KR100983377B1 - Method for preparing a stable pharmaceutical composition containing paclitaxel - Google Patents
Method for preparing a stable pharmaceutical composition containing paclitaxel Download PDFInfo
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- KR100983377B1 KR100983377B1 KR1020090079338A KR20090079338A KR100983377B1 KR 100983377 B1 KR100983377 B1 KR 100983377B1 KR 1020090079338 A KR1020090079338 A KR 1020090079338A KR 20090079338 A KR20090079338 A KR 20090079338A KR 100983377 B1 KR100983377 B1 KR 100983377B1
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- paclitaxel
- cyclodextrin
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- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 37
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 37
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 31
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- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 21
- 239000007972 injectable composition Substances 0.000 claims abstract description 13
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000003860 storage Methods 0.000 claims abstract description 12
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 8
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
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- 230000006641 stabilisation Effects 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
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- 206010006187 Breast cancer Diseases 0.000 description 1
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
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- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
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- 230000000996 additive effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
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- 239000008121 dextrose Substances 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물의 제조방법에 관한 것으로서, 더욱 상세하게는 비수용성 화합물인 파클리탁셀을 수용액 내에서 안정화시켜 제제화하기 위하여 시클로덱스트린과 폴리비닐피롤리돈(PVP)의 수용성 고분자를 증류수에 혼합하여 용해시키고 이를 동결건조하여 동결건조 조성물을 제조함으로써 기존 파클리탁셀 제제보다 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물의 제조방법에 관한 것이다.The present invention relates to a method for preparing a paclitaxel-containing injectable composition having excellent storage stability, and more particularly, to a water-soluble polymer of cyclodextrin and polyvinylpyrrolidone (PVP) for stabilizing and formulating a non-aqueous compound paclitaxel in an aqueous solution. The present invention relates to a method for preparing a paclitaxel-containing injectable composition having better storage stability than a conventional paclitaxel preparation by mixing and dissolving in distilled water and lyophilizing the same to prepare a lyophilized composition.
파클리탁셀, 시클로덱스트린, 수용성 고분자 Paclitaxel, Cyclodextrins, Water Soluble Polymers
Description
본 발명은 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물의 제조방법에 관한 것으로서, 더욱 상세하게는 비수용성 화합물인 파클리탁셀을 수용액 내에서 안정화시켜 제제화하기 위하여 시클로덱스트린과 폴리비닐피롤리돈(PVP)의 수용성 고분자를 증류수에 혼합하여 용해시키고 이를 동결건조하여 동결건조 조성물을 제조함으로써 기존 파클리탁셀 제제보다 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물의 제조방법에 관한 것이다.The present invention relates to a method for preparing a paclitaxel-containing injectable composition having excellent storage stability, and more particularly, to a water-soluble polymer of cyclodextrin and polyvinylpyrrolidone (PVP) for stabilizing and formulating a non-aqueous compound paclitaxel in an aqueous solution. The present invention relates to a method for preparing a paclitaxel-containing injectable composition having better storage stability than a conventional paclitaxel preparation by mixing and dissolving in distilled water and lyophilizing the same to prepare a lyophilized composition.
파클리탁셀은 택솔(Taxol)의 이름으로 잘 알려져 있다. 이 생성물은 악성 종양에 대해 생체 내에서 실질적인 활성을 보이며 비소세포 폐암, 난소암, 유방암 등에 있어 탁월한 효과를 지니고 있는 것으로 알려져 있다Paclitaxel is well known by the name of Taxol. This product has been shown to have substantial activity in vivo against malignant tumors and has excellent effects on non-small cell lung cancer, ovarian cancer and breast cancer.
불행하게도 파클리탁셀은 계면활성제 및 에탄올을 기재로 한 주사용 제제를 위한 배합물을 제조한 것을 필요로 할 만큼 낮은 수용성 용해도를 가진다. 에탄올은 이들을 가용화시킬 수 있는 가장 좋은 용매이다. Unfortunately paclitaxel has a water solubility that is low enough to require the preparation of a formulation for injectable preparations based on surfactants and ethanol. Ethanol is the best solvent to solubilize them.
예컨대, 1990년 8월 1일에 국영 암 연구소의 저널 82권, 15번, 1247-1529p. 에 보인 Rowinsky, Lorraine Cazenave 및 Donehower에 의한 출판물에 따르면, 에탄올과 크레모포어 이엘(Cremophor EL)로 구성되는 용매 혼합물 내에 택솔 약 6 mg/ml을 함유한 원액으로 칭하는 첫 번째 용액이 제조되어, 주사시 이 용액은 덱스트로스를 함유하는 관류액 또는 생리 식염수와 혼합되며 물리적 관점 및 화학적 관점 모두로부터 안정한 혼합물을 얻기 위하여 관류 용액 내 유효성분의 농도를 약 0.3 ~ 0.6 mg/ml의 농도까지 제한하는 것이 필요하다고 서술한다. See, for example, Journal of the National Cancer Institute, Vol. 82, No. 15, 1247-1529p. According to published publications by Rowinsky, Lorraine Cazenave and Donehower, a first solution was prepared called a stock solution containing about 6 mg / ml of taxol in a solvent mixture consisting of ethanol and Cremophor EL and injected. The solution is mixed with a perfusion solution containing dextrose or physiological saline solution and it is recommended to limit the concentration of the active ingredient in the perfusion solution to a concentration of about 0.3 to 0.6 mg / ml to obtain a stable mixture from both physical and chemical viewpoints. State that it is necessary.
그러나 항암 치료에 유용하게 사용하기 위해서는 충분한 투여량의 유효성분을 주사할 수 있는 것이 바람직하고, 이 목적을 위하여 임상의학자는 약 0.3 ~ 1 mg/ml 농도의 유효 성분을 주사하기를 원한다. 이들 투여량 이상에서는 주로 크레모포어에 기인하는 조정하기 어려운 아나필라틱 쇼크(anaphylactic shock) 현상이 나타난다. 또한, 이 출판물에 따르면 상기 농도의 유효성분을 주사하기 위해서는 에탄올이 상당량 함께 투여되므로 알콜 중독의 발현을 야기하는 결과를 가져온다고 언급하고 있다. However, it is desirable to be able to inject a sufficient dose of the active ingredient to be useful for anticancer treatment, and for this purpose, the clinician wants to inject the active ingredient at a concentration of about 0.3 to 1 mg / ml. Above these doses, an uncontrolled anaphylactic shock, mainly due to cremophores, is present. The publication also notes that a significant amount of ethanol is administered together to inject the active ingredient at this concentration, resulting in the expression of alcoholism.
특허 WO 98/30205는 계면 활성제로 페길레이티드 비타민 E(PEGylated Vitamin E)에 의한 방법을 개시했고, US2004/0127551에서는 비타민 E 티피지에스 (Vitamin E TPGS, d-alpha-tocopheryl polyethylene glycol 1000 succinate)를 이용하는 방법을 개시하였으나, 높은 농도의 유효성분을 안정적으로 함유하는 조성물을 제조하지 못했다. Patent WO 98/30205 discloses a method by PEGylated Vitamin E as a surfactant, and US2004 / 0127551 discloses Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate). Although the method of using was disclosed, the composition containing the high concentration of the active ingredient stably was not manufactured.
한국 등록 특허 제310839호에서는 폴리비닐피롤리돈을 혼합한 혼합 매트릭스를 제조하여 이를 무수에탄올과 폴리옥시에틸렌 글리세롤 리시노레이트, 폴리소르 베이트 80, 무수에탄올, 폴리에틸렌글리콜 등의 용제와 혼합하여 주사액을 제조하는 방법을 개시하였다. In Korean Patent No. 310839, a mixed matrix obtained by mixing polyvinylpyrrolidone is prepared and mixed with a solvent such as anhydrous ethanol and polyoxyethylene glycerol ricinolate, polysorbate 80, anhydrous ethanol, polyethylene glycol, and the like to inject the injection solution. Disclosed is a method of preparation.
그러나 상기 발명에서도 무수에탄올과 폴리소르베이트 80과 같이 알콜 중독이나 과민성 부작용을 유발할 수 있는 물질이 함유된다는 단점이 있다. However, the present invention also has a disadvantage that it contains a substance that can cause alcoholism or hypersensitivity side effects, such as anhydrous ethanol and polysorbate 80.
1997년에 출원한 특허 WO 99/24073에서는 상기의 계면 활성제를 사용하지 않고 시클로덱스트린을 이용하여 파클리탁셀의 수용성 용해도를 증가시켰다. 보다 상세하게는, 파클리탁셀을 소량의 에탄올에 용해하여 이를 아세틸 감마 시클로덱스트린(Ac-gamma-CD) 또는 히드록시프로펠메틸 베타 시클로덱스트린(HP-beta-CD)의 5% 덱스트로스 용액에 넣고 증발 또는 임의의 적절한 방법에 의해 에탄올을 최대한 제거한 후 이를 동결 건조하여 조성물을 얻었다. 이때 유효성분과 시클로덱스트린의 비율은 중량비로 1:25 내지 1:400이 적합하다. 이와 같이 얻어진 조성물을 5% 덱스트로스 용액에 다시 희석한 관류액의 농도는 0.3 내지 1.2 mg/ml로 72시간 이상의 물리적 안정도를 가지고 있다고 언급하고 있다. Patent WO 99/24073, filed in 1997, uses cyclodextrin to increase the water-soluble solubility of paclitaxel without the use of these surfactants. More specifically, paclitaxel is dissolved in a small amount of ethanol and evaporated in a 5% dextrose solution of acetyl gamma cyclodextrin (Ac-gamma-CD) or hydroxypropelmethyl beta cyclodextrin (HP-beta-CD). Or ethanol as much as possible by any suitable method and then lyophilized to obtain the composition. At this time, the ratio of the active ingredient and cyclodextrin is suitably 1:25 to 1: 400 by weight. It is mentioned that the concentration of the perfusate in which the composition thus obtained was diluted again in the 5% dextrose solution was 0.3 to 1.2 mg / ml, and has a physical stability of 72 hours or more.
그러나, 상기의 발명에 의한 공침 화합물의 희석액은 오히려 유효성분의 농도가 낮을 경우에는 침전물이 형성되거나 공침 화합물을 용해하거나 희석하여 사용할 경우 물리적 안정성이 떨어지는 단점이 있다. However, the diluent of the coprecipitation compound according to the present invention has a disadvantage in that physical stability is lower when a precipitate is formed or when the coprecipitation compound is dissolved or diluted when the concentration of the active ingredient is low.
이에, 본 발명자들은 비수용성 화합물인 파클리탁셀을 수용액 내에서 안정화시켜 제제화하기 위하여 파클리탁셀을 히드록시프로필 베타 시클로덱스트린 및 폴리비닐피롤리돈(PVP)의 수용성 고분자와 함께 증류수에 혼합하여 용해시키고 이를 동결건조하여 동결건조 조성물을 제조함으로써 기존 제제보다 용해도가 높고 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물을 제조함으로써 본 발명을 완성하게 되었다. Accordingly, the present inventors mixed and dissolved paclitaxel in distilled water together with a water-soluble polymer of hydroxypropyl beta cyclodextrin and polyvinylpyrrolidone (PVP) in order to formulate paclitaxel, which is a water-insoluble compound, in an aqueous solution. The present invention was completed by preparing a freeze-dried composition containing a paclitaxel-containing injectable composition having higher solubility and storage stability than a conventional formulation.
따라서, 본 발명은 저장안정성이 우수한 파클리탁셀 함유 주사제 조성물의 제조방법을 제공하는 데 그 목적이 있다. Accordingly, an object of the present invention is to provide a method for preparing a paclitaxel-containing injectable composition having excellent storage stability.
본 발명은 The present invention
1) 파클리탁셀, 시클로덱스트린 및 폴리비닐피롤리돈(PVP)의 수용성 고분자를 증류수에 혼합하는 단계;1) mixing water-soluble polymers of paclitaxel, cyclodextrin and polyvinylpyrrolidone (PVP) in distilled water;
2) 상기 혼합액을 교반하여 용해시키고 동결건조하여 동결건조 조성물을 제조하는 단계; 및2) preparing a lyophilized composition by stirring and dissolving the mixed solution and lyophilizing; And
3) 상기 동결건조 조성물을 덱스트로스 용액이나 생리 식염수에 희석하여 주사제 조성물을 제조하는 단계를 포함하는 저장 안정성이 우수한 파클리탁셀 함유 주사제 조성물을 제조하는 방법을 그 특징으로 한다.3) a method of preparing a paclitaxel-containing injectable composition having excellent storage stability, which comprises preparing the injectable composition by diluting the lyophilized composition in dextrose solution or physiological saline.
본 발명에 따른 파클리탁셀 함유 주사제 조성물은 원료 자체의 탁월한 저장안정성을 확보함으로써 장기간 저장이 가능하고 주사제로 용이하며, 생산 공정 중 발생할 수 있는 온도 및 습도의 영향에도 분해되지 않고 견딜 수 있는 효과가 있다. 또한, 최종 주사제 조성물 내에 에탄올과 폴리소르베이트 성분이 존재하지 않아 부작용이 거의 없다는 장점을 갖는다. The paclitaxel-containing injectable composition according to the present invention can be stored for a long time by securing excellent storage stability of the raw material itself, and is easy to use as an injectable, and has an effect that can withstand the effects of temperature and humidity that may occur during the production process without being degraded. In addition, the absence of ethanol and polysorbate components in the final injection composition has the advantage that there are almost no side effects.
이와 같은 본 발명을 상세하게 설명하면 다음과 같다.The present invention will be described in detail as follows.
본 발명은 파클리탁셀을 시클로덱스트린을 사용하여 안정화시키는 것으로, 파클리탁셀을 폴리비닐피롤리돈(PVP)의 수용성 고분자가 첨가된 증류수 중에서 반응시키며, 에탄올이나 폴리소르베이트와 같은 부작용을 일으키는 첨가제를 사용하지 않고 높은 농도의 주사제 원액을 제조하는 데 그 특징이 있다. The present invention stabilizes paclitaxel using cyclodextrin, and reacts paclitaxel in distilled water to which a water-soluble polymer of polyvinylpyrrolidone (PVP) is added, without using an additive causing side effects such as ethanol or polysorbate. It is characterized by the preparation of high concentrations of injection stock solutions.
먼저, 본 발명에 따른 파클리탁셀 함유 주사제 조성물을 제조하는 과정을 상세히 설명하고자 한다. First, the process of preparing the paclitaxel-containing injectable composition according to the present invention will be described in detail.
1) 단계는 파클리탁셀, 시클로덱스트린 및 폴리비닐피롤리돈(PVP)의 수용성 고분자를 증류수에 혼합하는 단계이다.Step 1) is mixing water-soluble polymers of paclitaxel, cyclodextrin and polyvinylpyrrolidone (PVP) in distilled water.
본 발명에서 파클리탁셀은 프리 폼(free form, 무염) 또는 이의 염의 형태로 사용된다.Paclitaxel is used in the present invention in the form of a free form (free salt) or a salt thereof.
시클로덱스트린류는 구조적으로 일정크기의 소수성 동공을 가지고 있어, 이 동공에 소수성 화합물들을 포접시켜 외부환경으로부터 보호하는 기능을 갖는다. 그 성질 및 크기에 따라 α-시클로덱스트린, β-시클로덱스트린, γ-시클로덱스트 린으로 분류되는데, 본 발명에서 사용될 수 있는 시클로덱스트린류로는 상기 3종류 외에도 시클로덱스트린 유도체를 모두 포함하며, 바람직하게는 동공의 지름이 6.0 ∼ 6.5 Å에 이르는 β-시클로덱스트린류 또는 이의 유도체가 적절하다. 보다 바람직하게는 히드록시프로필 베타 시클로덱스트린이 적절하다. 시클로덱스트린은 파클리탁셀 1 중량부에 대하여 5 ~ 400 중량부를 사용하는 것이 바람직하며, 더욱 바람직하게는 50 ~ 200 중량부를 사용하는 것이 좋다. 만약 시클로덱스트린을 너무 많이 사용하면 원액의 점도가 너무 높아지고, 너무 적게 사용하면 적절한 안정성을 확보하지 못하는 문제점이 있다. 히드록시프로필 베타 시클로덱스트린은 분자치환수(MS)가 0.2 ~ 1.0이 적절하며, 바람직하게는 0.4 ~ 0.8이 적절하다. 분자치환수가 너무 낮으면 용해도가 떨어지고, 너무 높으면 점도가 높아져 다루기 어려운 문제점이 있다. 상기 분자치환수(MS, molar substitution)는 몰 치환도로서, 글루코스 단위 당 치환체의 몰 평균수를 의미한다[국내 특허 출원 제2001-72412호 참조].Cyclodextrins structurally have a hydrophobic pupil of a certain size, and have a function of encapsulating hydrophobic compounds in the pupil to protect it from the external environment. According to the nature and size thereof, it is classified into α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The cyclodextrins that can be used in the present invention include all cyclodextrin derivatives in addition to the above three types, and are preferred. Preferably, β-cyclodextrins or derivatives thereof having a diameter of 6.0 to 6.5 mm 3 are suitable. More preferably hydroxypropyl beta cyclodextrin is suitable. The cyclodextrin is preferably used 5 parts by weight to 400 parts by weight with respect to 1 part by weight of paclitaxel, and more preferably 50 parts by weight to 200 parts by weight. If the cyclodextrin is used too much, the viscosity of the stock solution is too high, and if it is used too little, there is a problem in that it does not secure adequate stability. In the hydroxypropyl beta cyclodextrin, the molecular substitution number (MS) is appropriately 0.2 to 1.0, preferably 0.4 to 0.8. If the molecular substitution number is too low, the solubility is lowered, if too high, there is a problem that the viscosity is difficult to handle. The molar substitution (MS) is a molar substitution degree, and means a molar average number of substituents per glucose unit (see Korean Patent Application No. 2001-72412).
또한, 본 발명에서 사용하는 수용성 고분자는 반응 용액 내에서 가용성과 안정성을 증가시키며 통상적으로 사용되는 것으로는 폴리에틸렌글리콜(PEG), 폴리비닐피롤리돈(PVP), 카르복시메틸셀룰로오스(CMC), 히드록시프로필셀룰로오스(HPC), 히드록시메틸셀룰로오스(HMC), 히드록시에틸셀룰로오스(HEC), 히드록시프로필메틸 셀룰로오스(HPMC) 및 히드록시프로필에틸 셀룰로오스(HPEC) 등이 있으며, 본 발명에서 바람직하기로는 폴리비닐피롤리돈(PVP)을 사용한다. 폴리비닐피롤리돈의 경우에는 K-값이 10 ~ 20의 범위에서 선택되는 것이 더욱 바람직하다. 만일 폴리비닐피롤리돈의 K-값이 10 미만일 경우에는 용해도와 안정성이 현저히 낮아지는 문제가 있고, 20 초과시에는 점도가 높아 다루기 어려우며 주사제로 개발이 어려운 문제가 있을 수 있다. 상기 K-값은 분자량 함수를 나타내며, 25 ℃에서 세관형 점도계에 의해 측정된 상대적 점도로, Kline, G.M.의 문헌[“Polyvinylpyrollidone:, Modern Plastics p157(Nov. 1945)]에 기술된 피켄처(Fickentscher)의 등식[수학식 1]에 따라 계산된다.In addition, the water-soluble polymer used in the present invention increases the solubility and stability in the reaction solution, and commonly used polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxy Propyl cellulose (HPC), hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC) and hydroxypropylethyl cellulose (HPEC), and the like. Vinylpyrrolidone (PVP) is used. In the case of polyvinylpyrrolidone, it is more preferable that the K-value is selected in the range of 10-20. If the K-value of the polyvinylpyrrolidone is less than 10, there is a problem that the solubility and stability is significantly lowered, and when it exceeds 20, the viscosity is difficult to handle and difficult to develop as an injection. The K-value represents the molecular weight function and is the relative viscosity measured by a tubular viscometer at 25 ° C., which is described in Kline, GM, “Polyvinylpyrollidone: Modern Plastics p157 (Nov. 1945). Is calculated according to Equation 1).
c: 수성의 폴리비닐피롤리돈 용액 내 폴리비닐피롤리돈의 함량(w/w%)c: content of polyvinylpyrrolidone in aqueous polyvinylpyrrolidone solution (w / w%)
한편, 상기 수용성 고분자의 함량은 파클리탁셀 1 중량부에 대하여 0.1 ∼ 100 중량부가 바람직하며, 1.0 ∼ 5.0 중량부가 더욱 바람직하다. 만약 수용성 고분자를 0.1 중량부 미만으로 사용하면 가용화 및 안정화 효과가 줄게 되며, 100 중량부 초과 사용하면 반응용액의 점도가 지나치게 상승하여 여과, 세척이 불가능하여 조성물의 용해도가 낮아지는 단점이 있다. On the other hand, the content of the water-soluble polymer is preferably 0.1 to 100 parts by weight, more preferably 1.0 to 5.0 parts by weight with respect to 1 part by weight of paclitaxel. If the water-soluble polymer is used in less than 0.1 parts by weight, solubilization and stabilization effect is reduced, when used in excess of 100 parts by weight of the viscosity of the reaction solution is too high, there is a disadvantage that the solubility of the composition is lowered because the filtration, washing is impossible.
또한, 본 발명에서 사용하는 용액으로는 관류액으로 사용 가능한 모든 용액이 가능하며, 바람직하게는 증류수가 적절하다. In addition, as the solution used by this invention, all the solutions which can be used as a perfusate liquid are possible, Preferably distilled water is suitable.
2) 단계에서는 상기 혼합액을 가열, 교반하여 용해시키며 안정화를 유도하고, 동결 건조를 통하여 동결건조 조성물을 제조하는 단계로서, 상기 교반은 20 ～ 50 ℃ 온도 범위에서 수행하며, 바람직하게는 20 ~ 25 ℃에서 수행한다. 동결 건조를 위해 혼합액을 저온에서 얼린 후 -50 ~ -60 ℃에서 감압하여 동결 건조하여 백색 내지 노란색의 동결건조 조성물을 제조한다. In step 2), the mixed solution is heated, stirred to dissolve and induces stabilization, and a freeze-dried composition is prepared by freeze-drying. The stirring is performed at a temperature in a range of 20 to 50 ° C., preferably 20 to 25 It is carried out at ℃. The freeze-dried mixture is frozen at low temperature, and then freeze-dried at -50 to -60 ° C to prepare a freeze-dried composition of white to yellow color.
3) 단계는 상기 동결건조 조성물을 희석하는 단계로서, 희석액으로는 주사액으로 사용가능한 모든 용액이 적절하며, 바람직하게는 5 ~ 10% 덱스트로스 용액이나 0.9% 생리 식염수가 적절하다. 희석 농도는 제조 방법에 따라 다양하게 희석하여 원액을 제조하는데 파클리탁셀의 농도로 1 ~ 10.0 mg/ml이 적절하며, 보다 바람직하게는 4 ~ 8 mg/ml이 적절하다. Step 3) is a step of diluting the lyophilized composition, and any solution usable as an injection solution is appropriate as the diluent, preferably 5 to 10% dextrose solution or 0.9% physiological saline. Dilution concentration of 1 ~ 10.0 mg / ml is appropriate for the concentration of paclitaxel to prepare a stock solution by varying the dilution depending on the preparation method, more preferably 4 ~ 8 mg / ml.
이렇게 얻은 주사제 조성물의 원액은 원료자체의 온도 및 습도에 대한 탁월한 저장안정성을 확보함으로써 장기간 저장이 가능하고 주사제로 제제화가 용이하며, 생산공정 중 발생할 수 있는 온도 및 습도의 영향에도 분해되지 않고 견딜 수 있는 효과가 있다. The stock solution of the injectable composition thus obtained can be stored for a long time by securing excellent storage stability against temperature and humidity of the raw material itself, and can be easily formulated into an injectable, and can withstand the effects of temperature and humidity that may occur during the production process without being degraded. It has an effect.
또한, 최종 주사제 조성물에는 에탄올 성분이나 과민성 부작용을 일으킬만한 첨가제가 존재하지 않으므로 인체에 사용하는 데 전혀 해가 되지 않는다. In addition, the final injectable composition does not have any ethanol component or additives that may cause sensitizing side effects, and therefore, are not harmful to use in the human body.
이하, 본 발명은 다음 실시예에 의거하여 더욱 상세히 설명하겠는바, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.
실시예Example 1 One
파클리탁셀 10 mg, 폴리비닐피롤리돈 K-12 30 mg, 히드록시프로필 베타 시클 로덱스트린(MS=0.6) 1.0 g의 혼합물에 증류수 5 ml를 넣고 상온에서 균질하게 교반하여 용해시켰다. 이때의 용해도는 1.7 mg/ml였다. 완전히 용해되면 0.22 마이크로미터 여과지를 통과시켜 얻은 여과액을 -80 ℃로 냉각시킨 후 동결 건조하여 동결건조 조성물을 얻었다. 얻어진 동결건조 조성물을 5% 덱스트로스 용액 5 ml에 완전히 용해시켜 원액을 제조하였다. 5 ml of distilled water was added to a mixture of 10 mg of paclitaxel, 30 mg of polyvinylpyrrolidone K-12, and 1.0 g of hydroxypropyl beta cyclodextrin (MS = 0.6), followed by homogeneous stirring at room temperature to dissolve. The solubility at this time was 1.7 mg / ml. After complete dissolution, the filtrate obtained by passing through a 0.22 micron filter paper was cooled to -80 ° C and lyophilized to obtain a lyophilized composition. The resulting lyophilized composition was completely dissolved in 5 ml of 5% dextrose solution to prepare a stock solution.
실시예Example 2 2
파클리탁셀 30 mg, 폴리비닐피롤리돈 K-12 90 mg, 히드록시프로필 베타 시클로덱스트린(MS=0.6) 5.0 g의 혼합물에 증류수 5 ml를 넣고 상온에서 균질하게 교반하여 용해시켰다. 이때의 용해도는 3.0 mg/ml였다. 완전히 용해되면 0.22 마이크로미터 여과지를 통과시켜 얻은 여과액을 -80 ℃로 냉각시킨 후 동결 건조하여 동결건조 조성물을 얻었다. 얻어진 동결건조 조성물을 5% 덱스트로스 용액 5 ml에 완전히 용해시켜 원액을 제조하였다. 5 ml of distilled water was added to a mixture of 30 mg of paclitaxel, 90 mg of polyvinylpyrrolidone K-12, and 5.0 g of hydroxypropyl beta cyclodextrin (MS = 0.6), followed by homogeneous stirring at room temperature to dissolve. The solubility at this time was 3.0 mg / ml. After complete dissolution, the filtrate obtained by passing through a 0.22 micron filter paper was cooled to -80 ° C and lyophilized to obtain a lyophilized composition. The resulting lyophilized composition was completely dissolved in 5 ml of 5% dextrose solution to prepare a stock solution.
실시예Example 3 3
파클리탁셀 30 mg, 폴리비닐피롤리돈 K-18 90 mg, 히드록시프로필 베타 시클로덱스트린(MS=0.6) 5.0 g의 혼합물에 증류수 5 ml를 넣고 상온에서 균질하게 교반하여 용해시켰다. 이때의 용해도는 3.0 mg/ml였다. 완전히 용해되면 0.22 마이크로미터 여과지를 통과시켜 얻은 여과액을 -80 ℃로 냉각시킨 후 동결 건조하여 동결건조 조성물을 얻었다. 얻어진 동결건조 조성물을 5% 덱스트로스 용액 5 ml에 완전히 용해시켜 원액을 제조하였다. 5 ml of distilled water was added to a mixture of 30 mg of paclitaxel, 90 mg of polyvinylpyrrolidone K-18, and 5.0 g of hydroxypropyl beta cyclodextrin (MS = 0.6), followed by homogeneous stirring at room temperature to dissolve. The solubility at this time was 3.0 mg / ml. After complete dissolution, the filtrate obtained by passing through a 0.22 micron filter paper was cooled to -80 ° C and lyophilized to obtain a lyophilized composition. The resulting lyophilized composition was completely dissolved in 5 ml of 5% dextrose solution to prepare a stock solution.
비교예Comparative example 1 One
폴리비닐피롤리돈을 사용하지 않는 것 외에 상기 실시예 1과 동일하게 실시하여 흰색의 조성물을 얻었다. A white composition was obtained in the same manner as in Example 1 except that polyvinylpyrrolidone was not used.
시험예Test Example 1: 저장 안정성 시험 1: storage stability test
상기 실시예 1 ~ 3 및 비교예 1의 조성물의 농도와 안정성 시험을 상온 하에서 실시한 후 시간 경과에 따른 초기 대비 함량을 HPLC를 이용하여 측정하였다.After performing the concentration and stability tests of the compositions of Examples 1 to 3 and Comparative Example 1 at room temperature, the initial comparison content over time was measured using HPLC.
(㎎/㎖)Initial concentration
(Mg / ml)
용액 변화96 hours later
Solution change
상기 표 1에 나타낸 바와 같이, 본 발명에 따른 실시예 1 ~ 3의 조성물은 비교예 1에 비해 저장 안정성이 우수한 것으로 확인되었다.As shown in Table 1, the compositions of Examples 1 to 3 according to the present invention was confirmed to have excellent storage stability compared to Comparative Example 1.
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