Biodegradable vehicle and filler

• US 6,432,438 B1
• Filed: 06/28/2000
• Issued: 08/13/2002
• Est. Priority Date: 10/29/1997
• Status: Expired due to Fees

• Current Assignee: Atul J. Shukla
• Original Assignee: Atul J. Shukla
• Inventors: Shukla, Atul J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): WARE, TODD
• Application Number:
  US09/605,661
• Time in Patent Office: 776 Days
• Field of Search: 424/426, 424/423, 424/422, 424/400, 604/890.1
• US Class Current: 424/426
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: C08K 5/11 of acyclic polycarboxylic acids
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

A biodegradable vehicle and filler (referred to in this invention as biodegradable vehicle), which can be mixed with one or more biologically active substances (BAS), or can be used as a biodegradable filler to fill in cavities or body tissues in animals, birds and humans. The consistency and rheology, hydrophilicity and hydrophobicity, and in vivo degradation rates of the biodegradable vehicle is controlled by modulating the molecular weight of polymers and copolymers, concentration of plasticizers, ratios of two or more plasticizer in the blends, types of polymers and copolymers, copolymer ratios, and ratios of blends of polymers with different molecular weights or different copolymers. The biodegradable vehicle is mixed with one or more BAS (which is separately stored away from the biodegradable vehicle in an appropriate container) just prior to use. Mixing of the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stirring device, or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing. Alternatively, a device, which resembles two syringes, attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle. The mixing is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle. Modulating the polymer to plasticizer ratio, polymer molecular weight, copolymer ratio, and hydrophobicity and hydrophilicity of the plasticizer controls the release of the BAS from the biodegradable vehicle.

Claims

1. A method for the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group consisting of homopolymers or copolmers of polyesters, polyorhoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

2. The method of claim 1 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene gycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate, acetyltri-n-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PECs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

3. The method of claim 1 wherein said biologically active substance is a solid, liquid, semisolid or gas.

4. The method of claim 3 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

5. The method of claim 3 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mites of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

6. The method of claim 3 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

7. The met of claim 1 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antiinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

8. The method of claim 1 comprising at least two biodegradable polymers.

9. The method of claim 1 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.

10. The method of claim 9 wherein said biologically active agents are selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antiinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

11. The method of claim 9 wherein said biologically active substance is a solid, liquid, semisolid or gas.

12. The method of claim 11 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformity distributed throughout the matrix prepared with blends of inert excipient or excipients.

13. The method of claim 11 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

14. The method of claim 11 wherein said biologically active agent is

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

15. A method for enhancing the stability of the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or polymer selected from the group consisting of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, porno acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at leas two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

16. The method of claim 15 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate, acetyltri-n-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol captylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

17. The method of claim 15 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, algal agents, cavity and infection preventing agents, cardiovascular agents, antinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

18. The method of claim 15 wherein said biologically active substance is a solid, liquid, semisolid or gas.

19. The method of claim 18 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blend thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

20. The method of claim 15 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

21. The method of claim 15 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

22. The method of claim 15 comprising at least two biodegradable polymers.

23. The method of claim 15 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.

24. A method for modulating the release characteristics of the biologically active substance in the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group consisting of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

25. The method of claim 24 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol glycerol glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate,acetyltri-n-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6dioleate, polyglyceryl-3isostearate, PEG32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

26. The met of claim 24 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antiinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-in deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

27. The method of claim 24 wherein said biologically active substance is a solid, liquid, semisolid or gas.

28. The method of claim 27 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

29. The method of claim 27 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mix of vehicles.

30. The method of claim 27 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

31. The method of claim 24 comprising at least two biodegradable polymers.

32. The method of claim 24 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.

33. A method for modulating the dose of a bioactive agent in the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group consisting of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biological active substance-loaded biodegradable vehicle.

34. The method of claim 33 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate, acetyltri-n-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearte, glyceryl palmitostearate, and glyceryl triacetate.

35. The method of claim 33 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigen anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents antiinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

36. The method of claim 33 wherein said biologically active substance is a solid, liquid, semisolid or gas.

37. The method of claim 36 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

38. The method of claim 36 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

39. The method of claim 36 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

40. The method of claim 33 comprising at least two biodegradable polymers.

41. The method of claim 33 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.

42. A method for modulating the consistency or rheology of the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group consisting of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates;

polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

43. The method of claim 42 wherein said plasticizers are selected from the group consisting of citrates, phhalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate, acetyltri-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil, peanut oil sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

44. The method of claim 42 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antiinflammatory agents, vasodilators, brochiodilators, alkaloid, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agent derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

45. The method of claim 42 wherein said biologically active substance is a solid, liquid, semisolid or gas.

46. The method of claim 45 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

47. The method of claim 45 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

48. The method of claim 45 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

49. The method of claim 42 comprising at least two biodegradable polymers.

50. The method of claim 42 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.

51. A method for modulating the hydrophilicity or hydrophobicity of the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group costing of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

52. The method of claim 51 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-citrate, acetyltri-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil soy bean oil, almond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

53. The method of claim 51 wherein said biologically active substance is a solid, liquid, semisolid or gas.

54. The method of claim 53 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformly distributed throughout the matrix prepared with blends of inert excipient or excipients.

55. The method of claim 53 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

56. The method of claim 53 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolved or dispersed in a semisolid vehicle or vehicles.

57. The method of claim 51 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural issues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

58. The method of claim 51 comprising at least two biodegradable polymers.

59. The method of claim 51 wherein said biologically active substance loaded biodegradable vehicle comprises at least two biologically agent substances.

60. A method for modulating the degradation of the formulation of a biodegradable system comprising mixing:

(a) at least one biodegradable polymer or copolymer, said polymer or copolymer selected from the group consisting of homopolymers or copolymers of polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones polyhydroxybutyrates, polyhydroxyvalerates, polyamino acids, pseudopolyamino acids, polyamides and polyanhydrides;

(b) at least two plasticizers, wherein at least one plasticizer is hydrophilic and at least one plasticizer is hydrophobic; and

(c) at least one biologically active substance;

to produce a biologically active substance-loaded biodegradable vehicle.

61. The method of claim 60 wherein said plasticizers are selected from the group consisting of citrates, phthalates, glycol ethers, n-methyl pyrrolidone, 2 pyrrolidone, propylene glycol glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, butyryltri-n-hexyl-crate, acetyltri-hexyl citrate, sebacates, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate;

propylene glycol caprylate/caprate, caprylic/capric triglyceride, gamma butyrolactone, polyethylene glycols (PEGs), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton seed oil, soy bean oil, almond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-32 glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.

62. The method of claim 60 wherein said biologically active agent is selected from a group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS-agents), fertility regulating agents, antibodies, antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, antiinflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, growth promoting agents, natural tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid, and biological tissues.

63. The method of claim 60 wherein said biologically active substance is a solid, liquid, semisolid or gas.

64. The method of claim 63 wherein said biologically active agent is a solid, wherein said solid is:

(a) crystalline, amorphous, granular;

or

(b) granulated with or without added excipient or excipients;

or

(c) encapsulated in an appropriate encapsulating material such as a polymer, a wax or blends thereof;

or

(d) a matrix wherein the biologically active agent is uniformity distributed throughout the matrix prepared with blends of inert excipient or excipients.

65. The method of claim 63 wherein said biologically active agent is:

(a) a liquid;

or

(b) a solid, liquid or a gas dissolved in a liquid vehicle or mixtures of liquid vehicles;

or

(c) solid suspended in a liquid vehicle or mixtures of vehicles;

or

(d) liquid emulsified in a liquid vehicle or mixtures of vehicles.

66. The method of claim 63 wherein said biologically active agent is:

(a) a semisolid;

or

(b) a solid or a gas dissolve or dispersed in a semisolid vehicle or vehicles.

67. The method of claim 60 comprising at least two biodegradable polymers.

68. The method of claim 60 wherein said biologically active substance-loaded biodegradable vehicle comprises at least two biologically active substances.