Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom

• US 7,425,292 B2
• Filed: 02/14/2002
• Issued: 09/16/2008
• 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, Joseph M., Fuisz, Richard C., Myers, Gary L.
• Primary Examiner(s): Tucker; Philip C
• Assistant Examiner(s): Chan; Sing P
• Application Number:
  US10/074,272
• Publication Number:
  US 20030107149A1
• Time in Patent Office: 2,406 Days
• Field of Search: 264/172.19, 264/173.1, 264/175, 264/212, 264/217, 264/211.12, 264/260, 264/234, 424/484, 424/488, 484/434, 484/435, 345/09, 345/02, 344/93, 344/43
• US Class Current: 264/172.19
• 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 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4525 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 31/80 Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
• 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 47/38 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 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/10 : Expectorants
• CPC Class Codes: A61P 11/14 : Antitussive agents
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C08J 5/18 : Manufacture of films or sheets

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.

Claims

1. A process for making a self supporting, edible film having a substantially uniform distribution of components comprising:

(a) mixing an edible water-soluble polymer component, water and an active component comprising drug particles to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing;

(c) forming a wet film from said deaerated matrix by coating or coating the film;

(d) providing a surface having top and bottom sides;

(e) feeding said film onto said top side of said surface; and

(f) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidiy forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said bottom side of said surface with substantially no top air flow to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout.

2. The process according to claim 1, wherein said active component is taste masked.

3. The process according to claim 1, wherein said wet film has a thickness of at least about 30 μ

m.

4. The process according to claim 1, wherein said wet film has a thickness of at least about 500 μ

m.

5. The process according to claim 1, wherein said wet film has a viscosity of about 400cps to about 100,000cps.

6. The process according to claim 1, further comprising the step of removing said self-supporting film from said surface.

7. The process according to claim 6, further comprising the step of dividing said self-supporting film into individual dosage forms of substantially equal dimensions.

8. The process according to claim 7, further comprising the step of packaging each of said individual dosage forms.

9. The process according to claim 1, wherein said self-supporting film is formed in conjunction with a removable backing.

10. A process for making a self-supporting, edible film dosage unit having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing to prevent cavitation of the matrix in a manner which pulls air into the matrix;

(c) forming a wet film from said deaerated wet matrix by coating or casting the film;

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout; and

(e) dividing said self-supporting film into dosage forms of substantially equal dimensions, wherein each of said dosage forms is compositionally equal.

11. The process according to claim 10, wherein each of said dosage forms has substantially the same mass.

12. The process according to claim 10, wherein each of said dosage forms has substantially the same thickness.

13. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing to prevent cavitation of the matrix, thereby reducing formation of air bubbles;

(c) forming a wet film from said deaerated wet matrix by coating or casting the film, said film having a top surface, a bottom surface and a depth between said top and bottom surfaces; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidiy forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout, said dried film having a uniform distribution of said polymer and said solvent components, a uniform weight and a uniform thickness.

14. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing;

(c) forming a wet film from said deaerated wet matrix within a time period before the active degrades by coating or casting the film, said film having a top surface, a bottom surface and a depth between said top and bottom surfaces; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidiy forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film to initiate drying of the depth of said film prior to forming a polymer skin on said top surface of said film and to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout, said dried film having a uniform distribution of said polymer and said solvent components, a uniform weight and a uniform thickness.

15. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing to reduce formation of air bubbles;

(c) forming a wet edible film from said deaerated wet matrix by coating or casting the film, said film having a top surface and a bottom surface; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film, wherein said air currents are applied to said bottom surface of said film at a velocity greater than to said top surface of said film to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout.

16. The process according to claim 15, wherein said air currents applied to said top surface of said film are less than that which cause surface rippling or skinning prior to drying of the depth of said film.

17. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, a pharmaceutical active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing;

(c) forming a wet edible film from said deaerated wet matrix by coating or casting the film, said film having a top surface, a bottom surface and a depth of at least about 500μ

m between said top and bottom surfaces; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film, wherein said air currents are less than that which cause surface rippling or skinning prior to drying of the depth of said film, to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout.

18. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing;

(c) forming a wet edible film from said deaerated wet matrix by coating or casting the film, said film having a top surface, a bottom surface and a depth between said top and bottom surfaces; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film to prevent flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film, wherein said dried film is self-supporting and has drug particles uniformly distributed throughout and said top surface of said dried film is non-rippled.

19. A process for making a self-supporting, edible film having a substantially uniform. distribution of components comprising:

(a) combining and mixing an edible water-soluble polymer component, an active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of said components;

(b) deaerating said matrix by mixing to reduce air bubble inclusions and applying a vacuum;

(c) forming an edible film from said deaerated matrix by coating or casting the film, said film having a top surface and a bottom surface; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) drying said film from said bottom surface to said top surface by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said bottom surface of said film until a visco-elastic film having said drug particles uniformly distributed throughout is achieved within about the first 4.0 minutes; and

(ii) further drying said visco-elastic film to form a self supporting edible film having drug particles uniformly distributed throughout.

20. A process for making a self supporting, edible film having a substantially uniform distribution of components comprising:

(a) providing a wet matrix having a uniform distribution of edible components, said components comprising a water-soluble polymer component, an active component comprising drug particles water and to form an edible matrix with a compositionally uniform distribution of components;

(b) deaerating said matrix by mixing;

(c) forming a wet edible film from said deaerated wet matrix by coating or casting the film, said film having a top surface, a bottom surface and a depth between said top and bottom surfaces; and

(d) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i)rapidiy forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said film, wherein said air currents are insufficient to cause one or more of the following;

(i) surface skinning prior to drying the depth of said film;

(ii) surface rippling;

(iii) self aggregation of components;

(iv) non-uniformity in the thickness of said film; and

(v) non-uniformity of mass per unit volume; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout.

21. A process for making a self supporting, edible film having a substantially uniform distribution of components comprising:

(a) combining and mixing an edible water-soluble polymer component, an edible active component comprising drug particles and water to form an edible matrix with a compositionally uniform distribution of components;

(b) adding an anti-foaming agent to release oxygen from said mixture of components;

(c) further deaerating said matrix by mixing;

(d) forming a wet edible film from said deaerated matrix by coating or casting the film;

(e) providing a surface having top and bottom sides;

(f) feeding said wet film onto said top side of said surface; and

(g) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by directing hot air currents at temperatures of about 60°

C. to about 100°

C. at said bottom side of said surface to prevent air flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self-supporting edible film having drug particles uniformly distributed throughout.

22. A process for making a self-supporting, edible film having a substantially uniform distribution of components comprising:

(a) forming a masterbatch premix of an edible water-soluble polymer component and water;

(b) deaerating said premix by mixing;

(c) feeding a predetermined amount of said deaerated premix via a first metering pump and a control valve to at least one of a first mixer and a second mixer;

(d) adding an active component comprising drug particles that degrade with prolonged exposure to water to at least one of said first and second mixers;

(e) mixing said active component and said predetermined amount of said premix to form a matrix having a uniform distribution of components;

(f) feeding an amount of said matrix to a pan through at least one second metering pump;

(g) forming a wet film from said matrix within a time period before the active degrades by coating or casting the film with one or more rollers;

(h) providing a surface having top and bottom sides;

(i) feeding said film onto said top side of said surface;

(j) drying said film within about 10 minutes or fewer,

wherein said drying step further comprises;

(i) rapidly forming a visco-elastic film having said drug particles uniformly distributed throughout within about the first 4.0 minutes by applying hot air currents at temperatures of about 60°

C. to about 100°

C. to said bottom side of said surface with substantially no top air flow to prevent air flow migration and intermolecular forces from creating aggregates or conglomerates of said drug particles thereby maintaining the compositional uniform distribution of components; and

(ii) further drying said visco-elastic film to form a self supporting edible film having drug particles uniformly distributed throughout; and

(k) removing said self supporting film from said surface.