The method device having (i) a fastener to removably secure the drug may further include contacting the mixture with the oil. delivery device to a surface of the patient’s mouth; (ii) an 0084. In embodiments featuring delivery across the buc electrical or mechanical pump; and (iii) an oral liquid cal mucosa, the invention further includes delivering the impermeable drug reservoir having a volume of from 0.1 ml drug-containing composition into a location in the mouth to 5 ml including a Suspension or Solid containing baclofen Such that the drug has a residence time at or near the mucosa or a pharmaceutically acceptable salt thereof; (b) adminis of greater than 2 minutes, 5 minutes, 10 minutes, 30 minutes, tering into the patients mouth the baclofen continuously or or 60 minutes before being removed from contact with the semi-continuously; and (c) removing the drug delivery oral mucosa (e.g., by Saliva-dilution and/or Swallowing). device from the mouth of the subject. Several techniques and device configurations may be used to I0089. In a related aspect, the invention features a method obtain the desired residence time, optionally in combination for treating myasthenia gravis in a subject, the method with each other. In one embodiment, the drug-containing including: (a) inserting a drug delivery device into the composition is delivered into a portion of the mouth where Subjects mouth, the device having (i) a fastener to removably the flux of saliva is slow, e.g., into the cheek pocket between secure the drug delivery device to a surface of the patients the bottom teeth/gums and the cheek, and preferably not mouth; (ii) an electrical or mechanical pump; and (iii) an proximate a salivary gland. In a related embodiment, the oral liquid impermeable drug reservoir having a volume of composition may be mucoadhesive or include a mucoadhe from 0.1 ml to 5 ml including a solution or Suspension of sive to retain the drug proximate the mucosa. In yet another pyridostigmine or a pharmaceutically acceptable salt related embodiment, the drug-containing composition may thereof; (b) administering into the patient’s mouth the pyri be delivered into a material that retains the drug proximate dostigmine continuously or semi-continuously; and (c) the mucosa, Such as a sorbent. removing the drug delivery device from the mouth of the 0085. In a related aspect, the invention features a method Subject. for treating Parkinson's disease in a Subject, the method 0090. In an embodiment of any of the above devices, including: (a) inserting a drug delivery device into the methods, and pharmaceutical compositions, the drug can be Subject’s mouth, the device having (i) a fastener to remov an analgesic (e.g., lidocaine, bupivacaine, mepivacaine, ably secure the drug delivery device to a surface of the ropivacaine, tetracaine, etidocaine, chloroprocaine, prilo patient’s mouth; (ii) an electrical or mechanical pump; and caine, procaine, benzocaine, dibucaine, dyclonine hydro (iii) an oral liquid impermeable drug reservoir having a chloride, pramoxine hydrochloride, benzocaine, propara Volume of from 0.1 ml to 5 ml including a Suspension or caine, and their pharmaceutically acceptable salts) or an Solid containing levodopa or a levodopa prodrug; (b) admin opioid (e.g., buprenorphine, nor-buprenorphine, fentanyl. istering into the patient's mouth the levodopa or a levodopa methadone, levorphanol, morphine, hydromorphone, oxy prodrug continuously or semi-continuously; and (c) remov morphone codeine, oxycodone, hydrocodone, and their ing the drug delivery device from the mouth of the subject, pharmaceutically acceptable salts) administered for the wherein the subject has a score of 4 and 5 on the Hoehn and treatment of pain. Yahr Scale. In some embodiments, step (b) includes admin 0091. The invention features a method for treating dis istering into the Subject's mouth the levodopa or a levodopa ease in a subject suffering from delayed gastric emptying or US 2017/0172961 A1 Jun. 22, 2017

retarded gastrointestinal transit, the method including: (a) mouth of a patient using at a rate between 0.001 mL/hour inserting a drug delivery device into the Subject's mouth, the and 1.25 mL/hour, (iii) wherein the pharmaceutical compo device having (i) a fastener to removably secure the drug sition includes a paste, Solution or Suspension having a delivery device to a surface of the patients mouth; (ii) an viscosity greater than 100 poise and less than 500,000 poise electrical or mechanical pump; and (iii) an oral liquid at 37° C.; and (iv) the drug delivery device includes a impermeable drug reservoir having a volume of from 0.1 ml mechanical pump including a flow restrictor including an to 5 ml including a suspension or Solid containing a drug internal diameter between 0.05 mm and 3.00 mm and a useful for treating the disease; (b) administering into the length between 0.25 cm and 20 cm. In certain embodiments, patients mouth the drug continuously or semi-continuously the mechanical pump includes a propellant, the propellant at a frequency of at least once every 30 minutes; and (c) having a vapor pressure at about 37° C. greater than 1.2 bar removing the drug delivery device from the mouth of the and less than 50 bar. The solid drug particles and/or excipi Subject. In particular embodiments, an efficacious circulat ent particles can have a Doo between 0.1 um and 200 um and ing plasma concentration of the drug is continuously main a Ds between 0.1 Lum and 50 Lim when measured by light tained for a period of at least 8 hours during the adminis scattering with the particles dispersed in a non-solvent. In tration. The drug delivery device can include an automatic certain embodiments, the administration rate is greater than stop? start, a Suction-induced flow limiter, a temperature 0.03 mL/hour and less than 0.5 mL/hour; the viscosity induced flow limiter, and/or bite-resistant structural Sup greater than 200 poise and less than 100,000 poise; the flow ports. restrictor having an internal diameter between 0.1 mm and 0092. The invention features a drug delivery device con 0.7 mm and a length between 1 cm and 5 cm; and the figured for continuously or semi-continuously administering propellant has a vapor pressure at about 37° C. greater than a drug into the mouth of a patient, the drug delivery device 2.5 bar and less than 15 bar. The solid drug particles and/or including: a pharmaceutical composition including a paste, excipient particles can have a Doo between 0.1 um and 50 Solution or Suspension having a viscosity greater than 100 um and a Ds between 0.5um and 30 Lum when measured by poise and less than 500,000 poise at 37°C. and including the light scattering with the particles dispersed in a non-solvent. drug; and a mechanical pump including a flow restrictor, the In particular embodiments, the administration rate is greater flow restrictor including an internal diameter between 0.05 than 0.05 mL/hour and less than 0.2 mL/hour; the viscosity mm and 3.00 mm and a length between 0.25 cm and 20 cm, is greater than 500 poise and less than 75,000 poise; the flow configured and arranged to administer the pharmaceutical restrictor has an internal diameter between 0.2 mm and 0.5 composition at a rate between 0.001 mL/hour and 1.25 mm and a length between 1 cm and 2.5 cm; and the mL/hour. The mechanical pump can include a propellant. In propellant has a vapor pressure at about 37° C. greater than particular embodiments, the propellant has a vapor pressure 4 bar and less than 10 bar. The solid drug particles and/or at about 37° C. greater than 1.2 bar and less than 50 bar. The excipient particles can have a Do between 3 um and 30 um pharmaceutical composition includes solid drug particles and a Dso between 2 Lum and 20 um when measured by light and/or excipient particles can have a Doo between 0.1 um scattering with the particles dispersed in a non-solvent. and 200 um and a Dso between 0.1 um and 50 um when measured by light scattering with the particles dispersed in ABBREVIATIONS AND DEFINITIONS a non-solvent. The drug delivery device of can be configured 0094. The term “about, as used herein, refers to a such that: (i) the administration rate is greater than 0.03 number that is +10% of a value that this term precedes mL/hour and less than 0.5 mL/hour; (ii) the viscosity greater except when the value is that of a temperature. For tem than 200 poise and less than 100,000 poise; (iii) the flow peratures “about means-3°C. restrictor has an internal diameter between 0.1 mm and 0.7 (0095. The term “administration” or “administering” mm and a length between 1 cm and 5 cm; and (iv) the refers to a method of giving a dosage of a therapeutic drug, propellant has a vapor pressure at about 37° C. greater than such as LD and/or carbidopa (CD), to a patient. The drug 2.5 bar and less than 15 bar. In particular embodiments, the may be formulated as a fluid, such as a viscous Suspension. solid drug particles and/or excipient particles having a Do Fluids may be infused. The dosage form of the invention is between 1 um and 50 Lum and a Ds between 0.5um and 30 preferably administered into the mouth or nasal cavity, um when measured by light scattering with the particles optionally using a drug delivery device such as an infusion dispersed in a non-solvent. The drug delivery device of can pump, and the drug can be Swallowed and/or absorbed be configured such that: (i) the administration rate is greater anywhere within the mouth or alimentary canal, e.g., buc than 0.05 mL/hour and less than 0.2 mL/hour; (ii) the cally, Sublingually, or via the stomach, Small intestine, or viscosity is greater than 500 poise and less than 75,000 large intestine. Typical durations of administration from a poise; (iii) the flow restrictor has an internal diameter single device or drug reservoir are greater than 4, 8, 12, or between 0.2 mm and 0.5 mm and a length between 1 cm and 16 hours per day, up to and including 24 hours per day. 2.5 cm; and (iv) the propellant has a vapor pressure at about Administration can also take place over multiple days from 37° C. greater than 4 bar and less than 10 bar. In particular a single device or drug reservoir, e.g., administration of a embodiments, the Solid drug particles and/or excipient par drug for 2 or more days, 4 or more days, or 7 or more days. ticles having a Doo between 3 Lum and 30 Lum and a Dso 0096. As used herein, “aqueous” refers to formulations of between 2 um and 20 Lim when measured by light scattering the invention including greater than 10% or 20% (w/w) with the particles dispersed in a non-solvent. water and, optionally, a cosolvent (e.g., propylene glycol, 0093. The invention further features a method of admin glycerol or ethanol) or solute (e.g., a Sugar). istering a pharmaceutical composition to a patient, the 0097. By “alkyl saccharide' is meant a sugar ether of a method including: (i) inserting the drug delivery device into hydrophobic alkyl group (e.g., typically from 9 to 24 carbon the mouth of the patient; (ii) continuously or semicontinu atoms in length). Alkyl saccharides include alkyl glycosides ously administering the pharmaceutical composition into the and alkyl glucosides. Alkyl glycosides that can be used in US 2017/0172961 A1 Jun. 22, 2017

the pharmaceutical compositions of the invention include, immiscible phase (e.g., oil). An emulsion may remain Sub without limitation, Csa alkyl (e.g., octyl-, nonyl-, decyl-, stantially homogeneous, e.g., it may not substantially cream undecyl-, dodecyl-, tridecyl-, or tetradecyl-) ethers of a or or phase separate in 3 months at 25°C. and/or in 1 day at 37° B-D-maltoside, -glucoside or -Sucroside, alkyl thiomalto C. The term encompasses oil in water emulsions and water sides, such as heptyl, octyl, dodecyl-, tridecyl-, and tetrade in oil emulsions. cyl-B-D-thiomaltoside; alkylthioglucosides, such as heptyl 0108. As used herein the term “engineering plastic' is or octyl 1-thio C- or B-D-glucopyranoside; alkylthiosucro synonymous with the terms "engineered plastic”, “engi ses; and alkyl maltotriosides. For example, the pharmaceu neered polymer and “engineering polymer. The term tical composition can include a Surfactant selected from means a polymer differing from the most widely used octyl maltoside, dodecyl maltoside, tridecyl maltoside, and polymers in its Superior mechanical properties, or in its tetradecyl maltoside. Alkyl glucosides that can be used in the Superior resistance to chemicals or its lesser wetting by pharmaceutical compositions of the invention include, with water or by oils, or its lesser Swelling in water or in oils. out limitation, Csa alkyl (e.g., octyl-, nonyl-, decyl-, unde Exemplary engineering plastics include polyamides such as cyl-, dodecyl-, tridecyl-, or tetradecyl-) ethers of glucoside, Nylon 6, Nylon 6-6 and other Nylons; polyesters like Such as dodecyl glucoside or decyl glucoside. polybutylene terephthalate or polyethylene terephthalate: 0098. The term “automatic stop/start,” as used herein, polycarbonates; polyetheretherketones; polyetherketones; refers to an element Switching automatically between drug polyimides; polyoxymethylenes such as polyacetals or poly administering mode and non-administering mode upon formaldehydes; polyphenylene Sulfide; polyphenylene actuation by an external stimulus (e.g., detachment of the oxide; polysulphone; polytetrafluoroethylene; polyvi device of the invention from an intraoral Surface). Automatic nylidene difluoride; ultra-high-molecular-weight polyethyl stop? start encompasses automatically stopping delivery, ene; and strong elastomers such as highly crosslinked acry automatically starting delivery, or both. For example, the lonitrile butadiene styrene, and their co-polymers. automatic stop/start can be a pressure sensitive Switch, a 0109. By “ester saccharide' is meant a sugar ester of a clip, a fluidic channel that kinks, a clutch (see FIGS. 7E and hydrophobic alkyl group (e.g., typically from 8 to 24 carbon 7F). atoms in length). Ester saccharides include ester glycosides 0099. The term “bite-resistant structural supports, as and ester glucosides. Ester glycosides that can be used in the used herein, refers to structural elements in the drug delivery pharmaceutical compositions of the invention include, with device that enable them to withstand a patient’s bite with a out limitation, Cs, alkyl (e.g., octyl-, nonyl-, decyl-, unde force of at least 200 Newtons, without rupturing and without cyl-, dodecyl-, tridecyl-, or tetradecyl-) esters of a or f3-D- infusing a bolus of greater than 5% of the drug contents, maltoside, -glucoside or -Sucroside. For example, the when a fresh reservoir is newly inserted into the mouth. pharmaceutical compositions can include a Surfactant 0100. The term “CD” refers to Carbidopa. selected from Sucrose mono-dodecanoate, Sucrose mono 0101. As used herein, “co-administered’ or “co-infused’ tridecanoate, or Sucrose mono-tetradecanoate. refers to two or more pharmaceutically active agents, for 0110. As used herein, the term “fastener” refers to an mulated together or separately, and administered or infused element for attaching the device of the invention, or its into the mouth simultaneously or within less than 60, 30, 15, components, to a Surface of the mouth (e.g., to the teeth). or 5 minutes of each other. Exemplary methods of attachment are fasteners banded, 0102) The term “COMT refers to catechol-O-methyl adhered, cemented or glued to one, two or more teeth; dental transferase. appliances; splints; transparent retainers; metal wire Hawley 0103 As used herein “continuous administration” or retainers; partial retainers on one side of the mouth (e.g., “continuous infusion” refers to uninterrupted administration attached to 3, 4, or 5 teeth); thermo or vacuum-formed Essix or infusion of a drug in solid or fluid form. retainers typically including a polypropylene or polyvinyl 0104. As used herein the term “Do” is defined as the chloride material, typically 0.020" or 0.030" thick; thermo median for a Volume distribution (as opposed to a mass, formed Zendura retainers including polyurethane; bonded number, or surface distribution) of the particles. The particle (fixed) retainers including a passive wire bonded to the size can be measured by conventional particle size measur tongue-side of lower or upper teeth; muco-adhesives that ing techniques well known to those skilled in the art. Such adhere to the oral mucosal tissue and slowly erode; and techniques include, for example, optical microscopy, elec fasteners that conform or are molded to fit a patient’s teeth tron microscopy, sedimentation, field flow fractionation, or Soft tissue, similar to dental splints used to treat bruxism photon correlation spectroscopy, light scattering (e.g., with and sleep apnea. Similarly, the drug delivery devices, drug a Microtrac UPA 150, Malvern Mastersizer), laser diffrac pumps, drug reservoirs and other devices of the invention tion, and centrifugation. Dso values are commonly derived may be directly or indirectly attached to a removable den of particle size distributions of particles Suspended in a ture, a prosthetic tooth crown, a dental bridge, a moral band, non-solvent, the distributions measured by light scattering. a bracket, a mouth guard, or a dental implant. 0105. The term “DDC” refers to DOPA decarboxylase. 0111. As used herein the term “fluctuation index” refers 0106. As used herein, the term “drug particle' refers to to the magnitude of the rise and fall of drug level in plasma Solid particles including a drug. The drug particles can be relative to the average plasma concentration, and is defined included in the pharmaceutical compositions of the inven as C-Cl/C. The fluctuation index is measured over tion. For example, the pharmaceutical composition can a specified period of time. The time period can begin, for contain particulates containing or formed from LD, LD salts, example, after the drugs plasma concentration: has reached CD, or CD salts. the steady-state concentration; or has reached 90% of the 0107 As used herein the term "emulsion” refers to a steady-state concentration; or 30, 60, or 120 minutes after macroscopically Substantially homogeneous system typi any of the drug delivery devices of the invention has been cally including Solid drug particles, water, and a water inserted into the mouth and begun to deliver drug. The time US 2017/0172961 A1 Jun. 22, 2017 period can end, for example: at the end of the use period 1, 4, 8, 16, 24, 48 or 72 hours after placing a drug delivery specified in the instructions for use of the drug delivery device including a fresh reservoir in a patient’s mouth and device; when the drug reservoir is 90% depleted or substan initiating the administration, less than 5% (e.g., 3% or 1%) tially depleted; or about 4, 8, 16, 24, 72, or 168 hours after by weight of the drug-including pharmaceutical composition the start of the time period. in the reservoir includes an oral liquid. The one or more 0112. As used herein, the term “fluid encompasses any drugs may be in solid form or in fluid form. Oral liquids drug-including liquid, gel, or non-pourable Suspension that include any fluid originating from the mouth, including can be pumped or extruded. The fluid can be a Newtonian or saliva (or its water component) and other fluids commonly a non-Newtonian fluid; it can be an easy to deform solid or found in the mouth or that are commonly drunk or consumed a soft paste, which may move as a plug via slip flow. It can by the patient, including diluted oils and alcohols. Exem be, for example, a viscous Newtonian or non-Newtonian plary oral liquid impermeable reservoirs can be made of a Suspension. The term encompasses, for example, true solu metal, or a plastic that can optionally be elastomeric. Metal tions, colloidal solutions, emulsions, pastes, Suspensions, lic reservoirs can include, for example aluminum, magne and dense semi-solid toothpaste-like Suspensions deforming sium, titanium, iron, or alloys of these metals. When made under pressure sufficiently to be extruded into the mouth. of a plastic it can have a metallic barrier layer, or include The fluid infused can be aqueous, non-aqueous, single plastics or elastomers that do not substantially Swell in phase, two-phase, three-phase or multiphase. The emulsions water, used for example for packaging of food, or for can be, for example, oil-in-water or water-in-oil, and can drink-containing bottles, or in a fabric of washable clothing include micelles and/or liposomes. (e.g., polyamides like Nylon or polyesters like Dacron), or 0113. As used herein, “infused’ or “infusion' includes in stoppers or seals of drink containing bottles, or in Septums infusion into any part of the body, preferably infusion into of vials containing solutions of drugs. Examples include the mouth or nasal cavity. It is exemplified by extrusion into perfluoropolymers like PTFE or FPE or fluorinated the mouth. polyethers, polyolephins like polyethylene and polypropyl 0114. The term “LD” refers to levodopa, also known as ene; other vinylic polymers like polystyrene and polyvinyl L-DOPA, or a salt thereof. chloride; polyvinylidene chloride, polyacrylates and 0115. As used herein the term “lubricant’ means an oil, polymethacrylates, e.g., polymethyl methacrylate and grease or lamellar solid that reduces the friction between two polymethyl acrylate; and polycarbonates; and polysilicones parts of a system having a moving component. or their copolymers. The polymers can have glass transition 0116. The term "MAO-B' refers to monoamine oxidase temperatures greater than 37°C. Ingress of oral liquids into B. openings in the reservoir can be prevented or minimized by 0117. As used herein, "mechanical pump' means any the use of one or more valves, squeegees, baffles, rotating drug delivery device whose motive force is not electricity, augers, rotating drums, propellants, pneumatic pumps, dia magnetism, or gravity. Examples of mechanical pumps phragm pumps, hydrophobic materials, and/or hydrophobic include drug delivery devices wherein the drug is delivered fluids. In some embodiments, the invention features multiple by the force or pressure of a spring, an elastomer, a com doses of solid drug within multiple, impermeable reservoirs pressed gas, or a propellant. or compartments. The plastic of the reservoir can be fiber 0118. As used herein, “mouth' includes the areas of the reinforced, e.g., with carbon, glass, metal or strong polymer oral cavity, including those areas of the oral cavity adjacent fibers. the lips, cheeks, gums, teeth, tongue, roof of the mouth, hard 0.122 The abbreviation “M” means moles per liter. Usage palate, soft palate, tonsils, uvula, and glands. of the term does not imply, as it often does in chemistry, that 0119 The term “non-aqueous' can refer to the liquid the drug is dissolved. As used herein 1 M means that a 1 liter carrier in a formulation or to the typically water insoluble volume contains 1 mole of the combination of the undis liquid component in a formulation. The non-aqueous liquid solved (often solid) and/or the dissolved drug. For example, component typically melts or softens below 37° C. and 1 MLD means that there is 197 mg of solid (undissolved) contains less than 20% (w/w) water (e.g., less than 10%. 5%, and dissolved LD in one mL. 3%, 2%, 1.5%, 1%, 0.5%, or less than 0.1% (w/w). Exem (0123. The term “PD' refers to Parkinson's disease, plary liquid components include lipids, edible oils, non including patients with scores of 4 and 5 on the Hoehn and toxic esters of mid-range fatty acids. Such as triglyceride Yahr scale. esters of mid range fatty acids, butters, and paraffin oils (0.124. The term “PEG” refers to polyethylene glycol. melting or softening below 37° C. (0.125. As used herein, the term “pH refers to the pH 0120. As used herein, the term “operational life” means measured using a pH meter having a glass pH electrode the time period during which the infused formulation con connected to an electronic meter. taining the drug (e.g., LD or CD) is suitable for delivery into I0126. As used herein, the term “physically stable' refers a patient, under actual delivery conditions. The operational to a macroscopically Substantially homogenous composition life of the drugs (e.g., LD or CD) delivered by the devices including a suspension of drug particles, wherein the Sus of the invention can be greater than 12 hours, 24 hours, 48 pension does not exhibit Substantial sedimentation upon (a) hours, 72 hours, 96 hours (4 days), or 7 days. It typically storage at about 5°C. under at about 1 G gravity for a period requires that the product is not frozen or refrigerated. The of at least 3, 6, 12, or 18 months; (b) storage at about 25°C. product is typically infused at or near body temperature at about 1 G gravity for a period of at least 3, 6, 12, 18, or (about 37° C.) and typically remains substantially homoge more months; or (c) centrifugation at about 5,000 G, 10,000 neous during its infusion. G, or 16,000 G gravity for at least 30 minutes (e.g., for 60 0121. As used herein, an “oral liquid impermeable res minutes or longer) at about 25° C. For compositions that ervoir’ means a reservoir including one or more drugs to be include an emulsion including Suspended drug particles, administered into the patient's mouth, wherein, for example, physically stable compositions also do not exhibit Substan US 2017/0172961 A1 Jun. 22, 2017 tial creaming upon (a) storage at about 5° C. under ambient ceutical compositions of the invention can include polyeth conditions for a period of at least 3, 6, 12, or 18 months; (b) ylene glycol glyceride monoesters, diesters, and/or triesters storage at 25°C. under ambient conditions for a period of at of hexanoic, heptanoic, caprylic, nonanoic, capric, lauric, least 3, 6, 12, or 18 months; or (c) centrifugation at about myristic, palmitic, heptadecanoic, Stearic, arachidic, 5,000 G, 10,000 G, or 16,000 G gravity for at least 30 behenic, lignoceric, C-linolenic, Stearidonic, eicosapentae minutes (e.g., 60 minutes or longer) at about 25°C. Physi noic, docosahexaenoic, linoleic, Y-linolenic, dihomo-Y-lino cally stable Suspensions may also remain macroscopically lenic, arachidonic, oleic, elaidic, eicosenoic, erucic, or ner Substantially homogeneous when stored for about 8, 24, or Vonic acid, or mixtures thereof. The polyglycol moiety in a 48 hours at about 37°C. without agitation, Such as shaking, polyglycolized glyceride can be polydisperse; that is, they Subsequent to the storage or centrifugation described above. can have a variety of molecular weights. 0127. By “polyglycolized glyceride' is meant a polyeth I0128 By “polysorbate surfactant is meant an oily liquid ylene glycol glyceride monoester, a polyethylene glycol derived from pegylated sorbitan esterified with fatty acids. glyceride diester, a polyethylene glycol glyceride triester, or Common brand names for polysorbate Surfactant include a mixture thereof containing a variable amount of free AlkestTM, CanarcelTM and TweenTM. Polysorbate surfactants polyethylene glycol. Such as a polyethylene glycol-oil trans include, without limitation, polyoxyethylene 20 sorbitan esterification product. The polyglycolized glyceride can monolaurate (TWEENTM20), polyoxyethylene (4) sorbitan include either monodisperse (i.e., single molecular weight) monolaurate (TWEENTM 21), polyoxyethylene 20 sorbitan or polydisperse polyethylene glycol moieties of a predeter monopalmitate (TWEENTM 40), polyoxyethylene 20 sorbi mined size or size range (e.g., PEG2 to PEG 40). Polyeth tan monostearate (TWEENTM 60); and polyoxyethylene 20 ylene glycol glycerides include, for example: PEG glyceryl sorbitan monooleate (TWEENTM 80). caprate, PEG glyceryl caprylate, PEG-20 glyceryl laurate I0129. The term “pressure-invariant pump, as used (Tagat(R. L. Goldschmidt), PEG-30 glyceryl laurate (Tagat(R) herein, refers to a pump whose average rate of drug delivery L2, Goldschmidt), PEG-15 glyceryl laurate (Glycerox L decreases by less than about 10% (e.g., less than about 7%. series, Croda), PEG-40 glyceryl laurate (Glycerox L series, 5%, or 3%) at an ambient pressure of about 1.013 bar versus Croda), PEG-20 glyceryl Stearate (CapmulR EMG, its average rate of delivery at an ambient pressure of about ABITEC), and Aldo R. MS-20 KFG, Lonza), PEG-20 glyc 0.898 bar and/or increases by less than about 10% (e.g., as eryl oleate (Tagat(R. O. Goldschmidt), and PEG-30 glyceryl described herein) at an ambient pressure of about 0.898 bar oleate (TagatR) 02, Goldschmidt). Caprylocapryl PEG glyc versus its average rate of delivery at an ambient pressure of erides include, for example, caprylic/capric PEG-8 glyceride about 1.013 bar. (Labrasol(R), Gattefosse), caprylic/capric PEG-4 glyceride 0.130. As used herein, “pump' refers to any mechanism (LabrafacR. Hydro, Gattefosse), and caprylic/capric PEG-6 capable of administering a fluid formulated drug product glyceride (SOFTIGENR767, Huls). Oleoyl PEG glyceride over a period of 4 or more hours. Examples of pumps include, for example oleoyl PEG-6 glyceride, (Labrafil include battery-powered pumps (e.g., Syringe pumps, piezo M1944 CS, Gattefosee). Lauroyl PEG glycerides includes, electric, peristaltic pumps, or diaphragm pumps), mechani for example, lauroyl PEG-32 glyceride (GelucireR ELU cal devices with or without moving parts that are not CIRE 44/14, Gattefosse). Stearoyl PEG glycerides include, battery-powered (e.g., gas-driven pumps, spring-driven for example stearoyl PEG-32 glyceride (Gelucrire 50/13, pumps, shape memory alloy driven pumps, and elastomeric Gelucire 53/10, Gattefosse). PEG castor oils include PEG-3 pumps), and battery operated electroosmotic pumps (with or castor oil (Nikkol CO-3, Nikko), PEG-5, 9, and 16 castor oil without moving parts). (ACCONON CA series, ABITEC), PEG-20 castor oil, (Em 0131 The terms “semi-continuous administration' and alex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante “frequent administration, as used interchangeably herein, EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 refer to an administration (e.g., infusion) of a drug in Solid castor oil (Incrocas-35, Croda), PEG-38 castor oil (Emul or fluid form at a frequency of at least once every 120 gante EL 65, Condea), PEG-40 castor oil (Emalex C-40, minutes, and preferably at least every 90, 60, 30, 15, or 5 Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon minutes. Emulsion), PEG-56 castor oil (Eumulgin R, PRT 56, Pulcra (0132. As used herein, the term “shelf life” means the SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG shelf life of the drug delivered by the inventive device (e.g., 100 castor oil, PEG-200 castor oil (Eumulgin R, PRT 200, LD or CD), in its form as a product sold for use by Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, consumers, during which period the product is Suitable for Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7. use by a patient. The shelf life of the drugs (e.g., LD or CD) BASF), PEG-10 hydrogenated castor oil (Nikkol HCO-10, administered by the devices of the invention can be greater Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, than 3, 6, 12, 18, or preferably 24 months. The shelf life may Nikko), PEG-25 hydrogenated castor oil (SimulsolR 1292, be achieved when the product is stored frozen (e.g., at about Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, -18°C.), stored refrigerated (at 5+3°C., for example at 4+2 Nikko), PEG-40 hydrogenated castor oil (Cremophor RH C.), or stored at room temperature (e.g., at about 25°C.). The 40, BASF), PEG-45 hydrogenated castor oil (Cerex ELS drug (e.g., LD or CD) product sold to consumers may be the 450, Auschem Spa), PEG-50 hydrogenated castor oil (Em drug-containing Suspension, e.g., Suspension ready for infu alex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor Sion, or it may be its components. oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor 0.133 As used herein, “stable” refers to stable formula oil (Nikkol HCO-80, Nikko), and PEG-100 hydrogenated tions of any of the drugs administered by the devices of the castor oil (Nikkol HCO-100, Nikko). Additional polyethyl invention. Stable formulations exhibit physical stability (as ene glycol-oil transesterification products include, for defined above) and a reduced susceptibility to chemical example, stearoyl PEG glyceride (Gelucire R 50/13, Gatte transformation (e.g., oxidation) prior to administration into fosse). The polyglycolized glycerides useful in the pharma a patient. Stable drug formulations have a shelf life at about US 2017/0172961 A1 Jun. 22, 2017

5° C. and/or at about 25°C. of equal to or greater than 3, 6, 0.138. The term "suspension flow-enhancement element,” 12, 18, or 24 months, and an operational life of greater than as used herein, refers to one or more elements that Substan or equal to 8 hours, 12 hours, 16 hours, 24 hours, 48 hours, tially prevent pressure-induced separation of pumped, vis 72 hours, 96 hours, or 7 days. In the context of LD and/or cous Suspensions, e.g., formulations with particular multi CD containing formulations, “stable' refers to formulations modal particle size distributions, packing densities, and which are chemically stable and physically stable. Chemi flow-enhancing excipients; flaring of the orifice, tube, or cally stable formulations are those having a shelf life during flow restrictor; orifice, tube or flow restrictor inner diameters which less than 20% (e.g., 10%, 5%, 4%, 3%, 2% or less Substantially larger than the maximum particle size (e.g., the than 1%) of the LD and/or CD is chemically transformed Do Dos, or Dos); and selection of specific combinations of (e.g., oxidized) when stored for a period of 3, 6, 12, 18, or Viscosity, orifice/tube inner diameter, particle size, and pres 24 months. For formulations such as Suspensions and drug SUC. particle-containing emulsions, the term 'stable' also refers 0.139. The term “temperature-induced flow limiter,’ as to formulations that are physically stable. In the context of used herein, refers to one or more elements preventing the LD and CD, “stable” refers to formulations that are “oxi delivery of a bolus greater than about 5% of the contents of datively stable.” Stable formulations of LD and CD are those a fresh drug reservoir, when immersed for five minutes or for having a shelf life during which less than 10% (e.g., 5%, 4%, one minute in a stirred physiological saline Solution at about 3%, 2% or less than 1%) of the LD and CD is oxidized when 55° C. The temperature-induced flow limiter can include stored for a period of 3, 6, 12, 18, or 24 months. Stable insulation with a material of low thermal conductivity formulations of LD and CD have an operational life during proximate the drug reservoir and/or the pump. Optionally, which less than 10% (e.g., as described herein) of the LD the temperature-induced flow limiter includes an elastomer, and CD is oxidized over a period of 8 hours, 12 hours, 16 a spring, or a gas. hours, 24 hours, 48 hours, 72 hours, 96 hours, or 7 days. The 0140. As used herein, the term “treating refers to admin chemically stable formulations may contain less than 1.6 ug istering a pharmaceutical composition for prophylactic and/ of hydrazine per mg of LD and CD when stored for a period or therapeutic purposes. To “prevent disease' refers to of 3, 6, 12, 18, or 24 months at about 5° C. and/or at about prophylactic treatment of a patient who is not yet ill, but who 250 C. is susceptible to, or otherwise at risk of a particular disease. 0134. As used herein, “substantially free of oxygen To “treat disease' or use for “therapeutic treatment” refers to refers to compositions packaged in a container for storage or administering treatment to a patient already suffering from a for use wherein the packaged compositions are largely free disease to ameliorate the disease and improve the patients of oxygen gas (e.g., less than 10%, or less than 5%, of the condition. The term “treating also includes treating a gas that is in contact with the composition is oxygen gas) or patient to delay progression of a disease or its symptoms. wherein the partial pressure of the oxygen is less than 15 Thus, in the claims and embodiments, treating is the admin torr, 10 torr, or 5 torr. This can be accomplished, for istration to a patient either for therapeutic or prophylactic example, by replacing a part or all of the ambient air in the purposes. container with an inert gas, such as nitrogen, carbon dioxide, 0.141. As used herein “viscosity” means dynamic viscos argon, or neon, or by packaging the composition in a ity also known as shear viscosity. container under a vacuum. 0142. Other features and advantages of the invention will 0135 The term "suction-induced flow limiter,” as used be apparent from the following Detailed Description, the herein, refers to one or more elements preventing the deliv drawings, and the claims. ery of a bolus greater than about 5%, 3%, or 1% of the contents of a fresh drug reservoir, when the ambient pressure BRIEF DESCRIPTION OF THE DRAWINGS drops by 0.14 bar for a period of one minute. The suction 0.143 FIG. 1A depicts a drug delivery device that is induced flow limiter can include pressurized surfaces that removably attached to a tooth using a fastener 1. The pump are in fluidic (gas and/or liquid) contact with the ambient 2 and drug reservoir 3 are contained within a housing 4 and atmosphere via one or more ports or openings in the housing are disposable. FIG. 1B depicts an embodiment in which a of the drug delivery device. Alternatively, the suction portion 4 of the drug delivery device is reusable, and a induced flow limiter can be selected from a deformable removable pump 2 and drug reservoir 3 can be disposable. channel, a deflectable diaphragm, a compliant accumulator, FIG. 1C depicts an embodiment in which a pump 2 and a an inline vacuum-relief valve, and a float valve. drug reservoir 3 form a single component. 0136. As used herein, the term "suitable for continuous or 014.4 FIG. 2A depicts an embodiment of the drug deliv frequent intermittent intra-oral delivery” refers to drug par ery device in which the pump 2 and/or drug reservoir 3 is ticle Suspensions of the invention that are efficacious and fastened to either the upper or lower teeth using a transparent safe upon intra-oral delivery. For example, local adverse retainer 6. One, two or more pumps and/or one or more drug events in or near the mouth (if any) produced by continuous reservoirs are secured on the buccal side of the transparent or frequent intermittent intra-oral administration of the Sus retainer 6. One, two, or more drug pumps and/or drug pension are tolerable or mild. reservoirs may be secured unilaterally, on either the right or 0.137 As used herein the term "suspension” refers to a left sides, positioned in the buccal vestibule or, alternatively, mixture including a liquid and particles of at least one solid. on the lingual side of the teeth. FIG. 2B is a close up The liquid can be acqueous or non-aqueous or an emulsion. showing the pump 2 and drug reservoir 3 attached to the The non-aqueous liquid can be an edible oil and the emul transparent retainer 6 and dispensing drug to the lingual side sion can include an edible oil. Suspensions may be, for of the mouth through a tube 5. example, flowing Suspensions or Suspensions that are 0145 FIG. 3 depicts a drug delivery device in which the extruded, i.e., slipping as a plug (e.g., through a flow pump 2 and drug reservoir 3 are configured to be positioned controlling orifice, nozzle, or tubing). both on the lingual side of the teeth and in the bucal US 2017/0172961 A1 Jun. 22, 2017

vestibule. The drug reservoir is fastened on the lingual side reservoir 3 and a second, elastomeric reservoir 7 half-filled of the teeth, while a drug pump and an optional gas pump 11 with pressurized air or propellant. FIG. 11C illustrates the are positioned on the buccal side of the teeth. system when the drug reservoir 3 is close to empty. In 0146 FIG. 4A depicts a fastener in the form of a trans another embodiment, saliva can be pumped by the electronic parent retainer 6, including two bilateral housings 4 (shown pump 11 into the second elastomeric reservoir 7. empty) on the buccal side of the teeth into which drug pumps 0156 FIG. 12 shows a schematic of a typical two stage and/or drug reservoirs may be inserted. FIG. 4B depicts a gas pressure regulator. fastener in the form of an invisible retainer 6, including two (O157 FIGS. 13A and 13B illustrate a drug delivery bilateral housings 4 (shown filled) on the lingual side of the device including an expandable plastic (elastomeric or non teeth into which drug pumps and/or drug reservoirs 3 have elastomeric) compartment 61 containing propellant within a been inserted. rigid drug reservoir 3. The propellant within the expandable 0147 FIGS. 5A and 5B illustrate a drug delivery device plastic compartment has a vapor pressure that pressurizes including a pressurized, drug-filled polymer Such as an the drug compartment at a specific pressure when exposed to elastomer. The elastomer provides pressure that delivers the body temperature, and pushes the drug through a narrow drug at a constant rate through a narrow internal diameter bore tubing. FIG. 13A shows the compressed expandable tubing, with the rate determined by the properties of the plastic compartment 61 containing propellant within the full elastomer and the inner diameter of the narrow bore tubing. drug reservoir 3. FIG. 13B shows the nearly empty drug FIG. 5A is a representation of an empty elastomeric drug reservoir 3 and the expanded expandable plastic compart delivery device, while FIG. 5B represents a fresh, pressur ment 61 containing propellant. ized, drug-filled elastomeric drug delivery device. 0158 FIGS. 14A, 14B, 14C, and 14D illustrate a propel 0148 FIGS. 5C and 5D illustrate an elastomeric band lant-driven drug delivery device for the delivery of suspen driven pump employing a rubber band 10 to pull a piston 13 sions. to apply pressure to the drug reservoir 3. 0159 FIGS. 15A, 15B, 16A, 16B, 16C, 16D, 17A, 17B, 0149 FIG. 6 illustrates the use of a motor to rotate two and 17C illustrate mechanisms which make the drug deliv columnar or conical shaped drums 29 that are attached to the ery rate of drug delivery devices insensitive to ambient oral liquid impermeable drug reservoir 3. pressure changes in the mouth. 0150 FIGS. 7A, 7B, 7C, and 7D illustrate spring-driven (0160 FIGS. 18A and 18B are graphs of the temperature pumps in which a constant force spring is used to compress in two locations in the mouth after ingestion of a hot the drug reservoir 3. beverage. 0151 FIGS. 7E and 7F illustrate a spring loaded clutch (0161 FIGS. 19A and 19B are graphs of the temperature mechanism 85 useful in the devices of the invention. The in two locations in the mouth after ingestion of a cold clutch mechanism engages the piston 39 to inhibit the force beverage. transmission to the drug reservoir 3 prior to use. When the 0162 FIG. 20 illustrates an embodiment of efficient drug device is removed from the mouth, the protrusion 84 is packing using drug particles with a tri-modal size distribu disengaged, stopping the release of drug from the drug tion. reservoir 3. 0163 FIGS. 21A and 21B are micrographs depicting LD 0152 FIG. 8 illustrates a constant force compression particles formed by jet milling to reduce the average size of spring driven pump delivering a drug Suspension. the particles (excluding fines) (see Example 6). 0153 FIG. 9 illustrates two coaxial compression springs wherein, upon compression, a first spring with a first diam 0164 FIG. 22 illustrates a drug reservoir 4 with a tapered eter is wholly or partially nested within a second spring with flow path leading to the orifice 75. (0165 FIGS. 23A, 23B, and 23C illustrate an embodiment a second, larger diameter. of a propellant-driven pump including a propellant-contain 0154 FIG. 10 illustrates a disk 54 which contains com ing chamber and a pharmaceutical composition-containing partments filled with drug suspension 55 that are injected by chamber separated by a flexible and/or deformable dia an air pressure bolus at a pre-determined rate through an phragm. orifice 56 that is fixed in place with respect to the rotating disk. The rotation of the disk, via a spring mechanism 37, 0166 FIG. 24 shows a port 102 in a pump housing 101 exposes a single compartment and the bolus of air delivers forming a wall of a chamber 89 containing a pharmaceutical the drug from that compartment to the mouth. composition with an elastomeric grommet 94 inserted into (O155 FIGS. 11A, 11B, and 11C illustrate a drug delivery the port. A filling nozzle 95 may be inserted through the device wherein a first elastomeric drug reservoir 3 is com grommet to fill the drug-containing chamber 89 with the pressed by a second elastomeric reservoir or balloon 7 pharmaceutical composition. containing gas or propellant (partially or mostly liquified). 0.167 FIG. 25 illustrates a port 102 in a pump housing In FIG. 11A, the drug delivery device includes a housing 101 forming a wall of a chamber 89 containing a pharma containing a first, full elastomeric drug reservoir 3; a second ceutical composition with an elastomeric grommet 94 elastomeric reservoir 7 substantially empty of gas and inserted into the port. After filling the drug-containing optionally containing liquid propellant; and an optional gas chamber through the port, the port may then be removed and pump 11 and electronics. In one embodiment air is pumped replaced with the delivery nozzle 96. by the electronic (e.g., piezoelectric) pump 11 into the 0168 FIG. 26 illustrates a propellant-driven pump second elastomeric reservoir 7. The pressure from the sec including grooves in the Surfaces of the chamber including ond elastomeric reservoir 7 compresses the first elastomeric the pharmaceutical composition. drug reservoir 3 containing the drug, forcing the drug out of 0169 FIG. 27 illustrates titantium coupons that were the reservoir through a flow restrictor 58 at a constant rate. resistance welded, (i.e., brazed) to silver diaphragms by FIG. 11B illustrates the system with a first, half-full drug applying an electrical current pulse or pulses. US 2017/0172961 A1 Jun. 22, 2017

0170 FIG. 28 is a schematic drawing of a stamp die reservoir and its delivery device must occupy a small block, cover plate, and punch designed to form flexible Volume. In the exemplary management of Parkinson's dis and/or deformable metal diaphragms. ease the concentration of the orally infused LD and/or CD (0171 FIG. 29 shows a tool used to make flexible and/or including fluid of the invention can be typically greater than deformable metal diaphragms. 1 M, such as greater than 1.5 M, 2 M, 2.5 M, 3 M, 3.5 M, 0172 FIG. 30 shows a flexible and/or deformable metal 4M or 4.5M. These are substantially higher concentrations diaphragm. than the 0.1 M LD concentration of the Duodopa (also 0173 FIG. 31 shows schematics for a titanium test hous known as DuopatM) gels that are commercially available for ing including fittings that allowed for testing for hermeticity. jejunal, gastric or nasogastric infusions. The concentrated The test housing is welded to a silver diaphragm. drug Suspension can be viscous, for example its dynamic 0.174 FIG. 32 shows a test housing for a propellant viscosity at 37° C. can be much greater than 100 cp, such as driven pump. greater than 10,000 cB, 100,000 cB, or 1,000,000 cB. The 0175 FIG.33 is a graph showing the time dependence of Suspension can have, for example, Viscosity equal to or the mass of the delivered pharmaceutical composition for greater than that of toothpaste, the viscosity being greater the device of FIG. 32. The graph shows that the slope, i.e., than about 20,000 cB, for example greater than 50,000 cF. the rate of delivery, was not constant over the 100 min such as greater than 500,000 cp. The earlier practice of extrusion period. infusion of viscous fluids through long tubings, typically 0176 FIG. 34 is a graph showing the time dependence of longer than 50 cm, such as those used for nasogastric, gastric rate of delivery, i.e., rate of extrusion, of the pharmaceutical or jejunal infusions, required that their internal diameter be composition for the device of FIG. 33. The graph shows that large and/or that the pumping pressure be high. Furthermore, the rate was not constant over the 100 min extrusion period. when the earlier Suspensions were infused through the 0177 FIG. 35 shows incomplete emptying of the phar longer tubings, the likelihood of blockage of the flow maceutical composition from the device of FIG. 32. because of clustering of the Suspended LD particles 0.178 FIG. 36 shows flow-enhancing grooves in the increased and translucent, very fine particle colloids were interior housing wall of the drug-containing chamber for a used to reduce blockage. In contrast, the herein disclosed propellant-driven pump. orally infused, more much concentrated Suspensions of the 0179 FIG. 37 is a graph showing the time dependence of invention are typically opaque because they can contain the mass of the delivered, i.e., extruded, pharmaceutical large Solid particles scattering visible-wavelength light. The composition for the device of FIG. 36. much more concentrated and much more viscous orally 0180 FIG.38 is a graph of showing the time dependence infused suspensions can be rich in particle sizes greater than of the rate of delivery, i.e., extrusion, of the pharmaceutical 1 Lim, 5um, 10um, or even 50 Lum. The Suspensions can be composition for the device of FIG. 36. orally infused, for example, using orifices in reservoirs that 0181 FIG. 39 shows the housing of a propellant-driven are narrower than 2 mm or 1 mm, and/or through optionally pump including two tubes that include flow channels for the plastic tubings or nozzles that can be shorter than 5 cm, e.g., drug-including pharmaceutical composition. shorter than 4 cm, 3 cm, 2 cm or 1 cm. 0182 FIG. 40 is a graph showing that the time depen 0189 The invention addresses the problem of formulat dence of the mass of the pharmaceutical composition deliv ing a pharmaceutical Suspension that is sufficiently concen ered for the device of FIG. 39 is linear, i.e., that the rate of trated to be useful for oral infusion as described above and delivery of the drug-including fluid is constant. that is sufficiently physically and chemically stable for 0183 FIG. 41 is a graph showing the time dependence of long-term storage at room temperature and for infusion over the rate of delivery, i.e., the rate of extrusion of the phar a prolonged period of time. Thus, the invention features a maceutical composition for the device of FIG. 39. The rate pharmaceutical composition Suitable for continuous or fre of delivery, i.e., extrusion, is about constant. quent intermittent intra-oral delivery. The composition can 0184 FIG. 42 is a bar chart showing the fluctuation index be a Suspension of Solid drug particles in a carrier that is for each two hour interval during on Day 2 and on Day 3 physically stable at about 25° C. and/or at a physiological during the clinical trial described of Example 53. temperature, such as 37° C. The Suspension can contain 0185 FIG. 43 is a bar chart showing the OFF time of each from about 35% (w/w) to about 70% (w/w) of the drug, this patient on Day2 and on Day 4 during the clinical trial weight percentage including the Solid drug particles and the described of Example 53. drug dissolved in the carrier. The carrier can include a 0186 FIG. 44 illustrates the drug delivery device con continuous hydrophilic phase, e.g., it can be an oil-in-water figured to be removably inserted in a patient’s mouth and for emulsion. It can contain more oil than water by weight, even continuous or semi-continuous intraoral administration a when the continuous phase is hydrophilic or when it is an drug. oil-in-water system. Alternatively, it can include a continu ous hydrophobic (i.e., water-immiscible) phase including an DETAILED DESCRIPTION oil or a water-in-oil emulsion. 0187. The devices, compositions, and methods of the 0190. Physical stability of the solid drug particle contain invention are useful for continuous or semi-continuous oral ing Suspension can be enhanced by the combined presence delivery of medicaments. of an oil, water and a surfactant, each in an amount Sufficient 0188 While syringes, drug reservoirs and pumps outside to inhibit or retard sedimentation and/or phase separation. the mouth can be large because space is typically available, 0191 The invention also features levodopa and carbi space in the mouth for a drug delivery device is limited and dopa formulations that are chemically stable, with chemical is particularly limited when a drug delivery device is so degradation products of the levodopa and carbidopa (e.g., Small that it does not interfere with speaking, Swallowing, oxidation product and hydrolysis products) of less than 5%, drinking, or eating. Consequently, the delivered drug, its 2%, or 1% of the starting amount of the drugs. In particular, US 2017/0172961 A1 Jun. 22, 2017 20 the invention features CD and LD/CD formulations with low 0203 Cancer: capecitabine (1,000-10,000 mg per day, hydrazine concentrations, even after prolonged storage or 42-417 mg/hr) and other 5-fluorouracil prodrugs. exposure to elevated temperatures under air. 0204 Dementia: Rivastigmine. 0192 Administration in the Mouth 0205 Diabetes: oral insulins 0193 The drugs may be administered intraorally (i.e., 0206 Diabetic nephropathy: angiotensin receptor blockers. onto or near any intraoral Surface, e.g., the lips, cheeks, 0207 Disordered sleep: Zaleplon (3-20 mg per day, gums, teeth, tongue, roof of the mouth, hard palate, soft 0.38-0.83 mg/hr for 8 hours at night), gamma hydroxy palate, tonsils, uvula, and glands). The drugs administered butyrate (10-200 mg per day, 1.3-25 mg/hr for 8 hours intraorally are typically Swallowed by the patient, together at night), Zolpidem (3-20 mg per day 0.38-0.83 mg/hr with the patient’s saliva. The drugs can be diluted by the for 8 hours at night), triazolam. patient’s saliva and can optionally be partly or fully dis 0208 Epilepsy and seizures: Oxcarbazepine (300-3, solved in the saliva. The drugs can be absorbed in the 000 mg per day, 12.5-125 mg/hr), topiramate (200-500 patient’s gastrointestinal tract, e.g., in the Small intestines or mg per day, 8.3-20.8 mg/hr), lamotrigine (100-700 mg large intestines. In some cases, absorption of drugs delivered per day, 4.2-29.2 mg/hr), gabapentin (600-3,600 mg per by the drug delivery devices of the invention may take place day, 25-150 mg/hr), carbamazepine (400-1,600 mg per partially or even primarily through the mucous membranes day, 16.7-66.7 mg/hr), valproic acid (500-5,000 mg per in the mouth, e.g., buccal or Sublingual absorption. day, 20.1-208 mg/hr), levetiracetam (1,000-3,000 mg 0194 Medications and Diseases per day, 41.7-125 mg/hr), pregabalin (150-600 mg per 0195 The devices and methods of the invention are day, 6.25-25 mg/hr). suitable for the administration of a variety of drugs that have 0209 Heart failure: ACE inhibitors, angiotensin recep a short half-life and/or a narrow therapeutic range. Comple tor blockers. mentary drugs may be co-administered or co-infused with 0210 Hypertension: Prazosin (0.2-5 mg per day, 0.01 these drugs. Such complementary drugs may improve the 0.21 mg/hr). ACE inhibitors, angiotensin receptor pharmacokinetics, improve the efficacy, and/or reduce the blockers. side effects of the primary drugs. 0211 Orthostatic hypotension: droxidopa, fludrocorti 0196. Exemplary diseases/medical conditions that may Sone, midodrine. be treated with the devices and methods of the invention, 0212 Mood disorders: Oxcarbazepine (300-3,000 mg and corresponding drugs and exemplary ranges of daily per day, 12.5-125 mg/hr), lithium. doses and of average administration rates, are listed below: 0213 Mucositis: pilocarpine, topical anesthetics or 0.197 Parkinson's disease: levodopa, levodopa prod analgesics (e.g., lidocaine), mucosal coating agents rugs, and dopamine agonists (such as Pramipexole (e.g., benzydamine HCl), and Sialagogues. (0.1-10 mg per day, 0.004-0.42 mg/hr), Bromocriptine, 0214. Organ transplantation: Cyclosporine (150-1,500 Ropinirole (0.25-10 mg per day, 0.01-0.42 mg/hr), mg per day, 6.3-62.5 mg/hr), Tacrolimus (3-25 mg per Lisuride, Rotigotine). Examples of complementary day, 0.13-1.04 mg/hr). drugs for Parkinson's disease, which may optionally be 0215 Pain: Fentanyl (0.05-2.0 mg per day, 0.002-0. co-infused, are DDC inhibitors (such as carbidopa and 083 mg/hr), Dilaudid (2-50 mg per day, 0.83-2.1 benserazide (50-600 mg per day, 2.1-25 mg/hr)), mg/hr). COMT inhibitors (such as entacapone, tolcapone and 0216) Post-traumatic stress disorder: Prazosin (0.25-5 opicapone), MAO-B inhibitors (such as Rasagiline and mg per day, 0.01-0.21 mg/hr). Selegiline), adenosine A2 receptor antagonists (such as 0217 Spasticity: Baclofen. Istradefylline), and gastroparesis drugs (such as Dom 0218. Hyperammonaemia associated with N-acetyl peridone, Nizatidine, Relamorelin, Monapride and glutamate synthase deficiency, isovaleric acidaemia, Cisapride). methymalonic acidaemia, propionic acidaemia: carglu 0198 Allergies: antigens or allergens (e.g., pollen, a mic acid. part of a mite, or a component of the feline or canine 0219 Lambert-Eaton disease: Amifampridine (15-60 skin, or an extract or a conversion product thereof) mg per day, 0.625-2.5 mg/hour). 0199 Anesthesia: bupivacaine, lidocaine. 0220 Myasthenia gravis: pyridostigmine (60-1,500 0200 Anxiety: oxcarbazepine (300-3,000 mg per day, mg per day, 2.5-62.5 mg/hour. A typical dose is about 12.5-125 mg/hr), prazosin (0.2-5 mg per day, 0.01-0.21 600 mg per day or about 25 mg/hour.) mg/hr). 0221 Exemplary diseases/medical conditions that may 0201 Arrhythmia: quinidine (300-2,000 mg per day, be treated with the devices and methods of the invention, 12.5-83 mg/hr) and corresponding drugs and exemplary ranges of daily 0202 Bacterial infections: beta-lactam antibiotics doses and of average administration rates include those that (e.g., cephalosporins). are listed below in Tables A-C. TABLE A Delivery Daily Daily Dose Range (mg)

Drug Indication Route Formulation Hours Low High Typical

Baclofen Multiple sclerosis, GI B, C 16 30 1OO 50 cerebral palsy, spastic conditions US 2017/0172961 A1 Jun. 22, 2017 21

TABLE A-continued Delivery Daily Daily Dose Range (ng

Drug Indication Route Formulation Hours Low High Typical Tizanidine Multiple sclerosis, GI, C, F 16 12 36 18 cerebral palsy, spastic Buccal conditions Dantrolene Multiple sclerosis, GI A. 16 25 400 1OO cerebral palsy, spastic conditions DroxiDOPA Neurogenic orthostatic GI 16 1800 1,000 hypotension Midodrine Neurogenic orthostatic GI 16 25 35 30 hypotension Penicillamine Wilson's disease GI 16 250 2OOO 500 Penicillamine Cystinuria GI 24 2OOO 4OOO 3,000 Penicillamine Refractory rheumatoid GI 24 250 750 500 arthritis Zinc acetate Wilson's disease GI 24 1OO 200 150 Zinc Wilson's disease GI 24 30 8O 50 compounds Water or stomach acid soluble, dose representing the Zn" content only Magnesium Parkinson's disease; GI 24 500 SOOO 3,000 compounds, Alzheimer disease; Water or cognitive diseases; stomach acid learning disabilities soluble, dose representing the Mg' content only L-DOPA Parkinson's disease GI 16 3OO 3OOO 1,200 Pyridostigmine Myasthenia gravis GI 16 60 1SOO 600 Neostigmine Myasthenia gravis Buccal 16 50 70 60 Miglustat Type-1 Gaucher GI 24 2OO 400 3OO disease, Type C Niemann-Pick disease Cromoglicic Eosinophilic GI A. 24 40 1OOO 800 acid (cromolyn) gastroenteritis, chronic mastocytosis, ulcerative colitis Metoclopramide Gastroparesis, GI 24 40 30 nausea, gastro oesophageal reflux, gastroenteritis, hyperemesis gravidarum Trientine Wilson's disease GI 16 12OO 2400 1,800 Temozolomide Glioblastoma GI 24 3OO 400 350 multiformae, anaplastic astrocytoma Captopril Primary hypertension, GI 16 40 60 50 coronary heart disease, congestive heart failure, angina Acarbose Type 2 diabetes GI 24 350 3OO Iloprost PH Buccal 16 O.048 Beraprost PH Buccal 16 O.36 Treprostinil PH GI B 16 12 Ciclesonide COPD, PH Buccal 16 O.S O.24 Flunisolide COPD, PH Buccal 16 2.5 1.2 Budesonide COPD, PH Buccal 16 3 1.5 Becomethason COPD, PH Buccal 16 3 1.5 Bosentan COPD, PH GI 16 500 250 MometaSone COPD, PH Buccal 16 1 O48 Vilanterol COPD Buccal 24 O.24 Bitolterol COPD; Asthma GI 24 10 4.8 Levosalbutamol COPD; Asthma Buccal 24 5 2.4 sulfate Salbutamol COPD; Asthma Buccal 24 5 2.4 Salmeterol COPD; Asthma Buccal 24 O.25 O.1 Glycopyrronium COPD GI 24 O.1 O.048 bromide US 2017/0172961 A1 Jun. 22, 2017 22

TABLE A-continued Delivery Daily Daily Dose Range (ng Drug Indication Route Formulation Hours Low High Typical Ipatropium COPD GI F 24 O.3 1.5 0.72 bromide Aclidinium COPD GI F 24 O.3 1.5 0.72 bromide Carbocisteine COPD GI A. 24 1 3 1SOO Erdosteine COPD GI A. 24 O.3 1 600 Ambroxol COPD GI A. 24 O.08 O.24 120 Acetylcysteine COPD GI A. 24 O.S 1.5 840 Erythromycin Gastroparesis GI A. 24 50 500 250 Erythromycin Bacterial infection GI A. 24 500 1SOO 1OOO control in COPD Clarithromycin Bacterial infection GI A. 24 3OO 900 500 control in COPD Hexoprenaline Asthma Buccal F 24 O.S 2.5 1.2 sulfate Pirbuterol Asthma Buccal F 24 O.S 2.5 1.2 Fenoterol Asthma Buccal F 24 2 10 4.8 Terbutaline Asthma Buccal F 24 1.6 8 4 Metaproterenol Asthma Buccal F 24 2 10 4.8 Trimebutine IBS GI A. 24 2OO 1OOO 630 Mebeverine IBS GI A. 24 1OO 500 3OO Dicycloverine IBS GI A. 24 40 200 8O Flavoxate Overactive bladder; GI A. 24 2OO 1OOO 720 Oxybutinin urinary urge GI B, C 24 2O 100 14.4 Tolterodine incontinence GI F 24 5 25 3.6 tartarate Darilfenacin GI C 24 10 50 7.2 Curcumin Cancer, e.g. colon, GI A. 24 2000 SOOO 4000 breast, ovarian Curcumin Cancer, e.g. colon, analogs EF24, breast, ovarian GI A. 24 2000 SOOO 4000 EF31, UBS109 or FLLL12

TABLE B Exemplary Concentrations Dose Rate (nghir mg/mL. Drug Low High Typical Low Middle High Baclofen 1875 6.25 3.12S 2O 85 150 Tizanidine 0.75 2.25 1.125 10 30 50 Dantrolene 1.563 25 6.25 600 725 850 DroxiDOPA 18.75 112.5 62.5 600 725 850 Midodrine 1.563 2.188 1875 2O 85 150 Penicillamine 15.625 125 31.25 600 725 850 Penicillamine 83.333 166.667 125 600 725 850 Penicillamine 10.417 31.25 20.833 600 725 850 Zinc acetate 4.167 8.333 6.25 100 3OO 500 Zinc compounds water 1.25 3.333 2.083 30 90 150 or stomach acid soluble, dose representing the Zn" content only Magnesium compounds, 20.833 208.333 125 200 400 600 water or stomach acid soluble, dose representing the Mg’" content only L-DOPA 18.75 187.5 75 600 725 850 Pyridostigmine 3.75 93.75 37.5 600 725 850 NeoStigmine 3.12S 4.375 3.75 2O 85 150 Miglustat 8.333 16.667 12.5 600 725 850 Cromoglicic acid 1.667 41.667 33.333 600 725 850 (cromolyn) Metoclopramide O 1.667 1.25 2O 85 150 Trientine 75 150 112.5 600 725 850 Temozolomide 12.5 16.667 14.583 600 725 850 Captopril 2.5 3.75 3.12S 2O 85 150 US 2017/0172961 A1 Jun. 22, 2017 23

TABLE B-continued Exemplary Concentrations Dose Rate (nghir mg/mL. Drug Low High Typical Low Middle High Acarbose 10.417 14.583 12.5 600 725 850 Iloprost O.OO1 O.OO6 O.OO3 O.1 O3 O.S Beraprost O.O13 O.O31 O.O23 O.S 1.75 3 Treprostinil O.25 1.25 0.75 2O 60 100 Ciclesonide O.OO6 O.O31 O.O15 0.4 1.2 2 Flunisolide O.O31 O.156 0.075 2 6 10 Budesonide O.O38 O.188 O.O94 3 9 15 Becomethasone O.O38 O.188 O.O94 3 9 15 Bosentan 6.25 31.25 15.625 500 675 850 MometaSone O.O13 O.O63 O.O3 O.8 2.4 4 Vilanterol O.OO)4 O.O21 O.O1 O.S 1.S. 2.5 Bitolterol O.O83 O417 O.2 10 30 50 Levosalbutamol sulfate O.O21 O.208 O.1 2.5 13.75 25 Salbutamol O.O21 O.208 O.1 2.5 13.75 25 Salmeterol O.OO2 O.O1 O.004 O.1 1.3 2.5 Glycopyrronium O.OO1 O.OO)4 O.OO2 O.1 O3 O.S bromide Ipatropium bromide O.O13 O.O63 O.O3 1 3 5 Aclidinium bromide O.O13 O.O63 O.O3 1 3 5 Carbocisteine O.042 O.12S 62.5 600 725 850 Erdosteine O.O13 O.042 25 600 725 850 Ambroxol O.OO3 O.O1 5 500 6SO 800 Acetylcysteine O.O21 O.O63 35 600 725 850 Erythromycin 2.083 20.833 10.417 400 600 800 Erythromycin 20.833 62.5 41.667 700 775 850 Clarithromycin 12.5 37.5 20.833 600 700 800 Hexoprenaline sulfate O.O21 O.104 O.OS 2 6 10 Pirbuterol O.O21 O.104 O.OS 2 6 10 Fenoterol O.O83 O417 O.2 8 24 40 Terbutaline O.O67 O.333 O.167 4 12 2O Metaproterenol O.O83 O417 O.2 8 24 40 Trimebutine 8.333 41.667 26.25 600 725 850 Mebeverine 4.167 20.833 12.5 600 725 850 Dicycloverine 1.667 8.333 3.333 500 6SO 800 Flavoxate 8.333 41.667 30 600 725 850 Oxybutinin O.833 4.167 O.6 40 95 150 Tolterodine tartarate O.208 1.042 O.15 10 2O 30 Darifenacin O.417 2.083 O.3 2O 35 50 Curcumin 83.333 208.333 166.667 600 725 850 Curcumin analogs EF24, 83.333 208.333 166.667 600 725 850 EF31, UBS109 or FLLL12

TABLE C TABLE C-continued Exemplary Delivery Exemplary Daily Exemplary Delivery Exemplary Daily Rates (LL/hr Volume (mL Rates (IL/hr) Volume (mL) Drug Low Middle High Low High Drug Low Middle High Low High - - - - Magnesium 34.7 312.5 1,041.70 1 8 compounds, Baclofen 12.5 36.8 312.5 O.3 0.7 water or stomach Tizanidine 15 37.5 225 0.4 0.7 acid soluble, Dantrolene 1.8 8.6 41.7 O.04 0.7 dose representing DroxiDOPA 22.1 86.2 187.5 O.3 2.5 the Mg' content Midodrine 10.4 22.1 109.4 O.2 0.7 only L-DOPA 22.1 103.4 312.5 0.4 4 Penicillamine 18.4 43.1 208.3 O.3 3 Pyridostigmine 4.4 51.7 156.3 O.S 2 Penicillamine 98 1724 277.8 2.5 4 NeoStigmine 20.8 44.1 218.8 O.3 O.S Penicillamine 12.3 28.7 S2.1 O.3 O.9 Miglustat 9.8 17.2 27.8 O.25 O.8 Zinc acetate 8.3 20.8 83.3 O.2 O.8 Cromoglicic acid 2 46 694 O.S 1.5 Zinc compounds 8.3 23.1 111.1 O.2 O.8 (cromolyn) water or stomach Metoclopramide O 14.7 83.3 O.3 0.7 Trientine 88.2 155.2 250 1.5 3 acid soluble, dose Temozolomide 14.7 20.1 27.8 0.4 O.6 representing the Captopril 16.7 36.8 187.5 O.3 0.7 Zn’t content only Acarbose 12.3 17.2 24.3 O.3 O.S US 2017/0172961 A1 Jun. 22, 2017 24

TABLE C-continued saliva stimulants such as organic acids (e.g., citric acid, ascorbic acid, malic acid) or their acidic salts and parasym Exemplary Delivery Exemplary Daily pathomimetic drugs (e.g., choline esters such as pilocarpine Rates (LIL/hr Volume (mL hydrochloride, and cholinesterase inhibitors). Examples of Drug Low Middle High Low High drugs for dysphagia are Scopolamine, Tropicamide, Glyc copyrolate, and Botulinum Toxin. Examples of drugs for loprost 2.5 10 62.5 O.04 O.2 Beraprost 4.2 12.9 62.5 O.O7 0.7 excess salivation are anticholinergics such as glycopyrro Treprostinil 2.5 12.5 62.5 O. O.S late. In a preferred embodiment, drugs for the treatment of Ciclesonide 3.1 12.5 78.1 O. O.S Xerostomia, hyposalivation, and/or dysphagia are co-admin Funisolide 3.1 12.5 78.1 O. O.S istered with the LD or CD, using the drug delivery devices Budesonide 2.5 10.4 62.5 O. O.S Becomethasone 2.5 10.4 62.5 O. O.S and methods of the invention. In another preferred embodi Bosentan 7.4 23.1 62.5 O.2 0.7 ment, intra-oral administration of an anti-Parkinson's medi MometaSone 3.1 12.5 78.1 O. O.S cation itself stimulates increased salivation and/or more Vilanterol 1.7 6.7 41.7 O. O.S frequent or improved Swallowing. Bitolterol 1.7 6.7 41.7 O. O.S Levosalbutamol O.8 7.3 83.3 O. O.S 0225 Gastroparesis, or delayed gastric emptying, is com Salbutamol O.8 7.3 83.3 O. O.S mon in people with PD, especially in patients with scores of Salmeterol O.8 3.2 104.2 O. O.S 4 and 5 on the Hoehn and Yahr scale. Drugs for the treatment Glycopyrronium 1.7 6.7 41.7 O. O.S bromide of gastroparesis may be delivered using the devices and patropium 2.5 10 62.5 O. O.S methods of the invention. In one embodiment, drugs for the bromide treatment of gastroparesis are co-administered with the LD Aclidinium 2.5 10 62.5 O. O.S or CD, using the drug delivery devices and methods of the bromide Carbocisteine O 86.2 O.2 1 3 invention. In another embodiment, drugs for the treatment of Erdosteine O 34.5 O.1 O6 1.5 gastroparesis are administered using other methods of drug Ambroxol O 7.7 O O. O.3 delivery known in the art (i.e., they are not administered via Acetylcysteine O 48.3 O.1 O.S 1.5 continuous or frequent intra-oral delivery) while LD or CD Erythromycin 2.6 17.4 S2.1 O. O.8 Erythromycin 24.5 53.8 89.3 O6 2 are infused intra-orally. Examples of drugs for the treatment Clarithromycin 15.6 29.8 62.5 0.4 1 of gastroparesis are Metoclopramide, Cisapride, Erythromy Hexoprenaline 2.1 8.3 S2.1 O. O.S cin, Domperidone, Sildenafil Citrate, Mirtazapine, Nizati sulfate dine, Acotiamide, Ghrelin, LevoSulpiride, Tegaserod, Bus Pirbuterol 2.1 8.3 S2.1 O. O.S Fenoterol 2.1 8.3 S2.1 O. O.S pirone, Clonidine, Relamorelin, Serotonin 5-HT4 agonists Terbutaline 3.3 13.9 83.3 O. O.S and dopamine D2 or D3 antagonists. Metaproterenol 2.1 8.3 S2.1 O. O.S 0226 Methylation of LD, whereby 3-methoxy-levodopa Trimebutine 9.8 36.2 69.4 O.3 1 (3-OMD) is produced, is one of the major metabolic paths Mebeverine 4.9 17.2 34.7 O.2 O.8 Dicycloverine 2.1 S.1 16.7 O.08 O.3 of L.D. It increases the amount of LD required by Parkin Flavoxate 9.8 41.4 69.4 O6 1.2 son's disease patients and because the conversion shortens Oxybutinin S.6 6.3 104.2 O.2 0.4 the half-life of plasma LD, it also increases the frequency at Tolterodine 6.9 7.5 104.2 O.2 0.4 which LD or LD/CD or CD need to be administered in order tartarate Darifenacin 8.3 8.6 104.2 O.2 0.4 to manage the symptoms of Parkinson's disease. The con Curcumin 98 229.9 347.2 3 7 version of LD to 3-OMD is catalyzed by the enzyme Curcumin 98 229.9 347.2 3 7 catechol-O-methyl transferase, COMT. Administration of a analogs EF24, COMT inhibitor can reduce the required dosage of LD or EF31, UBS109 or FLLL12 LD/CD, or in earlier stages of PD, even provide for man aging the disease without LD or LD/CD. The two most frequently used COMT inhibitors, entacapone and tolcapone are, however short-lived. Abbreviations for Tables A-C: 0227 Entacapone does not cross the blood-brain barrier 0222 PH: pulmonary hypertension, including pulmonary and can be less toxic than Tolcapone, which crosses the arterial hypertension barrier. The plasma half-life of Entacapone is, however, IBS: irritable bowel syndrome merely 0.4-0.7 hours, making it difficult to maintain a COPD: chronic occlusive pulmonary disease Sufficient plasma level of the drug without administering 0223) The drugs and methods of the invention may be large and frequent doses of the drug. In clinical practice, one used for treating dental and maxillofacial conditions, such as 200 mg tablet is often administered with each LD/CD or Xerostomia, dental caries, local infections (e.g., fluconazole, LD/Benserazide dose. The maximum recommended dose is diflucan, nystatin, or clotrimazole for thrush) in the mouth or 200 mg ten times daily, i.e., 2,000 mg. Continuous oral throat, and local pain in the mouth or throat (e.g., lidocaine). administration of Entacapone could reduce the dosage and/ 0224 Dry mouth (xerostomia) and hyposalivation are or frequency of administration of the drug and its side more prevalent in older patients and are a common side effects. The reduced dosage could alleviate side effects such effect of medications, including medications for the treat as dyskinesia and/or gastrointestinal problems, nausea, ment of PD. Patients with PD also commonly experience abdominal pain or diarrhea. difficulty Swallowing (dysphagia), which often results in 0228. Entacapone could be continuously orally adminis drooling (sialorrhea). Drugs for the treatment of Xerostomia, tered in a daily dose of less than 1000 mg per 16 hours while hyposalivation, dysphagia and/or sialorrhea may be deliv the patient is awake (such as less than 500 mg per 16 awake ered using the devices and methods of the invention. hours), for example as an aqueous Suspension including Examples of drugs for Xerostomia and hyposalivation are Small particles, e.g., less than 100 um average diameter. Such US 2017/0172961 A1 Jun. 22, 2017

as less than 30 Jum, 10 Jum, 3 um or 1 um particles of active ingredient, optionally in the form of a pharmaceuti Entacapone. Alternatively, it could be administered as a cally acceptable salt of the active ingredient. Drugs which Suspension in a non-aqueous Solution, such an edible oil, may be delivered in accordance with the invention include, cocoa-butter, propylene glycol, or glycerol. without limitation, analgesics and antiinflammatory agents 0229. Tolcapone is a reversible COMT inhibitor of 2-3 (e.g., aloxiprin, auranofin, azapropaZone, benorylate, hour half-life. It exerts its COMT inhibitory effects in the diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbipro central nervous system as well as in the periphery. Its use is fen, ibuprofen, indomethacin, ketoprofen, meclofenamic limited by its hepatotoxicity. The typical dose of Tolcapone acid, mefenamic acid, nabumetone, naproxen, oxyphenbuta in PD management is 100-200 mg three times daily. Tolca pone may also be effective in the treatment of Hallucinogen Zone, phenylbutaZone, piroxicam, Sulindac), antihelmintics Persisting Perception Disorder, decreasing visual symptoms. (e.g., albendazole, bephenium hydroxynaphthoate, camben Continuous oral administration of Tolcapone could reduce dazole, dichlorophen, ivermectin, mebendazole, oxam its dosage and/or frequency of administration and its hepa niquine, Oxfendazole, oxantel embonate, praziquantel, pyr totoxicity. The reduced dosage could alleviate its hepato antel embonate, thiabendazole), anti-arrhythmic agents toxicity. Its daily dose could be less than 500 mg per 16 (e.g., amiodarone HCl, disopyramide, flecainide acetate, awake hours. Such as less than 300 mg per 16 awake hours. quinidine Sulphate, anti-bacterial agents (e.g., benethamine It could be continuously orally administered, for example, as penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, a suspension of the invention including Small particles, e.g., clofazimine, cloxacillin, demeclocycline, doxycycline, less than 100 um average diameter, such as less than 30 um, erythromycin, ethionamide, imipenem, nalidixic acid, nitro 10 um, 3 Lim or 1 um particles of the drug. furantoin, rifampicin, spiramycin, Sulphabenzamide, Sulpha 0230. Because administration according to this invention doxine, Sulphamerazine, Sulphacetamide, Sulphadiazine, is typically into the mouth, it is preferred that the drugs Sulphafurazole, Sulphamethoxazole, Sulphapyridine, tetracy selected for administration are those whose taste is neutral or cline, trimethoprim), anti-coagulants (e.g., dicoumarol, pleasant, as perceived by a majority of patients. Taste dipyridamole, nicoumalone, phenindione), antidepressants masking or modifying excipients may be added to the (e.g., amoxapine, maprotiline HCl, mianserin HCl, nortrip formulations of drugs whose taste is unpleasant, as per tyline HCl, trazodone HCl, trimipramine maleate), antidi ceived by a majority of patients. abetics (e.g., acetohexamide, chlorpropamide, glibencl 0231. Other drugs that may usefully be delivered in amide, gliclazide, glipizide, tolaZamide, tolbutamide), anti accordance with the invention include methylphenidate, epileptics (e.g., beclamide, carbamazepine, clonazepam, prostaglandins, prostacyclin, treprostinil, beraprost, nimo ethotoin, methoin, methsuximide, methylphenobarbitone, dipine, and testosterone. oXcarbazepine, paramethadione, phenacemide, phenobarbi 0232 Examples of drugs that are often prescribed to be tone, phenytoin, phensuximide, primidone, Sulthiame, Val dosed four times per day include: proic acid, topirimate, lamotrigine, gabapentin, levetirac 0233. Amoxicillin infection etam, pregabalin), antifungal agents (e.g., amphotericin, 0234 Cephalexin (Keflex) infection butoconazole nitrate, clotrimazole, econazole nitrate, flu 0235 Chlorpromazine (Thorazine) neuroleptic for conazole, flucytosine, griseofulvin, itraconazole, ketocon migraine azole, miconazole, natamycin, nystatin, Sulconazole nitrate, 0236 Diazepam (Valium)—anxiety and sleep terbinafine HCl, terconazole, tioconazole, undecenoic acid), 0237 Diclofenac (Voltaren)–arthritis antigout agents (e.g., allopurinol, probenecid, Sulphin-pyra 0238. Diltiazem-calcium channel blocker Zone), antihypertensive agents (e.g., amlodipine, benidipine, 0239) Erythromycin infection darodipine, dilitazem HCl, diaZoxide, felodipine, guanabenz 0240 Holperiodol (Haldol)—neuroleptic for migraine acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, 0241 Impramine psychotropic nimodipine, phenoxybenzamine HCl, praZosin HCl, reser pine, teraZosin HCl), antimalarials (e.g., amodiaquine, chlo 0242. Ipratropium (Atrovent)—Anticholinergic roquine, chlorproguanil HCl, halofantrine HCl, mefloquine 0243 Metoclopramide (Reglan) gastroesophageal HCl, proguanil HCl, pyrimethamine, quinine Sulphate), anti reflux, migraine migraine agents (e.g., dihydroergotamine meSylate, ergot 0244 Niledpine—calcium channel blocker amine tartrate, methysergide maleate, pizotifen maleate, 0245 Olanzapine (Zyprexa)—neuroleptic for Sumatriptan Succinate), anti-muscarinic agents (e.g., atro migraine pine, benzhexol HCl, biperiden, ethopropazine HCl, 0246 Prochlorperazine (Compazine) neuroleptic for hyoscyamine, mepenZolate bromide, oxyphencylcimine migraine HCl, tropicamide), anti-neoplastic agents and immunosup 0247 Promethazine (phenergan)—neuroleptic for pressants (e.g., aminoglutethimide, amsacrine, azathioprine, migraine buSulphan, chlorambucil, cyclosporin, dacarbazine, estra 0248 Salbutamolasthma mustine, etoposide, lomustine, melphalan, mercaptopurine, 0249 Tetracycline infection methotrexate, mitomycin, mitotane, mitoZantrone, procar (0250) Theophylline (Theolair) COPD, asthma bazine HCl, tamoxifen citrate, testolactone), anti-protazoal 0251 Trazodone psychotropic agents (e.g., benZnidazole, clioquinol, decoquinate, diiodo 0252) Drugs delivered as solids may be formulated with hydroxyquinoline, diloxanide furoate, dinitolmide, furzoli excipients to increase disintegration or dispersion. done, metronidazole, nimorazole, nitrofuraZone, ornidazole, 0253) Many types of drugs may be delivered in accor tinidazole), anti-thyroid agents (e.g., carbimazole, propylth dance with the invention. Drugs which may in principle be iouracil), anxiolytic, sedatives, hypnotics and neuroleptics used for treatment according to the invention are any known (e.g., alprazolam, amylobarbitone, barbitone, bentazepam, drugs, wherein the drugs may be present in the form bromazepam, bromperidol, brotizolam, butobarbitone, car according to the invention as such, or in the form of the bromal, chlordiazepoxide, chlormethiazole, chlorpromaz US 2017/0172961 A1 Jun. 22, 2017 26 ine, clobazam, clotiazepam, clozapine, diazepam, droperi carbidopa at frequency of about 6-12 times/hour also stabi dol, ethinamate, flunanisone, flunitrazepam, fluopromazine, lizes the plasma concentration of L-DOPA and reduces by flupenthixol decanoate, fluiphenazine decanoate, flurazepam, about 43% the OFF time of PD patients. Without limiting the haloperidol, lorazepam, lormetazepam, medazepam, mepro scope of this invention by a theory or model, we have bamate, methaqualone, midazolam, nitrazepam, oxazepam, observed that the reported gastric delay of drugs does not pentobarbitone, perphenazine pimozide, prochlorperazine, necessarily apply when the drugs are continuously orally Sulpiride, temazepam, thioridazine, triazolam, Zopiclone), infused and are dissolved. Thus, it can be advantageous to B-Blockers (e.g., acebutolol, alprenolol, atenolol, labetalol, infuse into the mouths of patients a suspension or paste metoprolol, nadolol, Oxprenolol, pindolol, propranolol), car including Solid drug particles at a rate that equals or is diac inotropic agents (e.g., amrinone, digitoxin, digoxin, slower than the rate of dissolution of the solid drug particles enoXimone, lanatoside C. medigoxin), corticosteroids (e.g., in body fluids secreted in the mouth, such that the drug beclomethasone, betamethasone, budesonide, cortisone passing through the esophagus to the stomach is already acetate, desoxymethasone, dexamethasone, fludrocortisone Substantially dissolved. Such that the remaining solid drug acetate, flunisolide, flucortolone, fluticaSone propionate, particles are substantially dissolved in fluid secreted in the hydrocortisone, methylprednisolone, prednisolone, pred stomach, and/or such that the still remaining drug particles nisone, triamcinolone), diuretics: acetazolamide, amiloride, are substantially dissolved in fluid secreted in the duode bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, num, then, if solid drug particles still remain, these are ethacrynic acid, frusemide, metolaZone, spironolactone, tri substantially dissolved in fluids secreted in the jejunum, then amterene), anti-parkinsonian agents (e.g., bromocriptine if still present, substantially dissolved in fluids secreted in mesylate, lysuride maleate), gastrointestinal agents (e.g., the ileum, and eventually if still present, substantially dis bisacodyl, cimetidine, cisapride, diphenoxylate HCl, dom solved in fluids secreted in the colon. The secreted body fluid peridone, famotidine, loperamide, mesalazine, nizatidine, in which the Solid drug may dissolve can be, for example, omeprazole, ondansetron HCl, ranitidine HCl, Sulphasala saliva secreted in the mouth (e.g., by the Submandibular and Zine), histamine H.-receptor antagonists (e.g., acrivastine, parotid glands) mostly in the awake hours. In healthy astemizole, cinnarizine, cyclizine, cyproheptadine HCl, persons the rate of secretion can be between about 50 dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, mL/hour and about 100 mL/hour. Considering that the oXatomide, terfenadine), lipid regulating agents (e.g., beza solubility of LD can be about 50 mg/mL and considering fibrate, clofibrate, fenofibrate, gemfibrozil, probucol), that even if a patient would require as much as 200 mg LD nitrates and other anti-anginal agents (e.g., amyl nitrate, per hour, as little as about 4 mL/hour of saliva could dissolve glyceryl trinitrate, isosorbide dinitrate, isosorbide mononi the orally delivered solid L.D. The drug could not only be trate, pentaerythritol tetranitrate), opioid analgesics (e.g., dissolved, but its solution might be diluted before reaching codeine, dextropropyoxyphene, diamorphine, dihydroco the stomach even in patients (e.g., patients with PD or deine, meptazinol, methadone, morphine, nalbuphine, pen Xerostomia) secreting less saliva than healthy people. For tazocine), sex hormones (e.g., clomiphene citrate, danazol. rapid dissolution in saliva it could be advantageous to ethinyl estradiol, medroxyprogesterone acetate, mestranol, disperse the drug particles (e.g., by administering their methyltestosterone, norethisterone, norgestrel, estradiol. Surfactant-including Suspension) where the size of the drug conjugated oestrogens, progesterone, stanozolol, Stibestrol, particles could be small (e.g., typically less than about 100 testosterone, tibolone), and stimulants (e.g., amphetamine, um in average diameter. Such as less than 50 um in average dexamphetamine, dexfenfluramine, fenfluramine, mazin diameter, Such as less than 20 um in average diameter, Such dol). as less than 10 um in average diameter). 0254 The above-stated compounds are predominantly 0256. Other drugs, such as baclofen or pyridostigmine, stated by their international nonproprietary name (INN) and that are administered in lesser daily amounts than LD could are known to the person skilled in the art. Further details be adsorbed on Small particles of a solid excipient, Such as may be found, for example, by referring to International an amino acid like tyrosine. For continuous oral delivery, the Nonproprietary Names (INN) for Pharmaceutical Sub paste of the drug-containing excipient could be extruded into stances, World Health Organization (WHO). the mouth where the excreted saliva would dissolve the 0255 Gastroparesis, delayed or erratic gastric emptying, sorbed drug as well as any Solid drug particles, if present. and other abnormalities or diseases of the stomach, intestine, (0257 Drug Delivery Devices pylorus, jejunum, duodenum impact the transport of food 0258. The drug delivery devices of the present invention and medication from the stomach to the duodenum and are designed to address the requirements for a device that is through the Small and large intestines. Such conditions of the inserted into the mouth by the patient or caregiver, and that GI tract are commonly caused by or associated with various resides in the mouth while it is administering drug, and that diseases and conditions, including Parkinson's disease, dia can be removed from the mouth by the patient or caregiver. betes, autonomic neuropathy, and cancer treatments. Preferred drug delivery devices include oral liquid imper Reduced, delayed, or erratic transport of medication from meable reservoirs. the stomach to the duodenum and through the Small and 0259. The drug delivery devices typically have a total large intestines decreases the benefits or effectiveness of volume of less than about 10 mL, and preferably less than many drugs, including levodopa. It is for this reason that the 7.5, 5.0, or 3.0 mL. Preferred volumes for the drug delivery DuopaTM (also known as DuodopaTM) LD/CD delivery sys devices are 0.5-3.0 mL, to minimize interference with the tem infuses a LD/CD Suspension into the jejunum or duo patient's mastication, Swallowing and speech. denum, even though intrajejunal delivery requires Surgical 0260 The drug delivery devices of the invention prefer implantation of a PEG tube and suffers from a high rate of ably contain bite-resistant structural Supports that enable PEG tube related complications. The inventors discovered them to withstand a patient’s bite with a force of at least 200 that the oral intake of an aqueous solution of L-DOPA and Newtons, without rupturing and without infusing a bolus of US 2017/0172961 A1 Jun. 22, 2017 27 greater than 5% of the drug contents, when unused reser impermeable, plastic, Such as poly(vinylidene chloride), voirs are newly inserted into the mouth. Bite-resistant struc poly(vinyl chloride), poly(triflurorochloro)ethylene, poly tural Supports, for example, can include a structural housing (ethylene terephthalate)), polyether polycarbonate, or high that encapsulates the entire drug reservoir, propellant reser density, high crystallinity polyethylene. Alternatively, the voir and pump components, either protecting individual drug delivery device may include a metal. Such as stainless components, the entire device, or both. Structural housings steel or alloyed titanium, aluminum or magnesium. In an can be constructed of any tough, impact-resistant, material alternative embodiment, the drug delivery device includes that is compatible with the oral anatomy. Metals such as multiple segments connected by flexible connectors, so that stainless steel or titanium, composites, optionally fiber rein the drug delivery device is able to conform to the shape of forced polymers such as poly (methyl methacrylate) and the surface on which it is mounted. strong polymers such as Kevlar, are examples of tough 0263. The drug delivery devices of the invention may be materials that are compatible with the oral anatomy. Other attached to the teeth or other interior surfaces of the mouth structural elements can include posts or ribs in the housings by a fastener, as shown in FIGS. 1A and 1B. The fastener 1, that are placed in locations such that compression is not the one or more pumps 2, and the one or more drug possible due to the stiffness of the housing components reservoirs 3 may include a single unit or they may include being increased. In another example, structural elements, separate components, with the fastener remaining in the Such as ribs and posts, allow some flexure of the housing, but mouth when the one or more pumps or one or more do not allow sufficient flexure to deform the components of reservoirs are removed. FIG. 1A shows an embodiment the pump. In another example, the pump housing can be where a pump 2, and a drug reservoir 3 include a single made of a material that allows some flexure and there is removable component that can be attached to the fastener 1. Sufficient Volume within the housing Such that the drug Drug is delivered into the mouth via a tube 5 which may reservoir and or propellant reservoir, can deform or become optionally include a flow restrictor. FIG. 1B shows an displaced when pressure is applied but maintain their struc embodiment including a reusable housing 4, and a dispos tural integrity. In another embodiment, Some of the previ able pump 2 and drug reservoir 3. The fastener 1, one or ously described elements can be incorporated into a design, more drug pumps and one or more drug reservoirs may be and the entire internal volume of the device can be potted removably attached to each other using magnets, clips, with a tough biocompatible material Such as an epoxy or a clasps, clamps, flanges, latches, retaining rings, Snap fasten thermoplastic. ers, screw mounts, or other attachment mechanisms known 0261) To prevent their being accidentally Swallowed or in the art. In preferred embodiments, the fastener includes a aspirated into the trachea, the drug delivery devices of the transparent retainer or a partial retainer on one side of the invention are either secured in the mouth or are of a shape mouth (e.g., attached to 3, 4, or 5 teeth). FIG. 10 depicts an and size that cannot be swallowed or aspirated into the embodiment in which a pump 2 and a drug reservoir 3 form trachea. They may be secured to any interior surface of the a single component. mouth, such as one or more teeth, the roof of the mouth, the 0264. An embodiment of the device is shown in FIGS. gums, the lips or the cheek within the mouth of the patient. 2A and 2B, where the pump and/or oral liquid impermeable In order to obtain a secure and comfortable fit, the devices reservoir is secured to either the upper or lower teeth using may be molded to fit on or attach to a surface within the a transparent retainer 6. One, two or more pumps and/or one mouth of a patient, such as the teeth or the roof of the mouth, or more drug reservoirs are secured on the buccal side of the or they may conform to at least one cheek. In some embodi transparent retainer. One, two, or more drug pumps 2 and/or ments, the drug delivery devices are secured Such that they drug reservoirs 3 may be secured unilaterally, on either the are positioned on the teeth, on a cheek, between the gums right or left sides, positioned in the buccal vestibule or, and the cheek, between the gums and the lips, or at the roof alternatively, on the lingual side of the teeth. The drug pump of the mouth. Alternatively, the drug delivery device and reservoir are attached to the transparent retainer via a includes a shape and size that cannot be Swallowed. housing 4. Drug is delivered into the mouth via a tube 5 Examples are a curved, elongated shape of greater than 4 cm which may optionally include a flow restrictor. The tube 5 length in its curved form (e.g., greater than 5, 6 or 7 cm) that serves to carry the drug from the buccal to the lingual side can be placed between the gums and the cheek and lips; or of the teeth, where the drug may be more readily swallowed. drug delivery devices positioned adjacent to both cheeks and The tube may be molded into the retainer. connected with a bridge, optionally forming fluidic contacts 0265. In a related embodiment, illustrated in FIG. 3, the with both the left and the right parts. pumps 2 and reservoirs 3 can be configured to be positioned 0262 Although the housing of the typical drug delivery both on the lingual side of the teeth and in the buccal device of the invention can be a strong material Such as a vestibule. In this embodiment, the pump 2 is used to fill an metal or a ceramic, the device may include in Some embodi expandable polymeric (e.g., elastomeric or non-elastomeric) ments a rigid plastic, a strong elastomer, a deformable compartment 7, described in greater detail in FIGS. 11A, plastic or a plastic that optionally deforms such that it can 11B, and 11C, which drives the drug from the drug reservoir conform to contours of the mouth of the patient (for 3. In another related embodiment, illustrated in FIGS. 4A example, to contours of the cheek, or of the roof mouth, or and 4B, one, two or more pumps and/or oral liquid imper the floor of the mouth, or the front gum near a lip, or the meable reservoirs may be secured bilaterally, on both the teeth). The plastic may optionally be fiber reinforced, i.e., it right and left sides, positioned in the buccal vestibule or on may be re-inforced, for example, by carbon, metal, glass the lingual side of the teeth, or both buccally and lingually. fibers, or by fibers of a strong polymer, Such as a polyimide. FIG. 4A depicts a fastener in the form of an invisible retainer The plastic may include, for example, elastomeric butyl 6, including two bilateral housings 4 (shown empty) on the rubber, elastomeric silicone or polyurethane. It can be a less buccal side of the teeth into which drug pumps and/or drug deformable, for example Substantially oxygen or water reservoirs may be inserted. FIG. 4B depicts a fastener in the US 2017/0172961 A1 Jun. 22, 2017 28 form of an invisible retainer 6, including two bilateral one, two or more flow restrictors may include metal tubes housings 4 (shown filled) on the lingual side of the teeth into that are molded into the fastener (e.g., a transparent retainer which drug pumps and/or drug reservoirs have been or a partial retainer). By incorporating flow restrictors into inserted. a reusable fastener, the disposable drug delivery device 0266 Optionally, two or more oral liquid impermeable and/or oral liquid impermeable reservoir need not include a drug reservoirs may be in fluidic contact with each other. flow restrictor that accurately controls the rate of infusion. Optionally, the transparent retainer 6 may include 2, 3, 4 or 0271 In another embodiment, a reusable fastener (e.g., a more layers of different hardness, to ease insertion and transparent retainer or a partial retainer) may include a pump removal of the transparent retainer from the teeth. For and/or power source. With a reusable pump and/or power example, the transparent retainer 6 may include a dual Source incorporated into the fastener, the disposable portion laminate with a softer, inner, tooth-contacting layer, and a of the drug delivery device and/or the oral liquid imperme harder, outer layer contacting the cheeks and tongue. able reservoir need not include the pump and/or power 0267. The one or more pumps and/or oral liquid imper Source, thereby reducing overall cost. For example, the meable reservoirs may be removably attached to the trans fastener may include a piezoelectric or battery driven elec parent retainer using magnets, clips, clasps, clamps, flanges, troosmotic pump, and/or a battery. The battery may option latches, retaining rings, Snap fasteners, screw mounts, or ally be rechargeable. other attachment mechanisms known in the art. In one 0272. The fastener or its components, such as the hous embodiment, the transparent retainer includes one, two, or ings, may be manufactured using methods known in the art, more housings into which one, two, or more pumps and/or Such as thermoforming, injection molding, pressure mold the oral liquid impermeable reservoir are inserted. The one, ing, and laminating. two or more housings may be molded or formed to the shape 0273. The drug delivery device may be a single unit, or of the one, two or more pumps and/or oral liquid imperme it may have two, three, four, five or more components. The able reservoirs. drug delivery device may have one, two, three, four, five or 0268 For delivery of some drugs, such as LD or CD, it more oral liquid impermeable reservoirs in which the solid can be desirable to administer the drug-including Solid or or fluid drug formulation is contained. These one or more fluid on the lingual side of the teeth, rather than on the buccal reservoirs may form a single component, or they may form side of the teeth, in order to minimize the residence time of multiple components. the drug in the mouth, thereby avoiding potential accumu 0274 The drug delivery devices may be reusable, dis lation of the drug in the buccal vestibule and minimizing posable, or they may have one or more reusable components potentially irritating exposure of the buccal tissue to the and one or more disposable components. In a preferred drug. In a preferred embodiment, the fastener (e.g., a trans embodiment, the fastener is reusable, and may be reused for parent retainer or a partial retainer) includes one, two, or a period of equal to or greater than 7, 30, 60 or 180 days, or more fluidic channels to transport the drug-including fluid one year or two years. In another preferred embodiment, the into the mouth from the one, two or more pumps and/or oral one or more oral liquid impermeable reservoirs are single liquid impermeable reservoirs. The fluidic channels can use, disposable components. The pump may be either reus transport the drug-including fluid from one, two, or more able or disposable. A flow restrictor, if present, may be a oral liquid impermeable reservoirs located on the buccal side single use disposable or may be reused. of the teeth to the lingual side of the teeth. For example, the 0275. The oral liquid impermeable reservoir may be fluidic channels can include one, two or more tubes that are refillable with a solid or fluid drug formulation. In a pre molded into the fastener. The fluidic channels can, for ferred embodiment, the oral liquid impermeable reservoir is example, pass behind the rear molars, above the mandibular a single use disposable. The oral liquid impermeable reser arch, so that they do not cross the biting surface of the teeth. voir may be filled by the user. In preferred embodiments, the The fluidic channels may include an inner diameter of less oral liquid impermeable reservoir is prefilled. than 0.25 mm, 0.25-1 mm, 1-2 mm, 2-3 mm, or greater than 0276. The drug delivery device further includes one, two, 3 mm. The fluidic channels may include a fluidic path length three, four or more orifices for releasing the drug from the in the fastener of less than 1 mm, 1-3 mm, 3-5 mm, 5-10 device into the mouth. mm, or greater than 10 mm, Such as 1-2 cm, 2-3 cm or 3-4 0277 Durations of administration from a single drug C delivery device or oral liquid impermeable reservoir typi 0269. The one, two or more pumps and/or one, two, or cally exceed 4, 8, 12, or 16 hours per day, up to and more oral liquid impermeable drug reservoirs can be in fluid including 24 hours per day. Administration can also take communication with the one, two, or more fluidic channels place over multiple days from a single device or oral liquid in the fastener (e.g., a transparent retainer or a partial impermeable reservoir, e.g., administration of a drug for 2 or retainer) via any type of leak-free fluidic connector known more days, 4 or more days, or 7 or more days. The devices in the art, such as leak-free Snap fastener or screw-mount. can be designed such that they can be worn when the patient The leak-free fluidic connector preferably includes metal, to is awake or asleep. improve durability. Optionally, the one, two or more pumps 0278. It is desirable that the patient be able to temporarily and/or the one, two, or more oral liquid impermeable remove the drug delivery device from the mouth, for reservoirs do not deliver drug when they are not mounted on example, to eat meals, brush teeth, or at times when the the fastener, while mounting these on the fastener initiates patient does not want or need the medication (e.g., at night). delivery of the drug. Similarly, drug delivery can be tem Consequently, the drug delivery devices and/or some of its porarily halted when the pumps and/or oral liquid imper components (such as the pump and/or the oral liquid imper meable reservoirs are dismounted from the fastener. meable reservoirs) can be temporarily removable. It is, 0270. In one embodiment, the one, two or more fluidic however, acceptable for some components, such as the channels may include one, two or more flow restrictors. The fastener, to remain in the mouth if these do not interfere with US 2017/0172961 A1 Jun. 22, 2017 29 the patient’s activities. For example, a band, a fastener example it can be less than one half of t, less than /3rd of cemented or glued to one or more teeth, a retainer, or a ta, or less than /4 of t, or less than /10th of t. muco-adhesive patch adhered to the oral mucosa, and which 0284. For fluid drug formulations, it is desirable to holds the pump and/or oral liquid impermeable reservoir in deliver the Solutions or Suspensions of the invention using place, may remain in the mouth when the pump and/or the drug delivery devices that are Small, efficient, inexpensive, oral liquid impermeable reservoir are removed. and reliable. This can be particularly challenging when these 0279. The drug delivery device preferably can have a fluids are viscous. It is also desirable to minimize the shape that is comfortable in the mouth. Typically such a pressure required to pump the fluid. In preferred drug shape has rounded edges. Shapes such as obround shapes are delivery devices for fluids of greater than 100 cp, for typically more comfortable than cylindrical shapes. example, 100-1000 cB, 1,000-10,000 cB, 10,000-100,000 cB. 100,000-500,000 cP 500,000-2,500,000 cB, or greater than 0280. It is desirable that the drug delivery device include 2,500,000 cp, the drug can exit the device through a tube, an indicator of the quantity remaining of one or more drugs; nozzle, channel, or orifice of less than 4 cm, 3 cm, 2 cm, 1 the infusion time remaining until empty; and/or that one or cm, 0.5 or 0.2 cm length. For example, the fluid may be more of the oral liquid impermeable reservoirs is empty and delivered through an optionally flexible cannula, or it may should be replaced. be delivered through an orifice without utilizing any type of 0281. The drug delivery devices of the current invention tubing or cannula. To further minimize the pressure required are configured and arranged to administer one or more solid to pump the fluid, the tube, channel or orifice through which or fluid drug formulations from one or more oral liquid the drug exits the device may have an internal diameter of impermeable reservoirs including a total volume of 0.1-10 greater than 0.5, 1, 2, 3, 4, or 5 mm, for example, 1 mm-5 mL of drugs, e.g., 0.1-1.0, 1.0-2.0, 2.0-3.0, 3.0-4.0, 4.0–5.0, mm, 1 mm-3 mm, 2 mm-4 mm, or 3 mm-5 mm. Preferred 5.0-6.0, 6.0–7.0, 7.0-8.0, 8.0-9.0, or 9.0-10 mL. They are minimum internal diameters are 0.1-2 mm (0.1-0.7 mm, configured and arranged to administer the one or more Solid 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or or fluid drug formulations at a rate in the range of 0.03-1.25 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as mL/hour, e.g., 0.03-0.10, 0.10-0.20, 0.20-0.30, 0.30-0.40, 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 0.40-0.50, 0.50-0.60, 0.60-0.70, 0.70-0.80, 0.80-0.90, 0.90 cm, 2-3 cm, 3-4 cm, or 4-5 cm). 1.0, 1.0-1.1, or 1.1-1.25 mL/hour. In some embodiments, (0285 Pumps they are configured and arranged to administer the drug, 0286 The pumps for the drug delivery devices must be (i.e., the active pharmaceutical ingredient) at an average rate suitable for miniature devices carried safely and comfortably of 0.01-1 mg per hour, 1-10 mg per hour, 10-100 mg per in the mouth. Any Suitable pump may be used. The pump hour, or greater than 100 mg per hour. In other embodiments, and the oral liquid impermeable reservoir may be distinct. the drug product (i.e., the active pharmaceutical ingredient 0287 Miniature pumps are advantageous for placement plus excipients) is delivered at an average rate of 0.01-1 mg in the mouth. For example, the extruded fluid including the per hour, 1-10 mg per hour, 10-100 mg per hour or greater drug may occupy more than 33%, 50%. 66%, or 75% of the than 100 mg per hour. total volume of the drug delivery device. 0282. The one or more drugs may be administered at a (0288. Non-Electric Pumps. constant rate or at a non-constant rate that varies over the 0289 Pumps that do not require a battery can be smaller course of the administration period. For example, the drug and have fewer moving parts than battery-requiring electri delivery device may be programmed to administer drugs cal pumps. One group of nonelectric disposable pumps of according to a drug delivery profile over the course of the the invention is based on the physical principle that administration period. The drug delivery device may also mechanical restriction within the flow path can determine have an on-demand bolus capability, whereby the patient or the flow rate of a pressurized fluid. The pressure on the fluid caregiver may initiate the delivery of a bolus of drug. may be generated by a variety of mechanisms using non 0283. In preferred embodiments, the drug delivery device electric power, including a stretched elastomer, a com administers one or more solid or fluid drug formulations via pressed elastomer, a compressed spring, a chemical reaction, continuous and/or frequent administration, e.g., infusion. In a propellant, and a cartridge of pressurized gas. The restric a preferred embodiment, the solid or fluid drug administra tion of flow may be provided by an orifice (e.g., in the drug tion rate is held constant or near constant for a period of 4. reservoir), by narrow-bore tubing (Such as a metal, glass or 8, 12, 16 or 24 hours during the day. For example, the plastic pipe), or by a channel, or by a capillary, or a administered volume may vary by less than +10% or +20% flow-controlling nozzle. Optionally, the flow-controlling per hour, or by +10% or +20% per 15 minute period, over nozzles, channels or tubes can be made of a plastic Such as a period of 4, 8, 12, 16 or 24 hours. In another embodiment, an engineering plastic, or made of a metal or a ceramic Such the solid or fluid drug administration rate is held about as a glass. The nozzles, channels or tubes can have an constant during the awake hours of the day. In another internal diameter less than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm embodiment, the solid or fluid drug formulation administra and they can be shorter than 10 cm, 5 cm, 2 cm or 1 cm Such tion rate is held about constant during the asleep hours. In as 0.5 cm. Preferred minimum internal diameters are 0.1-2 another embodiment, the solid or fluid drug formulation mm (0.1-0.7 mm, 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, administration rate is held about constant during the awake 1.0-1.5 mm, or 1.5-2.0 mm) and preferred lengths are 0.25-5 hours of the day, except for the delivery of a bolus at about cm (such as 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, the time of waking. In one embodiment, the administration 0.75-1 cm, 1-2 cm, 2-3 cm, 3-4 cm, or 4-5 cm). rate can be set prior to insertion in the mouth by the patient 0290 Because different patients may require different or by the caregiver. In another embodiment, the administra doses of drug, it is desirable for the drug delivery devices of tion is semi-continuous and the period between the infusions the invention to be available as a product line of multiple is less than the biological half-life of the drug t for products, each product having a different drug administra US 2017/0172961 A1 Jun. 22, 2017 30 tion rate. The desired flow rate may be obtained by selecting to 5 bar at about 37° C.), or the pressurizing gas can be a flow restrictor of the appropriate inner diameter and length. chemically generated, for example electrolytically gener In one embodiment, the plastic flow restricting nozzle or ated, (e.g., by electrolyzing water). tubing may be cut to the length providing the desired flow 0297. The drug delivery device may be kept in the mouth rate. Use of a narrow-bore tubing as a flow restrictor while the patient is eating and drinking, or may be removed simplifies the manufacturing process for Such a product line. for eating or drinking. Preferably, the introduction into the During the manufacturing process a narrow-bore tubing with mouth of food or liquid, including food or liquids that are constant inner diameter may be cut into multiple segments hot, cold, acidic, basic, oily, or alcoholic, does not have a offixed length A, to provide reproducible flow restrictors for clinically significant effect on the drug delivery. For products with one flow rate. A different portion of the example, such conditions may affect the solubility of the narrow-bore tubing with constant inner diameter may be cut drug; the Volume of the drug-including fluid in the reservoir; into multiple segments of fixed length B, to provide repro the Viscosity of the drug-including fluid in the oral liquid ducible flow restrictors for products with a second flow rate. impermeable reservoir; the volume of the gas in the reser 0291. In another embodiment, when the reservoir is voir (if present); the diffusivity of mass-transport limiting metallic one or more pinholes in the reservoir wall can membranes (if present); and/or the force exerted by elasto include the flow restrictor, i.e., a desired flow rate can be mers or springs (if present). Some drug delivery technolo obtained by the number of pinholes and the diameter of the gies, such as controlled release muco-adhesive drug delivery one or more pinholes. patches, can deliver large drug boluses when in contact with 0292. In yet another embodiment, the flow restrictor can a hot, cold, acidic, basic, oily, or alcoholic liquid in the include an orifice with an adjustable diameter, similar to the mouth. Such boluses may result in undesirable clinical user-adjustable aperture of a camera. Instead each device effects, and should be minimized. In one embodiment, the being able to infuse at only a single infusion rate Such a solid or fluid drug delivery devices of the invention deliver user-adjustable orifice could allow the physician or the a bolus of less than 5%, 4%, 3%, or 2% of the contents of patient to set the infusion rate, thereby providing more a fresh oral liquid impermeable reservoir when immersed for flexibility and convenience. 5 minutes or for 1 minute in a beaker containing a stirred 0293. The preferred nozzles, channels or tubes can be aqueous 0.14 M saline solution that is hot (e.g., at about 55° made of an engineering plastic, can have an internal diam C.), cold (e.g., at about 1° C.), acidic (e.g., at about pH 2.5), eter less than 1 mm, 0.6 mm, 0.3 mm or 0.1 mm and can be basic (e.g., at about pH 9), oily (e.g., emulsion of 5% by shorter than 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. weight of olive oil in 0.14 M aqueous saline solution), or Preferred minimum internal diameters are 0.1-2 mm (0.1-0.7 alcoholic (e.g., a 0.14 M saline solution containing 5% by mm, 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, weight ethanol). For example, a LD delivery device may or 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as deliver abolus of less than 0.5, 0.25, 0.12, or 0.06 millimoles 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 of LD under these conditions. cm, 2-3 cm, 3-4 cm, or 4-5 cm). 0298 Battery Powered Pumps. 0294 Flow rate can be affected by the pressure gradient 0299. Other than powering the pump, the battery can across the flow restrictor and by fluid viscosity. A significant power optional electronic controls and communication capa Source of inaccuracy in existing pump products can be that bilities (e.g., radio frequency receivers) for programmed Viscosity is strongly affected by temperature. An important drug delivery and remote control of the drug delivery by a benefit of carrying within the mouth the drug delivery transmitting device. A miniature battery may be used to devices of the invention is that the temperature is held nearly drive the pump or dispensing mechanism for the delivery of constant at about 37° C., thereby minimizing variations in the solid or fluid drug. Any low power pump drive mecha the rheological properties (such as viscosity) and therefore nism known in the art may be used. Such as Syringe, in the infusion rate. The nearly constant about 37°C. is also hydraulic, gear, rotary vane, screw, bent axis, axial piston, advantageous in maintaining a stable pumping pressure radial piston, peristaltic, magnetic, piezoelectric, electroos when a gas, such as from a liquid propellant, is used to drive motic, diaphragm and memory alloy, such as initinol, based. the pump. 0300. An advantage of battery powered pumps for use in 0295 The formulations of the invention are often viscous the mouth is that it is possible to temporarily stop the drug Suspensions. Use of viscous Suspensions is often desired to delivery from the device if the patient wishes to temporarily achieve the Small Volumes, high concentrations, uniform remove the drug delivery device from the mouth. This can drug dispersion, storage stability, and operational stability be accomplished, for example, by turning off the electric desired for the drugs and methods of the invention. Conse power to the pump. quently, it is often desired to employ pump mechanisms that 0301 One embodiment of a battery powered pump is a can provide the pressures required to pump the Viscous miniature diaphragm pump that uses the motion of a piezo fluids. electric crystal to fill a chamber with drug from a reservoir 0296. The pressure generated by elastomeric, spring in one motion and to expel the drug from the chamber in the driven and gas-driven pumps on fluid is typically in the opposite motion. Typically, the frequency of oscillation of range of 250 mm Hg to 5,000 mm Hg, depending on flow the piezoelectric crystal is less than about 20,000 Hz, 5,000 rate and cannula size, but can be higher. For example, the HZ, or 1,000 Hz, so as to avoid the higher frequencies where pressure may be 250-500 mm Hg, 500-750 mm Hg, 750-1, biological membranes are ultrasonically disrupted or where 000 mm Hg, 1,000-1250 mm Hg, 1,250–2,500 mm Hg, free radicals are more likely to be generated through a 2,500-5,000 mm Hg, or greater than 5,000 mm Hg. The Sonochemical process. A significant advantage to the dia pressurizing gas can be a propellant that condenses to a phragm pump is that it can be used to very accurately deliver liquid at a pressure greater than 1 bar (such from 1 bar to 2 materials of both high and low viscosity, as well as Solids bar, from 2 bar to 3 bar, from 3 bar to 4 bar, or from 4 bar Such as granules or powders. US 2017/0172961 A1 Jun. 22, 2017

0302) Another embodiment of a battery powered pump is membranes of elastomeric pumps may include both natural a miniature electroosmotic pump as disclosed, for example, and synthetic (e.g., thermoplastic) elastomers (e.g., isoprene in U.S. Patent Publication Nos. 2013/0041353, 2013/ rubber, neoprene, latex, silicon, and polyurethanes), and can 0156615, 2013/0153797 and 2013/0153.425, in PCT Publi be made of a single or multiple layers. The type of elastomer cation No. WO2011/112723, and in Korean Patent Publica and the geometry of the elastomeric balloon 9 determine the tion No. KR101305149, each of which is incorporated pressure generated on the fluid when the balloon is stretched. herein by reference. Typically the volume of the miniature Multiple-layer elastomeric membranes can generate higher electroosmotic pump, including its battery or batteries, is pressures than the single-layer membranes. Higher driving smaller than the volume of the fluid in the unused oral liquid pressures are of benefit for achieving faster flow rates and impermeable reservoir. For example, the volume of the for pumping viscous fluids. pump can be less than half, less than %", less than 4", or 0308 To minimize the change in flow rate as the fluid is less than %" of the volume of the unused oral liquid delivered, it is preferred to utilize sufficiently high tension in impermeable reservoir. When an electroosmotic pump is the elastomeric membrane such that the difference between used with a refillable reservoir, the battery powering the the starting and ending pressure on the fluid is less than 30%, pump can be replaced upon refilling. To provide different 20%, or 10% of the starting pressure. patients with different dose rates, oral liquid impermeable 0309 Another embodiment of an elastomer-driven pump reservoirs may be filled with the drug at different concen is the use of an elastomeric band 10 (e.g., a rubber band, see trations. Alternatively, the flow rate of the electroosmotic FIGS. 5C and 5D) to apply a constant force to a drug pump can be adjusted by controlling the applied Voltage or reservoir 3 driving the drug through a narrow bore tubing 8 the applied current, or by varying the cross sectional fluid with a check valve 16 (or one-way valve) at the downstream contacting area of the membrane Sandwiched between the end. Elastomers are known to have material properties electrodes. Optionally, the applied Voltage or current can be where large strain values can be imparted on them with remotely adjusted by incorporating a short range RF receiver relatively small changes in stress and, in Some regions of the in the insert. stress-strain curve with very little change in stress. In one 0303 Another category of battery powered pumps is that embodiment of an elastomeric band pump, a stretched of positive displacement pumps. Two examples of battery polyisoprene band is used. Polyisoprene has desirable mate powered positive displacement pumps that can be used to rial properties in that, within a specific region of the stress deliver the drug are gear pumps and peristaltic pumps. One strain curve, significant changes in strain result in virtually of the main advantages of the use of a positive displacement no change in stress. In this embodiment, the elastomeric pump is that the delivery rate is not affected by changes in rubber band 10 is used within the range in the stress-strain ambient pressure. The gear pump, in one embodiment, uses curve where the stress remains within the elastic region from two rotors that are eccentrically mounted and intermeshed the beginning to the end of the stroke of the motion of the with their cycloid gearing. As a result a system of several piston. In this embodiment, one end of the elastomeric band sealed chambers exists at all times and are moved toward the 10 is placed onto the post 12 attached to the piston 13 while outlet of the pump, one at a time. An example of a gear pump the other end is placed onto the stationary post 14. The is the Micro annular gear pump m2r-2521 from HNP Mik tension on the elastomeric band 10 applies a force to the rosysteme GmbH. A second type of battery powered positive drug reservoir and in order to eliminate the effect of ambient displacement pump is the peristaltic pump. Peristaltic pumps pressure differences, a vent hole 15 allows the drug reservoir use a series of rollers to pinch a tube creating a vacuum to 3 to be exposed, on all sides, to ambient pressure. The check draw the material from a reservoir, thereby creating and valve 16 also serves to keep saliva from entering the narrow moving a volume of drug within Subsequent roller volumes bore tubing 8 while the drug is not flowing. FIGS. 5C and to deliver the drug toward the outlet of the pump. An 5D show the device with a full drug reservoir 3 and a example of a battery powered peristaltic pump is the RP-TX partially emptied drug reservoir 3, respectively. series micro peristaltic pump from Takasago Electric, Inc. 0310. Yet another embodiment of a nonelectric dispos 0304 Elastomeric Infusion Pumps. able pump including a pressurized fluid and a flow restrictor 0305. In elastomeric infusion pumps, the pressure on the involves the use of a volume of elastomer in a fixed volume fluid is generated by the force of a stretched or compressed drug reservoir. The elastomer may, optionally, be a closed elastomer. An example of an elastomeric, partially dispos cell elastomer. The elastomer can be compressed and the able, constant-rate medication infusion pump with flow Subsequent controlled expansion of the elastomer provides restrictor is the CeOur PaO insulin patch pump, described in the force to deliver the drug. In continuous pumping using U.S. Ser. No. 12/374,054 and U.S. Pat. No. 8,547,239, each a gas-including closed-cell elastomer, a drug-including fluid incorporated herein by reference. is pumped at an about constant flow rate by maintaining in 0306 FIGS. 5A and 5B show an embodiment of an the fixed volume, oral liquid impermeable reservoir an about elastomeric drug reservoir that can be filled with a drug to constant pressure. For maintaining the about constant pres pressurize the drug and to pump the fluid at a controlled rate sure in the reservoir a substantially compressible elastomer through the use of a narrow-bore tubing 8 that serves as a is placed in the reservoir. The substantially compressible flow restrictor. FIG. 5A shows the elastomeric reservoir 9 elastomer can be compressed by applying a pressure in the when empty of drug and FIG. 5B shows the elastomeric reservoir that is typically less than about 100 bar (for balloon 9 when pressurized due to expansion of the elasto example less than 10 bar) to a volume of elastomeric mer by filling with the drug. material. The Volume of the compressed elastomeric mate 0307 Preferably, the elastomeric membrane is protected rial in the pressurized reservoir can be less than about 67%, by an outer protective shell. The outer protective shell can 50%, or 25% of the volume of the elastomer at about either be a conformable elastomer or a more rigid plastic, sea-level atmospheric pressure. An exemplary family of which may be molded to a surface of the mouth. The such compressible elastomers includes closed cell rubbers, US 2017/0172961 A1 Jun. 22, 2017 32 also known as closed-cell rubber foams. Closed cell rubbers 0314. To minimize the change in flow rate when the have fully rubber-enclosed gas pores, the pores containing a patient drinks a hot beverage, it is preferred to utilize gas, such as N, CO, or air. At about sea-level atmospheric elastomeric materials whose force is relatively independent pressure the density of the closed pore elastomer can be less of temperature in the range of 37° C.-55° C. For example, than 67% of the density of the elastomer without the gas, for the force in a fresh reservoir may increase by less than 30%, example between 67% and 33% of the elastomer without the 20% or 10% when the temperature is raised from 37° C. to gas, between 33% and 25% of the elastomer without the gas, 550 C. between 25% and 12% of the elastomer without the gas, or 0315 Spring Driven Pumps. less than 12% of the density of the elastomer without the gas. 0316 Positive-pressure spring-powered pumps are pow The volume percent of the gas in the elastomer at about ered by energy stored in a compressed spring. In one sea-level atmospheric pressure can be greater than 20 Vol embodiment, the spring is compressed during the reservoir ume '%, for example greater than 50 volume 96, or greater filling process, as the volume of the solid or fluid in the than 75 volume 96. The elongation of the gas-including reservoir increases. In another embodiment, the spring is elastomer can be greater than about 25%, for example relaxed prior to use, for example during storage and shipping between 50% and 200%, between 200% and 450%, or of the product, and the spring is compressed during the greater than 450%. The gas containing elastomer can be of process of inserting the pump component into the re-usable any shape fitting in the fixed Volume drug reservoir. It can oral appliance. In yet another embodiment, the spring is be a single piece, Such as a block, or an optionally folded relaxed prior to use and the spring is compressed during the sheet, or it can be multiple pieces, such as Small gas-filled process of placing the oral appliance into the mouth. spheres. Typical gas pore enclosing elastomers can include 0317. A significant advantage of spring-driven pumps for cross-linked polymers and copolymers, for example of use in the mouth is that it is possible to temporarily stop the dienes (exemplified by isoprene, chloroprene (neoprene), drug delivery from the device if the patient wishes to butadiene); exemplary copolymers include acrylonitrile temporarily remove the drug delivery device from the butadiene-styrene, acrylonitrile-butadiene, or elastomeric mouth. This can be accomplished, for example, by retracting polyacrylates, or elastomeric olefins such as ethylene-pro the spring, restricting the further expansion or contraction of pylene rubbers, or elastomeric silicones and fluorosilicones, the spring, or blocking or closing the flow restrictor, e.g., the or elastomeric polyurethanes. In general the less gas per glass capillary or narrow bore tubing. meable, particularly less water vapor permeable elastomers, 0318. The spring of the invention is preferably an about are preferred. constant force spring. To minimize the change in flow rate 0311 Drug delivery devices including closed cell elas as the solid or fluid is delivered, it is preferred to utilize a tomeric pumps are preferrably configured and arranged to Sufficiently long spring, or a coaxial coupled spring set, or a continuously or semi-continuously administer the drug into Sufficiently high tension in the spring such that the difference the patient’s mouth at an average rate for a delivery period between the starting and ending force applied by the spring of not less than 4 hours and not more than 7 days at a rate is less than 30%, 20%, or 10% of the starting force. in the range of 80%-120% of the average rate. 0319. To minimize the change in drug administration rate 0312. During the delivery of the drug-including suspen when the patient drinks a hot beverage, it is preferred to sion at a constant rate the gas-including elastomer expands utilize spring materials whose force is relatively independent such that it occupies most or all of the volume vacated by the of temperature in the range of 37-55° C. For example, the already delivered Suspension and there are large gas bubbles force in a fresh reservoir may increase by less than 30%, within the elastomer. In an exemplary method of production 20% or 10% when the temperature is raised from about 37° and operation of a system delivering the drug at an about C. to about 55° C. constant rate, a closed-cell elastomer can be placed in a drug 0320. The springs of the invention may be any type of reservoir equipped with an closed outlet or outlets for drug spring, including traditional metal springs or a compressible delivery and optionally equipped with a septum for filling elastomer. For example, the compressible elastomer may be the reservoir. The drug reservoir can have walls made of a a Solid Such as isoprene, or it may contain closed gas cells material that does not substantially deform at the operating (e.g., neoprene). pressure in the reservoir, for example the deformation of the 0321) An example of a spring-driven, fully disposable, wall under the applicable pressure changing the reservoir constant-rate medication infusion pump with flow restrictor volume typically by less than 5%, for example by less than is the Valeritas V-go insulin patch pump, described in U.S. 1%. The drug containing Suspension can be then injected Ser. No. 13/500,136, incorporated herein by reference. through the septum, compressing the gas-containing closed 0322. In embodiments in which the drug is delivered into cells of the rubber and pressurizing thereby the reservoir. the mouth via a tube or channel, the oral liquid impermeable Opening the outlet or outlets initiates the flow of the drug reservoir may be kept free of oral liquids by using a drug-including Suspension, e.g., into the mouth. The about tube or channel coated with a hydrophobic or non-stick constant pressure in the reservoir during the delivery of the material (e.g. paraffin, PTFE or fluorinated polyether), and/ drug can be controlled, for example, by the type of the or designed with a diameter that would require a sufficiently closed cell rubber. high pressure so as to not allow saliva to enter. 0313 An advantage of elastomeric infusion pumps for 0323. Another embodiment of a spring driven drug use in the mouth is that it is possible to temporarily stop the pump, illustrated in FIG. 6, includes the use of a spring drug delivery from the device if the patient wishes to motor to rotate two columnar or conical shaped drums 29 temporarily remove the drug delivery device from the that are attached to the oral liquid impermeable drug reser mouth. This can be accomplished, for example, by blocking voir 3 containing a suspension. The drums 29 are con or closing the flow restrictor, e.g., the orifice, the glass structed of a hydrophobic or non-stick material, and can be capillary, or the narrow bore tubing. configured with a tight tolerance to prevent introduction of US 2017/0172961 A1 Jun. 22, 2017

saliva into the reservoir. The rotation of these drums can end of the spring 37 is attached to a compression plate 39, draw the suspension from the drug reservoir 3, through the and pulls the compression plate 39 toward the drug reservoir drums 29, and into the mouth. The drums can be configured nozzle 8. FIG. 7C shows the location of the spring 37 and Such that a cutout 30 defines the dosage, and the frequency compression plate 39 when the drug reservoir 3 is full and of rotation of the drums 30 defines the drug delivery rate. In the spring 37 is fully extended. FIG. 7D shows the location another embodiment, the cutout 30 would not be present and of the compression plate 39 and spring 37 when the retrac the spacing between the drums 29 along with the speed of tion of the spring 37 has delivered all or most of the drug rotation of the drums 29 would define the drug delivery rate. from the reservoir 3. FIGS. 7C and 7D also have a vent hole In order to maintain constant feeding and eliminate the 15 incorporated into the design, to eliminate any effect of potential for gaps of drug to the drums, a spring 31 and ambient pressure on the drug delivery rate. piston 32 are employed within the housing 4. 0328. In a further embodiment of a spring pump, one or 0324. In another embodiment of a compression spring more compression springs can be used to apply an approxi driven drug delivery device, FIG. 8 illustrates a compres mately constant force to a piston or plunger that applies that Sion-spring driven pump delivering a drug Suspension. One force to the drug reservoir. Using a very long compression or more constant force compression springs 31 are used to spring with a low spring rate, one could apply a force across push a compression plate 39 toward an orifice 75. The drug a short stroke with relatively constant force. As an example, is contained in an oral liquid impermeable reservoir with a 10 inch long spring with a spring rate of 0.05 lbF/in would rigid walls 4. For example, the rigid walls and compression be compressed to 8.5 inch and would apply a force of 0.425 plate may include a syringe barrel and a plunger which lbF. If the spring were allowed to expand to 7.5 inches (a 1 creates a seal that prevents leakage of the drug into the inch total stroke), the resulting force would be 0.375 lbF, compartment containing the spring. In order to eliminate the which is a decrease of 12.5% throughout the stroke. In effect of changes in ambient pressure on the drug delivery preferred embodiments, the spring force is in the range of rate, a vent hole 15 is present within the device to allow both 0.25-10 lbF and is preferably less than 10 lbF, 5 lbF, or 1 lbF: the drug reservoir 3 and the drug reservoir nozzle 80 to be the spring rate is in the range of 0.01-1 lbF/inch and is exposed to ambient pressure, which reduces or eliminates preferably less than 1 lbF/inch, 0.5 lbF/inch, or 0.05 lbF/ the effect of change in ambient air pressure (e.g., by the inch; the stroke length is in the range of 0.5-1 inch and is patient Sucking on the device and/or change in altitude). The preferably less than 2 inches, 1 inch, or 0.5 inches; and the drug delivery device may optionally include a one-way difference between the starting and ending force across the valve 16. stroke is less than 15%, 10%, or 5%. 0325 As illustrated in FIG. 9, a particularly advanta 0329 Pneumatic Pumps. geous embodiment is the use of two coaxial compression 0330 Pneumatic pumps generate a driving force using a springs 31 and 19 connected via a coupler 18 wherein, upon pressure head of air. In one embodiment, a diaphragm pump compression, a first spring with a first diameter is wholly or generates a pressure head that pushes a discreet amount of partially nested within a second spring with a second, larger drug, in Solid form (e.g., particles, granules or powder), from diameter. Such an embodiment provides for a smaller over a reservoir and into the mouth. An example of such a design, all length and a reduced variation in force across the stroke illustrated in FIG. 10, is a rotating disk 54 that contains length, as compared to the use of a single spring. compartments filled with suspension 55 that is injected by an 0326 In a further embodiment of a coil spring-driven air pressure bolus 57 at a pre-determined rate through an drug delivery device, FIGS. 7A and 7B illustrate an embodi ment in which one or more constant force springs are used orifice 56 that is fixed in place with respect to the rotating to pull a compression plate toward an orifice. A flexible disk 54. The rotation of the disk 54 exposes a single and/or deformable oral liquid impermeable reservoir within compartment and the bolus of air 57 delivers the drug from a housing contains the drug. The end of the spring rides that compartment to the mouth at a specific rate. The housing along a track on the inside of the housing. FIG. 7A, shows can be formed from a clear material that would allow the the location of the spring 37, spring axle 38 and compression user to observe how much drug remains in the device. In plate 39 when the reservoir 3 is full and the spring 37 is fully another embodiment, the disk can contain a single compart extended. FIG. 7B shows the location of the compression ment that rotates and alternately fills the compartment from plate 39 and spring 37 when the retraction of the spring 37 the reservoir and delivers the drug with a bolus of air. In this has delivered all of the drug from the reservoir 3. In a related configuration, the air not only delivers the drug material, but embodiment, the drug can be contained within the housing also removes any saliva prior to re-filling the compartment itself and the compression plate would create a seal and act from the reservoir. as a plunger to deliver the drug in a manner similar to a 0331 Negative Pressure Pumps. Syringe. In this embodiment, the spring rides inside of the 0332 Negative-pressure pumps generate a driving force housing and inside of the drug chamber, within a sealed from the pressure difference across two sides of the pumps sleeve, protecting the drug from exposure to the spring. In low-pressure chamber wall, with one side being at low order to eliminate the effect of changes in ambient pressure pressure (e.g., inside a partial vacuum chamber) and another on the drug delivery rate, an optional vent hole 15 is present side being at atmospheric pressure. The low pressure in the within the device to allow both the drug reservoir 3 and the vacuum chamber may be created during the reservoir filling drug reservoir nozzle 8 to be exposed to ambient pressure, process. Expansion of the oral liquid impermeable reservoir, which reduces or eliminates the effect of change in ambient e.g., upon adding the drug-containing fluid to the reservoir, air pressure (e.g., by the patient sucking on the device and/or causes simultaneous expansion of the reduced pressure change in altitude). chamber, thus creating a significant vacuum. During admin 0327. In another embodiment illustrated in FIGS. 7C and istration of the solid or fluid drug, pressure on the movable 7D, a constant force spring 37 remains fixed in space; one wall plunger is generated by the large pressure difference US 2017/0172961 A1 Jun. 22, 2017 34 between its two sides, causing it to move and compress the Miniature Cylinder) manufactured by Clippard Instrument Solid or fluid in the drug-containing chamber. Laboratory, Inc. (7390 Colerain Avenue, Cincinnati, Ohio 0333. A significant advantage of negative pressure pumps 45239). The gas from the miniature cartridge or cylinder can for use in the mouth is that it is possible to temporarily stop be used to compress the oral liquid impermeable drug the drug delivery from the device if the patient wishes to reservoir, thereby delivering the drug. The gas-pressurized temporarily remove the drug delivery device from the cartridge can be used in conjunction with a one or two-stage mouth. This can be accomplished, for example, by blocking regulator in order to provide a constant pressure gas flow as or closing the flow restrictor, e.g., the glass capillary or the drug reservoir is emptied. FIG. 12 shows a schematic narrow bore tubing. diagram of a commercially available two-stage regulator. 0334 Gas-Driven Infusion Pumps. Examples of miniature two-stage regulators are the product 0335. In one embodiment, a gas-driven drug delivery categories PRD2 and PRD3 manufactured by Beswick Engi device includes two or more compartments, with pressurized neering Co., Inc. (284 Ocean Rd, Greenland, N.H. 03840 gas in at least one compartment and the Suspension to be 2442). A two-stage regulator is used to gradually reduce the administered in at least one separate oral liquid impermeable pressure from high to very low, in this example from the drug reservoir. The pressurized gas provides the driving cartridge to the piston chamber of the pump. The first stage force. The two compartments are separated by a movable 59 reduces the gas pressure to an intermediate pressure. The member (such as a flexible and/or deformable diaphragm) gas at that intermediate pressure then enters the second stage that transmits the force from the gas compartment to the 60 and is further reduced by the second stage 60 to the Suspension. working pressure. In a related embodiment, a gas cartridge 0336. The housing containing the two compartments is contains an optionally reversibly CO-absorbing or adsorb typically constructed to have a fixed volume that does not ing Solid that maintains, e.g. in its Henry region, an about vary significantly as the drug is dispensed and the internal constant CO pressure at about 37°C. The reversibly CO pressure declines in the compartment containing the pres absorbing or adsorbing Solid can be, for example, a high Surized gas. An example is a reservoir in the shape of a specific Surface activated carbon, silica, e.g., silica gel. Syringe barrel including: a fluid dispensing orifice at the modified with n-propylamine or with another amine or distal end of the syringe barrel; a sealed proximal end of the heterocyclic nitrogen compound. The BET (Brunauer-Em Syringe barrel; a mobile rubber or elastomeric plunger in the mett–Teller) specific surface of the materials can be greater Syringe barrel, which separates the Syringe barrel into two than 50 m/g such as, between 50 m/g and 500 m/g, or compartments; a drug-including fluid located in the distal greater than 500 m/g. The materials can contain more than compartment; and a pressurized gas in the proximal com 0.5 millimoles of amine functions per gram, for example partment. In another example, the drug compartment may between 1-5 millimoles of amine functions per gram. Exem have a bellows shape and may be surrounded by the gas plary reversibly CO-absorbing or adsorbing solids are compartment, Such that the pressurized gas compresses the described, for example, by Z. Bacsik, N. Ahlsten, A. Ziadi, bellows and forces the drug-including fluid through a flow G. Zhao, A. E. Garcia-Bennett, B. Martin-Matute, and N. restrictor. Hedin “Mechanisms and Kinetics for Sorption of CO on 0337 FIGS. 11A, 11B, and 11C illustrate another Bicontinuous Mesoporous Silica Modified with n-Pro embodiment, wherein a first elastomeric drug reservoir 3 is pylamine Langmuir 2011, 27, 11118-11128 incorporated compressed by a second elastomeric compartment 7 con herein by reference and in the references cited by Bacsik et taining gas or propellant. In FIG. 11A, the drug delivery al, also incorporated herein by reference. The materials may device includes a housing containing a first, full elastomeric also be in the MIL-53 family of soft porous crystals, such as drug reservoir 3; a second empty, elastomeric compartment MIL-53(AI), MIL-53(AI)-11.1% NH2, MIL-53(AI)-20% 7; and an optional gas pump 11 and electronics. In one NH, MIL-53(AI)-50% NH, MIL-53(AI)-66.7% NH, and embodiment air and/or saliva is pumped by the electronic MIL-53(AI)-NH, as described by M. Pera-Titus, T. (e.g., piezoelectric) pump 11 into the second elastomeric Lescouet, S. Aguado, and D. Farrusseng "Quantitative Char reservoir 7. In another embodiment the second elastomeric acterization of Breathing upon Adsorption for a Series of reservoir 7 contains a compressed gas or propellant, and no Amino-Functionalized MIL-53” (J. Phys. Chem. C 2012, pump is required. In either embodiment, the pressure from 116,9507-9516). In general, the reversibly CO absorbing the second elastomeric reservoir 7 compresses the first amine-modified carbon, Zeolite, silica or silica gel adsorbs elastomeric reservoir containing the drug. 3, forcing the drug CO when the silica also contains bound water. The mate out of the reservoir through a flow restrictor 58 at a constant rials may also include high Surface area carbon or activated rate. FIG. 11B illustrates the system when the drug reservoir carbon as described for example in "Fixed bed adsorption of 3 is half-full. FIG. 11C illustrates the system when the drug CO2/H2 mixtures on activated carbon: experiments and reservoir 3 is close to empty. modeling by N. Casas, J. Schell, R. Pini, M. Mazzotti 0338. In one embodiment, a gas (e.g., carbon dioxide, Adsorption (2012) 18:143-161 and “Pure and binary adsorp nitrogen) is contained in a miniature gas cartridge or cylin tion of CO, H, and N on activated carbon by J Schell, N der. The gas cartridges have an external Volume of less than Casas, R Pini, M Mazzotti in Adsorption (2012) 18:49-65. or equal to 5 mL, 2 mL, or 1 mL and have stored pressures of 100-500 psi, 500-1,000 psi, 1,000-4,000 psi, or greater 0339. The materials may provide an about constant CO than 4,000 psi. Exemplary gas cartridges are product num pressure of greater than 1 bar, for example between 1.2 and bers 40106 (1.00" CO, Filled: 0.75 grams) and 2.0 bar, or between 2.0 and 5.0 bar, or between 5 bar and 20 40106IIN21750 Nitrogen cylinder (1.00" N, Filled; 0.135 bar. grams) manufactured by Leland Gas Technologies (2614 0340. In yet another related embodiment the gas cartridge South Clinton Ave, South Plainfield, N.J. 07080) and prod may contain a solid metal hydride, providing at about 3° C. uct number SM-2 (%2" Single Acting, Spring Return, Sub an about constant hydrogen pressure. The metal hydride may US 2017/0172961 A1 Jun. 22, 2017

include an alloy, for example of a rare earth like lanthanum, 0344. In a preferred embodiment, the propellant and a and a transition metal like nickel, and may also include Solid or fluid drug are contained within a rigid metal housing magnesium. (e.g., titanium or titanium alloy) that does not significantly deform under the pressure of the propellant. The housing 0341. In some embodiments, the pressurized gas material includes a liquid impermeable drug reservoir. The propellant remains in the gaseous state through the temperature range and the drug are separated within the housing by a flexible of 0°C.-37°C. A disadvantage of such embodiments is that and/or deformable diaphragm, which transmits the pressure the drug infusion rate tends to decline as the drug is from the propellant compartment to the drug compartment. dispensed because the gas pressure declines as the gas The flexible and/or deformable diaphragm may include a expands. For this reason, it is preferred to utilize sufficiently Substantially pinhole free metal sheet, Such as a tin-contain high gas pressures in the pump such that the difference ing sheet or silver-containing sheet, typically of a thickness between the starting and ending gas pressure is less than between 10 um and 250 um, e.g., between 20 Lum and 125 30%. 20%, or 10% of the starting gas pressure. um, Such as between 25um and 75um. To obtain a hermetic 0342. To minimize the change in flow rate when the seal of the propellant compartment, the metal diaphragm patient drinks a hot beverage, it is preferred to minimize the may be welded to the metal housing, e.g. by resistance volume of the gas relative to the volume of the drug welding (i.e., by application of an electrical current pulse or including fluid. The volume of the gas can be less than 40%, pulse sequence). 30%. 20% or 10% of the volume of the drug-including fluid 0345. In one embodiment, the gas can be contained in a in a fresh reservoir. For example, the force in a fresh gas-impermeable, non-flexible material. Such as metallized reservoir may increase by less than 30%. 20% or 10% when Mylar R, which is folded such that the expansion of the gas the temperature is raised from 37 to 55° C. unfolds the gas compartment and allows the pressurization 0343. In a preferred embodiment, the drug delivery of the solid or fluid drug to occur. Optionally, the unfolding device includes a volatile propellant in one compartment and compartment can be coil or bellows-like. the drug in a second compartment, the propellant boiling at 0346. In another embodiment of a gas-driven pump, a sea level atmospheric pressure at a temperature less than propellant can be used to deliver a Suspension containing a about 37° C. The propellant is under greater than 1 bar drug. In FIGS. 14A and 14B, the propellant, contained pressure, such that part or most of it is liquid at 37° C. and within propellant chamber 63 pushes the piston 64 which in its Volume is Small. Optionally, the partly or mostly liquid turn applies a constant pressure to a column of the drug propellant in the device has at about 37° C. a saturated vapor suspension. The flow rate of the drug suspension 66 can be pressure greater than about 1 bar and less than about 50 bar, affected by the friction at the interface of the suspension and for example greater than about 1.5 bar and less than about the inner drug reservoir wall as well as by the check valve 25 bar, such as greater than about 1.5 bar and less than about 65 located at the outlet port. The resistance to flow can thus 20 bar, Such as greater than about 2 bar and less than about change as the drug reservoir 3 is emptied. To alleviate or 15 bar, such as between 2 bar and 10 bar, such as between eliminate this change, the resistance of the plunger move 3 bar and 10 bar. In this embodiment, a propellant-driven ment, i.e. the friction, can be made Sufficiently greater than drug delivery device can include an oral liquid impermeable the resistance of the Suspension to maintain the flow rate drug reservoir with a pressure-liquefied propellant, i.e., a within the desired tolerance. In a related embodiment, a vent propellant-containing compartment within the drug delivery within the housing of a propellant driven piston allows the device. Such that the pressurized, Volatile, propellant liquid piston to be exposed to ambient pressure, thereby eliminat and the fluid including the infused drug reside in the ing the effect of changes in ambient pressure on the flow rate different compartments. Optionally, the wall material of the of the drug. This embodiment is illustrated in FIGS. 14C and propellant-containing compartment can be expandable or 14D. FIG. 14C shows the drug reservoir 3 in its full state. plastically easily deformable, such as elastomeric or non The piston 64 is positioned against the drug reservoir 3 on elastomeric, allowing for expansion of the propellant-con one end and within the propellant chamber 67 on its opposite taining compartment as the drug-containing fluid is end. The piston 64 forms a seal with the propellant chamber depleted. Typically, Some of the propellant is a gas at 1 bar 67 such that the propellant is allowed to pressurize and pressure at 37°C. It can maintain an about constant pressure maintains its pressure within the volume created by the when the drug-including formulation is infused in the propellant chamber 67 and the piston 64. As the propellant mouth. In an embodiment shown in FIGS. 13A and 13B, the is exposed to body temperature, the propellant pressurizes gas compartment is encapsulated by an expandable mem pushing the piston 64 against the drug reservoir 3. A vent 15 brane 61 and resides within the oral liquid impermeable drug maintains ambient pressure around the drug reservoir 3. reservoir 3. The propellant exerts an about constant pressure FIG. 14D shows the device after some time has elapsed and on the expandable membrane 61 as the expandable mem the collapsible drug reservoir 3 has emptied some of its brane 61 expands and pushes the solid or fluid drug from the contents. A filling septum 68 is located on the opposite end oral liquid impermeable drug reservoir 3 through a narrow of the piston 64 allowing filling of the propellant chamber bore tubing 8. Optionally, a narrow bore tubing may serve as 67. a flow restrictor to control the delivery rate, or there may be 0347 In a further embodiment, the drug delivery device a separate flow restrictor. FIG. 13A shows the compressed includes a propellant and a drug together in the same expandable compartment 61 containing propellant within compartment. The Saturated vapor pressure of the propellant the full drug reservoir 3. FIG. 13B shows the nearly empty at 37°C. can be between about 1 bar and 50 bar, (e.g., 1.5-20 drug reservoir 3 and the expanded expandable compartment bar, 2-10 bar, or 1.5 and 6 bar). Part of the propellant can be 61 containing propellant. The advantage of this embodiment gas and part liquid at 37° C. at the pressure within the is that the drug delivery rate does not decline as the drug is compartment. In this embodiment, a propellant-driven drug dispensed. delivery device can include an oral liquid impermeable drug US 2017/0172961 A1 Jun. 22, 2017 36 reservoir with a pressure-liquefied propellant, i.e., volatile can be about constant at the constant about 37° C. tempera liquid propellant in the reservoir, such that both the pres ture in the mouth, making the flow rate about constant. Surized, Volatile, propellant liquid and the Suspension 0353 Examples of continuously subcutaneously drug including the infused drug reside in the same compartment. infusing compressed air or FreonTM pressurized pumps The propellant may not be substantially dissolved in the include those described in U.S. Pat. Nos. 4,265,241, 4,373, drug-containing composition, but could be dispersed in it to 527, 4,781,688, 4,931,050, 4,978,338, 5,061,242, 5,067,943, form an about homogeneous mixture. The propellant can 5,176,641, 6,740,059, and 7,250,037, each of which is maintain an about constant pressure when the drug including incorporated herein by reference. When the reservoir is formulation is infused in the mouth. refillable and when the pumping is by pressurization, the 0348 Because separation or segregation of the liquid reservoir can be pressurized upon its refilling. propellant and the drug formulation could lead to oral delivery of propellant-enriched or propellant-poor fluid and 0354 An example of a propellant-driven, implanted hence to lesser or greater than intended drug dosing, the medication infusion pump is the Codman pump described in liquid propellant can be dissolved or co-dispersed in the U.S. Pat. No. 7,905,878, European Patent Nos. EP2177792 Suspension. The propellant liquid can be homogeneously B1 and EP 1527794 B1, each of which is incorporated herein dispersed in any of the phases, for example in a non-aqueous by reference. phase, which may optionally be part of an emulsion, formed 0355 To provide different patients with different dose optionally by adding an emulsifier, Such as a lecithin, or by rates, fluids with different drug concentrations can be placed Pickering emulsification, where small solid drug or other in the reservoirs, thereby not necessitating modifications to particles stabilize the emulsion. In general, the emulsions the drug delivery device or to the flow rate. Alternatively, the can be stable for at least 24 hours and can be re-formed by drug concentration in the reservoir can be held constant and agitation, for example by shaking. The optional emulsions the flow rate can be changed, for example by changing the can be foamable or non-foamable and can include an emul diameter or length of the flow restrictor. sifier Such as lecithin, a protein, or a Surfactant that can be 0356. Exemplary volatile propellant compounds for use non-ionic, including for example a glyceryl monoester, like in the devices of the invention include hydrocarbons (e.g., glyceryl monooleate, a Tween or a Polysorbate. Examples of pentane; isopentane: 1-pentene; trans-2-pentene; trans-dim emulsifiers in propellant including mixtures are listed for ethylcyclopropane; ethylcyclopropane; 1,4-pentadiene; example in U.S. Pat. No. 6.511,655 and in U.S. Patent 2-methyl-1,3-butadiene; and methyl-1-butane: 2-butyne); Publication No. 2003/0049214, each of which is incorpo halocarbons (e.g., trichlorofluoromethane; difluoromethane; rated by reference. 1,1-dichloro-1-fluoroethane; 2,2-dichloro-1,1,1-trifluo 0349. Alternatively the liquid propellant can be dissolved roethane: 1-fluorobutane: 2-fluorobutane; perfluoropentane: in the carrier liquid of a solid drug including formulation, 1,1-dichloroethylene; cis-1-chloropropene; and 2-chloro e.g. when the carrier liquid is non-aqueous, for example propene); esters (e.g., methyl formate); ethers (e.g., diethyl when it is edible oil or medicinal paraffin oil. The propellant ether), and hydrofluoroalkanes. Preferred propellants are dissolving carrier liquid may optionally be a temperature those approved by the FDA for use in medication inhalers, sensitive liquid Such as cocoa butter. such as 1,1,1,2 tetrafluoroethane (sold as DuPontTM Dymel(R) 0350. As the drug is dispensed and the internal pressure (r) 134a/P); and 1,1,1,2,3,3,3 heptafluoropropane, sold as falls in the gas compartment, Volatile liquid propellant 227ea/P (sold as DuPontTM Dymel(R) 227ea/P). Also pre evaporates, thereby maintaining an about constant pressure ferred are propellants approved by the FDA for topical within the oral liquid impermeable reservoir. The advantage applications, such as 1.1.1.3.3.3 hexafluoropropane (sold as of such an embodiment is that the drug infusion rate does not DuPontTM Dymel(R) 236fa); and propellants approved for use decline as the drug is dispensed. in food and over the counter anticarie drug products. Such as 0351. In a related embodiment, a gas-driven drug deliv octafluorocyclobutane and isopentane, respectively. ery device includes an oral liquid impermeable drug reser 0357 Exemplary pressurized liquid propellants and their voir having one or more compartments, with a non-toxic vapor pressures at 37° C. are listed in Table 1. propellant gas (formed from the optionally substantially immiscible pressurized liquid when the pressure is reduced TABLE 1. to about 1 bar) and the drug to be infused both present in at least one compartment. The propellant gas provides the Approximate driving force. The pressure-liquefied gas can optionally be Pressure, bars at insoluble in the fluid containing the drug, such that the Propellant 37o C. pressure in the reservoir remains about constant at the about diethyl ether 1.1 1-fluorobutane 1.3 constant body temperature near 37° C. in the mouth. isopentane 1.4 0352 Alternatively, a pressurizing gas can be dissolved 2-fluorobutane 1.6 in the drug-including fluid. For example, when the fluid 1,2-difluoroethane 1.9 neopentane 2.4 infused in the mouth is aqueous, or when it includes ethanol, methyl ethyl ether 3 and the reservoir is pressurized, the pressurizing gas can be 2-butene 3.2 CO. When the fluid infused in the mouth includes an edible butane 3.5 oil such as a vegetable oil, a monoglyceride, a diglyceride or 1-fluoropropane 4.1 a triglyceride, or paraffin oil, and the reservoir is pressurized, 1-butene 4.2 2-fluoropropane 5 the pressurizing gas can be a flurorohydrocarbon, a FreonTM, 1,1-difluoroethane 8.4 or a saturated hydrocarbon or a non-Saturated hydrocarbon propane 12.8 Such as an olefin. When the pressurizing gas dissolves in the propene 15.5 fluid in the oral liquid impermeable reservoir the pressure US 2017/0172961 A1 Jun. 22, 2017 37

TABLE 1-continued continuous intraoral drug administration is configured to be removably inserted in a patient's mouth. The pump can be Approximate propellant-driven. The drug delivery device includes a Pressure, bars at chamber containing a propellant, a chamber containing a Propellant 37o C. drug-including fluid Such as a paste, and a flexible and/or 1,1,1,2-tetrafluoroethane 9.3 deformable diaphragm separating the propellant chamber 1,1,1,2,3,3,3-hepta-fluoropropane 6.4 from the drug chamber. The housing of the device can be 1,1,1,3,3,3 hexafluoropropane 4.0 rigid and can be gas and liquid impermeable, for example octafluorocyclobutane 4.3 impermeable to gaseous and liquid propellant, gaseous nitrogen, gaseous or dissolved oxygen, gaseous or dissolved 0358. When the pressurized gas and the drug are located air, water vapor, liquid water, saliva and/or gaseous helium; in the same compartment, the gas can be selected to be safe, the drug reservoir can be an oral liquid impermeable reser non-toxic, and non-irritating when delivered into the mouth voir. In a preferred embodiment, the rigid housing forms a and inhaled into the lungs at the delivery rates of the wall of a chamber containing the drug-including fluid and a invention. Furthermore, the gas can be selected so as not to wall of a chamber containing the propellant, and the two adversely affect the stability of the drug and formulation in chambers are separated by a diaphragm. The separating the reservoir. Chemically inert gases, meaning gases that do diaphragm includes a metal, i.e., the diaphragm can be not react at body temperature with any of the components of metallic or a metallized polymer. The device dispenses at the orally infused composition, are therefore preferred. least 50% (e.g., 50%-99%, 60%-95%, 75%-95%, 51%-60%, Preferably, the propellant used in the drug delivery device of 61%-70%, 71%-80%, 81%-90%, 91%-95%, or 95%-99%) the invention is n-butane, isopentane, 1-butene, 1-fluoropro of the weight of the drug-including fluid (e.g., paste) in the pane, trifluorochloromethane, difluoromethane, dichloro chamber, preferably while the rate of drug delivery, meaning fluoromethane, 1,1,1,2,3,3,3-heptafluoropropane, 1.1.1.3.3. the flow rate or extrusion rate, varies by less than +20% 3-hexafluoropropane, or 1,1,1,2-tetrafluoroethane. (e.g., less than +15%, less than +10%, or less than +5%) over 0359 A source of inaccuracy in propellant pressurized a period of greater than or equal to 4, 8, 16, or 24 hours. devices is that the pressure. Such as the vapor pressure of a 0365. The rigid wall of the drug and the propellant liquid propellant, increases with temperature. An important including chambers (which can include part of the housing) benefit of carrying within the mouth the drug delivery can be strong, dense and it can be metallic. In a preferred devices of the invention is that the pressure is held nearly embodiment, the rigid housing forms a wall of the drug constant at about 37° C., thereby minimizing variations in containing chamber and/or a wall of the propellant-contain the infusion rate. ing chamber. The rigid housing of the chamber wall can be 0360. In another embodiment, gas is generated by the strong and includes a metal, ceramic, or a composite of a gas-driven drug delivery device. For example, a low current polymer reinforced by fibers. The fibers reinforcing the electrolyzer may be used to generate hydrogen gas. Exem polymer can include, for example, carbon fibers, glass fibers, plary hydrogen gas generating Systems are the hydrogen gas or metal fibers. The housing can include a material having at generating cells sold by VARTAMicrobattery GmbH Daim about 25+3° C. a tensile yield strength greater than 100 MPa, lerstr. 1, D-73479 Ellwangen/Jagst Germany. The VARTA such as greater than 200 MPa, 300 MPa, 400 MPa, or 500 systems are capable of generating 130 ml, 260 ml or more MPa, and/or the housing can include a material having at ultrapure H at high back pressure. An advantage of such a 25+3° C. a modulus of elasticity (Young's modulus) greater system is that gas need not be stored in the drug delivery than 30 GPa such as greater than 50 GPa, 75 GPa, or 100 device prior to its use. GPa; and/or the housing can include a material having at 0361. An advantage of gas-driven infusion pumps for use 25+3° C. a Brinell hardness greater than 200 MPa, such as in the mouth is that it is possible to temporarily stop, or greater than 400 MPa or 600 MPa.; and/or the housing can greatly reduce, the drug delivery from the device if the include a material having at 25+3° C. a density greater than patient wishes to temporarily remove the drug delivery 2.5 g/cm, such as greater than 3.5 g/cm, such as about device from the mouth. This can be accomplished, for equal to or greater than 4.5 g/cm, 5.5 g/cm, 6.5 g/cm, or example, by blocking or closing the flow restrictor, e.g., the 7.5 g/cm. When metallic, the metal of the housing can be orifice, the glass capillary or the narrow bore tubing or by selected from the group titanium, iron, aluminum, molyb cooling to a temperature below that in the mouth, for denum, or tungsten, or an alloy of titanium, iron, aluminum, example to the typically 20° C.-25°C. room temperature or molybdenum, or tungsten; it can include, for example, by placing the device in a refrigerator typically at 3° C.-8 titanium or an alloy of titanium. C 0366 The diaphragm separating the chamber containing 0362 Propellant-Driven Pumps the drug-including fluid from the chamber containing the 0363 The following sections provide additional details propellant can be a flexible and/or deformable metal foil or on designs and manufacturing processes of propellant it includes a flexible and/or deformable metal foil. In a driven pumps for the delivery of pharmaceutical composi preferred embodiment, the diaphragm separating the cham tions including LD/CD pastes. It will be recognized that ber containing the drug-including fluid from the chamber similar designs and manufacturing processes may be used containing the propellant can be metallic or includes a metal. with other pumps and drug formulations of the invention. It can be a flexible and/or deformable, pinhole-free metal 0364 The devices of the invention can be propellant foil. The density of the diaphragm metal can be greater than pumped, rigid walled, intraoral, continuously drug deliver 2.0 g per cm at 25°C. It can be for example greater than 2.5 ing devices having a drug compartment and a propellant g per cm. Such as greater than 4.0 g per cm, 7.0 g per cm, compartment separated by an optionally metallic diaphragm. or 10.0 g per cm at 25°C. Optionally, the tensile strength In one embodiment, the device for continuous or semi of the diaphragm material can be greater than 25 MPa, for US 2017/0172961 A1 Jun. 22, 2017

example it can be greater than 50 MPa, 75 MPa, or 100 MPa pharmaceutical composition (e.g., a LD/CD Suspension) at 25+3° C. and/or its elastic modulus can be greater than with an elastomeric grommet 94 inserted into the port. A about 20 GPa, such as greater than 30 GPa, 40 GPa, or 50 filling nozzle 95 may be inserted through the grommet to fill GPa. The metallic diaphragm can include, for example, the drug-containing chamber 89 with the pharmaceutical silver or an alloy of silver; alternatively, it can include tin or composition. The filling nozzle 95 may then be removed and an alloy of tin; or it can include aluminum or an alloy of replaced with the delivery nozzle 96. aluminum; or it can include magnesium or an alloy of magnesium; or it can include titanium or an alloy of tita 0370 Preferably, the housing wall of the propellant nium; or it can include copper or an alloy of copper. The chamber includes a second, Sealable port (e.g., containing a diaphragm can be a pinhole-free flexible and/or deformable grommet, septum, or similar resealable member) for filling foil of silver, tin, aluminum, magnesium or copper. When the propellant chamber with propellant. A propellant deliv heated, the metallic diaphragm can optionally alloy the ery nozzle can be inserted into the septum and the propellant metal of the housing, Such that the diaphragm is welded at chamber is filled. Preferably, the drug chamber is filled first its rim to the housing wall to form a hermetic, gas-imper and the propellant chamber is subsequently filled. meable seal (e.g. impermeable to propellant and/or helium). 0371 Patient compliance depends on the drug delivery The diaphragm can be shaped to Substantially conform to the device and retainer being comfortable when worn in the interior housing wall of the drug chamber, to the interior mouth. Preferably, the system does not substantially affect housing wall of the propellant chamber, or to the interior the appearance of the wearer, impede speech, or impede housing walls of both chambers. As illustrated in FIGS. Swallowing and drinking. For comfort and in order to avoid 23A-C, in a preferred embodiment the propellant-driven Substantial change in the appearance of the face of the pump includes a drug chamber 89 and a propellant chamber wearer the oral pump may have a substantially obround 93 separated by a diaphragm 90. The diaphragm 90 is shape. An exemplary location of the pump in the mouth is attached to the two housings by a weld 91. The pump further a maxillary location. In general it is preferred that the pump includes a sealable port 92 for introduction of the propellant, and/or its drug outlet be located such that the likelihood of e.g., via needle or nozzle injection. FIG. 23 A shows the excessive drug accumulation in the buccal vestibule is initial configuration of the pump where the drug and pro avoided. In order to avoid irritation of tissue the surfaces of pellant chambers are full. FIG. 23 B shows the pump the pump is Smooth. For examples, pump Surfaces contact partially full and FIG. 23 C shows the pump upon comple ing buccal tissue may have protrusions that are less than tion of the delivery of the drug. about 100 um, e.g., less than about 30 um, 10um, 5um, or 0367 The housing can be made of two or more parts 1 Jum. joined together. The parts may be joined together by welding 0372. The pump may contain between about 0.1 mL and (optionally with a diaphragm) or by forming a compression about 2 mL of the drug-including fluid, Such as between seal (meaning a seal formed by pressing the parts together), about 0.2 mL and about 1.2 mL, for example between about the parts optionally separated by Sealant exemplified by a 0.6 mL and about 1 mL. An exemplary pump with a 0.8 mL polymer or a soft metal like tin. The interior housing wall of drug reservoir contains about 1 g of an about 1.25 g/mL the propellant chamber and interior housing wall of drug density composition. In some compositions, there can be chamber can be substantially mirror images of each other, 800 mg/mL of the mostly solid containing composition, the meaning that they can be substantially symmetrical with solid being mostly the solid drug itself or mostly solid respect to a central plane, excepting that their ports differ and excipient. When the solid is a drug of about 1.5 g/mL density an interior housing wall of the drug chamber may have grooves or similar flow-enhancing features while the mir such as LD or CD, the reservoir can contain about 0.64 g of roring interior housing wall of the propellant chamber may mostly solid drug. not have grooves or similar flow-enhancing features. 0373 The pump can be, for example, substantially 0368. In a preferred embodiment the housing wall of the obround shaped or it can be substantially flattened teardrop drug chamber can include a sealable port that allows for the shaped. The dimensions of the substantially obround-shaped introduction of a pharmaceutical composition. The port may pump are width, measured from the vestibular surface of the be temporarily or permanently sealed prior to or after the teeth outward, height measured in the direction of tooth filling process, e.g., by a grommet, septum, drug delivery eruption, and length measured along the direction of a series nozzle, flow restrictor, or delivery tube. The port may of teeth, typically including a molar. The width (outer optionally also be used for delivery of the drug during dimension, OD) of the pump housing can be between about operation of the device, e.g., by attaching a drug delivery 3 mm and about 10 mm; its height (OD) can be between nozzle, flow restrictor, or delivery tube. Optionally, the about 5 mm and about 18 mm; its length (OD) can be flow-controlling nozzles, channels or tubes can be made of between about 10 mm and about 30 mm. Preferably, the a plastic, Such as an engineering plastic. The nozzles, length of the pump housing can be such that the pump channels or tubes can have an internal diameter less than 1 housing spans one or two teeth, but not three teeth. The mm, 0.6 mm, 0.3 mm or 0.1 mm and they can be shorter than thickness of the wall of the housing can be between about 10 cm, 5 cm, 2 cm or 1 cm such as 0.5 cm. Preferred 0.2 mm and about 2 mm, such as between about 0.3 mm and minimum internal diameters are 0.1-2 mm (0.1-0.7 mm, about 1.0 mm. 0.2-0.5 mm, 0.5-0.75 mm, 0.75-1.0 mm, 1.0-1.5 mm, or 0374. The width of the substantially flattened teardrop 1.5-2.0 mm) and preferred lengths are 0.25-5 cm (such as shaped pump, its length and the thickness of the housing of 1-2.5 cm, 1-5 cm, 0.25-0.5 cm, 0.5-0.75 cm, 0.75-1 cm, 1-2 the wall can be similar to those of the obround pump. The cm, 2-3 cm, 3-4 cm, or 4-5 cm). height of its anterior side when residing in the buccal 0369 FIG. 24 and FIG. 25 show a port 102 in a pump vestibule can be less than the height of its posterior side. The housing 101 forming a wall of a chamber 89 containing a posterior side can be, for examples, between 1.1 times and US 2017/0172961 A1 Jun. 22, 2017 39 twice as high as the anterior side, such as between 1.3 times cally sealable or sealed ports for filling with drug and/or for and 1.8 times as high, e.g., between 1.4 and 1.6 times as drug delivery. The ports are hermetically sealable or sealed high. after filling. 0375. In one embodiment the metallic diaphragm is about 0378. The housing wall of the drug including chamber uniformly thick and it is free of pinholes. The thickness of can include one or more sealable or sealed ports for drug the pinhole-free metallic diaphragm can be between about delivery. The propellant containing chamber can be hermeti 10 um and about 1 mm. The diaphragm can be, for example, cally sealed and can include a hermetically sealable or between about 10 um and 250 um, e.g., between 20 um and sealed port for filling with propellant. 125um, such as between 25 um and 75 lum. The thickness 0379 When stored, the pump can be hermetically sealed. and the associated rigidity of the diaphragm, meaning its When in use, the drug can flow or be extruded through the resistance to change of shape under stress, can vary by less one, two, or more drug delivery ports, to which a flow than +25% across the diaphragm, such as by less than +10%. controlling tubing or pipe can be attached or which can itself In some embodiments the rim of the diaphragm is thicker control the flow. than the about uniformly thick center in order to facilitate 0380. As shown in FIGS. 23 A-C, for hermetic enclosure sealing, e.g., creation of a hermetic Seal via welding. The the drug chamber 89, propellant chamber 93, and diaphragm about uniformly thick center can constitute about 80% or 90 are joined by a hermetically sealing weld 91, the her more of the area of the diaphragm, the thicker rim consti metically sealing weld 91 preventing, for example, the influx tuting typically less than about 20% of the area of the of air or water vapor, or the out-flux of optionally inert gas diaphragm. The rim of the diaphragm can be more than 1.5 (e.g., nitrogen or argon), or of water vapor, or of saliva, or times as thick as its center, e.g., 1.5-2 times as thick as the the out-flux of any constituent of the drug including com center, or 2-3 times as thick, or more than 3 times thicker position from the drug chamber, or the out-flux of propellant than the center. In another embodiment, the diaphragm has from the propellant chamber during the rated shelf-life of the a non-uniform thickness along its length and/or width. This device, which can be longer than 3 months, such as longer variable thickness allows the diaphragm to counteract inter than 6, 12, 18, or 24 months. Optionally, the weld can nal forces and deflect in a predictable manner. prevent the influx of helium into and/or out-flux of helium from the drug-including chamber, and/or from the propel 0376. The peripheral rim of the diaphragm is shaped and lant-including chamber, or from both chambers. The her sized to match the peripheral rim of the central cross metically sealing weld can be a weld between a metallic sectional plane of the typically obround or flattened teardrop housing and a metallic diaphragm, where the metals of the shaped housing. The diaphragm can be made, for example, housing and the diaphragm are the same or they can differ. by forcing a sheet of metal. Such as annealed about pure The weld can be, for example between a metal forming a silver foil or tin foil of a thickness between 0.02 mm and wall of the housing, meaning the wall of a drug-including 0.10 mm into a mold. Alternatively, the diaphragm can be and/or a propellant-including chamber, and a different metal made by Stamping a formable metal foil or sheet, typically of the diaphragm, typically melting at a lower temperature of a thickness between 0.02 mm and 0.10 mm. Parameters than the metal of the housing. For example, the housing can that can affect formability include the strain, or work include titanium or an alloy of titanium to which a metallic hardening, exponent of the metal (termed its n-value) and diaphragm is welded. The diaphragm welded to the titanium the strain ratio in the width and thickness directions (termed or titanium alloy housing can include, for example, silver or its r-value). Typical r-values of the silver of which the an alloy of silver. The hermetically sealing weld can include diaphragms are made are from 0.75 to 1.0 and typical an alloy of silver and titanium. Alternatively, the housing can n-values are from 0.2 to 0.4. The height of the stamped, include iron or an iron alloy, such as steel exemplified by a metallic, optionally obround, cup-shaped diaphragm stainless Steel, and the diaphragm can include silver or a (matching about the width of the housing) can be between silver alloy or tin. The hermetically sealing weld can be about 3 mm and about 10 mm; its width (matching the height between a metallic diaphragm that can be welded to iron or of the housing) can be between about 5 mm and about 18 an alloy of iron. The weld can include, for example, an alloy mm; and its length can be between about 10 mm and about including silver and iron or silver and nickel. The method of 30 mm. The optionally obround diaphragm may be folded, forming the hermetic weld can include, for example, resis pleated, or scored. It can be formed, for example, by tance welding, laser welding or electron beam welding. The hydroforming or by stamping, optionally with heating by method of welding can include additional steps like pre hot-stamping. It can be formed by stamping or deep draw heating, i.e., heating the diaphragm and the housing prior to ing, optionally with heating, or it can be formed by electro their welding, and/or annealing after welding, optionally at plating or by electroless plating. a temperature between 400° C. and 700° C. typically for 15 0377 Optionally, the flexible and/or deformable metallic min or more. diaphragm separating the drug and propellant chambers can 0381. The devices of the invention can include channels, be welded to the housing to form hermetically sealed grooves, or tubes providing constant rate delivery of most or chambers with propellant filling and drug delivery ports. The nearly all of the drug. During the delivery of the drug the pump can be hermetically sealed, meaning that its drug diaphragm may deform such that it partially or completely including chamber and its propellant including chamber are isolates a volume of the drug-including fluid within the hermetically sealed, except for the one, two or more drug drug-containing chamber from the outlet port or ports. Such delivery ports from the drug chamber. Each of the chambers isolation can result in stoppage of drug flow or reduction in can include one or more ports for filling and for release of the flow rate of the drug including fluid while the chamber gas, such as air or nitrogen or any inert gas present in the still contains a substantial fraction of the fluid. In order to chamber while it is being filled. The housing wall of the drug deliver at an about constant rate most or nearly all of the including chamber can include one, two, or more hermeti drug including fluid in the chamber, the device can include US 2017/0172961 A1 Jun. 22, 2017 40 channels that reduce or eliminate blockage by the diaphragm exhaustion. For example, the diaphragm may be shaped and when it extends into the drug-including chamber during the sized so that it contacts 0%-10%, 11%-20%, 21%-30%, delivery. Exemplary blockage reducing or preventing chan 31%-40%, or 41%-50% of the interior surface area of the nels are tubes inserted in the drug including chamber and drug chamber (excluding the Surface area of the diaphragm connected to one outlet port or several outlet ports in the itself) after delivery of 85%, 90%, or 95% of the starting chamber; or a groove-including insert in the chamber, or a drug product in the drug chamber. The interior surface of the groove or grooves in a wall of the chamber. For example, a drug chamber may include, for example, an interior wall of grooved plate or a tube can be inserted in the drug including the pump housing. In a particular embodiment, the flexible chamber to form a channel or multiple channels in which the and/or deformable diaphragm may be shaped and sized Such drug can flow. The tube, tubes, groove or grooves can form that it does not contact the drug exit orifice from the drug a channel or multiple channels that remain open and chamber after delivery of 85%, 90%, or 95% of the starting unblocked by the diaphragm after more than 50% (such as drug product in the drug chamber. more than 60%, 70%, 75%, 80%, 85%, 90%, or 95%) of the 0385 Typically, neither the metal of the rigid housing nor weight of the drug in the chamber can be delivered. Option of the diaphragm may corrode visibly after 3 months when ally, there are multiple grooves forming multiple flow chan the housing metal and the diaphragm metal are electrically nels that are optionally interconnected, the interconnections shorted and are immersed in a Substantially de-oxygenated allowing flow between the channels. FIGS. 26A and 26B 0.1 M citrate buffer solution of about pH 4 at about 23+3° show exemplary grooves in Surfaces of the drug including C. The de-oxygenated solution can be a solution kept under chamber. In one embodiment illustrated in FIG. 26A, the nitrogen. Typically, neither the metal of the rigid housing nor grooved flow channels 97 cause flow from individual loca of the diaphragm may corrode visibly after 3 months while tions within the pump to channel to the nozzle 98. In another the housing metal and the diaphragm metal are electrically embodiment illustrated in FIG. 26B, the interconnected flow shorted and are immersed in an air-exposed 0.1 M citrate channels 99 form a network of channels that feed into a buffer solution of about pH 4.0 at about 23+3° C. The single central channel 100 in the housing wall 101. density of the current flowing between two electrically 0382. The groove or grooves are typically 1 mm to 20 shorted electrodes of about equal area, one of the metal of mm long, 0.5 mm to 3 mm wide, and 0.5 mm to 3 mm deep. the rigid housing, the other of the metal of the diaphragm, The tube or tubes are typically 1 mm to 20 mm long, 0.5 mm can less than 2 LA cm such as less than 0.5 LLA cm, for to 3 mm wide, and of 0.5 mm to 3 mm diameter. The number example less than 0.1 LA cm’ when the electrodes are of optionally interconnected flow channels 99 formed by the immersed in a substantially de-oxygenated about pH4 0.1 M grooves is typically between 1 and 10. Typically at least one citrate buffer solution at 23+3° C. for 24 hours or more. groove-associated flow channel remains open after the dia 0386. In order to obtain the desired rate of delivery of the phragm has been fully extended into the drug chamber at or pharmaceutical composition without clogging the flow near the exhaustion of the drug contained in the chamber. restrictor (e.g., the nozzle) the apparent viscosity and the 0383. In a preferred embodiment, greater than 60% (e.g., particle size of the pharmaceutical composition, the vapor 75%-85%. 86%-95%, or greater than 95%) of the drug pressure, as well as the diameter and length of the flow including fluid can be dispensed while the delivery rate restrictor are simultaneously controlled. Table D provides varies by less than +20% (e.g., less than +15%, it 10%, or exemplary ranges for these simultaneously controlled t5%) over a period of greater than or equal to 4 hours (e.g., parameters for an intra-oral drug delivery device and for greater than or equal to 8, 16, or 24 hours). mulation of the invention. TABLED Exemplary parameter ranges for continuous intra-oral drug delivery devices and formulations Propellant Drug or Drug or Viscosity Flow Vapor Oral Excipient Excipient at about Flow Restrictor Pressure, Extrusion Particle Particle 37° C., Restrictor Length, bar at about Rate, Size, Doo, Size, Dso, Poise ID, mm Cl 37o C. mL/hour Im. im: Possible 100 O.OS-3.OO O.25-20 1.2-SO O.OO1-1.OOO 0.1-2OO O. 1-50 500,000 Typical 200 O.1-0.7 10-5.O 2.5-1S.O O.O3-O.S 1.0-50 OS-30 100,000 Preferred SOO O.2-OS 1.00-25 4.0-10.O O.OS-O2 3.0-30 2.OO-2O.O 75,000 *Measured by light scattering when the particles are suspended in a non-solvent, e.g. with a Malvern Ltd (UK) Mastersizer, Typically the viscous compositions contain drug particles and or excipient particles and can be pastes; they can, however, also be gels or true solutions, e.g., thickened (made viscous by a dissolved macromolecule) particularly when the drug concentration is low and or the drug is highly soluble (its concentration being, e.g., between 0.001 mg/mL and 500 mg/mL),

0384. In a related embodiment, the flexible and/or 0387. The oral device can continuously or semi-continu deformable diaphragm may be shaped and sized such that it ously extrude or infuse a viscous drug-containing composi contacts only a limited portion (or even none) of the interior tion into the mouth; it can also include a mechanical pump wall Surface of the drug chamber (excluding the Surface area comprising, for example, a spring, pressurized gas, or pro of the diaphragm itself) as the drug chamber approaches pellant. The device can include a flow restrictor such as a US 2017/0172961 A1 Jun. 22, 2017

noZZle, a channel, a tube or any other flow or extrusion taining solution, or a viscous drug-containing Suspension, at restricting component. The extrusion or flow rate through an extrusion rate or flow rate between 0.001 mL/hour and the nozzle can depend on its internal diameter, on its length, 1.25 mL/hour, the paste, Solution or Suspension can have a and on the vapor pressure of the liquid propellant. viscosity greater than 100 poise and less than 500,000 poise; 0388. The oral device can include a viscous drug-con the extrusion rate or the flow rate can be controlled mostly taining paste, or a viscous orally infused drug-containing by a flow restrictor (e.g., nozzle) having an internal diameter Solution, or a viscous orally-infused drug containing Sus between 0.05 mm and 3.00 mm and a length between 0.25 pension extruded or infused into the mouth at a rate that can cm and 20 cm; the extrusion or infusion can be driven by a be between 0.001 mL/hour and 1.25 mL/hour (e.g., 0.015 mechanical pump. The mechanical pump can include a 1.25 mL/hour). The viscosity of the paste, the solution or the propellant, the propellant can have a vapor pressure at about Suspension can be greater than 100 poise and less than 37° C. greater than 1.2 bar and less than 50 bar. The paste 500,000 poise at about 37° C.; its extrusion rate or flow or the Suspension or the Solution can include Solid drug restrictor (e.g., nozzle) can have an internal diameter and/or excipient particles whose particle size distribution between 0.05 mm and 3.00 mm and a length between 0.25 (when dispersed in a non-solvent and when measured by cm and 20 cm (e.g., 0.5-4 cm); the device can include a light scattering) can have a Doo between 0.1 um and 200 um propellant having a vapor pressure at about 37° C. greater and a Ds between 0.1 Lum and 50 m. than 1.2 bar and less than 50 bar (e.g., 1.5-10 bar). When a 0391. In a typical method of oral extrusion or infusion the paste including drug particles and/or excipient particles is extrusion or flow rate can be greater than 0.03 mL/hour and extruded into the mouth, the particle size distribution, mea less than 0.5 mL/hour and the typical paste, Suspension or sured by light scattering (e.g. with a Malvern Mastersizer Solution can have a viscosity greater than 200 poise and less after dispersing the paste in a liquid non-solvent) can have than 100,000 poise; the typical flow restrictor (e.g., nozzle) a Doo between 0.1 um and 200 um and a Dso between 0.1 um can have an internal diameter can be between 0.1 mm and and 50 lum. 0.7 mm and the typical nozzle length can be between 1 cm 0389. A typical device can include a viscous drug-con and 5 cm; a typical propellant can have a vapor pressure at taining paste, or a viscous orally infused drug-containing about 37° C. greater than 2.5 bar and less than 15 bar. The Solution, or a viscous orally-infused drug-containing Sus typical paste or the Suspension or the solution can include pension, extruded or infused into the mouth at a rate that can Solid drug and/or excipient particles whose particle size be between 0.03 mL/hour and 0.5 mL/hour. The typical distribution (when dispersed in a non-solvent and when viscosity of the paste, solution or suspension can be greater measured by light scattering) can have a Do between 1 Jum than 200 poise and less than 100,000 poise at about 37°C.; and 50 Lum and a Dso between 0.5 um and 30 Lum. its extrusion rate or flow rate can be controlled mostly by a 0392. In a preferred method of oral extrusion or infusion flow restrictor (e.g., nozzle) which can have an internal the flow rate can be greater than 0.05 mL/hour and less than diameter between 0.1 mm and 0.7 mm and can be between 0.2 mL/hour; the preferred paste, Suspension or solution can 1 cm and 5 cm long; the typical device can also include a have a viscosity greater than 500 poise and less than 75,000 mechanical pump. The mechanical pump can include a poise; a preferred flow restrictor (e.g., nozzle) can have an propellant having a vapor pressure at about 37° C. that can internal diameter between 0.2 mm and 0.5 mm and a length be greater than 2.5 bar and can be less than 15 bar. When a between 1 cm and 2.5 cm; and a preferred propellant can paste including drug particles and/or excipient particles is have a vapor pressure at about 37° C. greater than 4bar and extruded into the mouth, the particle size distribution mea less than 10 bar. The preferred paste or suspension can Sured by light scattering (e.g., with a Malvern Mastersizer include solid drug and/or excipient particles whose particle after dispersing the paste in a liquid non-solvent) can have size distribution (when dispersed in a non-solvent and when a Doo between 1 um and 50 Lum and a Dso between 0.5 um and 30 um. In a preferred embodiment the device can measured by light scattering) can have a Do between 3 Jum include a viscous drug-containing paste, or a viscous orally and 30 Lum and a Dso between 2 Lum and 20 Lum. infused drug-containing Solution, or a viscous orally-infused 0393 Ambient-Pressure and Suction Independent Pump drug containing Suspension, extruded or infused into the Designs mouth at a rate 0.05 mL/hour and 0.2 mL/hour. The paste, 0394 The invention includes intra-oral drug delivery or the Solution, or the Suspension can have a viscosity devices whose rates of drug delivery are substantially inde greater than 500 poise and less than 75,000 poise; its pendent of increases or decreases in ambient pressure in the extrusion rate or flow rate can be controlled mostly by a flow mouth and/or in the atmosphere, e.g., devices that do not restrictor (e.g., nozzle), which can have an internal diameter deliver clinically significant, undesired boluses as the ambi between 0.2 mm and 0.5 mm and a length between 1 cm and ent pressure changes. A source of inaccuracy in many device 2.5 cm; the device can also include a propellant having a designs, including many pumps pressurized by a spring, a vapor pressure at about 37° C. that can be greater than 4bar propellant or by compressed gas can be that the rate of drug and can be less than 10 bar. When a paste including drug delivery can vary as (a) the ambient air pressure changes, particles and/or excipient particles is extruded into the e.g., at sea level (14.7 psia or 1 bar) versus at 7,000 feet mouth, the particle size distribution measured by dispersing elevation or in an airplane (both about 11.3 psia or 0.78 bar), the particles in a liquid non-solvent by light scattering (e.g., and (b) the patient sucks on the drug delivery device. The with a Malvern Mastersizer after dispersing the paste in a invention includes pressure-invariant pumps whose drug liquid non-solvent) can have a Doo between 3 um and 30 Jum delivery rate can be substantially insensitive to changes in and a Dso between 2 Lum and 20 Jum. atmospheric pressure. The invention also includes Suction 0390 Also disclosed is the method of continuously or induced flow limiters that substantially reduce or eliminate semi-continuously orally extruding or infusing a viscous the delivery of a drug bolus when a patient Sucks on the drug drug-containing paste, or for infusing a viscous drug-con delivery device. US 2017/0172961 A1 Jun. 22, 2017 42

0395. In some embodiments, the spring or propellant and halting flow through the nozzle 78. Another example of compartment is hermetically sealed so that the components a means of addressing the issue of bolus delivery of the drug are not exposed to saliva, food, liquids, and potentially due to low pressure in the mouth is the use of an inline deleterious conditions (e.g., acids, bases, alcohols, oils, and vacuum-relief valve, such as a float valve that closes the Solvents in the mouth). In preferred embodiments, drug fluidic channel when a vacuum is created and releases the delivery devices of the invention include spring or propel fluidic channel once the vacuum is released. lant-pressurized Surfaces in the spring or propellant com 0398. In another embodiment, the drug delivery device partments that are in fluidic (gas and/or liquid) contact with includes a compliant accumulator reservoir downstream of the ambient atmosphere via one or more ports or openings the drug reservoir. This accumulator includes a compliant in the housing of the drug delivery device. Preferred designs material that collapses and plugs the outlet port from the for ambient pressure independent spring-driven and propel drug reservoir when the ambient pressure decreases below a lant-driven pumps are those in which both the drug outlet specified level. FIGS. 16A and 16B illustrates the mecha and the spring or propellant-pressurized surface (e.g., a nism of operation of the accumulator. FIG. 16A shows the pressure plate or plunger) are exposed to the ambient concept during normal operation. Drug from the drug res pressure, i.e., the pressurized surface is not enclosed within ervoir 3 is pushed through an orifice 75 and into the a hermetically sealed chamber. With Such a design, changes accumulator 79 prior to entering the nozzle tube 8 and then in ambient pressure are the same at the drug outlet and at the exiting the nozzle via one-way valve 16. In FIG. 16B, an pressurized surface, resulting in no change to the rate of drug external vacuum is applied to the environment that the delivery. device occupies. This causes the accumulator 79 to collapse, 0396. In another embodiment, the system can be blocking the orifice 75 from flow and halting flow through designed to keep the change in the rate of drug delivery the nozzle 8. Another embodiment is a compliant member within a desired limit by using a Sufficiently high pressure that collapses with external vacuum pressure. A compliant inside the device. For example, for the flow rate to vary by tubing 80 is placed in line and is in fluid communication less than about 10% across the range of about 1.013 to about with the drug reservoir 3 and the ambient environment. FIG. 0.782 bar pressure (sea level to about 7,000 feet) the system 16C shows the device in normal operation. FIG. 16D shows can be calibrated Such that it delivers drug at its target rate the collapsed compliant tubing 80 when an external vacuum at the pressure midpoint, i.e., about 0.898 bar. Then, for a pressure is applied to the system, collapsing the compliant 0.116 bar ambient pressure change to cause less than a 10% tubing 80 and blocking flow from exiting the one-way valve change in the rate of drug delivery it is necessary for the drug 16. delivery device to have an internal pressure of greater than 0399 FIGS. 17A, 17B, and 17C illustrate an additional about 1.00+(0.116/0.1)=2.16 bar. In such a manner it is mechanism that prevents bolus delivery in the mouth when possible to achieve any desired accuracy across a specified a patient Sucks on the drug delivery device, and changes in ambient pressure change. For example, to achieve accura drug delivery rate when the ambient pressure changes. FIG. cies within +20%, 15%, +10%, +5%, or +3% across the 17A shows the concept during normal operation. Drug from ambient pressure range of 1.013 to 0.782 bar requires the drug reservoir 3 is pushed through an orifice tube 81 propellant pressures of about 1.58, 1.77, 2.16, 3.31, and 4.85 prior to entering the nozzle tube 8 and then exiting the bar, respectively. Preferred spring-driven, gas-driven, or nozzle with one-way valve 16. In FIG. 17B, an external propellant-driven drug delivery devices of the invention vacuum is applied to the environment that the device occu maintain an internal pressure of greater than or equal to pies. This causes the float valve 82 to compress the spring 83 about 1.5, 1.75, 2, 3, 4, or 5 bar. and move in the direction of blocking flow from entering the 0397. A low pressure condition can be created within the orifice tube 81 and halting flow through the one-way valve mouth if the patient Sucks air out of the mouth or Sucks 16. In FIG. 17C, an external positive pressure is applied to directly on the drug delivery device. Humans are able to the environment that the device occupies. This causes the draw a negative pressure of up to about 0.14 bar in the float valve 82 to compress the spring 83 and move in the mouth. The lowered pressure can cause a drug bolus to be direction of blocking flow from exiting the orifice tube 81. delivered from the drug reservoir into the mouth. In some 0400. In preferred embodiments of these designs for embodiments, a means is provided for preventing premature Substantially ambient-pressure independent drug delivery evacuation of the drug from the drug reservoir under the devices, the drug delivery device is configured to deliver a Suction conditions created within the mouth. One example bolus of less than about 5%, 3%, or 1% of the contents of a of Such means is a fluidic channel designed such that when fresh drug reservoir, when the device is sucked on by a the drug is being infused via a pressure head the fluidic patient for a period of about one minute; or when the channel inflates, and when the pressure in the mouth is low ambient pressure drops by about 2 psi for a period of about the fluidic channel collapses, the collapse causing it to kink one minute. and temporarily halting the infusion of the drug. In another 04.01 Ambient-Temperature Independent Pump Designs embodiment, low ambient pressure in the mouth causes a and Methods diaphragm to deflect and block the drug flow channel, 0402. While the flow rate of electric pumps is typically examples of which can be seen in FIGS. 15A and 15B. FIG. substantially independent of the ambient temperature the 15A shows drug delivery during normal operation. Drug same is not true of passive pumps, such as elastomeric, from the drug reservoir 3 is pushed through the orifice 75 in spring-driven, gas-driven, propellant-driven, or osmotic the diaphragm 76 and into a chamber 77 prior to entering the pumps. The invention includes designs and methods of nozzle tube 78 and then out the nozzle with one-way valve achieving accurate drug delivery as the ambient temperature 16. In FIG. 15B, an external vacuum is applied to the Surrounding the drug delivery device increases or decreases, environment that the device occupies. This causes the dia i.e., devices that do not deliver clinically significant, unde phragm 76 to be displaced, blocking the orifice 75 from flow sired boluses as the ambient temperature changes. Osmotic US 2017/0172961 A1 Jun. 22, 2017 pumps, drug delivery patches and other diffusion-based drug natural rubbers, such as highly cross-linked polyisoprene delivery systems are particularly sensitive to changes in the and synthetic elastomers such as neoprene. ambient temperature, and transient temperature excursions 04.07 For spring-driven pumps, to minimize the change may permanently change the drug transport characteristics in drug administration rate when the patient drinks a hot of the diffusion-controlling membranes or pores in these beverage, it is preferred to utilize spring materials whose devices. In a preferred embodiment the drug delivery force is relatively independent of temperature in the range of devices of the invention do not substantially change their about 37° C. to about 55° C. For example, the force in a fresh average long-term rate of drug delivery after exposure to a reservoir may increase by less than 30%, 20%, or 10% when transient temperature excursion. In preferred embodiments, the temperature is raised from about 37° C. to about 55° C. the invention includes one or more temperature-induced Examples of materials with low sensitivity to temperature flow limiters which substantially reduce or eliminate the changes in this range, that are safe for use in the oral delivery of a drug bolus when a patient consumes a hot anatomy are 300 series stainless steels, such as 301, tita drink. nium, Inconel, and fully austenitic Nitinol (above its aus 0403 FIG. 18A shows the temperature-time profile in the tenite finish temperature). lower buccal vestibule when a hot drink is sipped. FIG. 18B 0408 For gas-driven pumps, to minimize the change in shows the temperature-time profile in the upper buccal flow rate when the patient drinks a hot beverage, it is vestibule when a hot drink is sipped. FIG. 19A shows the preferred to minimize the volume of the gas relative to the temperature-time profile in the lower buccal vestibule when volume of the drug-including fluid. The volume of the gas a cold drink is sipped. FIG. 19B shows the temperature-time can be less than about 40%, 30%, 20%, or 10% of the profile in the upper buccal vestibule when a cold drink is volume of the drug-including fluid in a fresh reservoir. For Sipped. All experiments were performed in a single male example, the force in a fresh reservoir may increase by less patient. A thermocouple was placed in the vestibular space than about 30%, 20%, or 10% when the temperature is raised to obtain baseline oral temperature. A beverage was held in from about 37° C. to about 55° C. the mouth and Swished over the location of the thermo 04.09 For propellant-driven pumps, it is preferred to use couple for approximately three seconds. The data demon propellants whose vapor pressure increases by less than strate that transient temperature excursions routinely occur about 80%, 60%, or 40% when the temperature is raised in the mouth when a hot or cold beverage is consumed, with from about 37° C. to about 55° C. As examples, the vapor excursions possible of over about 53° C. and below about pressure of Dupont Dymel HFC-134a (1,1,1,2-tetrafluo 24°C. The data also demonstrate that temperature excur roethane) increases from 938 kPa (absolute) at 37° C. to sions tend to be significantly reduced in the upper buccal 1,493 kPa (absolute) at 55° C., an increase of 59%. The vestibule than in the lower buccal vestibule, with a maxi vapor pressure of Dupont Dymel HFC-227ea/P (1,1,1,2- mum temperature recorded of about 45° C. vs. 53° C. and a tetrafluoroethane) increases from about 700 kPa (absolute) minimum temperature recorded of 29° C. vs. 24° C. Con at 37° C. to 1,000 kPa (absolute) at 55° C., an increase of sequently, in a preferred embodiment the drug delivery 42%. In order to minimize the effect of temperature fluc devices of the invention are located in the upper buccal tuations on the propellants, a number of methods can be vestibule rather than in the lower buccal vestibule. employed. In one embodiment, an insulating material can be 0404 Generally, it is a greater concern when the intra used to decrease the sensitivity to changes in ambient oral temperature increases rather than decreases, because temperature by insulating the propellant and drug reservoirs many non-electric pumps will provide an undesired drug with materials of low thermal conductivity. Materials such bolus that may be clinically significant. When the tempera as closed cell neoprene foams, can be used in this embodi ture decreases, many non-electric pumps will provide a ment. In another embodiment, a material with very low transient reduction in drug delivery that is generally not thermal conductivity can be utilized, such as a ceramic. clinically significant. 0410 Pump Automatic Stop/Start Safety Feature 0405. In a preferred embodiment, the drug delivery 0411 When the pump is removed from the mouth, it is device is configured to deliver a bolus of less than 5% of the preferred that the drug delivery be temporarily stopped. This contents of a fresh drug reservoir, when immersed for five is desirable so that drug is not wasted and, more importantly, minutes or for one minute in a stirred physiological saline so that dispensed drug does not accumulate on the Surface of solution at about 55° C. In another preferred embodiment, the device. Such an unquantified accumulation of drug on the drug delivery device is configured to change its average the surface of the device might lead to the undesired delivery rate of drug delivery over a period of one hour in a of a bolus of an unknown quantity of drug to the patient physiological saline solution of pH 7 at 37° C. by less than when the device is reinserted in the mouth. In preferred about 5% after immersion for five minutes or for one minute embodiments, the drug delivery device includes one or more in a stirred physiological saline solution at about 55° C., as automatic stop/start elements. compared to its average rate of drug delivery immediately 0412. In one embodiment, the drug delivery device has prior to exposure to the temperature excursion. an on/off switch or other mechanism for use by the patient. 0406 For elastomeric pumps, to minimize the change in In a preferred embodiment, the drug delivery device auto flow rate when the patient drinks a hot beverage, it is matically stops delivering drug when (1) the drug delivery preferred to utilize elastomeric materials whose force is device, the pump, and/or the oral liquid impermeable res relatively independent of temperature in the range of about ervoir are removed from the mouth; (2) the drug delivery 37° C. to about 55° C. For example, the force in a fresh device, the pump, and/or the oral liquid impermeable res reservoir may increase by less than about 30%, 20%, or 10% ervoir are disconnected from their attachment to the interior when the temperature is raised from about 37° C. to about Surface of the mouth, either directly (e.g., when secured to 55° C. Examples of elastomeric materials whose mechanical the teeth), or indirectly (e.g., when secured to a fastener properties change little within these temperature ranges are which is secured to the teeth); or (3) the oral liquid imper US 2017/0172961 A1 Jun. 22, 2017 44 meable reservoir is disconnected from the pump or from the mannitol and xylitol. The liquids or their infused mixtures reusable component (e.g., the fastener). In another preferred melt or sufficiently soften for pumping typically below about embodiment, the drug delivery device automatically starts 370 C. delivering drug when (1) the drug delivery device, the pump, 0418 Formulations of the inventions are typically sus and/or the oral liquid impermeable reservoir are inserted into pensions including one or more drugs (which can be mostly the mouth; (2) the drug delivery device, the pump, and/or the Solid particles) and a liquid (which can be an emulsion). The oral liquid impermeable reservoir are connected to their emulsion is typically an oil in water emulsion but can also attachment to the interior surface of the mouth, either be a water in oil emulsion. The emulsion typically includes: directly (e.g., when secured to the teeth), or indirectly (e.g., particles of the one or more drugs; water, a non-toxic, when secured to a fastener which is secured to the teeth); or Substantially water-insoluble organic compound that is liq (3) the oral liquid impermeable reservoir is connected to the uid at 37° C., or a mixture of substantially water insoluble pump or to the reusable component (e.g., the fastener). organic compounds that are liquid at 37°C.; and at least one 0413. In another embodiment, the flow of drug begins surfactant. The weight fraction of the solid drug can be when a cap is removed from the orifice from which the drug greater than the weight fraction of the substantially water is delivered into the mouth and halts when the cap is placed immiscible organic compound or mixture of organic com back onto the orifice. In a different embodiment, a clip can pounds; the weight fraction of the Substantially water immis be placed over the fluidic channel carrying the drug, causing cible organic compounds or mixture of organic compounds a kink or blockage, thereby halting the flow of drug to the can be greater than the weight fraction of water, and the patient. The flow of drug is restored to the patient once the weight fraction of the water can be greater than the weight clip is removed. In yet another embodiment, the flow of drug fraction of the surfactant or surfactants. Typically the weight is halted due to the release of a pressure sensitive switch that fraction of the one or more mostly solid drugs in the breaks the circuit of power to the pump, halting the flow of Suspension can be greater than 0.3. Such as greater than 0.4. drug when the device is removed from the mouth. The act of Such as greater than 0.5, or such as greater than 0.6. The replacing the device back onto the dentition closes the suspended solid drug can include LD and/or CD. The weight pressure sensitive Switch, restoring power to the pump and fraction of the suspended LD can be greater than the weight the flow of drug to the patient. In a further embodiment, the fraction of the suspended CD; it can be, for example, at least fluidic channel kinks, halting the flow of drug, when the twice that of CD, such as at least three times that of CD. The device is removed from the patient due to a change in the density of the suspension can be greater than 1.1 g/cm, for radius of curvature of the fluidic channel. example it can be greater than 1.12 g/cm, 1.15 g/cm, 1.20 0414. In another embodiment, illustrated in FIGS. 7E and g/cm, or 1.22 g/cm. The water immiscible organic com 7F, a protrusion 84 in the drug delivery device is attached to pound or mixture of organic compounds can include, for a spring loaded clutch mechanism 85 employed in the device example, triglycerides (exemplified by triglycerides of cap that engages the piston 39 to inhibit the force transmission roic acid and caprylic acid) or an oil (Such as canola oil). to the drug reservoir 3 prior to use. This protrusion 84 is 0419. In some embodiments the infused fluid can include depressed when the drug delivery device is placed onto the drug-containing micelles or liposomes. tooth or teeth, releasing the piston 39 and allowing the piston 0420 Typically the continuous phase of the emulsion is 39 to transmit force to the drug reservoir 3. When the device hydrophilic and it can be an oil in water emulsion, which is is removed from the mouth, the protrusion 84 is disengaged, preferred because it is rapidly dispersed in saliva and other which again engages the clutch mechanism 85, stopping the fluids of the gastrointestinal tract, which are aqueous. It can piston 39 from applying force to the drug reservoir 3. also be hydrophobic and it can be a water in oil emulsion. Typically the weight fraction of the oil in the emulsion is 0415. In another embodiment, an actuator-connected sen greater than the weight fraction of water. The weight fraction sor detects when the device is placed in the mouth. For of the oil can be, for example, at least twice the weight example an optical sensor can send a signal to turn the fraction of water, for example the weight fraction of the oil device off, the connected actuator halting flow from the can be three times the weight fraction of water or more, even pump. In another example, an actuator-connected moisture when the continuous phase is water, i.e., the emulsion is an sensor can signal the connected actuator to turn the device oil in water emulsion. The drug or drugs can be mostly solid, on, initiating flow from the pump. with only some drug dissolved in one of the carrier liquid 0416 Concentrated Drug Formulations emulsion phases, e.g., in the water phase of the emulsion. 0417 Formulations of drugs to be delivered via the drug 0421. The physical and chemical stability of suspensions delivery devices of the invention (such as LD, LD prodrugs, including emulsions, particularly oil in water emulsions, can DDC inhibitors, and other drugs) may include non-toxic be Superior to their stability in aqueous Suspensions, i.e., in aqueous or non-aqueous carrier liquids, Such as water, suspensions without oil. The superior stability to oxidation ethanol, glycerol, propylene glycol, polyethylene glycols, by dissolved oxygen may be attributed to the lesser solu ethyl lactate and edible oils such as vegetable oils, lipids, bility of drugs like LD and CD in oil than in water and to the monoglycerides, diglycerides or triglycerides, paraffin oil, greater viscosity of the emulsion, reducing the rate of and their mixtures. The monoglycerides, diglycerides or reaction of diffusionally reacting dissolved molecules. Some triglycerides can be of any non-toxic carboxylic acid, the liquids provide the benefit of particularly low drug solubil carboxylic acid having typically an even number of carbon ity, the low solubility providing the further benefit of slower atoms. The formulations may also include esters of non Ostwald ripening when the drug particles are Small. In toxic polyols and carboxylic acids, such as carboxylic acids Ostwald ripening Solid particles grow over time by disso having an even number of carbon atoms. The esterified, lution from highly curved (and therefore highly energetic) partially esterified or non-esterified non-toxic polyol can be, particle Surfaces and their re-deposition on Surfaces of larger for example, erythritol, sorbitol, arabitol, lactitol, maltitol, particles having with lower curvature. US 2017/0172961 A1 Jun. 22, 2017

0422. In preferred embodiments, the intra-orally admin as a Miglyol(R) (e.g., Miglyol(R) 812). The oil can be a istered formulation includes a suspension at body tempera triglyceride of one or more C-C (e.g., C-C) fatty acids. ture, the Suspension including Solid drug particles of a Alternatively, the oil can be a triglyceride of Cs-C fatty concentration greater than or equal to 2 M. Such as greater acids, Ca-Cs fatty acids, or Co-C fatty acids, or a than 3 M. greater than 4M, or greater than 4.4M (e.g., from mixture thereof. The Suspension can contain less than or 2 M to 4.4M). For example, the concentration of the one or equal to about 30% (w/w) (e.g., less than or equal to 29% more drugs in the Suspension of the invention can be from (w/w), less than or equal to about 27% (w/w), or less than about 35% (w/w) to about 70% (w/w). The suspensions can or equal to about 25% (w/w)) of the oil. The suspension can remain free of sedimented solid drug for about 1 month or contain greater than or equal to about 19% (w/w) (e.g., more or for about 1 year or more at about 25° C. and 1 G. greater than or equal to about 21% (W/w) or greater than or Accelerated testing of the Suspensions for physical stability equal to about 23% (w/w)) of the oil. The suspension can can be conducted via centrifugation. For example, physi contain about 24% (w/w) of the oil. Even though the weight cally stable Suspensions can Sustain centrifugation at 25°C. percentage of oil can be greater than that of water, the oil at about 16,000 G (meaning 16,000 times the acceleration of phase may not constitute the continuous phase of the emul sea level) gravity for at least 30, 60, or 90 minutes without sions, i.e., the emulsion can include a continuous aqueous sedimenting or creaming. phase in which Solid drug particles and oil droplets are 0423. In addition to the components described herein, the Suspended. pharmaceutical compositions of the invention can further 0430 Drug Particles contain preservatives and antimicrobial agents such as ben 0431 Drug particles for use in the pharmaceutical com Zoic acid, sodium benzoate, EDTA or its salts, or other positions of the invention can be made by using any method transition metal chelating agents or their salts, methylpara known in the art for achieving the desired particle size ben, propylparaben, potassium Sorbate, methyl hydroxyben distributions. Useful methods include, for example, milling, Zoate, or propyl hydroxybenzoate; and/or Sweeteners like homogenization, Supercritical fluid fracture, or precipitation saccharine Sodium, flavorings like citric acid, Sodium citrate, techniques. Exemplary methods are described in U.S. Pat. and antifoaming or defoaming agents like polydimethylsi Nos. 4,540,602; 5,145,684; 5,518, 187; 5,718,388; 5,862, loxanes and their combinations. They may also include 999; 5,665,331; 5,662,883: 5,560,932; 5,543,133: 5,534, poly-N-vinylpyrrolidone or polyethylene glycol. 270; and U.S. Pat. Nos. 5,510,118; 5,470,583, each of which 0424 Viscosity of the Suspensions is specifically incorporated by reference. 0425 The suspensions may have a shear (dynamic) vis 0432. In one approach, the drug, or a salt thereof, is cosity greater than 100 Poise, or even greater than 1,000 milled in order to obtain micron or submicron particles. The Poise. For example, the Suspensions may have viscosities of milling process can be a dry process, e.g., a dry roller milling 100-1000 cP, 1,000-10,000 cP, 10,000-100,000 cP 100,000 process, or a wet process, i.e., wet-grinding. A wet-grinding 500,000 cB, 500,000-2,500,000 cB, or greater than 2,500,000 process is described in U.S. Pat. Nos. 4,540,602; 5,145,684; cP. Typically the suspensions can’t be poured at about 25° 6,976,647; and EP Patent Publication No. EP498482 (the C., even though they can easily deform under pressure. disclosures of which are hereby incorporated by reference). 0426 Aqueous Phase Thus, the wet grinding process can be practiced in conjunc 0427. The suspensions of the invention are typically tion with a liquid dispersion medium and dispersing or Suspensions of solid drug particles (e.g., Solid LD and/or CD wetting agents such as described in these publications. particles) in emulsions. The Suspensions can contain less Useful liquid dispersion media include safflower oil, etha than or equal to about 16% (w/w) (e.g., less than or equal to nol, n-butanol, hexane, or glycol, among other liquids about 13% (w/w), less than or equal to about 11% (w/w), or selected from known organic pharmaceutical excipients (see less than or equal to about 9% (w/w)) of water. The U.S. Pat. Nos. 4,540,602 and 5,145,684), and can be present Suspensions of the invention can contain greater than or in an amount of about 2.0%–70%, 3%-50%, or 5%-25% by equal to about 1% (w/w) (e.g., greater than or equal to about weight based on the total weight of the drug in the formu 2% (w/w) or greater than or equal to about 3% (w/w)) of lation. water. For example, the Suspension can contain between 0433 Drug particles can also be prepared by homoge about 6% (w/w) and about 9% (w/w) water, such as about neous nucleation and precipitation in the presence of a 8% (w/w) of water. Even though the weight percentage of Wetting agent or dispersing agent using methods analogous water is Small, water or the aqueous phase may constitute the to those described in U.S. Pat. Nos. 5,560,932 and 5,665, continuous phase of the emulsions, i.e., the emulsion in 331, which are specifically incorporated by reference. Such which solid drug particles are suspended can be an oil in a method can include the steps of: (1) dispersing drug in a water emulsion, the oil droplets being co-suspended in the Suitable liquid media; (2) adding the mixture from step (1) continuous aqueous phase. to a mixture including at least one dispersing agent or 0428 Water Immiscibe Hydrophobic or Oil Phase wetting agent such that at the appropriate temperature, the 0429 Suspensions of the invention include emulsions drug is dissolved; and (3) precipitating the formulation from that include a water-immiscible hydrophobic phase. The step (2) using an appropriate anti-solvent. The method can hydrophobic (i.e., water immiscible) phase can be an oil. be followed by removal of any formed salt, if present, by Exemplary oils include edible oils, such as vegetable oils; dialysis or filtration and concentration of the dispersion by monoglycerides, diglycerides, or triglycerides; and paraffin conventional means. In one embodiment, the drug particles oil. The oils can be coconut oil, palm oil, olive oil, soybean are present in an essentially pure form and dispersed in a oil, Sesame oil, corn oil, medium-chain triglycerides (MCT) Suitable liquid dispersion media. In this approach the drug oil, canola oil, or mineral oil. In certain embodiments, the oil particles are a discrete phase within the resulting mixture. is medium-chain triglycerides (MCT) oil or canola oil. The Useful dispersing agents, wetting agents, solvents, and anti oil can be coconut oil, or a medium chain triglyceride Such Solvents can be experimentally determined. US 2017/0172961 A1 Jun. 22, 2017 46

0434 Drug particles can also be prepared by high pres LD or CD) particles can be sized to have Do less than or sure homogenization (see U.S. Pat. No. 5,510,118). In this equal to about 1 Lim, 5um, or 25 Jum. In certain embodi approach drug particles are dispersed in a liquid dispersion ments, the drug (e.g., LD or CD) particles can be sized to medium and Subjected to repeated homogenization to reduce have Dos less than or equal to about 100 Lum (such as less the size of the drug particles to the desired Dso and distri than 50 um) and/or a Dso less than or equal to about 30 um bution. The drug particles can be reduced in size in the or about 45 um. presence of at least one or more dispersing agents or wetting 0438. The maximal solid drug particle diameters may be agents. Alternatively, the drug particles can be contacted bimodally or multimodally distributed. with one or more dispersing agents or wetting agents either before or after attrition. Other materials, such as a diluent, 0439 When the pharmaceutical composition is infused can be added to the drug/dispersing agent mixture before, and the flow is controlled by a flow-limiting tube or orifice, during, or after the size reduction process. For example, the peak diameter of the largest particles of the unimodal, unprocessed drug can be added to a liquid medium in which bimodal or multimodal particle size distribution is typically it is essentially insoluble to form a premix (i.e., about smaller than /10" of its diameter, in order to avoid blockage. 0.1%-60% w/w drug, and about 20%-60% w/w dispersing Typically, less than about 3% of the particles of the distri agents or wetting agents). In particular embodiments, the bution, for example less than 1% of the particles, have dispersing agent is a surfactant (e.g., a non-ionic Surfactant). diameters that are larger than /s" of the diameter of the The apparent viscosity of the premix Suspension is prefer flow-controlling component of the drug delivery device. For ably less than about 1,000 cp. The premix can then be example when the diameter of the flow controlling nozzle, transferred to a microfluidizer and circulated continuously orifice or pipe is 1 mm then fewer than 3% or 1% of the first at low pressures, and then at maximum capacity (i.e., particles have diameters greater than about 200 m, 150 um, 3,000 to 30,000 psi) until the desired particle size reduction 125um, 100 um, 75um, or 50 lum. Typically, the peak of the is achieved. The resulting dispersion of drug particles can be particle distribution, or when the distribution is multimodal included in a pharmaceutical composition of the invention. the peak of the distribution of the largest particles, can be of 100 um or less, for example 50 um or less, 30 um or less, or 0435 The drug particles can be prepared with the use of 10 um or less, or 3 um or less. In a bimodal distribution the one or more wetting and/or dispersing agents, which are, peaks for the Smaller particles might be correspondingly e.g., adsorbed on the Surface of the drug particle. The drug about 20 um or less, 6 um or less, 2 um or less or 0.6 um or particles can be contacted with wetting and/or dispersing less, respectively. Typically the infused Suspensions include agents either before, during, or after size reduction. Gener both LD and CD. The LD particles can be larger than the CD ally, wetting and/or dispersing agents fall into two catego particles (or vice versa) wherefore the particle size distri ries: non-ionic agents and ionic agents. The most common bution can be bimodal. For example the diameters of the LD non-ionic agents are excipients which are contained in particles can peak in the distribution at diameters 1.5 times classes known as binders, fillers, Surfactants and wetting or even larger than the peak diameters of CD particles. The agents. Limited examples of non-ionic Surface stabilizers are resulting bimodal distribution can provide for denser pack hydroxypropylmethylcellulose, polyvinylpyrrolidone, Plas ing of Solid particles in the emulsion, can increase the done, polyvinyl alcohol, Pluronics, Tweens and polyethyl concentration of the drug, reduce the size of the reservoir ene glycols (PEGs). Ionic agents are typically organic mol containing the daily dose, and reduce the likelihood of ecules bearing an ionic bond Such that the molecule is flow-impeding aggregation of the particles. charged in the formulation, such as long chain Sulfonic acid salts (e.g., sodium lauryl Sulfate and dioctyl sodium sulfo 0440 Surfactants Succinate) or fatty acid salts. 0441 The Suspensions of the invention can contain a 0436 The drug particles can include, for example, LD Surfactant in an amount Sufficient to provide physical sta and/or CD, and may optionally further include a COMT bility adequate for continuous or frequent intermittent inhibitor. intraoral administration of the pharmaceutical composition 0437. The drug particles present in the suspension of the of the invention. The surfactant can be selected based on its invention can be sized to have Dso less than or equal to 500 hydrophilic-lipophilic balance (HLB) to match the surface um, e.g., less than or equal to 250 um, 200 um, 150 um, 100 properties of drug particles and the continuous phase (e.g., um, 75 um, or 50 Lum. The drug particles present in the of water). The Surfactant can be an ionic or a neutral Suspension of the invention can be sized to have Dso greater Surfactant. In general, non-ionic Surfactants are preferred than or equal to 1 Lim, e.g., greater than or equal to 3 um, 5 and surfactants where the hydrophilic function includes um, 10 Lim, or 25 um. In some embodiments, the drug polyethylene oxide are especially preferred. particles are sized to have Dso in the range of from about 1 0442. Non-limiting examples of ionic surfactants are um to about 500 um (e.g., from about 3 um to about 250 um, sodium dodecyl sulfate (SDS), phospholipids (e.g., lecithin), from about 10 um to about 250 lum, from about 25 um to quaternary ammonium salts (e.g., cetrimonium bromide), about 200 um, from about 3 um to about 100 um, from about pyridinium salts (e.g., cetylpyridinium chloride), and fatty 5um to about 50 lum, or from about 7 Lum to about 30 m). acid salts. Non-limiting examples of non-ionic Surfactants In particular embodiments, the drug particles are sized to are poloxamers (also known under tradenames Cremo have Ds in the range of from about 1 um to about 25 um phor(R), Kolliphor R, Lutrol(R), PluronicR), and Symperonic R), (e.g., from 1 um to about 10 um). In certain embodiments, poloxamines, polysorbates (also known under tradename the drug (e.g., LD or CD) particles can be sized to have Dso Tween(R), fatty acid esters of sorbitan (also known under less than or equal to about 75 lum. In further embodiments, tradename SpanR), polyethylene glycol alkyl ethers (also the drug (e.g., LD or CD) particles can be sized to have Doo known under tradename BrijR), fatty acid esters of poly less than or equal to about 20 um, 50 lum, 100 m, 150 um, ethylene glycol (also known under tradenames Solutol(R) and 200 um, or 250 um. In certain embodiments, the drug (e.g., Myr(R), alkyl polyglycosides (e.g., alkyl polyglucosides US 2017/0172961 A1 Jun. 22, 2017 47

(also known under tradenames Triton(R) and EcotericR)), and 0447 Type A Formulations fatty acid monoglycerides (e.g., monolaurin). 0448 Type A formulations are pharmaceutical composi 0443) The suspension of the invention can contain a tions including a suspension, which is typically a highly Surfactant that is an emulsifier (e.g., a hydrophobic emulsi Viscous but nevertheless extrudable paste, the Suspension fier (such as a surfactant having HLB from 3 to 8) or a including hydrophilic emulsifier (such as a surfactant having HLB from 10 to 18)). In certain embodiments, the surfactant is a 0449 (i) from about 35% to about 80% (w/w) (e.g., from poloxamer or a polysorbate. The Suspension of the invention about 35% to about 70%, from about 35% to about 65%, from about 35% to about 60%, from about 35% to about can contain less than or equal to about 7% (w/w) (e.g., less 55%, from about 35% to about 50%, from about 35% to than or equal to about 6% (w/w) or less than or equal to about 45%, from about 35% to about 40%, from about 40% about 5% (w/w)) of the surfactant. The suspension of the to about 45%, from about 40% to about 45%, from about invention can contain greater than or equal to about 2% 40% to about 50%, from about 40% to about 55%, from (w/w) (e.g., greater than or equal to about 2% (W/w) or about 40% to about 60%, from about 40% to about 65%, greater than or equal to about 4% (w/w)) of the surfactant. from about 40% to about 65%, from about 40% to about In particular embodiments, the Suspension of the invention 70%, from about 40% to about 75%, from about 45% to contains about 5% (w/w) of the surfactant. about 75%, from about 50% to about 75%, from about 55% 0444 The surfactant may be selected from a wide variety to about 75%, from about 60% to about 75%, from about of soluble non-ionic Surface active agents including Surfac 65% to about 75%, from about 70% to about 75%, or from tants that are generally commercially available under the about 50% to about 65%) undissolved solid drug particles IGEPALTM trade name from GAF Company. The IGEPALTM and dissolved drugs, or salts of the Solid or dissolved drugs, liquid non-ionic Surfactants are polyethylene glycol p-isooc the solid drugs or their salts decomposing without melting, tylphenyl ether compounds and are available in various molecular weight designations, for example, IGEPALTM or melting above 45° C., or softening above 45° C.; CA720, IGEPALTM CA630, and IGEPALTM CA890. Other 0450 (ii) from about 19% to about 40% (w/w) (e.g., from Suitable non-ionic Surfactants include those available under about 19% to about 28%, from about 19% to about 26%, the trade name TETRONICTM 909 from BASF Wyandotte from about 19% to about 24%, from about 19% to about Corporation. This material is a tetra-functional block copo 22%, from about 19% to about 21%, from about 21% to lymer Surfactant terminating in primary hydroxyl groups. about 24%, from about 21% to about 30%, from about 24% Suitable non-ionic surfactants are also available under the to about 30%, from about 26% to about 30%, from about VISTA ALPHONICTM trade name from Vista Chemical 28% to about 30%, or from about 31% to about 40%) of one Company and Such materials are ethoxylates that are non or more water-immiscible compounds melting or softening ionic biodegradables derived from linear primary alcohol at or below 45° C., blends of various molecular weights. The Surfactant may 0451 (iii) from about 2% to about 40% (w/w) (e.g., from also be selected from poloxamers, such as polyoxyethylene about 2% to about 15%, from about 2% to about 13%, from polyoxypropylene block copolymers, such as those available about 2% to about 12%, from about 2% to about 10%, from under the trade names Symperonic PE series (ICI), about 2% to about 8%, from about 2% to about 6%, from Pluronic(R) series (BASF), Supronic, Monolan, PluracareTM, about 2% to about 4%, from about 4% to about 13%, from and PlurodacTM; polysorbate surfactants, such as Tween(R) 20 about 6% to about 13%, from about 8% to about 13%, from (PEG-20 sorbitan monolaurate); nonionic detergents (e.g., about 6% to about 10%, from about 10% to about 13%, nonyl phenoxypolyethoxylethanol (NP-40), 4-octylphenol from about 13% to about 16%, from about 16% to about polyethoxylate (Triton-X100TM), Brij nonionic surfactants): 25%, from about 25% to about 30%, or from about 31% to and glycols such as ethylene glycol and propylene glycol. In about 40%) water, and particular embodiments, the Surfactant is a non-ionic Sur factant including a polyglycolized glyceride, a poloxamer, 0452 (iv) from about 1% to about 10% (w/w) (e.g., from about 1% to about 7%, from about 1% to about 5%, from an alkyl saccharide, an ester saccharide, a polysorbate about 1% to about 3%, from about 3% to about 8%, or from Surfactant, or a mixture thereof. about 5% to about 8%) surfactant, wherein the pharmaceu 0445. The weight fraction of the one or more solid drugs tical composition is physically stable and Suitable for con in the Suspension can be greater than about 0.6. The Sus pension can be non-pourable. The Suspensions can be tinuous or frequent intermittent intra-oral delivery. pumped or extruded into the mouth, for example, by slip 0453. In some embodiments, the Type A formulations page also known as plug-flow, or by a combination of flow include at about 25°C. greater than about 500 mg/mL of the and slippage. Slippage or plug-flow means that parts of the drug, e.g., between about 500 mg/mL and about 850 mg/mL Suspension, or even all of the Suspension move, e.g., through of the drug. a flow-controlling tube or orifice as a unit or as multiple 0454. In some embodiments, the pharmaceutical compo units, each unit a plastically deformable block Such as a sition includes a drug particle-containing emulsion. In other cylindrical block. The movement, i.e., flow of the block or embodiments, the solid drug particle containing pharmaceu blocks can be retarded by friction between the moving block tical composition can be macroscopically substantially and the wall of the flow-controlling tube. An optional homogeneous, when examined at a resolution of 5 mm, 3 lubricant can reduce the friction and facilitate the extrusion mm, 1 mm, or 0.5 mm. In any of the preceding aspects, the as described below. Suspension may be an extrudable, non-pourable emulsion. In 0446 Pharmaceutical compositions including the drugs Some embodiments, the Suspension is physically stable for in Table A may be formulated using a variety of formula about 12 months at about 5° C. In other embodiments, the tions. Five formulations (A, B, C, D, and F) for these and Suspension is physically stable for about 12 months at about other drugs are described below. 25°C. In certain embodiments, after 12 months (e.g., after US 2017/0172961 A1 Jun. 22, 2017 48

13 months, after 14 months, after 15 months, or more) the 13+3% (w/w) water. In some embodiments the suspension suspension is physically stable for about 48 hours at about includes 25+15% (w/w) water. 370 C. 0461. In any of the preceding Type A formulations, the 0455. In any of the preceding Type A formulations, the one or more water-immiscible compounds may include an pharmaceutical composition may include a continuous oil selected from a saturated fatty acid triglyceride, an hydrophilic phase. unsaturated fatty acid triglyceride, a mixed Saturated and 0456. In any of the preceding Type A formulations, the unsaturated fatty acid triglyceride, a medium-chain fatty concentration of drug in a pharmaceutical composition may acid triglyceride, canola oil, coconut oil, palm oil, olive oil, be at least 1.75 M (e.g., more than 1.80 M, 1.85 M, 1.90 M, Soybean oil, Sesame oil, corn oil, or mineral oil. In some 1.95 M, 2.0 M, 2.5 M, 3.0 M, or even 3.5 M). In some embodiments, the oil is a saturated fatty acid triglyceride. In embodiments, the pharmaceutical composition includes other embodiments, the oil is a medium-chain fatty acid from about 50% to about 70% (w/w) (e.g., from about 50% triglyceride oil. For example, the oil can be a Miglyol(R) or to about 65%, from about 50% to about 60%, from about chemical equivalent. In certain embodiments, the oil is a 50% to about 55%, from about 55% to about 70%, from canola oil. In particular embodiments, the oil is a coconut about 60% to about 70%, or from about 65% to about 70%) oil. In some embodiments, the oil is a triglyceride or one or drug particles, the concentration of drug in the pharmaceu more C-C fatty acids, such as a triglyceride of one or tical composition being at least 3.0 M (e.g., 3.1 M, 3.2 M. more Cs-C fatty acids. For example, the oil can be a 3.5 M, or more). triglyceride of Cs-C fatty acids, Ca-Cs fatty acids, or C-C fatty acids, or a mixture thereof. In some embodi 0457. In some embodiments, the suspension of any of the ments, at least 50% (w/w) of the one or more water preceding aspects includes one or more water-immiscible immiscible compounds is a triglyceride of one or more compounds that melts or softens below 45° C. (e.g., at 40° Cs-C fatty acids. In certain embodiments, the Suspension C., 37°C., 35°C., or less). In some embodiments, the weight includes less than or equal to about 30% (w/w) (e.g., about ratio of the one or more water-immiscible compounds to 29% (w/w), about 27% (w/w), or about 25% (w?w)) of the water is greater than 1.0 (e.g., greater than 1.5, greater than oil. In particular embodiments, the Suspension includes 2.0, greater than 3.0, or greater than 5.0). greater than or equal to about 19% (w/w) (e.g., about 21% 0458. In some embodiments, the one or more water (w/w), or about 23% (w/w)) of the oil. In certain embodi immiscible compounds of any of the preceding aspects ments, the suspension includes 20+2% (w/w) of the oil. In includes an oil. In some embodiments, the Suspension other embodiments, the suspension includes 24+2% (w/w) includes a continuous hydrophilic phase. In certain embodi of the oil. In some embodiments, the Suspension includes ments, the Suspension includes an oil in water emulsion. In 28+2% (w/w) of the oil. Some embodiments, the Suspension is free of polymers of a 0462. In any of the preceding Type A formulations, the molecular mass greater than 1,000 Daltons (e.g., greater than pharmaceutical composition may include a Surfactant. A about 1,100 Daltons, greater than about 1,200 Daltons, Surfactant of a pharmaceutical composition may be a non greater than about 1,500 Daltons, greater than about 1,700 ionic Surfactant. In some embodiments, the non-ionic Sur Daltons, or greater than about 2,000 Daltons). In some factant includes a polyglycolized glyceride, a poloxamer, an embodiments, the Suspension has a dynamic viscosity of at alkyl saccharide, an ester Saccharide, or a polysorbate Sur least 100 cB (e.g., greater than 500 cF, 1,000 cB. 5,000 cB. factant. In certain embodiments, the non-ionic Surfactant 10,000 cP, 50,000 cp, or 100,000 cP) at 37° C. includes a poloxamer. In other embodiments, the non-ionic 0459. In any of the preceding Type A formulations, the Surfactant includes a polyglycolized glyceride that is a Suspension may include greater than 50% (w/w) (e.g., polyethoxylated castor oil. In particular embodiments, the greater than 55%, greater than 60%, greater than 65%, or non-ionic Surfactant includes a polysorbate Surfactant that is greater than 70%) drug particles. In some embodiments, the Polysorbate 60. In some embodiments, the suspension Ds of the drug particles is less than or equal to about 500 includes less than or equal to about 10% (w/w) (e.g., about um, about 250 lum, about 200 um, about 150 um, about 125 9% (w/w), 8% (w/w), 7% (w/w), about 6% (w/w), or about um, or about 100 um. In some embodiments, the Dso of the 5% (w/w)) of the surfactant. In some embodiments, the drug particles is greater than or equal to about 1 um, about Suspension includes greater than or equal to about 2% (W/w) 3um, about 5um, about 10um, or about 25um. In particular (e.g., about 3% (w/w) or about 4% (w/w)) of the surfactant. embodiments, the Dso of the drug particles is 25-24 Lum; In certain embodiments, the Suspension includes about 1-10 um; 11-20 um; 21-30 um: 31-40 um; or 41-50 um. In 6+3% (w/w) of the surfactant. other embodiments, the Ds of the drug particles is 75+25 0463. In some embodiments of the Type A formulations, um; 51-75 um; or 76-100 um. In certain embodiments, the a pharmaceutical composition of any of the preceding Ds of the drug particles is 125+25um. In further embodi aspects further includes an antioxidant Such as Vitamin E, ments, the Dso of the drug particles is 175-t25um. TPGS, ascorbylpalmitate, a tocopherol, thioglycerol, thio 0460. In any of the preceding Type A formulations, the glycolic acid, cysteine, N-acetyl cysteine, Vitamin A, propyl Suspension may include less than or equal to about 40% gallate, octyl gallate, butylhydroxyanisole, or butylhydroxy (w/w), such as less than about 35% (w/w), about 25% (w/w), toluene. In some embodiments, the antioxidant is oil soluble. 16% (w/w), about 13% (w/w), about 12% (w/w), about 11% In other embodiments, the pH of the suspension of any of the (w/w), or about 9% (w/w) water. In some embodiments, the preceding aspects is less than or equal to about 7.0, about Suspension includes greater than or equal to about 1% (W/w), 5.0, or about 4.0. In certain embodiments, the pH is greater about 2% (w/w), or about 3% (w/w) water. In certain than or equal to about 3.0. In some embodiments, the shelf embodiments, the suspension includes 4+2% (w/w) water. In life of the pharmaceutical composition is 1 year or longer at particular embodiments, the Suspension includes 8+2% 5+3° C. In particular embodiments, the shelf life of the (w/w) water. In other embodiments, the Suspension includes pharmaceutical composition is 1 year or longer at 25-3°C. US 2017/0172961 A1 Jun. 22, 2017 49

0464. In any of the preceding Type A formulations, the about 21% to about 30%, from about 31% to about 40%, Suspension may not cream or sediment when centrifuged for from about 41% to about 50%, from about 51% to about 1 hour at an acceleration of about 5,000 G or greater (e.g., 50%, from about 51% to about 60%.) drug particles, or salts about 7,000 G, about 9,000 G, about 10,000 G, or about thereof; 16,000 G) at 25+3° C. In some embodiments, the pharma 0472 (iii) from about 19% to about 30% (w/w) (e.g., ceutical composition does not cream or sediment when from about 19% to about 28%, from about 19% to about Stored for 12 months at 53° C. or 25-3° C. In some 26%, from about 19% to about 24%, from about 19% to embodiments, after the centrifugation or storage the con about 22%, from about 19% to about 21%, from about 21% centrations of drug in the layer containing the top 20 volume to about 24%, from about 21% to about 30%, from about % and the layer containing the bottom 20 volume 96 of the 24% to about 30%, from about 26% to about 30%, or from composition differ by less than 10%. In particular embodi about 28% to about 30%) of one or more water-immiscible ments, after the centrifugation or storage the concentrations compounds; of drug in the layer containing the top 20 volume 96 and the 0473 (iv) from about 2% to about 25% (w/w) (e.g., from layer containing the bottom 20 volume 96 of the composition about 2% to about 20%, from about 2% to about 15%, from differ by less than 6% (e.g., 5%, 4%. 3%, 2%, 1%, or less). about 2% to about 13%, from about 2% to about 12%, from In any of these embodiments, after the centrifugation or about 2% to about 10%, from about 2% to about 8%, from storage a pharmaceutical composition may exhibit no visible about 2% to about 6%, from about 2% to about 4%, from creaming or sedimentation. about 4% to about 13%, from about 6% to about 25%, from 0465. In any of the preceding Type A formulations, the about 6% to about 20%, from about 6% to about 13%, from pharmaceutical composition may have Substantially no taste. about 8% to about 13%, from about 6% to about 10%, from 0466 Type A formulations typically include at about 25° about 10% to about 13%, from about 13% to about 16% C. (a) between 500 mg/mL and 850 mg/mL of the drug when from about 13% to about 25%, from about 17% to about the drug is mostly or entirely a compound having a density 25%) water; and of about 1.7 g/mL or less, e.g., of between about 1.3 g/mL 0474 (v) from about 1% to about 10% (w/w) (e.g., from and about 1.7 g/mL.; (b) when the formulation includes a about 1% to about 7%, from about 1% to about 5%, from compound of a metal. Such as a compound of magnesium, about 1% to about 3%, from about 3% to about 8%, or from Zinc or iron, the density of which can exceed about 1.7 g/mL, about 5% to about 8%) surfactant; then the composition can include more than 850 mg/mL of 0475 wherein the pharmaceutical composition is physi the drug, such as between 850 mg/mL and about 2.5 g/mL. cally stable and suitable for continuous or frequent inter The density of the formulations at about 25° C. can be mittent intra-oral delivery; and greater than about 1.15 g/mL, Such as greater than 1.20 0476. In some embodiments, the Type B formulations g/mL, such as 1.25 g/mL or greater. The formulations can be include at about 25°C. between about 50 mg/mL and about non-pourable at about 25° C. but can be extruded at body 500 mg/mL of the drug. In some embodiments, the Type B temperature, typically 37+2°C. formulations include between 200 mg/mL and about 800 0467. An exemplary physically stable paste composition mg/mL (such as between 200 mg/mL and 750 mg/mL) of the of an organic compound drug can include about 60-64 Solid excipient. weight% of the drug. 23-26 weight% of an oil like Miglyol 0477. In some embodiments of the Type B formulations, 812TM, 7-9 weight % of water, and 4-6 weight % of a the Solid excipient includes an organic compound. Exem surfactant like Poloxamer 188. An exemplary physically plary organic excipients include cellulose and its deriva stable paste composition of an inorganic or metal-organic tives, such as non-Swelling cellulose derivative, or amino compound drug, such as a compound of magnesium or Zinc, acids like L-tyrosine or L-phenylalanine. In other embodi can include about 60-80 weight % of the drug. 8-26 weight ments the solid excipient includes an inorganic excipient, % of an oil like Miglyol 812TM, 3-15 weight% of water and Such as titanium dioxide or calcium silicate, or calcium 2-6 weight % water of a surfactant like Poloxamer 188. phosphate, which can be of higher density and its weight 0468. Type B Formulations percentage can exceed 80% (w/w). 0469 Type B formulations are pharmaceutical composi 0478. In some embodiments of the Type B formulations, tions including a suspension, the Suspension including the Solid drug particle containing pharmaceutical composi 0470 (i) from about 25% to about 80% (w/w) (e.g., from tion includes a drug particle-containing emulsion. In other about 25% to about 35%, from about 35% to about 70%, embodiments, the pharmaceutical composition is macro from about 35% to about 65%, from about 35% to about scopically Substantially homogeneous when examined at a 60%, from about 35% to about 55%, from about 35% to resolution of 5 mm, 3 mm, 1 mm, or 0.5 mm. In any of the about 50%, from about 35% to about 45%, from about 35% preceding aspects, the Suspension may be an extrudable, to about 40%, from about 40% to about 45%, from about non-pourable emulsion. In some embodiments, the Suspen 40% to about 45%, from about 40% to about 50%, from sion is physically stable for about 12 months at about 5°C. about 40% to about 55%, from about 40% to about 60%, In other embodiments, the Suspension is physically stable from about 40% to about 65%, from about 40% to about for about 12 months at about 25°C. In certain embodiments, 65%, from about 40% to about 70%, from about 40% to after 12 months (e.g., after 13 months, after 14 months, after about 75%, from about 45% to about 75%, from about 50% 15 months, or more) the Suspension is physically stable for to about 75%, from about 55% to about 75%, from about about 48 hours at about 37° C. 60% to about 75%, from about 65% to about 75%, from 0479. In any of the preceding Type B formulations, the about 70% to about 75%, or from about 50% to about 65%) pharmaceutical composition may include a continuous of one or more solid excipients. hydrophilic phase. 0471 (ii) from about 5% to about 60% (w/w) (e.g., from 0480. In any of the preceding aspects, the concentration about 5% to about 10%, from about 11% to about 20%, from of drug in a pharmaceutical composition may be between US 2017/0172961 A1 Jun. 22, 2017 50

0.15 M and 1.0 M (e.g., 0.15-0.25M, 0.25-0.35M, 0.35-0. canola oil. In particular embodiments, the oil is a coconut 45M, 0.45-0.55M, 0.55-0.65M, 0.65-0.75M, 0.75-0.85M, or oil. In some embodiments, the oil is a triglyceride or one or 0.85-1.0 M). more C-C fatty acids, such as a triglyceride of one or 0481. In some embodiments of the Type B formulations, more Cs-C fatty acids. For example, the oil can be a the Suspension of any of the preceding aspects includes one triglyceride of Cs-C fatty acids, Ca-Cs fatty acids, or or more water-immiscible compounds that melts or softens C-C fatty acids, or a mixture thereof. In some embodi below 45° C. (e.g., at 40°C., 37°C., 35° C., or less). In some ments, at least 50% (w/w) of the one or more water embodiments, the weight ratio of the one or more water immiscible compounds is a triglyceride of one or more immiscible compounds to water is greater than 1.0 (e.g., Cs-C fatty acids. In certain embodiments, the suspension greater than 1.5, greater than 2.0, greater than 3.0, or greater includes less than or equal to about 30% (w/w) (e.g., about than 5.0). 29% (w/w), about 27% (w/w), or about 25% (w?w)) of the 0482 In some embodiments of the Type B formulations, oil. In particular embodiments, the Suspension includes the one or more water-immiscible compounds of any of the greater than or equal to about 19% (w/w) (e.g., about 21% preceding aspects includes an oil. In some embodiments, the (w/w), or about 23% (w/w)) of the oil. In certain embodi Suspension includes a continuous hydrophilic phase includ ments, the suspension includes 20+2% (w/w) of the oil. In ing greater than 50% (w/w) (e.g., 55%, 60%. 65%, 70%, or other embodiments, the suspension includes 24+2% (w/w) 75%) drug particles. In certain embodiments, the Suspension of the oil. In some embodiments, the Suspension includes includes an oil in water emulsion. In some embodiments, the 28+2% (w/w) of the oil. Suspension is free of polymers of a molecular mass greater 0486 In any of the preceding Type B formulations, the than 1,000 Daltons (e.g., greater than about 1,100 Daltons, pharmaceutical composition may include a Surfactant. A greater than about 1,200 Daltons, greater than about 1,500 Surfactant of a pharmaceutical composition may be a non Daltons, greater than about 1,700 Daltons, or greater than ionic Surfactant. In some embodiments, the non-ionic Sur about 2,000 Daltons). In some embodiments, the suspension factant includes a polyglycolized glyceride, a poloxamer, an has a dynamic viscosity of at least 100 cp (e.g., greater than alkyl saccharide, an ester Saccharide, or a polysorbate Sur 500 cP, 1,000 cB, 5,000 cP 10,000 cP, 50,000 cP, or 100,000 factant. In certain embodiments, the non-ionic Surfactant cP) at 37° C. includes a poloxamer. In other embodiments, the non-ionic 0483. In some embodiments of the Type B formulations, Surfactant includes a polyglycolized glyceride that is a the Dso of the drug particles and/or of the one or more solid polyethoxylated castor oil. In particular embodiments, the excipients is less than or equal to about 500 um, about 250 non-ionic surfactant includes a polysorbate surfactant that is um, about 200 um, about 150 lum, about 125 um, or about Polysorbate 60. In some embodiments, the suspension 100 m. In some embodiments, the Ds of the drug particles includes less than or equal to about 8% (w/w) (e.g., about and/or of the one or more solid excipients is greater than or 7% (w/w), about 6% (w/w), or about 5% (w?w)) of the equal to about 1 um, about 3 um, about 5um, about 10 um, Surfactant. In some embodiments, the Suspension includes or about 25 Jum. In particular embodiments, the Dso of the greater than or equal to about 2% (w/w) (e.g., about 3% drug particles and/or of the one or more solid excipients is (w/w) or about 4% (w/w)) of the surfactant. In certain 25+24 um: 1-10 um; 11-20 um; 21-30 um: 31-40 um; or embodiments, the suspension includes about 5+2% (w/w) of 41-50 um. In other embodiments, the Ds of the drug the Surfactant. particles and/or of the one or more solid excipients is 75+25 0487. In some embodiments of the Type B formulations, um; 51-75 um; or 76-100 um. In certain embodiments, the a pharmaceutical composition of any of the preceding Ds of the drug particles and/or of the one or more solid aspects further includes an antioxidant Such as Vitamin E, excipients is 125+25um. In further embodiments, the Ds of TPGS, ascorbylpalmitate, a tocopherol, thioglycerol, thio the drug particles and/or of the one or more solid excipients glycolic acid, cysteine, N-acetyl cysteine, Vitamin A, propyl is 175+25 um. gallate, octyl gallate, butylhydroxyanisole, or butylhydroxy 0484. In any of the preceding Type B formulations, the toluene. In some embodiments, the antioxidant is oil soluble. Suspension may include less than or equal to about 16% In other embodiments, the pH of the suspension of any of the (w/w), about 13% (w/w), about 12% (w/w), about 11% preceding aspects is less than or equal to about 7.0, about (w/w), or about 9% (w/w) water. In some embodiments, the 5.0, or about 4.0. In certain embodiments, the pH is greater Suspension includes greater than or equal to about 1% (W/w), than or equal to about 3.0. In some embodiments, the shelf about 2% (w/w), or about 3% (w/w) water. In certain life of the pharmaceutical composition is 1 year or longer at embodiments, the suspension includes 4+2% (w/w) water. In 5+3° C. In particular embodiments, the shelf life of the particular embodiments, the Suspension includes 8+2% pharmaceutical composition is 1 year or longer at 25-3°C. (w/w) water. In other embodiments, the Suspension includes 0488. In any of the preceding Type B formulations, the 13+3% (w/w) water. Suspension may not cream or sediment when centrifuged for 0485. In any of the preceding Type B formulations, the 1 hour at an acceleration of about 5,000 G or greater (e.g., one or more water-immiscible compounds may include an about 7,000 G, about 9,000 G, about 10,000 G, or about oil selected from a saturated fatty acid triglyceride, an 16,000 G) at 25+3° C. In some embodiments, the pharma unsaturated fatty acid triglyceride, a mixed saturated and ceutical composition does not cream or sediment when unsaturated fatty acid triglyceride, a medium-chain fatty Stored for 12 months at 53° C. or 25-3° C. In some acid triglyceride, canola oil, coconut oil, palm oil, olive oil, embodiments, after the centrifugation or storage the con Soybean oil, Sesame oil, corn oil, or mineral oil. In some centrations of drug in the layer containing the top 20 volume embodiments, the oil is a saturated fatty acid triglyceride. In % and the layer containing the bottom 20 volume 96 of the other embodiments, the oil is a medium-chain fatty acid composition differ by less than 10%. In particular embodi triglyceride oil. For example, the oil can be a Miglyol(R) or ments, after the centrifugation or storage the concentrations chemical equivalent. In certain embodiments, the oil is a of drug in the layer containing the top 20 volume 96 and the US 2017/0172961 A1 Jun. 22, 2017

layer containing the bottom 20 volume 96 of the composition mm, or 0.5-2 mm). Although it can be longer or shorter, the differ by less than 6% (e.g., 5%, 4%. 3%, 2%, 1%, or less). length of the flow restrictor for a Type D true solution is In any of these embodiments, after the centrifugation or typically 0.2 cm-10 cm. storage a pharmaceutical composition may exhibit no visible 0496 Type F Formulations creaming or sedimentation. 0497. Type F formulations are liquid solutions or gels 0489. In any of the preceding Type B formulations, the including between 0.1 mg/mL and 20 mg/mL of the drug. pharmaceutical composition may have Substantially no taste. The formulations can contain water or they can be non 0490 The density of the formulations at about 25°C. can aqueous (e.g., <1% water). They can include water and/or an be greater than about 1.15 g/mL. Such as greater than 1.20 excipient that is liquid at or below about 45° C., such as at g/mL, such as 1.25 g/mL or greater. The formulations can be or below 37° C. Examples of such excipients include DMSO non-pourable at about 25°C., but can be extruded at body and liquids having a dynamic viscosity greater than about 50 temperature, typically 37+2°C. cP (such as greater than 100 cp at about 25°C.) such as glycerol and polyethylene glycols. They can optionally 0491 An exemplary physically stable paste composition further include surfactants. When water-including, they can where the excipient is an amino acid like L-tyrosine can optionally contain a gelling agent or viscosity increasing include about 10-15 weight % of the drug, 45-55 weight % agent, such as a water Soluble polymer or a water-swollen of the excipient, 23-26 weight% of an oil like Miglyol 812, polymer Such as hyaluronic acid, polyacrylic acid, 7-9 weight % of a surfactant like Poloxamer 188, and 4-6 polymethacrylic acid, alginic acid or a salt of these acids. weight 96 water. Another exemplary physically stable paste Typically, the added excipient raises the dynamic viscosity composition, where the excipient is non-Swelling cellulose of the formulations to above 100 cB, such as above 1000 cB. derivative, can include 5-12 weight % of the drug. 20-30 above 10,000 cP, or above 100,000 cPat about 37° C. When weight% excipient, 20-30 weight% water, 7-9 weight% of dispensed through a flow restrictor, the preferred nozzles, a surfactant like Kolliphor RH40, and 25-35 weight% of an channels or tubes for Type F formulations that are true oil like MiglyolTM 812. The paste can be non-pourable at Solutions can have an internal diameter of 10 um-2 mm (e.g., about 25° C. and can be extruded at about 37° C. into the 10 um-100 um, 0.1 mm-0.5 mm, or 0.5-2 mm). Although it mouth, can be longer or shorter, the length of the flow restrictor for 0492 Type C Formulations a Type F true solution is typically 0.2 cm-10 cm. 0493 Type C formulations include between 20 mg/mL 0498 Levodopa Formulations and 150 mg/mL (for example between 20 mg/mL and 100 0499 LD is poorly soluble in most non-toxic solvents, mL, or between 20 mg/mL and 50 mg/mL) of the drug. Type including water and alcohols. For example, we have found C formulations include true Solutions, oil-in-water emul that in a citrate buffered solution of about pH 4.5 the sions or water-in-oil emulsions, or Solid particle including solubility of LD at 25° C. is only about 0.68 g/100 mL, or Suspensions. The formulations can include an excipient that 34 mM. LD is even less soluble in alcohols. To deliver a is liquid at or below about 45° C., such as at or below 37° typical daily dose of 1,000 mg approximately 150 mL of C. Examples of such excipients include DMSO and liquids saturated LD aqueous Solution would be required, which is having at about 25° C. a dynamic viscosity greater than incompatible with the Volume requirements for a drug about 50 cp such as greater than 100 cp, such as glycerol and delivery device placed in the mouth. polyethylene glycols. They can optionally further include 0500 DDC inhibitors such as CD are typically co-ad Surfactants. Typically, the added excipient raises the ministered with LD, and it is usually desirable to co-infuse dynamic viscosity of the formulations to above 100 cp, such LD and CD. CD is also poorly soluble in non-toxic solvents as above 1000 cP, above 10,000 cP, or above 100,000 cPat Such as water, further increasing the required Volume of about 37° C. When dispensed through a flow restrictor, the infused solution. preferred nozzles, channels or tubes for Type C formulations 0501. This invention features pharmaceutical composi that are true solutions can have an internal diameter of 10 tions including COMT inhibitors. The exemplary COMT um-2 mm (e.g., 10 um-100 um, 0.1 mm-0.5 mm, or 0.5-2 inhibitor entacapone is poorly soluble in water, is adminis mm). Although it can be longer or shorter, the length of the tered in large daily doses, often of greater than 1 g/day, and flow restrictor for a Type C true solution is typically 0.2 has a physiological half-life of less than 1 hour, making it cm-10 cm. advantageous to continuously or frequently orally co-admin 0494 Type D Formulations ister it with LD or LD-CD in suspensions of this invention. 0495 Type D formulations include aqueous solutions, It can be co-administered, for example, at a rate between 25 gels or Suspensions of metal compounds, such as com mg/hour and 100 mg/hour. pounds of magnesium, Zinc or iron. Their pH is typically 0502. The invention features a pharmaceutical suspen between pH 3 and pH 10, such as between pH 4 and pH 9. sion containing a carrier and levodopa particles optionally Optionally, they contain a gelling agent or viscosity increas admixed with CD (e.g., LD/CD molar ratio is from about 2:1 ing agent, which can be a water Soluble polymer, or a to about 6:1, such as about 4:1). Preferred suspensions water-Swollen polymer, such as hyaluronic acid, polyacrylic include LD and CD. One or more additional drugs for the acid, polymethacrylic acid, alginic acid or a salt of these treatment of Parkinson's disease may be included in the acids. Typically, the added excipient raises the dynamic pharmaceutical compositions of the invention, e.g., a DDC viscosity of the formulations to above 100 cp, such as above inhibitor, a COMT inhibitor, a drug to treat gastroparesis, a 1000 cP or above 10,000 cP, above 10,000 cP, or above MAO-B inhibitor, adenosine A2 receptor antagonists, or a 100,000 cPat about 37° C. When dispensed through a flow dopamine agonist. restrictor, the preferred nozzles, channels or tubes for Type 0503. The preferred dynamic viscosities of the suspen D formulations that are true Solutions can have an internal sions at about 25°C. are typically greater than 100 cp (i.e., diameter of 10 um-2 mm (e.g. 10 um-100 um, 0.1 mm-0.5 1 Poise), e.g., they can be greater than 10, 100, 1,000, or US 2017/0172961 A1 Jun. 22, 2017 52 even 10,000 Poise. Typically the more viscous suspensions, The pharmaceutical composition may include a Sulfur-in such as suspensions having viscosities of 1,000 Poise or cluding compound, such as a thiol reacting at 25-3°C. with more, are not pourable. While they can’t be poured, they can dopaquinone or with the quinone formed by oxidation of be extruded into the mouth. The advantage of highly vis carbidopa, exemplified by cysteine or N-acetylcysteine. cous, non-pourable but extrudable emulsions is that they are 0507. In general, the color of the emulsion-based suspen physically stable, meaning that upon standing, for example sions of LD and CD when exposed to air at ambient for a month, 3 months, 6 months, 1 year, 2 years, or longer temperature (about 25°C.) remains off-white for at least one than 2 years their suspended solid drug does not sediment. week, e.g., 2 weeks or more or 1 month or more. Furthermore, when the viscous Suspensions include an 0508. The densities of the emulsion-including suspen emulsion, their aqueous and organic or oil phases may not sions in the absence of trapped air can be between about 1.15 separate. Another advantage of the Viscous Suspensions is g/cm and about 1.3 g/cm, such as between about 1.20 that the oxidation of their drugs by dissolved oxygen, the g/cm and 1.27 g/cm. Most of the trapped air can be rate of which can be diffusion and therefore viscosity removed by centrifugation. dependent, is greatly slowed. While air-exposed solutions of (0509 Method of Preparing the Concentrated Formula LD or CD can turn dark, even black, in one day because of tions of the Invention air oxidation, the Suspensions remain off-white when air 0510. The invention also features a method of preparing exposed for a month. At the high viscosity also the rate of the pharmaceutical composition of the invention. The O-oxidation of CD whereby toxic hydrazine is produced is method can involve contacting (e.g., mixing) solid particles reduced, greatly increasing the shelf life, which can be at the of the drug with an aqueous solution containing a Surfactant typical ambient temperature of 25° C.3° C. longer than 3 and water, whereby a mixture of the solid particles with the months. Such as longer than 6 months, or even longer than aqueous Surfactant Solution is produced, followed by mixing 1 year, in which the hydrazine can be less than 8 Jug (e.g., 7 with an oil. Pharmaceutical compositions that can be pre Lig, 6 Lig, 5 Lig. 4 Lig, 3 Lig. 2 Lig, or 1 Lig) per mg of carbidopa. pared according to this method are described herein. 0504. Other than the exemplary emulsion-including sus 0511 Control of Hydrazine Formation pensions of the Solid drugs, viscous Suspensions of Solid 0512 Stored CD is known to degrade such that hydrazine drugs could be made with thickeners, such as carboxymeth is produced. In animal studies, hydrazine shows notable ylcellulose. Concentrated Sugar Solutions, such as Sucrose systemic toxicity, particularly upon inhalation. Hydrazine is Solutions, are also viscous. For example, the solid drugs may also hepatotoxic, has CNS toxicities (although not described be suspended in a Sugar (e.g., sucrose, dextrose, glucose) after oral treatment), and is genotoxic as well as carcino solution containing 40%–70% sugar by weight, e.g., 40%- genic. Consequently, it is important to minimize hydrazine 50% sugar by weight, 50%-60% sugar by weight, or 60%- formation during storage of CD or LD/CD formulations. 70% sugar by weight. As previously discussed, the LD and 0513 DuodopaTM, a LD/CD suspension for continuous CD formulations may include multimodal particle size dis intraduodenal infusion, produces hydrazine during storage. tributions. The average recommended daily dose of Duodopa is 100 0505. The pH of the formulations including those of the mL, containing 2 g levodopa and 0.5 g CD. The maximum emulsion including LD and/or CD Suspensions can be recommended daily dose is 200 mL. This includes hydrazine between 2.5 and 9.5, the more acidic solutions damaging the at up to an average exposure of 4 mg/day, with a maximum enamel of teeth and the more basic Solutions having bad of 8 mg/day. In order to meet these exposure limits, Duodo taste. The pH range between about 3 and 7.5 is preferred and pa’s labeling (outside the USA) states that its refrigerated, the range between 3 and 5 is most preferred, because of unopened shelf life is just 15 weeks, and that once removed slower air-oxidation of LD and CD, resulting in the case of from the refrigerator and opened the product may only be CD also in a lesser rate of formation of toxic hydrazine and used for up to 16 hours. In the United States, Duodopa (sold consequently in a longer shelf life when the shelf life is in the USA as Duopa) requires frozen storage and its labeled limited by the hydrazine content, as it is in the jejunally shelf life is 12 weeks refrigerated (after thawing). The infused DuodopaTM. concentrations of LD and CD in Duodopa are 20 mg/mL and 0506. The LD/CD including pharmaceutical composi 5 mg/mL, respectively. tions can have an apparent pH (meaning a pH measured by 0514. A stable fluid formulation of CD that does not inserting a glass walled pH electrode into the composition) contain high levels of hydrazine and that can be stored of more than pH 2 but less than pH 5 (e.g., less than pH 4. unrefrigerated for extended periods of time is desirable. less than pH 3.5, between about pH 2.7 and about pH 3.3, Hydrazine is produced almost entirely by oxidation of CD in or about pH 3) and it can remain less than pH 5 (e.g., less solution; as more of the dissolved CD is degraded over time, than pH 4, less than pH 3.5, or about pH 3) after 3 months more of the suspended CD is dissolved and is itself storage at 25+3° C. The compositions can include a bacte degraded. In this way significant amounts of hydrazine can riostatic and/or a fungistatic agent, such as benzoic acid or accumulate over time. Hydrazine is not produced in signifi a benzoate salt. The combined concentrations of benzoic cant quantities by oxidation of Suspended CD particles. acid and benzoate Salt Such as its sodium salt is between 0.1 Therefore, the amount of hydrazine produced is greatly weight% and 1.0 weight% (such as between 0.2 weight % reduced by simultaneously minimizing the amount of aque and 0.6 weight 96) of the pharmaceutical composition and ous or non-aqueous liquid in which the hydrazine can can optionally include more benzoic acid than benzoate salt, dissolve, and maximizing the concentration of the Sus e.g. sodium benzoate. The compositions can also include a pended solid CD. Such an approach maximizes the ratio of transition metal ion complexing agent Such as EDTA and/or the suspended solid CD to the dissolved CD. The invention its salts, such as its sodium salts. The concentration of the features an oral liquid impermeable reservoir containing a EDTA and its salts (e.g. sodium salts) is between 0.05 weight suspension of CD in a fluid volume of 0.20-5.0 mL, wherein % and 0.25 weight % of the pharmaceutical composition. the concentration of solid CD suspended in the fluid is US 2017/0172961 A1 Jun. 22, 2017

50-500 mg/mL. The invention features a CD suspension maintain a fixed dose rate by controlling the flow. Sedimen containing less than about 4 mg, 1 mg. or 0.25 mg of tation leading to filtering may be alleviated when the Sus hydrazine per 500 mg of CD after storage of the suspension pended particle sizes are bimodally or multimodally distrib at 5+3° C. for 1 year, or at 25+3° C. for 3 months, 6 months, uted. Suspensions with multimodal particle size 12 months, or 24 months. Preferred reservoirs are substan distributions tend to have superior flow characteristics over tially free of oxygen and are Substantially impermeable to particles with unimodal particle size distributions, thereby oxygen. Preferably, LD is also present in the drug reservoir. reducing or eliminating the of separation or sedimentation of Preferrably the drug is formulated with a carrier (e.g., an the Solids from the liquid carrier that can occur when a emulsion) in which CD has a very low solubility, such as Suspension is pumped. Filtering could be reduced or avoided water-oil emulsion. Because of the poor solubility of CD in by increasing, through the bimodally or multimodally dis the carrier used in the Suspensions of the invention, most of tributed particle sizes, the Volume fraction, i.e., packing the CD is in the solid, particulate form. Because hydrazine density, of the Suspended solid drug, typically to greater than is formed mostly or exclusively of dissolved CD, not of solid about 0.64, for example to between 0.65 and 0.69. A particulate CD, the decomposition of CD, with concomitant two-dimensional example of an optimal trimodal distribu formation of hydrazine, is minimized. tion of particle sizes is illustrated in FIG. 20. The largest 0515. To further reduce the formation of hydrazine, the particle 86 is shown packed with a second smaller particle CD-including pharmaceutical compositions can have an 87 and a further smaller third particle size 88. Particle 88 is apparent pH (meaning a pH measured by inserting a glass approximately /$" the diameter of 87 and particle 87 is walled pH electrode into the composition) of more than pH approximately /s" the diameter of the particle 86. 2 but less than pH 5 (e.g., less than pH 4, less than pH 3.5, 0520. The invention includes suspensions for infusion between about pH 2.7 and about pH 3.3, or about pH 3) and into the mouth including bimodal or multimodal particle size it can remain less than pH 5 (e.g., less than pH 4, less than distributions, optionally wherein the ratio of the average pH 3.5, or about pH 3) after 3 months storage at 25+3° C. particle diameters for the peaks is in the range of 2:1 to 7:1, The compositions can also include a transition metal ion e.g., about 3:1, 4:1, 5:1, 6:1, or 7:1. In the bimodal or complexing agent Such as EDTA and/or its salts, such as its multimodal distributions particle sizes can peak, for sodium salts. The concentration of the EDTA and its salts example, between 0.5um and 100 um, such as between 1 um (e.g. sodium salts) is between 0.05 weight % and 0.25 and 50 lum, or between 1 um and 30 um, or between 1 um weight '% of the pharmaceutical composition. The pharma and 15um. In general, proximal particle sizes at the maxima ceutical composition may include a sulfur-including com of the bimodal or multimodal distribution differ twofold or pound. Such as a thiol reacting at 25-3°C. with dopaquinone more, for example between two and fourfold, or between or with the quinone formed by oxidation of carbidopa, four and six-fold. In an exemplary bimodal distribution the exemplified by cysteine or N-acetylcysteine. weight-based amount of the larger particles can equal or be 0516 Pump-Driven Suspension Separation greater than that of the Smaller particles. Typically the large 0517. The inventors observed that some suspensions with particle: Small particle weight ratio is typically greater than high solid drug concentrations maintain their uniformity of 1; it can be, for example, between 1 and 2. Such as between composition, i.e., may not show sedimentation upon storage 1.2 and 1.8, such as about 1.5. at about 25° C., for at least two days, yet when a flow 0521. The invention includes reduction or elimination of causing pressure is applied the Suspensions can become pump-driven Suspension separation in the intra-oral drug non-uniform. The invention includes compositions and delivery devices by use of one or more of the following methods for preventing pressure-induced separation of Suspension flow enhancement elements: pumped, viscous Suspensions. When viscous Suspensions are pumped under pressure, separation of the Solids from the 0522 Formulation of pumped suspensions with mul liquid carrier is often observed. Typically, the pump delivers timodal particle size distributions that increase the a fluid that contains a reduced amount of Solids and the volume fraction of solids. As previously described, the solids accumulate behind the orifice and are not delivered to invention includes Suspensions for infusion into the the patient. In preferred embodiments, the drug delivery mouth including multimodal particle size distributions, devices of the invention include one or more Suspension preferably wherein the ratio of the volume weighted flow-enhancement elements that Substantially prevent pres average particle diameters at the peaks is in the range Sure-induced separation of pumped, Viscous Suspensions. of 1.5:1 to 7:1, such as between 3:1 to 7:1. 0518. For example, this phenomenon was observed dur 0523 Use of surfactants that facilitate the extrusion of ing an experiment to deliver a suspension of LD and water the particle-including Suspensions through the orifice with a viscosity of approximately 50,000 cp. The driving or tube, exemplified by surfactants used as food addi pressure was approximately 41 inches HO through a nozzle tives, such as monoesters of glycerol and fatty acids with an inner diameter of 0.603 mm. The suspension sepa like glyceryl monooleate or glyceryl monostearate, or a rated and a murky fluid dripped from the end of the nozzle. polysorbate like Polysorbate 80, 65, 60 or 20, or a As the pressure was increased to 60 and then 80 in H2O, the KolliphorTM such Kolliphor RH 40, or a Poloxamer separation persisted, with increasing clarity of the exuding such as Poloxamer 188. fluid. As the pressure was decreased by increasing the nozzle 0524. Use of coatings that modify the surface of the diameter, the effect was lessened, but was not eliminated. orifice or tube, facilitating the extrusion of the particle 0519. This and other experiments showed that pressure rich Suspension through the orifice or tube, Such as a induced flow can cause formation of a filtering plug, the plug fatty acids, or coating the orifice with a perfluorinated passing more of the carrier fluid and less of the Solid drug. polymer, exemplified by TeflonTM or its lubrication Such pressure or flow-induced sedimentation, i.e., filtering with a fluorinated hydrocarbon like KrytonTM or fluo plug formation, makes it difficult, if not impossible, to rinated polyether such a Fomblin.T.M. Alternatively, the US 2017/0172961 A1 Jun. 22, 2017 54

orifice or tube can be made of a fluorinated polymer, inner Surface of the tubing. The goal of the coating is to Such as a perfluorinated polymer. prevent wetting of the tubing. By diminishing the released 0525 Flaring of the orifice to enhance the flow of Surface energy of the tubing upon wetting by saliva (e.g., by particles through the orifice or tube. making it of, or by its coating with, a difficult to wet 0526 Use of an orifice inner diameter of at least 5, 10, perfluorocarbon like TeflonTM, or its lubrication by a difficult or preferably 20 times the maximum particle size (i.e., to wet fluorinated hydrocarbon like KrytonTM, or by a the Doo Dos, or Dos). difficult to wet fluorinated polyether like a FomblinTM) a 0527 Selection of a formulation viscosity, concentra greater than 90 degree contact angle between the saliva and tion, and flow rate, and an orifice inner diameter, Such the inner Surface of the tubing can be achieved and capillary that the pressure on the Suspension is less than 10 bars, climb can be reduced or prevented. Another method to limit and preferably less than 5 bars. ingress of saliva is the use of a check valve 16 (illustrated in 0528. The invention features combinations of these FIGS. 15A and 15B). In times where the flow is halted or designs and methods such that the drug concentration in the paused, the pressure gradient across the check valve 16 is suspension delivered by the drug delivery device varies by eliminated, closing the valve and preventing the flow of drug less than 20%, 10%, 5%, and preferably 3% from the and the ingress of saliva. average during each one hour interval over a period of 8, 16. 0532. For ergonomic reasons, the drug reservoirs and/or or 24 hours. devices of the invention may include Syringes, barrels and 0529 Oral Liquid Impermeable Drug Reservoirs plungers that are not the customary cylindrical shapes. An 0530. The preferred drug reservoirs of the invention are example of an alternative shape for the drug reservoir (e.g., oral liquid impermeable reservoirs. For such oral liquid a syringe and plunger) is an obround shape. Alternatively, a impermeable drug reservoirs, 1, 4, 8, 16, 24, 48, or 72 hours non-cylindrical (e.g., obround) housing may include two or after placing a drug delivery device including a fresh res more cylindrically shaped syringes, barrels and/or plungers ervoir in a patient’s mouth and initiating the administration, arranged side-by-side. less than 5%, 3%, or 1% by weight of the drug-including 0533. A drug reservoir used in the drug delivery device of Solid or drug-including fluid in the reservoir includes an oral the invention can be a syringe assembly including a plunger liquid (e.g., less than 1% after 1 hour, less than 1% after 24 and a barrel, where the plunger is in a slidable arrangement hours, less than 3% after 8 hours, less than 5% after 4 hours, with the barrel. Administration of a drug from the drug or less than 5% after 72 hours). The oral liquid impermeable reservoir can involve relative, slidable displacement of the reservoirs may contain one or more drugs in solid form or in barrel and the plunger by a drug pump (e.g., a mechanical fluid form. Oral liquids include any fluid originating from pump. Such as a spring-driven drug pump or a propellant the mouth, including saliva (or its water component) and driven pump), such that the volume enclosed by the barrel other fluids commonly found in the mouth or that are and the plunger is decreased. The Syringe assembly may commonly drunk or consumed by the patient, including include a seal fitted over the plunger, the seal being in diluted oils and alcohols. Exemplary oral liquid imperme contact with the barrel to seal the interface between the able reservoirs can be made of a metal, or a plastic that can barrel and the plunger. The seal can be an O-ring. To reduce be elastomeric or fiber-reinforced. Metallic reservoirs can variability in drug delivery due to friction or stickiness of the include, for example aluminum, magnesium, titanium or Syringe. Some or all of the interior Surfaces of the Syringe iron alloys of these. When made of a plastic it can have a (e.g., the barrel, the plunger, or the seal) may include a metallic barrier layer, or a non-metallized plastic or elasto non-stick coating Such as a fluorinated polymer, e.g., Tef mer used for packaging of food, or for drink-containing lonTM or a fluorinated polymer like KrytonTM or FomblinTM. bottles, or in a fabric of washable clothing (e.g., Nylon or The interior surfaces can be non-wettable by oil or by water Dacron), or in stoppers or seals of drink containing bottles, (e.g., by the preferred pharmaceutical composition of the or in Septums of vials containing Solutions of drugs. Ingress invention, which is typically an emulsion including a Sus of oral liquids into openings in the reservoir can be pre pension of Solid particles). vented or minimized by the use of one or more valves, 0534. In some embodiments, the drug delivery device can Squeegees, baffles, rotating augers, rotating drums, propel include a tapered flow path for the pharmaceutical compo lants, pneumatic pumps, diaphragm pumps, hydrophobic sition as it approaches the flow restrictor, exit orifice, or materials, and/or hydrophobic fluids. In some embodiments, tube. The taper can make the flow of the pharmaceutical multiple doses of fluid or solid drug are contained within composition more reproducible. FIG. 22 illustrates a drug multiple, impermeable reservoirs or compartments. reservoir 4 in the shape of a syringe barrel with a tapered 0531 While the extrusion into the mouth of a highly flow path at the exit orifice 75. The angle of the taper, C. can Viscous plug Substantially decreases the potential for saliva be equal to or less than about 60 degrees, 45 degrees, or 30 ingress, other methods that Substantially prevent the ingress degrees. of saliva can be utilized. Saliva ingress could result of 0535 To achieve reproducible and accurate drug deliv capillary climb, associated with wetting of the inner Surface ery, it is preferred that the components of the Syringe be of the drug delivering tube or orifice by saliva. Capillary made of materials that do not Substantially deform, e.g. climb occurs when the adhesive forces between the surface creep or yield, under the stress resulting of the force exerted of the tubing and the saliva are stronger than the cohesive to deliver the drug. It is also preferred that the components forces (surface tension) of the saliva. One method to reduce of the Syringe have matched or similar thermal expansion or eliminate capillary climb is to reduce the cohesive forces characteristics so that the friction between the barrel and the by utilizing a large diameter tubing between the drug res piston or seal remains about constant as the temperature ervoir and the exit orifice. Another method to eliminate varies, and so that there is minimal leakage of the drug capillary climb is to reduce the adhesive force of the surface Suspension during Storage. This can be accomplished, for of the tubing through the use of a hydrophobic coating on the example, by using barrels, plungers and/or seals with glass US 2017/0172961 A1 Jun. 22, 2017 transition temperatures of greater than 37° C., preferably than about 0.01 mg per day. Exemplary plug materials in greater than 45° C., more preferably greater than 60°C., and which the solubilities of water and/or oil and/or propellant most preferably greater than 90° C.; and by using Syringe are low include perfluorinated or fluorinated or chlorofluo components made from the same material so that they have rinated oils and greases. The oils and greases may include the same thermal expansion coefficients. Examples of Such Solid and preferably inorganic particles to reduce their materials are polycarbonate, polystyrene, non-creeping per permeabilities, such as particles of carbon, silica, alumina, fluorinated polymers, polyamides like Nylon 6-6, polymeth titania, or halogenated, particularly fluorinated, solid poly ylmethacrylate, and PET. Materials such as polypropylene mer particles, exemplified by polytetrafluoroethylene par are less desirable due to their low glass transition tempera ticles. The carbon particles can be, for example, particles of ture and consequent easy deformation at 37° C. graphite, Such as graphite flakes. The Solid particles may 0536 Alternatively, the moving surface and the nearby have densities between about 1.5 g/mL and about 3 g/mL, stationary Surface (e.g., the inner Surface of a syringe barrel) for example between about 1.6 g/mL and about 2.5 g/mL, can be rendered non-sticky by a lubricant. As the lubricant may come in contact with the pharmaceutical composition Such as between 1.6 g/mL and 2.1 g/mL. The average or of the invention inside the drug delivery device of the mean size of these particles in the grease can be between invention, the lubricant should exhibit low or no solubility about 0.5um and about 250 um, for example between about in the pharmaceutical composition of the invention. In some 1 um and about 100 um. Typically, the incorporated solid embodiments, the lubricant has an oil solubility less than 3% particles scatter and/or absorb visible light. Exemplary oils (w/w) at about 25°C. (e.g., less than 2% (w/w) at about 25° and greases may include fluorinated polyethers or polymeric C., less than 1% (w/w) at about 25°C., or less than 0.5% fluorinated alkanes such as perfluoroalkanes. Some fluori (w/w) at about 25°C.). In other embodiments, the lubricant nated polyether oils and greases are sold under the trade has aqueous solubility less than 2% (w/w) at about 25°C. name “FomblinTM and some fluorinated hydrocarbon oils (e.g., less than 1% (w/w) at about 25°C., less than 0.5% and greases are sold under the trade name "KrytoxTM”. The (w/w) at about 25°C., or less than 0.2% (w/w) at about 25° oil or grease may wet the walls of the compartment or may C.). The lubricant can be a halogenated polymeric oil (e.g., not be repelled from the walls, as indicated, for example, by a halogenated polymeric oil having an average molecular a concave meniscus or no meniscus when the oil is in an mass of equal to or greater than about 1,000 Daltons, or optionally cylindrical compartment, and the absence of a having an average molecular mass of equal to or greater than convex meniscus when the oil is in an optionally cylindrical about 2,000 Daltons). Certain lubricants can be a perfluo compartment. Optionally, the plug may include one or more rinated polymer, a chlorofluorinated polymer, or a fluori Solid Supports to provide the plug with greater structural nated polyether. integrity, to further reduce the rate of permeation of gasses 0537. In another embodiment, the lubricant includes two or drug through the plug, and to reduce leaching of materials organic fluid phases, such as two organic immiscible phases. from the plug into the drug or into the propellant. For These phases may be pourable or non-pourable. An example example, the plug may include a metal or polymeric mesh or is lubricant including both a silicone oil or grease and a cage, or a metal or polymeric cap on one or both ends. fluorinated polyether oil or grease. Another example is a 0539 Methods of Use and Methods of Treating Disease lubricant including both hydrocarbon oil or grease and a fluorinated polyether oil or grease. 0540. The drug delivery devices of the invention can be 0538. In yet another embodiment, the compartment used to orally administer drugs to patients in therapeutically including the driving element (e.g., the propellant or spring) effective amounts. Similarly, the formulations of the inven may be separated from the compartment including the drug tion can be administered to patients in therapeutically effec Suspension (e.g., LD and CD Suspension in a syringe barrel) tive amounts. For example, an amount is administered which by a plug of material. The plug replaces a solid plunger and prevents, delays, reduces, or eliminates the symptoms of a provides reduced friction and more reproducible drug deliv disease. Such as PD, mucositis, bacterial infections, cancer, ery. The plug may be deformable and/or mobile, and may pain, organ transplantation, disordered sleep, epilepsy and optionally be non-pourable. The pressure of the propellant seizures, anxiety, mood disorders, post-traumatic stress dis causes the plug to move and/or deform, and transmits the order, cancer, arrhythmia, hypertension, heart failure, spas pressure to the Suspension. Use of a non-pourable plug ticity, diabetic nephropathy, and allergy. They can also be serves to keep the propellant and the Suspension separate by used to manage allergies, e.g. by delivering agents used for preventing penetration of the propellant gas into the drug, Sublingual immunotherapy Such that the delivered agents assuring that the Suspension, and not the gas, is delivered to contact a mucous membrane or tissue of the mouth. Using the patient. Preferably the rate of permeation of the com the drug delivery devices of the invention, a drug appropri ponents of the drug Suspension in the plug, and optionally ate for the treatment of a given disease to be treated can be also of the propellant in the plug, is low. The rate of formulated and administered using the methods, composi permeation of water through the plug can be, for example, tions, and devices described herein. less than about 10 mg per day at about 25+2°C., for example 0541. Many drugs with narrow therapeutic indices ben less than 1 mg per day or less than 0.1 mg per day. Similarly, efit from drug delivery devices and methods that result in the rate of permeation of oil through the plug can be, for Small fluctuation indices. For example, Table 2 Summarizes example, less than about 10 mg per day at about 25+2°C., the fluctuation indices of extended release tablet formula for example less than 1 mg per day or less than 0.1 mg per tions of anti-epileptic drugs reported in various studies (from day. Furthermore, the rate of permeation of the optionally “Extended-release antiepileptic drugs: A comparison of used propellant, used to drive the plug, can be less than pharmacokinetic parameters relative to original immediate about 1 mg per day at about 25+2°C., for example less than release formulations”, Ilo E. Leppik and Collin A. Hovinga, about 1 mg per day or less than about 0.1 mg per day, or less Epilepsia, 54(1):28-35, 2013). US 2017/0172961 A1 Jun. 22, 2017 56

TABLE 2 5umole/kg and about 50 umole/kg. For example, the typical daily dose for a patient weighing 75 kg is from about 1.5 Fluctuation indices of anti-epileptic drug extended release tablets. millimoles to about 15 millimoles of LD or LD prodrug. Drug Fluctuation Index (SD) Optionally, a molar amount of a DDC inhibitor between about 10% and about 40% of the molar amount of the LD or Carbamazepine 0.31 (0.1) LD prodrug, for example between 15% and 30%, may be 0.26 (0.1) added. O.47 O.49 0547 Preferred modes of administration of the drug Divalproate sodium 0.39 (0.15) including solid or fluid are via drug delivery devices that are 0.67 (0.16) 0.34 (0.15) removably secured in the mouth, and which administer the 0.67 (0.17) drug into the mouth or into the nasal cavity for a period of 0.59 (0.27) at least 4 hours. The drug may be administered at a variable 0.46 (0.16) rate, although constant rate administration is preferred. 0.71 (0.20) Lamotrigine O.341 Administration is preferably continuous or semi-continuous. O.817 0548. The administration into the mouth can be for 24 O.209 hours daily or it can be limited to the awake period, typically O.S.45 O.986 about 16 hours. When limited to the awake period it can be O.318 advantageous to administer a morning bolus to more rapidly Oxcarbazepine 0.39 (0.08) raise the plasma concentration of the LD than a constant rate 0.54 (0.09) administration would. The morning bolus can be delivered, Levetiracetam 1.19 for example, through an orally taken pill or pills of LD and 1.27 a DDC inhibitor or it can be through administration of a Solid or fluid drug into the mouth using the drug devices of 0542. The invention includes a method of treating a the invention. Alternatively, the exterior of the drug delivery disease or medical condition using any of the devices, drugs, device may include a drug, such that a bolus of the drug is formulations, and methods disclosed herein, wherein the delivered into the mouth when the device is first inserted into fluctuation index is less than or equal to 2.0, 1.5, 1.0, 0.75, the mouth. 0.50, 0.25, or 0.15. For example, the disease or medical 0549. The invention includes methods of administering condition to be treated may be Parkinson's disease, bacterial into the mouth one or more drugs (e.g., LD and CD) from infections, cancer, pain, organ transplantation, disordered one or more drug reservoirs residing in the cavity of the sleep, epilepsy and seizures, anxiety, mood disorders, post mouth including a total Volume of 0.1-10 mL of drugs (e.g., traumatic stress disorder, cancer, arrhythmia, hypertension, 0.1-1.0 mL, 1.0-2.0 mL, 2.0-3.0 mL, 3.0-4.0 mL, 4.0–5.0 heart failure, spasticity, dementia, diabetic nephropathy, mL, 5.0-6.0 mL, 6.0–7.0 mL, 7.0-8.0 mL, 8.0-9.0 mL, or gastroparesis, Xerostomia, and dementia. 9.0-10 mL). The invention includes methods of administer 0543. Drug dosages administered using the methods of ing the one or more drugs (in either solid or fluid form) at the invention may be higher or lower than those adminis a rate in the range of 0.03-1.25 mL/hour (e.g., 0.03-0.10 tered using traditional, infrequent dosing regimens. A lower mL/hour, 0.10-0.20 mL/hour, 0.20-0.30 mL/hour, 0.30-0.40 daily dose is possible without loss of efficacy when con mL/hour, 0.40-0.50 mL/hour, 0.50-0.60 mL/hour, 0.60-0.70 tinuous or semi-continuous administration reduces troughs mL/hour, 0.70-0.80 mL/hour, 0.80-0.90 mL/hour, 0.90-1.0 in the drug's steady state circulating plasma concentration, mL/hour, 1.0-1.1 mL/hour, or 1.1-1.25 mL/hour). The inven enabling the drugs plasma concentration to remain above tion includes methods of administering the one or more the minimum effective plasma concentration without the drugs at an average rate of less than 1 mg per hour, 1-10 mg need for high peak concentrations. A higher daily dose is per hour, 10-25 mg per hour, 25-50 mg per hour, 50-75 mg possible without increased side effects when continuous or per hour, 75-100 mg per hour, 100-125 mg per hour, or semi-continuous administration reduces peaks in the drugs greater than 125 mg per hour. The invention includes steady state circulating plasma concentration, enabling an methods of administering one or more drugs via continuous increase in the drugs average plasma concentration without and/or semi-continuous administration. In a preferred the need for high peak concentrations. embodiment, the method includes holding the average 0544 The methods of the invention provide a dosing administration rate constant or near constant for a period of regimen having an improved safety profile as adverse events 4, 8, 12, 16, or 24 hours during the day. For example, the associated with peak plasma concentrations (i.e., a C, Volume administered every hour may vary from the average characteristic of oral unit dosage forms) are eliminated. hourly administration rate during the infusion period by less Thus, the methods, compositions, and devices of the inven than +10% or +20% per hour, or by +10% or +20% per 15 tion can be used to deliver drugs having a narrow therapeutic minute period. The invention includes methods of adminis window in the patient population being treated (i.e., patients tering one or more drugs into the mouth using any of the refractory to standard therapeutic regimens). Details pro drug delivery devices described herein. vided below for the treatment of PD can be applicable to the 0550 Continuous or semi-continuous administration formulation and administration of drugs for the treatment of using the drug delivery devices and formulations of the other diseases. invention can reduce concentration fluctuations of the thera 0545 Treatment of PD peutic drug in body fluid, for example in blood, plasma or 0546 For the treatment of PD, typical administered dose serum. It can provide, for example, a plasma concentration ranges are from about 20 Jumole/kg to about 200 umole/kg profile where the difference between peak concentrations of LD or LD prodrug per day. The typical daily dose of the and nadir concentrations of the therapeutic drug is less than optionally co-administered DDC inhibitor is between about +70% of the average concentration through a period in US 2017/0172961 A1 Jun. 22, 2017 57 which the drug is administered, for example it can be less achieved within 60 minutes of the initiation of the infusion. than +50%, less than +30%, less than +20%, or less than The LD suspension can be administered into the mouth at +10% of the time averaged concentration over a period of Such a rate that a circulating plasma LD concentration less greater than or equal to 4 hours (e.g., 8, 12, 16, or 24 hours). than 7,500 ng/mL, 5,000 ng/mL, 3,500 ng/mL, 3,000 ng/mL, 0551. The invention features a method of treating a 2,500 ng/mL, or 2,000 ng/mL is continuously maintained for disease in a patient, the method including: (a) inserting a a period of at least 8 hours during the administration. In drug delivery device into the patient’s mouth; (b) starting a particular embodiments, the patient receives an average drug administration from the device; (c) administering into daily dose of less than 10 mL, 7.5 mL, 5 mL, 3 mL, or 2 mL the patient’s mouth one or more drugs, using continuous or of the LDSuspension. The LDSuspension can be adminis semi-continuous administration, for a period of 4 hours to 7 tered into the mouth at such a rate that the circulating LD days at an hourly rate in the range of 0.015-1.25 mL/hour or plasma concentration varies by less than +20%, 15%, or 1-125 mg/hour, and (d) removing the drug delivery device +10% from its mean for a period of at least 1 hour, 2 hours, from the mouth; wherein the drug delivery device includes 3 hours, or 4 hours. a oral liquid impermeable reservoir of 0.1-5 mL volume 0554. The method can further include the co-administra (e.g., 0.1-1 mL, 0.5-3 mL, or 3-5 mL), and the reservoir tion of an effective amount of a DDC inhibitor such as includes a Solid or fluid including a drug. Optionally, the benserazide, carbidopa or carbidopa prodrug. Carbidopa can method may also include the optional step of: (e) stopping be co-administered as a solid, Suspension or emulsion, or as the drug delivery from the device. The invention further a solution of one of its highly water soluble prodrug salts, includes a method wherein steps a, b, c, d and e are exemplified by carbidopa ethyl ester hydrochloride, by performed at least twice over a period of 4 hours to 7 days. carbidopa methyl ester hydrochloride or by carbidopa amide The drug may include a total of greater than 1 millimole of hydrochloride. The molar amount of the co-administered LD. DDC inhibitor can be between one-tenth and one-half of the 0552. The invention features a method of treating a molar amount of LD, preferably about 4"it'/8" of the molar disease in a patient, the method including: (a) inserting a amount of L.D. Preparations of the carbidopa prodrugs, drug delivery device into the patient’s mouth; (b) starting a recognized to be LD decarboxylase inhibitors, are described, drug administration from the device; (c) administering into for example, in U.S. Pat. Nos. 3,895,052 and 7,101,912, and the patient’s mouth one or more drugs, using continuous or Patent Publication Nos. DE2062285A and FR2052983A1. semi-continuous administration, for a period of 4 hours to 7 In one particular embodiment, a LDSuspension includes a days at an hourly rate in the range of 0.015-1.25 mL/hour or greater than 0.5 M LD (e.g., 0.5+0.1, 0.6+0.1, 0.7+0.1, 1-125 mg/hour; (d) removing the drug delivery device from 0.8.0.2, 1.0+0.3, 1.5-0.5, 2.0+0.5, 0.6-0.3, 0.75-0.25, the mouth; and (e) stopping the drug delivery from the 1.0+0.5, 1.5+0.5, 2.0+0.5, 2.5+0.5, 3.0+0.5, 3.5+0.5, greater device, wherein: (1) the drug delivery device includes a than 1.5, greater than 2, greater than 2.5, or greater than 3.5 reservoir of 0.1-5 mL volume (e.g., 0.1-1 mL, 0.5-3 mL, or moles per liter). In particular embodiments, the LD and the 3-5 mL), and the reservoir includes a solid or fluid including DDC inhibitor are co-administered separately, or are con a drug, and (2) steps a, b, c, d and e are performed at least tained in a single Solid or fluid and administered into the twice over a period of 4 hours to 7 days. The drug may patient. include a total of greater than 1 millimole of L.D. 0555. The method can alleviate a motor or non-motor 0553. The invention features a method for treating Par complication in a patient afflicted with Parkinson's disease, kinson's disease in a patient (including in patients with Such as tremor, akinesia, bradykinesia, dyskinesia, dystonia, scores of 4 and 5 on the Hoehn and Yahr scale), the method cognitive impairment, and disordered sleep. including: (a) removably inserting a drug delivery device into the patient’s mouth, the drug delivery device including 0556) Mucosal Delivery an oral liquid impermeable reservoir of 0.1-5 mL volume 0557. In some embodiments, e.g. those where the daily (e.g., 0.1-1 mL, 0.5-3 mL, or 3-5 mL), and the reservoir dose of the drug is less than 100 mg, for example less than including a solid or fluid including a total of greater than 1 50 mg, a part or most of the drug in the continuously pumped millimole of LD; (b) administering into the patient’s mouth composition can be transported into, i.e. absorbed by, the the solid or fluid for a period of at least 8 hours at an hourly buccal or Sublingual mucosa and optionally through the rate in the range of 0.03-1.25 mL/hour or 30-150 mg/hour, mucosa to the blood. It could reach through venules the Such that a circulating plasma LD concentration greater than facial vein, then the jugular vein and the heart, delivering 400 ng/mL and less than 7,500 ng/mL is continuously part of the drug-including blood to the brain, the lungs or maintained for a period of at least 8 hours during the other organs, without the drug-containing blood passing the administration; and (c) removing the drug delivery device liver or the kidneys where the drug could be eliminated. from the patient’s mouth. In certain embodiments, the LD Transport of the drug to and/or through the mucosa can be Suspension is administered into the mouth at Such a rate that enhanced by additives and or physical means described, for a circulating plasma LD concentration greater than 800 example, in “Enhancing the Buccal Mucosal Delivery of ng/mL, 1,200 ng/mL, 1,600 ng/mL, or 2,000 ng/mL (e.g., Peptide and Protein Therapeutics' Pharm Res (2015) 32: from 800 to 1,500, from 1,000 to 2,000, from 1,600 to 2,500, 1-21 by T. Caon, L. Jin, C. M. O. Simóes, R. C. Norton or from 1,500 to 3,000 ng/mL, depending upon the condition and/or J. A. Nicolazzo; and/or “Mucoadhesive polymers for of the patient) is continuously maintained for a period of at buccal drug delivery.' Drug Dev Ind Pharm. (2014) 40(5): least 2 hours, 3 hours, 4 hours, 8 hours, 16 hours, or 24 hours 591-8 by F. Laffleur, both incorporated herein by reference. during the administration. In particular embodiments, the Typically the composition is pumped within a Zone from LDSuspension is administered into the mouth at Such a rate which more than about one half of the drug is transported to that a circulating plasma LD concentration greater than 400 the mucosa in less than about 60 minutes, such as less than ng/mL, 800 ng/mL, 1,200 ng/mL, 1,600 ng/mL, or 2,000 is 30 minutes, 10 minutes, 5 minutes, or 2 minutes. US 2017/0172961 A1 Jun. 22, 2017

0558. The invention further includes delivering the drug 0561. This invention includes the following itemized containing composition into a location in the mouth Such aspects and embodiments. that the drug has a residence time at or near the mucosa of 0562. 1. A pharmaceutical composition comprising a greater than 2 minutes, 5 minutes, 10 minutes, 30 minutes, Suspension that is a drug particle-containing emulsion com or 60 minutes before being removed from contact with the prising (i) from 35% to 70% (w/w) drug particles compris oral mucosa (e.g., by Substantial saliva-dilution followed by ing levodopa and/or carbidopa, or salts thereof, (ii) from Swallowing). Several techniques and device configurations 19% to 30% (w/w) of one or more water-immiscible com may be used to obtain the desired residence time, optionally pounds, (iii) from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w) surfactant, wherein the pharmaceutical com in combination with each other. In one embodiment, the position is physically stable and Suitable for continuous or drug-containing composition is delivered into a portion of frequent intermittent intra-oral delivery. the mouth where the flux of saliva is slow, e.g., into the 0563. 2. A pharmaceutical composition comprising a cheek pocket between the bottom teeth/gums and the cheek, suspension comprising (i) from about 35% to 70% (w/w) and preferably not proximate a salivary gland. In a related drug particles, (ii) from 19% to 30% (w/w) of one or more embodiment, the composition may be mucoadhesive or water-immiscible compounds, (iii) from 2% to 16% (w/w) include a mucoadhesive to retain the drug proximate the water, and (iv) from 1% to 8% (w/w) surfactant, wherein the mucosa. In yet another related embodiment, the drug-con pharmaceutical composition is physically stable and Suitable taining composition may be delivered into a material that for continuous or frequent intermittent intra-oral delivery. retains the drug proximate the mucosa, Such as a Sorbent. 0564 3. A pharmaceutical composition comprising a 0559 The accuracy and repeatability of dosing of the Suspension comprising (i) an excess of one or more water drug into the buccal or Sublingual mucosa can be enhanced immiscible compounds over water, and (ii) from about 35% by locating the distal end of the composition-delivering e.g. to 70% (w/w) drug particles, wherein the pharmaceutical plastic tubing or metallic pipe proximal to the buccal or composition is physically stable for 6 months or more at 5° Sublingual mucosa within a Zone bounded in part by a water C. vapor and gas permeable membrane that is not saliva-wetted 0565. 4. The pharmaceutical composition of item 2 or 3, i.e. is saliva-repelling. The saliva-repelling gas permeable wherein said pharmaceutical composition comprises an membrane can delay dilution or extraction of the pumped emulsion. composition by saliva, keeping it near the mucosa until the 0566 5. The pharmaceutical composition of any one of uptake of its drug by the mucosa. The membrane can include items 1 to 4, wherein said suspension is an extrudable, fibers coated with a fluorinated polymer, or its fibers can non-pourable emulsion. include, e.g. be made of a fluorinated polymer. Exemplary 0567 6. The pharmaceutical composition of any one of waterproof, breathable fabric membranes are sold by W. L. items 1 to 5, wherein said Suspension is physically stable for Gore and Associates under the trade name GORE-TEX(R). 12 months at 5° C. The GORE-TEXR. The membranes repel liquid water and 0568 7. The pharmaceutical composition of any one of can repel saliva, yet allow passage of water vapor and other items 1 to 5, wherein said Suspension is physically stable for gases. Pumping of the pharmaceutical composition into a 12 months at 25° C. Zone enclosed in part or entirely by the saliva-repelling 0569 8. The pharmaceutical composition of items 6 and membrane can increase the fraction of the drug that is 7, wherein after said 12 months said Suspension is physically buccally or sublingually absorbed, reducing the flux of the Stable for 48 hours at 37° C. composition or its drug from the proximity of the mucous 0570) 9. The pharmaceutical composition of any one of membrane into a part the oral cavity where it is diluted by items 1 to 8, wherein said Suspension comprises a continu saliva, then Swallowed. The saliva-repelling membrane can ous hydrophilic phase. have a rim adhering to the buccal or Sublingual tissue. For 0571 10. The pharmaceutical composition of any one of adhesion to the buccal or Sublingual tissue, the rim can have items 1 to 9, wherein the concentration of drug in the a mucoadhesive polymer coating described, for example, in pharmaceutical composition is at least 1.75 M. U.S. Pat. Nos. 4,900,552, 5,723,143, 5,744,155, 5,900,247, 0572 11. The pharmaceutical composition of any one of 5,989,535, 5,989,535, 7,914,645, 8,735,374, 9,017,771, items 1 to 9, comprising from about 50% to about 70% 9,044,475, 9,044,500 or 9,161,890, each of which is incor (w/w) drug particles, wherein the concentration of drug in porated herein by reference. the pharmaceutical composition is at least 3.0 M. 0560 For buccal or sublingual delivery an optionally 0573) 12. The pharmaceutical composition of any one of flow-controlling metallic pipe or polymeric tubing can be items 1 to 11, wherein said one or more water-immiscible connected at one end to the reservoir and at the other end to compounds melts or softens below 45° C. a mucosa-contacting, e.g. buccal or Sublingual mucosa 0574 13. The pharmaceutical composition of item 12, contacting, manifold having one or more openings through wherein said one or more water-immiscible compounds which the composition flows as a liquid or is extruded as a melts or softens below 37° C. paste or gel. The pipe or tubing can be, for example 1-15 cm 0575 14. The pharmaceutical composition of any one of long, such as 5-10 cm long. Its inner diameter can be items 1 to 13, wherein the weight ratio of said one or more between about 5um and about 1 mm, such as between about water-immiscible compounds to water is greater than 1.0. 10 um mm and about 0.5 mm. When metallic, the pipe can 0576. 15. The pharmaceutical composition of item 14, include, for example, titanium or one of its alloys, such as wherein the weight ratio of said one or more water-immis annealed titanium of greater than about 98 weight% purity: cible compounds to water is greater than 1.5. or a stainless steel; when polymeric, it could include, for 0577. 16. The pharmaceutical composition of item 15, example polyethylene terephthalate, a polyamide or a fluo wherein the weight ratio of said one or more water-immis rinated polymer. cible compounds to water is greater than 2.0.