Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof

• US 6,375,963 B1
• Filed: 06/15/2000
• Issued: 04/23/2002
• Est. Priority Date: 06/16/1999
• Status: Active Grant

• Current Assignee: University of Mississippi, Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: University of Mississippi
• Inventors: Repka, Michael A., Repka, Staci L., McGinity, James W.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): WARE, TODD
• Application Number:
  US09/594,294
• Time in Patent Office: 677 Days
• Field of Search: 424/402, 424/404, 424/447, 424/448, 424/449, 424/434, 424/435, 424/436
• US Class Current: 424/402
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0063 Periodont
• 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: A61L 15/225 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow

Abstract

The present invention includes a hot-melt extruded film and method of preparation thereof. The film is made from a precursor composition containing at least a water soluble or water swellable thermoplastic polymer, preferably HPC and/or PEO, and a bioadhesive polymer. The film can also contain a therapeutic agent, preservative, buffering agent, antioxidant, super-disintegrant or absorbent, flavorant, colorant, water insoluble polymer, organic acid, surfactant, film modifier, and/or cross-linking agent. The film does not contain a conventional plasticizer or a material which is generally recognized in the art as a plasticizer for extruded films. The film can be sized and shaped to provide a controlled delivery of a therapeutic agent to the buccal, rectal, uterine, vaginal, abdominal, cranial, ophthalmic, nasal, sinus, or otic cavities. The film can also be used for the treatment of wounds.

Claims

1. A hot-melt extruded composition comprising:

about 30-95% wt. of one or more water-soluble or water-swellable thermoplastic polymers;

about 1-25% wt. of polycarbophil;

about 1-60% wt. of poly(ethylene oxide);

about 0.1-10% wt. of an organic acid;

about 0.01-10% wt. of an antioxidant; and

about 0-50% wt. of a therapeutic agent;

wherein the composition has been hot-melt extruded without extensive degradation in the absence of a plasticizer.

2. The composition according to claim 1 further comprising a buffering agent present in an amount of about 0.1-10.0% wt.

3. The composition according to claim 1 further comprising a preservative present in an amount of about 0.01-0.5% wt.

4. The composition according to claim 1 further comprising about 0.1-20% wt. of a super-disintegrant or absorbent.

5. The composition according to claim 4, wherein the super-disintegrant or absorbent is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, cross-linked PVP, veegum, clay, alginate, PVP, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, corn starch, potato starch, pregelatinized starch, modified starch, cellulosic agent, gum, agar, pectin, and tragacanth.

6. The composition of claim 2, wherein the buffering agent is selected from the group consisting of potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate, salt of an inorganic acid, salt of an organic acid, salt of an inorganic base, and salt of an organic base.

7. The composition of claim 1, wherein the therapeutic agent is selected from the group consisting of analgesics, anesthetics, anti-inflammatory agents, antihistamines, decongestants, antibiotics, anti-caries agents, antibacterials, antifungals, anti-acne agents, antiseptics, chemotherapeutic agents, vitamins, minerals, hormones, proteins, peptides, enzymes, and combinations thereof.

8. The composition of claim 1, wherein the antioxidant is selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, vitamin C, BHT, BHA, sodium bisulfite, vitamin E and its derivatives, propyl gallate, and a sulfite derivative.

9. The composition of claim 1, wherein the thermoplastic polymer is HPC.

10. The composition of claim 1 further comprising up to about 20% wt. of a material selected from the group consisting of polyethylene, ethyl cellulose, polyvinylpyrrolidone, xylitol, sucrose, a surface-active agent, and a combination thereof.

36. The composition according to any one of claims 1-10, wherein the composition is a film.

11. A hot-melt extruded film comprising:

about 50-99% wt. of one or more water-soluble or water-swellable thermoplastic polymer or polymers;

about 0-50% wt. of a therapeutic agent; and

about 1-25% polycarbophil;

wherein the film has been hot-melt extruded without extensive degradation in the absence of a plasticizer.

13. A hot-melt extruded film according to claim 11 or 12 wherein the film is a denture adhesive when wetted with an aqueous solution or oral fluids.

14. A hot-melt extruded film according to claim 11 or 12, wherein a therapeutic agent is present, and the film is adapted for controlled delivery of the therapeutic agent to the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic or otic cavity.

15. A powdered adhesive comprising a granulated and/or pulverized hot-melt extruded film according to claim 11 or 12.

16. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises one or more cross-linking agents present in an amount of about 0.1-15% wt.

17. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises one or more film modifiers present in an amount of up to about 20% wt.

18. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises two or more layers.

19. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises a super-disintegrant or super-absorbent present in an amount of about 0.1-20% wt.

20. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises a ph-modifiing agent present in an amount of about 0.1-10.0% wt.

21. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises a preservative present in an amount of about 0.01-0.5% wt.

22. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises an organic acid present in an amount of about 0.1-10% wt.

23. A hot-melt extruded film according to claim 11 or 12, wherein the film further comprises a water insoluble polymer present in an amount of about 1.0 to 20%.

35. A hot-melt extruded film according to claim 11 or 12, wherein the film is comprised in a bandage or wound dressing.

12. A hot-melt extruded film comprising:

about 50-99% wt. of one or more water-soluble or water-swellable thermoplastic polymer or polymers;

about 0-50% wt. of a therapeutic agent; and

about 1-25% wt. of a bioadhesive polymer selected from the group consisting of polycarbophil, carbopol, a co-polymer of methyl vinyl ether and maleic acid or anhydride, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride, a combination thereof and their salts, wherein the film has been hot-melt extruded without extensive degradation in the absence of a plasticizer.

24. A process for preparing a hot-melt extruded film comprising the steps of:

providing a precursor composition comprising about 50-99% wt. of one or more water-soluble or water-swellable thermoplastic polymers;

about 0-50% wt of a therapeutic agent; and

about 1-25% wt. of a bioadhesive polymer; and

hot-melt extruding the precursor composition in the absence of a plasticizer to form a first film.

25. The process of claim 24 further comprising the step of drying the precursor composition or its components prior to hot-melt extruding the composition.

26. The process of claim 25, wherein the moisture content of the precursor composition is less than about 2% wt. after drying.

27. The process of claim 24, wherein the precursor composition comprises a therapeutic agent.

28. The process of claim 24, wherein the hot-melt extruding step forms a first film having a thickness in the range of about 1-120 mils.

29. The process of claim 24, wherein the thermoplastic polymer is selected from the group consisting of HPC, PEO and a combination of HPC and PEO.

30. The process of claim 29, wherein the bioadhesive polymer is selected from the group consisting of polycarbophil, carbomer, one or more acrylic polymers, one or more polyacrylic acids, copolymers of these polymers, a water soluble salt of a co-polymer of methyl vinyl ether and maleic acid or anhydride, a combination thereof and their salts.

31. The process of claim 30, wherein the precursor composition further comprises one or more of the following additional components:

a) one or more film modifiers present in an amount of up to about 20% wt.;

b) one or more cross-linking agents present in an amount of about 0.1-1 5% wt.;

c) a super-disintegrant or super-absorbent present in an amount of about 0.1-20% wt.;

d) a pH-modifying agent present in an amount of about 0.1-10.0% wt.;

e) a preservative present in an amount of about 0.01-0.5% wt.;

f) an organic acid present in an amount of about 0.1-10% wt.; and

g) a water insoluble polymer present in an amount of about 1.0-20%.

32. The process of claim 31 wherein the precursor composition comprises at least two additional components.

33. The process of claim 24 further comprising the steps of extruding a second composition to form a second film and laminating the first and second films.

34. The process of claim 24 further comprising the step of cutting or shaping the film to adapt it for delivery of the therapeutic agent to the buccal, oral, rectal, vaginal, abdominal, cranial, ophthalmic, uterine, nasal, sinus or otic cavity.