CN1551785A - 微晶肽混悬剂的持续释放 - Google Patents
微晶肽混悬剂的持续释放 Download PDFInfo
- Publication number
- CN1551785A CN1551785A CNA028173775A CN02817377A CN1551785A CN 1551785 A CN1551785 A CN 1551785A CN A028173775 A CNA028173775 A CN A028173775A CN 02817377 A CN02817377 A CN 02817377A CN 1551785 A CN1551785 A CN 1551785A
- Authority
- CN
- China
- Prior art keywords
- suspensoid
- peptide
- water suspension
- hydrophobic peptide
- gnrh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 44
- 239000000725 suspension Substances 0.000 title abstract description 3
- 238000013268 sustained release Methods 0.000 title description 2
- 239000012730 sustained-release form Substances 0.000 title description 2
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 239000002474 gonadorelin antagonist Substances 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 15
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 10
- 230000002045 lasting effect Effects 0.000 claims description 8
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000000968 intestinal effect Effects 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000007951 isotonicity adjuster Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000012736 aqueous medium Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 108010023617 abarelix Proteins 0.000 claims description 3
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 claims description 3
- 229960002184 abarelix Drugs 0.000 claims description 3
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 claims description 3
- 229940127233 azaline B Drugs 0.000 claims description 3
- 108700008462 cetrorelix Proteins 0.000 claims description 3
- 229960003230 cetrorelix Drugs 0.000 claims description 3
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 claims description 3
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 claims description 3
- 108700032141 ganirelix Proteins 0.000 claims description 3
- 229960003794 ganirelix Drugs 0.000 claims description 3
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 claims description 3
- 108010083551 iturelix Proteins 0.000 claims description 3
- QRYFGTULTGLGHU-NBERXCRTSA-N iturelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CCCCNC(=O)C=1C=NC=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)CCCNC(=O)C1=CC=CN=C1 QRYFGTULTGLGHU-NBERXCRTSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000012530 fluid Substances 0.000 abstract 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical compound C([C@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 NOENHWMKHNSHGX-IZOOSHNJSA-N 0.000 description 16
- 108010070670 antarelix Proteins 0.000 description 16
- 229950011372 teverelix Drugs 0.000 description 15
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 5
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- -1 acetate Chemical class 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- LQRJAEQXMSMEDP-XCHBZYMASA-N peptide a Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)NCCCC[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)C(\NC(=O)[C@@H](CCCCN)NC(=O)CNC(C)=O)=C/C=1C=CC=CC=1)C(N)=O)C(=O)C(\NC(=O)[C@@H](CCCCN)NC(=O)CNC(C)=O)=C\C1=CC=CC=C1 LQRJAEQXMSMEDP-XCHBZYMASA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/31—Somatostatins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及一种防止疏水性肽的凝胶形成的方法，该方法是将疏水性肽与一定量和摩尔比的、足以形成液体乳状微晶肽的水混悬剂、而非形成凝胶的抗衡离子相接触。本发明还涉及疏水性肽和水中的抗衡离子的液体的、乳状微晶的水混悬剂，其中，肽和抗衡离子是以一经混合就足以形成混悬剂、而非凝胶剂的量和摩尔比存在。
Description
发明背景
经常需要将生物活性的肽类做成活性成分能持续释放的制剂来传输给动物或人类。可以将活性成分掺入生物可降解并且生物学相容的聚合物中，以微囊、微粒或植入棒的形式，或者使用机械装置如微型泵或生物不可降解的容器来提供这样的制剂。如果肽在水介质中是高度可溶的，可以将其与不可降解的聚合物如纤维素衍生物一起制成复合体，或者将其与聚合物溶液相混合，一经非肠道注射就能形成凝胶，活性肽再从凝胶中缓慢释放。
上面提到的所有制剂都有其缺点和局限性，如悬浮液的容积大、不可降解的装置必需除去。就形成凝胶的肽类来说，经常存在生物可利用率的问题，这干扰了期望获得的活性成分的持续起效。
归因于肽类的物理化学方面的一些问题已经在R.Deghenghi的论文“Antarelix in Treatment with GnRH Analogs：Controversies andPerspectives”中描述过，由M.Filicori和C.Flamigni编辑，TheParthenon Publishing Group，纽约和伦敦1996，第89-91页。另外的一些问题在J.Rivier发表在GnRH Analogues上面的文章“GnRHanalogues towards the next millennium”中阐明，由B.Lunenfeld编辑，The Parthenon Publishing Group，纽约和伦敦1999，第31-45页。还有一些问题在其它的专著，例如M.F.Powell等人发表在Pharmaceutical Research，Vol.8，1258-1263(1991)上面的文章“Parenteral Peptide Formulations：Chemical and Physical Propertiesof Native LHRH and Hydrophobic Analogues in Aqueous Solution”中阐明。
因此，有必要开发能避免这些问题的新的制剂和给药方法，本发明就满足了这种需要。
发明概述
本发明涉及一种防止疏水性肽的凝胶形成的方法。该方法有利地包括将疏水性肽与抗衡离子(counter-ion)相接触，二者的量和摩尔比应足以形成肽的液体的、乳状的、微晶水混悬剂，而不是形成凝胶。
本发明也涉及疏水性肽和水中的抗衡离子的液体的、乳状的、微晶水混悬剂，其中，肽和抗衡离子是以一经混合就足以形成混悬剂、而非凝胶剂的量和摩尔比存在。
避免形成凝胶使得可以配制可注射的混悬剂。当这样的水混悬剂给哺乳动物，例如人，进行非肠道(也就是皮下或肌内)注射时，可以获得疏水性肽的超时持续释放。
优选地，抗衡离子是强酸盐，如三氟醋酸或硫酸的盐。并且疏水性肽可以是GnRH类似物，优选是GnRH拮抗剂。更优选的GnRH拮抗剂选自Azaline B、Abarelix、Antide、Ganirelix、Cetrorelix或FE200486的强酸盐，例如三氟醋酸盐或硫酸盐。最优选的化合物是Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2三氟醋酸盐以及Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2硫酸盐。
疏水性肽盐优选是以等于或大于25mg/ml的浓度悬浮在水介质中，并且酸∶肽的摩尔比至少是1.6∶1。至少一部分肽盐是以粒径介于大约5到150μm之间的针晶的形式存在。
如果需要的话，水混悬剂可以包含等渗剂，如甘露醇。水混悬剂还可以包含药学可接受的赋形剂。有利地，混悬剂被干燥至冻干状态，它能通过与水或缓冲液混合而重新组成混悬剂。包含这些干燥混悬剂的冻干组合物以及制备干燥混悬剂的方法在本发明的其它部分将会具体描述。
附图简述
附图1说明了给大鼠皮下注射本发明的teverelix三氟醋酸盐混悬剂以后所获得的药代动力学效果(睾酮抑制)；并且
附图2说明了在注射了本发明的teverelix三氟醋酸盐混悬剂的大鼠体内teverelix肽连续几周的持续释放。
优选方案的具体描述
我们意外的发现，分子式为Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu-lys(iPr)-Pro-D-Ala-NH2(teverelix，一种GnRH拮抗剂)的肽的三氟醋酸盐(TFA)或硫酸盐的高浓度水混悬剂并不像根据它的疏水性所预期的那样会形成凝胶，而是形成了易于给动物或人进行非肠道注射、持续几周释放活性成分的微晶乳状混悬剂(参见附图1和2)。对于其它盐如醋酸盐，这种性质却表现不出来，而是形成了预期中的、但并不需要的、体内生物利用度很低的凝胶剂。
当获得微晶高浓度混悬剂形式的疏水性肽类的延长持续输送时，针对如何抑制疏水性肽类的凝胶化的问题，我们的发明提供了一种简单雅致的解决办法。
我们的发现的另一个优点是这样的混悬剂容积很小，可以用细针进行非肠道注射，也因此提高了对注射物质的局部耐受性。在这样的注射剂中，肽的量大约是0.1到5mg/kg欲以混悬剂给药的哺乳动物的体重。
抗衡离子的量优选超过成盐所需要的量。代表性地，其数量至少是1.6mol酸/mol肽，优选2mol/mol或更多。另外，可注射的混悬剂应当被浓缩至可获得最期望的释放效果。浓缩的意思是肽在整个制剂中的重量百分比含量应当大于2.5％。
混悬剂能通过冻干或喷雾干燥形成冻干组合物，该冻干组合物能被很好地储存，在制备注射剂时仅用水或缓冲液就能重新组成混悬剂。
实施例
实施例1
将200μL 5％的甘露醇加到大约15mg的LHRH拮抗剂teverelix的三氟醋酸盐中。涡流搅拌一分钟即可获得流动的乳状珍珠似的混悬剂。混悬剂由大约10μm长的微晶组成。微晶能丛生在一起形成刺猥样结构。给大鼠皮下注射该混悬剂(1mg)能提供超过45天的睾酮抑制的药代动力学效果(附图1)。药代动力学分析显示，肽有多达几个星期的持续释放(附图2)。
实施例2
将200μL的水加到大约15mg的LHRH拮抗剂teverelix的三氟醋酸盐中。涡流搅拌一分钟即可获得流动的乳状珍珠似的混悬剂。
实施例3
将200μL的水加到大约15mg的LHRH拮抗剂teverelix的醋酸盐中。涡流搅拌一分钟即可获得透明的凝胶。将20μL TFA(3mols/mol)加到凝胶中形成液体的、流动的乳状珍珠似的混悬剂。
实施例4
将200μL 100mM的TFA加到大约15mg的LHRH拮抗剂teverelix的醋酸盐(2mols/mol)中，以获得流动的乳状混悬剂。另外，将200μL 75mM的TFA与大约15mg LHRH拮抗剂teverelix的醋酸盐(1.5mol/mol)混合，得到透明的凝胶。在另一项研究中，将100μL各种浓度的TFA加到7.5mg LHRH拮抗剂teverelix的醋酸盐中，TFA/Teverelix的摩尔比范围是1到3，当摩尔比≥1.6时得到流动的乳状混悬剂，其它的摩尔比则得到凝胶。
实施例5
将200μL 150mM的TFA加到5至30mg的LHRH拮抗剂teverelix的醋酸盐中(浓度范围25到150mg/ml)。浓度直到100mg/ml都可以获得流动的乳状混悬剂。
实施例6
将200μL 150mM的TFA加到大约15mg的LHRH拮抗剂teverelix的醋酸盐(3mols/mol)中，混合后得到流动的乳状混悬剂。混悬剂被整晚冻干。将200μL的水或5％甘露醇加到冻干物中，混合并重新构成以后得到流动的乳状混悬剂。
实施例7
将1mL 150mM的TFA加到大约75mg的LHRH拮抗剂teverelix的醋酸盐(3mols/mol)中，混合后得到流动的乳状混悬剂。混悬剂被整晚冻干。将1mL的水和0.2M pH4.0的醋酸盐缓冲液加到冻干物中，混合并重新构成以后得到流动的乳状混悬剂。在室温下，这些混悬剂至少能稳定保存3天。
实施例8
将100μL 250mM的H2SO4加到7.5mg的LHRH拮抗剂teverelix的醋酸盐(5mols/mol)中，几个小时后得到流动的乳状混悬剂。混悬剂由大约100μm长的微晶组成。微晶能聚合到一起形成刺猥样结构。混悬剂被整晚冻干。将100μL的水或5％甘露醇加到冻干物中，混合并重新构成以后得到流动的乳状混悬剂。
Claims (29)
1.防止疏水性肽的凝胶形成的方法，包括将疏水性肽与抗衡离子相接触，二者的量和摩尔比应足以形成液体的、乳状微晶的肽的水混悬剂，而不会形成凝胶。
2.权利要求1的方法，其中，抗衡离子是三氟醋酸或硫酸的盐。
3.权利要求1的方法，其中，疏水性肽是GnRH类似物。
4.权利要求3的方法，其中，GnRH类似物是GnRH拮抗剂。
5.权利要求4的方法，其中，GnRH拮抗剂是Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2三氟醋酸盐。
6.权利要求4的方法，其中，GnRH拮抗剂是Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2硫酸盐。
7.权利要求4的方法，其中，GnRH拮抗剂选自三氟醋酸盐或硫酸盐形式的Azaline B、Abarelix、Antide、Ganirelix、Cetrorelix或FE200486。
8.权利要求1的方法，其中，疏水性肽盐是以等于或大于25mg/ml的浓度悬浮在水介质中。
9.权利要求8的方法，其中，水混悬剂被非肠道地注射给哺乳动物，以获得疏水性肽的超时持续释放。
10.权利要求8的方法，其中，水混悬剂被非肠道地注射给人，以获得疏水性肽的超时持续释放。
11.权利要求10的方法，其中，用于注射的混悬剂中的肽的量大约是0.1到5mg/千克哺乳动物体重。
12.权利要求1的方法，其中，水混悬剂包含等渗剂。
13.权利要求12的方法，其中，等渗剂是甘露醇。
14.权利要求1的方法，其中，水混悬剂包含药学可接受的赋形剂。
15.权利要求1的方法，其中，水混悬剂是从冻干的肽盐临时获得。
16.疏水性肽和水中的抗衡离子的液体的、乳状微晶的、水混悬剂，其中，肽和抗衡离子是以一经混合就足以形成混悬剂、而非凝胶剂的量和摩尔比存在。
17.权利要求16的混悬剂，其中，抗衡离子是三氟醋酸或硫酸的盐。
18.权利要求16的混悬剂，其中，疏水性肽是GnRH类似物。
19.权利要求18的混悬剂，其中，GnRH类似物是GnRH拮抗剂。
20.权利要求19的混悬剂，其中，GnRH拮抗剂是Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2三氟醋酸盐。
21.权利要求19的混悬剂，其中，GnRH拮抗剂是Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2硫酸盐。
22.权利要求19的混悬剂，其中，GnRH拮抗剂选自三氟醋酸盐或硫酸盐形式的Azaline B、Abarelix、Antide、Ganirelix、Cetrorelix或FE200486。
23.权利要求16的混悬剂，其中，疏水性肽盐是以等于或大于25mg/ml的浓度悬浮在水介质中。
24.权利要求15的混悬剂，其中，水混悬剂包含等渗剂。
25.权利要求24的混悬剂，其中，等渗剂是甘露醇。
26.权利要求16的混悬剂，其中还包含药学可接受的赋形剂。
27.权利要求26的混悬剂，其中，肽的量大约是0.1到5mg/kg欲以混悬剂给药的哺乳动物的体重。
28.权利要求15的混悬剂，其中，微晶是以粒径介于大约5到150μm之间的针晶的形式存在。
29.包含权利要求15的干燥混悬剂的冻干组合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31761601P | 2001-09-06 | 2001-09-06 | |
| US60/317,616 | 2001-09-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1551785A true CN1551785A (zh) | 2004-12-01 |
| CN100386116C CN100386116C (zh) | 2008-05-07 |
Family
ID=23234486
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028173775A Expired - Lifetime CN100386116C (zh) | 2001-09-06 | 2002-08-27 | 微晶肽混悬剂的持续释放 |
Country Status (27)
| Country | Link |
|---|---|
| US (5) | US7098305B2 (zh) |
| EP (2) | EP1423150B1 (zh) |
| JP (3) | JP2005504787A (zh) |
| KR (2) | KR100818904B1 (zh) |
| CN (1) | CN100386116C (zh) |
| AR (1) | AR042592A1 (zh) |
| AT (1) | ATE463258T1 (zh) |
| AU (1) | AU2002337025B2 (zh) |
| BR (1) | BR0212333A (zh) |
| CA (1) | CA2459309C (zh) |
| CY (1) | CY1118642T1 (zh) |
| DE (1) | DE60235896D1 (zh) |
| DK (1) | DK2198888T3 (zh) |
| ES (2) | ES2362505T3 (zh) |
| HK (1) | HK1062148A1 (zh) |
| HU (1) | HUP0402099A2 (zh) |
| IL (1) | IL160443A0 (zh) |
| MX (1) | MXPA04002185A (zh) |
| NO (1) | NO20040938L (zh) |
| NZ (1) | NZ531734A (zh) |
| PL (1) | PL368056A1 (zh) |
| PT (1) | PT2198888T (zh) |
| RU (1) | RU2311195C2 (zh) |
| TW (1) | TWI249409B (zh) |
| UA (1) | UA79435C2 (zh) |
| WO (1) | WO2003022243A2 (zh) |
| ZA (1) | ZA200401390B (zh) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105579055A (zh) * | 2013-07-29 | 2016-05-11 | 益普生制药股份有限公司 | Lhrh类似物的水性缓释组合物 |
| CN110248679A (zh) * | 2017-01-30 | 2019-09-17 | 安迪威有限公司 | 包含至少一种GnRH拮抗剂的组合物 |
| CN112423776A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
| CN112423775A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 替维瑞克-tfa组合物 |
| CN112423777A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 可重构的替维瑞克-tfa组合物 |
| CN112423776B (zh) * | 2018-07-05 | 2024-05-31 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
Families Citing this family (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6828415B2 (en) * | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
| US8119159B2 (en) * | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| US20070148228A1 (en) * | 1999-02-22 | 2007-06-28 | Merrion Research I Limited | Solid oral dosage form containing an enhancer |
| US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
| US7358330B2 (en) * | 2001-03-29 | 2008-04-15 | Biotempt B.V. | Immunoregulatory compositions |
| US7098305B2 (en) * | 2001-09-06 | 2006-08-29 | Ardana Bioscience Limited | Sustained release of microcrystalline peptide suspensions |
| PT1545613E (pt) * | 2002-07-31 | 2011-09-27 | Seattle Genetics Inc | Conjugados de auristatina e sua utilização para tratamento do cancro, de uma doença autoimune ou de uma doença infecciosa |
| PE20050285A1 (es) * | 2003-06-24 | 2005-06-09 | Novartis Ag | Composicion farmaceutica que comprende analogos ciclicos de somatostatina |
| GB0320806D0 (en) | 2003-09-05 | 2003-10-08 | Astrazeneca Ab | Therapeutic treatment |
| SG10201701737XA (en) | 2003-11-06 | 2017-04-27 | Seattle Genetics Inc | Monomethylvaline compounds capable of conjugation to ligands |
| GB0428151D0 (en) * | 2004-12-22 | 2005-01-26 | Novartis Ag | Organic compounds |
| EP1674082A1 (de) * | 2004-12-22 | 2006-06-28 | Zentaris GmbH | Verfahren zur Herstellung von sterilen Suspensionen oder Lyophilisaten schwerlöslicher basischer Peptidkomplexe, diese enthaltende pharmazeutische Formulierungen sowie ihre Verwendung als Arzneimittel |
| GB0511269D0 (en) * | 2005-06-02 | 2005-07-13 | Creative Peptides Sweden Ab | Sustained release preparation of pro-insulin C-peptide |
| WO2007084460A2 (en) * | 2006-01-18 | 2007-07-26 | Qps, Llc | Pharmaceutical compositions with enhanced stability |
| KR101191322B1 (ko) * | 2006-04-07 | 2012-10-16 | 메리온 리서치 Ⅲ 리미티드 | 증진제를 함유하는 고형 경구용 투여 제형 |
| WO2008071984A1 (en) * | 2006-12-13 | 2008-06-19 | Ardana Bioscience Limited | Administration of the gonadotropin-releasing hormone antagonist teverelix |
| RU2557319C2 (ru) | 2007-07-16 | 2015-07-20 | Дженентек, Инк. | ГУМАНИЗИРОВАННЫЕ АНТИТЕЛА ПРОТИВ CD79b И ИММУНОКОНЪЮГАТЫ И СПОСОБЫ ПРИМЕНЕНИЯ |
| SG183023A1 (en) | 2007-07-16 | 2012-08-30 | Genentech Inc | Anti-cd79b antibodies and immunoconjugates and methods of use |
| WO2009099728A1 (en) | 2008-01-31 | 2009-08-13 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates and methods of use |
| TW200950799A (en) * | 2008-05-07 | 2009-12-16 | Merrion Res Iii Ltd | Compositions of GnRH related compounds and processes of preparation |
| US20100215743A1 (en) * | 2009-02-25 | 2010-08-26 | Leonard Thomas W | Composition and drug delivery of bisphosphonates |
| CN105663059A (zh) * | 2009-05-01 | 2016-06-15 | 辉凌公司 | 用于治疗前列腺癌的组合物 |
| CN105456206B (zh) | 2010-01-13 | 2018-12-14 | 益普生制药股份有限公司 | 用于延缓释放生长抑素类似物的药物组合物的制备方法 |
| US20110182985A1 (en) * | 2010-01-28 | 2011-07-28 | Coughlan David C | Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof |
| US9089484B2 (en) * | 2010-03-26 | 2015-07-28 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor Xa inhibitors for oral administration |
| US8927687B2 (en) | 2010-07-09 | 2015-01-06 | Amylin Pharmaceuticals, Llc | Microcrystalline Y receptor agonists |
| JP2014501784A (ja) | 2011-01-07 | 2014-01-23 | メリオン・リサーチ・Ｉｉｉ・リミテッド | 経口投与用の鉄の医薬組成物 |
| CA2891280C (en) | 2012-11-24 | 2018-03-20 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| EP2823808A1 (en) | 2013-07-09 | 2015-01-14 | Ipsen Pharma S.A.S. | Pharmaceutical composition for a sustained release of lanreotide |
| CN104844694A (zh) * | 2014-02-17 | 2015-08-19 | 深圳翰宇药业股份有限公司 | 一种醋酸加尼瑞克的制备方法 |
| PT3122757T (pt) | 2014-02-28 | 2023-11-03 | Hangzhou Dac Biotech Co Ltd | Ligantes carregados e as suas utilizações em conjugação |
| AU2015320678B2 (en) | 2014-09-23 | 2021-07-22 | Genentech, Inc. | Method of using anti-CD79b immunoconjugates |
| JP7211704B2 (ja) | 2015-01-29 | 2023-01-24 | ノヴォ ノルディスク アー／エス | Ｇｌｐ－１アゴニスト及び腸溶コーティングを含む錠剤 |
| EP3319936A4 (en) | 2015-07-12 | 2019-02-06 | Suzhou M-conj Biotech Co., Ltd. | PLACES OF CONDUCT FOR THE CONJUGATION OF CELL BINDING MOLECULES |
| US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
| JP7138350B2 (ja) | 2016-11-14 | 2022-09-16 | ハンジョウ ディーエーシー バイオテック シーオー．，エルティディ． | 共役連結体、該連結体を含有する細胞結合分子－薬物共役体、並びに該共役体及び連結体の使用及び製造方法 |
| JP2020525528A (ja) | 2017-06-30 | 2020-08-27 | アンテブ リミテッド | 急性尿閉を治療するための組成物を含むシリンジ |
| EP3560555A1 (en) * | 2018-04-26 | 2019-10-30 | LifeArc | A composition for treating one or more estrogen related diseases |
| MA52794A (fr) * | 2018-05-28 | 2021-04-14 | Jiangyin Usun Pharmaceutical Co Ltd | Nouvelle utilisation pharmaceutique |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2668866A (en) * | 1951-08-14 | 1954-02-09 | Shell Dev | Isomerization of paraffin wax |
| GB1245187A (en) | 1969-02-14 | 1971-09-08 | Continental Can Co | Hot melt adhesive composition |
| JPS5242506A (en) | 1975-10-02 | 1977-04-02 | Toa Nenryo Kogyo Kk | Hydrotreating process of petroleum wax |
| JPS5335705A (en) * | 1976-09-14 | 1978-04-03 | Toa Nenryo Kogyo Kk | Hydrogenation and purification of petroleum wax |
| US4186078A (en) * | 1977-09-12 | 1980-01-29 | Toa Nenryo Kogyo Kabushiki Kaisha | Catalyst and process for hydrofining petroleum wax |
| US4239546A (en) * | 1978-07-21 | 1980-12-16 | Petrolite Corporation | Hydrocarbon polymers to improve the hardness of waxes |
| US4256737A (en) * | 1979-06-11 | 1981-03-17 | Syntex (U.S.A.) Inc. | Long acting depot injectable formulations for LH-RH analogues |
| US4266737A (en) * | 1979-11-05 | 1981-05-12 | Arrow Converting Equipment, Inc. | Air differential mandrel and method of differentially winding and rewinding tapes |
| US4415649A (en) * | 1981-02-25 | 1983-11-15 | E. I. Du Pont De Nemours & Co. | Flexographic printing plates containing blended adhesives |
| US4839422A (en) * | 1987-12-23 | 1989-06-13 | Exxon Chemical Patents Inc. | Ternary adhesive compositions |
| EP0328090A3 (en) | 1988-02-10 | 1990-08-16 | Abbott Laboratories | Lhrh analogs |
| US5110904A (en) * | 1989-08-07 | 1992-05-05 | Abbott Laboratories | Lhrh analogs |
| JP2672677B2 (ja) | 1989-02-09 | 1997-11-05 | タツプ・フアーマシユーテイカルズ・インコーポレイテツド | Ｌｈｒｈ同族体 |
| ES2052488T3 (es) * | 1991-04-25 | 1997-01-01 | Romano Deghenghi | Peptidos antagonistas de la hormona de liberacion de la hormona luteinizante. |
| EP0625069B1 (de) * | 1992-10-26 | 1998-12-30 | Schwarz Pharma Ag | Verfahren zur herstellung von mikrokapseln |
| CA2136078A1 (en) | 1992-12-04 | 1994-06-23 | Jonathan Greer | 6-position modified decapeptide lhrh antagonists |
| ES2164096T3 (es) | 1992-12-18 | 2002-02-16 | Abbott Lab | Antagonistas de lhrh que comprenden restos de aminoacilo modificados en posicion 5 y 6. |
| DE4342092B4 (de) * | 1993-12-09 | 2007-01-11 | Zentaris Gmbh | Langwirkende Injektionssuspension und Verfahren zur Herstellung |
| CA2178592C (en) * | 1993-12-09 | 2009-07-28 | Jurgen Engel | Long-acting injection suspensions and a process for their preparation |
| JP3101695B2 (ja) | 1996-07-24 | 2000-10-23 | 日本航空電子工業株式会社 | 軟ｘ線光学素子用多層膜 |
| US5968895A (en) | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
| DE19813849A1 (de) * | 1998-03-27 | 1999-09-30 | Degussa | Verfahren zur einstufigen Umsalzung und Aufreinigung von Oligopeptiden |
| CO5160256A1 (es) | 1999-02-08 | 2002-05-30 | Zentaris Ag | Sales de peptidos farmaceuticamente activos para la liberacion sostenida y proceso de produccion |
| DE10040700A1 (de) * | 2000-08-17 | 2002-02-28 | Asta Medica Ag | Salze von biologisch aktiven Peptiden, ihre Herstellung und Verwendung |
| US7098305B2 (en) * | 2001-09-06 | 2006-08-29 | Ardana Bioscience Limited | Sustained release of microcrystalline peptide suspensions |
| JP4505750B2 (ja) | 2006-01-27 | 2010-07-21 | 東海ゴム工業株式会社 | 制振装置 |
-
2002
- 2002-02-19 US US10/080,130 patent/US7098305B2/en not_active Expired - Lifetime
- 2002-08-27 JP JP2003526373A patent/JP2005504787A/ja active Pending
- 2002-08-27 DE DE60235896T patent/DE60235896D1/de not_active Expired - Lifetime
- 2002-08-27 ES ES02772214T patent/ES2362505T3/es not_active Expired - Lifetime
- 2002-08-27 HU HU0402099A patent/HUP0402099A2/hu unknown
- 2002-08-27 AT AT02772214T patent/ATE463258T1/de active
- 2002-08-27 AU AU2002337025A patent/AU2002337025B2/en not_active Ceased
- 2002-08-27 UA UA2004031905A patent/UA79435C2/uk unknown
- 2002-08-27 KR KR1020047003371A patent/KR100818904B1/ko active IP Right Grant
- 2002-08-27 EP EP02772214A patent/EP1423150B1/en not_active Expired - Lifetime
- 2002-08-27 DK DK10003046.9T patent/DK2198888T3/en active
- 2002-08-27 NZ NZ531734A patent/NZ531734A/en not_active IP Right Cessation
- 2002-08-27 RU RU2004110615/15A patent/RU2311195C2/ru not_active IP Right Cessation
- 2002-08-27 EP EP10003046.9A patent/EP2198888B1/en not_active Expired - Lifetime
- 2002-08-27 ES ES10003046.9T patent/ES2618777T3/es not_active Expired - Lifetime
- 2002-08-27 PT PT100030469T patent/PT2198888T/pt unknown
- 2002-08-27 CA CA2459309A patent/CA2459309C/en not_active Expired - Lifetime
- 2002-08-27 CN CNB028173775A patent/CN100386116C/zh not_active Expired - Lifetime
- 2002-08-27 IL IL16044302A patent/IL160443A0/xx unknown
- 2002-08-27 BR BR0212333-9A patent/BR0212333A/pt not_active IP Right Cessation
- 2002-08-27 MX MXPA04002185A patent/MXPA04002185A/es not_active Application Discontinuation
- 2002-08-27 PL PL02368056A patent/PL368056A1/xx unknown
- 2002-08-27 WO PCT/EP2002/009537 patent/WO2003022243A2/en active Application Filing
- 2002-08-27 KR KR1020077021972A patent/KR20070107161A/ko not_active Application Discontinuation
- 2002-08-29 TW TW091119713A patent/TWI249409B/zh not_active IP Right Cessation
- 2002-09-05 AR ARP020103358A patent/AR042592A1/es unknown
-
2004
- 2004-02-20 ZA ZA200401390A patent/ZA200401390B/en unknown
- 2004-03-04 NO NO20040938A patent/NO20040938L/no not_active Application Discontinuation
- 2004-07-15 HK HK04105185.0A patent/HK1062148A1/xx not_active IP Right Cessation
-
2006
- 2006-06-12 US US11/450,293 patent/US20060228385A1/en not_active Abandoned
- 2006-06-12 US US11/450,292 patent/US20060229238A1/en not_active Abandoned
-
2010
- 2010-01-28 JP JP2010016716A patent/JP5757686B2/ja not_active Expired - Lifetime
- 2010-06-07 US US12/795,246 patent/US20100239683A1/en not_active Abandoned
-
2011
- 2011-09-01 US US13/224,105 patent/US8415300B2/en not_active Expired - Lifetime
-
2013
- 2013-06-10 JP JP2013122235A patent/JP2013177449A/ja active Pending
-
2017
- 2017-02-02 CY CY20171100156T patent/CY1118642T1/el unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105579055A (zh) * | 2013-07-29 | 2016-05-11 | 益普生制药股份有限公司 | Lhrh类似物的水性缓释组合物 |
| CN110248679A (zh) * | 2017-01-30 | 2019-09-17 | 安迪威有限公司 | 包含至少一种GnRH拮抗剂的组合物 |
| CN112423776A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
| CN112423775A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 替维瑞克-tfa组合物 |
| CN112423777A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 可重构的替维瑞克-tfa组合物 |
| CN112423775B (zh) * | 2018-07-05 | 2024-03-15 | 安迪威有限公司 | 替维瑞克-tfa组合物 |
| CN112423776B (zh) * | 2018-07-05 | 2024-05-31 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100386116C (zh) | 微晶肽混悬剂的持续释放 | |
| AU2002337025A1 (en) | Sustained release of microcrystalline peptide suspensions | |
| US6503534B1 (en) | Pharmaceutical compositions for prolonged peptide release and preparation method | |
| RU2427383C2 (ru) | Фармацевтические композиции с повышенной стабильностью | |
| AU737664B2 (en) | Non-aqueous protic peptide formulations | |
| IL167415A (en) | Form of delivery with delayed release of pharmaceutically active peptides and method of production | |
| AU2002210439B2 (en) | Method for producing peptide salts, their use, and pharmaceutical preparations containing these peptide salts | |
| BRPI0706558B1 (pt) | Composição polimérica injetável, métodos para preparar uma composição polimérica injetável e métodos para preparar um sal de um análogo de hormônio de liberação de hormônio luteínico (lhrh) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: ADANA BIOLOGY SCIENCE CO., LTD. Free format text: FORMER OWNER: ZANTARISCORP CORP. Effective date: 20050603 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20050603 Address after: Edinburgh Applicant after: Ardana Bioscience Ltd. Address before: Frankfurt, Germany Applicant before: Zentaris GmbH |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: TECHNOLOGY DEPARTMENT, BRITISH MEDICAL RESEARCH CO Free format text: FORMER OWNER: ADANA BIOLOGICAL SCIENCE CO. LTD. Effective date: 20100721 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: UK EDINBURGH TO: LONDON, UK |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20100721 Address after: London, England Patentee after: British Medical Research Council technical department Address before: Edinburgh, UK Patentee before: Ardana Bioscience Ltd. |
|
| CX01 | Expiry of patent term |
Granted publication date: 20080507 |
|
| CX01 | Expiry of patent term |