Compositions and methods for forming stabilized compositions with reduced CSA agglomeration
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-009/16
A61K-009/48
A61K-031/575
A61K-009/14
B06B-001/00
A61K-031/56
출원번호
US-0642905
(2015-03-10)
등록번호
US-10220045
(2019-03-05)
발명자
/ 주소
Darien, Benjamin J.
Savage, Paul B.
출원인 / 주소
BRIGHAM YOUNG UNIVERSITY
대리인 / 주소
Workman Nydegger
인용정보
피인용 횟수 :
0인용 특허 :
40
초록▼
Compositions and methods for preparing stabilized CSA compositions having reduced agglomeration and increased stability. The compositions have increased efficacy in killing microbes and reduced cytotoxicity to mammals. The compositions include a liquid carrier, micelles formed from an amphiphilic ma
Compositions and methods for preparing stabilized CSA compositions having reduced agglomeration and increased stability. The compositions have increased efficacy in killing microbes and reduced cytotoxicity to mammals. The compositions include a liquid carrier, micelles formed from an amphiphilic material, and CSA molecules encapsulated by the micelles. The CSA compositions can be formed by blending together a solvent or liquid carrier, a plurality of CSA molecules, and a micelle-forming agent and causing or allowing the micelle-forming agent to form micelles encapsulating at least a portion of the CSA molecules so that no more than 25% of the CSA molecules form agglomerates larger than 1 μm in size. The CSA compositions can be used to treat mammals, such as mammals suffering from microbial diseases or infections.
대표청구항▼
1. A CSA-containing composition comprising: a polar solvent or aqueous carrier;a plurality of cationic steroidal antimicrobial (CSA) molecules; anda micelle-forming agent comprising an amphiphilic compound or composition forming micelles,wherein the amphiphilic compound or composition forming micell
1. A CSA-containing composition comprising: a polar solvent or aqueous carrier;a plurality of cationic steroidal antimicrobial (CSA) molecules; anda micelle-forming agent comprising an amphiphilic compound or composition forming micelles,wherein the amphiphilic compound or composition forming micelles encapsulates at least a portion of the CSA molecules so that no more than 25% of the CSA molecules form agglomerates larger than 1 μm in size, andwherein the CSA-containing composition maintains or increases efficacy in killing microbes and reduces or minimizes cytotoxicity to mammalian cells. 2. A CSA-containing composition as in claim 1, wherein the hydrophilic solvent or aqueous carrier comprises at least one of water, hydrophilic organic solvent, surfactant, nonionic surfactant, anionic surfactant, or hydrophilic organic liquid. 3. A CSA-containing composition as in claim 1, wherein the micelle-forming agent is selected from the group consisting of modified celluloses, modified nonionic hydroxyethyl cellulose, natural polyoxyethylene sorbitol ester, hydroxyethyl cellulose, 2-hydroxyethyl cellulose with a molecular weight between 90,000 and 750,000 and a viscosity between 50-500 cps in solutions between 1% and 5% water at temperatures between 20° C. and 25° C., modified aqueous solutions of polysorbate nonionic surfactants, polyoxyethylene sorbitan mono-, di-, and tri-(C12-C18)-alkanoates, poloxamers, hydroxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, alkyl triammonium methosulfate, and ceteraryloctanoate. 4. A CSA-containing composition as in claim 1, wherein the amphiphilic compound or composition comprises one or more surfactants having separate hydrophobic and hydrophilic regions. 5. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that no more than about 15% of the CSA molecules form agglomerates larger than 1 μm in size. 6. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that no more than about 25% of the CSA molecules form agglomerates larger than about 500 nm in size. 7. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that no more than about 25% of the CSA molecules form agglomerates larger than about 250 nm in size. 8. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that no more than about 25% of the CSA molecules form agglomerates larger than about 100 nm in size. 9. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually encapsulated particles less than 1 μm in size. 10. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually encapsulated particles less than about 500 nm in size. 11. A CSA-containing composition as in claim 1, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually encapsulated particles less than about 100 nm in size. 12. A CSA-containing composition as in claim 1, wherein the CSA molecules comprise one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof: whereinrings A, B, C, and D are independently saturated, or are fully or partially unsaturated, provided that at least two of rings A, B, C, and D are saturated;m, n, p, and q are independently 0 or 1;R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkylaminoalkylamino, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkyloxyalkyl, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkyl-carboxamido, a substituted or unsubstituted di(alkyl)aminoalkyl, a substituted or unsubstituted C-carboxyalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted azidoalkyloxy, a substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidine-alkyloxy, a substituted or unsubstituted quaternary ammonium alkylcarboxy, and a substituted or unsubstituted guanidinoalkyl carboxy, where Q5 is a side chain of any amino acid, and P.G. is an amino protecting group; andR5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted alkyloxyalkyl, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted di(alkyl)aminoalkyl, a substituted or unsubstituted C-carboxyalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, P.G. is an amino protecting group,provided that at least two or three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aminoalkyloxy, a substituted or unsubstituted alkylcarboxyalkyl, a substituted or unsubstituted alkylaminoalkylamino, a substituted or unsubstituted alkylaminoalkylaminoalkylamino, a substituted or unsubstituted aminoalkylcarboxy, a substituted or unsubstituted arylaminoalkyl, a substituted or unsubstituted aminoalkyloxyaminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkylaminocarbonyl, a substituted or unsubstituted aminoalkyl-carboxyamido, a quaternary ammonium alkylcarboxy, a substituted or unsubstituted di(alkyl)aminoalkyl, a substituted or unsubstituted C-carboxyalkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted guanidinoalkyloxy, and a substituted or unsubstituted guanidinoalkylcarboxy. 13. A CSA-containing composition as in claim 12, wherein R1 through R4, R6, R7, R11, R12, R15, R16, and R18 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) hydroxyalkyl, a substituted or unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylamino-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) haloalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) aminoalkylcarboxy, a substituted or unsubstituted (C1-C18) aminoalkyl-aminocarbonyl, a substituted or unsubstituted (C1-C18) amino-alkylcarboxamido, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, a substituted or unsubstituted C-carboxy(C1-C18) alkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted (C1-C18) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C18) guanidine-alkyloxy, a substituted or unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, and a substituted or unsubstituted (C1-C18) guanidinoalkyl carboxy, where Q5 is a side chain of any amino acid, and P.G. is an amino protecting group;R5, R8, R9, R10, R13, R14 and R17 are independently deleted when one of rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or R5, R8, R9, R10, R13, and R14 are independently selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) hydroxyalkyl, a substituted or unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted (C1-C18) haloalkyl, a substituted or unsubstituted (C2-C6) alkenyl, a substituted or unsubstituted (C2-C6) alkynyl, oxo, a linking group attached to a second steroid, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) aminoalkylcarboxy, a substituted or unsubstituted (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, a substituted or unsubstituted C-carboxy(C1-C18) alkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted (C1-C18) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C18) guanidinoalkyloxy, and (C1-C18) guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, and P.G. is an amino protecting group;provided that at least two or three of R1-4, R6, R7, R11, R12, R15, R16, R17, and R18 are independently selected from the group consisting of a substituted or unsubstituted (C1-C18) aminoalkyl, a substituted or unsubstituted (C1-C18) aminoalkyloxy, a substituted or unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, a substituted or unsubstituted alkylamino-(C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino (C1-C18) alkylamino, a substituted or unsubstituted (C1-C18) aminoalkylcarboxy, a substituted or unsubstituted arylamino (C1-C18) alkyl, a substituted or unsubstituted (C1-C18) aminoalkyloxy (C1-C18) aminoalkylaminocarbonyl, a substituted or unsubstituted (C1-C18) aminoalkyl-aminocarbonyl, a substituted or unsubstituted (C1-C18) aminoalkylcarboxyamido, a substituted or unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, a substituted or unsubstituted di(C1-C18 alkyl)aminoalkyl, a substituted or unsubstituted C-carboxy(C1-C18) alkyl, H2N—HC(Q5)-C(O)—O—, H2N—HC(Q5)-C(O)—N(H)—, a substituted or unsubstituted (C1-C18) azidoalkyloxy, a substituted or unsubstituted (C1-C18) cyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C1-C18) guanidinoalkyloxy, and a substituted or unsubstituted (C1-C18) guanidinoalkylcarboxy. 14. A CSA-containing composition as in claim 12, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof comprises a compound of Formula (IA): 15. A CSA-containing composition as in claim 12, wherein each of rings A, B, C, and D is independently saturated. 16. A CSA-containing composition as in claim 12, wherein R3, R7, R12, and R18 are independently selected from the group consisting of hydrogen, an unsubstituted (C1-C18) alkyl, unsubstituted (C1-C18) hydroxyalkyl, unsubstituted (C1-C18) alkyloxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylcarboxy-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkyl, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino, unsubstituted (C1-C18) alkylamino-(C1-C18) alkylamino-(C1-C18) alkylamino, an unsubstituted (C1-C18) aminoalkyl, an unsubstituted arylamino-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkyloxy, an unsubstituted (C1-C18) aminoalkyloxy-(C1-C18) alkyl, an unsubstituted (C1-C18) aminoalkylcarboxy, an unsubstituted (C1-C18) aminoalkylaminocarbonyl, an unsubstituted (C1-C18) aminoalkylcarbox-amido, an unsubstituted di(C1-C18 alkyl)aminoalkyl, unsubstituted C-carboxy(C1-C18) alkyl, unsubstituted (C1-C18) guanidinoalkyloxy, unsubstituted (C1-C18) quaternary ammonium alkylcarboxy, and unsubstituted (C1-C18) guanidinoalkyl carboxy; andR1, R2, R4, R5, R6, R8, R9, R10, R11, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen and unsubstituted (C1-C6) alkyl. 17. A CSA-containing composition as in claim 12, wherein R3, R7, R12, and R18 are independently selected from the group consisting of hydrogen, an unsubstituted (C1-C6) alkyl, unsubstituted (C1-C6) hydroxyalkyl, unsubstituted (C1-C16) alkyloxy-(C1-C5) alkyl, unsubstituted (C1-C16) alkylcarboxy-(C1-C5) alkyl, unsubstituted (C1-C16) alkylamino-(C1-C5) alkyl, (C1-C16) alkylamino-(C1-C5) alkylamino, unsubstituted (C1-C16) alkylamino-(C1-C16) alkylamino-(C1-C5) alkylamino, an unsubstituted (C1-C16) aminoalkyl, an unsubstituted arylamino-(C1-C5) alkyl, an unsubstituted (C1-C5) aminoalkyloxy, an unsubstituted (C1-C16) aminoalkyloxy-(C1-C5) alkyl, an unsubstituted (C1-C5) aminoalkylcarboxy, an unsubstituted (C1-C5) aminoalkylaminocarbonyl, an unsubstituted (C1-C5) aminoalkyl-carboxamido, an unsubstituted di(C1-C5 alkyl)amino-(C1-C5) alkyl, unsubstituted C-carboxy(C1-C18) alkyl, unsubstituted (C1-C5) guanidinoalkyloxy, unsubstituted (C1-C16) quaternary ammonium alkylcarboxy, and unsubstituted (C1-C16) guanidinoalkylcarboxy. 18. A CSA-containing composition as in claim 12, wherein R1, R2, R4, R5, R6, R8, R10, R11, R14, R16, and R17 are each hydrogen; and R9 and R13 are each methyl. 19. A CSA-containing composition as in claim 12, wherein R3, R7, R12, and R18 are independently selected from the group consisting of aminoalkyloxy; aminoalkylcarboxy; alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl; di(alkyl)aminoalkyl; C-carboxyalkyl; alkoxycarbonylalkyl; and alkylcarboxyalkyl. 20. A CSA-containing composition as in claim 12, wherein R3, R7, and R12 are independently selected from the group consisting of aminoalkyloxy and aminoalkylcarboxy; andR18 is selected from the group consisting of alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl; C-carboxyalkyl; alkylaminoalkyl; alkyoxycarbonylalkyl; and alkylcarboxyalkyl. 21. A CSA-containing composition as in claim 12, wherein R3, R7, and R12 are the same. 22. A CSA-containing composition as in claim 12, wherein R3, R7, and R12 are aminoalkyloxy or aminoalkylcarboxy. 23. A CSA-containing composition as in claim 12, wherein R18 is alkylaminoalkyl, alkoxycarbonylalkyl, di(alkyl)aminoalkyl, or alkylcarboxyalkyl. 24. A CSA-containing composition as in claim 12, wherein R3, R7, R12, and R18 are independently selected from the group consisting of amino-C3-alkyloxy; amino-C3-alkyl-carboxy; C8-alkylamino-C5-alkyl; C8-alkoxy-carbonyl-C4-alkyl; C8-alkyl-carbonyl-C4-alkyl; di-(C5-alkyl)amino-C5-alkyl; C-carboxy-C4-alkyl; C13-alkylamino-C5-alkyl; C6-alkoxy-carbonyl-C4-alkyl; and C6-alkyl-carboxy-C4-alkyl. 25. A CSA-containing composition as in claim 12, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof comprises a compound of Formula (IB) or a pharmaceutically acceptable salt thereof: 26. A CSA-containing composition as in claim 25, wherein the compound of Formula (IB) or pharmaceutically acceptable salt thereof comprises at least one member selected from the group of: and pharmaceutically acceptable salt thereof. 27. A CSA-containing composition as in claim 25, wherein the compound of Formula (IB) or pharmaceutically acceptable salt thereof comprises: or a pharmaceutically acceptable salt thereof. 28. A CSA-containing composition as in claim 12, wherein the pharmaceutically acceptable salt is a hydrochloride salt or a tri-hydrochloride salt. 29. A CSA-containing composition comprising: a polar solvent or aqueous carrier;a plurality of cationic steroidal antimicrobial (CSA) molecules; anda micelle-forming agent comprising one or more surfactants having separate hydrophobic and hydrophilic regions,the micelle-forming agent forming micelles encapsulating at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually encapsulated particles less than 1 μm in size, andwherein the CSA-containing composition maintains or increases efficacy in killing microbes and reduces or minimizes cytotoxicity to mammalian cells. 30. A CSA-containing composition as in claim 29, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually encapsulated particles less than about 100 nm in size. 31. A CSA-containing composition as in claim 29, wherein the micelle-forming agent is selected from the group consisting of modified celluloses, modified nonionic hydroxyethyl cellulose, natural polyoxyethylene sorbitol ester, hydroxyethyl cellulose, 2-hydroxyethyl cellulose with a molecular weight between 90,000 and 750,000 and a viscosity between 50-500 cps in solutions between 1% and 5% water at temperatures between 20° C. and 25° C., modified aqueous solutions of polysorbate nonionic surfactants, polyoxyethylene sorbitan mono-, di-, and tri-(C12-C18)-alkanoates, poloxamers, hydroxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, alkyl triammonium methosulfate, and ceteraryloctanoate. 32. A CSA-containing composition comprising: a polar solvent or aqueous carrier;a plurality of cationic steroidal antimicrobial (CSA) molecules; anda micelle-forming agent forming micelles encapsulating at least a portion of the CSA molecules so that no more than 25% of the CSA molecules form agglomerates larger than 500 nm in size, wherein the micelle-forming agent is selected from the group consisting of hydroxyethyl cellulose, polyoxyethylene sorbitol ester, modified aqueous solutions of polysorbate nonionic surfactants, polyoxyethylene sorbitan mono-, di-, and tri-(C12-C18)-alkanoates, nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), hydroxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, alkyl triammonium methosulfate, ceteraryloctanoate, and combinations thereof,wherein at least about 75% of the CSA molecules are in the form of individually sequestered particles less than 500 nm in size. 33. A CSA-containing composition as in claim 32, wherein the micelle-forming agent encapsulates at least a portion of the CSA molecules so that at least about 75% of the CSA molecules are in the form of individually sequestered particles less than about 100 nm in size. 34. A CSA-containing composition as in claim 32, wherein the micelle-forming agent is selected from the group consisting of 2 hydroxyethyl cellulose with a molecular weight between 90,000 and 750,000 and a viscosity between 50-500 cps in solutions between 1% and 5% water at temperatures between 20° C. and 25° C., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), hydroxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and combinations thereof.
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