CN108066335A - A kind of pharmaceutical composition containing taxol or its analog and preparation method thereof - Google Patents
A kind of pharmaceutical composition containing taxol or its analog and preparation method thereof Download PDFInfo
- Publication number
- CN108066335A CN108066335A CN201611004643.9A CN201611004643A CN108066335A CN 108066335 A CN108066335 A CN 108066335A CN 201611004643 A CN201611004643 A CN 201611004643A CN 108066335 A CN108066335 A CN 108066335A
- Authority
- CN
- China
- Prior art keywords
- solvent
- pharmaceutical composition
- taxol
- analog
- solubilizer
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 47
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 46
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 62
- 239000000203 mixture Substances 0.000 claims abstract description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 235000019441 ethanol Nutrition 0.000 claims abstract description 23
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229920001304 Solutol HS 15 Polymers 0.000 claims abstract description 20
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 4
- -1 hydroxy group stearic acid macrogol esters Chemical class 0.000 claims abstract description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008117 stearic acid Substances 0.000 claims abstract description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- 238000010257 thawing Methods 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000003002 pH adjusting agent Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 claims 1
- 229920001214 Polysorbate 60 Polymers 0.000 abstract description 9
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 229940123237 Taxane Drugs 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
- 230000006838 adverse reaction Effects 0.000 abstract description 2
- 230000007794 irritation Effects 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 238000011835 investigation Methods 0.000 description 12
- 229940126062 Compound A Drugs 0.000 description 11
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 11
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229960003668 docetaxel Drugs 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000005286 illumination Methods 0.000 description 6
- 229940090044 injection Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229940093181 glucose injection Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 208000030961 allergic reaction Diseases 0.000 description 3
- 230000001351 cycling effect Effects 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- RMLNAEPKTRCSRH-UHFFFAOYSA-N C1C2NCCCC12 Chemical compound C1C2NCCCC12 RMLNAEPKTRCSRH-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 244000050510 Cunninghamia lanceolata Species 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000025090 microtubule depolymerization Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000012106 negative regulation of microtubule depolymerization Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of using taxol or its analog as the pharmaceutical composition of active ingredient, the composition further includes the ten penta hydroxy group stearic acid macrogol esters (Solutol HS15) as solubilizer.The present invention using ten penta hydroxy group stearic acid macrogol esters (Solutol HS15) be used as preferred solubilizer, solve the problems, such as existing taxol, taxanes preparation using Crodaret, polyoxyethylene sorbitan monoleate as accessory strips come adverse reaction.It in addition, described pharmaceutical composition optimizes the selection of solvent, and is removed after preparation, solves the problems, such as that existing taxol, taxanes preparation are strong as solvent irritation is redissolved using ethyl alcohol.The present invention has obtained a kind of pharmaceutical composition of high quality, with preferable stability and therapeutic activity, has high promotional value.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of pharmaceutical composition containing taxol or its analog and
Its preparation method.
Background technology
Taxol or its analog form micro-pipe as promotion from tubulin dimer, while consistent microtubule depolymerization is made
With making microtubule stabilization, blocks cellular and G2 and M phases, so as to inhibit the mitosis of cell and multiplication, and then cell caused to wither
It dies, there is anticancer, be currently known and can be applied to treatment oophoroma, breast cancer, head and neck cancer, non-small cell lung cancer etc., face
Bed is also applied to prostate cancer, liver cancer, stomach cancer etc..But the solubility based on it in water is very low and physically unstable
The problem of, at present, substantial amounts of polyoxyethylene sorbitan monoleate or polyethylene glycol hydrogenated is with the addition of in the taxol of listing or its analog formulations
Castor oil etc., substantial amounts of polyoxyethylene sorbitan monoleate and Crodaret can cause more serious immediate allergic anti-in vivo
Should, it clinically needs now to take antihistaminic and glucocorticoid, polyoxyethylene sorbitan monoleate may interfere with drug and haemocyanin in addition
It is combined in the form of concentration dependant, changes the internal behavior of drug, make it in nonlinear pharmacokinetics, to medical staff and trouble
Person makes troubles and pain.Now there are no preferable pharmaceutical composition can promote to limit its application clinically.
Therefore, these problems of many taxols or its analog are by numerous studies.Especially since its dissolubility is poor, for
Injection is made into have any problem.
Therefore, it is proposed that of the invention, such preparation stability is poor, solubilizer toxicity used is high to solve, and hemolytic is strong
The problem of.
The content of the invention
The first object of the present invention is to provide one kind with taxol or its analog pharmaceutical composition as active component
Object.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of pharmaceutical composition, it includes：One or more of the following taxol of structural formula or its analog (as
Active ingredient, preferably only one)：
And the ten penta hydroxy group stearic acid macrogol esters (Solutol HS15) as solubilizer.
Wherein, whenWhen, the taxol or its analog are actual for docetaxel；
WhenWhen, the taxol or its analog it is actual be compound A (for this hair
The bright active ingredient it is preferred)；
WhenWhen, the taxol or its analog are actual for taxol.
Pharmaceutical composition of the present invention using taxol or its analog as active ingredient, is equipped with solubilizer
Solutol HS15 can improve dissolubility and toxicity is low, it is ensured that pharmaceutical composition is in 5% glucose injection or 0.9% chlorine
Changing in sodium injection, there is certain compatibility to stablize.
Preferably, the quality dosage of the solubilizer is 10~150 times of the taxol or its analog, preferably 40~
120 times.
Further, the first solvent is further included in described pharmaceutical composition, first solvent is selected from propylene glycol, PEG-
400 or one kind in glycerine or arbitrary two kinds of mixture, it is preferably propylene glycol.
Above-mentioned first solvent can ensure that drug sample under room temperature (20~30 DEG C) is in achromatism and clarity thick liquid nano, convenient
Clinical practice.
Further, the quality dosage of first solvent is 0~100 times of the taxol or its analog, preferably 5
~75 times.
Pharmaceutical composition of the present invention is additionally included in the raw material for preparing described pharmaceutical composition in preparation process
The second solvent that can be sufficiently removed, wherein, second solvent in ethyl alcohol, propyl alcohol, isopropanol, the tert-butyl alcohol or water one
Kind or arbitrary a variety of mixture, preferred alcohol.
Wherein, mass percentage content of second solvent in the raw material for preparing described pharmaceutical composition for 40~
85% is advisable, and preferably 55%~80%.
Preferably, in the raw material for preparing described pharmaceutical composition, the volumetric usage ratio of the first solvent and solubilizer is 10:1
~1:15, it is preferably 5:1~1:12；
More preferable first solvent is propylene glycol, and second solvent is ethyl alcohol.
Pharmaceutical composition of the present invention prepares and pH adjusting agent is further included in the raw material of described pharmaceutical composition, described
The species of pH adjusting agent is one kind or several in sodium hydroxide, hydrochloric acid, phosphoric acid, citric acid, lactic acid, acetic acid, boric acid and its salt
Kind, preferably pH adjusting agent is citric acid and/or lactic acid.Using above-mentioned pH adjusting agent, can to the pH value of pharmaceutical composition into
On the basis of row controls (the suitable control range of pH value of pharmaceutical composition of the present invention is 3-4), ensure the stability of drug,
Prevent the drug effect caused by the degradation of drug from reducing.
More specifically, pharmaceutical composition of the present invention in parts by mass, by the raw material for including at least following component
It is prepared：Taxol or 1 part of its analog, 10-150 parts of solubilizer, 0-100 parts of the first solvent；Second solvent 150-350
Part.It is further preferable that the composition is in parts by mass, it is prepared by the raw material for including at least following component：It is preferred that Japanese yew
Alcohol or 1 part of its analog, solubilizer Solutol HS15 are 40-120 parts, 5-75 parts of the first solvent propylene glycol, the second solvent second
200-300 parts of alcohol.
In said program, the taxol or its analog are preferably compound A (i.e. described taxol or its analog
In,)。
Under above-mentioned prescription, described pharmaceutical composition can be in 5% glucose injection or 0.9% sodium chloride injection
After dilution, 7 interior stabilizations when small have no precipitation phenomenon.It is highly effective for clinical administration.When with above-mentioned taxol or its analog
During as active ingredient, using toxic side effect can be avoided after HS15, more preferably anticancer effect is obtained.
Pharmaceutical composition of the present invention is preferably injection, more specifically, has certain viscosity for achromatism and clarity
Parenteral solution.
Invention also provides the preparation method of aforementioned pharmaceutical compositions, the preparation method includes the following steps：
(a) solubilizer is melted under 30-70 DEG C of environment；
(b) taxol or its analog, pH adjusting agent are added in the second solvent and adjust pH value, obtain mixture；
(c) solubilizer after thawing or the solubilizer after thawing and the first solvent are added to step (b) mixture
In, it stirs evenly；
(d) by step (c) it is agitated uniformly after mixture volatilized, rotated, be dried under reduced pressure or lyophilized cause wherein institute
The second solvent stated remove to get.
Preferably, the described process for volatilizing, rotate, being dried under reduced pressure or freezing carries out under the following conditions：
(1) sample vacuum degree is less than 3000Pa；
(2) carried out in the case where removing the temperature and pressure of second solvent enough.
Using above-mentioned preparation method, achromatism and clarity, which can be prepared, has the medicine of thick liquid parenteral solution of certain fluidity
Compositions, the pharmaceutical composition are solid-state at a temperature of 20 DEG C, are liquid in 20 DEG C of temperature.
In use, pharmaceutical composition made from the above method is first placed makes pharmaceutical composition be nothing at room temperature higher than 20 DEG C
Then the clear and bright thick liquid nano of color takes 3~5ml, 5% glucose injections to dissolve pharmaceutical composition complete, is re-introduced into surplus
Remaining in 5% glucose injection, shake up injection.
The present invention has obtained a kind of preferably with taxol or its analog pharmaceutical composition as active component for the first time
(injection) has and avoids using urgency more serious caused by substantial amounts of polyoxyethylene sorbitan monoleate and Crodaret
Property allergic reaction, while also avoid to the advantages of injecting substantial amounts of ethyl alcohol in vivo, available for the treatment of various cancers, such as ovary
Cancer, breast cancer, head and neck cancer, non-small cell lung cancer etc. have high promotional value.
Specific embodiment
The present invention is further described by the following examples, but should not be construed as limiting the invention.Implement below
Involved all raw materials are known substance in example, can be by commercially available.
Embodiment 1 prepares taxol or its analog (such as compound A) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 30 DEG C of environment；
(b) compound A, lactic acid are added in absolute ethyl alcohol and adjust acidity to pH3.2, obtain mixture；
(c) the Solutol HS15 after propylene glycol and thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture volatilize, by absolute ethyl alcohol remove to get.
Embodiment 2 prepares taxol or its analog (such as compound A) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 40 DEG C of environment；
(b) compound A, phosphoric acid are added in 95% ethyl alcohol and adjust acidity to pH3.6, obtain mixture；
(c) the Solutol HS15 after PEG-400 and thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture rotate by 95% ethyl alcohol remove to get.
Embodiment 3 prepares taxol or its analog (such as compound A) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 50 DEG C of environment；
(b) compound A, boric acid are added in 75% ethyl alcohol and adjust acidity to pH3.3, obtain mixture；
(c) the Solutol HS15 after glycerine and thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture be dried under reduced pressure by 75% ethyl alcohol remove to get.
Embodiment 4 prepares taxol or its analog (such as compound A) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 60 DEG C of environment；
(b) compound A, acetic acid, sodium acetate are added in the tert-butyl alcohol and adjust acidity to pH3.3, obtain mixture；
(c) the Solutol HS15 after propylene glycol and thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture freezed by the tert-butyl alcohol remove to get.
Embodiment 5 prepares taxol or its analog (such as docetaxel) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 70 DEG C of environment；
(b) docetaxel, hydrochloric acid (1mol/L) are added in propyl alcohol and adjust acidity to pH3.5, obtain mixture；
(c) the Solutol HS15 after PEG-400 and thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture freezed by propyl alcohol remove to get.
Embodiment 6 prepares taxol and paclitaxel analogs (such as taxol) preparation
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) Solutol HS15 are melted under 60 DEG C of environment；
(b) taxol, citric acid are added in isopropanol and adjust acidity to pH3.2, obtain mixture；
(c) the Solutol HS15 after thawing are added in step (b) mixture, stirred evenly；
(d) by step (c) it is agitated uniformly after mixture be dried under reduced pressure by isopropanol remove to get.
Comparative example 1 prepares formulation for paclitaxel
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) taxol is added in absolute ethyl alcohol, stirring is to being completely dissolved；
(b) will Crodaret add in step (a) described mixture in, stir evenly to get.
Comparative example 2 prepares docetaxel injecta
Formula：
The present embodiment provides the preparation method of above-mentioned preparation simultaneously, specifically comprises the following steps：
(a) docetaxel is added in ethyl alcohol, stirring is to being completely dissolved solubilizer；
(b) will polyoxyethylene sorbitan monoleate add in step (a) described mixture in, stir evenly to get.
(c) by step (b) it is agitated uniformly after mixture be dried under reduced pressure and remove ethyl alcohol to get bottle A.
(d) 13% ethanol solution is prepared to get bottle B.
Two bottled preparation of docetaxel is made in A+ bottles of B of bottle.
Experimental example pharmaceutical preparation quality evaluation
Experimental subjects：
1~2 preparation-obtained medicine group of 1~6 preparation-obtained pharmaceutical composition of the embodiment of the present application and comparative example
Object is closed, 1~2 prescription of comparative example is from taxol listing preparation taxol and the drug explanation of docetaxel listing preparation taxotere
Book；
Experimental method：To investigate the reasonability of preparation prescription, according to《Chinese Pharmacopoeia》Version 9001 in 2015《Material medicine with
Preparation stability test direction principle》It designs this preparation and investigates condition：
A. hot test test sample is put in suitable clean container, is placed 10 days at a temperature of 60 DEG C, in the 5th day and the 10th day
Sampling, is detected by stability high spot reviews project.
B. room temperature experiment test sample is put in suitable clean container, is placed 10 days at a temperature of 25 DEG C, in the 5th day and the 10th day
Sampling, is detected by stability high spot reviews project.
C. strong illumination experiment test sample is placed on equipped in the lighting box of fluorescent lamp or other suitable illumination apparatus, Yu Zhao
Spend to be placed 10 days under conditions of 4500lx scholar 500lx, in the 5th day and the 10th day sample, by stability high spot reviews project into
Row detection, it is important to note that the cosmetic variation of test sample.
D. freezing and thawing test test sample is placed 2 days prior to -20~-10 DEG C, then is placed 2 days at 40 DEG C, is cycled three times altogether,
It samples at the end of Xun Huan, is detected by stability high spot reviews project every time.
E. low-temperature circulating experiment test sample is placed 2 days prior to 2~8 DEG C, then is placed 2 days at 40 DEG C, is cycled three times altogether, every time
It samples at the end of cycling, is detected by stability high spot reviews project.
Experimental result：It is shown in Table 1~table 13.
Table 1：Each 0 temporal quality of experimental preparation investigates result：
Table 2：Each lower 5 days quality investigation results of experimental preparation illumination condition：
Table 3：Each lower 10 days quality investigation results of experimental preparation illumination condition：
Table 4：5 days quality investigation results under the conditions of each 60 DEG C of experimental preparation high temperature：
Table 5：10 days quality investigation results under the conditions of each 60 DEG C of experimental preparation high temperature：
Table 6：Each experimental preparation 5 days quality investigation results under room temperature：
Table 7：Each experimental preparation 10 days quality investigation results under room temperature：
Table 8：Each experimental preparation low-temperature primary cycles quality investigation result：
Table 9：Each experimental preparation low temperature secondary cycle quality investigation result：
Table 10：Each experimental preparation low temperature cycles quality investigation result three times：
Table 11：Each experimental preparation freeze thawing one cycle quality investigation result：
Table 12：Each experimental preparation freeze thawing secondary cycle quality investigation result：
Table 13：Each experimental preparation freeze thawing cycles quality investigation result three times：
In addition, pharmaceutical composition obtained by Example 1-6 takes 3-5ml5% glucose injections to inject as sample respectively
Into sample, concussion is completely dissolved up to each sample, will be dissolved complete sample and is injected into the remaining hot parenteral solution of 5% grape
In, it shakes up, stands observation sample compatibility stability, result of the test is as shown in table 14：
Table 14：Each sample compatibility stability result of the test
It is above-mentioned the experimental results showed that, 1~6 preparation-obtained pharmaceutical composition of the embodiment of the present application is in illumination (4500lx
Scholar 500lx), high temperature (60 DEG C), room temperature, low temperature cycle three times and freeze thawing carries out factors influencing under cycling condition three times, remove
Related substance slightly increases outer under hot conditions, and indices meet《Chinese Pharmacopoeia》Version requirement in 2015, preparation items matter
Figureofmerit is in acceptability limit.1~2 preparation-obtained pharmaceutical composition of comparative example is in illumination (4500lx scholar 500lx), height
Warm (60 DEG C), room temperature, low temperature cycle three times and freeze thawing carries out factors influencing under cycling condition three times, except having under hot conditions
It closes outside substance slightly growth, indices meet《Chinese Pharmacopoeia》Version requirement in 2015, preparation items quality index are being closed
In the range of lattice.
It can improve sample appearance character after adding propylene glycol in sample, make sample rapidly dissolvable, facilitate Clinical practice,
Compatibility stability of the sample in 5% glucose injection can be enhanced simultaneously.
Composition of the present invention uses Solutol HS15 to avoid having used taxol and Taxotere as solubilizer
Crodaret and polyoxyethylene sorbitan monoleate used in the existing listing preparation of alcohol.Crodaret easily draws
It playing patient and generates allergic reaction, patient need to carry out antiallergy process in advance before administration, in addition, multiple studies have shown that, it is noting
It penetrates during agent use, for polyoxyethylene sorbitan monoleate there are direct or indirect toxic action, what is generally accepted is that it has haemolysis,
It should draw attention.And prescription provided by the present invention in terms of medicine stability with taxol and the existing listing of Docetaxel
Preparation is suitable, but solubilizer SolutolHS15 used then can be to avoid the generation of allergic reaction, the contrast effect (phase of the two
With under experiment condition) refer to table 15-16.
Table 15：It is injected intravenously the haemocylolysis of descendant's red blood cell and the serum histamine levels of dog
Table 16：Histamine levels (injection dosage 100mg/kg dogs)
In conclusion the invention has the advantages that：1. solves existing purple as solubilizer using Solutol HS15
China fir alcohol, taxanes preparation using Crodaret, polyoxyethylene sorbitan monoleate as accessory strips come adverse reaction problem；
2. preferred alcohol removes after preparation as the second solvent, solves existing taxol, taxanes preparation using ethyl alcohol as multiple
The problem of solvent irritation is strong；3rd, preferably propylene glycol improves formulation aesthetics character as the first solvent, facilitates Clinical practice.
4, which adopt new technology, effectively controls Residual ethanol；5. solve the problems, such as the clinical application of the paclitaxel analogs such as compound A；It is 6. logical
Influence factor is crossed experiments have shown that formulation chemist stability is stablized.
Embodiment in above-described embodiment can be further combined or replace, and embodiment is only to the present invention's
Preferred embodiment is described, and not the spirit and scope of the present invention are defined, and is not departing from design philosophy of the present invention
Under the premise of, various changes and modifications that professional and technical personnel in the art make technical scheme belong to this hair
Bright protection domain.
Claims (10)
1. a kind of pharmaceutical composition, it includes：One or more of the following taxol of structural formula or its analog：
X=-H,
X=-Ac,
X=-Ac,
And the ten penta hydroxy group stearic acid macrogol esters as solubilizer.
2. composition according to claim 1, it is characterised in that：The quality dosage of the solubilizer for the taxol or
10~150 times of its analog, preferably 40~120 times.
3. composition according to claim 1 or 2, it is characterised in that：The first solvent is further included in described pharmaceutical composition,
The one kind or arbitrary two kinds of mixture of first solvent in propylene glycol, PEG-400 or glycerine are preferably propylene glycol.
4. composition according to claim 3, it is characterised in that：The quality dosage of first solvent is the taxol
Or 0~100 times of its analog, preferably 5~75 times.
5. according to Claims 1 to 4 any one of them composition, it is characterised in that：Prepare the raw material of described pharmaceutical composition
In be additionally included in the second solvent that can be sufficiently removed in preparation process, second solvent be selected from ethyl alcohol, propyl alcohol, isopropanol,
One kind or arbitrary a variety of mixture in the tert-butyl alcohol or water, preferred alcohol；
It is highly preferred that mass percentage content of second solvent in the raw material for preparing described pharmaceutical composition for 40~
85%, most preferably 55%~80%.
6. composition according to claim 5, it is characterised in that：In the raw material for preparing described pharmaceutical composition, first is molten
The volumetric usage of agent and solubilizer ratio is 10:1~1:15, it is preferably 5:1~1:12；More preferable first solvent is the third two
Alcohol, second solvent are ethyl alcohol.
7. according to claim 1~6 any one of them composition, it is characterised in that：Prepare the raw material of described pharmaceutical composition
In further include pH adjusting agent, the species of the pH adjusting agent is sodium hydroxide, hydrochloric acid, phosphoric acid, citric acid, lactic acid, acetic acid, boron
One or more of acid and its salt, preferably pH adjusting agent are citric acid and/or lactic acid.
8. according to claim 1~7 any one of them composition, it is characterised in that：The composition in parts by mass, by wrapping
The raw material for including at least following component is prepared：1 part of taxol or its analog, 10~150 parts of solubilizer, the first solvent 0~
100 parts；Second 150~350 parts of solvent；
It is preferred that the composition is in parts by mass, it is prepared by the raw material for including following component：Taxol or its analog 1
Part, solubilizer Solutol HS15 are 40~120 parts, 5~75 parts of the first solvent propylene glycol, the second etoh solvent 200~300
Part；
Wherein described taxol or the preferred X=-Ac of its analog,
9. according to claim 1~8 any one of them composition, it is characterised in that：The pharmaceutical composition is injection.
10. a kind of be used to prepare such as the method for any one of claim 1~9 described pharmaceutical composition, it is characterised in that：The side
Method includes the following steps：
(a) solubilizer is melted under 30~70 DEG C of environment；
(b) taxol or its analog, pH adjusting agent are added in the second solvent and adjust pH value, obtain mixture；
(c) solubilizer after thawing or the solubilizer after thawing and the first solvent are added in step (b) mixture, stirred
It mixes uniformly；
(d) by step (c) it is agitated uniformly after mixture volatilized, rotate, be dried under reduced pressure or it is lyophilized cause it is wherein described
Second solvent remove to get.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611004643.9A CN108066335B (en) | 2016-11-11 | 2016-11-11 | A pharmaceutical composition containing paclitaxel or its analogues and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611004643.9A CN108066335B (en) | 2016-11-11 | 2016-11-11 | A pharmaceutical composition containing paclitaxel or its analogues and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108066335A true CN108066335A (en) | 2018-05-25 |
| CN108066335B CN108066335B (en) | 2020-02-21 |
Family
ID=62162580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611004643.9A Active CN108066335B (en) | 2016-11-11 | 2016-11-11 | A pharmaceutical composition containing paclitaxel or its analogues and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108066335B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020135647A1 (en) * | 2018-12-28 | 2020-07-02 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1606437A (en) * | 2001-12-20 | 2005-04-13 | 布里斯托尔-迈尔斯斯奎布公司 | Pharmaceutical compositions of orally active taxane derivatives having enhanced bioavailability |
| CN1660071A (en) * | 2004-12-09 | 2005-08-31 | 天津大学 | Application of Taxanes Instant Solid Injection in the Preparation of Anti-tumor Metastasis Drugs |
| CN101366696A (en) * | 2008-10-16 | 2009-02-18 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
| CN102988285A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Docetaxel injection composition and preparation method thereof |
| CN103800909A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating HS15 clouding formation phenomenon and application of composition in medicinal preparation |
| CN103980232A (en) * | 2014-06-05 | 2014-08-13 | 北京诺普德医药科技有限公司 | 10-acetyldocetaxel and application thereof |
-
2016
- 2016-11-11 CN CN201611004643.9A patent/CN108066335B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1606437A (en) * | 2001-12-20 | 2005-04-13 | 布里斯托尔-迈尔斯斯奎布公司 | Pharmaceutical compositions of orally active taxane derivatives having enhanced bioavailability |
| CN1660071A (en) * | 2004-12-09 | 2005-08-31 | 天津大学 | Application of Taxanes Instant Solid Injection in the Preparation of Anti-tumor Metastasis Drugs |
| CN101366696A (en) * | 2008-10-16 | 2009-02-18 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
| CN103800909A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating HS15 clouding formation phenomenon and application of composition in medicinal preparation |
| CN102988285A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Docetaxel injection composition and preparation method thereof |
| CN103980232A (en) * | 2014-06-05 | 2014-08-13 | 北京诺普德医药科技有限公司 | 10-acetyldocetaxel and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020135647A1 (en) * | 2018-12-28 | 2020-07-02 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition and preparation method thereof |
| TWI758674B (en) * | 2018-12-28 | 2022-03-21 | 大陸商蘇州亞盛藥業有限公司 | Pharmaceutical composition and preparation method thereof |
| US11872237B2 (en) | 2018-12-28 | 2024-01-16 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108066335B (en) | 2020-02-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3292860B1 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| US10568890B2 (en) | Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method thereof | |
| US10842770B2 (en) | Non-aqueous taxane pro-emulsion formulations and methods of making and using the same | |
| US9763880B2 (en) | Non-aqueous taxane formulations and methods of using the same | |
| JP2016174907A (en) | Resin container filled with antifungal drug composition | |
| TWI593430B (en) | Liquid composition including taxane active ingredient, method for producing the same and liquid formulation | |
| CN111603439B (en) | Long-acting epipiprazole in-situ phase change gel injection and preparation method thereof | |
| CN108066335A (en) | A kind of pharmaceutical composition containing taxol or its analog and preparation method thereof | |
| MX2011001402A (en) | Injectable taxane pharmaceutical composition. | |
| US20150265640A1 (en) | Lipiodol-based anti-tumour emulsion for treating cancer | |
| US20180280295A1 (en) | Single vial ready to use cabazitaxel formulations with increased stability and methods of preparations | |
| WO2012156999A4 (en) | Ready to use docetaxel formulation | |
| CN107496352A (en) | A kind of Docetaxel pharmaceutical composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210111 Address after: 102200 401 (1), 4th floor, building 3, No.7 courtyard, Science Park Road, Huilongguan town, Changping District, Beijing (Changping Demonstration Park) Patentee after: Beijing Kang Chen biological science and Technology Co.,Ltd. Address before: 101500 No.11, Xingsheng South Road, Miyun Economic Development Zone, Beijing Patentee before: BEIJING KONRUNS PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right |