Process for making a film having a substantially uniform distribution of components

• US 8,900,497 B2
• Filed: 08/23/2013
• Issued: 12/02/2014
• 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., Myers, Garry L., Fuiz, Richard C., Fuiz, Joseph M.
• Primary Examiner(s): Lee, Edmund H.
• Application Number:
  US13/974,389
• Publication Number:
  US 20140000800A1
• Time in Patent Office: 466 Days
• Field of Search: None
• US Class Current: 264/172.19
• 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 41/24 for making articles of indefinite length
• 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 making a film having a substantially uniform distribution of components, comprising the steps of:

(a) forming a flowable polymer matrix comprising an edible polymer, a solvent and a desired amount of at least one active, said matrix having a substantially uniform distribution of said at least one active;

(b) casting said flowable polymer matrix;

(c) rapidly evaporating at least a portion of said solvent upon initiation of drying to form a visco-elastic film within about the first 4.0 minutes to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active within said visco-elastic film;

(d) further drying said visco-elastic film to form a self-supporting edible film having a substantially uniform distribution of said at least one active component; and

wherein said substantially uniform distribution of said at least one active component is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

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 film provides administration of said active to an individual through the buccal cavity of said individual.

8. The process of claim 1, wherein said film provides administration of said active to an individual through gingival application of said 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 10, wherein said 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.

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

13. The process of claim 12, wherein said second film layer is coated onto said film.

14. The process of claim 12, wherein said film provides administration of said active to an individual through sublingual application of said film.

15. The process of claim 12, wherein said second film layer is cast onto said film.

16. The process of claim 12, wherein said second film layer is extruded onto said film.

17. The process of claim 12, wherein said second film layer is sprayed onto said film.

18. The process of claim 12, wherein said second film layer is laminated onto said film.

19. The process of claim 12, wherein said film is laminated onto said second film layer.

20. The process of claim 12, wherein said second film layer comprises an active.

21. The process of claim 12, wherein said active in said second film layer is different from said active in said film.

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

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

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

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

26. A process for making a film having a substantially uniform distribution of components, comprising the steps of:

(a) forming a flowable polymer matrix comprising an edible polymer, a solvent and a desired amount of at least one active, said matrix having a substantially uniform distribution of said at least one active;

(b) casting said flowable polymer matrix;

(c) rapidly evaporating at least a portion of said solvent upon initiation of drying to form a visco-elastic film within about the first 4.0 minutes to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active within said visco-elastic film;

(d) further drying said visco-elastic film to form a self-supporting edible film having a substantially uniform distribution of said at least one active component and having a water content of about 10% or less; and

wherein said substantially uniform distribution of said at least one active component is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

27. A process for making a film having a substantially uniform distribution of components, comprising the steps of:

(a) forming a flowable polymer matrix comprising a cellulosic polymer, a solvent and a desired amount of at least one active, said matrix having a substantially uniform distribution of said at least one active;

(b) casting said flowable polymer matrix;

(c) rapidly evaporating at least a portion of said solvent upon initiation of drying to form a visco-elastic film within about the first 4.0 minutes to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active within said visco-elastic film;

(d) further drying said visco-elastic film to form a self-supporting edible film having a substantially uniform distribution of said at least one active component and having a water content of about 10% or less; and

wherein said substantially uniform distribution of said at least one active component is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

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.

30. A process for manufacturing a resulting film suitable for commercialization and regulatory approval, said regulatory approval including analytical chemical testing which meets the standards of the U.S. Food and Drug Administration relating to variation of an active in individual dosage units, said film having a substantially uniform distribution of components comprising a substantially uniform distribution of said active in individual dosage units of said resulting film, comprising the steps of:

(a) forming a flowable polymer matrix comprising a water-soluble polymer, a solvent and said active, said active selected from the group consisting of bioactive actives, pharmaceutical actives and combinations thereof, said matrix having a substantially uniform distribution of said active;

(b) casting said flowable polymer matrix, said flowable polymer matrix having a viscosity from about 400 to about 100,000 cps;

(c) controlling drying through a process comprising conveying said flowable polymer matrix through a drying apparatus to evaporate at least a portion of said solvent to form a visco-elastic film, having said active substantially uniformly distributed throughout, within about the first 4 minutes by rapidly increasing the viscosity of said flowable polymer matrix upon initiation of drying to maintain said substantially uniform distribution of said active by locking-in or substantially preventing migration of said active within said visco-elastic film, such that uniformity of content in the amount of said active in substantially equal sized individual dosage units, sampled from different locations of said visco-elastic film, varies by no more than 10%, and wherein during said drying said flowable polymer matrix temperature is 100°

C. or less;

(d) forming said resulting 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 and wherein said substantially uniform distribution of active by said locking-in or substantially preventing migration of said active is maintained, such that uniformity of content in the amount of said active in substantially equal sized individual dosage units, sampled from different locations of said resulting film, varies by no more than 10%; and

(e) performing analytical chemical tests for uniformity of content of said active in substantially equal sized individual dosage units of said sampled resulting film, said tests indicating that uniformity of content in the amount of said active varies by no more than 10% and said resulting film is suitable for commercial and regulatory approval, wherein said regulatory approval is provided by the U.S. Food and Drug Administration.