SK132893A3 - Somatotropine composition with the guided release and the method of its preparation - Google Patents
Somatotropine composition with the guided release and the method of its preparation Download PDFInfo
- Publication number
- SK132893A3 SK132893A3 SK1328-93A SK132893A SK132893A3 SK 132893 A3 SK132893 A3 SK 132893A3 SK 132893 A SK132893 A SK 132893A SK 132893 A3 SK132893 A3 SK 132893A3
- Authority
- SK
- Slovakia
- Prior art keywords
- somatotropin
- tocopherol
- composition
- somatotropic
- release
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 69
- 238000000034 method Methods 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 6
- 108010051696 Growth Hormone Proteins 0.000 claims description 44
- 102000018997 Growth Hormone Human genes 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 10
- 150000003611 tocopherol derivatives Chemical class 0.000 claims description 10
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 9
- 239000000787 lecithin Substances 0.000 claims description 9
- 235000010445 lecithin Nutrition 0.000 claims description 9
- 229940067606 lecithin Drugs 0.000 claims description 9
- 238000013270 controlled release Methods 0.000 claims description 7
- 108010006025 bovine growth hormone Proteins 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000011732 tocopherol Substances 0.000 claims description 6
- 229960001295 tocopherol Drugs 0.000 claims description 6
- 229940042585 tocopherol acetate Drugs 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 108020004511 Recombinant DNA Proteins 0.000 claims description 3
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 2
- 101000868138 Ovis aries Somatotropin Proteins 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000003883 ointment base Substances 0.000 claims description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 2
- WGVKWNUPNGFDFJ-CBIUGAAKSA-N (2R)-2,5,8-Trimethyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol Chemical compound OC1=CC(C)=C2O[C@@](CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-CBIUGAAKSA-N 0.000 claims 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims 1
- IZQZNLBFNMTRMF-UHFFFAOYSA-N acetic acid;phosphoric acid Chemical compound CC(O)=O.OP(O)(O)=O IZQZNLBFNMTRMF-UHFFFAOYSA-N 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 210000003462 vein Anatomy 0.000 claims 1
- 150000003785 γ-tocopherols Chemical class 0.000 claims 1
- 238000002347 injection Methods 0.000 description 25
- 239000007924 injection Substances 0.000 description 25
- 238000009472 formulation Methods 0.000 description 20
- 230000000694 effects Effects 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 11
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- 238000012360 testing method Methods 0.000 description 7
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 5
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 5
- 235000013336 milk Nutrition 0.000 description 5
- 239000008267 milk Substances 0.000 description 5
- 210000004080 milk Anatomy 0.000 description 5
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- 241000282898 Sus scrofa Species 0.000 description 4
- 229940066595 beta tocopherol Drugs 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000011590 β-tocopherol Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000006651 lactation Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- 241000772415 Neovison vison Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 235000007680 β-tocopherol Nutrition 0.000 description 1
- 150000003781 β-tocopherols Chemical class 0.000 description 1
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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Dispersion Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Somatotropftý prostriedok s riadeným uvoľňovaním a spôsob jeho prípravySomatotrophic controlled release formulation and process for its preparation
Oblasť technikyTechnical field
Vynález sa týka somatotropného prostriedku s riadeným uvoľňovaním, ktorý má dlhý in vivo poločas a ktorý vy kazuje malé vedľajšie účinky na živočíchy. Tento vynález sa tiež týka spôsobu prípravy tohoto prípravku.The invention relates to a controlled release somatotropic composition which has a long in vivo half-life and which exhibits minor animal side effects. The present invention also relates to a process for preparing the composition.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Somatotropné prostriedky, eventuálne formulácie, ktoré sú najviac biologicky aktívne, majú relatívne krátky in vivo poločas. Aby sa dosiahlo dostatočne vysokých biologických účinkov a udržala sa predĺžená biologická účinnosť somatotropínu, podával sa tento prostriedok v prebytku a/alebo veľmi často, čo však môže spôsobiť živočíchom, ktorým sa tento prostriedok podáva, vážne potiaže. Preto sa pri podávaní somatotropínu vyžaduje (pri podávaní somatotropínu in vivo) benigná schéma predĺženia jeho účinku, pre uspokojenie týchto požiadavkov boli vyvíjané rôzne spôsoby prípravy takéhoto somatotropného prostriedku, ktorý by mal predĺžené vlastnosti pri uvoľňovaní a súčasxpe by u neho bolo možné podávanie nižších dávok a frekvencia podávania tiež nižšia.The somatotropic compositions, or the formulations most biologically active, have a relatively short in vivo half-life. In order to achieve sufficiently high biological effects and to maintain the prolonged biological activity of somatotropin, the composition has been administered in excess and / or very often, which may, however, cause serious difficulties to the animals receiving the composition. Therefore, when administering somatotropin in vivo, a benign pattern of prolongation of its effect is required, to meet these requirements, various methods of preparing such a somatotropic composition having sustained release properties and, at the same time, lower dosages have been developed and the frequency of administration is also lower.
Napríklad v US patente č.4 985 440 je popísaný prostriedok obsahujúci komplex prechodného kovu, obzvlášť komplex zinku a somatotropínu v oleji suspenzovanom vehikulu, vyrobenom z rastlinného alebo minerálneho oleja, zmiešaného s masťovým základom a adjuvans. Tento spôsob je komplikovaný a vyžaduje komplex somatotropípnu s kovom, alebo komplex somatotropínu s prechodήjým kovom. Napríklad komplex zinku a somatotropínu sa pripravuje adíciou chloriduFor example, U.S. Patent No. 4,985,440 discloses a composition comprising a transition metal complex, particularly a zinc-somatotropin complex in an oil-suspended vehicle made from a vegetable or mineral oil mixed with an excipient and an adjuvant. This process is complicated and requires a complex of somatotropin with a metal or a complex of somatotropin with a transition metal. For example, a zinc-somatotropin complex is prepared by the addition of chloride
-2zinku a roztoku somatotropínu za prísne vymedzených podmienok a prebytok chloridu zinku sa potom vymýva z tejto suspenzie, obsahujúcej žiadaný komplex, v niekoľkých stupňoch, pomocou odstreďovania: Potom sa finálny roztok lyofilizuje, čím sa celý spôsob stáva veľmi zdĺhavým a náročným hlavne z časového hladiská.-2 zinc and somatotropin solution under strictly defined conditions and the excess zinc chloride is then eluted from this suspension containing the desired complex by centrifugation in several stages: The final solution is then freeze-dried, making the process very time consuming and time consuming .
European Patent Publication No. 216 485 popisuje prostriedok , obsahujúci komplex zinku a somatotropínu, dispergovaný v niektorom oleji, ako je napríklad arašidový olej. Typické je podávanie 8 mg prostriedku a 40 mg somatotropínu prasatám, kedj? predĺžený účinok pre uvojľnovanie je len krátky a to 9 dní. Okrem tohoto je tento spôsob podobne komplikovaný ako v prípade už uvedeného patentu US Patent 4 985 404.European Patent Publication no. No. 216,485 discloses a composition comprising a zinc-somatotropin complex dispersed in an oil, such as arachis oil. Typically, administration of 8 mg of the formulation and 40 mg of somatotropin to pigs is indicated. the prolonged release effect is only 9 days short. In addition, the method is similarly complicated as in the aforementioned U.S. Patent 4,985,404.
US Patent No. 4 863 736 poskytuje spôsob pre výrobu implantovateľných piluliek, obsahujúcich vlákna somatotropínu s parciálnymi prepážkami z ochranných polymérov ako je šelak, včelí vosk a celulóza. Tieto pilulky uvoľňujú somatotropin in vivo. Podobne European Patent No. 374 120 poskytuje spôsob výroby implantovateľného prostriedku, obsahujúceho somatotropin, v osmotickom zariadení. European Patent Publication No. 246 540 pojednáva o spôsobe syntetizovania implantovateľných prostriedkov, obsahujúcich polypeptid a mastnú kyselinu.U.S. Pat. No. 4,863,736 provides a method for making implantable pills comprising somatotropin fibers with partial baffles of protective polymers such as shellac, beeswax and cellulose. These pills release somatotropin in vivo. Similarly, European patent no. No. 374,120 provides a method of manufacturing an implantable composition comprising somatotropin in an osmotic device. European Patent Publication no. No. 246,540 discloses a method of synthesizing implantable compositions comprising a polypeptide and a fatty acid.
US Patent No. 4 786 501 ilustruje spôsob výroby implantovateľnej formulácie vo forme piluliek, pričom tento spôsob zahŕňa stupne miešania somatotropínu, sacharózy a etylcelulózy a následné potahovanie pórovitým a nepórovitým polyetylénom. US patent No. 1 761 203 popisuje spôsob pre výrobu implantovateľnej formulácie, zahrňujúci zmiešanie somatotropínu a vo vode nerozpustných polymérov, pridanie vo vode nerozpustného rozpúšťadla a sušenie. Hoci tieto implantovateľné formulácie majú tr^valý účinok, vyžadujú pre aplikáciu chirurgickú operáciu alebo špeciálny aparát, tedaU.S. Pat. No. 4,786,501 illustrates a method of making an implantable pill formulation, the method comprising the steps of mixing somatotropin, sucrose and ethylcellulose, followed by coating with porous and non-porous polyethylene. U.S. Pat. No. 1,761,203 discloses a method for making an implantable formulation, comprising mixing somatotropin and water-insoluble polymers, adding a water-insoluble solvent, and drying. Although these implantable formulations have a lasting effect, they require surgery or a special apparatus for application, i.e.
-3— dispergovaný v dextrán, ako Publication No.-3- dispersed in dextran, as Publication no.
vyžadujú relatívne komplikované a nekonvenčné spôsoby aplikácie.require relatively complicated and unconventional modes of application.
Na druhej strane definuje European Patent Publication No. 193 917 prostriedok, obsahujúci vo vode dispergovateľné a vo vode rozpustné sacharidové, glycidové polyméry a biologicky aktívnu molekulu rastového hormónu. European Patent Publication No. 314 421 ukazuje prostriedok, obsahujúci polypeptid oleji so sacharidovým polymérom, ako je nosným materiálom. European Patent 211 691 uvádza prostriedok, obsahujúci polypeptid, dispergovaný v oleji s niekoľkými voskami, ako f£os_/r_7ými materiálmi, avšak má podobné vady ako uvedený prostriedok v European Patent Publication No. 193 917. V prípade týchto prostriedkov často živočíchy reagujú na sacharidový polymér, ako je dextran, ako na anigén a citlivo reagujú, čo znemožňuje trvalé užívanie týchto prostriedkov.On the other hand, European Patent Publication No. 193 917 a composition comprising a water-dispersible and water-soluble carbohydrate, carbohydrate polymers and a biologically active growth hormone molecule. European Patent Publication no. 314,421 shows a composition comprising a polypeptide of an oil with a carbohydrate polymer as a carrier material. European Patent 211 691 discloses a composition comprising a polypeptide dispersed in a plurality of waxes of oil as a film material but having defects similar to that of the composition in European Patent Publication No. WO 01/30911. For these compositions, animals often respond to a carbohydrate polymer, such as dextran, as an anigen, and respond sensitively, making it impossible to sustain the use of the compositions.
Korean Patent Laid-open Publication No. 91-15302 uvádza prostriedok, obsahujúci živočíšny somatotropín, dispergovaný v acetáte tokoferolu s adjuvants pre trvalé uvoľňovanie. Pretože má vysokú viskozitu, obtiažne možno tento prostriedok aplikovať injekčné a je tendencia zotrvávať pri podávaní a aplikovaní v tkanive, čo nepôsobí na tkanivo priaznivo.Korean Patent Laid-open 91-15302 discloses a composition comprising animal somatotropin dispersed in tocopherol acetate with sustained release adjuvants. Because it has a high viscosity, this composition is difficult to inject and tends to persist in administration and application in the tissue, which does not favor the tissue.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom tohoto vynálezu je poskytnutie spôsobu pre prípravu stornatotropného prostriedku majúceho dlhý in vivo poločas, s malými vedľajšími účinkami na živočíchy, ktorým sa aplikuje tento prostriedok.It is an object of the present invention to provide a method for the preparation of a steroatotropic composition having a long in vivo half-life, with little side effects on the animals to which the composition is administered.
Podľa ďalšieho predmetu tohoto vynálezu sa ponúka prostriedok, ktorý je slpmatotoropným prostriedkom, pripraveným podľa spôsobu uvedeného v tomto vynáleze.According to another aspect of the present invention, there is provided a composition which is a slopototoric composition prepared according to the method of the present invention.
-4V súlade s týmto vynálezom sa poskytuje spôsob prípravy somatotropného prostriedku, ktorého in vivo uvoľňovanie je časovo riadené, pričom tento spôsob pozostáva z nasledujúcich stupňov:In accordance with the present invention, there is provided a process for the preparation of a somatotropic composition wherein the in vivo release is time-controlled, the process comprising the following steps:
rozpustenie lecitínu a somatotropínu vo vodnom roztoku za vzniku lipoáomného somatotropného roztoku; lyofilizácia alebo lyofilizovanie uvedeného lipo2.,omného somatotropného roztoku za podmienok, obvyklých pre lyofilizáciu; a suspenzovanie uvedeného lyofilizovaného liposomného somatotropínu v tokoferolovom deriváte tak, aby sa utvoril nový prostriedok podľa tohoto vynálezu. Popis obrázkovdissolving lecithin and somatotropin in an aqueous solution to form a lipoamous somatotropic solution; lyophilizing or lyophilizing said lipo2, omic somatotropic solution under conditions customary for lyophilization; and suspending said lyophilized liposomal somatotropin in the tocopherol derivative to form a novel composition of the invention. Description of pictures
Tomuto vynálezu možno úplne porozumieť s odkazom na doprovodné obrá zky, kde:This invention can be fully understood with reference to the accompanying drawings, wherein:
Obrázok la 2 ukazuje vplyv prostriedku podľa tohoto vynálezu na produkciu mlieka, ak sa aplikuje kravám, dávajúcim mlieko.Figure 1 a shows the effect of the composition of the invention on milk production when applied to cows giving milk.
Obrázok 3 ukazuje vplyv koncentrácie somatotropínu v sére pri aplikácií nového prostriedku na rast prasiat. Obrázok 4 ukazuje vplyv koncentrácie dusíky močoviny v sére pri aplikácií prostriedku podľa tohoto vynálezu na rast prasiat.Figure 3 shows the effect of serum concentration of somatotropin on the growth of pigs when the new formulation is applied. Figure 4 shows the effect of serum urea nitrogen concentration when the composition of the invention is applied to pig growth.
Obrázok 5 popisuje koncentráciu inzulínu podobného rastového faktoru I v sére, ak sa aplikuje prostriedok podľa tohoto vunálezu prasatám, a tó vplyv na rast prasiat.Figure 5 describes the serum concentration of insulin-like growth factor I when administered to pigs and the effect on pig growth.
Podľa tohoto vynálezu sa roztok somatotropínu mieša s lecitínom v homogenizére a vzniknutý roztok sa spracováva v mikrofluidizére za vziku homogénnej zmesi. Táto zmes sa potom lyofilizuje podľa konvenčných spôsobov a suspenzuje sa v tokoferolovom deriváte, čím sa získa prostriedok · podľa tohoto vynálezu. V tomto vynáleze možfno použiť mnoho typov somatotropínu, pokiaľ majú žiadanú biologickú účinnosť. Medzi takéto typy patria napríklad: hovädzí somatotropín, bravčový somatotropín, ovčí somatotropín a pod. Hoci saAccording to the invention, the somatotropin solution is mixed with lecithin in a homogenizer and the resulting solution is processed in a microfluidizer to form a homogeneous mixture. This mixture is then lyophilized according to conventional methods and suspended in the tocopherol derivative to give the composition of the invention. Many types of somatotropin can be used in the present invention as long as they have the desired biological activity. Such types include, for example: bovine somatotropin, pork somatotropin, sheep somatotropin and the like. Though
-5nevyžaduje podľa tohoto vynálezu použitie komplexov somatotropínu s kovmi alebo s prechodnými kovmi, alebo modifikovaný somatotropin s nízkou hydrogenáciou, možno použit aj tieto typy somatotropínu. Oblasť použiteľných typov somatotropí^nu zahrňuje aj tie, ktoré sú produkované za použitia rekombinantnej DNA technológie z hostiteľských .buniek ako je E. coli a droždie aj prírodný somatotropin extraho^vaný zo žľazy mozkového podvezku takých zvierat, ako hovädzí a bravčový dobytok a ovce.According to the present invention, the use of somatotropin metal or transition metal complexes, or modified somatotropin with low hydrogenation, does not require the use of these types of somatotropin. The field of useful types of somatotropin also includes those produced using recombinant DNA technology from host cells such as E. coli and yeast as well as natural somatotropin extracted from the gland of the cerebral gland of animals such as bovine and porcine and sheep.
Medzi tokoferolové deriváty, ktoré môžu byť použité v tomto vynáleze, patria napríklad: dl-p£-tokoferol, dl-pZ. -tokoferol acetát, dl- oZ. -tokoferol sukcinát, dl-X -tokoferol fosfát, 1-tokoferol, 1-pZtokoferol acetát, l-frAtokoferol sukcinát, 1-pZ-tokoferol fosfát a /// ^2 -tokoferolové derriváty, pričom výhodný je</ -tokoferol acetát. Tokoferolové deriváty podporujú normálny reprodukčný mechanizmus takých živočíchov, ako sú krysy, myši, morské prasce, prasce a hydina, pomáhajú pri prevencií defektov vo vývoji svalov u zvierat, a tiež hrajú dôležitú úlohu ako nosiče u časovo riadeného uvoľňovania somatotropínu in vivo. Okrem toho majú tokoferolové deriváty sklon zabraňovať nepravidelným pohybom svalov, alebo tuhnutiu svalov u kuriat a tiež steatóze u noriek, prasiat, mačiek. Množstvo tokoferolových derivátov, používaných v prostriedku, sa pohybuje v rozmedzí od 85 do 99% hmotnostných, s výhodou od 90 do 99% hmotnostných, vzhľadom na celkovú hmotnosť prostriedku.The tocopherol derivatives that may be used in this invention include, for example: dl-β-tocopherol, dl-pZ. -tocopherol acetate, dl-oZ. tocopherol succinate, dl-X-tocopherol phosphate, 1-tocopherol acetate, 1-β-tocopherol acetate, 1-β-tocopherol succinate, 1-β-tocopherol phosphate, and β-tocopherol derivatives, with N -tocopherol acetate being preferred. The tocopherol derivatives promote the normal reproductive mechanism of animals such as rats, mice, swine, pigs and poultry, help prevent defects in muscle development in animals, and also play an important role as carriers for the time-controlled release of somatotropin in vivo. In addition, tocopherol derivatives tend to prevent irregular muscle movement or muscle stiffness in chickens, as well as steatosis in mink, pig, and cat. The amount of tocopherol derivatives used in the composition ranges from 85 to 99% by weight, preferably from 90 to 99% by weight, based on the total weight of the composition.
Biologicky aktívny somatotropin, používaný v tomto vynáleze, sa mieša s lecitínom v pomere ležiacom v rozmedzí od 7:3 do 8:2 hmotnostné. Pokiaľ je obsah somatotropínu menší ako nižší limit (tj. 70% hmotnostných), prejavuje sa jeho biologická aktivita obtiažne. Pokiaľ obsah somatotropínu prevyšuje horný limit (tj. 80% hmotnostných), tvorí obtiažne lipozómnuThe biologically active somatotropin used in the present invention is mixed with lecithin in a ratio ranging from 7: 3 to 8: 2 by weight. If the content of somatotropin is less than the lower limit (i.e. 70% by weight), its biological activity is difficult to manifest. If the content of somatotropin exceeds the upper limit (ie 80% by weight), it forms a difficult liposome
-6somatotropnú zmes.-6somatotropic mixture.
Lecitín, prítomný v prostriedku podľa vynálezu, riadi dobu uvoľňovania somatotropínu v tele živočíchov. Lecitín, vhodný pre použitie v prostriedku podľa tohoto vynálezu, môže byť napríklad: fosfatidylcholin, lysofosfolipid, plazmalogén a sfingomyelín.The lecithin present in the composition of the invention controls the time of somatotropin release in the animal body. The lecithin suitable for use in the composition of the invention may be, for example: phosphatidylcholine, lysophospholipid, plasma halogen and sphingomyelin.
Do prostriedku podľa tohoto vynálezu môžu byť ďalej pridané vhodné vehikulum a/alebo adjuvans, teda masťové základy a pomocné látky, podľa rôznych druhov aplikácií.Further, a suitable vehicle and / or adjuvant, i.e. ointment bases and excipients, may be added to the composition of the present invention, according to various applications.
Ako už bolo diskutované, je u známych prostriedkov treba, aby bol somatotropín vo forme komplexu s kovom alebo s prechod/njým kovom, čo ymplikuje spôsoby ku ktorým patrí dialýza, pretože jeho rozpustnosť in vivo musí byť nižšia, aby sa získal žiadaný účinok riadenia doby uvoľňovania. Tiež musí byť somatotropín aplikovaný v prebytku, aby sa dosiahol iniciačný efekt prasknutia.As previously discussed, somatotropin is required to be in the form of a complex with a metal or transition metal, which implies methods such as dialysis, since its in vivo solubility must be lower in order to obtain the desired time control effect release. Also, somatotropin must be applied in excess to achieve the initiating rupture effect.
Naproti tomu formulácia, pripravená podľa tohoto vynálezu obsahuje lyofilizovaný lipozómny somatotropín, suspenzovaný v tokoferolovom vehikule, uvoľňuje biologicky aktívny somatotropín s riadenou dobou uvoľňovania pri aplikovaní živočíchom, bez potreby tvorby uvedeného komplexu, teda uvedená formulácia a spôsob aplikovania je velmi jednoduchý a ekonomický. Velmi dôležité je, že formulácia podľa tohoto vynálezu prejavuje vynikajúci profil uvoľňovania spolu s nízkym iniciačným uvoľňovaním alebo prasknutím somatotropínu in vivo.In contrast, the formulation prepared according to the invention comprises a lyophilized liposomal somatotropin suspended in a tocopherol vehicle, releases biologically active somatotropin with controlled release time when administered to an animal, without the need for complex formation, thus said formulation and method of administration is very simple and economical. Very importantly, the formulation of the present invention exhibits an excellent release profile along with a low initiation release or somatotropin rupture in vivo.
Zatiaľčo kov, alebo prechodný kov, používaný vo formulácií s komplexom somatotropínu s kovom podľa spôsobu znám^om v danej oblasti techniky, prejavuje nežiadúce vedľajšie účinky, prostriedok podľa tohoto vynálezu prejavuje len nepatrné vedľajšie účinky. Okrem toho majú tokoferolové deriváty, tu používané, určité prednostné farmakologické účinky in vivo a zmierňujú alebo zabraňujú negatívnym telesným odozvám a reakciám pri používaní prostriedku.While the metal or transition metal used in the formulations of the somatotropin-metal complex according to a method known in the art exhibits undesirable side effects, the composition of the present invention exhibits only minor side effects. In addition, the tocopherol derivatives used herein have certain preferred pharmacological effects in vivo and ameliorate or prevent negative body responses and reactions when using the composition.
-ΊĎalej budú uvedené príklady, ktoré majú za úlohu bližšie ilustrovať tento vynález, pričom ho však nijakým spôsobom necí^nedzujú a to ako z hľadiska obsahu, tak aj rozsahu.The following examples are intended to illustrate the invention in more detail, but are not intended to be limiting in either its content or scope.
Príklad 1Example 1
300 ml roztoku ho^vädzieho somatotropínu (30.03 mg/1 roztoku hovädzieho somatotropínu vyrobeného pomocou rekombinantnej DNA technológie firmou Lucky Ltd.) sa zm^ía s 3 g L- ťZ-fosfatidylcholínu IV-S (L-^-lecitín) extrahovaným zo sóje v homogenizéri po dobu 5 minút pri teplote 4°C, potom sa naleje do banky, rýchle sa ochladí na teplotu -70eC, suší sa v ľadovú iq acetónov^ kúpeli a potom sa lyofilizuje. 133.3 mg lyofilizovaného prášku, obsahujúceho L- cZ -fosfatidylcholin a hovädzí somatotropín, sa homogénne premieša s 1 ml pZrtokoferol acetátu v homogenizéri po dobu 10 min.300 ml of a bovine somatotropin solution (30.03 mg / l bovine somatotropin solution produced by recombinant DNA technology from Lucky Ltd.) was mixed with 3 g of L-β-phosphatidylcholine IV-S (L-β-lecithin) extracted from soybean. in a homogenizer for 5 min at 4 DEG C., then poured into the flask, rapidly cooled to -70 and C, dry ice in acetone iq ^ bath and then lyophilized. 133.3 mg of lyophilized powder, containing L-C 2 -phosphatidylcholine and bovine somatotropin, are mixed homogeneously with 1 ml of pZrtocoferol acetate in a homogenizer for 10 min.
Na desiatich Holsteinových kravách v strednej perióde laktácie sa robí nasledujúci test. Uvedená formulácia sa injekčné aplikuje v množstve 5 ml na hlavu a to šesťkrát každé dva týždne. Päť kráv bolo použitých pre testovanie a päť kráv bolo v porovnávacej skupine, ktorá injekcie nedostávala. Formulácia bola aplikovaná podkožné v suprascapulárnej oblasti. Po aplikácií injekcie sa denne merala produkcia mlieka, ako ukazuje rfThe following test is performed on ten Holstein cows in the middle lactation period. The formulation is injected at a rate of 5 ml per head six times every two weeks. Five cows were used for testing and five cows were in the comparator group that did not receive the injections. The formulation was applied subcutaneously in the suprascapular region. After injection, milk production was measured daily as shown by rf
Tabulka 1 a Obrázok 1.Table 1 and Figure 1.
-8Tabulka 1-8Table 1
Vplyv prostriedku podľa vynálezu na dennú produkciuEffect of the composition of the invention on daily production
Príklad 2Example 2
Formulácia sa priprav^rovnakým spôsobom ako v príklade 1, okrem toho, že sa 333.35 mg lyofilizovaného hovädzieho somatotropínu a 37.02 mg lecitínu mieša s 1 ml pZ-tokoferolacetátu.The formulation was prepared in the same manner as in Example 1 except that 333.35 mg of lyophilized bovine somatotropin and 37.02 mg of lecithin were mixed with 1 ml of β-tocopherol acetate.
Testovanie sa prevádza na Holsteinových kravách v ich strednej dobe laktácie. Uvedená formulácia sa aplikuje injekčné v množstve 2 ml na hlavu vždy dva týždne šesťkrát. Šesť kráv bolo v porovnávacej skupine a šesť v kráv bolo v testovacej skupine. Test sa robil rovnakým spôsobom ako v príklade 1 a výsledok je uk-pzaný v Tabuľke 2 a na Obrázku 2.Testing is performed on Holstein's cows at their mean lactation time. The formulation is injected 2 ml per head every two weeks six times. Six cows were in the comparator group and six in the cows were in the test group. The test was performed in the same manner as in Example 1 and the result is shown in Table 2 and Figure 2.
Tabuľka 2Table 2
Vplyv prostriedku podľa vynálezu na dennú produkciu mlieka (kg)Effect of the composition of the invention on daily milk production (kg)
-9Pred injekciami-9Before injections
1. injekcia1. injection
2. injekcia2. injection
3. injekcia3. injection
4. injekcia4. injection
5. injekcia5. injection
6. injekcia týždne po 6. injekcií 186th injection week after 6th injection 18
Príklad 3Example 3
Kontrolná skupina 26.14 22.6 23.8Control group 26.14 22.6 23.8
22.3 22.0 20.7 21.022.3 21.0
Skupina s 25. 23.8 25.6Group s 25. 23.8 25.6
24.24th
24.24th
23.23rd
injekciami 50injections 50
66
5 0.5 0.
23.223.2
19.319.3
Formulácia prasačieho somatotropínu sa pripraví rovnakým spôsobom ako v príklade 1. Test sa prevádza na štrnástich prasatách, z ktorých každé má hmotnosť 60 kg. Formulácia bola aplikovaná injekčné v množstve 1.5 ml na hlavu dvakrát vždy po troch týždňoch a to siedmim prasatám. Ďalších sedem prasiat bolo v porovnávacej skupine, ktorá nedostávala injekcie. Tri týždne po injekcií sa merala spotreba krmiva. Vypočítavala sa účinnosť kŕmenia (feed efficiency - FE). Tabuľka 3 ukazuje priemerný denný prírastok (average daily gain ADG, kg/deň) a účinnosť kŕmenia (FE = množstvo priatého krmiva/hodnota zvýšenia telesnej hmotnosti).The porcine somatotropin formulation is prepared in the same manner as in Example 1. The test is carried out on fourteen pigs, each weighing 60 kg. The formulation was injected at 1.5 ml per head twice every three weeks, to seven pigs. The other seven pigs were in the comparator group that did not receive the injections. Feed consumption was measured three weeks after injection. Feed efficiency (FE) was calculated. Table 3 shows the average daily gain (ADG, kg / day) and feeding efficiency (FE = feed intake / weight gain).
Tabulka 3Table 3
Denný prírastok a účinnosť kŕmeniaDaily increment and feeding efficiency
Kontrolná skupina Skupina s injekciamiControl group Injection group
-10Príklad 4-10Example 4
Formulácia prasačieho somatotropínu sa pripraví rovnako ako v príklade 1. Test sa prevádza na šiestich prasatách, ktorých každé má hmotnosť 60 kg.The porcine somatotropin formulation is prepared as in Example 1. The test is carried out on six pigs each weighing 60 kg.
Formulácia sa aplikuje injekčné v množstve 1.5 ml na hlavu trom prasatám. Ďalšie tri prasatá sú v kontrolnej skupine bez injekcií. Meralo sa u nich: koncentrácia séra prasačieho somatotropínu (PST), dusík močoviny v krvi (BUN) a inzulínu podobný rastový faktor I ✓The formulation is injected at 1.5 ml per head of three pigs. The other three pigs are in the control group without injections. They measured: serum concentration of porcine somatotropin (PST), blood urea nitrogen (BUN) and insulin-like growth factor I ✓
(koncentrácia IGF-I). Výsledky su v tabulke 4 a na obrázku 4 a 5.(IGF-I concentration). The results are shown in Table 4 and in Figures 4 and 5.
Tabuíka 4Table 4
Koncentrácia séra PST, BUN a inzulínu pod. rastového faktoru ISerum concentration of PST, BUN and insulin below. growth factor I
Ako je z vyššie uvedeného zrejmé, formulácia pripravená podía tohoto vynálezu preukazuje dlhý poločas in vivo pri aplikácií živočíchom, pričom preukazuje velmi malé vedľajšie účinky a je vhodná pre aplikáciu ako injekcia vzhľadom ku svojej nízkej viskozite, ktorá uľahčuje jej používanie. Prostriedok preto možno aplikovať bez chirurgickej operácie alebo špeciálneho aparátu. Ďalej je veľmi výhodné, že spôsb prípravy tohoto prostriedku je velmi jednoduchý a ekonomický.As can be seen from the above, the formulation prepared according to the invention exhibits a long half-life in vivo when administered to animals, showing very little side effects and is suitable for administration as an injection due to its low viscosity, which facilitates its use. Therefore, the composition can be administered without surgery or special apparatus. Furthermore, it is very advantageous that the preparation of this composition is very simple and economical.
-11Tento vynález popisuje uvedený prostriedok predovšetkým z hľadiska vyššie uvedeného špecifického prevedenia, avšak sú možné rozmanité modifikácie a obmeny, ktoré sa prejavia pri používaní tohoto vynálezu, bez akéhokoľvek <^nedzovania obsahu a rozsahu vynálezu v zmysle, v ktorom sú ďalej uvedené patentové nároky.The present invention describes the composition in particular with respect to the specific embodiment described above, but various modifications and variations are possible in the application of the present invention without departing from the scope and scope of the invention as set forth in the claims.
Priemyslová využiteľnosťIndustrial usability
Prostriedok podľa tohoto vynálezu sa pripravuje spôsobom, uvedeným vo vynáleze a možno jeho prípravy použiť v zodpovedajúcej oblasti farmaceutických výrob v danom priemyslovom odvetví.The composition of the invention is prepared according to the method of the invention and can be used in the corresponding field of pharmaceutical production in the industry.
Claims (9)
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| KR1019920022551A KR940011013A (en) | 1992-11-27 | 1992-11-27 | Method for preparing sustained release somatropin formulation |
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| SK132893A3 true SK132893A3 (en) | 1994-07-06 |
| SK279352B6 SK279352B6 (en) | 1998-10-07 |
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| KR (1) | KR940011013A (en) |
| CN (1) | CN1103601C (en) |
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| KR100423895B1 (en) * | 2001-02-19 | 2004-03-24 | 주식회사 엘지생명과학 | Compositions of suspensions of ceftiofur hydrochloride |
| CN103751769B (en) * | 2013-12-25 | 2015-08-19 | 楼秀余 | A kind of lyophilizing recombinant human somatropin capsule and preparation method thereof |
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| US4861580A (en) * | 1985-10-15 | 1989-08-29 | The Liposome Company, Inc. | Composition using salt form of organic acid derivative of alpha-tocopheral |
| WO1987004592A1 (en) * | 1986-02-10 | 1987-08-13 | Liposome Technology, Inc. | Controlled-release liposome delivery system |
| ATE118348T1 (en) * | 1987-12-04 | 1995-03-15 | Liposome Co Inc | HIGH STABILITY LIPOSOMES AND METHOD FOR THE PRODUCTION AND USE. |
-
1992
- 1992-11-27 KR KR1019920022551A patent/KR940011013A/en not_active Ceased
-
1993
- 1993-02-06 MY MYPI93000193A patent/MY134714A/en unknown
- 1993-02-24 CN CN93101680A patent/CN1103601C/en not_active Expired - Lifetime
- 1993-11-26 SK SK1328-93A patent/SK279352B6/en not_active IP Right Cessation
- 1993-11-26 CZ CZ932552A patent/CZ280429B6/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR940011013A (en) | 1994-06-20 |
| CN1087277A (en) | 1994-06-01 |
| MY134714A (en) | 2007-12-31 |
| SK279352B6 (en) | 1998-10-07 |
| CZ280429B6 (en) | 1996-01-17 |
| CN1103601C (en) | 2003-03-26 |
| CZ255293A3 (en) | 1994-06-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4A | Expiry of patent |
Expiry date: 20131126 |