System and method for fabrication of uniform polymer films containing nano and micro particles via continuous drying process

Patent metadata

Field	Value
Publication number	US-10646452-B2
Application number	US-201414777191-A
Country	US
Kind code	B2
Filing date	Mar 17, 2014
Priority date	Mar 15, 2013
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The present disclosure provides improved stripfilm based pharmaceutical products (e.g., for enhancing dissolution and bioavailability). More particularly, the present disclosure provides improved systems/methods for fabricating stripfilm based pharmaceutical products by utilizing higher viscosity film forming precursors and drying methods that accomplish improved/faster drying and provide improved/excellent content uniformity of active pharmaceutical agents in the stripfilm based pharmaceutical products. Exemplary systems/methods advantageously use high viscosity, bio-compatible polymeric precursors, (optional use of surface modified drug powders), and convective drying for fabrication of thin films loaded with nano and/or micro sized particles of poorly water-soluble active pharmaceutical ingredients (APIs) to achieve improved active content uniformity and very fast dissolution from poorly water soluble actives, while accomplishing fast drying during the fabrication process. The present disclosure provides for the fast drying (e.g., via low temperature forced convection) of biocompatible polymer films loaded with poorly water-soluble drug nano-particles.

First claim

What is claimed is:

1. A method for fabricating a pharmaceutical product, comprising:
providing an aqueous film forming precursor composition that includes one or more superdisintegrants;
providing active agent nano-particles;
mixing the aqueous film forming precursor composition and the one or more superdisintegrants with the active agent nano-particles to form a mixture, the mixture formed prior to formation of a stripfilm fabricated from the mixture, the mixture of the aqueous film forming precursor composition and the active agent nano-particles having a viscosity of from about 100 cP to about 25,000 cP; and
drying and fabricating the mixture to form the stripfilm fabricated from the mixture;
wherein the mixture is dried at about 0° C. to about 80° C. for about 10 minutes to about 90 minutes to form the stripfilm.

2. The method of claim 1 , wherein the film forming precursor composition includes one or more water-soluble polymers, or one or more water-insoluble polymers;
wherein the active agent nano-particles include one or more pharmaceutical active agent nano-particles;
wherein the active agent nano-particles include one or more poorly water-soluble drug nano-particles; and
wherein the mixture is a suspension of the aqueous film forming precursor composition and the active agent nano-particles.

3. The method of claim 1 , wherein the active agent nanoparticles include one or more nano-particles that are soluble in the mixture.

4. The method of claim 1 , wherein the drying step includes convective drying in laminar flow conditions to form the stripfilm.

5. The method of claim 1 , wherein the drying step includes drying the mixture at about 20% relative humidity to about 90% relative humidity.

6. The method of claim 1 , wherein the step of providing the active agent nano-particles includes preparing a suspension of the active agent nano-particles by utilizing a top down approach or a bottom up approach.

7. The method of claim 1 , wherein the active agent nano-particles are distributed uniformly within an interior of the stripfilm; and
wherein about 80% or more of the active agent nano-particles from the dried stripfilm dissolve within thirty minutes in an in vitro dissolution test.

8. The method of claim 1 , wherein the step of providing the active agent nano-particles includes preparing a suspension of the active agent nano-particles by an emulsion step.

9. The method of claim 1 , wherein the step of providing the active agent nano-particles includes providing the active agent nano-particles in dry powder form; and
wherein the active agent nano-particles are surface modified with one or more hydrophilic substances.

10. The method of claim 1 , wherein the stripfilm has an active agent nano-particle loading of from about 0.01 weight % to about 50 weight %.

11. The method of claim 1 , wherein the active agent nano-particles are in crystalline or amorphous form or combinations thereof;
wherein the film forming precursor composition includes one or more viscosity enhancers or disintegrants; and
wherein the stripfilm is formed by casting the mixture onto a substrate.

12. The method of claim 1 , wherein the stripfilm has an active agent nano-particle loading uniformity throughout an interior of the stripfilm, the active agent nano-particle loading uniformity varying in uniformity of active agent loading by less than 6% relative standard deviation over average active agent nano-particle mass per unit area of the stripfilm.

13. The method of claim 1 , wherein the stripfilm has an active agent nano-particle loading uniformity throughout an interior of the stripfilm, the active agent nano-particle loading uniformity varying in uniformity of active agent loading by less than 3% relative standard deviation over average active agent nano-particle mass per unit area of the stripfilm; and
wherein the fabricated stripfilm has a water content of from about 5 weight % to about 8 weight %.

14. The method of claim 1 , wherein the mixing step includes mixing the aqueous film forming precursor composition and the active agent nano-particles with a vibratory or planetary mixer.

15. The method of claim 1 ,
wherein the mixture of the aqueous film forming precursor composition and the active agent nano-particles has a viscosity of from about 4,000 cP to about 25,000 cP;
wherein due to a high swelling capacity of the one or more superdisintegrants, their addition to the aqueous film forming precursor composition raises the viscosity of the mixture.

16. The method of claim 1 , wherein the stripfilm has an active agent nano-particle loading of from about 0.50 weight % to about 30 weight %; and
wherein the content uniformity of the active agent nano-particles in the stripfilm indicated by the relative standard deviation of the active agent nano-particle content in the stripfilm is less than about 6%.

17. The method of claim 1 , further comprising the step of re-dispersing the fabricated stripfilm in a medium to form a re-dispersion, the re-dispersing step including re-dispersing about a 0.7 cm 2 circular area of the stripfilm: (i) in about three ml to about 10 ml of water via vortex mixing for about one minute to about five minutes, or (ii) in about 15 ml of water via magnetic stirring for about 10 minutes;
wherein the active agent particles, prior to mixing with the aqueous film forming precursor composition, have a first D50 particle size distribution value and the re-dispersion of the fabricated stripfilm in the medium has a second D50 particle size distribution value, the first and second D50 particle size distribution values varying from one another by about 20% or less.

18. The method of claim 1 , wherein the active agent nano-particles are about 5 nm to about 20,000 nm in size.

19. The method of claim 18 , wherein the active agent nano-particles are about 30 nm to about 5,000 nm in size.

20. The method of claim 18 , wherein the active agent nano-particles are about 50 nm to about 5,000 nm in size.

21. The method of claim 18 , wherein the active agent nano-particles are about 50 nm to about 300 nm in size.

22. The method of claim 1 , further comprising the step of re-dispersing the fabricated stripfilm in a medium to form a re-dispersion.

23. The method of claim 1 , wherein due to a high swelling capacity of the one or more superdisintegrants, their addition to the aqueous film forming precursor composition increases stabilization of the mixture, aids in heterogenous uniformity of mixing of the active agent non-particles in a non-aggregated state, and contributes with re-dispersion and full-fast dissolution of the mixture.

24. A method for fabricating a pharmaceutical product comprising:
providing a film forming precursor composition that includes one or more superdisintegrants;
providing active agent nano-particles;
mixing the aqueous film forming precursor composition and the one or more superdisintegrants with the active agent nano-particles to form a mixture, the mixture formed prior to formation of a stripfilm fabricated from the mixture, the mixture having a viscosity of from about 4,000 cP to about 25,000 cP, wherein due to the high swelling capacity of the one or more superdisintegrants, their addition to the aqueous film forming precursor composition raises the viscosity of the mixture; and
drying and fabricating the mixture to form the stripfilm fabricated from the mixture;
wherein the mixture is dried at about 0° C. to

Assignees

• New Jersey Inst Technology
• Univ Rutgers

Inventors

• Dave Rajesh N
• Susarla Ramani
• Khusid Boris
• Bhakay Anagha A
• Bilgili Ecevit A
• Muzzio Fernando

Classifications

• A61K31/216

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61K9/006

  Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays · CPC title

• A61F13/00063

  comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic (drug delivery dressings A61K9/70; chemical aspect of the additives A61L15/00) · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K9/7007 Primary

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