Recipe for in-situ gel, and implant, drug delivery system formed thereby

• US 9,757,330 B2
• Filed: 09/17/2014
• Issued: 09/12/2017
• Est. Priority Date: 10/18/2013
• Status: Active Grant

• Current Assignee: Industrial Technology Research Institute
• Original Assignee: Industrial Technology Research Institute
• Inventors: Cheng, Felice, Lu, Maggie J. M., Ko, Yi-Ju, Lin, Min-Ying, Chou, Shuen-Hsiang
• Primary Examiner(s): Lieb, Jeanette
• Application Number:
  US14/488,431
• Publication Number:
  US 20150111834A1
• Time in Patent Office: 1,091 Days
• Field of Search: None
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears

Abstract

The disclosure provides a recipe for in-situ gel, formed by dissolving at least one polymer and at least one gel prevention agent in a polar solvent to form a solution and placing the solution in a condition for in-situ forming gels. The disclosure also provides an implant and a drug delivery system formed by the recipe.

Claims

1. A composition, comprising

at least one polymer,

at least one gel prevention agent and

at least one polar solvent,

wherein a ratio of the polymer and the gel prevention agent is 1:

5˜

1;

200 by weight,

wherein the gel prevention agent diffuses from the polymer when the composition is placed in an aqueous environment or a living tissue and thereby an in-situ gel is formed,

wherein the polymer comprises a polymer with an upper critical solution temperature (UCST), biopolymer, synthetic ABA triblock copolymer, zwitterionic homopolymer or a combination thereof, and

wherein the synthetic ABA triblock copolymer comprises a copolymer synthesized with N-(3-(methacryoylamino)propyl)-N,N-dimethyl-N-(3-sulfopropyl)ammonium hydroxide as the A block and 2-(2-methoxtethoxy) ethyl methacrylate as the B block, or wherein the zwitterionic homopolymer comprises phosphobetaines, sulfobetaines, carboxybetaines, or a combination thereof.

2. The composition as claimed in claim 1, wherein the polymer with the upper critical solution temperature (UCST) comprises agarose, agar, gelatin, collagen, agarose-graft-poly[3-dimethyl (methacryloyloxyethyl) ammonium propanesulfonate], poly(N-ethyl-N-methacrylamide), poly (acrylamide-co-acrylic acid), polystyrene-block-poly(methyl acrylate), poly[6-(acryloyloxymethyl)uracil], poly(-ethyl-2-oxazoline), poly(2-ethyl-2-oxazoline-stat-2-propyl-2-oxazoline), poly(-ethyl-N-vinylimidazole), poly(3-ethyl-1-vinyl-2-pyrrolidinone), poly(N-isopropylacrylamide), poly(isobutyl vinyl ether-co-2-hydroxyethyl vinyl ether), poly(vinyl alcohol), poly(N-propylacrylamide), polyvinyl glycine, poly(hydroxyethyl methacrylate), poly(methyl methacrylate).

3. The composition as claimed in claim 1, wherein the biopolymer comprises alginate, chitosan, polynucleotides, collagen, polypeptides, proteins, or a combination thereof.

4. The composition as claimed in claim 1, wherein the gel prevention agent comprises at least one selected from the group consisting of urea, thiourea, N-methylmorpholine N-oxide, guanidinium chloride, magnesium chloride and sodium dodecyl sulfate.

5. The composition as claimed in claim 1, wherein the polar solvent is biocompatible.

6. The composition as claimed in claim 5, wherein the polar solvent comprises at least one selected from the group consisting of water, carbonates, hydroxides, esters, ether and amides.

7. The composition as claimed in claim 5, wherein the polar solvent is poly ethylene glycol.

8. The composition as claimed in claim 1, wherein the polymer and the gel prevention agent in the composition is 30˜

80% by weight.

9. The composition as claimed in claim 1, further comprising a pharmaceutically active ingredient.

10. The composition as claimed in claim 9, wherein the pharmaceutically active ingredient comprises at least one selected from the group consisting of chemotherapeutics, antibiotics, steroids, antipsychotics, prostaglandin analogs, alpha 2-adrenergic agonists, alpha agonists, growth factors and hormones.

11. The composition as claimed in claim 9, wherein the pharmaceutically active ingredient comprises paclitaxel, docetaxel, risperidone, paliperidone, latanoprost, bimatoprost, travoprost, brimonidine, apracolonidine, epinephrine, progestoterone, corticosteroids, aldosterones, cortisol, testosterone, estrogen, aminoglycosides, ansamycines, carbacephem, carbapenems, cephalosporine, glycopeptides, lincosamindes, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, butyriophenones, phenothiazine, thioxanthenes, clozapine, olanzapiones, quetiaphine, ziprasidone, amisulpride, asenapine, lioperidone, iloperidone, zotepine, sertindole or lurasidone.

12. The composition as claimed in claim 9, wherein the composition is injected intraperitoneally, intramuscularly, subcutaneously or intraocularly.

13. The composition as claimed in claim 9, wherein the composition is formulated as eye drops.

14. An implant, comprising an in-situ gel formed by the composition as claimed in claim 1.

15. A drug delivery system, comprising an in-situ gel formed by the composition as claimed in claim 1.

16. The drug delivery system as claim in claim 15, further comprising an pharmaceutically active ingredient selected from the group consisting of paclitaxel, docetaxel, risperidone, paliperidone, latanoprost, bimatoprost, travoprost, brimonidine, apracolonidine, epinephrine, progestoterone, corticosteroids, aldosterones, cortisol, testosterone, estrogen, aminoglycosides, ansamycines, carbacephem, carbapenems, cephalosporine, glycopeptides, lincosamindes, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, butyriophenones, phenothiazine, thioxanthenes, clozapine, olanzapiones, quetiaphine, ziprasidone, amisulpride, asenapine, lioperidone, iloperidone, zotepine, sertindole and lurasidone.

17. The composition as claimed in claim 1, wherein the composition exists in liquid form at room temperature and normal pressure, and when the composition is introduced into an aqueous environment or a living tissue, the composition forms a gel.

18. A composition, comprising at least one polymer, at least one gel prevention agent and at least one polar solvent, wherein a ratio of the polymer and the gel prevention agent is 1:

5˜

1;

200 by weight, and wherein the gel prevention agent is diffused from the polymer as placing the composition within the aqueous environment or living tissues and thereby an in-situ gel is formed,

wherein the composition further comprising a pharmaceutically active ingredient, and wherein the composition is formulated as eye drops.

19. The composition as claimed in claim 18, wherein the pharmaceutically active ingredient comprises at least one selected from the group consisting of chemotherapeutics, antibiotics, steroids, antipsychotics, prostaglandin analogs, alpha 2-adrenergic agonists, alpha agonists, growth factors and hormones.

20. The composition as claimed in claim 18, wherein the pharmaceutically active ingredient comprises paclitaxel, docetaxel, risperidone, paliperidone, latanoprost, bimatoprost, travoprost, brimonidine, apracolonidine, epinephrine, progestoterone, corticosteroids, aldosterones, cortisol, testosterone, estrogen, aminoglycosides, ansamycines, carbacephem, carbapenems, cephalosporine, glycopeptides, lincosamindes, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, butyriophenones, phenothiazine, thioxanthenes, clozapine, olanzapiones, quetiaphine, ziprasidone, amisulpride, asenapine, lioperidone, iloperidone, zotepine, sertindole or lurasidone.