Process for manufacturing a resulting multi-layer pharmaceutical film

• US 9,108,340 B2
• Filed: 08/23/2013
• Issued: 08/18/2015
• Est. Priority Date: 10/12/2001
• Status: Expired due to Fees

• 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): LEE, EDMUND H
• Application Number:
  US13/974,413
• Publication Number:
  US 20140008832A1
• Time in Patent Office: 725 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61J 2200/20 Extrusion means, e.g. for producing pharmaceutical forms
• CPC Class Codes: A61J 3/00 Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: B29C 39/003 characterised by the choice of material
• CPC Class Codes: B29C 39/14 for making articles of indefinite length by depositing material on a substrate and stripping off the shaped article B29C41/24
• CPC Class Codes: B29C 71/02 Thermal after-treatment B29C71/0063 and B29C71/0072 take precedence
• CPC Class Codes: F26B 13/104 supported by fluid jets only; Fluid blowing arrangements for flotation dryers, e.g. coanda nozzles

Abstract

The invention relates to the film products and methods of their preparation that demonstrate a non-self-aggregating uniform heterogeneity. Desirably, the films disintegrate in water and may be formed by a controlled drying process, or other process that maintains the required uniformity of the film. The films contain a polymer component, which includes polyethylene oxide optionally blended with hydrophilic cellulosic polymers. Desirably, the films also contain a pharmaceutical and/or cosmetic active agent with no more than a 10% variance of the active agent pharmaceutical and/or cosmetic active agent per unit area of the film.

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 Non-Newtonian visco-elastic polymer matrix, comprising a polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, polyacrylic acid, sodium carboxymethyl cellulose, ethylcellulose, polyacrylates, cellulosic polymers, carboxymethyl cellulose, polyethylene oxide and combinations thereof;

a solvent selected from the group consisting of water, a polar organic solvent and combinations thereof, and the active selected from the group of opiates and opiate-derivatives and combinations thereof, which polymer matrix 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 evaporating at least a portion of said solvent to rapidly form a visco-elastic film having said pharmaceutical active 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 substantially 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;

(d) forming the resulting pharmaceutical film from said visco-elastic film, wherein the 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;

(e) sampling the resulting pharmaceutical film at different locations of the resulting pharmaceutical film, wherein said sampled resulting pharmaceutical film has a water content of 10% or less; and

(f) performing analytical chemical tests for content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said sampled resulting pharmaceutical film said tests indicating that uniformity of content in the amount of the active varies by no more than 10% from the desired amount of the active.

2. The process of claim 1, wherein step (d) forming the resulting pharmaceutical film further comprises controlling drying through a process comprising drying at a temperature differential ranging from 5°

C. to 30°

C. between polymer matrix inside temperature and outside exposure temperature to minimize degradation wherein the water content of said resulting film is 10% or less.

3. The process of claim 1, wherein said drying apparatus uses air currents, which have forces below a yield value of the polymer matrix during drying.

4. A process for manufacturing a resulting multi-layer pharmaceutical film suitable for commercialization and regulatory approval, said resulting multi-layer pharmaceutical film having a substantially uniform distribution of pharmaceutical active, comprising the steps of:

(a) forming a Non-Newtonian visco-elastic polymer matrix, comprising a polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, polyacrylic acid, sodium carboxymethyl cellulose, ethylcellulose, polyacrylates, cellulosic polymers, carboxymethyl cellulose, polyethylene oxide and combinations thereof;

a solvent selected from the group consisting of water, and a polar organic solvent and combinations thereof, which polymer matrix 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 evaporating at least a portion of said solvent to rapidly form a visco-elastic film within about the first 4 minutes, wherein the temperature of the polymer matrix is 100°

C. or less;

(d) depositing a layer comprising a pharmaceutical active selected from the group consisting of opiates and opiate-derivatives and combinations thereof onto said visco-elastic film to form the resulting multi-layer pharmaceutical film;

(e) sampling said resulting pharmaceutical film at different locations of said resulting multi-layer pharmaceutical film, wherein said sampled resulting multi-layer pharmaceutical film has a water content of 10% or less; and

(f) performing analytical chemical tests for content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said sampled resulting multi-layer pharmaceutical film, said tests indicating that the uniformity of content in the amount of the pharmaceutical active varies by no more than 10%.

5. 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 Non-Newtonian 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 a pharmaceutical active, which polymer matrix 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 evaporating at least a portion of said solvent to rapidly form a pharmaceutical 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 substantially uniform distribution of said pharmaceutical active by locking-in or substantially preventing migration of said pharmaceutical active, wherein content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said pharmaceutical film is such that the amount of pharmaceutical active varies by no more than 10% of the desired amount;

(e) sampling the resulting pharmaceutical film at different locations of the resulting pharmaceutical film, wherein said sampled resulting pharmaceutical film has a water content of 10% or less and a thickness of from about 0.1 mils to about 10 mils; and

(f) performing analytical chemical tests for content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said sampled resulting pharmaceutical film, said tests indicating said substantially uniform distribution of the pharmaceutical active, in that the amount of the pharmaceutical active varies by no more than 10% of the desired amount.

6. The process of claim 5, 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.

7. The process of claim 5, wherein the pharmaceutical 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.

8. The process of claim 5, wherein said pharmaceutical 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.

9. The process of claim 5, wherein the pharmaceutical active is a protein or a glycoprotein.

10. The process of claim 5, wherein the pharmaceutical active is insulin.

11. The process of claim 5, wherein said resulting pharmaceutical film provides administration of said active to an individual through the buccal cavity of said individual.

12. The process of claim 5, wherein said resulting pharmaceutical film provides administration of said active to an individual through gingival application of said resulting pharmaceutical film.

13. The process of claim 5, wherein said pharmaceutical active is a hormone.

14. The process of claim 5, wherein said pharmaceutical active is an opiate or opiate-derivative.

15. The process of claim 5, wherein said pharmaceutical active is taste-masked.

16. The process of claim 5, wherein said pharmaceutical active is coated with a controlled release composition and said controlled release composition provides at least one of the following:

an immediate release, a delayed release, a sustained release or a sequential release.

17. The process of claim 5, further comprising a step of providing a second film layer.

18. The process of claim 17, wherein said second film layer is coated onto said resulting pharmaceutical film.

19. The process of claim 17, wherein said resulting pharmaceutical film provides administration of said active to an individual through sublingual application of said resulting pharmaceutical film.

20. The process of claim 17, wherein said second film layer is cast onto said resulting pharmaceutical film.

21. The process of claim 17, wherein said second film layer is extruded onto said resulting pharmaceutical film.

22. The process of claim 17, wherein said second film layer is sprayed onto said resulting pharmaceutical film.

23. The process of claim 17, wherein said second film layer is laminated onto said resulting pharmaceutical film.

24. The process of claim 17, wherein said resulting pharmaceutical film is laminated onto said second film layer.

25. The process of claim 17, wherein said second film layer comprises an active.

26. The process of claim 17, wherein said active in said second film layer is different from said pharmaceutical active in said resulting pharmaceutical film.

27. The process of claim 5, wherein said resulting pharmaceutical film provides administration of said active to an individual through a mucosal membrane of said individual.

28. The process of claim 5, wherein said resulting pharmaceutical film provides administration of said active to an individual by administration within the body of the individual during surgery.

29. The process of claim 5, wherein said pharmaceutical active is in the form of a particle.

30. The process of claim 5, wherein said matrix comprises a dispersion.