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

• US 9,931,305 B2
• Filed: 02/21/2017
• Issued: 04/03/2018
• 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): Wax, Robert A
• Assistant Examiner(s): Mercier, Melissa S
• Application Number:
  US15/438,458
• Publication Number:
  US 20170224628A1
• Time in Patent Office: 406 Days
• Field of Search: None
• 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 drug delivery composition for making individual unit doses in a self-supporting film-dosage form, which individual unit doses cut from a self-supporting continuously cast film contain a desired amount of at least one active, said composition comprising:

(i) said self-supporting continuously cast film having said active substantially uniformly stationed therein, said self-supporting continuously cast film formed from a flowable water-soluble or water swellable film-forming matrix comprising a polymer selected from the group consisting of cellulose, a cellulose derivative, polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, polysaccharides, sodium alginate, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof;

wherein said matrix has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of said active substantially locked-in the matrix; and

(ii) a taste-masking agent selected from the group consisting of flavors, sweeteners, flavor enhancers, and combinations thereof to provide taste-masking of said active;

wherein said active has a particle size of 200 microns or less; and

wherein the uniformity of the self-supporting continuously cast film is measured by substantially equally sized individual unit doses cut from a self-supporting continuously cast film which do not vary by more than 10% of said desired amount of said at least one active.

2. The drug delivery composition of claim 1, wherein the polymer is selected from the group consisting of cellulose, a cellulose derivative, polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol and combinations thereof.

3. The drug delivery composition of claim 1, where the PEO comprises molecular weights in the range of 100,000 to 900,000.

4. The drug delivery composition of claim 1, where the PEO comprises molecular weights selected from the range of 100,000 to 300,000, 600,000 to 900,000 and combinations thereof.

5. The drug delivery composition of claim 1, wherein the polymer is selected from the group consisting of cellulose or a cellulose derivative, polyvinyl pyrrolidone, pullulan, polyvinyl alcohol and combinations thereof.

6. The drug delivery composition of claim 1, wherein said uniformity is measured by substantially equally sized individual unit doses which do not vary by more than 5% of said desired amount of said at least one active.

7. The drug delivery composition of claim 1, wherein the taste-masking agent is present in the amount of about 0.1% to about 30% by weight of the drug delivery composition.

8. The drug delivery composition of claim 1, wherein said active is selected from the group consisting of anxiolytics, central nervous system stimulants, ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents, 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, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, vasoconstrictors, antibiotics, tranquilizers, anti-psychotics, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.

9. The drug delivery composition of claim 1, wherein said active is a drug selected from the group consisting of an opiate, opiate derivative, an analgesic, biological response modifiers, urinary tract agents, tadalafil, anti-convulsants, apomorphine, migraine treatments, hormones, alprazolam and combinations thereof.

10. The drug delivery composition of claim 1, wherein each individual unit dose comprises multiple layers.

11. The drug delivery composition of claim 10, wherein at least one of said multiple layers does not include an active.

31. The drug delivery composition of claim 1, wherein the unit doses comprise a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, methylene chloride, and combinations thereof in an amount of less than about 10% by weight solvent.

12. An oral film for mucosal delivery of a desired amount of at least one pharmaceutical and/or bioactive active in substantially equal sized individual unit doses cut from said film, said film comprising:

(a) a first film layer comprising;

an ingestible, polymer matrix formed from at least one water soluble or water-swellable film-forming polymer; and

(b) one or more additional film layer(s) comprising;

an ingestible, polymer matrix formed from at least one water-soluble or water-swellable polymer; and

wherein at least one of said first film layer and said additional film layer(s) include at least one pharmaceutical and/or bioactive active comprised of particles having a size of 200 microns or less and the matrix of said first film layer or said additional film layer(s) that includes said at least one pharmaceutical and/or bioactive active has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of said at least one pharmaceutical and/or bioactive active substantially locked-in the matrix, said pharmaceutical and/or bioactive active being substantially uniformly distributed and substantially locked-in said flowable water-soluble or water swellable polymer matrix of said first layer or said additional layer(s);

wherein at least one of said first film layer or said additional film layer(s) further comprise a component selected from the group consisting of a taste masking agent, a controlled release agent and combinations thereof;

wherein at least one of said first film layer or said additional film layer(s) was continuously cast; and

wherein said film is self-supporting and said pharmaceutical and/or bioactive active is substantially uniformly distributed within at least one of said first film layer or said one or more additional film layers, whereby said substantially uniform distribution is such that substantially equal sized individual unit doses cut from said film do not vary by more than 10% from said desired amount of said at least one pharmaceutical and/or bioactive active.

13. The film of claim 12, wherein said active is selected from the group consisting of anxiolytics, central nervous system stimulants, ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents, 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, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, antibiotics, tranquilizers, anti-psychotics, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.

14. The film of claim 12, where said active is selected from the group consisting opiates, opiate derivatives, analgesics, biological response modifiers, urinary tract agents, tadalafil, anti-convulsants, apomorphine, migraine treatments, hormones, alprazolam and combinations thereof.

15. The film of claim 12, wherein the water soluble or water-swellable polymer in the polymer matrix of at least one of said first film layer and said additional film layer(s) is selected from the group consisting of cellulose, a cellulose derivative, polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, saccharides, sodium alginate, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof.

16. The film of claim 15, wherein the polyethylene oxide (PEO) comprises molecular weights selected from the range of 100,000 to 900,000.

17. The film of claim 12, wherein said active is coated with or intimately associated with a taste-masking agent and/or a controlled release agent.

18. The film of claim 17, wherein the taste-masking agent and/or controlled release agent is selected from the group consisting of a flavor, sweetener, flavor enhancer, anesthetic, ion exchange resin and combinations thereof.

19. The film of claim 12, wherein the first layer is configured relative to the second layer such that the layer containing said active is available for direct contact with a mucosal surface when administered to a patient.

32. The oral film of claim 12, wherein the unit doses comprise a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, methylene chloride, and combinations thereof in an amount of less than about 10% by weight solvent.

20. An oral film for mucosal delivery of a desired amount of an active selected from the group consisting of opiates, opiate derivatives, analgesics, biological response modifiers, urinary tract agents, tadalafil, apomorphine, migraine treatments, hormones, alprazolam and combinations thereof, in substantially equal sized individual unit doses cut from said film, said film comprising:

(a) a first film layer comprising;

(i) an ingestible, polymer matrix formed from at least one water soluble or water-swellable film-forming polymer; and

(b) one or more additional film layer(s) comprising;

(i) an ingestible, polymer matrix formed from at least one water soluble or water-swellable film-forming polymer; and

wherein at least one of said first film layer or said additional film layer(s) include at least one active selected from the group consisting of opiates, opiate derivatives, analgesics, biological response modifiers, urinary tract agents, tadalafil, apomorphine, migraine treatments, hormones, alprazolam and combinations thereof and the matrix of said first film layer or said additional film layer(s) that includes said at least one active has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of said at least one active substantially locked-in the matrix, said active comprised of particles having a size of 200 microns or less and being substantially uniformly distributed and substantially locked-in said flowable water-soluble or water swellable polymer of said first layer and/or said additional layer(s);

wherein at least one of said first film layer or said additional film layer(s) further comprises a component selected from the group consisting of flavors, sweeteners, flavor enhancers, anesthetics, and combinations thereof;

wherein at least one of said first film layer and said additional film layer(s) was continuously cast; and

wherein said at least one active is substantially uniformly distributed within at least one of said first film layer or said additional film layer(s), whereby said substantially uniform distribution is such that substantially equal sized individual unit doses are cut from said film do not vary by more than 10% from said desired amount of said at least one active; and

wherein said individual unit doses are self-supporting.

21. The film of claim 20, wherein the polymer matrix of at least one of said first film layer and said additional film layer(s) is selected from the group consisting of cellulose, a cellulose derivative, polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, polysaccharides, sodium alginate, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof.

22. The film of claim 20, wherein the first layer is configured relative to the second layer such that the layer containing said active is available for direct contact of a mucosal surface when administered to a patient.

23. The film of claim 22 where the polymer matrix of at least one of said first film layer and said additional film layer(s) is selected from the group consisting of cellulose, a cellulose derivative, polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol.

24. The film of claim 22, including an ion exchange resin.

25. The film of claim 22, wherein at least 2 layers includes an active.

33. The oral film of claim 20, wherein the unit doses comprise a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, methylene chloride, and combinations thereof in an amount of less than about 10% by weight solvent.

26. A drug delivery composition comprising:

(i) a continuously cast film produced on a manufacturing line comprising a flowable water-soluble or water swellable film-forming matrix comprising one or more substantially water soluble or water swellable polymers; and

at least one active;

wherein said matrix has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of the active in the matrix;

(ii) a particulate active substantially uniformly stationed in the matrix; and

(iii) a taste-masking agent selected from the group consisting of flavors, sweeteners, flavor enhancers, and combinations thereof to provide taste-masking of the active;

wherein the particulate active has a particle size of 200 microns or less and said flowable water-soluble or water swellable film-forming matrix is capable of being continuously cast on the manufacturing line without loss of substantial uniformity in the stationing of said particulate active therein; and

wherein said uniformity of the-continuously cast film is measured by substantially equally sized individual unit doses cut from the continuously cast film which do not vary by more than 10% of a desired amount of said at least one active.

27. The drug delivery composition of claim 26, wherein the particulate active has a particle size of 100 microns or less.

28. The drug delivery composition of claim 26, wherein said uniformity of active subsequent to continuously casting and drying of the matrix is measured by substantially equally sized individual unit doses cut from the cast and dried film which do not vary by more than 5%.

29. The drug delivery composition of claim 26, wherein said taste-masking agent is present in the amount of about 0.01-10% by weight of the drug delivery composition.

30. The drug delivery composition of claim 26, wherein said active is an opiate or opiate derivative.

34. The drug delivery composition of claim 26, wherein the unit doses comprise a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, methylene chloride, and combinations thereof in an amount of less than about 10% by weight solvent.