CN101829052A - Self-emulsifying preparation of taxane compound and preparation method thereof - Google Patents
Self-emulsifying preparation of taxane compound and preparation method thereof Download PDFInfo
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- CN101829052A CN101829052A CN201010124634A CN201010124634A CN101829052A CN 101829052 A CN101829052 A CN 101829052A CN 201010124634 A CN201010124634 A CN 201010124634A CN 201010124634 A CN201010124634 A CN 201010124634A CN 101829052 A CN101829052 A CN 101829052A
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- Prior art keywords
- oil
- composition
- phospholipid
- paclitaxel
- polyoxyethylene castor
- Prior art date
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- -1 taxane compound Chemical class 0.000 title claims abstract description 64
- 229940123237 Taxane Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 128
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 91
- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 80
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 80
- 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 claims abstract description 77
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000003921 oil Substances 0.000 claims abstract description 58
- 239000004359 castor oil Substances 0.000 claims abstract description 52
- 235000019438 castor oil Nutrition 0.000 claims abstract description 52
- 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 claims abstract description 52
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 48
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 36
- 239000004310 lactic acid Substances 0.000 claims abstract description 33
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 33
- 239000004094 surface-active agent Substances 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 15
- 235000019198 oils Nutrition 0.000 claims description 57
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 51
- 238000002347 injection Methods 0.000 claims description 42
- 239000007924 injection Substances 0.000 claims description 42
- 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 35
- 239000000787 lecithin Substances 0.000 claims description 35
- 229940067606 lecithin Drugs 0.000 claims description 35
- 235000010445 lecithin Nutrition 0.000 claims description 35
- 239000003549 soybean oil Substances 0.000 claims description 35
- 235000012424 soybean oil Nutrition 0.000 claims description 35
- 239000000839 emulsion Substances 0.000 claims description 30
- 230000001804 emulsifying effect Effects 0.000 claims description 26
- 238000012856 packing Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 22
- 229960004756 ethanol Drugs 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 18
- 239000008158 vegetable oil Substances 0.000 claims description 18
- 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 claims description 15
- 210000000582 semen Anatomy 0.000 claims description 14
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- 239000008344 egg yolk phospholipid Substances 0.000 claims description 12
- 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 9
- 229940079593 drug Drugs 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 235000005713 safflower oil Nutrition 0.000 claims description 6
- 239000003813 safflower oil Substances 0.000 claims description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 229940083466 soybean lecithin Drugs 0.000 claims description 5
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 claims description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 3
- 235000019489 Almond oil Nutrition 0.000 claims description 3
- AERBNCYCJBRYDG-UHFFFAOYSA-N D-ribo-phytosphingosine Natural products CCCCCCCCCCCCCCC(O)C(O)C(N)CO AERBNCYCJBRYDG-UHFFFAOYSA-N 0.000 claims description 3
- 235000010469 Glycine max Nutrition 0.000 claims description 3
- 235000019484 Rapeseed oil Nutrition 0.000 claims description 3
- 240000001890 Ribes hudsonianum Species 0.000 claims description 3
- 235000016954 Ribes hudsonianum Nutrition 0.000 claims description 3
- 235000001466 Ribes nigrum Nutrition 0.000 claims description 3
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- 239000008168 almond oil Substances 0.000 claims description 3
- 235000021324 borage oil Nutrition 0.000 claims description 3
- 239000000828 canola oil Substances 0.000 claims description 3
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- 150000002270 gangliosides Chemical class 0.000 claims description 3
- 239000004006 olive oil Substances 0.000 claims description 3
- 235000008390 olive oil Nutrition 0.000 claims description 3
- AERBNCYCJBRYDG-KSZLIROESA-N phytosphingosine Chemical compound CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO AERBNCYCJBRYDG-KSZLIROESA-N 0.000 claims description 3
- 229940033329 phytosphingosine Drugs 0.000 claims description 3
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 claims description 3
- 239000010775 animal oil Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 27
- 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 abstract description 12
- 229940093181 glucose injection Drugs 0.000 abstract description 7
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 abstract description 5
- 229940090044 injection Drugs 0.000 description 41
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 35
- 159000000000 sodium salts Chemical class 0.000 description 30
- 238000001914 filtration Methods 0.000 description 21
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 20
- 239000012982 microporous membrane Substances 0.000 description 20
- 239000011734 sodium Substances 0.000 description 16
- 229940108949 paclitaxel injection Drugs 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- 206010002198 Anaphylactic reaction Diseases 0.000 description 12
- 241001116500 Taxus Species 0.000 description 12
- 208000003455 anaphylaxis Diseases 0.000 description 12
- 230000036783 anaphylactic response Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229920001427 mPEG Polymers 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- OXWJSRNDLBHVPW-DRRLCDGFSA-N C(O)CN.P(=O)(O)(O)OC[C@@H](COCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC Chemical compound C(O)CN.P(=O)(O)(O)OC[C@@H](COCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC OXWJSRNDLBHVPW-DRRLCDGFSA-N 0.000 description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 8
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- 230000000052 comparative effect Effects 0.000 description 6
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- 238000009472 formulation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 206010018910 Haemolysis Diseases 0.000 description 5
- 206010070834 Sensitisation Diseases 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
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- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 230000008313 sensitization Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KOTXAHKUCAQPQA-AAUVPWARSA-N taxine Chemical compound C1([C@@H]([C@@H](O)C(=O)O[C@@H]2C=3/C[C@@](C([C@H](O)C4=C(C)[C@@H](OC(C)=O)CC(C4(C)C)[C@@H](OC(C)=O)\C=3)=O)(C)[C@@H](O)C2)N(C)C)=CC=CC=C1 KOTXAHKUCAQPQA-AAUVPWARSA-N 0.000 description 5
- 229930189271 taxine Natural products 0.000 description 5
- QEHCYTDFERPPPU-KDXMTYKHSA-N (2s)-2,3-dioctadecoxypropan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCCCC QEHCYTDFERPPPU-KDXMTYKHSA-N 0.000 description 4
- PAZGBAOHGQRCBP-DDDNOICHSA-N 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-DDDNOICHSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- AAAFQZIIIFLWHO-BKJQSOHOSA-N OCC(O)CO.P(=O)(O)(O)OC[C@@H](COCCCCCCCCCCCCCCCC)OC(CCCCCCC\C=C/CCCCCCCC)=O Chemical compound OCC(O)CO.P(=O)(O)(O)OC[C@@H](COCCCCCCCCCCCCCCCC)OC(CCCCCCC\C=C/CCCCCCCC)=O AAAFQZIIIFLWHO-BKJQSOHOSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 4
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- 238000006243 chemical reaction Methods 0.000 description 4
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 4
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a self-emulsifying medical composition for delivering taxane medicaments and a preparation method thereof. The self-emulsifying medical composition is transparent liquid, comprises an effective dose of taxane compound, an oil component, a surface active agent and alcohol and preferentially comprises lactic acid, wherein the surface active agent consists of phospholipid and polyoxyethylenated castor oil. After the self-emulsifying composition is added to a glucose injection, the composition can self-emulsify into micro emulsion the mean grain size of which is 50-300nm, and the micro emulsion can stabilize for more than 12 hours at room temperature. The preferential taxane compound in the invention is taxol.
Description
Technical field
The present invention relates to a kind of self emulsifying Pharmaceutical composition of bearing taxanes, particularly a kind of can be through the taxanes self emulsifying Pharmaceutical composition of intravenously administrable.
Background technology
The general name of isomer, analog and the derivant of the taxine kind of bearing taxanes one class taxine kind and the similar taxine kind of molecule result, it is the first-line treatment medicine that is used for the treatment of transitivity ovarian cancer, pulmonary carcinoma, the esophageal carcinoma at present, comprise paclitaxel, Docetaxel, red pulp mycin, red pulp mycin diacetate, Paclitaxel B etc., wherein, the most frequently used bearing taxanes is paclitaxel and Docetaxel in clinical.
Paclitaxel has the structure of formula I, is white crystalline powder, and odorless is tasteless, and its English name is Paclitaxel or Taxol, and molecular formula is C
47H
51NO
14, molecular weight is 853.92.
Docetaxel is a kind of semisynthetic taxanes, has another name called taxotere, docetaxel, English Docetaxel by name or Taxotere, molecular formula C
43H
53NO
14, white powder, water insoluble, dissolve in dichloromethane, methanol, have formula II structure:
Because the taxane medicine utmost point is insoluble in water, therefore its preparation that is prepared into intravenous injection or infusion is existed bigger technical difficulty.The paclitaxel injection of listing is a kind of water white transparency or slightly yellowy viscosity solution at present, contain 6mg paclitaxel, 527mg polyoxyethylene castor oil (or title Cremophor EL in every milliliter of paclitaxel injection, Cremophor EL) and 49.7% dehydrated alcohol, but the problem that said preparation exists mainly contains: the 1. a high proportion of anaphylaxis that causes of the toxicity of solvent and sensitization comprises the bronchospasm that anaphylaxis causes that caused by the adjuvant polyoxyethylene castor oil, rapid breathing, tired, hypotension etc.; Syringe, transfusion bag in container and the clinical practice contacts with polyoxyethylene castor oil and can leach a large amount of plasticizer phthalic acid diethyl ethyl phosphonate in process of production in addition, causes anaphylaxis.2. paclitaxel injection dilution back is unstable: after said preparation is diluted, if surpass 24h, the graininess precipitation can occurs, and the analysis showed that this precipitation is not a paclitaxel, therefore will use filter in transfusion device in the time of quiet.3. compatibility changes: clinical 60 kinds of medicines commonly used can cause that with the paclitaxel injection compatibility transfusion is muddy, and some drugs and paclitaxel are competed and combined plasma protein and can make the toxicity increase.4. the permanent damage of the serious or potentiality of the severe pain of injection site, injection point place or peripheral vessels.
Clinical when using above paclitaxel injection, in order to prevent to take place above untoward reaction, treated preceding 12 hours and 6 hours oral dexamethasones at paclitaxel injection, treat and gave diphenhydramine, quiet notes cimetidine 300mg or ranitidine 50mg in preceding 30～60 minutes.And paclitaxel injection list pharmaceutical quantities is controlled to be 135～200mg/m
2, under granulocyte colony-stimulating factor was supported, dosage can reach 250mg/m
2, it is 0.3～1.2mg/mL that paclitaxel injection is diluted to final concentration with normal saline or 5% glucose saline, after the microporous membrane that is no more than 0.22u m through diameter filters, quiet 3 hours; Drug combination dosage is 135～175mg/m
2, 3～4 weeks repeated.
The above technical problem that exists for the paclitaxel injection that solves present listing, dissolubility, the stability of the untoward reaction that the technical staff causes at polyoxyethylene castor oil for many years, increase paclitaxel, reduce toxicity, increase bioavailability and launched a large amount of research, also can industrialization carry out deep exploration simultaneously the technical scheme that is adopted.The method of being attempted at present comprises prodrug method, emulsion process and makes methods such as micelle, liposome, nanoparticle, microemulsion, microsphere, cyclodextrin clathrate and topical that wherein more promising is that paclitaxel is made microemulsion.
Yet, present yew alcohol micro-emulsion also rests on laboratory stage, some has strict demand to manufacturing machine equipment, particularly need high-pressure emulsification or need high temperature emulsifying or need high-speed stirred emulsifying, this method complex process, the cost height is unfavorable for industrialization production, and prepared emulsion stability is poor, can not satisfy clinical needs.
WO2006037089 discloses a kind of Emulsion of paclitaxel, comprise paclitaxel, vegetable oil, MCT, glycerol, phospholipid, water etc., yet, it needs high shear force to puddle the device stirring in the preparation, under the operating pressure of 18000-23000psi, pass through the microjet homogenizer 5 times then, technology cost height can't carry out industrialization production.
Chinese patent application CN101450040A also discloses a kind of taxane Emulsion, contains paclitaxel, PEG-(CH
2) n-cholesterol, soybean oil, oleic acid, poloxamer, glycerol, phospholipid and water; in the preparation; also need to get colostrum 50 ℃ of-80 ℃ of following high-speed stirred earlier; be transferred to then in the equal machine of high pressure breast; the emulsion droplet of emulsifying to mean diameter≤1 micron repeatedly, and production process needs inflated with nitrogen protection.The preparation method of this Emulsion is also complicated, and relatively difficulty is produced in industrialization.
Chinese patent application CN100341485C discloses a kind of self emulsifying preconcentrate of paclitaxel, form by oil phase, ethanol or propylene glycol such as surfactants such as paclitaxel, polyoxyethylene castor oil, medium chain triglycerides, yet, from the technical scheme of its enforcement as can be seen, its prepared product is unstable after forming Emulsion, therefore only can oral administration, can not give the patient with intravenous form.
Chinese patent application CN1822859A also discloses a kind of self-emulsifiable preparation of paclitaxel, comprises paclitaxel, POE castor oil hydrogenated, medium chain triglyceride and cosurfactant, and cosurfactant wherein is glyceryl monooleate, PG monolaurate etc.Yet said preparation can not be stablized after adding entry and forming Emulsion for a long time, therefore also can only oral administration, can not use as the intravenous injection product.
Chinese patent application CN1602854A discloses a kind of self-emulsifiable preparation, comprise paclitaxel, polyoxyethylene castor oil (Cremophor EL), Pluronic F68, phospholipid, soybean oil and ethanol, said preparation in joining glucose injection after, but self emulsifying forms Emulsion.Yet after forming Emulsion, stabilization time is not long, and paclitaxel is separated out from solution easily, influences clinical use, and because dosage of surfactant is big, zest is still very big during use.
Therefore as seen, present technical scheme also can not satisfy paclitaxel clinical application demand far away, prior art still need a kind of prepare simple, easy to use, zest is little, cost is low, stable taxane ejection preparation that can industrialization production.
Summary of the invention
The present inventor is paying under the situation of a large amount of creative works, by experiment repeatedly, work out a kind of delivery system of bearing taxanes, said preparation is clarifying liquid, and preparation is simple, is easy to industrialization production, after being added to the water, preparation promptly can form Emulsion by self emulsifying, and the Emulsion that forms can keep stable for a long time, can safe ready ground be used for clinical, thereby finished the present invention.
Compositions of the present invention has the following advantages: (1) can be for the clinical injection use; (2) Emulsion of Xing Chenging can directly use and keep＞24 hours stability; (3) can adopt the mode of filtration sterilization; (4) composition that it adopted is the used for intravenous injection composition that FSDA allows employing; (5) production technology is simple, does not adopt high-speed shearing device, is easy to industrialization production; (6) do not stimulate blood vessel; (7) hypoallergenic; (8) do not produce haemolysis; (9) the more existing formulation for paclitaxel of untoward reaction is low.
On the one hand, the invention provides a kind of medical composition in order to the delivering taxoids medicine, be clear liquid, it is a kind of self-emulsifiable preparation, the bearing taxanes, oils composition, surfactant and the ethanol that comprise effective dose, wherein said surfactant are the combination of phospholipid and polyoxyethylene castor oil (Cremophor EL).
The weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil will reach within the certain limit in the compositions of the present invention, just can reach the described technique effect of the application, otherwise after emulsifying, the poor stability of microemulsion, be difficult to satisfy the effect of clinical use, the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1 among the present invention: 3-10: 30-80: 20-50, preferred 1: 3-8: 30-50: 20-40, preferred especially 1: 4-6: 35-45: 25-30.
Bearing taxanes described in the present invention; the taxine medicine of containing or the isomer of taxine medicine; analog or derivant; include but not limited to paclitaxel; Docetaxel; Paclitaxel; Ramulus et folium taxi cuspidatae ether; spicatin; Yunnan China fir alcohol; paclitaxel-2; the 13-diketone; 5 β; 9 β; 10 β-trihydroxy-ring-9; 10-acetal and acetone or acetate; paclitaxel-2; the 13-diketone; 5 β; 9 β; 10 β-trihydroxy-ring-9; 10-acetal and acetone or acetate; paclitaxel-2 β; 15 β; 9 β; 10 β-tetrol-ring-9; 10-acetal and acetone or acetate; N-takes off benzoyl Paclitaxel A; Cephalomannine; Cephalomannine-7-xyloside; 7-ring-10-deacetylation-Cephalomannine; 10-deacetylation-Cephalomannine; red pulp mycin; red pulp mycin diacetate; red pulp mycin I-VI; 7-ring-red pulp mycin III; red pulp mycin A; 7-(4-nitrine-benzoyl)-red pulp mycin III; the red pulp mycin of O-acetyl group IV; 7-(triethyl group is silica-based)-red pulp mycin III; 7; 10-two-O-[(2; 2; 2-trichlorine ethoxy)-carbonyl]-red pulp mycin III; 13-(2 ', 3 '-dihydroxy-3 '-phenyl propiono)-red pulp mycin III; red pulp mycin III13-O-acetate; Paclitaxel B; the Pacific Rim paclitaxel; 10-deacetylation-7-Pacific Rim paclitaxel; 10-takes off the acetyl Paclitaxel; 10-takes off acetyl Paclitaxel B or C; 7-xylose-10-takes off the pure and mild 10-of acetyl Pacific yew and takes off acetyl Paclitaxel-7-xyloside.Wherein, the preferred taxane compounds of the present invention is paclitaxel and Docetaxel, most preferably is paclitaxel.
Above medical composition has suitable viscosity, can carry out packing easily, for clinical use.When clinical use, compositions of the present invention is joined in the glucose injection, can form microemulsion by self emulsifying, this microemulsion has the particle diameter of 1nm-1000nm, the particle diameter that preferably has 10-800nm, the particle diameter that more preferably has 50-500nm most preferably has the particle diameter of 50-300nm, can be directly used in patient's administration.Formed microemulsion can not separated out precipitation at ambient temperature, keeps stablizing more than 8 o'clock, preferably stablizes more than 12 hours, more preferably stablizes more than 18 hours, most preferably stablizes more than 24 hours, especially preferably stablizes more than 30 hours.
Oils composition among the present invention can be selected from pharmaceutically conventional oil-phase component, includes but not limited to monoglyceride, double glyceride, triglyceride, or its mixture.
In some embodiments, described oils composition is " vegetable oil ".Described vegetable oil is the oil derived from plant seed or nut.Vegetable oil is generally " long chain triglycerides class ", its by tri-fatty (according to oil the source difference, normal length about 14 has the unsaturated bond of different numbers and position to about 22 carbon) form ester bonds and generate with three hydroxyls on the glycerol.Vegetable oil includes but not limited to soybean oil, almond oil, borage oil, black currant pip oil, Oleum Ricini, Semen Maydis oil, safflower oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, cupu oil, Petiolus Trachycarpi oil, Canola oil, Semen Lini oil, Oleum Camelliae, safflower oil, Oleum Gossypii semen, Radix Oenotherae erythrosepalae wet goods, preferred soybean oil.
In some embodiments, use safety and the stability of high-purity oil plant usually to guarantee preparation.In some embodiments, can also use hydrogenated vegetable oil, its controlled hydrogenation by vegetable oil makes.
In other embodiments, described oil refers to " MCT class ".(MCT ' s) is another kind of triglyceride oil to the MCT class, and it can be natural or composite, is to be generally about 8 fatty acids to about 12 carbon from length to make.The same with vegetable oil, MCT ' s has been widely used in the Emulsion that is designed for injection, as the patient's of the non-enteral nutrition of needs origin of heat.This class oil can obtain by the commercial channel, as Miglyol 210 and Miglyol 812, and CRODAMOLGTCC-PN, Neobees M-5 wet goods.
In the other embodiment, the oils composition can also be the oil from animal.It also comprises the triglyceride class, but the length of its three fatty acid chains is different with wherein unsaturated bond and vegetable oil.The Animal fat that is solid-state oil sources (for example: Adeps Bovis seu Bubali, Adeps Sus domestica, etc.) gained under room temperature can optionally be processed into liquid state.This tallow for liquid state at room temperature of other form comprises various fish oil, for example, can be common fish oil, herring oil, trout oil or tunny fish oil, or the like.
Phospholipid among the present invention can be a kind of phospholipid or the mixture of phospholipid more than two kinds.
Described phospholipid is meant the triglyceride with two fatty acids and a phosphate ion.Can be used in phospholipid of the present invention includes but not limited to lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, has about 4 to about 22 carbon atoms and be more typically about 10 phosphatidic acid to about 18 carbon atoms and different saturation.
Can be used for the phospholipid that phospholipid of the present invention can be natural origin.Naturally occurring phospholipid comprises soybean lecithin, egg lecithin, hydrogenated soy phosphatidyl choline, hydrogenation egg lecithin, sphingosine, ganglioside and phytosphingosine, and combination.Natural lecithin is the mixture that is connected in the cholinester of phosphoric acid for stearic acid, Palmic acid and oleic double glyceride, is commonly referred to as phosphatidylcholine, and can derives from various sources, for example: egg and Semen Glycines.Soybean lecithin and egg lecithin (hydrogenated products that comprises these chemical compounds) have permanent safety history, have comprehensive emulsifying and dissolution characteristics, and become innocuous substance than the easier very fast disintegrate of most of synthetic surfactant, above product all can be buied on market.The preferred phospholipid of the present invention is egg lecithin.
In some embodiments of the present invention, phospholipid also can be synthetic phospholipid, include but not limited to: the diglyceride class, for example 1,2. two lauroyl-sn-glycerol (DLG), 1,2-Er Beans myristoyl-sn-glycerol (DMG), 1,2-two palmityls-sn-glycerol (DPG), 1,2-distearyl-sn-glycerol (DSG); The phospholipid acids, for example 1,2--Beans myristoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DMPA, Na), 1,2-two palmityls-sn-glycerol-3-phosphatidic acid, sodium salt (DPPA, Na), 1,2-stearoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DSPA, Na); The phosphocholine class, for example 1,2-two lauroyl-sn-glycerol-3-phosphocholine (DLPC), 1,2-Beans myristoyl-sn-glycerol-3-phosphocholine (DMPC), 1,2-two palmityls-sn-glycerol-3-phosphocholine (DPPC), 1,2-distearyl-sn-glycerol-3-phosphocholine (DSPC); The phosphoethanolamine class, for example 1,2-lauroyl-sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-Beans myristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine (DPPE), 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine (DSPE); The phosphoglycerol esters, for example 1,2-two lauroyl-sn-glycerol-3-phosphate glycerol, sodium salt (DLPG), 1,2-Beans myristoyl-sn-glycerol-3-phosphate glycerol, sodium salt (DMPG), 1,2-Beans myristoyl-sn-glycerol-3-phosphate-sn-1-glycerol, ammonium salt (DMP-sn-1-G, NH
4), 1,2-palmityl-sn-glycerol-3-phosphate glycerol, sodium salt (DPPG, Na), 1,2-distearyl-sn-glycerol-3-phosphate glycerol, sodium salt (DSPG, Na), 1,2---stearoyl-sn-glycerol-3-phosphate-sn-1-glycerol, sodium salt (DSP-sn-1G, Na); The phosphoserine class, for example 1,2-two palmityls-sn-glycerol-3-phosphate-L-serine, sodium salt (DPPS, Na); The combination chain phospholipid, for example 1-palmityl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), 1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, sodium salt (POPG, Na), 1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, ammonium salt (POPG, NH
4); Lysophosphatide class, for example 1-palmityl-2-haemolysis-sn-glycerol-3-phosphocholine (P-lyso-PC), 1-stearoyl-2-haemolysis-sn-glycerol-3-phosphocholine (S-lyso-PC); The ethylene glycol phospholipid, N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DPPE for example, 1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DPPE, 1,2-palmityl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 750)-MPEG-750-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt etc.
Ethanol in the present composition plays a part to regulate composition viscosity, makes compositions be easy to packing and filtration sterilization.
In some embodiments, the present composition also further contains lactic acid.The applicant is through a large amount of experimentatioies, find to add lactic acid in the present composition, can not only be used for regulating pH value, increase the stability of paclitaxel, reduce the degraded of paclitaxel and the generation of related substance, the more important thing is, add lactic acid in the system of the present invention, with add other pharmaceutically common acid compare, can make compositions add glucose injection form Emulsion after the stable longer time, produced the beyond thought effect of those skilled in the art.
Therefore, the present invention also provides a kind of medical composition in order to the delivering taxoids medicine, be clear liquid, it is a kind of self-emulsifiable preparation, comprise or be made up of following ingredients basically: the bearing taxanes of effective dose, oils composition, surfactant, ethanol and lactic acid, wherein said surfactant are the combination of phospholipid and polyoxyethylene castor oil.Above medical composition has suitable viscosity, can carry out packing easily, for clinical use.When clinical use, compositions of the present invention is joined in the glucose injection, can form microemulsion by self emulsifying, this microemulsion has the particle diameter of 1nm-1000nm, the particle diameter that preferably has 10-800nm, the particle diameter that more preferably has 50-500nm most preferably has the particle diameter of 50-300nm, can be directly used in the patient infusion administration.The pharmaceutical composition of bearing taxanes, oils composition, phospholipid, polyoxyethylene castor oil, ethanol and lactic acid that contains provided by the present invention is after forming microemulsion, has very superior stability, can not separate out precipitation at ambient temperature, keep stablizing more than 12 hours, preferably stablize more than 18 hours, more preferably stablize more than 24 hours, most preferably stablize more than 30 hours, considerably beyond using the formed preparation of other organic or inorganic acid, help clinical use greatly.
In above compositions, the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1: 3-10: 30-80: 20-50, preferred 1: 3-8: 30-50: 20-40, preferred especially 1: 4-6: 35-45: 25-30.Wherein, described bearing taxanes is paclitaxel and Docetaxel preferably, most preferably is paclitaxel.
In some concrete embodiments, the self-emulsifying composition of bearing taxanes of the present invention comprises following composition or is grouped into by following one-tenth, and wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 0.2～10%
Lecithin 10～55%
Polyoxyethylene castor oil 5～55%
Lactic acid 0.01～0.3%
Preferably, the self-emulsifying composition of taxoids of the present invention comprises following composition or is grouped into by following one-tenth, and wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 1～10%
Lecithin 15～40%
Polyoxyethylene castor oil 10～30%
Lactic acid 0.02～0.2%
Ethanol 40～70%.
Most preferably, the self-emulsifying composition of taxoids of the present invention comprises following composition or is grouped into by following one-tenth, and wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 2～3%
Lecithin 18～25%
Polyoxyethylene castor oil 10～20%
Lactic acid 0.05～0.2%
Ethanol 50～70%.
Wherein, described bearing taxanes is paclitaxel and Docetaxel preferably, most preferably is paclitaxel.
In certain embodiments, the present composition can also further comprise other suitable acceptable accessories, include but not limited to acidify, alkalization, buffering, chelating, compound and stabilizing agent, antioxidant and microbial resistance antiseptic, suspension and/or viscosity modifier and other bio-compatibility material or therapeutic agent etc.Described stabilizing agent can be selected from one or more in glycerol, oleic acid, linoleic acid, sodium cholate, sodium deoxycholate, glycerol monostearate, ethyl oleate, the Ethyl linoleate; Described antioxidant comprises one or more in ascorbyl palmitate, Butylated hydroxyanisole (BHA), the dibenzylatiooluene (BHT); Described chelating agen includes but not limited to one or more in EDTA, pentaacetic acid and the sulphite.
Paclitaxel self-emulsion composition of the present invention is made injection after can disperseing with various media such as normal saline or glucose, injection such as carries out in vein, subcutaneous, muscle, the sheath; Also can be made into liquid preparation, solid preparation, suppository, external preparation or lyophilized formulations of further making other types or the like.Concrete dosage form includes but not limited to injection, lyophilized injectable powder, capsule, soft capsule, drop pill, Emulsion, percutaneous plaster etc.
On the other hand, the present invention also provides a kind of microemulsion, comprises bearing taxanes, oils composition, surfactant, ethanol and the D/W of effective dose, and surfactant wherein is the mixture of phospholipid and polyoxyethylene castor oil.Preferably, microemulsion of the present invention also contains lactic acid.The lactic acid that is contained in the Emulsion of the present invention can not only be used for regulating pH value, increase the stability of bearing taxanes, reduce the degraded of bearing taxanes and the generation of related substance, the more important thing is, with other pharmaceutically common acid compare, the adding of lactic acid can make this microemulsion stablize the longer time, has produced the beyond thought effect of those skilled in the art.Emulsion of the present invention can not separated out precipitation at ambient temperature, keeps stablizing more than 12 o'clock, preferably stablizes more than 18 hours, more preferably stablize more than 24 hours, most preferably stablize more than 30 hours,, help clinical use greatly considerably beyond using the formed preparation of other organic or inorganic acid.Wherein, bearing taxanes of the present invention is paclitaxel and Docetaxel preferably, most preferably is paclitaxel.
Oils composition in the above-mentioned Emulsion can be selected from pharmaceutically conventional oil-phase component, includes but not limited to monoglyceride, double glyceride, triglyceride, or its mixture.
In some embodiments, described oils composition is " vegetable oil ".Described vegetable oil is the oil derived from plant seed or nut.Vegetable oil is generally " long chain triglycerides class ", its by tri-fatty (according to oil the source difference, normal length about 14 has the unsaturated bond of different numbers and position to about 22 carbon) form ester bonds and generate with three hydroxyls on the glycerol.Vegetable oil includes but not limited to soybean oil, almond oil, borage oil, black currant pip oil, Oleum Ricini, Semen Maydis oil, safflower oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, cupu oil, Petiolus Trachycarpi oil, Canola oil, Semen Lini oil, Oleum Camelliae, safflower oil, Oleum Gossypii semen, Radix Oenotherae erythrosepalae wet goods, preferred soybean oil.
In some embodiments, use safety and the stability of high-purity oil plant usually to guarantee preparation.In some embodiments, can also use hydrogenated vegetable oil, its controlled hydrogenation by vegetable oil makes.
In other embodiments, described oil refers to " MCT class ".(MCT ' s) is another kind of triglyceride oil to the MCT class, and it can be natural or composite, is to be generally about 8 fatty acids to about 12 carbon from length to make.The same with vegetable oil, MCT ' s has been widely used in the Emulsion that is designed for injection, as the patient's of the non-enteral nutrition of needs origin of heat.This class oil can obtain by the commercial channel, as Miglyol 210 and Miglyol 812N, and CRODAMOLGTCC-PN, Neobees M-5 wet goods.
In the other embodiment, the oils composition can also be the oil from animal.It also comprises the triglyceride class, but the length of its three fatty acid chains is different with wherein unsaturated bond and vegetable oil.The Animal fat that is solid-state oil sources (for example: Adeps Bovis seu Bubali, Adeps Sus domestica, etc.) gained under room temperature can optionally be processed into liquid state.This tallow for liquid state at room temperature of other form comprises various fish oil, for example, can be common fish oil, pilchardine, trout oil or tunny fish oil, or the like.
Described phospholipid can be a kind of phospholipid or the mixture of phospholipid more than two kinds.Phospholipid is meant the triglyceride with two fatty acids and a phosphate ion.Can be used in phospholipid of the present invention includes but not limited to lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, has about 4 to about 22 carbon atoms and be more typically about 10 phosphatidic acid to about 18 carbon atoms and different saturation.
Can be used for the phospholipid that phospholipid of the present invention can be natural origin.Naturally occurring phospholipid comprises soybean lecithin, egg lecithin, hydrogenated soy phosphatidyl choline, hydrogenation egg lecithin, sphingosine, ganglioside and phytosphingosine, and combination.Natural lecithin is the mixture that is connected in the cholinester of phosphoric acid for stearic acid, Palmic acid and oleic double glyceride, is commonly referred to as phosphatidylcholine, and can derives from various sources, for example: egg and Semen Glycines.Soybean lecithin and egg lecithin (hydrogenated products that comprises these chemical compounds) have permanent safety history, have comprehensive emulsifying and dissolution characteristics, and become innocuous substance than the easier very fast disintegrate of most of synthetic surfactant, above product all can be buied on market.The preferred phospholipid of the present invention is egg lecithin.
In some embodiments of the present invention, phospholipid also can be synthetic phospholipid, include but not limited to: the diglyceride class, for example 1,2. two lauroyl-sn-glycerol (DLG), 1,2-Er Beans myristoyl-sn-glycerol (DMG), 1,2-two palmityls-sn-glycerol (DPG), 1,2-distearyl-sn-glycerol (DSG); The phospholipid acids, for example 1,2--Beans myristoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DMPA, Na), 1,2-two palmityls-sn-glycerol-3-phosphatidic acid, sodium salt (DPPA, Na), 1,2-stearoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DSPA, Na); The phosphocholine class, for example 1,2-two lauroyl-sn-glycerol-3-phosphocholine (DLPC), 1,2-Beans myristoyl-sn-glycerol-3-phosphocholine (DMPC), 1,2-two palmityls-sn-glycerol-3-phosphocholine (DPPC), 1,2-distearyl-sn-glycerol-3-phosphocholine (DSPC); The phosphoethanolamine class, for example 1,2-lauroyl-sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-Beans myristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine (DPPE), 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine (DSPE); The phosphoglycerol esters, for example 1,2-two lauroyl-sn-glycerol-3-phosphate glycerol, sodium salt (DLPG), 1,2-Beans myristoyl-sn-glycerol-3-phosphate glycerol, sodium salt (DMPG), 1,2-Beans myristoyl-sn-glycerol-3-phosphate-sn-1-glycerol, ammonium salt (DMP-sn-1-G, NH
4), 1,2-palmityl-sn-glycerol-3-phosphate glycerol, sodium salt (DPPG, Na), 1,2-distearyl-sn-glycerol-3-phosphate glycerol, sodium salt (DSPG, Na), 1,2---stearoyl-sn-glycerol-3-phosphate-sn-1-glycerol, sodium salt (DSP-sn-1G, Na); The phosphoserine class, for example 1,2-two palmityls-sn-glycerol-3-phosphate-L-serine, sodium salt (DPPS, Na); The combination chain phospholipid, for example 1-palmityl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), 1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, sodium salt (POPG, Na), 1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, ammonium salt (POPG, NH
4); Lysophosphatide class, for example 1-palmityl-2-haemolysis-sn-glycerol-3-phosphocholine (P-lyso-PC), 1-stearoyl-2-haemolysis-sn-glycerol-3-phosphocholine (S-lyso-PC); The ethylene glycol phospholipid, N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DPPE for example, 1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DPPE, 1,2-palmityl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 750)-MPEG-750-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt, N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DSPE, 1,2-distearyl-sn-glycerol-3-phosphate ethanolamine, sodium salt etc.
In the microemulsion of the present invention, the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1: 3-10: 30-80: 20-50, preferred 1: 3-8: 30-50: 20-40, preferred especially 1: 4-6: 35-45: 25-30.。
In certain embodiments, Emulsion of the present invention can also further comprise other suitable acceptable accessories, include but not limited to acidify, alkalization, buffering, chelating, compound and stabilizing agent, antioxidant and microbial resistance antiseptic, suspension and/or viscosity modifier and other bio-compatibility material or therapeutic agent etc.
Emulsion of the present invention can self emulsifying forms in the glucose injection by above-mentioned bearing taxanes, oils composition, surfactant, the alcoholic acid self-emulsifying composition that contains effective dose joined, and does not need high-shear device.Wherein, described surfactant is phospholipid and polyoxyethylene castor oil.
Preferably, Emulsion of the present invention can join that self emulsifying forms in the glucose injection by the self-emulsifying composition with the above-mentioned bearing taxanes that contains effective dose, oils composition, surfactant, ethanol, lactic acid, does not need high-shear device.Wherein, described surfactant is phospholipid and polyoxyethylene castor oil.
Wherein, described bearing taxanes is paclitaxel and Docetaxel preferably, most preferably is paclitaxel.
In some embodiments, this Emulsion has the particle diameter of 1nm-1000nm, preferably has the particle diameter of 10-800nm, more preferably has the particle diameter of 50-500nm, most preferably has the particle diameter of 50-300nm.
In other concrete embodiments, the average diameter of this Emulsion preferably less than 400nm, is more preferably less than 300nm less than about 500nm, 400nm, 300nm, 200nm, 150nm or 100nm, most preferably less than 200nm.
At last, the present invention also provides a kind of above-mentioned taxol self-emulsifying preparation of compositions method, may further comprise the steps: paclitaxel, oils composition, phospholipid, polyoxyethylene castor oil, ethanol and lactic acid are mixed, after stirring, filter packing.
The content of taxol of compositions unit formulation of the present invention can be 10～300mg, preferred 20～200mg, more preferably 30～100mg.For example, in the compositions unit formulation of the present invention content of taxol can be 10,20,30,50,60,100,150,180,200,300mg.The volume of unit formulation can be 2～60ml, preferred 3～30ml, most preferably 5～20ml.For example, the volume of compositions unit formulation of the present invention can be 2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,20,30,40,50,60ml.Those skilled in the art are according to the volume and the content of medicines of clinical needs and techniques well known unit of adjustment preparation.In the compositions of the present invention, the more former paclitaxel injection of polyoxyethylene castor oil consumption significantly reduces, it only is below 50% of former paclitaxel injection, be preferably below 30% of former paclitaxel injection, and soybean oil, lecithin all have good biocompatibility, main composition branch as the injection fat milk is widely used, and does not see the report of serious toxic and side effects, so this prescription is expected significantly to reduce probability and the degree that anaphylaxis takes place.
Compositions of the present invention can be used for treatment for cancer, and the cancer of preferred therapeutic is ovarian cancer, breast carcinoma, non-small cell carcinoma, a cancer or neck cancer.
Description of drawings
The particle size determination figure of the Emulsion that forms behind the accompanying drawing 1 embodiment of the invention 1 compositions self emulsifying.
Each compositions dilution rear stability comparison diagram in accompanying drawing 2 experimental examples 1 of the present invention.
The paclitaxel crystallization microscopic quantitative criteria that accompanying drawing 3 experimental examples 5 of the present invention are adopted.
The specific embodiment
Following embodiment only is to be used for illustrating the present invention, scope of the present invention is not limited.Those skilled in the art can carry out various corresponding changes according to affiliated field common practise after understanding spirit of the present invention, these all should be within protection scope of the present invention.In content thereafter, unless specialize, described lecithin is egg lecithin.The lecithin that uses in the specific embodiment of the invention is commercially available Lipod E80, certainly, adopts other commercially available lecithin and those skilled in the art also can be used for the present invention and obtain identical technique effect according to the lecithin of prior art for preparing.The particle diameter of the Emulsion that forms behind the product self emulsifying of following examples adopts laser light scattering instrument to measure.
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin 1250g
Lactic acid 5ml
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 2
Paclitaxel 30g
Injection soybean oil 120g
Lecithin 1050g
Lactic acid 4ml
Polyoxyethylene castor oil 750g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 3
Paclitaxel 30g
Injection soybean oil 180g
Lecithin 1350g
Lactic acid 6ml
Polyoxyethylene castor oil 900g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin 1210g
Lactic acid 5ml
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin 968g
Lactic acid 5ml
Polyoxyethylene castor oil 1000g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 6
Paclitaxel 30g
Injection soybean oil 90g
Lecithin 900g
Lactic acid 4ml
Polyoxyethylene castor oil 600g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 7
Paclitaxel 30g
Injection soybean oil 240g
Lecithin 1500g
Lactic acid 6ml
Polyoxyethylene castor oil 1200g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Paclitaxel 30g
Injection soybean oil 300g
Lecithin 2400g
Lactic acid 5ml
Polyoxyethylene castor oil 1500g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Paclitaxel 30g
Injection soybean oil 156.8g
Lecithin 1210g
Lactic acid 5ml
Polyoxyethylene castor oil 790g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Paclitaxel 30g
Injection soybean oil 142.5g
Lecithin 1250g
Lactic acid 5ml
Polyoxyethylene castor oil 750g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 11
Paclitaxel 30g
Injection soybean oil 145g
Lecithin 1300g
Lactic acid 5ml
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 12
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin 1250g
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 13
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin 1250g
Acetic acid 2ml
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 14
Paclitaxel 30g
Injection soybean oil 128g
Lecithin 1089g
Lactic acid 5ml
Polyoxyethylene castor oil 900g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Docetaxel 30g
Injection soybean oil 128g
Lecithin 1089g
Lactic acid 5ml
Polyoxyethylene castor oil 900g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 16
Paclitaxel 30g
Injection soybean oil 90g
Lecithin 900g
Polyoxyethylene castor oil 600g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Embodiment 17
Paclitaxel 30g
Injection soybean oil 300g
Lecithin 2400g
Polyoxyethylene castor oil 1500g
Dehydrated alcohol adds to 6000ml
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.Product is a clear liquid.
Annotate: among the above embodiment 1-17, adopted the dehydrated alcohol standardize solution but not the mode of ethanol weight shows the composition of compositions.In fact, though the consumption of other composition has certain variation in each example composition, through practical measurement, the ethanol weight change that adds among the above embodiment is also little, according to practical situation, for about about 3000g.
The comparative example 1
Paclitaxel 30g
Injection soybean oil 100g
Lecithin 500g
Polyoxyethylene castor oil 1000g
Dehydrated alcohol 500g
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.
The comparative example 2
Paclitaxel 30g
Medium chain length fatty acid triglyceride 138g
Cremophor～EL???????126.5g
Phospholipid 83g
Cholesterol sodium sulfate 8g
Vitamin E 12g
Ethanol 60g
With each composition, ultrasonic, 35 ℃ of stirring and dissolving, mixing.
The comparative example 3
Paclitaxel 30g
Injection soybean oil 80g
Lecithin 562.5g
Pluronic?F68????????????562.5g
Polyoxyethylene castor oil 790g
Dehydrated alcohol 800g
Above composition is mixed, and after stirring, is the filtering with microporous membrane of 0.22 μ m with the aperture, packing, promptly.
Experimental example 1
Compositions and each 5ml of commercially available Taxol of getting embodiment 1-3, comparative example 1 and 2 are injected into emulsifying in 50ml 5% glucose solution, measure paclitaxel concentration in the microemulsion, in contrast.Placed 24 hours down for 25 ℃, get above-mentioned microemulsion respectively at 1.5,6,9,12,24 hours, filter the back and measure content of taxol in the microemulsion, compare, calculate content of taxol and change with contrast.The results are shown in accompanying drawing 2.
Experimental example 2 present compositions are to the toleration of various intense environment
1. the yew alcohol micro-emulsion injection is to the toleration of strong illumination
The compositions of embodiment 1 preparation is placed under 4500Lux strong illumination condition, and aspects such as 24 hours stability of clarity before injection appearance luster after 5 days, 10 days (before the emulsifying, after the emulsifying), pH value, the emulsifying, related substance, peroxide number, emulsifying, drug content were compared with 0 day does not have significant change.
Table 1 yew alcohol micro-emulsion injection is to the toleration of strong illumination
2. the yew alcohol micro-emulsion injection is to pyritous toleration
The compositions of embodiment 1 preparation is placed under 60 ℃ of hot conditionss, measures after 0 day, 5 days, 10 days, and data see Table 2.
Table .2 yew alcohol micro-emulsion injection is to the toleration of high temperature (60 ℃)
3. the yew alcohol micro-emulsion injection is to cryogenic toleration
The compositions of embodiment 1 preparation is placed under 2-8 ℃ of condition, after 0 day, 5 days, 10 days its quality is measured, and the results are shown in Table 3.
Table 3 yew alcohol micro-emulsion injection is to cryogenic toleration
Experimental example 3 experimental study that keeps sample for a long time
With the pharmaceutical composition of embodiment 1-3, place 2-8 ℃ of cold room, measured relevant index in the 0th, 3,6,9,24 month.
2-8 ℃ of result of the test that keeps sample for a long time of table 4. yew alcohol micro-emulsion injection
Experimental example 4 hypersensitive tests
Get male guinea pig and be divided into 4 groups at random, 7 every group, be respectively commercially available paclitaxel injection (Taxol
), yew alcohol micro-emulsion injection, negative control (5% glucose solution) behind the yew alcohol micro-emulsion injection behind the compositions self emulsifying of embodiment 1, comparative example's 3 the compositions self emulsifying, the priming dose of commercially available paclitaxel injection, yew alcohol micro-emulsion injection is 2mg/kg, and booster dose is 5mg/kg.Lumbar injection sensitization, totally 3 times, be respectively 0,2,4 day, last injection back the 14th day is administered once by the Cavia porcellus anterior tibial veins and excites.
Observation index and evaluation of result standard: at once to 30 minutes, observe the reaction of every animal, the appearance and the extinction time of symptom in detail after the intravenous injection by table table 5 symptom.And press table 6 and judge the anaphylaxis occurrence degree.Comprehensively judge according to anaphylaxis incidence rate and occurrence degree.The results are shown in Table 7.
Table 5 symptoms of allergic
| 0 is normal | 7 rapid breathing | 14 instability of |
| 1 is restless | 8 urinate | 15 jump |
| 2 |
9 defecation | 16 pant |
| 3 |
10 shed tears | 17 |
| 4 scratch nose | 11 dyspnea | 18 |
| 5 sneezes | 12 wheezing sounds | 19 Cheyne-Stokes respiration |
| 6 coughs | 13 |
20 death |
Table 6. whole body sensitization evaluation criterion
????????????????????????????????????????????????
Symptoms of allergic anaphylaxis intensity
????????????????????????????????????????????????
0-anaphylaxis feminine gender
1-4 symptom+anaphylaxis is weak positive
The 5-10 symptom ++ the anaphylaxis positive
The 11-19 symptom +++anaphylaxis strong positive
20 ++ ++ the extremely strong positive of anaphylaxis
????????????????????????????????????????????????
Table 7 Cavia porcellus sensitization experimental result
*Death in the 8th day after first time sensitization
Experimental example 5 self emulsifyings form rear stability research
Get each 5ml of pharmaceutical composition of embodiment 1,4,6,7,11,12 and comparative example 1-3 preparation, join among the 5% glucose injection 50ml, place under the room temperature, adopt the microscopic examination method, the quality of prescription is judged in the paclitaxel crystallization of separating out in microscopically direct observation yew alcohol micro-emulsion liquid by the result who observes under different time points.
The crystallization of paclitaxel in microemulsion is needle-like or bunch shape usually, has obvious characteristic, easy and other materials differentiations at microscopically.Set up the crystalline microscopic examination standard of paclitaxel according to these characteristics, the paclitaxel crystallization degree is quantified as " ,+/-,+, ++, +++, ++ ++ " six grades, wherein be judged as the positive more than "+".In order to avoid take a sample difference and omission as far as possible, viewing area is enlarged about 25 field ranges, to observed crystallization number count, and according to criteria grade shown in table 8 and the accompanying drawing 3.The results are shown in Table 9.
Table 8 microscopic examination criterion
Table 9 microemulsion Study on Stability
Claims (20)
1. the self-emulsifying drug compositions of a taxone, the bearing taxanes, oils composition, surfactant and the ethanol that comprise effective dose, wherein said surfactant is phospholipid and polyoxyethylene castor oil, and the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1: 3-10: 30-80: 20-50.
2. according to the pharmaceutical composition of claim 1, wherein the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1 in the compositions: 3-8: 30-50: 20-40.
3. according to the pharmaceutical composition of claim 2, wherein the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1 in the compositions: 4-6: 35-45: 25-30.
4. according to each pharmaceutical composition among the claim 1-3, bearing taxanes wherein is paclitaxel or Docetaxel.
5. according to the pharmaceutical composition of claim 4, bearing taxanes wherein is a paclitaxel.
6. according to the pharmaceutical composition of above each claim, also further contain lactic acid in the compositions.
7. according to the pharmaceutical composition of above each claim, described oils composition is vegetable oil, MCT class, animal oil or its mixture.
8. according to the pharmaceutical composition of claim 7, vegetable oil wherein is soybean oil, almond oil, borage oil, black currant pip oil, Oleum Ricini, Semen Maydis oil, safflower oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, cupu oil, Petiolus Trachycarpi oil, Canola oil, Semen Lini oil, Oleum Camelliae, safflower oil, Oleum Gossypii semen, Radix Oenotherae erythrosepalae oil or its mixture.
9. pharmaceutical composition according to Claim 8, vegetable oil wherein is a soybean oil.
10. according to the pharmaceutical composition of above each claim, phospholipid wherein is soybean lecithin, egg lecithin, hydrogenated soy phosphatidyl choline, hydrogenation egg lecithin, sphingosine, ganglioside and phytosphingosine.
11. according to the pharmaceutical composition of claim 10, phospholipid wherein is egg lecithin.
12. according to the pharmaceutical composition of above each claim, comprise following composition, wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 0.2～10%
Lecithin 10～55%
Polyoxyethylene castor oil 5～55%
Lactic acid 0.01～0.3%
Ethanol 30～70%.
13. according to claim 12 compositions, comprise following composition, wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 1～10%
Lecithin 15～40%
Polyoxyethylene castor oil 10～30%
Lactic acid 0.02～0.2%
Ethanol 40～70%.
14. according to the pharmaceutical composition of claim 13, comprise following composition, wherein each composition is by weight percentage:
Taxoids 0.1～1%
Soybean oil 2～3%
Lecithin 18～25%
Polyoxyethylene castor oil 10～20%
Lactic acid 0.05～0.2%
Ethanol 50～70%.
15., be prepared from by following composition according to the pharmaceutical composition of claim 14:
Paclitaxel 30g
Injection soybean oil 147.5g
Lecithin (Lipod E80) 1250g
Lactic acid 5ml
Polyoxyethylene castor oil 800g
Dehydrated alcohol adds to 6000ml.
16. the microemulsion of a bearing taxanes, the bearing taxanes, oils composition, surfactant, ethanol and the D/W that comprise effective dose, wherein said surfactant is phospholipid and polyoxyethylene castor oil, and the weight ratio of bearing taxanes, oils composition, phospholipid and polyoxyethylene castor oil is 1: 3-10: 30-80: 20-50.
17., also further comprise lactic acid in the Emulsion according to the microemulsion of claim 16.
18. according to the microemulsion of claim 16 or 17, this Emulsion is that the self-emulsifying drug compositions with claim 1-15 joins that self emulsifying forms in the D/W.
19. according to the microemulsion of claim 18, wherein Emulsion can not separated out precipitation at ambient temperature, keeps stablizing more than 12 hours.
20. the preparation method of self-emulsifying composition among the claim 1-16 may further comprise the steps: each composition is mixed, after stirring, filter packing.
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| CN201010124634XA CN101829052B (en) | 2010-03-16 | 2010-03-16 | Self-emulsifying preparation of taxane compound and preparation method thereof |
| PCT/CN2011/000398 WO2011113301A1 (en) | 2010-03-16 | 2011-03-14 | Self-emulsifying formulation of taxanes and preparation method thereof |
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| WO2014178789A1 (en) * | 2013-05-03 | 2014-11-06 | Lipidor Ab | Topical composition and carrier for administration of pharmaceutical or cosmetic active ingredients |
| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
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| CN109589305A (en) * | 2018-12-03 | 2019-04-09 | 昆明积大制药股份有限公司 | Docetaxel-ciclosporin A contains self-emulsifiable preparation and preparation method thereof altogether |
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| CN102670504B (en) * | 2012-05-22 | 2015-04-15 | 北京大学 | CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation |
| CN102670504A (en) * | 2012-05-22 | 2012-09-19 | 北京大学 | CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation |
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| WO2014178789A1 (en) * | 2013-05-03 | 2014-11-06 | Lipidor Ab | Topical composition and carrier for administration of pharmaceutical or cosmetic active ingredients |
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| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
| WO2016071365A1 (en) * | 2014-11-03 | 2016-05-12 | Spherium Biomed, S.L. | Topical pharmaceutical compositions of paclitaxel |
| CN109589305A (en) * | 2018-12-03 | 2019-04-09 | 昆明积大制药股份有限公司 | Docetaxel-ciclosporin A contains self-emulsifiable preparation and preparation method thereof altogether |
| CN109589305B (en) * | 2018-12-03 | 2021-03-19 | 昆明积大制药股份有限公司 | Docetaxel-cyclosporine A co-entrapped self-emulsifying preparation and preparation method thereof |
| CN113425683A (en) * | 2021-08-19 | 2021-09-24 | 谢彩华 | Triazamidine sustained-release injection and preparation method thereof |
| CN113425683B (en) * | 2021-08-19 | 2022-09-20 | 谢彩华 | Triazamidine sustained-release injection and preparation method thereof |
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| WO2011113301A1 (en) | 2011-09-22 |
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Denomination of invention: Self-emulsifying preparation of taxane compound and preparation method thereof Effective date of registration: 20180801 Granted publication date: 20111214 Pledgee: Haidian Beijing science and technology enterprise financing Company limited by guarantee Pledgor: YINGU PHARMACEUTICAL Co.,Ltd. Registration number: 2018990000636 |
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Date of cancellation: 20190715 Granted publication date: 20111214 Pledgee: Haidian Beijing science and technology enterprise financing Company limited by guarantee Pledgor: YINGU PHARMACEUTICAL Co.,Ltd. Registration number: 2018990000636 |
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Address after: No.18a, No.13, Jingsheng South 4th Street, Jinqiao Science and technology industrial base, Tongzhou Park, Zhongguancun Science and Technology Park, Tongzhou District, Beijing Patentee after: YINGU PHARMACEUTICAL Co.,Ltd. Address before: Room 2303, Yingu Building, No. 9 North Fourth Ring West Road, Haidian District, Beijing, 100190 Patentee before: YINGU PHARMACEUTICAL Co.,Ltd. |
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