Therapeutic treatment and prevention of infections with a bioactive material(s) encapuslated within a biodegradable-bio-compatable polymeric matrix
First Claim
1. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which may contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncap and end-capped biodegradable-biocompatible copolymer wherein said composition comprises a capacity to completely release histatin in an aqueous physiological environment within from 1 to 40 days with a 99/1 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 48/52 to 52/48, and a molecular weight less than 15,000.
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Accused Products
Abstract
Novel burst-free, sustained release biocompatible and biodegrable microcapsules which can be programmed to release their active core for variable durations ranging from 1-100 days in an aqueous physiological environment. The microcapsules are comprised of a core of polypeptide or other biologically active agent encapsulated in a matrix of poly(lactide/glycolide) copolymer having a molar composition of lactide/glycolide from 90/10 to 40/60, which may contain a pharmaceutically-acceptable adjuvant, as a blend of uncapped free carboxyl end group and end-capped forms ranging to ratios from 100/0 to 1/99.
193 Citations
154 Claims
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1. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which may contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncap and end-capped biodegradable-biocompatible copolymer wherein said composition comprises a capacity to completely release histatin in an aqueous physiological environment within from 1 to 40 days with a 99/1 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 48/52 to 52/48, and a molecular weight less than 15,000.
- View Dependent Claims (2)
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3. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which may contain pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein said active material is histatin and wherein said composition is characterized by a capacity to release up to 90% of the histatin in an aqueous physiological environment from 28-70 days with a 1/99 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 48/52 to 52/48 and a molecular weight range of 10,000-40,000 daltons.
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4. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein said active material is histatin and wherein said composition is characterized by the capacity to release up to 80% of histatin in an aqueous physiological environment from 56-100 days with a 1/99 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio or 75/25 and a molecular weight of less than 15,000 daltons.
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5. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) a biologically active agent and (2) a cattier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer wherein the biologically active agent comprises a polypeptide leutinizing hormone releasing hormone (LHRH) that is a decapeptide of molecular weight 1182 in its acetate form, and having the structure;
p-EHWSYGLRPG.
- (1) a biologically active agent and (2) a cattier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer wherein the biologically active agent comprises a polypeptide leutinizing hormone releasing hormone (LHRH) that is a decapeptide of molecular weight 1182 in its acetate form, and having the structure;
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6. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material comprising a polypeptide and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncupped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein the entrapped polypeptide is any of the vaccine agents against enterotoxigenic E. coli (ETEC) selected from the group consisting of CFA/I, CFA/II, CS1, CS3,CS6 and CS17, ETEC-related enterotoxins, and combinations thereof.
- View Dependent Claims (7, 8)
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9. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein said agent is selected from the group consisting of water-soluble hormone drugs, antibiotics, antitumor agents, and inflammatory agents, antipyretics, analgesics antitussivess expectorants, sedatives, muscle relaxants, antiepileptics, antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, antihypertensives, diuretics, anticoagulants, antinarcotics, in the molecular weight range of 100-100,000 daltons.
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10. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biogradable-biocompatible poly(lactide/glycolide) copolymer, wherein the entrapped polypeptide is active at a low pH, and comprises LHRH, adrenocorticotropic hormone, epidermal growth factor, or calcitonin released polypeptide.
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11. A composition for the burst-free, sustained, progammable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein when the entrapped polypeptide is inactive at a low pH, a non-ionic surfactant such an polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween
20) and polyoxyethylene—
polyoxypropylene block copolymers (Fluronics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide.
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein when the entrapped polypeptide is inactive at a low pH, a non-ionic surfactant such an polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween
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12. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein when the entrapped polypeptide such as histatin is inactive at a low pH, a pH-stabilizing agent of inorganic salts is added to the inner aqueous phase to maintain biological activity of the released peptide, and further wherein placebo spheres loaded with the pH-stabilizing agents are coadministered with polypeptide-loaded spheres to maintain the solution pH around the microcapsules and preserve the biological activity of the released peptide in instances where the addition of pH-stabilizing agents in the inner aqueous phase is undesirable for the successful encapsulation of the acid pH sensitive polypeptide.
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13. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein when the entrapped polypeptide is inactive at a low pH, a non-ionic surfactant such an polyoxyethylene sorbitian fatty acid esters (Tween 80, Tween 60 and Tween
20) and polyoxyethylene-polyoxypropylene block copolymers (Flutonics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide, and further wherein placebo spheres loaded with non-ionic surfactant are coadministered with polypeptide-loaded spheres to maintain biological activity of the released peptide where the addition of non-ionic surfactants in the inner aqueous phase is undesirable for successful encapsulation of the acid pH sensitive polypeptide.
- (1) an entrapped polypeptide as an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein when the entrapped polypeptide is inactive at a low pH, a non-ionic surfactant such an polyoxyethylene sorbitian fatty acid esters (Tween 80, Tween 60 and Tween
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14. A composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide copolymer), wherein complete solubilization of the copolymer leaves no residual polymer at the site of administration and occurs concurrently with the complete release of the entrapped agent.
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15. A process of treating humans with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, said process comprising administering said composition via parenteral route selected from intramuscular and subcutaneous.
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16. A process of treating humans with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, said process comprising administering said composition via topical route.
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17. A process of treating humans with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, said process comprising administering said composition via oral routes.
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18. A process of treating humans with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, said process comprising administering said composition via nasal, transdermal, rectal, and vaginal routes.
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19. A process of treating humans with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, said process comprising administering said composition in the form of an oral or nasal inhalant for the respiratory tract.
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20. A process for preparing controlled release compositions characterized by burst-free, sustained, programmable release of biologically active agents, comprising:
- dissolving biodegradable poly(lactide/glycolide), in uncapped form in methylene chloride, and dissolving a biologically active agent or active core in water;
adding the aqueous layer to the polymer solution and emulsifying to provide an inner water-in-oil (w/o) emulsion;
stabilizing the w/o emulsion in a solvent-saturated aqueous phase containing a oil-in-water (o/w) emulsifier;
adding said w/o emulsion to an external aqueous layer containing oil-in-water emulsifier to form a ternary emulsion; and
stirring the resulting water-in-oil-in-water (w/o/w) emulsion for sufficient time to remove said solvent, and rinsing hardened microcapsules with water and lyophilizing said hardened microcapsules. - View Dependent Claims (21, 22, 24)
- dissolving biodegradable poly(lactide/glycolide), in uncapped form in methylene chloride, and dissolving a biologically active agent or active core in water;
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23. A process for preparing controlled release compositions characterized by burst-free, sustained, programmable release of biologically active agents, comprising:
dissolving biodegradable poly(lactide/glycolide) uncapped and end-capped form in methylene chloride, and dissolving a biologically active agent or active core in water;
adding the aqueous layer the polymer solution and emulsifying to provide an inner water-in-oil emulsion;
stabilizing the w/o emulsion in a solvent-saturated aqueous phase containing a oil-in-water (o/w) emulsifier;
adding said w/o emulsion to an external aqueous layer containing oil-in-water emulsifier to form a ternary emulsion; and
stirring a resulting water-in-oil-water (w/o/w) emulsion for sufficient time to remove said solvent; and
rinsing heardened microcapsules with water; and
lyophilizing said hardened microcapsules.- View Dependent Claims (25, 26)
- 27. A method for the protection against infection of a mammal in need thereof by pathogenic organisms comprising administering orally to said mammal an immunogenic amount of an immunostimulating composition comprising an antigenic synthetic peptide encapsulated within a poly(lactide/glycolide) matrix, wherein said poly(lactide/glycolide) matrix comprises a blend of uncapped and end-capped forms, in a ratio of 100/0 to 1/99.
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36. A vaccine for the immunization of a mammal in need thereof against infection caused by pathogenic organisms prepared from a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer.
- View Dependent Claims (37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 102, 103, 104, 105, 107, 108, 109)
- 79. A vaccine for the immunization of a mammal in need thereof, against infection by pathogenic organisms comprising an antigen in the amount of 0.1 to 1% encapsulated within a biodegradable-biocompatible polymeric poly(DL-lactide-coglycolide) matrix wherein the polymer is uncapped or a blend of uncapped and end-capped polymers.
- 89. An immunostimulating composition comprising encapsulating-microspheres, which may contain a pharmaceutically-acceptable adjuvant, wherein said microspheres having a diameter between 1 nanogram (ng) to 10 microns (um) are comprised of (a) a biodegradable-biocompatible poly(DL-lactide-co-glycolide) as the bulk matrix, wherein the copolymer (lactide to glycolide L/G) ratio for uncapped and end-capped polymer is 100/0 to 1/99 and (b) an immunogenic substance comprising a bacteria, virus, fungus, parasite, or derivative thereof, that serves to elicit the production of antibodies in animal subjects.
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101. A diagnostic assay for bacterial infections comprising a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) a biologically active agent and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer.
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110. A method for the protection against or therapeutic treatment of bacterial infection in the soft tissue or bone of a mammal in need thereof comprising administering locally to said mammal a bactericidally-effective amount of a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer, wherein the active material is an antibiotic which is controlled release within a period of about 1 to 100 days.
- View Dependent Claims (111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130)
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131. The process comprising treating humans in need, thereof, suffering from diseases and/or ailments selected from the group consisting of:
- viral infections;
bacterial infections;
fungal infections;
parasitic infections and more specific diseases and/or ailments;
such as, aids;
alzheimer'"'"'s dementia;
angiogenesis diseases;
aphthour ulcers in AIDS patients;
asthma;
atopic dermatitis;
psoriasis;
basal cell carcinoma;
benign prostatic hypertrophy;
blood substitute;
blood substitute in surgery patients;
blood substitute in trauma patients;
breast cancer;
breast cancer;
cutaneous &
metastatic;
cachexia in AIDS;
campylobacter infection;
cancer;
pnemonia;
sexually transmitted diseases (STDs);
cancer;
viral dieases;
candida albicians in AIDS and cancer;
candidiasis in HIV infection;
pain in cancer;
pancreatic cancer;
parkinson'"'"'s disease;
peritumoral brain edema;
postoperative adhesions (prevent);
proliferative diseases;
prostate cancer;
ragweed allergy;
renal disease;
restenosis;
rheumatoid arthritis;
rheumatoid arthritis;
allergies;
/rotavirus infection;
scalp psoriasis;
septic shock;
small-call lung cancer;
solid tumors;
stroke;
thrombosis;
type I diabetes;
type I diabetes w/kidney transplants;
type II diabetes;
viseral leishmaniasis;
malaria;
periodontal or gum disease;
cardiac rthythm;
disorders;
central nervous system diseases;
central nervous system disorders;
cervical dystonia (spasmodic torticollis);
choridal neovascularization;
chronic hepatitis c, b and a;
colitis associated with antibiotics;
colorectal cancer;
coronary artery thrombosis;
cryptosporidiosis in AIDS;
cryptosporidiun, paryum diarrhea in AIDS;
cystic fibrosis;
cytomegalovirus disease;
depression;
social phobias;
panic disorder;
diabetic complications;
disabetic eye disease;
diarrhea associated with antibiotics;
erectile dysfunction;
genital herpes;
graft-vs host disease in transplant patients;
growth hormone deficiency;
head and neck cancer;
head trauma;
stroke;
heparin neutralization after cardiac bypass;
hepatocallular carcinoma;
HIV;
HrV infection;
huntington'"'"'s disease;
CNS diseases;
hypercholesterolemia;
hypertension;
inflammation;
inflammation and angiogensis;
inflammation in cardiopulmonary bypass;
influenza;
migrain head ache;
interstitial cystitis;
kaposion sarcoma;
kaposils coma in AIDS;
lung cancer;
melanoma;
molluscum contagiosum in AIDS;
multiple sclerosis;
neoplastic meningitis from solid tumors;
non-small call lung cancer;
organ transplant rejection;
osteoarthritis;
rheumatoid arthritis;
osteoporosis;
drug addiction;
shock;
ovarian cancer;
Amebiasis;
Babesiasis;
Chagas'"'"' disease (Trypanosoma cruzi);
Cryptosporidiosis;
Cysticetcosis;
Fascioliasis;
Filariasis;
Echinococcosis;
Giardiasis;
Leishmaniasis;
Malaria;
Paragonimiasis;
Toxoplasmosis;
Trichinellosis;
Trichomoniasis;
yeast infection; and
pain, with a composition for the burst-free, sustained, programmable release of active material(s) over a period from 1-100 days, which comprises;
(1) an active material and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer.
- viral infections;
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132. A vaccine prepared from a composition for the burst-free, sustained, programmable release of active martials(s) over a period from 1-100 days, which comprises:
- (1) an active material and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer to prevent the occurrence in humans in need thereof of diseases and/or ailments selected from the group consisting of viral infections;
bacterial infections;
fungal infections;
parasitic infections and more specific diseases and/or ailments;
such as, aids;
alitimer'"'"'s dementia;
angiogenesis diseases;
aphthour ulcers in AIDS patients;
asthma;
atopic dermatitis;
psoriasis;
basal call carcinoma;
benign prostatic hypertrophy;
blood substitute;
blood substitute in surgery patients;
blood substitute in trauma patients;
breast cancer;
breast cancer;
cutaneous &
metastatic;
cachexia in AIDS;
campylobacter infection;
cancer;
pneumonia;
sexually transmitted diseases (STDs);
cancer;
viral diseases;
candida albicians in AIDS and cancer;
candidiasis in HIV infection;
pain in cancer;
pancreatic cancer;
parkinson'"'"'s disease;
periturmoral brain edema;
postoperative adhesions (prevent);
proliferative diseases;
prostate cancer;
ragweed allergy;
renal disease;
restenosis;
rheumatoid arthritis;
rheumatoid arthritis;
allergies;
rotavirus infection;
scalp psoriasis;
septic shock;
small-cell lung cancer;
solid tumors;
stroke;
thrombosis;
type I diabetes;
type I diabetes w/kidney transplant;
type II diabetes;
viseral leishmaniasis;
malaria;
periodontal or gun disease;
cardiac rthythm disorders;
central nervous system diseases;
central nervous system disorders;
cervical dystonia (spasmodic torticoillis);
choridal neovascularization;
chronic hepatitis c, b and a;
colitis associated with antibiotics;
colorectal cancer, coronary artery thrombosis;
cryptosporidiosis in AIDS;
ryptosporidium paryum diarrhea in AIDS;
cystic fibrosis;
cytomegalovirus disease;
depression;
social phobias;
panic disorder;
diabetic complications;
disabetic eye disease, diarrhea associated with antibiotics;
erectile dysfunction;
genital herpes;
graft-vs host disease in transplant patients;
growth hormone deficiency;
head and neck cancer;
head trauma;
stroke;
heparin neutralization after cardiac bypass;
hepatocellular carcinoma;
HIV;
HIV infection;
huntington'"'"'s disease;
CNS diseases;
hypercholesterolemia;
hypertension;
inflammation;
inflammation and angiogensis;
inflammation in cardiopulmonary bypass;
influenza;
migrain head ache;
interstitial cystitis;
kaposils sarcoma;
kaposils sarcoma in AIDS;
lung cancer;
melanoma;
molluscum contagiosum in AIDS;
multiple sclerosis;
neoplastic meningitis from solid tumors;
non-small call lung cancer;
organ transplant rejection;
ostsoarthritis;
rheumatoid arthritis;
osteoporosis;
drug addiction;
shock;
ovarian cancer;
Amebiasis;
Babesiasis;
Chagas'"'"' disease (Trypanosoma cruzi);
Cryptosporidiosis;
Cysticercosis;
rascioliasis;
Filariasis;
Echinococcosis;
Giardiasis;
Leishmaniasis;
Xalaria;
Paragonimiasis;
Pneunocystosis;
Schistosomiasis;
Strongylodiasis;
Toxocariasis;
Toxoplasmosis;
Trichinellosis;
Trichomoniasis;
yeast infection; and
pain.
- (1) an active material and (2) a carrier which contains pharmaceutically-acceptable adjuvant, comprised of a blend of uncapped and end-capped biodegradable-biocompatible poly(lactide/glycolide) copolymer to prevent the occurrence in humans in need thereof of diseases and/or ailments selected from the group consisting of viral infections;
Specification