WO2008119260A1 - A medicinal composition of carmustine, preparation method and application - Google Patents

A medicinal composition of carmustine, preparation method and application Download PDF

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Publication number
WO2008119260A1
WO2008119260A1 PCT/CN2008/000680 CN2008000680W WO2008119260A1 WO 2008119260 A1 WO2008119260 A1 WO 2008119260A1 CN 2008000680 W CN2008000680 W CN 2008000680W WO 2008119260 A1 WO2008119260 A1 WO 2008119260A1
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Prior art keywords
acid
pharmaceutical composition
composition according
tween
carmustine
Prior art date
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PCT/CN2008/000680
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French (fr)
Chinese (zh)
Inventor
Shouzhu Hao
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Beijing Century Biocom Pharmaceutical Technology Co., Ltd.
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Publication of WO2008119260A1 publication Critical patent/WO2008119260A1/en

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition of carmustine, a process for the preparation of the composition and use thereof.
  • Carmustine is a nitrosourea-based deuteration agent that covalently binds to DNA to disrupt the structure and function of DNA. It also inhibits DNA polymerase and inhibits DNA and RNA synthesis. It has a non-specific cell cycle, has the strongest effect on cells in the GS transition phase, and has a retarding effect on the S phase, and can also act on the G 2 phase.
  • the drug is characterized by a broad spectrum of anti-tumor, rapid effect, high fat solubility, and incomplete cross-resistance between other sputum agents.
  • Carmustine is able to pass the blood-brain barrier, so it is a brain tumor (glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma), brain metastases It is effective for meningeal leukemia, and is effective for malignant melanoma in combination with other drugs for malignant lymphoma and multiple myeloma.
  • carmustine has extremely low solubility in water and is unstable, so there are certain difficulties in preparing a preparation.
  • the currently marketed carmustine injection is a solution of 125 mg of carmustine raw material dissolved in 2 g of polyethylene glycol 400, which is only valid for 6 months, and needs to be shaded, sealed, and stored in a cold place.
  • Clinical application is extremely inconvenient.
  • the inventors of the present invention have unexpectedly discovered that the addition of one or more of the co-solvent glycerin or polyethylene glycol while adding a certain amount of Tween to the formulation can greatly reduce the amount of Tween and significantly increase Camo.
  • Statin's solubility in water forms a clear, stable composition.
  • the prepared composition can be kept at room temperature for more than 8 hours, and can be directly added to the glucose injection solution or physiological saline to simplify the operation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising carmustine comprising a therapeutically effective amount of carmustine, a Tween-based surfactant, a cosolvent glycerin or a polyethylene glycol.
  • the Tween-based surfactant is selected from the group consisting of Tween-20, Tween-40, and Tween-60.
  • Tween-80 preferably Tween-80.
  • the co-solvent is selected from the group consisting of glycerin, polyethylene glycol or a mixture thereof, and the polyethylene glycol therein has an average molecular weight of 200 to 10,000, preferably PEG200, PEG400, PEG800.
  • the weight ratio of carmustine to Tween surfactant and cosolvent is 1: 2-80: 1-50, preferably 1: 5-50: 2-30, most Preferably 1: 8-20: 3-10
  • the pharmaceutical composition of the present invention can be administered by injection, for example, it can be an injection solution or a dosage form further prepared into a lyophilized powder for injection.
  • concentration of carmustine in the solution of the present invention or before the freeze-dried powder freeze-drying is 5 mg to 50 mg/ml, preferably 10 mg to 30 mg/ml, and the concentration of the co-solvent is 10 mg to 300 mg/ml.
  • concentration is preferably from 30 mg to 100 mg/ml
  • the concentration of the Tween-based surfactant is from 30 mg to 500 mg/ml, preferably from 100 mg to 200 mg/ml.
  • the pharmaceutical composition of the present invention may further comprise other conventional adjuvants for injection or lyophilized powder for injection.
  • These conventional adjuvants include, but are not limited to, lyophilized excipients, preservatives, stabilizers, pH adjusting agents, isotonic agents.
  • the excipient may be selected from, but not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc.; Mannitol or glucose.
  • the preservative may be selected from, but not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben.
  • the stabilizer may be selected from, but not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol, One of methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, disodium edetate Or several.
  • PH regulators include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate, hydrogencarbonate Potassium, amine carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-hexamethylenediamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, sodium metaphosphate One or several of them.
  • the pH of the pharmaceutical composition of the present invention is in the range of 8 or less, preferably pH 3-5, and the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid.
  • the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid.
  • hydrochloric acid, citric acid One or several, preferably hydrochloric acid, citric acid.
  • the composition of the present invention may further contain a bile acid or a salt thereof, and the stability of the composition of the present invention may be increased upon addition.
  • the bile acid is selected from the group consisting of free bile acids, bile acids, or a mixture of the two, and the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid Acid or the like, preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is the carboxy group in the above free bile acid a product of an aldehyde bond with an amino group in a glycine (NCH 2 C00H) or taurine (H 2 NCH 2 C S0:, H) or other amino group-containing compound, preferably glycocholic acid, glycine deoxygenation Cholic acid, glycine
  • the amount of carmustine is not particularly limited and may be any dose which is usually used in the injection.
  • “Therapeutically effective amount” means the usual amount of carmustine to achieve a therapeutic effect, and the doctor can make appropriate adjustments depending on the condition of the patient and other aspects. ⁇ 80mg/ ⁇ rad
  • the content of carmustine in the composition of the present invention is 0. l-80mg/mliff
  • the pharmaceutical composition of carmustine of the present invention may be in the form of a clear injectable aqueous solution or in the form of a lyophilized powder for injection.
  • the frozen powder can be directly dissolved in water for injection, 5% or 10% glucose solution or 0.9% sodium chloride solution to obtain a clear injection.
  • the carmustine composition of the present invention has the following characteristics - the above composition does not require a dedicated solvent, and can be directly diluted with glucose injection or a 0.9% sodium chloride solution and used after dilution.
  • the powder injection is a dry solid mass or powder, which can prevent the influence of carmustine oxidation and hydrolysis in the solution, increase the stability during storage of the product, and greatly extend the expiration date of the preparation.
  • the powder injection preparation process is simple, the quality control is simple, the product stability is good, and the industrial production is convenient.
  • the content of the present invention has a low minimum eutectic point and can be pre-frozen at a temperature of -40 Torr, and has a good appearance.
  • the powder injection can have a moisture content of less than 1%, and is generally controlled within 5%.
  • the prepared solution and the equivalent turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution should be clarified and not deeper than the No. 1 turbidity standard solution.
  • the carmustine injection of the present invention or the lyophilized powder for injection is suitable for intramuscular injection or intravenous injection.
  • the present invention provides a method for improving the solubility of carmustine comprising the steps of mixing and stirring carmustine with a co-solvent, a Tween-based surfactant.
  • the method may further comprise the step of preparing the above mixture into an injection solution, specifically comprising adding an aqueous solvent (aqueous solution, aqueous mannitol solution, or an aqueous solution containing any other auxiliary agent) to the mixture, mixing and adding activated carbon to stir, passing through 0 After the 8 ⁇ ⁇ filter is coarsely decarbonized, Then use 0.22 ⁇ ⁇ filter to remove bacteria and dispense.
  • an aqueous solvent aqueous solution, aqueous mannitol solution, or an aqueous solution containing any other auxiliary agent
  • the concentration of the co-solvent in the injection solution is 10 mg to 300 mg/ml, and the concentration of the tween-based surfactant is 30 mg to 500 mg/ml.
  • the method may further comprise the step of freeze-drying the above-mentioned injection solution to form a lyophilized powder needle, wherein the freeze-drying adopts a conventional freeze-drying technique of a freeze-dried injection in the field of pharmaceuticals, and the person skilled in the art according to the prior art and the textbook The technical teaching in it can be done without creative labor.
  • the method comprises the steps of stirring the carmustine and the co-solvent, the solubilizing agent, and adding the aqueous solvent to a clear solution.
  • the weight ratio of carmustine to Tween surfactant and cosolvent is 1: 2-80: 1-50, preferably 1: 5-50: 2-30, most Preferably it is 1: 8-20: 3-10.
  • a third aspect of the invention is the use of the carmustine composition of the invention for the treatment of brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, compartment)
  • brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, compartment
  • Brain metastases and meningeal leukemia can also be used to treat malignant lymphoma, multiple myeloma, or in combination with other drugs to treat malignant melanoma.
  • the carcinol was stirred for 20 minutes.
  • the solution was added to a solution of 0.1% activated carbon for 20 minutes.
  • the solution was mixed with mannitol, and the solution was added to a solution of mannitol.
  • the solution was de-carbonized by a coarse filtration of 0.8 ⁇ m ⁇ , and then sterilized with a 0.22 ⁇ m filter and dispensed into a vial.
  • the prepared solution and the equivalent turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution.
  • Example 2
  • the carmustine was mixed with polyethylene glycol 400 and Tween 80, stirred, and added to a mannitol aqueous solution, mixed, adjusted to pH 4 with 1% hydrochloric acid, and the solution was added with 0.1% activated carbon for 20 minutes.
  • the solution was de-carbonized by coarse filtration through a 0.8 ⁇ m filter, then sterilized with a 0.22 ⁇ m filter and dispensed into a vial.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella shed lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the turbidity standard is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella shed lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the turbidity standard is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx.
  • the solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution.
  • the carmustine injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity glass. In the tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard solution. .
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx, from the horizontal direction. Observed, compared, the prepared solution was clarified and not deeper than the No. 1 turbidity standard solution.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx.
  • the solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid.
  • the solutions prepared in Examples 1 to 17 were freeze-dried as follows:
  • Pre-freezing The temperature of the product drops to a temperature of 45 ° C, and the sublimation drying can be carried out after 3 hours of heat preservation;
  • Sublimation drying temperature is controlled below 12 ° C;
  • Re-drying The maximum temperature in the re-drying stage is controlled at 35'C, and the weight loss on drying should meet the requirements;
  • the rubber plug is pressed in the box, and the aluminum cover is released from the box. After the finished product is inspected, the package is obtained.
  • the lyophilized product is further dissolved by adding 3 ⁇ 15ml of water for injection.
  • the prepared solution and the equivalent turbidity standard solution are respectively placed in the paired turbid glass tube. After 5 minutes of preparation of the turbidity standard solution, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was 1000 Lx. The solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After the solution was allowed to stand at room temperature for 8 hours, it remained clear. Comparative example 1
  • Carmustine cannot be dissolved in glycerin and water for injection. A clear solution cannot be formed before freezing. After lyophilization, 10 ml of water for injection is added and turbid. Comparative example 2
  • the lyophilized product obtained by the method of Examples 1-17 has the characteristics required for the lyophilized composition of the present invention.
  • the sample was stored under accelerated conditions for 6 months, and the change in the content and related substances was determined.
  • the content of the sample was between 98 and 101.5%, and the content of the substance was less than 0.8%, which met the requirements. It indicates that the obtained lyophilized product is stable and the validity period can be predicted to 2 years.
  • the lyophilized product prepared according to the method of Example 1- ⁇ was subjected to vascular irritation.
  • the method was to take 6 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely, the carmustine test group and the sodium chloride injection control group. Rabbits were dosed according to the clinical adult dose, and were injected slowly from the left ear vein of rabbits. The control group was given an equal volume of sodium chloride injection for 5 consecutive days. The results of the test showed that compared with the sodium chloride injection group, intravenous bolus injection was given for injection of carmustine. After the administration and 24 hours after the last administration, no visible swelling of the blood vessels and surrounding tissues was observed by the naked eye.
  • Rabbit ear vein structure is clear, individual blood vessels expand It is obvious that the wall thickness is uniform, the inner wall is smooth, and there is no inflammatory exudate around the tube. It indicated that the injection of carmustine had no obvious stimulating effect on rabbit ear veins under the experimental conditions.

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Abstract

The invention discloses a medicinal composition of carmustine, comprising cure effective quantity of carmustine, Tween type surface active agent and latent solvent. The latent solvent is chosen from one or more of glycerin or polyethyleneglycol. This composition can be injection or frozen powder injection. Solubility of carmustine can be increased by adding Tween and latent solvent. This invention further discloses method of preparing this medicinal composition.

Description

一种卡莫司汀的药用组合物、 制备方法及用途 技术领域  Medicinal composition of carmustine, preparation method and use thereof
本发明涉及一种卡莫司汀的药用组合物， 该组合物的制备方法及其用途。  The present invention relates to a pharmaceutical composition of carmustine, a process for the preparation of the composition and use thereof.
背景技术  Background technique
卡莫司汀是亚硝脲类垸化剂， 能与 DNA发生共价结合， 使 DNA的结构和功能破坏； 还可抑制 DNA聚合酶， 抑制 DNA和 RNA合成。 具有细胞周期非特异性， 对 G-S过渡期 细胞作用最强， 对 S期有延缓作用， 也可以作用于 G2期。 本药的作用特点是抗瘤谱较 广、 显效快、 脂溶性高， 于其它垸化剂之间有不完全的交叉耐药性。 卡莫司汀因能够 通过血脑屏障， 故对脑瘤 （恶性胶质细胞瘤、 脑干胶质瘤、 成神经管细胞瘤、 星形胶 质细胞瘤、 室管膜瘤） 、 脑转移瘤和脑膜白血病有效， 对恶性淋巴瘤、 多发性骨髓瘤， 与其他药物合用对恶性黑色素瘤有效。 Carmustine is a nitrosourea-based deuteration agent that covalently binds to DNA to disrupt the structure and function of DNA. It also inhibits DNA polymerase and inhibits DNA and RNA synthesis. It has a non-specific cell cycle, has the strongest effect on cells in the GS transition phase, and has a retarding effect on the S phase, and can also act on the G 2 phase. The drug is characterized by a broad spectrum of anti-tumor, rapid effect, high fat solubility, and incomplete cross-resistance between other sputum agents. Carmustine is able to pass the blood-brain barrier, so it is a brain tumor (glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma), brain metastases It is effective for meningeal leukemia, and is effective for malignant melanoma in combination with other drugs for malignant lymphoma and multiple myeloma.
然而， 卡莫司汀在水中溶解度极低， 而且不稳定， 因此在制备成制剂时存在一定 困难。 例如， 目前上市的卡莫司汀注射液， 是 125mg 卡莫司汀原料溶解于 2g聚乙二 醇 400制成的溶液， 有效期仅有 6个月， 而且需要遮光， 密闭， 在冷处保存， 临床应 用极为不便。  However, carmustine has extremely low solubility in water and is unstable, so there are certain difficulties in preparing a preparation. For example, the currently marketed carmustine injection is a solution of 125 mg of carmustine raw material dissolved in 2 g of polyethylene glycol 400, which is only valid for 6 months, and needs to be shaded, sealed, and stored in a cold place. Clinical application is extremely inconvenient.
为解决卡莫司汀的溶解度和稳定性问题， 已有多篇文献报道了将其和磷脂、 固醇 等制成粉针剂， 使用时用水溶液和粉针剂混合， 形成卡莫司汀脂质体注射液； 另有文 献报道将其制成由缓释微球和溶媒组成的抗癌缓释注射剂等制剂， 然而， 以上制剂存 在着制备工艺复杂、 成本高等缺点。 因此， 需要一种操作简单、 溶解度提高且稳定性 好的卡莫司汀新制剂。  In order to solve the solubility and stability problems of carmustine, many literatures have reported that it can be used as a powder injection with phospholipids and sterols. When used, it is mixed with aqueous solution and powder injection to form carmustine liposome. Injectable solution; it has been reported in the literature to prepare a preparation such as an anti-cancer sustained-release injection composed of sustained-release microspheres and a solvent. However, the above preparations have the disadvantages of complicated preparation process and high cost. Therefore, there is a need for a new carmustine formulation that is simple to handle, has improved solubility, and is stable.
发明内容 Summary of the invention
本发明的发明人意外地发现， 在制剂中加入一定量吐温的同时加入助溶剂甘油或 聚乙二醇中的一种或多种， 可以大大降低吐温的用量， 并显著地提高卡莫司汀在水中 的溶解度， 形成澄清、 性质稳定的组合物。 所制备的组合物， 在室温条件下能保持澄 清 8小时以上， 可以直接加入葡萄糖注射液、 生理盐水即可使用， 简化了操作。  The inventors of the present invention have unexpectedly discovered that the addition of one or more of the co-solvent glycerin or polyethylene glycol while adding a certain amount of Tween to the formulation can greatly reduce the amount of Tween and significantly increase Camo. Statin's solubility in water forms a clear, stable composition. The prepared composition can be kept at room temperature for more than 8 hours, and can be directly added to the glucose injection solution or physiological saline to simplify the operation.
本发明提供了一种含有卡莫司汀的药物组合物， 包含治疗有效量的卡莫司汀、 吐 温类表面活性剂、 助溶剂甘油或聚乙二醇。  The present invention provides a pharmaceutical composition comprising carmustine comprising a therapeutically effective amount of carmustine, a Tween-based surfactant, a cosolvent glycerin or a polyethylene glycol.
在本发明的药物组合物中， 吐温类表面活性剂选自吐温 -20， 吐温 -40、 吐温 -60 和吐温 -80中的一种或多种， 优选吐温- 80。 In the pharmaceutical composition of the present invention, the Tween-based surfactant is selected from the group consisting of Tween-20, Tween-40, and Tween-60. One or more of Tween-80, preferably Tween-80.
在本发明的药物组合物中， 助溶剂选自甘油、 聚乙二醇或它们的混合物，'其中的 聚乙二醇的平均分子量为 200〜10000， 优选 PEG200、 PEG400、 PEG800。  In the pharmaceutical composition of the present invention, the co-solvent is selected from the group consisting of glycerin, polyethylene glycol or a mixture thereof, and the polyethylene glycol therein has an average molecular weight of 200 to 10,000, preferably PEG200, PEG400, PEG800.
在本发明的药物组合物中， 卡莫司汀与吐温类表面活性剂、 助溶剂的重量比为 1 : 2-80： 1-50, 优选为 1： 5-50： 2-30, 最优选为 1： 8-20: 3-10  In the pharmaceutical composition of the present invention, the weight ratio of carmustine to Tween surfactant and cosolvent is 1: 2-80: 1-50, preferably 1: 5-50: 2-30, most Preferably 1: 8-20: 3-10
本发明的药物组合物可以注射给药， 例如可以是注射液或进一步制备成注射用冻 干粉针的剂型。 在本发明的注射液中或冻干粉针冷冻干燥前的溶液中卡莫司汀的浓度 为 5mg〜50mg/ml，优选为 10mg〜30mg/ml，助溶剂的浓度为 10mg〜300mg/ml , 优选为 30mg〜100mg/ml， 吐温类表面活性剂的浓度为 30mg〜500mg/ml， 优选为 100mg ~ 200mg/ml。  The pharmaceutical composition of the present invention can be administered by injection, for example, it can be an injection solution or a dosage form further prepared into a lyophilized powder for injection. The concentration of carmustine in the solution of the present invention or before the freeze-dried powder freeze-drying is 5 mg to 50 mg/ml, preferably 10 mg to 30 mg/ml, and the concentration of the co-solvent is 10 mg to 300 mg/ml. The concentration is preferably from 30 mg to 100 mg/ml, and the concentration of the Tween-based surfactant is from 30 mg to 500 mg/ml, preferably from 100 mg to 200 mg/ml.
本发明的药物组合物还可以包括用于注射液或注射用冻干粉针的其它常规的辅 剂。 这些常规的辅剂包括但不限于冷冻干燥赋型剂， 防腐剂、 稳定剂、 PH调节剂、 等 渗剂。 其中赋型剂可选自但不限于是甘露醇、 乳糖、 葡萄糖、 山梨醇、 氯化钠、 水解 明胶、 右旋糖酐、 蔗糖、 甘氨酸、 聚乙烯吡咯垸酮等中的一种或几种； 优选为甘露醇 或葡萄糖。 防腐剂可以选自但不限于是苯酚、 甲酚、 三叔丁醇、 苯甲醇、 尼泊金中的 一种或几种。 稳定剂可以选自但不限于亚硫酸钠、 亚硫酸氢钠、 焦亚硫酸钠、 硫代硫 酸钠、 硫脲、 维生素 C、 叔丁基对羟基茴香醚、 二丁基苯酚、 没食子酸丙酯、 生育酚、 甲硫氨酸、 盐酸半胱氨酸、 乙酰半胱氨酸、 N-乙酰 -DL-甲硫氨酸、 抗坏血酸棕榈酸酯、 乙二胺四乙酸、 乙二胺四乙酸二钠中的一种或几种。 PH调节剂包括但不限于盐酸、 枸 橼酸、 酒石酸、 磷酸、 偏磷酸、 聚偏磷酸、 碳酸、 氢氧化钠、 氢氧化钾、 枸橼酸钠、 枸橼酸钾、 碳酸氢钠、 碳酸氢鉀、 碳酸胺、 磷酸氢二钠、 磷酸氢二钾、 乙醇胺、 二乙 醇胺、 三乙醇胺、 1 , 2-已二胺、 碳酸钠、 酒石酸钠钾、 偏磷酸钾、 聚偏磷酸钾、 偏磷 酸钠中的一种或几种。  The pharmaceutical composition of the present invention may further comprise other conventional adjuvants for injection or lyophilized powder for injection. These conventional adjuvants include, but are not limited to, lyophilized excipients, preservatives, stabilizers, pH adjusting agents, isotonic agents. Wherein the excipient may be selected from, but not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc.; Mannitol or glucose. The preservative may be selected from, but not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben. The stabilizer may be selected from, but not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol, One of methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, disodium edetate Or several. PH regulators include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate, hydrogencarbonate Potassium, amine carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-hexamethylenediamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, sodium metaphosphate One or several of them.
优选地， 本发明的药物组合物的 pH在 8以下的范围， 优选为 pH为 3- 5, PH调节 剂包括但不限于盐酸、 枸橼酸、 酒石酸、 磷酸、 偏磷酸、 聚偏磷酸中的一种或几种， 优选为盐酸、 枸橼酸。  Preferably, the pH of the pharmaceutical composition of the present invention is in the range of 8 or less, preferably pH 3-5, and the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid. One or several, preferably hydrochloric acid, citric acid.
本发明的组合物中还可以进一步含有胆汁酸或其盐， 加入后可以使本发明组合物 的稳定性增加。 其中， 胆汁酸选自游离胆汁酸、 结合胆汁酸或二者的混合物， 游离胆 汁酸包括胆酸、 石胆酸、 去氧胆酸、 鹅去氧胆酸、 熊去氧胆酸、 猪去氧胆酸等， 优选 为胆酸、 去氧胆酸、 鹅去氧胆酸、 猪去氧胆酸； 结合胆汁酸为上述游离胆汁酸中的羧 醛与甘氨酸 （ NCH2C00H) 或牛磺酸 （H2NCH2C S0:,H) 或其他含有氨基的化合物中的氨 基形成酰胺键后的产物， 优选为甘氨胆酸、 甘氨去氧胆酸、 甘氨鹅去氧胆酸、 甘氨熊 去氧胆酸、 牛磺胆酸、 牛磺去氧胆酸、 牛磺鹅去氧胆酸、 牛磺熊去氧胆酸； 胆汁酸盐 为上述游离胆汁酸或结合胆汁酸成盐后的产物， 包括但不限于钾盐、 钠盐、 钙盐、 镁 盐、 锌盐、 硒盐、 铁盐等， 优选为钠盐和钾盐。 The composition of the present invention may further contain a bile acid or a salt thereof, and the stability of the composition of the present invention may be increased upon addition. Wherein, the bile acid is selected from the group consisting of free bile acids, bile acids, or a mixture of the two, and the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid Acid or the like, preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is the carboxy group in the above free bile acid a product of an aldehyde bond with an amino group in a glycine (NCH 2 C00H) or taurine (H 2 NCH 2 C S0:, H) or other amino group-containing compound, preferably glycocholic acid, glycine deoxygenation Cholic acid, glycine chenodeoxycholic acid, glycine ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid; bile acid salt The product after the above-mentioned free bile acid or bile acid-binding salt includes, but is not limited to, a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a zinc salt, a selenium salt, an iron salt and the like, and preferably a sodium salt and a potassium salt.
在本发明的药物组合物中， 卡莫司汀的用量没有特别的限制， 可以是在注射液中 通常使用的任何剂量。 "治疗有效量"是指卡莫司汀达到治疗效果的通常用量， 医生 可以根据患者的病情以及其他方面的情况作出适当的调整。 一般地， 本发明的组合物 中卡莫司汀的含量为 0. l-80mg/ml„  In the pharmaceutical composition of the present invention, the amount of carmustine is not particularly limited and may be any dose which is usually used in the injection. "Therapeutically effective amount" means the usual amount of carmustine to achieve a therapeutic effect, and the doctor can make appropriate adjustments depending on the condition of the patient and other aspects.至80mg/毫升„ The content of carmustine in the composition of the present invention is 0. l-80mg/ml „
本发明的卡莫司汀的药用组合物可以是澄明的可注射的水溶液形式， 或为注射用 冻干粉针的形式。 可以用注射用水、 5%或 10%葡萄糖溶液或 0. 9%氯化钠溶液直接溶解 冻千粉针， 得到澄明的注射液。  The pharmaceutical composition of carmustine of the present invention may be in the form of a clear injectable aqueous solution or in the form of a lyophilized powder for injection. The frozen powder can be directly dissolved in water for injection, 5% or 10% glucose solution or 0.9% sodium chloride solution to obtain a clear injection.
本发明的卡莫司汀组合物具有以下特点- 以上组合物不需要专用溶媒， 可以直接用葡萄糖注射液或者 0. 9%氯化钠溶液溶解 稀释后使用。  The carmustine composition of the present invention has the following characteristics - the above composition does not require a dedicated solvent, and can be directly diluted with glucose injection or a 0.9% sodium chloride solution and used after dilution.
粉针剂为干燥固体块状物或粉末， 能防止卡莫司汀在溶液中氧化、 水解等因素的 影响， 增加制品储存过程中的稳定性， 极大的延长制剂的有效期。  The powder injection is a dry solid mass or powder, which can prevent the influence of carmustine oxidation and hydrolysis in the solution, increase the stability during storage of the product, and greatly extend the expiration date of the preparation.
因粉针剂以固体状态存在， 便于运输。  Because the powder injection exists in a solid state, it is easy to transport.
该粉针剂制备工艺简单， 质量控制简便， 产品稳定性好， 便于工业化生产。  The powder injection preparation process is simple, the quality control is simple, the product stability is good, and the industrial production is convenient.
本发明中内容物的最低共熔点高， 在- 40Ό的温度下预冻即可， 外观较好。  The content of the present invention has a low minimum eutectic point and can be pre-frozen at a temperature of -40 Torr, and has a good appearance.
该粉针剂所含水分可达 1%以下， 一般控制在 5%以内即可。 The powder injection can have a moisture content of less than 1%, and is generally controlled within 5%.
按照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度 标准液分别置于配对的比浊用玻璃管中， 在浊度标准液制备 5分钟后， 在暗室内垂直 同置于伞棚灯下， 照度为 lOOOLx, 从水平方向观察、 比较， 制备的溶液应澄清， 不深 于 1号浊度标准液。  According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution should be clarified and not deeper than the No. 1 turbidity standard solution.
本发明的卡莫司汀注射液或注射用冻干粉针适合于肌肉注射、 静脉注射。  The carmustine injection of the present invention or the lyophilized powder for injection is suitable for intramuscular injection or intravenous injection.
另一方面,本发明提供了一种改善卡莫司汀溶解度的方法， 包括将卡莫司汀和助溶 剂、 吐温类表面活性剂混合、 搅拌的步骤。 该方法还可进一步包括将以上混合物制备 成注射液的步骤， 具体包括在上述混合物中加入水性溶媒 (水溶液、 甘露醇水溶液、 或 含有其他任意辅剂的水溶液）， 混合后加入活性炭搅拌， 经过 0. 8 μ πι滤膜粗滤脱炭后， 再用 0. 22 μ πι滤膜除菌， 分装。 所述注射液中助溶剂的浓度为 10mg〜300mg/ml ， 吐 温类表面活性剂的浓度为 30mg〜500mg/ml。 另外该方法还可以再进一步包括将上述注 射液冷冻干燥制成冻干粉针的步骤， 其中的冷冻干燥采用药剂领域中冷冻干燥注射剂 的常规冻干技术， 本领域技术人员根据现有技术以及教科书中的技术教导不需要创造 性劳动即可以完成。 In another aspect, the present invention provides a method for improving the solubility of carmustine comprising the steps of mixing and stirring carmustine with a co-solvent, a Tween-based surfactant. The method may further comprise the step of preparing the above mixture into an injection solution, specifically comprising adding an aqueous solvent (aqueous solution, aqueous mannitol solution, or an aqueous solution containing any other auxiliary agent) to the mixture, mixing and adding activated carbon to stir, passing through 0 After the 8 μ πι filter is coarsely decarbonized, Then use 0.22 μ πι filter to remove bacteria and dispense. The concentration of the co-solvent in the injection solution is 10 mg to 300 mg/ml, and the concentration of the tween-based surfactant is 30 mg to 500 mg/ml. Further, the method may further comprise the step of freeze-drying the above-mentioned injection solution to form a lyophilized powder needle, wherein the freeze-drying adopts a conventional freeze-drying technique of a freeze-dried injection in the field of pharmaceuticals, and the person skilled in the art according to the prior art and the textbook The technical teaching in it can be done without creative labor.
在一优选的实施方式中， 所述方法包括将卡莫司汀和助溶剂、 增溶剂搅拌， 再加 入水性溶媒搅拌成澄清溶液的步骤。  In a preferred embodiment, the method comprises the steps of stirring the carmustine and the co-solvent, the solubilizing agent, and adding the aqueous solvent to a clear solution.
在其中一优选的实施方式中，卡莫司汀与吐温类表面活性剂、助溶剂的重量比为 1 : 2-80： 1-50, 优选为 1 : 5-50： 2-30， 最优选为 1 : 8-20: 3-10。  In a preferred embodiment, the weight ratio of carmustine to Tween surfactant and cosolvent is 1: 2-80: 1-50, preferably 1: 5-50: 2-30, most Preferably it is 1: 8-20: 3-10.
本发明的第三个方面是将本发明的卡莫司汀组合物用于治疗脑瘤 （恶性胶质细胞 瘤、 脑干胶质瘤、 成神经管细胞瘤、 星形胶质细胞瘤、 室管膜瘤） 脑转移瘤和脑膜白 血病， 也可用于治疗恶性淋巴瘤、 多发性骨髓瘤， 或与其他药物合用治疗恶性黑色素 瘤。  A third aspect of the invention is the use of the carmustine composition of the invention for the treatment of brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, compartment) Tumor tumors Brain metastases and meningeal leukemia can also be used to treat malignant lymphoma, multiple myeloma, or in combination with other drugs to treat malignant melanoma.
本发明的各种改进和变化对本领域技术人员是显而易见的， 并不违背本发明的精 神和范围。 以下具体优选实施方式描述了本发明， 但应理解要求保护的本发明不应限 制于以下具体实施方案。 对于所属技术领域的技术人员来讲， 是明显的实施本发明所 述方式的各种改进均被本发明覆盖。  Various modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope of the invention. The invention is described in the following specific preferred embodiments, but it should be understood that the invention is not limited to the following specific embodiments. It will be apparent to those skilled in the art that various modifications which are obvious to the embodiments of the invention are covered.
具体实施方式  detailed description
实施例 1  Example 1
卡莫司汀 125mg  Carmustine 125mg
聚乙二醇 200 450mg  Polyethylene glycol 200 450mg
吐温- 80 1200mg  Tween - 80 1200mg
甘露醇 800mg  Mannitol 800mg
注射用水 至 7ml  Water for injection to 7ml
将卡莫司汀和聚乙二醇 200、 吐温 80混合、 搅拌， 加入甘露醇水溶液， 混合， 用 1%盐酸溶液调 pH为 4, 溶液加入 0. 1%活性炭搅拌 20分钟。溶液经过 0. 8 μ πι滤膜粗滤 脱炭后，再用 0. 22 μ m滤膜除菌，分装至西林瓶中。按照《中国药典 2005年版（二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平 方向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 2 The carcinol was stirred for 20 minutes. The solution was added to a solution of 0.1% activated carbon for 20 minutes. The solution was mixed with mannitol, and the solution was added to a solution of mannitol. The solution was de-carbonized by a coarse filtration of 0.8 μm πι, and then sterilized with a 0.22 μm filter and dispensed into a vial. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution. Example 2
卡莫司汀 125mg  Carmustine 125mg
聚乙二醇 400 350mg  Polyethylene glycol 400 350mg
吐温- 80 1600mg  Tween - 80 1600mg
甘露醇 lOOOmg  Mannitol lOOOOmg
注射用水 至 10ml  Water for injection to 10ml
将卡莫司汀和聚乙二醇 400、 吐温 80混合、 搅拌， 加入甘露醇水溶液， 混合， 用 1%盐酸调 pH为 4， 溶液加入 0. 1%活性炭搅拌 20分钟。溶液经过 0. 8 μ m滤膜粗滤脱炭 后， 再用 0. 22 y m滤膜除菌， 分装至西林瓶中。 按照 《中国药典 2005年版 （二部）》 附录 IX Β方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平 方向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 3:  The carmustine was mixed with polyethylene glycol 400 and Tween 80, stirred, and added to a mannitol aqueous solution, mixed, adjusted to pH 4 with 1% hydrochloric acid, and the solution was added with 0.1% activated carbon for 20 minutes. The solution was de-carbonized by coarse filtration through a 0.8 μm filter, then sterilized with a 0.22 μm filter and dispensed into a vial. According to the Chinese Pharmacopoeia 2005 Edition (Part 2) Appendix IX Β method, the prepared solution and the equivalent amount of turbidity standard solution were placed in the paired turbidity glass tube, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution. Example 3:
卡莫司汀 125mg  Carmustine 125mg
聚乙二醇 400 500mg  Polyethylene glycol 400 500mg
吐温- 80 1300mg  Tween - 80 1300mg
甘露醇 900mg  Mannitol 900mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1 的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx , 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 4  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella shed lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the turbidity standard is not deeper than the No. 1 turbidity standard. liquid. Example 4
卡莫司汀 125mg  Carmustine 125mg
甘油 250mg  Glycerin 250mg
聚乙二醇 400 200mg  Polyethylene glycol 400 200mg
吐温- 80 800mg 甘露醇 700mg Tween - 80 800mg Mannitol 700mg
注射用水 至 7ml  Water for injection to 7ml
按实施例 1 的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 5  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 5
卡莫司汀 125mg  Carmustine 125mg
甘油 350mg  Glycerin 350mg
吐温- 80 1600mg  Tween - 80 1600mg
甘露醇 lOOOmg  Mannitol lOOOOmg
注射用水 至 9ml  Water for injection to 9ml
按实施例 1的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 6  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 6
卡莫司汀 125mg  Carmustine 125mg
甘油 600mg  Glycerin 600mg
吐温 -80 1600mg  Tween -80 1600mg
甘露醇 1200mg  Mannitol 1200mg
注射用水 至 10ml  Water for injection to 10ml
按实施例 1 的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 卡莫司汀 125mg The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Carmustine 125mg
甘油 500mg  Glycerin 500mg
吐温- 80 HOOmg  Tween - 80 HOOmg
甘露醇 900mg  Mannitol 900mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1 的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 1000Lx， 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 8  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 8
卡莫司汀 125mg  Carmustine 125mg
甘油 300mg  Glycerin 300mg
聚乙二醇 400 200mg  Polyethylene glycol 400 200mg
吐温- 80 2200mg  Tween - 80 2200mg
甘露醇 1200mg  Mannitol 1200mg
注射用水 至 11ml  Water for injection to 11ml
按实施例 1 的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx , 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 9  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella shed lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the turbidity standard is not deeper than the No. 1 turbidity standard. liquid. Example 9
卡莫司汀 125tng  Carmustine 125tng
甘油 350mg  Glycerin 350mg
吐温- 20 2500mg  Tween - 20 2500mg
甘露醇 1200mg  Mannitol 1200mg
注射用水 至 10ml  Water for injection to 10ml
按实施例 1的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 0 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 10 The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, in 0 After the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx. The solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. Example 10
卡莫司汀 125mg  Carmustine 125mg
甘油 350mg  Glycerin 350mg
吐温- 40 800mg  Tween - 40 800mg
甘露醇 500mg  Mannitol 500mg
注射用水 至 5ml  Water for injection to 5ml
按实 例 1的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 11  The carmustine injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity glass. In the tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard solution. . Example 11
卡莫司汀 125mg Carmustine 125m g
聚乙二醇 400 550mg  Polyethylene glycol 400 550mg
吐温- 60 1200mg  Tween - 60 1200mg
甘露醇 l lOOmg  Mannitol l lOOmg
注射用水 至 10ml  Water for injection to 10ml
按实施例 1的方法制备卡莫司汀注射液， 按照 《中国药典 2005年版 （二部）》 附 录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在 浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 1000Lx， 从水平方 向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 12  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 12
卡莫司汀 125mg  Carmustine 125mg
聚乙二醇 400 600mg  Polyethylene glycol 400 600mg
吐温- 80 1200mg  Tween - 80 1200mg
胆酸 50mg 08 000680 甘露醇 900mg Cholic acid 50mg 08 000680 Mannitol 900mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 1000Lx， 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 13  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is 1000Lx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 13
卡莫司汀 125mg  Carmustine 125mg
甘油 200mg  Glycerin 200mg
聚乙二醇 400 250mg  Polyethylene glycol 400 250mg
吐温- 80 lOOOmg  Tween - 80 lOOOOmg
甘氨胆酸 150mg  Glycocholic acid 150mg
甘露醇 800mg  Mannitol 800mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1 的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 14  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 14
卡莫司汀 125mg  Carmustine 125mg
甘油 450mg  Glycerin 450mg
吐温- 80 lOOOmg  Tween - 80 lOOOOmg
牛磺胆酸 150mg  Taurocholic acid 150mg
甘露醇 950mg  Mannitol 950mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 15 The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx, from the horizontal direction. Observed, compared, the prepared solution was clarified and not deeper than the No. 1 turbidity standard solution. Example 15
卡莫司汀 125mg  Carmustine 125mg
甘油 500mg  Glycerin 500mg
吐温 -80 HOOmg  Tween -80 HOOmg
去氧胆酸 200mg  Deoxycholic acid 200mg
甘露醇 700mg .  Mannitol 700mg .
注射用水 ' 至 10ml  Water for injection ' to 10ml
按实施例 1 的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 16  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 16
卡莫司汀 20mg  Carmustine 20mg
甘油 300mg  Glycerin 300mg
吐温 -80 1200mg  Tween -80 1200mg
甘氨胆酸钠 200mg  Sodium glycocholate 200mg
甘露醇 800mg  Mannitol 800mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 实施例 17  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. Example 17
卡莫司汀 20mg  Carmustine 20mg
聚乙二醇 400 550mg  Polyethylene glycol 400 550mg
吐温- 80 1300mg 牛磺胆酸钠 400mg Tween - 80 1300mg Sodium taurocholate 400mg
甘露醇 400mg  Mannitol 400mg
注射用水 至 8ml  Water for injection to 8ml
按实施例 1的方法制备卡莫司汀注射液， 照 《中国药典 2005年版 （二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊 度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 lOOOLx, 从水平方向 观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 将实施例 1至 17制得的溶液按以下进行冷冻干燥：  The carmustine injection was prepared according to the method of Example 1, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2). In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. The solutions prepared in Examples 1 to 17 were freeze-dried as follows:
预冻： 制品温度下降至一 45°C， 保温 3小时后即可以进行升华干燥；  Pre-freezing: The temperature of the product drops to a temperature of 45 ° C, and the sublimation drying can be carried out after 3 hours of heat preservation;
升华干燥： 升华干燥温度控制在一 12°C以下；  Sublimation drying: Sublimation drying temperature is controlled below 12 ° C;
再干燥： 再干燥阶段最高温度控制在 35'C， 干燥失重应符合规定；  Re-drying: The maximum temperature in the re-drying stage is controlled at 35'C, and the weight loss on drying should meet the requirements;
干燥结束后， 箱内压胶塞， 出箱锁铝盖， 成品检验合格后包装即得。  After the drying is finished, the rubber plug is pressed in the box, and the aluminum cover is released from the box. After the finished product is inspected, the package is obtained.
冷冻干燥产品再加入 3〜15ml注射用水溶解， 按照《中国药典 2005年版（二部）》 附录 IX B方法， 将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中， 在浊度标准液制备 5分钟后， 在暗室内垂直同置于伞棚灯下， 照度为 1000Lx， 从水平 方向观察、 比较， 制备的溶液澄清， 不深于 1号浊度标准液。 溶液室温放置 8小时后， 仍保持澄清状态。 对照例 1  The lyophilized product is further dissolved by adding 3~15ml of water for injection. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution are respectively placed in the paired turbid glass tube. After 5 minutes of preparation of the turbidity standard solution, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was 1000 Lx. The solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After the solution was allowed to stand at room temperature for 8 hours, it remained clear. Comparative example 1
仅加甘油的处方：  Prescription with glycerin only:
卡莫司汀 125mg  Carmustine 125mg
甘油 800mg  Glycerin 800mg
注射用水 6ml  Water for injection 6ml
卡莫司汀不能溶解在甘油和注射用水中， 冷冻前无法形成澄明溶液， 冷冻干燥后 加 10ml注射用水， 混浊。 对照例 2  Carmustine cannot be dissolved in glycerin and water for injection. A clear solution cannot be formed before freezing. After lyophilization, 10 ml of water for injection is added and turbid. Comparative example 2
仅加吐温的处方：  Prescription with Tween only:
卡莫司汀 125mg 吐温- 80 1500mg Carmustine 125mg Tween - 80 1500mg
注射用水 至 6ml  Water for injection to 6ml
卡莫司汀虽然能溶解在吐温 -80和注射用水中， 但水溶液稳定性较差， 冷冻前无 法形成澄明溶液， 冷冻干燥后加 10ml注射用水， 混浊。 对照例 3  Although carmustine can be dissolved in Tween-80 and water for injection, the stability of the aqueous solution is poor, and a clear solution cannot be formed before freezing. After lyophilization, 10 ml of water for injection is added, and turbidity is observed. Comparative Example 3
仅加聚乙二醇的处方：  Prescription with only polyethylene glycol:
卡莫司汀 125mg  Carmustine 125mg
聚乙二醇 400 800mg  Polyethylene glycol 400 800mg
注射用水 6ml  Water for injection 6ml
卡莫司汀虽然能溶解在聚乙二醇和注射用水中， 但水溶液稳定性较差， 冷冻前无 法形成澄明溶液， 冷冻干燥后加 10ml注射用水， 混浊。 由此可以看出， 加入吐温和助溶剂组合可明显改善卡莫司汀溶液的稳定性和澄清 度， 而单加聚乙二醇、甘油或吐温均不能明显改善卡莫司汀水溶液的稳定性和澄清度。 实施例 18  Although carmustine can be dissolved in polyethylene glycol and water for injection, the stability of the aqueous solution is poor, and a clear solution cannot be formed before freezing. After lyophilization, 10 ml of water for injection is added and turbid. It can be seen that the addition of Tween and cosolvent combination can significantly improve the stability and clarity of carmustine solution, while the addition of polyethylene glycol, glycerol or Tween can not significantly improve the stability of carmustine aqueous solution. Sex and clarity. Example 18
加速条件下稳定性实验  Stability experiment under accelerated conditions
另外， 按照实施例 1-17的方法制得的冻干产物具有本发明的冻干组合物所需的特 性。 将各样品在加速实验条件下存放 6个月， 测定含量、 有关物质等指标的变化， 结 果含量均在 98〜101. 5%之间， 有关物质含量小于 0. 8%, 符合要求。表明所得冻干制品 稳定， 有效期可预测至 2年。 实施例 19刺激性研究  Further, the lyophilized product obtained by the method of Examples 1-17 has the characteristics required for the lyophilized composition of the present invention. The sample was stored under accelerated conditions for 6 months, and the change in the content and related substances was determined. The content of the sample was between 98 and 101.5%, and the content of the substance was less than 0.8%, which met the requirements. It indicates that the obtained lyophilized product is stable and the validity period can be predicted to 2 years. Example 19 Stimulating Study
将按照实施例 1-Π的方法制得的冻干产物进行动物血管的刺激性。方法是取健康、 耳缘无损伤家兔 6只， 按体重随机分为两组， 即注射用卡莫司汀试验组和氯化钠注射 液对照组。 以临床成人拟用剂量为依据设计家兔给药剂量， 从家兔左侧耳缘静脉缓慢 推注给药， 对照组给予等容积氯化钠注射液， 连续给予 5天。 试验结果表明， 与氯化 钠注射液组相比， 静脉推注给予注射用卡莫司汀,给药期间及末次给药 24小时后， 肉 眼观察未见血管及周围组织红肿， 组织切片检查可见兔耳静脉结构清晰， 个别血管扩 张明显， 管壁厚薄均匀， 内壁平滑， 管周无炎性渗出物。 表明实验条件下注射用卡莫 司汀对家兔耳缘静脉无明显刺激作用。 The lyophilized product prepared according to the method of Example 1-Π was subjected to vascular irritation. The method was to take 6 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely, the carmustine test group and the sodium chloride injection control group. Rabbits were dosed according to the clinical adult dose, and were injected slowly from the left ear vein of rabbits. The control group was given an equal volume of sodium chloride injection for 5 consecutive days. The results of the test showed that compared with the sodium chloride injection group, intravenous bolus injection was given for injection of carmustine. After the administration and 24 hours after the last administration, no visible swelling of the blood vessels and surrounding tissues was observed by the naked eye. Rabbit ear vein structure is clear, individual blood vessels expand It is obvious that the wall thickness is uniform, the inner wall is smooth, and there is no inflammatory exudate around the tube. It indicated that the injection of carmustine had no obvious stimulating effect on rabbit ear veins under the experimental conditions.

Claims

权 利 要 求 Rights request
1. 一种卡莫司汀药物组合物， 包含治疗有效量的卡莫司汀、 吐温类表面活性剂 以及助溶剂， 其中的助溶剂选自甘油、 聚乙二醇或它们的混合物。 A carmustine pharmaceutical composition comprising a therapeutically effective amount of carmustine, a Tween-based surfactant, and a co-solvent, wherein the cosolvent is selected from the group consisting of glycerin, polyethylene glycol, or a mixture thereof.
2. 根据权利要求 1的药物组合物，其中卡莫司汀与吐温类表面活性剂和助溶剂 的重量比为 1： 2-80： 1-50。  The pharmaceutical composition according to claim 1, wherein the weight ratio of carmustine to Tween-based surfactant and co-solvent is 1: 2-80: 1-50.
3. 根据权利要求 1 的药物组合物， 其中所述吐温类表面活性剂选自吐温- 20， 吐温- 40、 吐温 -60和吐温 -80中的一种或多种。  3. The pharmaceutical composition according to claim 1, wherein the Tween-based surfactant is one or more selected from the group consisting of Tween-20, Tween-40, Tween-60 and Tween-80.
4. 根据权利要求 1的药物组合物， 其中所述吐温类表面活性剂选自吐温 -80。  4. The pharmaceutical composition according to claim 1, wherein the Tween-based surfactant is selected from the group consisting of Tween-80.
5. 根据权利要求 1的药物组合物， 其中所述助溶剂为甘油。  5. The pharmaceutical composition according to claim 1, wherein the co-solvent is glycerin.
6. 根据权利要求 1的药物组合物， 其中所述助溶剂为聚乙二醇。  6. The pharmaceutical composition according to claim 1, wherein the co-solvent is polyethylene glycol.
7. 根据权利要求 6的药物组合物， 其中的聚乙二醇为聚乙二醇 200、 聚乙二醇 400、 聚乙二醇 800或其混合物。  The pharmaceutical composition according to claim 6, wherein the polyethylene glycol is polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 800 or a mixture thereof.
8. 根据权利要求 7的药物组合物， 其中的聚乙二醇为聚乙二醇 400。  8. The pharmaceutical composition according to claim 7, wherein the polyethylene glycol is polyethylene glycol 400.
9. 根据权利要求 1的药物组合物，其中在所述药物组合物中卡莫司汀与吐温类 表面活性剂和助溶剂的重量比为 1 : 5-50: 2-30。  The pharmaceutical composition according to claim 1, wherein the weight ratio of carmustine to tween-based surfactant and co-solvent in the pharmaceutical composition is 1:5-50: 2-30.
10. 根据权利要求 1的药物组合物，其中在所述药物组合物中卡莫司汀与吐温类 表面活性剂和助溶剂的重量比为 1 : 8-20： 3-10。  The pharmaceutical composition according to claim 1, wherein the weight ratio of carmustine to tween-based surfactant and co-solvent in the pharmaceutical composition is from 1:8 to 20:3 to 10.
1 1. 根据权利要求 1 的药物组合物， 其中所述药物组合物为注射液或冻干粉针 剂。  A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an injection or a lyophilized powder.
12. 根据权利要求 11的药物组合物， 组合物中还进一步包括药学上可接受的注 射剂辅剂。  12. The pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable adjuvant adjuvant.
13. 根据权利要求 1〜12中任一项权利要求的药物组合物，组合物中还包括胆汁 酸或其盐。  The pharmaceutical composition according to any one of claims 1 to 12, which further comprises a bile acid or a salt thereof.
14. 根据权利要求 13的药物组合物， 其中所述胆汁酸选自游离胆汁酸、 结合胆 汁酸或二者的混合物； 所述胆汁酸盐是胆汁酸成盐后的产物。  14. The pharmaceutical composition according to claim 13, wherein the bile acid is selected from the group consisting of free bile acids, bound bile acids or a mixture of the two; the bile acid salt is a product of bile acid salt formation.
15. 根据权利要求 14的药物组合物， 其中的游离胆汁酸为胆酸、 石胆酸、 去氧 胆酸、 鹅去氧胆酸、 熊去氧胆酸、 猪去氧胆酸或其混合物： 结合胆汁酸为上述游离胆 汁酸中的羧醛与甘氨酸或牛磺酸或其他含有氨基的化合物中的氨基形成酰胺键后的产 物或其混合物。 15. The pharmaceutical composition according to claim 14, wherein the free bile acid is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof: The bile acid is a product of a carboxaldehyde in the above free bile acid and an amide bond with glycine or an amino group in a taurine or other amino group-containing compound, or a mixture thereof.
16. 根据权利要求 15的药物组合物， 其中的游离胆汁酸为胆酸、 去氧胆酸、 鹅 去氧胆酸、 熊去氧胆酸、 猪去氧胆酸或其混合物； 其中的结合胆汁酸为甘氨胆酸、 甘 氨去氧胆酸、 甘氨鹅去氧胆酸、 甘氨熊去氧胆酸、 甘氨猪去氧胆酸、 牛磺胆酸、 牛磺 去氧胆酸、 牛磺鹅去氧胆酸、 牛磺熊去氧胆酸、 牛磺猪去氧胆酸或其混合物。 16. The pharmaceutical composition according to claim 15, wherein the free bile acid is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; wherein the bile acid is combined For glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, glycine ursodeoxycholic acid, glycine hyodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurofen Chenodeoxycholic acid, tauroursodeoxycholic acid, taurode hyodeoxycholic acid or a mixture thereof.
17. 根据权利要求 16的药物组合物， 其中的游离胆汁酸为胆酸、 去氧胆酸或其 混合物； 其中的结合胆汁酸为甘氨胆酸、 甘氨去氧胆酸、 牛磺胆酸、 牛磺去氧胆酸或 其混合物。  17. The pharmaceutical composition according to claim 16, wherein the free bile acid is cholic acid, deoxycholic acid or a mixture thereof; wherein the combined bile acid is glycocholic acid, glycodeoxycholic acid, taurocholic acid , taurodeoxycholic acid or a mixture thereof.
18. 根据权利要求 14的药物组合物， 其中的胆汁酸盐为胆汁酸的钾盐、 钠盐、 钙盐、 镁盐、 锌盐、 硒盐、 铁盐或其混合物。  18. The pharmaceutical composition according to claim 14, wherein the bile acid salt is a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a zinc salt, a selenium salt, an iron salt or a mixture thereof of the bile acid.
19. 根据权利要求 18的药物组合物， 其中的胆汁酸盐为胆汁酸的钾盐、 钠盐或 其混合物。 _  19. The pharmaceutical composition according to claim 18, wherein the bile acid salt is a potassium salt, a sodium salt or a mixture thereof of a bile acid. _
20. 以上任一项权利要求所述的药物组合物在制备治疗癌症中的用途。  20. Use of a pharmaceutical composition according to any of the preceding claims in the manufacture of a medicament for the treatment of cancer.
21. 根据权利要求 20的用途， 其中所述癌症选自脑瘤 （恶性胶质细胞瘤、 脑干 胶质瘤、 成神经管细胞瘤、 星形胶质细胞瘤、 室管膜瘤） 、 脑转移瘤、 脑膜白血病、 恶性淋巴瘤、 多发性骨髓瘤， 恶性黑色素瘤。  21. The use according to claim 20, wherein the cancer is selected from the group consisting of a brain tumor (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma), brain Metastatic tumor, meningeal leukemia, malignant lymphoma, multiple myeloma, malignant melanoma.
22. 权利要求 1〜18中任一权利要求所述的药物组合物的制备方法，包括将卡莫 司汀与助溶剂、 吐温类表面活性剂混合搅拌的步骤。  The process for producing a pharmaceutical composition according to any one of claims 1 to 18, which comprises the step of mixing and stirring carmustine with a co-solvent and a tween-based surfactant.
23. 根据权利要求 22的制备方法， 其中包括将紫杉垸类化合物与助溶剂、 吐温 类表面活性剂、 胆汁酸或其盐混合搅拌的步骤。  The production method according to claim 22, which comprises the step of mixing the docetaxan compound with a co-solvent, a Tween-based surfactant, a bile acid or a salt thereof.
24. 根据权利要求 22的制备方法， 其中还进一步包括加入溶媒， 加入活性炭、 过滤、 除菌的步骤。  24. The production method according to claim 22, which further comprises the steps of adding a solvent, adding activated carbon, filtering, and sterilizing.
25. 根据权利要求 24的制备方法， 还进一步包括将所述注射液冷冻干燥制成冻 干粉针的步骤。  The preparation method according to claim 24, further comprising the step of freeze-drying said injection liquid to form a lyophilized powder needle.
PCT/CN2008/000680 2007-04-03 2008-04-03 A medicinal composition of carmustine, preparation method and application WO2008119260A1 (en)

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