Details for Patent: 8,652,378

Title:	Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
Abstract:	The present invention relates to rapid dissolve thin film drug delivery compositions for the oral administration of active components. The active components are provided as taste-masked or controlled-release coated particles uniformly distributed throughout the film composition. The compositions may be formed by wet casting methods, where the film is cast and controllably dried, or alternatively by an extrusion method.
Inventor(s):	Yang; Robert K. (Flushing, NY), Fuisz; Richard C. (McLean, VA), Myers; Garry L. (Kingsport, TN), Fuisz; Joseph M. (Washington, DC)
Assignee:	MonoSol Rx LLC (Warren, NJ)
Filing Date:	Mar 29, 2013
Application Number:	13/853,237
Claims:	1. A process for manufacturing a resulting pharmaceutical film suitable for commercialization and regulatory approval said resulting pharmaceutical film having a substantially uniform distribution of a desired amount of a pharmaceutical active in individual doses of the resulting pharmaceutical film, comprising the steps of: (a) forming a visco-elastic polymer matrix by mixing, said matrix comprising a polymer selected from the group consisting of water-soluble polymers, water-swellable polymers and combinations thereof, a solvent selected from the group consisting of water, a polar organic solvent and combinations thereof, and pharmaceutical active, which polymer matrix during film casting is a shear-thinning pseudoplastic fluid when exposed to shear rates of 10-10.sup.5 sec.sup.-1, said polymer matrix having a substantially uniform distribution of said pharmaceutical active; (b) casting said polymer matrix; (c) conveying said polymer matrix through a drying apparatus and drying said polymer matrix, to rapidly remove at least a portion of said solvent from said matrix to form a visco-elastic film having said pharmaceutical active substantially uniformly distributed throughout by rapidly increasing the viscosity of said polymer matrix upon initiation of drying within about the first 4 minutes to maintain said uniform distribution of said pharmaceutical active by locking-in or substantially preventing migration of said pharmaceutical active, wherein the temperature of the polymer matrix is 100.degree. C. or less, wherein content uniformity of said active in substantially equal sized individual dosage units of said visco-elastic film is such that the amount of the active varies by no more than 10% from the desired amount; and (d) forming the resulting pharmaceutical film having a water content of 10% or less and a thickness of about 0.1 mils to about 10 mils from said visco-elastic film, wherein said resulting pharmaceutical film having said substantially uniform distribution of pharmaceutical active by said locking-in or substantially preventing migration of said pharmaceutical active is maintained, such that content uniformity of said active in substantially equal sized individual dosage units of said resulting pharmaceutical film is such that the amount of the active varies by no more than 10% from the desired amount. 2. The process of claim 1, wherein said polymer comprises a polymer selected from the group consisting of cellulose, a cellulose derivative, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carboxyvinyl copolymers, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium alginate, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof, alone or in combination with polyethylene oxide. 3. The process of claim 1, wherein the active is selected from the group consisting of ace-inhibitors, anti-anginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, antilipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, antiuricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, anti-obesity drugs, erythropoietic drugs, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof. 4. The process of claim 1, wherein said active is selected from the group consisting of antigens, allergens, spores, microorganisms, seeds, enzymes, vitamins, bioactive active, amino acid preparations, sildenafils, tadalafils, vardenafils, apomorphines, yohimbine hydrochlorides, alprostadils, anti-diabetic agents, non-steroidal anti-inflammatory agents, biological response modifiers, anti-Alzheimer's agents, anesthetic agents, analgesic agents and combinations thereof. 5. The process of claim 1, wherein the active is a protein or a glycoprotein. 6. The process of claim 1, wherein the active is insulin. 7. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said active to an individual through the buccal cavity of said individual. 8. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said active to an individual through gingival application of said resulting pharmaceutical film. 9. The process of claim 1, wherein said active is a hormone. 10. The process of claim 1, wherein said active is taste-masked. 11. The process of claim 1, wherein said active is coated with a controlled release composition. 12. The process of claim 11, wherein said controlled release composition provides at least one of the following: an immediate release, a delayed release, a sustained release or a sequential release. 13. The process of claim 1, further comprising a step of providing a second film layer. 14. The process of claim 13, wherein said second film layer is coated onto said resulting pharmaceutical film. 15. The process of claim 13, wherein said resulting pharmaceutical film provides administration of said active to an individual through sublingual application of said resulting pharmaceutical film. 16. The process of claim 13, wherein said second film layer is cast onto said resulting pharmaceutical film. 17. The process of claim 13, wherein said second film layer is extruded onto said resulting pharmaceutical film. 18. The process of claim 13, wherein said second film layer is sprayed onto said resulting pharmaceutical film. 19. The process of claim 13, wherein said second film layer is laminated onto said resulting pharmaceutical film. 20. The process of claim 13, wherein said resulting pharmaceutical film is laminated onto said second film layer. 21. The process of claim 13, wherein said second film layer comprises an active. 22. The process of claim 13, wherein said active in said second film layer is different from said active in said resulting pharmaceutical film. 23. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said active to an individual through a mucosal membrane of said individual. 24. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said active to an individual by administration within the body of the individual during surgery. 25. The process of claim 1, wherein said active is in the form of a particle. 26. The process of claim 1, wherein said matrix comprises a dispersion. 27. A process for manufacturing a resulting pharmaceutical film suitable for commercialization and regulatory approval said resulting pharmaceutical film having a substantially uniform distribution of a desired amount of a pharmaceutical active in individual doses of the resulting pharmaceutical film, comprising the steps of: (a) forming a visco-elastic polymer matrix by mixing, said matrix comprising a polymer selected from the group consisting of water-soluble polymers, water-swellable polymers and combinations thereof, a solvent selected from the group consisting of water, a polar organic solvent and combinations thereof, and pharmaceutical active, which polymer matrix during film casting is a shear-thinning pseudoplastic fluid when exposed to shear rates of 10-10.sup.5 sec.sup.-1, said polymer matrix having a substantially uniform distribution of said pharmaceutical active; (b) casting said polymer matrix; (c) conveying said polymer matrix through a drying apparatus and drying said polymer matrix, to rapidly remove at least a portion of said solvent from said matrix to form a visco-elastic film having said pharmaceutical active substantially uniformly distributed throughout by rapidly increasing the viscosity of said polymer matrix upon initiation of drying within about the first 4 minutes to maintain said uniform distribution of said pharmaceutical active by locking-in or substantially preventing migration of said pharmaceutical active, wherein the temperature of the polymer matrix is 100.degree. C. or less, wherein any top air flow does not overcome the inherent viscosity of the visco-elastic film and any top air flow is insufficient to cause one or more of the following: (i) surface skinning prior to drying the depth of the film; (ii) surface rippling; (iii) self-aggregation of components; (iv) non-uniformity in thickness of the film; and (v) non-uniformity of mass per unit volume, wherein content uniformity of said active in substantially equal sized individual dosage units of said visco-elastic film is such that the amount of the active varies by no more than 10% from the desired amount; and (d) forming the resulting pharmaceutical film from said visco-elastic film, wherein said resulting pharmaceutical film having said substantially uniform distribution of pharmaceutical active by said locking-in or substantially preventing migration of said pharmaceutical active is maintained, such that content uniformity of said active in substantially equal sized individual dosage units of said resulting pharmaceutical film is such that the amount of the active varies by no more than 10% from the desired amount. 28. The process of claim 27, wherein the active is an opiate or opiate-derivative. 29. The process of claim 27, wherein the active is an anti-emetic.