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WO 2015/069773 Al 14 May 2015 (14.05.2015) P O P C T

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WO 2015/069773 Al 14 May 2015 (14.05.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/069773 Al 14 May 2015 (14.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61M 37/00 (2006.01) A61K 9/22 (2006.01) kind of national protection available): AE, AG, AL, AM, A61C 7/08 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2014/064137 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 5 November 20 14 (05 .11.20 14) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/899,979 5 November 2013 (05. 11.2013) US kind of regional protection available): ARIPO (BW, GH, 61/926,022 10 January 2014 (10.01.2014) us GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/987,899 2 May 2014 (02.05.2014) us TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/042,553 27 August 2014 (27.08.2014) us TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant: SYNAGILE CORPORATION [US/US]; LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 3465 N. Pines Way, Suite 104, Pmb 218, Wilson, WY SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 83014 (US). GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: HELLER, Ephraim; 3465 N. Pines Way, Declarations under Rule 4.17 : Suite 104, Pmb 218, Wilson, WY 83014 (US). HELLER, — as to applicant's entitlement to apply for and be granted a Adam; 1801 Lavava Street, Apt. HE, Austin, TX 78701 patent (Rule 4.1 7(H)) (US). REHLAENDER, Bruce; 1805 1 Kelok Rd, Lake O s wego, OR 97034 (US). SPIRIDIGLOZZI, John; 9 W — as to the applicant's entitlement to claim the priority of the Broadway - Unit 609, Boston, MA 02127 (US). earlier application (Rule 4.1 7(in)) (74) Agents: BIEKER-BRADY, Kristina et al; Clark & El- Published: bing LLP, 101 Federal Street, 15th Floor, Boston, MA — with international search report (Art. 21(3)) 021 10 (US). [Continued on next page] (54) Title: DEVICES AND METHODS FOR CONTINUOUS DRUG DELIVERY VIA THE MOUTH m A © (57) Abstract: The invention features a drug delivery device held in the mouth and continuously administering either a fluid com o prising drug dissolved and/or dispersed in water or in a non-toxic liquid, or a drug in solid form. before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) DEVICES AND METHODS FOR CONTINUOUS DRUG DELIVERY VIA THE MOUTH FIELD OF THE INVENTION The invention features a drug delivery device anchored in the mouth for continuously administering a drug in solid form or a fluid in which a drug is dissolved or suspended. BACKGROUND This invention relates to devices and methods for continuous or sem i-continuous drug administration via the oral route. It is an aim of this invention to solve several problems related to drugs with short physiological half-lives of drugs (e.g. , shorter than 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 min, 20 min or 10 min) and/or narrow therapeutic windows of drugs that are currently dosed multiple times per day: it is inconvenient to take a drug that must be dosed multiple times per day or at night, the drug's pharmacokinetics and efficacy may be sub-optimal, and side effects may increase in frequency and/or severity. Continuous or semi-continuous adm inistration is particularly beneficial for drugs with a short half-life and/or a narrow therapeutic window, such as levodopa (LD) , anti-epileptics (e.g., oxcarbazepine, topiramate, lamotrigine, gabapentin, carbamazepine, valproic acid, levetiracetam , pregabalin) , and sleep medications (e.g. , zaleplon) . Continuous or semi-continuous infusion in the mouth can provide for lesser fluctuation in the concentration of a drug in an organ or fluid, for example in the blood or plasma. Convenient, automatic adm inistration of a drug can also increase patient compliance with their drug regimen, particularly for patients who must take medications at night and for patients with dementia. Medical conditions managed by continuously orally administered drugs include Parkinson's disease, bacterial infections, cancer, pain, organ transplantation, disordered sleep, epilepsy and seizures, anxiety, mood disorders, post-traumatic stress disorder, cancer, arrhythm ia, hypertension, heart failure, spasticity, dementia, and diabetic nephropathy. A challenge with most drug delivery devices in the prior art is that they are not designed for placement and operation in the mouth. Devices must be designed to be small, comfortable, and non- irritating , and to not interfere with speech, swallowing, drinking and/or eating. In the mouth saliva, food or drink may penetrate into the drug reservoir and/or the pump, thereby potentially unpredictably extracting and delivering the drug, or reacting with the drug, or clogging the delivery device. Pumps that have been suggested for operation in the mouth, such as osmotic tablets and mucoadhesive patches, often do not reliably provide constant rate drug delivery for extended periods of time under the conditions in the mouth. Drinking of hot or cold beverages may cause undesirable changes in drug delivery, e.g. , delivery of a drug bolus. Likewise, sucking on the device may cause delivery of an unwanted bolus. Exposure to foods and liquids such as oils, alcohols, and acids may temporarily or permanently increase or decrease the drug delivery rate from the device. Intra-oral drug delivery devices must also administer the drug into a suitable location in the mouth, e.g. , into a location where the drug does not accum ulate in an unwanted manner or to a location where it is immediately swallowed. There is, therefore, a need for improved drug delivery devices that can operate comfortably, safely and reliably in the mouth over extended periods of time. Intra-oral pumps have previously been proposed in inconvenient formats, e.g. , wherein the device is located within a replacement tooth. There is a need for improved intra-oral drug delivery devices that can conveniently be inserted and removed by the patient, without requiring the insertion or removal of a replacement tooth, dental bridge, or denture. A problem with these and other pumps that reside in the mouth and that can continuously deliver drug in the mouth, such as controlled release osmotic tablets and muco-adhesive drug delivery patches, is that once drug delivery has begun it cannot be temporarily stopped. Temporarily stopping the drug delivery is desirable so that drug is not wasted and, more importantly, so that dispensed drug does not accumulate on the surface of the device while the device is removed from the mouth. Such an unquantified accum ulation of drug on the surface of the device might lead to the undesired delivery of a bolus of an unknown quantity of drug to the patient when the device is placed back into the mouth. Maintenance of accurate rate of drug delivery when the ambient atmospheric pressure changes, e.g., during air-travel or at elevated locations, can also be challenging. The pumps of the invention can provide constant rate, continuous administration of drugs in the mouth, and can be temporarily stopped when the devices are removed from the mouth. Most drugs intended for oral administration are formulated as solids (e.g. , pills, tablets) , solutions or suspensions that are administered once or several times per day. Such drugs are not formulated to meet the requirements of continuous or semi-continuous, constant-rate, intra-oral adm inistration. For example, many suspensions and solutions are form ulated in relatively large daily volumes and/or in form ulations that are physically or chemically unstable over the course of a day at body temperature; and pills and tablets are rarely formulated in units and dosage amounts appropriate for dosing frequently throughout the day. Large quantities of drug must be adm inistered to treat some diseases. For example, 1,000 mg of levodopa is a typical daily dose administered to patients with advanced Parkinson's disease. In order to continuously administer such large quantities of drug into the mouth in a fluid volume that will fit comfortably in the mouth (typically less than 5 m l_) for many hours, it is sometimes necessary to employ concentrated, often viscous, fluid formulations of the drug. Use of viscous fluids can provide the small volumes, high concentrations, uniform drug dispersion , storage stability, and operational stability desired for the drugs and methods of the invention. Consequently, it is often necessary to employ miniaturized pumps tailored to provide the high pressures required to pump the viscous fluids. The drug devices and form ulations of the invention address these unmet needs.
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