USO09522120B2
(12) United States Patent (10) Patent No.: US 9,522,120 B2 Tengler et al. (45) Date of Patent: *Dec. 20, 2016
(54) COMPOSITIONS AND METHODS OF (52) U.S. Cl. MAKING SUSTAINED RELEASE LIQUID CPC ...... A61K 9/5078 (2013.01); A61K 9/0095 FORMULATIONS (2013.01); A61K 9/10 (2013.01); A61K 9/1629 (2013.01); A61K 36/02 (2013.01); A61K 36/06 (71) Applicant: NEOS THERAPEUTICS, LP, Grand (2013.01); A61K 45/06 (2013.01) Prairie, TX (US) (58) Field of Classification Search None (72) Inventors: Mark Tengler, R TX S; See application file for complete search history. Paul Taskey, Richard Hills, TX (US); Daniel Lockhart, Euless, TX (US); (56) References Cited Russell McMahen, Flower Mound, TX (US) U.S. PATENT DOCUMENTS
rsr rr 3,173,876 A 3/1965 Zobrist (73) Assignee: NEOs TERFEUTICs LP, Grand 3,276,586 A 10, 1966 Rosaen s (Continued) (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 277 days. WO WO O1/49272 T 2001 This patent is Subject to a terminal dis claimer. OTHER PUBLICATIONS (21) Appl. No.: 14/045,671 “Understanding High-Viscosity Mixing. Adhesive Magazine, Jun. 1, 2000. (22) Filed: Oct. 3, 2013 (Continued) (65) Prior Publication Data Primary Examiner — Nissa Westerberg US 2014/OO93577 A1 Apr. 3, 2014 (74) Attorney, Agent, or Firm – Hunton & Williams LLP Related U.S. Application Data (57) ABSTRACT The present invention includes compositions and methods (63) Continuation of priation.N. st filed O for the controlled release of active agents in a shelf-stable Nov. 26, 2012, now abandoned, Which 1S a liquid formulation by blending one or more controlled (Continued) release microbeads comprising one or more active agents, preparing a dense, thixotropic Solution having a density that (51) Int. Cl. is at, or about, the density of the one or more microbeads A6 IK 9/10 (2006.01) comprising a thixotropic agent, water and one or more A6 IK 9/00 (2006.01) preservatives under conditions that reduce bubble formation A 6LX 9/50 (2006.01) and mixing the microbeads and the thixotropic solutions in 3. %F.6. 3:08: a mixer that lacks scraping paddles. (Continued) 19 Claims, 8 Drawing Sheets
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Related U.S. Application Data 2003/0077297 A1 4/2003 Chen et al. 2003/O108575 A1 6, 2003 Lu continuation of application No. 11/068,124, filed on 2003/0175408 A1 9, 2003 Timm et al. Feb. 28, 2005, now Pat. No. 8,318,210. OTHER PUBLICATIONS (51) Int. Cl. A6 IK 36/06 Franck, "New Approach to Characterize Starch Dispersions'. TA (2006.01) Instruments, Retrieved from the Internet at www.tainstuments.com. A6 IK 45/06 (2006.01) tw/library download.aspx?. . . New approach-to characterize starch dispersions. ...Date Unknown. References Cited Tang et al., “Drum Drying. Encyclopedia of Agricultural Food and (56) Biological Engineering, pp. 211-214. (2003). U.S. PATENT DOCUMENTS First Office Action of the State Intellectual Property Office of the People's Republic of China issued Oct. 23, 2009 in Patent Appli 3,541,005 11, 1970 Strathmann et al. cation No. 200680014802.1. 3,541,006 11, 1970 Bixler et al. Remington: The Science and Practice of Pharmacy, 20th edition, p. 3,546,142 12, 1970 Michaels et al. 341-343, 2000. 4,285,987 8, 1981 Ayer et al. “About Triblender mixer Equipment'. http://www.fraingroup.com/ 4.427,681 1, 1984 Munshi sub cat Mixer-Liquid 153 Triblender 253.html, accessed 4,438,150 3, 1984 Gantwerker et al. Dec. 11, 2008. 4,692.462 9, 1987 Banerjee SXJ Series Side-Entering Mixers, http://www.lightninmixers.com/ 4,931,279 6, 1990 Bawa et al. SX series.asp, accessed Dec. 11, 2008. 5,368,852 11, 1994 Umemoto et al. Axial Flow Impellers, http:/ /www.lightninmixers.com/axial 5,563,177 10, 1996 Popli et al. flow imps.asp, accessed Dec. 11, 2008. 5,672.358 9, 1997 Tabibi et al. Amberlite(R). IRP64 product information page from Rohm-Haas, 5,674,533 10, 1997 Santus et al. accessed Dec. 11, 2008. 5,980,882 11, 1999 Eichman 5,980,945 11, 1999 Ruiz PCT Search Report and Written Opinion of the International Search 6,039,470 3, 2000 Conwell ing Authority for PCT/US2006/006670, dated Nov. 22, 2006. 6,120,787 9, 2000 Gustafsson et al. Dolz, M. et al., “A time-dependent expression for thixotropic areas. 6,550,955 4, 2003 D’Silva Application to Aerosil 200 hydrogels,” J. Pharm. Sci. (2000), vol. 6,613.358 9, 2003 Randolph et al. 89, No. 6, pp. 790-797. 6,709,675 3, 2004 Lombardin et al. European Search Report from EP 06736077.6, dated Dec. 3, 2012. 6,818.018 11, 2004 Sawhney Apr. 1, 2011, Declaration Under 37 C.F.R. S.1. 132 of Russ 6,838,449 1/2005 Asgharian McMahen, submitted in U.S. Appl. No. 11/068,124. U.S. Patent Dec. 20, 2016 Sheet 1 of 8 US 9,522,120 B2
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HEAT PROPYLENE 200 GLYCOL TO g60 C
PRESERVATIVES SURFACTANT
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CONTINUOUS MIXING FOR 21 HOUR
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FIGURE 4 U.S. Patent Dec. 20, 2016 Sheet 5 of 8 US 9,522,120 B2
MIXPRESERVATIVE MIX THXOTROPICAGENT, > 1 HOUR, NOBUBBLES
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Time (hrs) Figure 11 US 9,522, 120 B2 1. 2 COMPOSITIONS AND METHODS OF extended times. The microgranules have moguisteine core, MAKING SUSTAINED RELEASE LIQUID with one or more optional plasticizers and excipients, granu FORMULATIONS lated into microgranules having sizes Smaller than 500 um, uniform Surfaces, Substantially spherical shapes, apparent CROSS-REFERENCE TO RELATED densities of about 500 to 600 g/l and very low friabilities, APPLICATIONS made by wet-kneading micronised moguisteine using water or a mixture of water and other solvents. These initial This application is a continuation of U.S. Ser. No. 13/685, microgranules are given controlled-release properties by, a 496, filed Nov. 26, 2012, which, in turn, is a continuation of first coating having essentially hydrophilic characteristics, U.S. Ser. No. 11/068,124, filed Feb. 28, 2005, now U.S. Pat. 10 which isolates the microgranules; a second coating having No. 8.318,210. Each of the above is hereby incorporated by lipophilic characteristics on top of the first coating; and a reference in its entirety. third coating having hydrophilic characteristics. FIELD OF INVENTION SUMMARY OF THE INVENTION 15 The invention relates to compositions and methods of The present invention addressed the problems associated making liquid, Sustained-release formulations, and more with the delivery of one or more active agents in a liquid particularly, to the use of methods that eliminate the prob dosage form under controlled conditions. Liquid formula lems associated with the manufacture of the same. tions are preferred by many users due to the easy of delivery, namely, Swallowing thereby leading to increased compli BACKGROUND OF THE INVENTION ance with dosing regimens. It has been found that many children and adults fail to comply with dosing instructions Without limiting the scope of the invention, its back due to the size, shape, taste and/or mouth-feel of e.g., ground is described in connection with pharmaceutical tablets, caplets and even gelcaps. agents that are delivered in an extended or Sustained-release 25 The present inventors have recognized that delivery of form, as an example. agents in liquid formulation is not only preferred by many One Such method of making Sustained release particles is users, but also that many of the materials and processing taught in U.S. Pat. No. 6,120,787, issued to Gustafsson, et al. methods and equipment using in the industry today fail to which teach a method of preparing parenterally adminis deliver products and formulations that, e.g., are shelf-stable, trable Sustained release microparticles, that include prepar 30 do not separate on the shelf (both floating and settling), do ing core particles in an aqueous medium that is essentially not require vigorous shaking (which greatly affects dosing free from organic solvent, a biologically active substance consistency), the mouth-feel of the liquid (e.g., grainy, bitter, being entrapped therein during or after said preparation, slimy), provide actual controlled, Sustained, mixed or modi drying the core particles and coating the same with a fied release. Finally, it was recognized that despite many release-controlling polymer by air Suspension technique so 35 decades of research and development, controlled-release as to create a shell on the core particles without any formulations have not been amenable to large-scale produc detrimental exposure of the active Substance to organic tion in facilities and to amounts that are permissible for solvent. industrial applicability of controlled-release liquid formula Another Sustained-release composition includes an amor tions. phous polymer are taught in U.S. Pat. No. 6,613.358, issued 40 Furthermore, it was found that many known techniques to Randolph, et al., which provided for a sustained release for eliminating the problems commonly associated with the composition for Sustained release of a pharmaceutical Sub manufacture of controlled-release liquid formulations, and stance that includes a biocompatible polymer that is highly hence their widespread failure, did not solve the problems. amorphousand a pharmaceutical Substance in a hydrophobic Examples of techniques that failed in certain forms of the ion complex with an amphiphilic material. A compressed 45 development of the present invention included: inert gas antisolvent method for manufacturing the composition it Sparging. Vacuum, reducing mixer speeds and eliminating taught as are various product forms incorporating the com mixer (e.g., propeller) caviation in the mixing vessel. position and various uses for the composition. Despite using these techniques individually and in combi Yet another Sustained release drug formulation is taught in nation, none of these techniques solved the problems of, e.g., U.S. Pat. No. 5,980,945, issued to Ruiz in which a sustained 50 separation and Stability. A novel approach was needed to release drug formulation includes a drug; a biodegradable reach the present invention. polymer that is insoluble in water; and an oil vehicle in Following a detailed analysis of the many failures, it was which both the drug and the polymer are dissolved. The oil found that several problems associated with the actual vehicle contains 10-100% by volume of a pharmaceutically manufacturing steps and the compositions used were needed acceptable oil and 0-90% by volume a pharmaceutically 55 to address the problems solved herein. For example, it was acceptable liquid carrier for the drug or the polymer. observed that one problem associated with the use of con Finally, U.S. Pat. No. 5,674,533 issued to Santus, et al., trolled release beads, many examples of which are well teaches pharmaceutical compositions for the controlled known in the art, was the dissociation of the bead coating release of the anti-tussive, moguisteine, in a liquid Suspen during mixing, in which mixer paddles designed to scrape sion designed either as ready-to-use and time-stable liquid 60 the sides of the vessels to increase mixing efficiency were formulations with a shelf-life of at least two years, or as dry also causing the beads to shear and break, thereby eliminat formulations that are reconstituted with water when needed ing the Sustained-release nature of the beads. Another and then remain stable throughout the treatment period. example was the floating of beads as the liquid formulation Santus teaches the use of coated microgranules for the was tested for shelf-stability, as air bubbles introduced controlled release of moguisteine having sizes ranging from 65 during the manufacturing process were found to cling to, or 50 to 500 um, preferably from 90 to 300 um, which are form on, the beads thereby changing their nominal density capable of remaining easily in Suspension in a liquid for from that calculated based on its manufacture. US 9,522, 120 B2 3 4 More particularly, the present invention includes compo gen, allergen, antibody, antiviral, antifungal, antihelminthic, sitions and methods for preparing a liquid, controlled Substrate, metabolite, cofactor, inhibitor, drug, nutrient, release formulation by blending one or more controlled toxin, poison, explosive, pesticide, chemical warfare agent, release microbeads having one or more active agents, pre biowarfare agent, biohazardous agent, infectious agent, paring a dense, thixotropic Solution having a density that is prion, radioisotope, vitamin, heterocyclic aromatic com at or about the density of the one or more microbeads, pound, carcinogen, mutagen, narcotic, amphetamine, barbi wherein a thixotropic agent, water and one or more preser turate, hallucinogen. In some cases the liquid may be, eg., a vatives are mixed under conditions that reduce bubble vaccine for against a virus, bacterium, helminth and/or formation, e.g., using a mixer that lacks scraping paddles. fungi, fragments, receptors or toxins thereof, e.g., Salmo The one or more microbeads may include an enteric coat, a 10 nella, Streptococcus, Brucella, Legionella, E. coli, Giardia, resin coat, a lacquer coat, a pH-sensitive coating, a biode Cryptosporidium, Rickettsia, spore, mold, yeast, algae, gradable polymer matrix, a water Soluble matrix, an ionic amoebae, dinoflagellate, unicellular organism, pathogen, matrix, combinations and mixtures thereof. The one or more cell, combinations and mixtures thereof. The one or more microbeads may also includes one or more polymers active agents may be a pharmaceutical agent, an enzyme, a selected from cellulose, ethylcellulose, methylcellulose, 15 cytokine, a growth promoting agent, an antibody, an antigen, propylcellulose, methoxypropylcellulose, cellulose nitrate, a hormone, a vaccine, a cell, a live-attenuated pathogen, a poly(vinyl alcohol), poly(vinyl chloride), polystyrene, poly heat-killed pathogen, a virus, a bacteria, a fungi, a peptide, ethylene, polypropylene, poly(ethylene-co-vinyl acetate), a carbohydrate, a nucleic acid, a lipid, mixtures and com poly(hydroxybutyric acid), poly(hydroxyvalerianic acid-co binations thereof. hydroxybutyric acid), poly(lactic acid), poly(glycolic acid), Specific examples of active agents include: Steroids, poly(lactic acid-co-glycolic acid), poly(e(-caprolactones), respiratory agents, sympathomimetics, local anesthetics, poly(6-caprolactone-co-DL-lactic acid), poly(maleic anhy antimicrobial agents, antiviral agents, antifungal agents, dride), polyamides, gelatin, chitosan, collagen, poly(hy antihelminthic agents, insecticides, antihypertensive agents, droxyalkyl)-L-glutamines, poly(y-ethyl-L-glutaminate-co antihypertensive diuretics, cardiotonics, coronary vasodila glutamic acid), poly(L-leucine-co-L-aspartic acid), poly 25 tors, vasoconstrictors, B-blockers, antiarrhythmic agents, (proline-co-glutamic acid), poly(alkyl 2-cyanoacrylates), calcium antagonists, anti-convulsants, agents for dizziness, polyurethanes, poly(methyl methacrylate), poly(methyl tranquilizers, antipsychotics, muscle relaxants, drugs for methacrylate-co-methacrylic acid) and poly(methacrylate Parkinson's disease, respiratory agents, hormones, non co-hydroxypropyl methacrylate), polystyrene, polistirex, steroidal hormones, antihormones, vitamins, antitumor polacrilex and salts, combinations and mixtures thereof. 30 agents, miotics, herb medicines, herb extracts, antimuscar The method of the present invention increases the shelf inics, interferons, immunokines, cytokines, muscarinic cho life and stability of the actives agents, e.g., by preventing the linergic blocking agents, mydriatics, psychic energizers, separation of the components by taking steps to reduce or humoral agents, antispasmodics, antidepressant drugs, anti eliminate bubble formation during the manufacture of the diabetics, anorectic drugs, anti-allergenics, decongestants, controlled-release liquid formulation of the present inven 35 expectorants, antipyretics, antimigrane, anti-malarials, anti tion. Steps of the present invention for minimizing, reducing ulcerative, anti-estrogen, anti-hormone agents, anesthetic and/or eliminating bubble formation include, but are not agent, or drugs having an action on the central nervous limited to using the following steps alone or in combination: system. For example, for use in the treatment of cold/cough using a diaphragm pump to combine, e.g., the water and the symptoms the active agents may include one or more thixotropic agent and one or more preservatives, colorants 40 antihistamines, anti-tussives, expectorants and the like, e.g., and flavorants; placing the recirculating tube below the pseudoephedrine, chlorpheniramine, dextromethorphan, Surface of the liquid; adding liquids along the side of a vessel guaifenesin, and salts thereof or mixtures of salts thereof. holding the liquid; sprinkling beads (e.g., one or more beads The liquid formulation may also include an analgesic or that includes one or more active agents) onto the Surface of even a narcotic. the liquid; mixing the Solution in the absence of one or more 45 Examples of carriers for the actives of the present inven paddles that scrape the vessel; mixing the Solution with a tion include any degradable, partially degradable or non propeller mixer, mixing the solution with a propeller mixer degradable and generally biocompatible polymer, e.g., poly at a speed that reduces or minimizes cavitation and combi stirex, polypropylene, polyethylene, polacrilex, poly-lactic nations of two or more of these steps. acid (PLA), poly-glycolic acid (PGA) and/or poly-lactic The controlled-release liquid formulation may include a 50 polyglycolic acid (PGLA) in the form or a matrix or even a portion of the one or more beads with an immediate release bead. profile and another portion with a controlled or delayed The present invention also includes those liquid formu release profile. When using an ion-exchange matrix, bead or lations made by the methods disclosed and claimed herein. resin to retain the one or more active agents the liquid For example, specific liquid formulation may include one or Solution will in Some cases be a low-ionic strength, depend 55 more active agents available for immediate, modified and/or ing on the nature of the ion-exchange matrix and the one or extended or controlled release for use in treating cold/cough/ more active agents. The skilled artisan can easily determine allergy symptoms. The one or more actives for cold/cough/ the best matrix for a particular active, determine the amount allergy may include one or more of the following: anti of loading (theoretical and empirical), and the conditions for tussives, anti-histamines, expectorants and analgesics. For retention and release. 60 example, the actives may include: pseudoephedrine, chlo Examples of active agents that may be provided as part of rpheniramine, dextromethorphan, guaifenesin, and salts the liquid formulations of the present invention include thereof or mixtures of salts thereof. Vitamins, minerals, nutritional Supplements, herbal extracts, In another embodiment, the present invention includes a gums, gels, oils, salts, mixtures and combinations thereof. method for preparing a liquid, controlled-release formula Pharmaceutical active agents may include, e.g., protein, 65 tion by blending one or more controlled release beads peptide, carbohydrate, polysaccharide, glycoprotein, lipid, having one or more active agents with a dense, thixotropic hormone, growth factor, cytokine, interferon, receptor, anti Solution having a density that is at or about the density of the US 9,522, 120 B2 5 6 one or more beads and a thixotropic agent, water and one or applicable inventive concepts that can be embodied in a more preservatives under conditions that reduce bubble wide variety of specific contexts. The specific embodiments formation. A liquid formulation is made by the method. Yet discussed herein are merely illustrative of specific ways to another method for preparing a liquid, controlled-release make and use the invention and do not delimit the scope of formulation includes blending a mixture comprising one or 5 the invention. more controlled-release beads comprising one or more To facilitate the understanding of this invention, a number active agents, a thickening agent and a surfactant by mixing of terms are defined below. Terms defined herein have with a low cavitation propeller and recirculating the mixture meanings as commonly understood by a person of ordinary under the surface of the mixture so as to minimize bubble skill in the areas relevant to the present invention. Terms formation. In one embodiment, the formulation includes 10 such as “a”, “an and “the are not intended to refer to only between about 15-45 mg phenylephrine disposed in, on or a singular entity, but include the general class of which a about a resin, between about 2-8 mg chlorphineramine specific example may be used for illustration. The terminol disposed in, on or about a resin per dose. The formulation ogy herein is used to describe specific embodiments of the may also include between about 15-45 mg dextrometho invention, but their usage does not delimit the invention, rphan disposed in, on or about a resin. 15 except as outlined in the claims. Yet another embodiment of the present invention is a As used herein, the terms "extended release,” “sustained method of preparing a liquid, controlled-release formulation release,” and “delayed release' are used to define a release by blending a mixture comprising one or more active agents profile to effect delivery of an active over an extended period on or about a carrier a thickening agent under conditions that of time, defined herein as being between about 60 minutes minimize the introduction of air. The conditions that mini- 20 and about 2, 4, 6, 8 or even 12 hours. Extended release may mize, reduce and/or eliminate the introduction of air and/or also be defined functionally as the release of over 80 to 90 air bubbles include one or more of the following steps used percent (%) of the active ingredient after about 60 minutes alone, in combination and/or in any order: using a dia and about 2, 4, 6 or even 8 hours. Extended release as used phragm pump to combine, e.g., the water and the thixotropic herein may also be defined as making the active ingredient agent and one or more preservatives, colorants and fla- 25 available to the patient or subject regardless of uptake, as Vorants; placing the recirculating tube below the Surface of some actives may never be absorbed by the animal. Various the liquid; adding liquids along the side of a vessel holding extended release dosage forms may be designed readily by the liquid; sprinkling beads (e.g., one or more beads that one of skill in art as disclosed herein to achieve delivery to includes one or more active agents) onto the Surface of the both the Small and large intestines, to only the Small intes liquid; mixing the solution in the absence of one or more 30 tine, or to only the large intestine, depending upon the choice paddles that scrape the vessel; mixing the Solution with a of coating materials and/or coating thickness. propeller mixer, mixing the solution with a propeller mixer “Extended release” and “delayed release” formulations at a speed that reduces or minimizes cavitation and combi may be prepared and delivered so that release is accom nations of two or more of these steps. plished at Some generally predictable location in the lower Yet another method for preparing a liquid, controlled- 35 intestinal tract more distal to that which would have been release formulation of the present invention includes blend accomplished if there had been no delayed release altera ing a mixture of one or more controlled-release beads with tions. A method for delay of release is, e.g., a coating. Any one or more active agents on a carrier in a solution having coatings should be applied to a sufficient thickness such that a low ionic concentration and a thixotropic agent, under the entire coating does not dissolve in the gastrointestinal conditions that minimize the introduction of air bubbles. 40 fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting BRIEF DESCRIPTION OF THE DRAWINGS a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve For a more complete understanding of the features and delivery to the lower gastrointestinal tract. Polymers and advantages of the present invention, reference is now made 45 compatible mixtures thereof may be used to provide the to the detailed description of the invention along with the coating for the delayed or the extended release of active accompanying figures and in which: ingredients, and some of their properties, include, but are not FIG. 1 is a flow-chart of the basic steps of the present limited to: shellac, also called purified lac, a refined product invention; obtained from the resinous secretion of an insect. This FIG. 2 is a detailed flow chart of present invention; 50 coating dissolves in media of pH>7. FIG. 3 is another detailed flow chart of present invention; As used herein, the term “thixotropic' is used to describe FIG. 4 is another detailed flow chart of present invention; one or more agents, e.g., certain gels, which liquefy when FIG. 5 is a flowchart with the final steps of the present Subjected to vibratory forces like simple shaking, and then invention; Solidify again when left standing. Thixotropic behavior is FIG. 6-8 are graphs that demonstrate the release profile of 55 observed when long-chain molecules tend to orient them two active agents in a liquid formulation of the present selves in the direction of flow; as the applied force is invention; and increased, the resistance to flow is decreased. Yet when high FIG. 9-11 are graphs that demonstrate the release profile shear stress is removed, the solution will quickly revert to its of third active agents in a liquid formulation of the present original viscous state. Some celluloses exhibit thixotropic invention. 60 behavior wherein the solution returns to its viscous state over a period of time. Examples of thixotropic agents for use DETAILED DESCRIPTION OF THE with, e.g., food, pharmaceuticals, are well known in the art, INVENTION e.g., “A time-dependent expression for thixotropic areas. Application to Aerosil 200 hydrogels.” M. Dolz, F. While the making and using of various embodiments of 65 González, J. Delegido, M. J. Hernández, J. Pellicer, J. the present invention are discussed in detail below, it should Pharm. Sci., Vol. 89, No. 6, pages 790-797 (2000), relevant be appreciated that the present invention provides many portions incorporated herein by reference. Numerous US 9,522, 120 B2 7 8 examples of thixotropic agents, such as cellulose (e.g., microporous materials (bisphenol, a microporous poly(vi carboxymethylcellulose), gums (e.g., Xanthan), collagen, nylchloride), micro-porous polyamides, microporous gelatin, aerogels and others are well known in the art and modacrylic copolymers, microporous styrene-acrylic and its may be used with the present invention, e.g., U.S. Pat. Nos. copolymers); porous polysulfones, halogenated poly(vi 6,709,675; 6,838,449; 6,818,018, relevant portions incorpo nylidene), polychloroethers, acetal polymers, polyesters pre rated herein by reference. pared by esterification of a dicarboxylic acid or anhydride The pharmaceutical composition and/or the Solid carrier with an alkylene polyol, poly(alkylenesulfides), phenolics, particles can be coated with one or more enteric coatings, polyesters, asymmetric porous polymers, cross-linked olefin seal coatings, film coatings, barrier coatings, compress coat polymers, hydrophilic microporous homopolymers, copoly ings, fast disintegrating coatings, or enzyme degradable 10 mers or interpolymers having a reduced bulk density, and coatings. Multiple coatings may be applied for desired other similar materials, poly(urethane), cross-linked chain performance. Further, one or more of the actives may be extended poly(urethane), poly(imides), poly(benzimida provided for immediate release, pulsatile release, controlled Zoles), collodion, regenerated proteins, semi-solid cross release, extended release, delayed release, targeted release, linked poly(vinylpyrrolidone). synchronized release, or targeted delayed release. In fact, the 15 Additional additives and their levels, and selection of a formulation may include combinations of typical pharma primary coating material or materials will depend on the ceutical actives (e.g., pseudephedrin) and vitamins (e.g., following properties: resistance to dissolution and disinte Vitamin C), minerals (Ca, Mg., Zn, K) or other Supplements gration in the stomach; impermeability to gastric fluids and (e.g., St. John's Wort, echinacae, amino acids). For releasef drug/carrier/enzyme while in the stomach; ability to dissolve absorption control, Solid carriers can be made of various or disintegrate rapidly at the target intestine site; physical component types and levels or thicknesses of coats, with or and chemical stability during storage; non-toxicity; easy without an active ingredient. Such diverse Solid carriers can application as a coating (Substrate friendly); and economical be blended in a dosage form to achieve a desired perfor practicality. mance. The liquid formulations may be delivered to, and Dosage forms of the compositions of the present inven adapted for, oral, nasal, buccal, ocular, urethral, transmu 25 tion can also be formulated as enteric coated delayed release cosal, vaginal, topical or rectal delivery, although oral deliv oral dosage forms, i.e., as an oral dosage form of a phar ery is used mostly. maceutical composition as described herein that uses an When formulated with microparticles or nanoparticles, enteric coating to effect release in the lower gastrointestinal the one or more actives the release profile can easily be tract. The enteric coated dosage form will generally include adapted by adding, e.g., a hard or Soft gelatin coating, a 30 microparticles, microgranules, micropellets or microbeads starch coating, a resin or polymer coating and/or a cellulosic of the active ingredient and/or other composition compo coating. Although not limited to microparticles or nanopar nents, which are themselves coated or uncoated. The enteric ticles (as in, e.g., microcapsules or nanocapsules), Such coated oral dosage form may also be a capsule (coated or dosage forms may be further coated with, for example, a seal uncoated) containing pellets, beads or granules of the Solid coating, an enteric coating, an extended release coating, or 35 carrier or the composition, which are themselves coated or a targeted delayed release coating. The term “enteric coat uncoated. ing as used herein relates to a mixture of pharmaceutically Active Pharmaceutical Ingredients. The one or more acceptable excipients that is applied to, combined with, active agents that are formulated in a self-stable manner mixed with or otherwise added to the carrier or composition. using the present invention may include a wide variety of The coating may be applied to an active that is compressed, 40 uses, not just the traditional pharmaceutical agents. Actives molded or extruded and may also include: gelatin, and/or for use with the present invention in immediate and/or pellets, beads, granules or particles of the carrier or com controlled release formulations may include systemically position. The coating may be applied through an aqueous active therapeutic agents, locally active therapeutic agents, dispersion or after dissolving in appropriate solvent. The disinfecting agents, chemical impregnants, cleansing agents, carrier may or may not be fully or partially biodegradable. 45 deodorants, fragrances, dyes, animal repellents, insect repel Carriers for use with the present invention include per lents, fertilizing agents, pesticides, herbicides, fungicides, meable and semipermeable matrices or polymers that con and plant growth stimulants, and the like. Some non-limiting trol the release characteristics of the formulation. Such examples of active agents are listed hereinbelow. Those polymers include, for example, cellulose acylates, acetates, skilled in the art will appreciate that any of these compounds and other semi-permeable polymers such as those described 50 may be used in the form of their pharmaceutically accept in U.S. Pat. No. 4,285,987 (hereby incorporated by refer able salt forms, e.g., carboxylic acids, with counter-ions, ence), as well as the selectively permeable polymers formed e.g., potassium, Sodium, calcium; as ionic combinations by the coprecipitation of a polycation and a polyanioni as with, e.g., resins, polymers, beads, matrices; with Sugars or disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586: 3,541,005; Sugar derivatives, e.g., malate, tannate; amino acids, lipids, 3.541,006 and 3.546,142 (relevant portions incorporated 55 oils or combinations, mixtures and the like. In some embodi herein by reference). ments, the present inventors have found that certain actives Other carriers for use with the present invention include, may be provided with two different salts, each of which may e.g., starch, modified starch, and starch derivatives, gums, have a different solubility and/or release profile under, e.g., including but not limited to Xanthan gum, alginic acid, other physiologic conditions. In fact, liquid formulation of present alginates, benitonite, Veegum, agar, guar, locust bean gum, 60 invention includes combinations of one or more of the gum arabic, quince psyllium, flax seed, okra gum, arabinog following: immediate release, pulsatile release, controlled lactin, pectin, tragacanth, Scleroglucan, dextran, amylose, release, extended release, delayed release, targeted release, amylopectin, dextrin, etc., cross-linked polyvinylpyrroli or targeted delayed release. done, ion-exchange resins, such as potassium polymethacry Some examples of active ingredients suitable for use in late, carrageenan (and derivatives), gum karaya, biosyn 65 the pharmaceutical formulations and methods of the present thetic gum, etc. Other useful polymers include: invention include: hydrophilic, lipophilic, amphiphilic or polycarbonates (linear polyesters of carbonic acid); hydrophobic, and that can be solubilized, dispersed, or US 9,522, 120 B2 10 partially solubilized and dispersed, on or about a carrier. The loratadine, lovastatin, L-thrynoxine, lutein, lycopene, active agent-carrier combination may be coated further to medroxyprogesterone, mifepristone, mefloquine, megestrol encapsulate the agent-carrier combination. Alternatively, an acetate, methadone, methoXSalen, metronidazole, micon active ingredient may also be provided separately from the azole, midazolam, miglitol, minoxidil, mitoxantrone, mon Solid pharmaceutical composition, such as for co-adminis telukast, nabumetone, nalbuphine, naratriptan, nelfinavir, tration. Such active ingredients can be any compound or nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizati mixture of compounds having therapeutic or other value dine, omeprazole, oprevelkin, oestradiol, oxaprozin, pacli when administered to an animal, particularly to a mammal, taxel, paracalcitol, paroxetine, pentazocine, pioglitaZone, Such as drugs, nutrients, coSmaceuticals, nutraceuticals, pizofetin, pravastatin, prednisolone, probucol, progesterone, diagnostic agents, nutritional agents, and the like. The active 10 pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, agents listed below may be found in their native state, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, however, they will generally be provided in the form of a ritanovir, rizatriptan, rosiglitaZone, saquinavir, Sertraline, salt. The active agents listed below include their isomers, Sibutramine, sildenafil citrate, simvastatin, Sirolimus, analogs and derivatives. spironolactone, Sumatriptan, tacrine, tacrolimus, tamoxifen, In one embodiment, the active ingredient agent is hydro 15 tamsulosin, targretin, tazarotene, telmisartan, teniposide, phobic. Hydrophobic active ingredients are compounds with terbinafine, teraZosin, tetrahydrocannabinol, tiagabine, ticlo little or no water solubility. Intrinsic water solubilities (i.e., pidine, tirofibran, tizanidine, topiramate, topotecan, tore water solubility of the unionized form) for hydrophobic mifene, tramadol, tretinoin, troglitaZone, trovafloxacin, ubi active ingredients are less than about 1% by weight, and decarenone, Valsartan, Venlafaxine, Verteporfin, vigabatrin, typically less than about 0.1% or 0.01% by weight. Suitable Vitamin A, vitamin D. Vitamin E. Vitamin K. Zafirlukast, hydrophobic active ingredients are not limited by therapeu Zileuton, Zolmitriptan, Zolpidem, and Zopiclone. Of course, tic category, and can be, for example, analgesics, anti salts, isomers and derivatives of the above-listed hydropho inflammatory agents, antihelmimthics, anti-arrhythmic bic active ingredients may also be used, as well combina agents, anti-bacterial agents, anti-viral agents, anti-coagu tions and mixtures thereof. lants, anti-depressants, anti-diabetics, anti-epileptics, anti 25 In other embodiments, the active ingredient is hydro fungal agents, anti-gout agents, anti-hypertensive agents, philic, however, combination of hydrophilic, hydrophobic anti-malariale, anti-migrainc agents, anti-muscarinic agents, and non-polar agents may also be used. The water Solubility anti-neoplastic agents, erectile dysfunction improvement for hydrophilic active ingredients is generally greater than agents, immunosuppressants, anti-protozoal agents, anti about 0.1% by weight, and typically greater than about 1% thyroid agents, anxiolytic agents, sedatives, hypnotics, neu 30 by weight. Suitable hydrophilic active ingredients include: roleptics, beta.-Blockers, cardiac inotropic agents, corticos analgesics, anti-inflammatory agents, antihelminthics, anti teroids, diuretics, anti-parkinsonian agents, gastro-intestinal arrhythmic agents, anti-bacterial agents, anti-viral agents, agents, histamine receptor antagonists, keratolytics, lipid anti-coagulants, anti-depressants, anti-diabetics, anti-epilep regulating agents, anti-anginal agents, cox-2 inhibitors, leu tics, anti-fungal agents, anti-gout agents, anti-hypertensive kotriene inhibitors, macrollides, muscle relaxants, nutritional 35 agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, opioid analgesics, protease inhibitors, sex hormones, agents, anti-neoplastic agents, erectile dysfunction improve stimulants, muscle relaxants, anti-osteoporosis agents, anti ment agents, immunosuppressants, anti-protozoal agents, obesity agents, cognition enhancers, anti-urinary inconti anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, nence agents, nutritional oils, anti-benign prostate hypertro neuroleptics, beta.-Blockers, cardiac inotropic agents, cor phy agents, essential fatty acids, non-essential fatty acids, 40 ticosteroids, diuretics, anti-parkinsonian agents, gastro-in and mixtures thereof. Salts, isomers and derivatives of the testinal agents, histamine receptor antagonists, keratolytics, above-listed hydrophobic active ingredients may also be lipid regulating agents, anti-anginal agents, cox-2 inhibitors, used, as well as combinations and mixtures thereof. leukotriene inhibitors, macrollides, muscle relaxants, nutri Other examples of suitable hydrophobic active ingredi tional agents, opioid analgesics, protease inhibitors, sex ents include: acetretin, albendazole, albuterol, aminoglute 45 hormones, stimulants, muscle relaxants, anti-osteoporosis thimide, amiodarone, amlodipine, amphetamine, amphoteri agents, anti-obesity agents, cognition enhancers, anti-uri cin B, atorvastatin, atovaquone, azithromycin, baclofen, nary incontinence agents, nutritional oils, anti-benign pros beclomethasone, benezepril, benzonatate, betamethasone, tate hypertrophy agents, essential fatty acids, non-essential bicalutanide, budesonide, bupropion, buSulfan, butenafine, fatty acids, and mixtures thereof. calcifediol, calcipotriene, calcitriol, camptothecin, candesar 50 Other hydrophilic active ingredients include: a cytokine, tan, capsaicin, carbameZepine, carotenes, celecoxib, ceriv a peptidomimetic, a peptide, a protein, a toxoid, a serum, an astatin, cetirizine, chlorpheniramine, cholecalciferol, cil antibody, a vaccine, a nucleoside, a nucleotide, a portion of ostaZol, cimetidine, cinnarizine, ciprofloxacin, cisapride, genetic material, a nucleic acid, or a mixture thereof. Other clarithromycin, clemastine, clomiphene, clomipramine, examples of Suitable hydrophilic active ingredients include: clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, 55 acarbose; acyclovir, acetyl cysteine; acetylcholine, chloride; cyclosporin, danazol, dantrolene, dexchlorpheniramine, alatrofloxacin; alendronate; aglucerase; amantadine hydro diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, chloride; ambenomium; amifostine; amiloride hydrochlo dihydroergotamine, dihydrotachysterol, dirithromycin, ride; aminocaproic acid; amphotericin B; antihemophilic doneZepil, efavirenz, eposartan, ergocalciferol, ergotamine, factor (human), antihemophilic factor (porcine); antihemo essential fatty acid sources, etodolac, etoposide, famotidine, 60 philic factor (recombinant), aprotining asparaginase; fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, atenolol; atracurium besylate; atropine; azithromycin; flurbiprofen, fluvastatin, fosphenyloin, froVatriptan, fura aztreonam, BCG vaccine; bacitracin; becalermin; belladona; Zolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, bepridil hydrochloride; bleomnycin sulfate; calcitonin glyburide, glimepiride, griseofulvin, halofantrine, ibupro human; calcitonin Salmon; carboplatin: capecitabine; fen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, 65 capreomycin Sulfate; cefamandole nafate, cefazolin Sodium; itraconazole, ivermectin, ketoconazole, ketorolac, lam cefepime hydrochloride, cefixime; cefonicid sodium, cefop otrigine, lanSoprazole, leflunomide, lisinopril, loperamide, eraZone, cefotetan disodium, cefotaxime, cefoxitin Sodium; US 9,522, 120 B2 11 12 ceftizoxime; ceftriaxone, cefuroxime axetil, cephalexin; antihistamines (e.g., dimenhydrinate, diphenhydramine, cephapirin Sodium; cholera vaccine; chorionic gonadotro chlorpheniramine and dexchlorpheniramine maleate), anal pin; cidofovir, cisplatin: cladribine; clidinium bromide; clin gesics (e.g., aspirin, codeine, morphine, dihydromorphone, damycin and clindamycin derivatives; ciprofloxacin; clodro oxycodone, etc.), non-steroidal anti-inflammatory agents nate; colistimethate sodium; colistin Sulfate; corticotropin; (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, Sulin cosyntropin; cromolyn Sodium; cytarabine; dalteparin dac), anti-emetics (e.g., metoclopramide), anti-epileptics Sodium; danaparoid; desferrioxamine; denileukin diflitox; (e.g., phenyloin, meprobamate and nitreZepam), Vasodila desmopressin; diatrizoate meglumine and diatrizoate tors (e.g., nifedipine, papaverine, diltiazem and nicardirine), Sodium; dicyclomine; didanosine; dirithromycin; dopamine anti-tussive agents and expectorants (e.g., codeine phos hydrochloride; dornase alpha: doxacurium chloride, doxo 10 phate), anti-asthmatics (e.g. theophylline), antacids, anti rubicin; etidronate disodium; enalaprilat, enkephalin; enox spasmodics (e.g., atropine, Scopolamine), antidiabetics (e.g., aparin; enoxaprin Sodium; ephedrine; epinephrine; epoetin insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), alpha; erythromycin; esmolol hydrochloride; factor IX; fam anti-thypotensives (e.g., propranolol, clonidine), antihyper ciclovir, fludarabine; fluoxetine; foscarnet Sodium; ganci tensives (e.g., clonidine, methyldopa), bronchodilators (e.g., clovir, granulocyte colony stimulating factor, granulocyte 15 albuterol), Steroids (e.g., hydrocortisone, triamcinolone, macrophage stimulating factor; growth hormones— prednisone), antibiotics (e.g., tetracycline), antihemorrhoid recombinant human; growth hormone-bovine; gentamycin; als, hypnotics, psycho-tropics, antidiarrheals, mucolytics, glucagon; glycopyrolate; gonadotropin releasing hormone sedatives, decongestants, laxatives, vitamins, stimulants (in and synthetic analogs thereof, GnRH; gonadorelin; grepa cluding appetite Suppressants such as phenylpropa floxacin; haemophilus B conjugate vaccine; Hepatitis A nolamine), as well as salts, hydrates, and Solvates of the virus vaccine inactivated; Hepatitis B virus vaccine inacti same. The above list is not meant to be exclusive. vated; heparin Sodium; indinavir Sulfate; influenza virus In certain embodiments, the therapeutically active agent vaccine; interleukin-2, interleukin-3; insulin-human, insulin comprises hydromorphone, oxycodone, dihydrocodeine, lispro; insulin procine; insulin NPH; insulin aspart; insulin codeine, dihydromorphine, morphine, buprenorphine, salts, glargine; insulin detemir, interferon alpha; interferon beta; 25 hydrates and Solvates of any of the foregoing, mixtures of ipratropium bromide; ifosfamide; Japanese encephalitis any of the foregoing, and the like. In other embodiments, the virus vaccine; lamivudine; leucovorin calcium; leuprolide active agent is a locally active therapeutic agent and the acetate, levofloxacin; lincomycin and lincomycin deriva environment of use may be, e.g., the gastrointestinal tract, or tives; lobucavir, lomefloxacin; loracarbef mannitol, is body cavities such as the oral cavity, periodontal pockets, measles virus vaccine; meningococcal vaccine; menotro 30 Surgical wounds, the rectum or vagina. The liquid formula pins; mepenZolate bromide; mesalamine; methenamine; tions of the present invention may be provided orally, methotrexate; methscopolamine; metformin hydrochloride: topically, subcutaneously, intramuscularly, intraperitoneally, metoprolol; mezocillin Sodium; mivacurium chloride; intraocularly, intraossealy, nasally, urethrally, mucosally, mumps viral vaccine; nedocromil sodium; neostigmine bro vaginally, rectally, intradurally, epidurally and the like. The mide; neostigmine methyl sulfate; neurontin; norfloxacin; 35 liquid formulation of the present invention may also be octreotide acetate; ofloxacin; olpadronate; oxytocin, provided as a mist, e.g., to the deep lung (alveolarly). pamidronate disodium; pancuronium bromide; paroxetine; Locally active pharmaceutical agents of use with the perfloxacin; pentamidine isethionate; pentostatin: pentoxif present inveention include antifungal agents (e.g., ampho ylline; periciclovir, pentagastrin; pentholamine mesylate; tericin B, clotrimazole, nystatin, ketoconazole, miconazol. phenylalanine; physostigmine salicylate; plague vaccine; 40 etc.), antibiotic agents (penicillins, cephalosporins, erythro piperacillin Sodium; platelet derived growth factor-human; mycin, tetracycline, aminoglycosides, etc.), antiviral agents pneumococcal vaccine polyvalent; poliovirus vaccine inac (e.g., acyclovir, idoxuridine, etc.), breath fresheners (e.g. tivated; poliovirus vaccine live (OPV); polymyxin B sulfate; chlorophyll), antitussive agents (e.g., dextromethorphan pralidoxime chloride; pramlintide, pregabalin; propafenone; hydrochloride), anti-cariogenic compounds (e.g. metallic propenthaline bromide: pyridostigmine bromide; rabies vac 45 salts of fluoride, Sodium monofluorophosphate, Stannous cine; residronate; ribavarin, rimantadine hydrochloride; fluoride, amine fluorides), analgesic agents (e.g., methylsali rotavirus vaccine; Salmeterol Xinafoate: Sinealide; Smallpox cylate, Salicylic acid, etc.), local anesthetics (e.g., benzo vaccine; solatol; somatostatin; Sparfloxacin; spectinomycin; caine), oral anti-septics (e.g., chlorhexidine and salts stavudine; streptokinase; streptozocin, suxamethonium thereof, hexylresorcinol, dequalinium chloride, cetylpyri chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; 50 dinium chloride), anti-flammatory agents (e.g., dexametha ticarcillin; tiludronate; timolol; tissue type plasminogen acti Sone, betamethasone, prednisone, prednisolone, triamcino vator; TNFR:Fc: TNK-tRA; trandolapril; trimetrexate glu lone, hydrocortisone, etc.), hormonal agents (oestriol), conate; trospectinomycin; trovafloxacin; tubocurarine chlo antiplaque agents (e.g., chlorhexidine and salts thereof, ride; tumor necrosis factor, typhoid vaccine live; urea; octenidine, and mixtures of thymol, menthol, methysalicy urokinase; Vancomycin; Valacyclovir, Valsartan; varicella 55 late, eucalyptol), acidity reducing agents (e.g., buffering virus Vaccine live; vasopressin and vasopressin derivatives; agents such as potassium phosphate dibasic, calcium car vecuronium bromide; vinblastine; Vincristine; vinorelbine; bonate, sodium bicarbonate, sodium and potassium hydrox vitamin B 12; warfarin sodium; yellow fever vaccine; Zal ide, etc.), and tooth desensitizers (e.g., potassium nitrate). citabine; Zanamivir; Zolendronate; zidovudine; pharmaceu This list is not meant to be exclusive. Other embodiments of tically acceptable salts, isomers and derivatives thereof, and 60 the present invention include disinfecting agents, e.g., chlo mixtures thereof. rine compounds Such as calcium hypochlorite, and the A wide variety of therapeutically active agents can be environment of use is a Surrounding body of water, e.g. a used in conjunction with the present invention. The thera recreational pool. The active may be one or more cleansing peutically active agents (e.g. pharmaceutical agents) which agents, a germicide, a deodorant, a Surfactant, a fragrance, a may be used in the compositions of the present invention 65 perfume, a sanitizer, and/or a dye, and the environment of include both water soluble and water insoluble drugs. use is an aqueous Solution, e.g. a urinal or toilet bowl. Examples of Such therapeutically active agents include Examples of fragrances include: perfume oils, volatile US 9,522, 120 B2 13 14 compounds including esters, ethers aldehydes, alcohols, Other actives may also be included with the present unsaturated hydrocarbons, terpenes, and other ingredients invention, e.g., non-steroidal anti-inflammatory drugs well known in the art. (NSAIDs) such as propionic acid derivatives; acetic acid The liquid formulation may also include active agents derivatives; fenamic acid derivatives; biphenylcarboxylic with one or more chemical agents, e.g., fertilizers, animal acid derivatives; and oxicams. Examples of propionic acid repellents, insect repellents, pesticides, herbicides, fungi derivatives include: ibuprofen, naproxen, ketoprofen, flur cides, plant growth stimulants, and the environment of use biprofen, fenoprofen, Suprofen, fenbufen, and fluprofen may is, e.g., anywhere around the home, e.g. soil, trees etc. The be mentioned as preferred compounds. Acetic acid deriva fertilizer may be, for example, a nitrogen containing com tives derivatives include: tolmetin Sodium, Zomepirac, Sulin 10 dac and indomethacin. Fenamic acid derivatives derivatives pound such as urea, urea formaldehyde composites, potas include: mefenamic acid and meclofenamate Sodium. sium nitrate, potassium Sulfate, potassium chloride, ammo Diflunisal and flufenisal are biphenylcarboxylic acid deriva nium nitrate, ammonium sulfate, monoammonium tives, while oxicams include piroXicam, Sudoxicam and phosphate, dibasic ammonium phosphate, ammoniated isoxicam. Other analgesics for use with the present inven Super-phosphoric acid, micronutrient ingredients such as 15 tion include acetominophen and phenacetin. Naproxen may trace elements of iron, Zinc, manganese, copper, boron, be present in amounts of about 50 to about 250 milligrams molybdenum, and mixtures of any of the foregoing. In these per liquid dose, however, naproxen may be used in amounts embodiments, the thickness of the controlled release coating of between about 100 and about 150 milligrams per liquid will depend upon, among other things, the desired rate and dose. overall time period for release of an effective amount of the Phenylephrine may be present in amounts of between active agent. In some circumstances where a relatively long about 15 and about 60 milligrams per liquid dose. Phe time period of efficacy is desired, the substrate may be nylephrine is generally in amounts of about 5 to about 30 coated to a relatively high weight gain of, e.g., up to 50% or milligrams per liquid dose, with half or less of that amount O. used in a pediatric form of the formulation. In one example The examples herein include pharmaceutically active 25 of the present invention, phenylephrine is provided in the compounds useful in the practice of the present invention, amount of about 15 mg for extended release. Phenylephrine e.g., antihistamines, decongestants, antitussives and/or hydrochloride is an orally effective nasal decongestant. expectorants. Other actives for use with the present inven Chemically it is (S)-3-hydroxy-C(methylamino) methyl tion include, but are not limited to: non-steroidal anti benzenemethanol hydrochloride. Phenylepherine is a syn inflammatory drugs (NSAIDs) and other analgesic drugs 30 thetic, optically active sympathomimetic amine that has one Such as acetominophen and phenacetin. These materials are hydroxyl group on the benzene ring. The hydroxyl group is incorporated into the immediate or controlled release for placed in the position meta to the aliphatic side chain. The mulations of the invention in amounts governed by the meta position affords optimal activity and phenylepherine desired release characteristics of the material in Such excipi (neo-synephrine) replaced an older preparation, Synephrine, ent base and Such that conventional dosages comply with 35 in which the hydroxyl was in the para position. applicable federal Food and Drug Administration (FDA) or Phenylephrine hydrochloride is available in the form of other regulations. the levorotatory isomer, a white, odorless, non-hygroscopic, Decongestants useful with the present invention (along crystalline compound possessing a bitter taste. Phenyleph with a salt form) are phenylephrine (bitartrate, tannate, HBr, rine hydrochloride has a melting point of 140-145 degrees C. HCl), phenylpropanolamine (HCl) and pseudoephedrine 40 and is freely soluble in water and alcohol. Decongestant (HCl). Furthermore, a number of herbal and/or natural compounds in the form of their free bases as well as their decongestants are known in the art, all of which may be used salts, e.g., hydrochloride, citrate, maleate, tannate, etc., are with the present invention. well known. Expectorants for use with the present invention include, Dextromethorphan may be present in amounts of between e.g., guaifenesin, terpin hydrate, (glyceryl guaiacolate), 45 about 5 and about 20 milligrams per liquid dose, with a potassium (iodide, citrate) and potassium guaicolsulfonate. general range of about 10 to about 15 milligrams. Bromphe Other expectorants, whether individual ingredients or com niramine may be present in amounts of between about 0.5 binations of ingredients may be used with the present and about 4.0 milligrams per liquid dose with a general invention. Furthermore, a number of herbal and/or natural range of about 2.0 milligrams per liquid dose. Half or less of expectorants are known in the art, all of which may be used 50 that amount may be used in a pediatric form of the formu with the present invention, e.g., Oregano Leaf Extract lation. 25-500 mg (which may be a liquid extract), Red Clover The present invention may also include chlorpheniramine, 25-500 mg. Buckthorn Root 25-500 mg. or Fenugreek which is an antihistamine used to relieve, e.g., allergic 25-500 mg. or mixtures thereof. rhinitis (seasonal allergy). The symptoms of allergic rhinitis Examples of antihistamines for use with the present 55 include: Sneezing, runny nose, itching, and watery eyes. invention (e.g., in Salt form) are chlorpheniramine (maleate), Chlorpheniramine may also be used to treat immediate brompheniramine (maleate), dexchlorpheniramine allergic reactions. Chlorpheniramine may be provided alone (maleate), dexbrompheniramine (maleate), triprolidine and in combination with other prescription or nonprescrip (HCl), diphenhydramine (HCl), doxylamine (succinate), tion drugs, e.g., to treat symptoms of allergy, colds, and tripelennamine (HCl), cyproheptatine (HCl), bromodiphen 60 upper respiratory infections. hydramine (HCl), phenindamine (tartrate), pyrilamine The present invention may also include one or more (maleate, tannate) and azatadine (maleate). Antitussives that analgesics, e.g., acetaminophen may be present in amounts may be used with the present invention (with salt form) of up to about 600 milligrams per liquid dose. Generally, include: caramiphen (edisylate), dextromethorphan (HBr) acetaminophen is present in amounts of about 50 to about and codeine (phosphate, sulfate). A number of herbal and/or 65 200 milligrams per liquid dose. Another example is ibupro natural antihistamines are known in the art, all of which may fen, which may be used in amounts of, e.g., 150 milligrams, be used with the present invention. with a range of about 50 and about 150 milligrams per dose US 9,522, 120 B2 15 16 being used generally. Half or less of that amount may be mophenylsulfonic acid, propionic acid, p-toluenesulfonic used in a pediatric form of the formulation. acid, Salicylic acid, Stearic acid, Succinic acid, tannic acid, In one example of the present invention, an expectorant tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric (e.g., Guaifenesin DC) is provided at lower doses and is acid. made available immediately for absorption, followed by a In some formulations additives may also include: chelat lower dose of a decongestant (e.g., phenylephrine) which is ing agents (such as EDTA and EDTA salts); colorants or release slowly over, e.g., about 1 to 8 hrs. This release profile opaquants (such as titanium dioxide, food dyes, lakes, makes the product more efficacious since the large amount natural vegetable colorants, iron oxides, silicates, Sulfates, of expectorant begins to break up mucus prior to the time the magnesium hydroxide and aluminum hydroxide); coolants decongestant is released to provide long acting decongestant 10 (e.g., trichloroethane, trichloroethylene, dichloromethane, activity after mucus breakdown has begun. fluorotrichloromethane); cryoprotectants (such as trehelose, Generally, guaifenesin is present in amounts of about 10 phosphates, citric acid, tartaric acid, gelatin, dextran and to about 600 milligrams per liquid dose. Guaifenesin may be mannitol); and diluents or fillers (such as lactose, mannitol, present in amounts of 100, 150, 200, 300, 400, 440, 500 or talc, magnesium Stearate, sodium chloride, potassium chlo even 600 or more milligrams per liquid dose. In one 15 ride, citric acid, spray-dried lactose, hydrolyzed starches, example, guaifenesin is present in amounts of about 100 to directly compressible starch, microcrystalline cellulose, cel about 200 milligrams per liquid dose, with half or less of that lulosics, Sorbitol. Sucrose. Sucrose-based materials, calcium amount used in a pediatric form of the formulation. Sulfate, dibasic calcium phosphate and dextrose). In one example, 400 milligrams of guaifenesin are Substrates. A powder constitutes a finely divided (milled, included as an active for immediate release. Guaifenesin is micronized, nanosized, precipitated) form of an active ingre an expectorant that increases the output of phlegm (sputum) dient or additive molecular aggregates or a compound and bronchial Secretions by reducing adhesiveness and Sur aggregate of multiple components or a physical mixture of face tension. The increased flow of less viscous secretions aggregates of an active ingredient and/or additives. Such promotes cilliary action and facilitates the removal of substrates may be formed of various materials known in the mucus. Hence, expectorants such as guaifenesin change a 25 art, Such as, for example: Sugars, such as lactose, Sucrose or dry, unproductive cough to one that is more productive and dextrose; polysaccharides, such as maltodextrin or dextrates; less frequent. Guaifenesin, known chemically as 3 (2- starches; cellulosics, such as microcrystalline cellulose or methoxyphenoxy)-1,2-propanediol, is a crystalline powder microcrystalline cellulose/sodium carboxymethyl cellulose; soluble in water and alcohol. It is indicated in the USP Drug inorganics, such as dicalcium phosphate, hydroxyapitite, information as an expectorant for the symptomatic relief of 30 tricalcium phosphate, talc, or titania; and polyols, such as cough due to colds and minor upper respiratory infections. mannitol, xylitol, sorbitol or cyclodextrin. Excipients for use with the present invention are well It should be emphasized that a substrate need not be a known to those of skill in the art and include humectants solid material, although often it will be a solid. For example, Such as glycerin and propylene glycol, preservatives Such as the encapsulation coat on the Substrate may act as a solid Sodium benzoate and paraben, Sweeteners such as sodium 35 "shell Surrounding and encapsulating a liquid, semi-liquid, saccharin, corn syrup and Sorbitol Solutions, menthol and powder or other substrate material. Such substrates are also various flavoring and coloring agents. The pharmaceutically within the scope of the present invention, as it is ultimately active compounds and excipients for human use should be of the carrier, of which the substrate is a part, which must be a N.F. or U.S.P. grade. solid. For certain actives it may be useful to provide buffering 40 Excipients. The solid pharmaceutical compositions Sus agents (or bufferants), where the acid is a pharmaceutically pended in the liquid formulation of the present invention acceptable acid, such as hydrochloric acid, hydrobromic may include optionally one or more additives, sometimes acid, hydriodic acid, Sulfuric acid, nitric acid, boric acid, referred to as additives. The excipients may be contained in phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic an encapsulation coat in compositions, which include an acid, alkanesulfonic acid, amino acids, ascorbic acid, ben 45 encapsulation coat, or can be part of the solid carrier, Such Zoic acid, boric acid, butyric acid, carbonic acid, citric acid, as coated to an encapsulation coat, or contained within the fatty acids, formic acid, fumaric acid, gluconic acid, hyd components forming the Solid carrier. Alternatively, the roquinosulfonic acid, isoascorbic acid, lactic acid, maleic excipients can be contained in the pharmaceutical compo acid, methanesulfonic acid, oxalic acid, para-bromophenyl sition but not part of the solid carrier itself. Sulfonic acid, propionic acid, p-toluenesulfonic acid, Sali 50 Solubilizers. The pharmaceutical compositions of the cylic acid, Stearic acid, Succinic acid, tannic acid, tartaric present invention may include optionally one or more solu acid, thioglycolic acid, toluenesulfonic acid and uric acid, bilizers, i.e., additives to increase the solubility of the and where the base is a pharmaceutically acceptable base, pharmaceutical active ingredient or other composition com Such as an amino acid, an amino acid ester, ammonium ponents in the Solid carrier. It has been recognized by the hydroxide, potassium hydroxide, Sodium hydroxide, sodium 55 present inventors that guaifenesin, in fact, acts as a solubi hydrogen carbonate, aluminum hydroxide, calcium carbon lizer for phenylephrine, and is used as such in the examples ate, magnesium hydroxide, magnesium aluminum silicate, provided herein. Other solubilizers are known in the art. synthetic aluminum silicate, synthetic hydrotalcite, magne Mixtures of solubilizers are also within the scope of the sium aluminum hydroxide, diisopropylethylamine, etha invention and are readily available from standard commer nolamine, ethylenediamine, triethanolamine, triethylamine, 60 cial sources. triisopropanolamine, or a salt of a pharmaceutically accept The amount of solubilizer that may be included in com able cation and acetic acid, acrylic acid, adipic acid, alginic positions of the present invention is not particularly limited. acid, alkanesulfonic acid, an amino acid, ascorbic acid, Of course, when Such compositions are administered to a benzoic acid, boric acid, butyric acid, carbonic acid, citric patient, the amount of a given solubilizer is limited to a acid, a fatty acid, formic acid, fumaric acid, gluconic acid, 65 bioacceptable amount, which is readily determined by one hydroquinosulfonic acid, isoascorbic acid, lactic acid, of skill in the art. In some circumstances, it may be advan maleic acid, methanesulfonic acid, oxalic acid, para-bro tageous to include amounts of solubilizers far in excess of US 9,522, 120 B2 17 18 bioacceptable amounts, for example, to maximize the con the Surface mixing, as with a propeller driven, variable speed centration of active ingredient, with excess solubilizer mixer at speeds and rates that minimize, reduce or eliminate removed prior to providing the composition to a patient blade cavitation, thereby reducing the amount of gas or air using conventional techniques, such as distillation or evapo that enters the mixture. ration. The one or more active agents are selected and prepared The following are general instructions common to most (block 126), obtained or purchased. The amount of active is liquid manufacturing as will be known to the skilled artisan. calculated and the appropriate amounts are weighted (block For example, first, it is determined is all of the raw materials 128). If the active is not pre-coated, in block 130, the beads, are available for this manufacturing process. All of the raw particles, polymers, resins, etc. may be coated as described materials are checked for correct identity and Quality ASSur 10 hereinbelow or using any number of coating materials and ance release. All personnel involved in the manufacturing methods known to the skilled artisan. Generally, the density process must be familiar with the active ingredients Material and/or coefficient of viscosity of the final coated particles Safety Data Sheet and for those involved in the manufac with the active agent will beat, around or about that of the turing process, these must wear appropriate attire and use the combined thickening and thixotropic agent (to minimize the appropriate safety equipment. Standard microbiological pre 15 need for mixing of the liquid formulation prior to use). One cautions are followed, e.g., avoidance of contact with the advantage of using a thixotropic agent is that it reduces the raw materials and use of gloves during the manufacturing need to closely match the densities of the active particles and process. When using water, water purity is verified and use the final Solution, as the thixotropic agent 'gels' when of a Purified Water System is recommended. Prior to use standing, thereby limiting the amount of settling of the allow the water to run to waste for 15 seconds. Assure that active during a normal, short-term dosing period (e.g., 1-day the water quality is greater than 14 megohm-cm (MS2-cm) to 2 weeks). Finally, the active agents (which may still be on the second deionized water finishing tank. dry) may be mixed with one or more excipients, coating, FIG. 1 is a flow chart 100 that summarizes the basic steps flavorings, color and the like (which may also be dry) and in the method of the present invention. In this flow chart 100, the mixture is blended (block 132). four basic branches and processing steps or systems are used 25 The four branches depicted in flow chart 100 may be to reach a final mixing or blending step (102), each of which combined into less or divided into more branches depending provides one component that may be used with the present on the actives, excipients, thickeners and thixotropic agents invention. In block 104, a thickening agent is added to a used. For example, is the actives are dry and the colorants, vessel or container that will provide, e.g., density control to flavorants, etc., are not, then these may be added to a liquid the final solution. The thickening agent, e.g., a syrup (corn, 30 solution (e.g., at blocks 110, 118 and/or 124). It may also be rice, wheat, Soy, maple, pine) is heated to decrease its advantageous to mix actives (beads, particles, polymers, viscosity (block 106) for a sufficient time to provide an even etc.) in with liquid portions and/or in water. temperature and/or decrease its viscosity without burning the thickener. In block 108, water (room temperature or Example 1 heated) is slowly added to the thickening agent along the 35 sides of the vessel and at a rate that minimizes the intro Capsule shells and process: 7.5% phenylephrine imme duction of air or bubbles to the thickening agent. The mixing diate release beads where used as starting material. A portion step will generally use below the Surface mixing, as with a of this lot was transferred to a rotating pan. Phenylephrine propeller driven, variable speed mixer at speeds and rates was added to the beads using of pharmaceutical glaze. The that minimize, reduce or eliminate blade cavitation, thereby 40 beads were then allowed to roll and cure for 6 hours before reducing the amount of gas or air that enters the mixture. The Sustained release coating was added. In-order to develop the blended water and thickener are then allowed to rest at block product, four different levels of sustained release coating 110 and are stored pending further steps. amounts were added. In one example, 10.93 Kgs of phe In block 112, one or more preservatives are added to a nylephrine were added to the beads using 4.32 Kgs of vessel or container and dissolved in accordance with the 45 pharmaceutical glaze. The beads were then allowed to roll manufacturers instructions, e.g., by adding a solvent (block and cure for 6 hours before Sustained release coating was 114) that may be water or a polar or non-polar solvent. added. Alternatively, the encapsulation coat may be prepared Again, the mixing and blending will be conducted so as to by air Suspension chilling, air Suspension drying, compres minimize the introduction of air or bubbles into the mixture. Sion, cryopelletization, encapsulation, extrusion, lyophiliza To further reduce the likelihood of bubble formation, in 50 tion, molding, spheronization, spray chilling, spray congeal block 116, a surfactant is added, again taking care to ing, and spray drying. minimize bubble formation. In some cases it may be appro In order to develop the product four different levels of priate to de-gas the solution at this stage by, e.g., applying Sustained release coating amounts were added. The first was a vacuum or allowing the mixture to settle. Finally, in block 7.15 kgs of SR mix #1 and 4.96 kg's of pharmaceutical 118, the preservative/surfactant mixture is blended and 55 glaze. Once this loading was complete 5.0 kgs were stored for further processing. The mixing step will generally removed for drying and testing. The second load consisted use below the Surface mixing, as with a propeller driven, of 4.75 kgs of SR mix #1 and 2.68 kgs of pharmaceutical variable speed mixer at speeds and rates that minimize, glaze. Again 5.0 kgs of beaded material was removed for reduce or eliminate blade cavitation, thereby reducing the drying at 40°C. and testing. The third load consisted of 5.92 amount of gas or air that enters the mixture. 60 kg’s SR mix #1 and 3.43 kgs of glaze. After application In another branch of the flow chart 100, a thixotropic another 5.0 kgs of beaded material was removed from the agent is added (block 120) to a vessel and the water is added. pan for drying at 40°C. and testing. The fourth and final load The water added to the thixotropic agent may be room consisted of 7.78 kgs of SR mix #1 and 4.56 kg's of temperature or higher to allow the thixotropic agent to Swell pharmaceutical glaze. The entire pan was allowed to roll and (block 122). Finally, once the thixotropic agent has swelled 65 cure under heat lamps for 6 hours before sampling for study. it is mixed to clarify to the maximum extent possible at Below is a list of all theoretical percentages and actual block 124. Again, the mixing step will generally use below assay results for the, above, described material. US 9,522, 120 B2 20 If multiple lots of Dextromethorphan Polistirex Resin are Theoretical Dissolution required, multiply the calculated Assay Value of the partial lot(s) of Dextromethorphan Polistirex Resin by the kg SR Mix PEH% Actual PEH % 90 min, 3 hr, 6 hr available quantity required in kg (Dextromethorphan Poli #1 21.6% 20.8% 4.6%, 18.6%, 59.3% stirex Resin) to get the value. These values are recorded in #2 19.8% 19.3% 0.2%, 0.8%, 11.0% the conversion factor column and enter the kg available of #3 17.8% 17.3% 0.16%, 0.4%, 2.7% the partial(s) in the quantity required in kg (Dextrometho hia 15.5% 15.4% 0.6%, 0.8%, 2.6% rphan Polistirex Resin) column. Divide the remaining conversion factor required by the Based on assay and dissolution profile load #1 was 10 calculated Assay Value of the lot of Dextromethorphan selected for use in further development. The moisture con Polistirex Resin used to complete the weigh-up and enter the tent in load #4 may be higher than those loads dried in the result in the corresponding quantity required in kg (Dex tray drier. This may have contributed to why load #3 and #4 tromethorphan Polistirex Resin) column. Total the quantity have essentially the same dissolution profile despite the required in kg (Dextromethorphan Polistirex Resin) and increased SR mix. 15 enter this value in the Total quantity required in kg (Dex Dissolution: It was found that the dissolution rate of the tromethorphan Polistirex Resin) area. phenylephrine is accelerated when combined with Gaulife Divide each quantity required in kg (Dextromethorphan nesin DC. Due to this effect the testing of the dissolution rate Polistirex Resin) by 0.4 (this 0.4 is a conversion factor for, is achieved by first making a mock-up of the finished e.g., a 2000 Liter batch size) and enter the result(s) in the product. By doing so the suitability of the phenylephrine Amount per Dose in mg (Dextromethorphan Polistirex Resin) column. Total these values and enter the result in the beads was determined more accurately. Direct specifications Total Amount per Dose in mg (Dextromethorphan Polistirex for dissolution were determined once data was collected to Resin) area. The quantity required in kg is transferred accurately predict this rate change. (Dextromethorphan Polistirex Resin) and the amount per 25 dose in mg (Dextromethorphan Polistirex Resin) results to Example 2 the Formula & Weighup Sheet. If only one lot of raw material (Pseudoephedrine Polis Ionic Resin Mix tirex Resin) is required, divide the conversion factor of 34.63 by the calculated Assay Value and enter the result in Another method of controlling the rate of availability 30 the quantity required in kg (Pseudoephedrine Polistirex involves using controlled release matrices. One Such con Resin) column and in the Total quantity required in kg trolled release bead includes adding one or more active (Pseudoephedrine Polistirex Resin) area. Enter the conver agents to one or more resins or polymers. To control the rate sion factor column or N/A are required. of dissolution one or more of the following may be used: If multiple lots of Pseudoephedrine Polistirex Resin are Dextromethorphan Polistirex Resin (15% ETC); Pseu 35 required, multiply the calculated Assay Value of the partial doephedrine Polistirex Resin (15% ETC); and/or Chlorphe lot(s) of Pseudoephedrine Polistirex Resin by the kg avail niramine Polacrilex Resin (15% ETC). These resins may be able quantity required in kg (Pseudoephedrine Polistirex used to deliver therapeutically effective amounts of Chlo Resin) to get the Partial conversion factor. Enter the value rpheniramine Polacrilex equivalent to Chlorpheniramine in the conversion factor column. Enter the kg available of Maleate 6 mg/Dextromethorphan Polistirex equivalent to 40 the partial(s) in the quantity required in kg (Pseudoephed Dextromethorphan HBr 30 mg/Pseudoephedrine Polistirex rine Polistirex Resin) column. Subtract the Partial conver equivalent to Pseudoephedrine HC130 mg per 5 ml dose. sion factor(s) from 34.63 to determine the remaining con version factor required. Enter this value in the appropriate TABLE 1. Space. 45 Divide the remaining conversion factor required by the Basic Liquid Suspension calculated Assay Value of the lot of Pseudoephedrine Poli stirex Resin used to complete the weigh-up and enter the Item Description Amount per 5 ml Dose Quantity required result in the corresponding quantity required in kg (Pseu Purified Water, USP 874 kg doephedrine Polistirex Resin) column. Total the quantity High Fructose Corn Syrup 2800.00 mg 1120 kg 50 required in kg is determined and (Pseudoephedrine Polis Propylene Glycol, USP 387.50 mg 155 kg Split into 3 parts - 50 kg/ tirex Resin) this value is entered in the total quantity 95 kg/10 kg required in kg (Pseudoephedrine Polistirex Resin) area. Methylparaben 1.00 mg 0.40 kg Divide each quantity required in kg (Pseudoephedrine Poli Propylparaben 0.25 mg 0.10 kg stirex Resin) by 0.4 (this 0.4 is a conversion factor for, e.g., Polysorbate 80 25.00 mg 10.0 kg 55 Xanthan Gum, NF 14.00 mg 5.60 kg a 2000 Liter batch size) and enter the result(s) in the Amount (Rhodigel 200) per Dose in mg (Pseudoephedrine Polistirex Resin) column. Red Opatint Dye 1.50 mg 0.60 kg Total these values and enter the result in the Total Amount (DG-15008) per Dose in mg (Pseudoephedrine Polistirex Resin) area. Strawberry Flavor 5.25 mg 2.10 kg The quantity required in kg is transferred (Pseudoephedrine (133.19035) 60 Polistirex Resin) and the amount per dose in mg (Pseu doephedrine Polistirex Resin) results to the Formula & If only one lot of raw material Dextromethorphan Polis Weighup Sheet. tirex Resin (15% ETC) is required, the Assay Value is If only one lot of raw material (Pseudoephedrine Polis calculated and entered in the quantity required in kg (Dex tirex Resin) is required, divide the conversion factor of 8.08 tromethorphan Polistirex Resin) column and in the Total 65 by the calculated Assay Value and enter the result in the quantity required in kg (Dextromethorphan Polistirex Resin) quantity required in kg (Chlorpheniramine Polacrilex Resin) aca. column and in the Total quantity required in kg (Chlorphe US 9,522, 120 B2 21 22 niramine Polacrilex Resin) area. Enter 8.08 in the conver TABLE 3 sion factor column and N/A the unrequired rows. If multiple lots of Chlorpheniramine Polacrilex Resin are Basic Two Active Blend required, multiply the calculated Assay Value of the partial Amount lot(s) of Chlorpheniramine Polacrilex Resin by the kg avail per 5 ml able quantity required in kg (Chlorpheniramine Polacrilex Item Description Dose Resin) to get the Partial conversion factor. Enter this(these) Pseudoephedrine 30 mg Polistirex Resin (15% ETC) value(s) in the conversion factor column. Enter the kg Chlorpheniramine 6 mg available of the partial(s) in the quantity required in kg 10 Polacrilex Resin (15% ETC) (Chlorpheniramine Polacrilex Resin) column. Methocel ESLV 19.25 mg (hydroxypropyl methylcellulose, USP) Subtract the Partial conversion factor(s) from 8.08 to Purified Water, USP qs determine the remaining conversion factor required. Divide the remaining conversion factor required by the calculated Assay Value of the lot of Chlorpheniramine Polacrilex Resin 15 Suspension Blending Instructions. All personnel involved used to complete the weigh-up and enter the result in the in the manufacturing process must wear appropriate attire corresponding quantity required in kg (Chlorpheniramine and use the appropriate safety equipment. When using the Diaphragm Pump(s) allow the solution supply valve to be Polacrilex Resin) column. opened and the liquid from the feed solution is allowed to Total the quantity required in kg (Chlorpheniramine prime the pump prior to starting the pump. This is done to Polacrilex Resin) and enter this value in the Total quantity prevent the introduction of air into the feed solution. When required in kg (Chlorpheniramine Polacrilex Resin) area. using the Diaphragm Pump(s) to transfer any solution con Divide each quantity required in kg (Chlorpheniramine taining Propylene Glycol make sure that the lines are Polacrilex Resin) by 0.4 (this 0.4 is a conversion factor for completely drained to avoid the introduction of water into a 2000 Liter batch size) and enter the result(s) in the Amount 25 the solution. per Dose in mg (Chlorpheniramine Polacrilex Resin) col Check room and the oven (or heating device) and check umn. Total these values and enter the result in the Total the Processing Sweep Tank for cleanliness. All steps in the Amount per Dose in mg (Chlorpheniramine Polacrilex process should generally by recorded in the Cleaning, Main Resin) area. Transfer the quantity required in kg (Chlorphe tenance & Use Log(s). Check room and appropriately sized niramine Polacrilex Resin) and the Amount per Dose in mg 30 Open Top Processing Tank for cleanliness. Set up a Dia (Chlorpheniramine Polacrilex Resin) results to the Formula phragm Pump(s) and check for cleanliness. Record in the & Weighup Sheet. Cleaning, Maintenance & Use Log(s). Set up an 87 gallon Plastic Processing Tank, e.g., an 87 gallon processing tank, Resin Blending Instructions. Again, all personnel with a mixer and check for cleanliness. Set up an appropri involved in the manufacturing process must wear appropri 35 ately sized Electric Kettle and check for cleanliness. Verify ate attire and use the appropriate safety equipment. Rooms the cleanliness of the disassembled valves, hoses & connec and binder, e.g., a 20 ft3 V-Blender, are first checked for tions, and other miscellaneous equipment/hardware. Check cleanliness and the observations are record in the Cleaning, all utensils and containers for cleanliness. Label the room, Maintenance & Use Log(s). All equipment, utensils, and equipment, and containers as required. containers are also checked for cleanliness and the room, 40 As shown in FIG. 2, the thickening branch of the method equipment, and containers labeled as required. is depicted. First, the valves and connections of all the Transfer Methocel to the Blender. Blend for 2 minutes. vessels or containers are checked to ensure that they are Next, add Dextromethorphan Polistirex Resin to the clean and that all valves are in the closed position. In block Blender, Pseudoephedrine Polistirex Resin and Chlorpheni 200, the syrup is heated, e.g., corn syrup is placed in the ramine Polacrilex Resin to the Blender. Blend for 5 minutes. 45 heater/oven or alternate heating device at 45° C. for 8 to 12 Discharge the Blender into 2 separate medium sized, pre hours (generally greater than 6 hours, block 202). Next, in weighted, plastic-lined containers (s36 kg each) labeled block 204, the thickening agent is transferred, e.g., corn “Resin Blend'. Make sure that all of the material is removed syrup to the Processing Sweep Tank using a diaphragm from the blender and put aside for preparation of the liquid pump or like pump that minimizes or generally eliminates formulation. 50 the introduction of air or air bubbles into the syrup. If adding the thickening agent from the top of a vessel, the flow of the syrup from the pump to the tank should be directed to the TABLE 2 side of the tank at a volume and with flow slow enough that Basic 3 Active Blend the syrup slides down the side of the tank introduces as little 55 air as possible into the syrup, e.g., in a large batch 800 liters Amount per 5 ml (block 206) and the thickener and water are mixed with a Item Description Dose low or reduced cavitation propeller mixer, paddle mixer and the like. Alternatively, the vessel itself may be heated Dextromethorphan 30 mg thereby eliminating the need for transfer of the liquid; Polistirex Resin (15% ETC) Pseudoephedrine 30 mg 60 however, in Such circumstances the thickening agent should Polistirex Resin (15% ETC) still be introduced into the vessel so as to minimize bubble Chlorpheniramine 6 mg formation. In block 208, the thickener or syrup is allow to Polacrilex Resin (15% ETC) Methocel ESLV 19.25 mg rest for about 30 minutes or more to allow the syrup to settle (hydroxypropyl methylcellulose, USP) and if necessary to allow for cooling and or reduction of the Purified Water, USP qS 65 temperature to, e.g., room temperature. In block 210, the thickener is prepared for transfer into a larger vessel for final mixing using, e.g., a diaphragm or other like pump. US 9,522, 120 B2 23 24 For transfer of the thickener or syrup, the lines for transfer little air as possible (block 508). Rinse the open top pro will be flushed and/or primed through the diaphragm pump cessing tank to the processing Sweep tank with approxi with, e.g., 20 kg of purified water to the processing Sweep mately 50 kg of purified water. Install the electric mixer in tank. For final transfer to a larger final tank, the flow from the processing Sweep tank and Submerge the propeller to the the pump to the tank should be directed to the side of the interface of the corn syrup and the solution from the open tank slow enough that the corn Syrup/purified water slides top processing tank. Angle the mixer propeller so that it does down the side of the tank, introducing as little air as possible. not interfere with the tank sweepers and it does not introduce Allow the corn syrup to sit undisturbed (usually about 30 air to the Solution during operation or scrape the sides of the minutes) to allow any air bubbles to subside. vessel or tank. FIG. 3 summarizes the preparation of a polyethylene 10 Turn the Sweepers of the processing Sweep tank on at the glycol preservative mix. Transfer approximately 800 kg of minimum speed to check for clearance in relation to the purified water to the open top processing tank using the propeller of the electric interface mixer (block 510), without diaphragm pump (if needed) transfer the 50 kg portion of adding the scrapers or spatulas that are often used with propylene glycol to the electric kettle and heat this propyl general liquid mixing. Increase the speed of the tank Sweep ene glycol up to but not to exceed 60°C.) (block 300). Next, 15 ers to, e.g., 45 Hertz and turn on the tank mixer to, e.g., 31 in block 302 a preservative, e.g., methylparaben and/or Hertz. While still running the tank sweepers and the tank propylparaben to the electric kettle. Label the kettle “para mixer, turn on the electric interface mixer and mix for 15 ben solution'. The parabens may be transferred to the kettle minutes. If any air is being introduced into the solution turn at any point during the heating process. Intermittently mix off the electric interface mixer immediately and repeat the the paraben solution in the electric kettle until dissolved. propangle adjustment/sweeper interference procedure. Also in block 302, a Surfactant and/or emulsifying agent, Using the diaphragm pump at a maximum of e.g., 30 psi e.g., polysorbate 80, is added to the kettle containing the recirculate the Solution in the processing Sweep tank for 15 “paraben solution' and mix until the two phases combine to minutes. The flow of the solution from the pump to the tank form one clear phase. If the temperature of the solution has should be directed approximately one foot below the surface cooled significantly it may need to reheated (not to exceed 25 of the Suspension introducing as little air as possible. Turn 60° C.) to form one clear phase. Label the kettle “paraben/ off and remove the electric interface mixer and increase the polysorbate 80 solution.” Transfer the 95 kg portion of speed of the tank sweepers to, e.g., 90 Hertz, while main propylene glycol to a plastic processing tank. Transfer the taining the tank mixer at 31 Hertz. Unless otherwise speci “paraben/polysorbate 80 solution” to the 87 gallon plastic fied, the tank Sweepers and mixer should remain on through processing tank. Rinse the electric kettle to the 87 gallon 30 out the remainder of the manufacturing and packaging plastic processing tank with the 10 kg portion of propylene process. glycol. Turn off the sweepers (leave the mixer on) to the pro FIG. 4 is flow chart of the method for preparing a cessing Sweep tank and remove the recirculation pipe prior thixotropic agent. In block 400, a thixotropic agent such as to this qs step. Using the diaphragm pump qs to, e.g., 2400 Xanthan gum, is added to, e.g., the “paraben/polysorbate 80 35 kg with purified water. The flow of purified water from the Solution' in a processing tank and mix to slurry (usually pump to the tank should be directed to the side of the tank about 10 minutes) (block 402). The xanthan gum will slow enough that it slides down the side of the tank intro generally not dissolve in this slurry, therefore, it is preferable ducing as little air as possible. Immediately after the qs step that the slurry not be allowed to stand without mixing has been completed, turn the tank Sweepers back on at, e.g., because the xanthan gum will settle (block 404). Finally, in 40 90 Hertz. block 406, processing tank’s mixer is turned on and the Reinstall the recirculation pipe approximately one foot mixture is clarified and/or made generally homogenous, below the surface of the suspension. Continue to sweep and taking care to minimize bubble formation for about 1 hour mix, along with recirculation using the diaphragm pump at or more. The mixer may remain “on” for the remainder of a maximum of, e.g., 30 psi, the solution in the processing the manufacturing process. 45 Sweep tank for, e.g., 45 minutes. Generally and depending As shown in FIG. 5, the preservative mix, e.g., the on the materials, the following steps should be performed paraben/polysorbate 80/Xanthan gum mixture, is transferred quickly so that the solution does not sit without mixing. to the open top processing tank (block 500). Again, the flow Assure that all mixing is off (recirculation should remain on) of the solution to the tank should be directed to the side of and remove a small sample in a clear container. the tank so that as little air as possible is introduced. Mix the 50 Notify quality assurance that the batch is ready for Solution in the open top processing tank for a minimum of sampling if the tests performed in prior steps are acceptable. 1 hour, without introducing any air, until the Solution is Sample the batch below the Surface using the sampling tool. homogeneous (uniform appearance with no visible lumps). Make Sure that the appropriate samples are removed. Turn Next, in block 502, a colorant is added, e.g., red opatint dye, the sweeper (at 45 Hertz) and mixer (at 31 Hertz) back on. and flavorant, e.g., Strawberry flavor to the open top pro 55 Reset the recirculation pipe (at 30 psi) so that it is 1 foot cessing tank. Rinse each container to the open top process from the agitation plate of the sweeper. Unless otherwise ing tank with approximately 2 kg of purified water. At block specified herein, these settings may remain constant. Make 506, gradually sprinkle the “resin blend to the open top sure that a 10 mesh in-line filter is installed after the pump processing tank. Continue mixing for a minimum of 30 used to transfer the Suspension to the packaging line. minutes, without introducing any air, until the solution is 60 FIG. 6-8 are graphs that demonstrate the release profile of homogeneous (uniform appearance with no visible lumps). two active agents in a liquid formulation of the present Alternatively, using the diaphragm pump carefully transfer invention. The dissolution profiles of active agents in a the Solution in the open top processing tank to the processing Sustained-release liquid formulation of the present invention Sweep tank containing the thickening agent (block 504), e.g., was tested using, e.g., a standard low pH or a water the corn syrup. The flow of the solution from the open top 65 dissolution profile assays. Briefly, the sustained release processing tank to the processing Sweep tank should be actives were tested for percent release by dissolution in a 37 directed below the Surface of the corn Syrup introducing as degree Celsius water bath in one liter of deionized water into US 9,522, 120 B2 25 26 which 5.0 grams of potassium chloride was dissolved with wherein said formulation is shelf-stable and has a uniform paddles that mix the sample at 150 revolutions per minute appearance with no visible lumps, and (RPMs). A 5 milliliter test sample of the liquid formulation, further wherein said formulation is made by the method of neat or titrated, is added to the bath using a syringe (which obtaining one or more controlled release microbeads may be washed in the water/KCl mix). Aliquots of 2 ml are comprising one or more active agents in coated drug sampled at, e.g., 0.5, 1, 3 and 8 hours. The results of a two resin complexes; active agent formulation and release are shown for three preparing a dense, thixotropic Solution having a density different samples in FIGS. 6-8. The exact formulation used that is at or about the density of the one or more was taught hereinabove in example 2. microbeads, under conditions that reduce bubble for FIG. 9-11 are graphs that demonstrate the release profile 10 of third active agents in a liquid formulation of the present mation; and invention. These graphs demonstrate the release profile of mixing the microbeads and the solution under conditions three active agents in a liquid formulation of the present that minimize the introduction of bubbles in the liquid. invention. The dissolution profiles of active agents in a 2. The liquid formulation of claim 1, wherein the one or Sustained-release liquid formulation of the present invention 15 more active agents comprises pseudophedrine, an antihis was tested using, e.g., a standard low pH or a water tamine, chlorpheniramine, dextromethorphan, an analgesic, dissolution profile assays. Briefly, the sustained release an antitussive, or salts thereof or mixtures thereof. actives were tested for percent release by dissolution in a 37 3. A liquid, controlled-release formulation comprising degree Celsius water bath in one liter of deionized water into controlled release beads comprising one or more active which 5.0 grams of potassium chloride was dissolved with agents in coated drug-resin complexes and a dense, thixo paddles that mix the sample at 150 revolutions per minute tropic Solution having a density that is at or about the density (RPMs). A 5 milliliter test sample of the liquid formulation, of the one or more beads, neat or titrated, is added to the bath using a syringe (which wherein said formulation is shelf-stable and has a uniform may be washed in the water/KCl mix). Aliquots of 2 ml are appearance with no visible lumps, and sampled at, e.g., 0.5, 1, 3 and 8 hours. The results of a three 25 further wherein said formulation is made by the method of active agent formulation and release are shown for three blending one or more controlled release beads comprising different samples in FIGS. 6-8. one or more active agents in coated drug-resin com It will be understood that particular embodiments plexes with a dense, thixotropic Solution having a described herein are shown by way of illustration and not as density that is at or about the density of the one or more limitations of the invention. The principal features of this 30 beads, under conditions that minimize air bubbles invention can be employed in various embodiments without which cling to said beads. departing from the scope of the invention. Those skilled in 4. The liquid formulation of claim 3, wherein said method the art will recognize, or be able to ascertain using no more comprises the step of blending a mixture comprising one or than routine experimentation, numerous equivalents to the more controlled-release beads comprising one or more specific procedures described herein. Such equivalents are 35 active agents, a thickening agent and a Surfactant by mixing considered to be within the scope of this invention and are with a low cavitation propeller and recirculating the mixture covered by the claims. under the surface of the mixture so as to minimize bubble All publications and patent applications mentioned in the formation. specification are indicative of the level of skill of those 5. The liquid formulation of claim 1, wherein the one or skilled in the art to which this invention pertains. All 40 more microbeads comprise one or more of the following: an publications and patent applications are herein incorporated enteric coat, a resin coat, a lacquer coat, a pH-sensitive by reference to the same extent as if each individual publi coating, a biodegradable polymer matrix, a water soluble cation or patent application was specifically and individually matrix, an ionic matrix, combinations and mixtures thereof. indicated to be incorporated by reference. 6. The liquid formulation of claim 1, wherein the one or All of the compositions and/or methods disclosed and 45 more microbeads comprise one or more polymers selected claimed herein can be made and executed without undue from the group consisting of cellulose, ethylcellulose, meth experimentation in light of the present disclosure. While the ylcellulose, propylcellulose, methoxypropylcellulose, cellu compositions and methods of this invention have been lose nitrate, poly(vinyl alcohol), poly(vinyl chloride), poly described in terms of preferred embodiments, it will be styrene, polyethylene, polypropylene, poly(ethylene-co apparent to those of skill in the art that variations may be 50 vinyl acetate), poly(hydroxybutyric acid), poly applied to the compositions and/or methods and in the steps (hydroxyvalerianic acid-co-hydroxybutyric acid), poly or in the sequence of steps of the method described herein (lactic acid), poly(glycolic acid), poly(lactic acid-co without departing from the concept, spirit and scope of the glycolic acid), poly(e-caprolactones), poly(e-caprolactone invention. More specifically, it will be apparent that certain co-DL-lactic acid), poly(maleic anhydride), polyamides, agents which are both chemically and physiologically 55 gelatin, chitosan, collagen, poly(hydroxyalkyl)-L-gluta related may be substituted for the agents described herein mines, poly(Y-ethyl-L-glutaminate-co-glutamic acid), poly while the same or similar results would be achieved. All (L-leucine-co-L-aspartic acid), poly(proline-co-glutamic Such similar Substitutes and modifications apparent to those acid), poly(alkyl 2-cyanoacrylates), polyurethanes, poly(m- skilled in the art are deemed to be within the spirit, scope and ethyl methacrylate), poly(methyl methacrylate-co-meth concept of the invention as defined by the appended claims. 60 acrylic acid) and poly(methacrylate-co-hydroxypropyl methacrylate), polystirex, salts, combinations and mixtures What is claimed is: thereof. 1. A liquid, controlled-release formulation comprising 7. The liquid formulation of claim 1, wherein the condi controlled release microbeads comprising one or more tions that minimize the introduction of bubbles comprise the active agents in coated drug-resin complexes and a dense, 65 step of sprinkling the beads onto the Surface of the liquid, thixotropic Solution having a density that is at or about the and/or the step of mixing the Solution in the absence of density of the one or more microbeads, paddles that scrape the vessel. US 9,522, 120 B2 27 28 8. The liquid formulation of claim 1, wherein the condi agents, antihelminthic agents, insecticides, antihypertensive tions that reduce bubble formation and/or minimize the agents, antihypertensive diuretics, cardiotonics, coronary introduction of bubbles comprise: the step of mixing the Vasodilators, vasoconstrictors, B-blockers, antiarrhythmic solution with a propeller mixer, the step of mixing the agents, calcium antagonists, anti-convulsants, agents for solution with a propeller mixer at a speed that reduces dizziness, tranquilizers, antipsychotics, muscle relaxants, cavitation; the step of mixing the solution with a propeller drugs for Parkinson's disease, respiratory agents, hormones, that minimizes cavitation; the step of placing the recirculat non-steroidal hormones, antihormones, vitamins, antitumor ing tube below the surface of the liquid; and/or the step of agents, miotics, herb medicines, antimuscarinic, interferons, adding liquids along the side of a vessel holding the liquid. immunokines, cytokines, muscarinic cholinergic blocking 9. The liquid formulation of claim 1, wherein the condi 10 agents, mydriatics, psychic energizers, humoral agents, anti tions that reduce bubble formation and/or minimize the spasmodics, antidepressant drugs, anti-diabetics, anorectic introduction of bubbles comprise the steps of placing a drugs, anti-allergenics, decongestants, expectorants, anti recirculating tube below the surface of the liquid, adding pyretics, antimigrane, anti-malarials, anti-ulcerative, pep liquids along the side of a vessel holding the liquid, and tides, anti-estrogen, anti-hormone agents, antiulcer agents, using a mixer that lacks scraping paddles. 15 anesthetic agent, drugs having an action on the central 10. The liquid formulation of claim 1, wherein said nervous system, proteins, carbohydrates, polysaccharides, formulation further comprises one or more active agent glycoproteins, lipids, hormones, growth factors, cytokines, containing beads having an immediate release profile. receptors, antigens, allergens, antibodies, metabolites, 11. The liquid formulation of claim 1, wherein the for cofactors, inhibitors, drugs, pharmaceuticals, nutrients, tox mulation further comprises one or more flavorants, one or ins, poisons, pesticides, chemical warfare agents, prions, more surfactants, one or more dissolved active agents, one radioisotopes, vitamins, heterocyclic aromatic compounds, or more buffers, one or more excipients, or mixtures and carcinogens, mutagens, narcotics, amphetamines, barbitu combinations thereof. rates, hallucinogens, and vaccines against viruses, bacte 12. The liquid formulation of claim 1, wherein the one or rium, fungi, helminths, cancers. Salmonella, Streptococcus, more active agents are pharmaceutical agents, vitamins, 25 Brucella, Legionella, E. coli, Giardia, Cryptosporidium, minerals, nutritional supplements, herbal extracts, oils, salts, Rickettsia, spores, molds, yeasts, algae, amoebae, dinofla or mixtures and combinations thereof. gellates, unicellular organisms, and pathogens, and combi 13. The liquid formulation of claim 1, wherein the one or nations and mixtures thereof. more active agents is/are pharmaceutical agents selected 16. The liquid formulation of claim 1, wherein the one or from the group consisting of proteins, peptides, carbohy 30 more active agents are disposed on a poly-lactic acid (PLA), drates, polysaccharides, glycoproteins, lipids, hormones, poly-glycolic acid (PGA) and/or poly-lactic polyglycolic growth factors, cytokines, interferons, receptors, antigens, acid (PGLA) bead. allergens, antibodies, antiviral agents, antifungal agents, 17. A liquid, controlled-release formulation comprising antihelminthic agents, metabolites, cofactors, inhibitors, controlled release microbeads comprising one or more drugs, pharmaceuticals, nutrients, toxins, poisons, pesti 35 active agents in coated drug-resin complexes, a dense, cides, chemical warfare agents, prions, radioisotopes, vita thixotropic solution having a density that is at or about the mins, heterocyclic aromatic compounds, carcinogens, muta density of the one or more microbeads, said dense, thixo gens, narcotics, amphetamines, barbiturates, hallucinogens, tropic solution comprises a thixotropic agent, water and one and combinations and mixtures thereof. or more preservatives, 14. The liquid formulation of claim 1, wherein the one or 40 wherein said formulation is shelf-stable and has a uniform more active agents comprise a pharmaceutical agent, an appearance with no visible lumps. enzyme, a cytokine, a growth promoting agent, an antibody, 18. The liquid, controlled-release of claim 17, wherein the an antigen, a hormone, a vaccine, a peptide, a carbohydrate, microbeads are free of bubbles that cling to said microbeads a nucleic acid, a lipid, or mixtures and combinations thereof. and change their nominal density. 15. The liquid formulation of claim 1, wherein the one or 45 19. The liquid formulation of claim 1, wherein said more active agents is/are selected from the group consisting Solution comprises a thixotrophic agent, water, and one or of steroids, respiratory agents, sympathomimetics, local more preservatives. anesthetics, antimicrobial agents, antiviral agents, antifungal ck ck ck ci: C