Uniform films for rapid dissolve dosage form incorporating taste-masking compositions

• US 8,652,378 B1
• Filed: 03/29/2013
• Issued: 02/18/2014
• Est. Priority Date: 10/12/2001
• Status: Expired due to Term

• Current Assignee: Aquestive Therapeutics, Inc.
• Original Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Inventors: Yang, Robert K., Fuisz, Richard C., Myers, Garry L., Fuisz, Joseph M.
• Primary Examiner(s): Wollschlager, Jeffrey
• Assistant Examiner(s): YI, STELLA KIM
• Application Number:
  US13/853,237
• Time in Patent Office: 326 Days
• Field of Search: 264/636, 264/650, 264/555, 264/556, 264/212, 264/298, 264/299, 264/302, 264/605, 264/671
• US Class Current: 264/216
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/44 : Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 47/46 : Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 9/0056 : Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 : Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/14 : Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/501 : Inorganic compounds
• CPC Class Codes: A61K 9/5015 : Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5036 : Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61K 9/5047 : Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/7007 : Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61K 9/7015 : Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: B05D 3/0254 : After-treatment
• CPC Class Codes: B29C 48/022 : characterised by the choice of material

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.

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 10-10⁵ sec<sup>−

1</sup>, 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°

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 10-10⁵ sec<sup>−

1</sup>, 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°

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.