Dissolvable gel-forming film for delivery of active agents

Patent metadata

Field	Value
Publication number	US-2016008293-A1
Application number	US-201414769754-A
Country	US
Kind code	A1
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	Jan 14, 2016
Grant date	—

Abstract

Disclosed is a dissolvable, gel-forming film, and methods for its use, comprising a water-soluble cellulose ether, a hydrophilic rheological modifying agent, and an active proteolytic enzyme or other drug substance. The gel-forming film has a water content of less than 15% w/w and is capable of forming a hydrogel when contacted with water or other aqueous medium. The disclosed films achieve delivery of stable proteolytic enzymes to the desired site of action in a manner that provides uniform delivery of the enzymes.

First claim

1 . A dissolvable, gel-forming film comprising:
(a) a water-soluble cellulose ether; (b) a hydrophilic rheological modifying agent; and (c) a proteolytic enzyme, wherein the dissolvable, gel-forming film has a water content of less than 15% w/w, and the dissolvable, gel-forming film is capable of forming a hydrogel when contacted with water or other aqueous medium.

2 . The dissolvable, gel-forming film of claim 1 , wherein the proteolytic enzyme is in crystalline form.

3 . The dissolvable, gel-forming film of any of claims 1 - 2 , wherein the hydrogel that is formed has a viscosity of 1,000 to 100,000 cps, as measured using a Brookfield RV Model Viscometer using small sample adapter with spindle #SC4-14 and chamber #SC4-6R, at 10 rpm at room temperature, reading taken at 1 minute.

4 . The dissolvable, gel-forming film of any of claims 1 - 3 , wherein the proteolytic enzyme is themolysin, collagenase, or papain.

5 . The dissolvable, gel-forming film of claim 4 , wherein the proteolytic enzyme is thermolysin.

6 . The dissolvable, gel-forming film of any of claims 1 - 5 , wherein the thickness of the film ranges from 10 to 1000 μm.

7 . The dissolvable, gel-forming film of any of claims 1 - 6 , wherein the film is capable of dissolving in water at a rate from 100 to 0.1 mg/min.

8 . The dissolvable, gel-forming film of claim 7 , wherein the film is capable of dissolving in water at a rate from 0.5-10 mg/min.

9 . The dissolvable, gel-forming film of any of claims 1 - 8 , wherein the weight percent of the proteolytic enzyme is not less than 0.1% of the dry weight of the film and does not decrease by more than 10% when stored at room temperature for 24 months.

10 . The dissolvable, gel-forming film of any one of claims 1 - 9 , wherein the water-soluble cellulose ether is a hydroxyalkyl cellulose ether.

11 . The dissolvable, gel-forming film of claim 10 , wherein the hydroxyalkyl cellulose ether is hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose, or any combination thereof.

12 . The dissolvable, gel-forming film of any one of claims 1 - 11 , comprising 50 to 70% w/w or 55 to 65% w/w of the water-soluble cellulose ether or combinations thereof.

13 . The dissolvable, gel-forming film of any one of claims 1 - 12 , comprising 25 to 35% w/w of hydroxyethylcellulose and 25 to 35% w/w of hydroxypropylmethyl cellulose.

14 . The dissolvable, gel-forming film of any one of claims 1 - 13 , comprising 15 to 25% w/w of the hydrophilic rheological modifying agent.

15 . The dissolvable, gel-forming film of claim 14 , wherein the hydrophilic rheological modifying agent is a polyol.

16 . The dissolvable, gel-forming film of claim 15 , wherein the polyol is polyethylene glycol.

17 . The dissolvable, gel-forming film of claim 16 , wherein the polyethylene glycol is PEG-400.

18 . The dissolvable, gel-forming film of any one of claims 1 - 17 , comprising 5 to 15% w/w of the proteolytic enzyme.

19 . The dissolvable, gel-forming film of any one of claims 1 - 18 , wherein the hydrogel further comprises a metal salt.

20 . The dissolvable, gel-forming film of claim 19 , wherein the metal salt is sodium chloride or calcium chloride or mixtures thereof.

21 . The dissolvable, gel-forming film of any one of claims 1 - 20 , wherein the hydrogel further comprises a preservative.

22 . The dissolvable, gel-forming film of claim 21 , wherein the preservative is methylparaben, propylparaben, or phenoxyethanol, or mixtures thereof.

23 . The dissolvable, gel-forming film of any one of claims 1 - 22 , wherein the film is produced by:
(a) obtaining a first mixture comprising 3 to 7% w/w of the cellulose ether or combinations thereof, 1 to 3% w/w of the hydrophilic rheological modifying agent, and Tris Buffer (10 mM, pH=7.5); (b) obtaining a second mixture comprising a proteolytic enzyme, a metal salt, and Tris Buffer (10 mM, pH=7.5); (c) mixing the first and second mixtures together to obtain a hydrogel; and (d) drying the hydrogel from step (c) to obtain the dissolvable, gel-forming film.

24 . The dissolvable, gel-forming film of claim 23 , wherein the proteolytic enzyme is themolysin, collagenase, or papain.

25 . The dissolvable, gel-forming film of claim 24 , wherein the proteolytic enzyme is thermolysin.

26 . A method of debriding a wound comprising topically applying the dissolvable, gel-forming film from any one of claims 1 - 25 to a wound in need of debridement.

27 . The method of claim 26 , wherein the wound is a chronic wound.

28 . The method of claim 27 , wherein the chronic wound is a diabetic foot ulcer, a venous leg ulcer, an arterial leg ulcer, a decubitus ulcer, a stasis ulcer, a dermal ulcer, a burn, or a pressure ulcer.

29 . The method of any one of claims 26 - 28 , wherein the wound includes necrotic tissue.

30 . The method of claim 29 , wherein the necrotic tissue is an eschar.

31 . The method of any one of claims 26 - 30 , wherein an aqueous medium is applied to the wound before the dissolvable, gel-forming film is applied to the wound or wherein an aqueous medium is applied to the dissolvable, gel-forming film after said film is applied to the wound.

32 . The method of claim 31 , wherein the aqueous medium is a saline solution.

33 . The method of any one of claims 26 - 32 , wherein a bandage, wound dressing, or gauze is applied onto the dissolvable, gel-forming film after said film is applied to the wound.

Assignees

• Smith & Nephew Inc

Inventors

• Shi Lei
• Jovanovic Aleksa
• Carson Dennis

Classifications

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• A61L15/38

  containing enzymes · CPC title

• A61K9/7007 Primary

  Drug-containing films, membranes or sheets (A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence) · CPC title

• A61L15/60

  Liquid-swellable gel-forming materials, e.g. super-absorbents · CPC title

• C12Y304/24027

  Thermolysin (3.4.24.27) · CPC title