THIN FILM WITH NON-SELF-AGGREGATING UNIFORM HETEROGENEITY AND DRUG DELIVERY SYSTEMS MADE THEREFROM

• US 20130337148A1
• Filed: 03/29/2013
• Published: 12/19/2013
• Est. Priority Date: 04/11/2002
• Status: Active Grant

• Current Assignee: Aquestive Therapeutics, Inc.
• Original Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Inventors: Fuisz, Richard C., Myers, Garry L., Fuisz, Joseph M., Yang, Robert K.
• Granted Patent: US 10,111,810 B2
• Time in Patent Office: Days
• US Class Current: 427/2.14
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: B29C 48/08 flexible, e.g. films
• CPC Class Codes: B29C 48/91 Heating, e.g. for cross linking
• CPC Class Codes: B29C 48/919 using a bath, e.g. extruding into an open bath to coagulate or cool the material
• CPC Class Codes: F26B 13/10 Arrangements for feeding, heating or supporting materials; Controlling movement, tension or position of materials heating processes F26B3/00
• 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 film products containing desired levels of active components and methods of their preparation. 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. Desirably, the films may be exposed to temperatures above that at which the active components typically degrade without concern for loss of the desired activity.

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 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, 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 rapidly drying said polymer matrix, to 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 said drying apparatus uses air currents, which have forces below a yield value of the polymer matrix during drying, wherein content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said visco-elastic film is such that the amount of the pharmaceutical active varies by no more than 10% from the desired amount; and

(d) forming the resulting pharmaceutical film from said visco-elastic film by further 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 water content of said resulting film is 10% or less, 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 pharmaceutical active in substantially equal sized individual dosage units of said resulting pharmaceutical film is such that the amount of the pharmaceutical active varies by no more than 10% from the desired amount.

2. The process of claim 1, further comprising step (e) performing analytical chemical tests for content uniformity of said pharmaceutical active in substantially equal sized individual dosage units of said 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.

3. 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.

4. The process of claim 1, 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.

5. The process of claim 1, 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.

6. The process of claim 1, wherein the pharmaceutical active is a protein or a glycoprotein.

7. The process of claim 1, wherein the pharmaceutical active is insulin.

8. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said pharmaceutical active to an individual through the buccal cavity of said individual.

9. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said pharmaceutical active to an individual through gingival application of said resulting pharmaceutical film.

10. The process of claim 1, wherein said pharmaceutical active is a hormone.

11. The process of claim 1, wherein said pharmaceutical active is an opiate or opiate-derivative.

12. The process of claim 1, wherein said pharmaceutical active is taste-masked.

13. The process of claim 1, wherein said pharmaceutical active is coated with a controlled release composition.

14. The process of claim 13, 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.

15. The process of claim 1, further comprising a step of providing a second film layer.

16. The process of claim 15, wherein said second film layer is coated onto said resulting pharmaceutical film.

17. The process of claim 15, wherein said resulting pharmaceutical film provides administration of said pharmaceutical active to an individual through sublingual application of said resulting pharmaceutical film.

18. The process of claim 15, wherein said second film layer is cast onto said resulting pharmaceutical film.

19. The process of claim 15, wherein said second film layer is extruded onto said resulting pharmaceutical film.

20. The process of claim 15, wherein said second film layer is sprayed onto said resulting pharmaceutical film.

21. The process of claim 15, wherein said second film layer is laminated onto said resulting pharmaceutical film.

22. The process of claim 15, wherein said resulting pharmaceutical film is laminated onto said second film layer.

23. The process of claim 15, wherein said second film layer comprises an active.

24. The process of claim 15, wherein said active in said second film layer is different from said pharmaceutical active in said resulting pharmaceutical film.

25. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said pharmaceutical active to an individual through a mucosal membrane of said individual.

26. The process of claim 1, wherein said resulting pharmaceutical film provides administration of said pharmaceutical active to an individual by administration within the body of the individual during surgery.

27. The process of claim 1, wherein said pharmaceutical active is in the form of a particle.

28. The process of claim 1, wherein said matrix comprises a dispersion.