Mucoadhesive drug delivery devices and methods of making and using thereof

• US 8,529,939 B2
• Filed: 12/08/2004
• Issued: 09/10/2013
• Est. Priority Date: 12/08/2003
• Status: Active Grant

• Current Assignee: PetVivo Holdings, Inc.
• Original Assignee: Gel-Del Technologies, Inc. (PetVivo Holdings, Inc.)
• Inventors: Masters, David B., Berg, Eric P.
• Primary Examiner(s): WEBB, WALTER E
• Application Number:
  US11/007,053
• Publication Number:
  US 20050196440A1
• Time in Patent Office: 3,198 Days
• Field of Search: 426/531, 424/1.29
• US Class Current: 424/434
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 38/363 Fibrinogen
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00

Abstract

The present invention relates to mucoadhesive drug delivery devices and their methods of preparation and use. More specifically the present invention relates to mucoadhesive drug delivery devices comprising one or more biocompatible purified proteins combined with one or more biocompatible solvents and one or more mucoadhesive agents. The mucoadhesive drug delivery devices may also include one or more pharmacologically active agents. The drug delivery devices of the present invention adhere to mucosal tissue, thereby providing a vehicle for delivery of the pharmacologically active agent(s) through such tissue.

Claims

1. A mucoadhesive device, comprising one or more purified free-form proteins, wherein one of the purified proteins included in the mucoadhesive device is ovalbumin, combined with one or more pharmacologically active agents, one or more mucoadhesive agents and one or more biocompatible solvents formed into a cohesive body or solidified cohesive mass that is formed into a mucoadhesive device and having the purified proteins in an amount of about 15% to 85% by weight of the mucoadhesive device, and the mucoadhesive agents in an amount of about 0.1% to 35% by weight of the mucoadhesive device, wherein the mucoadhesive device is configured to have a form such that the mucoadhesive device is capable of adhering to mucosal tissue of a patient for the delivery of the one or more pharmacologically active agents to the patient.

2. The mucoadhesive device of claim 1, wherein the mucoadhesive device further includes one or more additional purified proteins selected from the group consisting of elastin, collagen, albumin, plakalbumin, lactalbumin, glycomacropeptide, lactoglobulin, prealbumin, glutamine oligopeptide, casein, keratin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, whey protein, betalactoglobulin, alphlactalbumin, rice protein, grape vine protein, grape leaf protein, maize protein, olive protein, canola protein, soy protein, cottonseed protein, cotton leaf protein, seaweed protein, wheat protein, agglutinen, tobacco proteins, F1 and F2 protein, chickpea protein, fish protein and combinations thereof.

3. The mucoadhesive device of claim 1, wherein the biocompatible solvent is selected from the group consisting of water;

saline;

dimethyl sulfoxide (DMSO);

methanol, ethanol, formic acid, olive oil, peanut oil and combinations thereof.

4. The mucoadhesive device of claim 3, wherein the biocompatible solvent is water.

5. The mucoadhesive device of claim 1, wherein the mucoadhesive agents are selected from the group consisting of glycerol, pectin, polyethylene glycol, sorbitol, maltitol, mannitol, hydrogenated glucose syrups, xylitol, polydextrose, glyceryl triacetate, propylene glycol, propylene glycol alginate, glycogen and combinations thereof.

6. The mucoadhesive device of claim 1, wherein the mucoadhesive agent is glycerol.

7. The mucoadhesive device of claim 1, further including an additive wherein the additive is selected from the group consisting of polyurethanes, vinyl homopolymers and copolymers, acrylate homopolymers and copolymers, polyethers, cellulosics, epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, poly(ethylene terephthalate), polyacetal, poly(lactic acid), poly(ethylene oxide)/poly(butylene terephthalate) copolymer, polycarbonate, poly(tetrafluoroethylene) (PTFE), polycaprolactone, polyethylene oxide, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol (PVA), 2-hydroxyethyl methacrylate (HEMA), polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), poly(ethylene oxide) (PEO), poly ortho esters, poly (amino acids), polycynoacrylates, polyphophazenes, polysulfone, polyamine, poly (amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, ceramics, bioceramics, glasses bioglasses, glass-ceramics, resin cement, resin fill, glass ionomer, hydroxyapatite, calcium sulfate, Al₂O₃, tricalcium phosphate, calcium phosphate salts, sugars, starches, carbohydrates, salts, polysaccharides, alginate, carbon, cobalt-based alloys, galvanic-based alloys, stainless steel-based alloys, titanium- based alloys, zirconium oxide, zirconia, silica, aluminum-based alloys, vanadium-based alloys, molybdenum-based alloys, nickel-based alloys, iron-based alloys, zinc phosphate, zinc polycarboxylate and combinations thereof.

8. The mucoadhesive device of claim 1, wherein the pharmacologically active agent is selected from the group consisting of proteins, peptides, polysaccharides, nucleic acids, oligonucleotides, steroids, cytotoxic agents, analgesics, antiinflammatories, anesthetics, aminoglycosides, dermatological agents, antiviral, antibiotics, antimicrobials, vesicles, antibodies, vitamins, cofactors, viruses, microorganisms, cells, blood clotting factors, clot inhibitors, clot dissolving agents, tissues, antiestrogens, antigens, antiandrogens, muscle relaxants, prostaglandins, iodine compounds, nutritional agents, allergens, protease inhibitors, antirheumatoid agents, obstetric drugs, ovulation inducers, diuretics, antidiuretics, antihistamines, ceramides, antifungals, quinolones, sulfa drugs, neuromuscular blocking agents, anticonvulsants, CNS stimulants, antianxiety drugs, neuroleptics, antidepressants, sedatives, hemostatic agents, vasodilators, adrenergic stimulants, antimigraine drugs, cardiotonic glycosides, beta-adrenergic blocking agents, antiangina agents, antiarrhyrthmics, calcium channel blockers, sodium channel blockers, antihypertensives, anticoagulants, thrombolytic agents, antipyretics, anti-alzheimer'"'"'s agents, anti-Parkinson'"'"'s agents, antiemetics, reductase inhibitors, pituitary hormones, thyroid hormones, hypoglycemic agents, hormones, antimalarials, anoretic agents, hypercalcemia, antitussives, expectorants, decongestants, bronchospasm relaxants, smoking cessation agents, vaccines and any combination or prodrugs thereof.

9. The mucoadhesive device of claim 1, wherein the one or more purified proteins is ovalbumin, the one or more biocompatible solvents is water and the one or more mucoadhesive agents is glycerol.

10. The mucoadhesive device of claim 9, wherein the one or more pharmacologically active agents are selected from the group consisting of peptides, antisense, anesthetics, analgesics, chemotherapy agents, antidiuretics, anti-inflammatories and neurotoxins.

11. The mucoadhesive device of claim 1, wherein the one or more biocompatible solvents are selected from the group consisting of water, saline and DMSO.

12. The mucoadhesive device of claim 1, wherein the cohesive body is compressed and formed into a wafer, tablet, cylinder, sheet or sphere.

13. The mucoadhesive device of claim 1, wherein the cohesive body is compressed and processed into particles.

14. The mucoadhesive device of claim 1, wherein the solidified cohesive mass is processed into particles.

15. The mucoadhesive device of claim 14, wherein a plurality of the particles are compressed into a mucoadhesive mass.

16. The mucoadhesive device of claim 15, wherein the mass is a tablet, sphere, cylinder, sheet or wafer.

27. The mucoadhesive device of claim 16, wherein the compressed cohesive body is formed into a wafer, tablet, cylinder, sheet or sphere.

17. A mucoadhesive device, comprising ovalbumin in a free-form state, combined with one or more pharmacologically active agents, one or more mucoadhesive agents and one or more biocompatible solvents and formed into a cohesive body or solidified cohesive mass that is formed into a mucoadhesive device having a homogenous distribution of the ovalbumin in an amount of about 15% to 85% by weight of the mucoadhesive device, pharmacologically active agents, mucoadhesive agents in an amount of about 0.1% to 35% by weight of the mucoadhesive device and biocompatible solvents, wherein the mucoadhesive device is configured to have a form such that the mucoadhesive device is capable of adhering to mucosal tissue of a patient for the delivery of the one or more pharmacologically active agents to the patient.

18. The mucoadhesive device of claim 17, wherein the biocompatible solvent is selected from the group consisting of water;

saline;

dimethyl sulfoxide (DMSO);

methanol, ethanol, formic acid, olive oil, peanut oil and combinations thereof.

19. The mucoadhesive device of claim 18, wherein the biocompatible solvent is water.

20. The mucoadhesive device of claim 17, wherein the mucoadhesive agents are selected from the group consisting of glycerol, pectin, polyethylene glycol, sorbitol, maltitol, mannitol, hydrogenated glucose syrups, xylitol, polydextrose, glyceryl triacetate, propylene glycol, propylene glycol alginate, glycogen and combinations thereof.

21. The mucoadhesive device of claim 20, wherein the mucoadhesive agents is glycerol.

22. The mucoadhesive device of claim 17, further including an additive wherein the additive is selected from the group consisting of polyurethanes, vinyl homopolymers and copolymers, acrylate homopolymers and copolymers, polyethers, cellulosics, epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, poly(ethylene terephthalate), polyacetal, poly(lactic acid), poly(ethylene oxide)/poly(butylene terephthalate) copolymer, polycarbonate, poly(tetrafluoroethylene) (PTFE), polycaprolactone, polyethylene oxide, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol (PVA), 2-hydroxyethyl methacrylate (HEMA), polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), poly(ethylene oxide) (PEO), poly ortho esters, poly (amino acids), polycynoacrylates, polyphophazenes, polysulfone, polyamine, poly (amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, ceramics, bioceramics, glasses bioglasses, glass-ceramics, resin cement, resin fill, glass ionomer, hydroxyapatite, calcium sulfate, Al₂O₃, tricalcium phosphate, calcium phosphate salts, sugars, starches, carbohydrates, salts, polysaccharides, alginate, carbon, cobalt-based alloys, galvanic-based alloys, stainless steel-based alloys, titanium-based alloys, zirconium oxide, zirconia, silica, aluminum-based alloys, vanadium-based alloys, molybdenum-based alloys, nickel-based alloys, iron-based alloys, zinc phosphate, zinc polycarboxylate and combinations thereof.

23. The mucoadhesive device of claim 17, wherein the pharmacologically active agent is selected from the group consisting of proteins, peptides, polysaccharides, nucleic acids, oligonucleotides, steroids, cytotoxic agents, analgesics, antiinflammatories, anesthetics, aminoglycosides, dermatological agents, antiviral, antibiotics, antimicrobials, vesicles, antibodies, vitamins, cofactors, viruses, microorganisms, cells, blood clotting factors, clot inhibitors, clot dissolving agents, tissues, antiestrogens, antigens, antiandrogens, muscle relaxants, prostaglandins, iodine compounds, nutritional agents, allergens, protease inhibitors, antirheumatoid agents, obstetric drugs, ovulation inducers, diuretics, antidiuretics, antihistamines, ceramides, antifungals, quinolones, sulfa drugs, neuromuscular blocking agents, anticonvulsants, CNS stimulants, antianxiety drugs, neuroleptics, antidepressants, sedatives, hemostatic agents, vasodilators, adrenergic stimulants, antimigraine drugs, cardiotonic glycosides, beta-adrenergic blocking agents, antiangina agents, antiarrhyrthmics, calcium channel blockers, sodium channel blockers, antihypertensives, anticoagulants, thrombolytic agents, antipyretics, anti-alzheimer'"'"'s agents, anti-Parkinson'"'"'s agents, antiemetics, reductase inhibitors, pituitary hormones, thyroid hormones, hypoglycemic agents, hormones, antimalarials, anoretic agents, hypercalcemia, antitussives, expectorants, decongestants, bronchospasm relaxants, smoking cessation agents, vaccines and any combination or prodrugs thereof.

24. The mucoadhesive device of claim 17, wherein the one or more biocompatible solvents is water and the one or more mucoadhesive agents is glycerol.

25. The mucoadhesive device of claim 17, wherein the one or more pharmacologically active agents are selected from the group consisting of peptides, antisense, anesthetics, analgesics, chemotherapy agents, antidiuretics, anti-inflammatories and neurotoxins.

26. The mucoadhesive device of claim 17, wherein the cohesive body is compressed.

28. The mucoadhesive device of claim 17, wherein the compressed cohesive body is processed into particles.

29. The mucoadhesive device of claim 17, wherein the solidified cohesive mass is processed into particles.

30. The mucoadhesive device of claim 28, wherein a plurality of the particles are compressed into a tablet, sphere, cylinder, sheet or wafer.

31. The mucoadhesive device of claim 29, wherein a plurality of the particles are compressed into a tablet, sphere, cylinder, sheet or wafer.

32. A method of delivering one or more pharmacologically active agents through the mucosal tissue of a patient comprising the steps of:

adhering a mucoadhesive device to the mucosal tissue of a patient, said mucoadhesive device including one or more purified free-form proteins, wherein one of the purified proteins included in the mucoadhesive device is ovalbumin, combined with one or more pharmacologically active agents, one or more mucoadhesive agents and one or more biocompatible solvents to form a coatable composition, wherein the solvent content of the coatable composition is reduced and formed into a mucoadhesive device having a homogenous distribution of the purified proteins, pharmacologically active agents, mucoadhesive agents and biocompatible solvents, wherein the mucoadhesive device is configured to have a form such that the mucoadhesive device adheres to the mucosal tissue of the patient for the delivery of the one or more pharmacologically active agents to the patient.

33. The method of delivering one or more pharmacologically active agents through mucosal tissue of a patient of claim 32, wherein the mucosal tissue is located at the cheek, gum, sublingual area, palate, tongue, periodontal pockets, nasal cavity, vaginal cavity, anal cavity, intestinal walls, pulmonary regions, ocular areas, or stomach cavity.

34. The method of delivering one or more pharmacologically active agents through mucosal tissue of a patient of claim 32, wherein the one or more biocompatible solvents is water and the one or more mucoadhesive agents is glycerol.

35. The method of delivering one or more pharmacologically active agents through mucosal tissue of a patient of claim 32, wherein the one or more pharmacologically active agents are selected from the group consisting of peptides, antisense, anesthetics, analgesics, chemotherapy agents, antidiuretics, anti-inflammatories, neurotoxins and vitamins.

36. The method of delivering one or more pharmacologically active agents through mucosal tissue of a patient of claim 32, where the mucoadhesive device is in a form selected from the group consisting of a wafer, tablet, cylinder, sheet, particles or sphere.

37. A method of making a mucoadhesive drug delivery device comprising:

(a) preparing a coatable composition including one or more biocompatible purified free-form proteins, wherein one of the purified proteins included in the mucoadhesive device is ovalbumin, one or more biocompatible solvents, one or more mucoadhesive agents and one or more pharmacologically active agents;

(b) partially drying the coatable composition to reduce bulk solvent present in the system to form a solidified cohesive mass including a substantially homogenous distribution of purified proteins, solvents, mucoadhesive agents and pharmacologically active agents; and

(c) processing the cohesive mass to form a mucoadhesive device, wherein the mucoadhesive device is processed to have a form such that the mucoadhesive device is capable of adhering to mucosal tissue of a patient for the delivery of the one or more pharmacologically active agents to the patient.

38. The method of making a mucoadhesive drug delivery device of claim 37, wherein the one or more biocompatible solvents is water and the one or more mucoadhesive agents is glycerol.

39. The method of making a mucoadhesive drug delivery device of claim 37, wherein the one or more pharmacologically active agents are selected from the group consisting of peptides, antisense, anesthetics, analgesics, chemotherapy agents, antidiuretics, anti-inflammatories, neurotoxins and vitamins.

40. The method of making a mucoadhesive drug delivery device of claim 37, wherein the mucoadhesive device is processed into a form selected from the group consisting of a wafer, tablet, cylinder, sheet, particles or sphere.