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

• US 10,111,810 B2
• Filed: 03/29/2013
• Issued: 10/30/2018
• Est. Priority Date: 04/11/2002
• Status: Expired due to Fees

• Current Assignee: Aquestive Therapeutics, Inc.
• Original Assignee: Aquestive Therapeutics, Inc.
• Inventors: Yang, Robert K., Fuisz, Richard C., Myers, Garry L., Fuisz, Joseph M.
• Primary Examiner(s): Packard, Benjamin
• Application Number:
  US13/853,290
• Publication Number:
  US 20130337148A1
• Time in Patent Office: 2,041 Days
• 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 continuously cast oral film for delivery of an active in individual self-supporting oral unit doses cut therefrom, said individual self-supporting oral unit doses containing a desired amount of said active, 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, ethanol, isopropanol, acetone, methylene chloride, and a combination thereof and said 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) continuously casting said polymer matrix;

(c) removing at least a portion of said solvent from said matrix to achieve a solvent content of no greater than 10% by weight of said continuously cast oral film;

wherein said continuously cast oral film has a substantially uniform distribution of said active substantially locked-in within said polymer matrix, wherein said active is selected from the group consisting of cosmetic agents, pharmaceutical agents, vitamins, bioactive agents and combinations thereof wherein said active is substantially uniformly distributed in said continuously cast film, whereby said substantially uniform distribution is measured by substantially equally sized individual self-supporting oral unit doses cut from said continuously cast film which do not vary by more than 10% of said desired amount of said active and

wherein said pharmaceutical active is an anti-parkinsonian agent.

2. The process of claim 1, wherein said active is apomorphine.

3. The process of claim 2, wherein said apomorphine is in the form of particles and said particles have an average particle size of 150 μ

m or less.

4. The process of claim 1, wherein:

a) said polymer matrix comprises a polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, and combinations thereof;

b) said active is apomorphine; and

c) said continuously cast oral film comprises;

i) a polyol selected from the group consisting of propylene glycol, glycerol, and combinations thereof;

ii) a sweetener;

iii) a flavor;

iv) a monoglyceride; and

v) a polysaccharide.

5. The process of claim 4, wherein said apomorphine is in the form of particles and said particles have an average particle size of 150 μ

m or less.

6. The process of claim 4, wherein said sweetener comprises sucralose.

7. The process of claim 4, wherein said flavor comprises menthol.

8. The process of claim 4, wherein said monoglyceride is a monoglyceride derived from a C₁₈-fatty acid.

9. The process of claim 1, wherein said continuously cast oral film film is a multi-layer film comprising at least a first layer and a second layer.

10. The process of claim 9, wherein said first layer, or said second layer, or both said first and said second layer comprise said anti-parkinsonian agent.

11. The process of claim 10, wherein said anti-parkinsonian agent is apomorphine.

12. The process of claim 11, wherein said apomorphine is in the form of particles and said particles have an average particle size of 150 μ

m or less.

13. The process of claim 9, wherein said first layer, or said second layer, or both said first and said second layer comprise a polyol.

14. The process of claim 13, wherein said polyol is selected from the group consisting of propylene glycol, glycerol, and combinations thereof.

15. The process of claim 9, wherein said first layer, or said second layer, or both said first and said second layer comprise a sweetener.

16. The process of claim 15, wherein said sweetener is sucralose.

17. The process of claim 9, wherein said first layer, or said second layer, or both said first and said second layer comprise a monoglyceride.

18. The process of claim 17, wherein said monoglyceride is a monoglyceride derived from a C₁₈-fatty acid.

19. The process of claim 18, wherein said first layer, or said second layer, or both said first and said second layer comprise a flavor.

20. The process of claim 19, wherein said flavor is menthol.

21. The process of claim 9, wherein said first layer, or said second layer, or both said first and said second layer comprise a component that will increase viscosity.

22. The process of claim 21, wherein said component that will increase viscosity is a polysaccharide.

23. The process of claim 9, wherein:

1) said first layer comprises;

a) a first polymer matrix comprising a polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, and combinations thereof;

b) apomorphine;

c) water; and

d) a first polyol selected from the group consisting of propylene glycol, glycerol, and combinations thereof;

e) a first monoglyceride derived from a C₁₈-fatty acid; and

f) a first polysaccharide, and

2) said second layer comprises;

a) a second polymer matrix comprising a polymer selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, and combinations thereof;

b) water; and

c) a second polyol selected from the group consisting of propylene glycol, glycerol, and combinations thereof; and

d) a second polysaccharide.

24. The process of claim 23, wherein said individual self-supporting oral unit doses provide for administration of said apomorphine by buccal, gingival, or sublingual application of said individual self-supporting oral unit doses.

25. The process of claim 23, wherein said apomorphine is in the form of particles and said particles have an average particle size of 150 μ

m or less.

26. The process of claim 23, wherein said first layer further comprises a first sweetener, or said second layer further comprises a second sweetener, or said first layer further comprises a first sweetener and said second layer further comprises a second sweetener.

27. The process of claim 26, wherein said first sweetener, or said second sweetener, or both said first sweetener and said second sweetener comprise sucralose.

28. The process of claim 23, wherein said first layer further comprises a first flavor, or said second layer further comprises a second flavor, or said first layer further comprises a first flavor and said second layer further comprises a second flavor.

29. The process of claim 28, wherein said first flavor, or said second flavor, or both said first flavor and said second flavor comprise menthol.

30. The process of claim 1, where sufficient water is removed to achieve a substantially solid film.