WO2022121190A1 - 吉西他滨单磷酸酯溶液制剂和应用 - Google Patents

吉西他滨单磷酸酯溶液制剂和应用 Download PDF

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WO2022121190A1
WO2022121190A1 PCT/CN2021/085145 CN2021085145W WO2022121190A1 WO 2022121190 A1 WO2022121190 A1 WO 2022121190A1 CN 2021085145 W CN2021085145 W CN 2021085145W WO 2022121190 A1 WO2022121190 A1 WO 2022121190A1
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gemcitabine
monophosphate
preparation
gemcitabine monophosphate
injection
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雷晓光
汪晓明
廖道红
张秀国
黄道飞
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江苏集萃分子工程研究院有限公司
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K47/02—Inorganic compounds
    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • the invention relates to the field of medicine, in particular to the preparation and therapeutic application of gemcitabine monophosphate preparations.
  • Gemcitabine hydrochloride is a nucleotide antitumor drug developed by Eli Lilly and Company. Approved in 1996 for the treatment of pancreatic cancer, it has since been used for non-small cell lung cancer, ovarian cancer, breast cancer, bladder cancer, etc. Gemcitabine binds to a phosphate group at the 5' position under the action of nucleoside phosphorylase in cells to form gemcitabine monophosphate, diphosphate and triphosphate. Among them, diphosphate and triphosphate are active products. Although gemcitabine hydrochloride is the preferred standard drug for the treatment of pancreatic cancer, the therapeutic effect is not ideal. Severe hematological toxicity limits dose escalation, thereby affecting the efficacy of treatment.
  • mice experiments showed that the median lethal dose (LD50) was 700, 200, 40, 15, and 5 mg/kg after administration for 1, 2, 3, 4, and 5 days, respectively.
  • Continuous administration has high toxicity and poor antitumor effect.
  • This pharmacological characteristic shows that changing the administration method can fundamentally change the efficacy and toxicity of the drug, and selecting the best treatment method can significantly improve the treatment effect.
  • 4 treatments have been clinically studied, (1) 30-minute infusion, (2) 2-hour infusion, (3) 6-hour infusion, and (4) 24-hour infusion. With the prolongation of the infusion time, the efficacy decreased and the toxicity increased. Therefore, the infusion time of 0.5 hours is the standard infusion administration time recommended by Eli Lilly, and it is also the shortest infusion administration treatment plan at present.
  • shortening the infusion administration time may further increase the efficacy, but there is no clinical research report at present. This is because the fastest way to administer gemcitabine hydrochloride injection is 30 minutes. Because the pH of gemcitabine hydrochloride injection is 3-4, rapid injection can cause acute toxicity and death. Another reason is that the dosage of gemcitabine hydrochloride injection drug is large and the solubility is low. Therefore, the standard infusion time recommended by Eli Lilly can only be 30 minutes.
  • the present invention finds that the use of intravenous bolus injection (administration within 1-2 minutes) in animals can improve the curative effect by 30-50% compared with intravenous drip for 30 minutes. If the gemcitabine hydrochloride preparation or its derivative preparation that can be injected quickly can be developed, the clinical therapeutic effect will be improved. However, there are no reports on derivatives or formulation technologies in this regard. After researches on various formulations and derivatives in the present invention, it is found that gemcitabine monophosphate, a metabolite of gemcitabine hydrochloride, is an ideal derivative for rapid administration.
  • the structural formula of gemcitabine monophosphate is as follows:
  • Gemcitabine monophosphate is the first product of gemcitabine metabolism. It is an old compound, but there are few studies on its pharmacology and application. What is the antitumor effect of gemcitabine monophosphate, especially whether it can meet the requirements of the present invention (1) High solubility (2) is non-irritating, and can be administered by intravenous rapid injection, and there is no prior art report on improving the therapeutic effect.
  • gemcitabine monophosphate and gemcitabine hydrochloride have completely different physicochemical properties.
  • Gemcitabine monophosphate has strong antitumor effect, high solubility, no irritation, low toxicity and good stability. Suitable for 1-2 minutes rapid intravenous administration.
  • rapid administration of gemcitabine monophosphate further increased the antitumor effect (Table 4). Accordingly, the present invention completes a new gemcitabine monophosphate preparation and a new tumor treatment plan. Improve the therapeutic effect, and have obvious use value and novelty.
  • the purpose of the present invention is to provide a gemcitabine monophosphate preparation with high solubility, low toxicity and stable properties for rapid (1-2 minutes) intravenous injection. It is found through research in this patent that the preparation concentration of gemcitabine monophosphate aqueous solution can reach 400mg/ml. The dosage for clinical patients is 2-4g each time, which can be prepared in 5-10ml of solvent, and it can be given by intravenous injection in 1-2 minutes.
  • the further invented preparation technology is to adjust the pH of the citabine monophosphate solution.
  • the pH value of the citabine monophosphate itself is about 4, and the toxicity of rapid injection is slightly higher.
  • the pH value of the alkaline substance gemcitabine monophosphate solution is adjusted at 5.0-6.0, the solution is stable and less toxic, and can be injected quickly. Since the pH of the injection solution is close to neutral, it is not irritating to the veins, so the upper limb phlebitis and pain caused by the infusion of gemcitabine hydrochloride can be avoided. The antitumor effect was increased by 30-50% compared with 30 minutes of intravenous infusion (Table 4). Therefore, the present invention provides an aqueous solution preparation of gemcitabine monophosphate for injection with a concentration of 400 mg/ml, and the pH value of the solution is 5.0-6.0.
  • the gemcitabine monophosphate aqueous solution formulation of the present invention adopts a pH regulator to adjust the pH of the solution, wherein the pH regulator is selected from: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, phosphoric acid salt, buffer solution.
  • the pH adjusting agent is selected from: sodium carbonate, sodium bicarbonate.
  • the present invention further provides a method for preparing an aqueous gemcitabine monophosphate preparation, the method comprising the following steps: dissolving gemcitabine monophosphate in water, adding sodium carbonate or sodium bicarbonate, wherein sodium carbonate (sodium bicarbonate): gemcitabine monophosphate Esters are 0.05-0.3:1 (M/M).
  • the preparation method of the preparation of the present invention includes a heating step, a pH adjustment step, a heating sterilization step at 100-121°C, and a filter sterilization step.
  • the preparation method of the preparation of the present invention may include the following steps: taking a certain amount of gemcitabine monophosphate, first adding 0.25% sodium bicarbonate, adding 500 mg/ml for injection, and adjusting with 10% sodium bicarbonate solution after dissolving
  • the pH was between 5.0-6.0, followed by the addition of water for injection to 400 mg/ml.
  • the drug was dissolved in water for injection, and the laboratory temperature was 20 °C. It was found that the solubility of gemcitabine monophosphate was 400mg/ml without precipitation after long-term storage, which was 10 times that of gemcitabine hydrochloride 40mg/ml (the maximum allowable concentration of gemcitabine hydrochloride did not exceed 40mg/ml).
  • the therapeutic amount of gemcitabine monophosphate for clinical patients can be dissolved in a solution of about 10ml, and the injection can be completed within 1-2 minutes to improve the therapeutic effect.
  • the content of the experimental sample was 400 mg/ml, sterilized at 100 °C for 30 minutes, and the content changes before and after sterilization and at 45 °C for 3 months were observed.
  • the concentration before the experiment was taken as 100%, and the results are shown in the following table. The results showed that the formulations with pH 4.0-6.5 were stable.
  • Example 4 The experimental results are shown in Example 4.
  • Gemcitabine monophosphate has very low acute toxicity and is close to nontoxic.
  • mice were injected with gemcitabine hydrochloride and gemcitabine monophosphate through the tail vein, and the redness and swelling of the tail of the mice were observed 24 hours later. There were no irritating changes in the tails of mice given gemcitabine monophosphate. The tails of animals given gemcitabine hydrochloride were markedly swollen. In clinical patients, instillation of gemcitabine hydrochloride often causes arm pain, and gemcitabine monophosphate can avoid this side effect.
  • gemcitabine monophosphate is a compound with extremely high water solubility, and its solubility can reach 400 mg/ml, which is 10 times that of gemcitabine hydrochloride 40 mg/ml.
  • the clinical dose of gemcitabine monophosphate can be dissolved in a solution of about 10ml, and the injection can be completed within 1-2 minutes.
  • the dose of gemcitabine hydrochloride needs to be about 100ml each time, and the 1-minute administration method cannot be used. It was further found that gemcitabine monophosphate injection has little stimulation and low transient toxicity. In a 2-minute rapid injection in mice, the maximum tolerated dose of gemcitabine monophosphate injection is 4500 mg/kg, and gemcitabine hydrochloride is 1000 mg/kg.
  • the pH of gemcitabine hydrochloride solution was 3.5, local irritation and redness and swelling of the tail occurred after the mice were injected into the tail vein. Infusion of gemcitabine hydrochloride in clinical patients caused irritating pain in the arm. There was no vascular irritation in the mouse tail after injection of gemcitabine monophosphate solution. Further experiments found that the 1-minute injection administration was more effective than the 30-minute infusion, and the anti-tumor effect was improved by 30-50%.
  • gemcitabine monophosphate The preparation process of gemcitabine monophosphate is simple. Gemcitabine hydrochloride is unstable in acid and alkali conditions, therefore, it needs to be made into lyophilized powder. Gemcitabine monophosphate aqueous solution is stable after high temperature sterilization at 100°C.
  • the gemcitabine monophosphate of this patent is not converted from gemcitabine by deoxycytidine kinase in vivo, but directly supplied.
  • the conversion of gemcitabine to gemcitabine monophosphate in vivo is a rate-limiting process. While gemcitabine is converted to gemcitabine monophosphate, a portion of gemcitabine is converted to inactive difluorodeoxyuridine. Therefore, direct injection of gemcitabine monophosphate provides more effective drug molecules and can have higher drug concentrations in cells. Animal experiments have shown that at the same dose, it has a better therapeutic effect than gemcitabine.
  • Figure 1 Comparison of antitumor effects of gemcitabine monophosphate intravenous injection and intravenous infusion for 30 minutes
  • Figure 2 Plasma concentrations of gemcitabine monophosphate intravenous injection and intravenous infusion for 30 minutes
  • the pharmaceutical preparation of the present invention is composed of:
  • Embodiment 2 Gemcitabine monophosphate 400g, take gemcitabine monophosphate, add 800ml of water for injection, put the above components into a stainless steel container, stir and dissolve, adjust pH5.0 with 10% sodium bicarbonate solution, and make up the water to 1000ml; Filtration, sterilization, degassing. The 0.22-micron membrane was filtered again to obtain a sterile liquid, which was divided into 5 ml vials to obtain an aqueous gemcitabine monophosphate preparation.
  • Example 3 300 g of gemcitabine monophosphate, take gemcitabine monophosphate, add 800 ml of water for injection, put the above components into a stainless steel container, stir and dissolve, adjust pH 5.5, and make up water to 1000 ml; filter, sterilize, and degas. Aseptically dispensed into 10ml vials, sterilized at 100-121°C, packaged, and stored to obtain an aqueous gemcitabine monophosphate preparation.
  • Example 6 compares the antitumor effects of gemcitabine monophosphate and gemcitabine hydrochloride.

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Abstract

涉及吉西他滨单磷酸酯溶液制剂和应用，其中所述吉西他滨单磷酸酯溶液制剂，吉西他滨单磷酸酯在水溶液中的浓度为400mg/ml，溶液的pH值为5.0-6.0。该制剂无刺激性、急性毒性小、稳定性好，适合于快速静脉给药，明显提高抗肿瘤活性。

Description

吉西他滨单磷酸酯溶液制剂和应用 技术领域:
本发明涉及医药领域，具体地说是吉西他滨单磷酸酯制剂制备和治疗应用。
技术背景
盐酸吉西他滨是美国礼来公司研制的核苷酸类抗肿瘤药。1996年批准治疗胰腺癌，之后用于非小细胞肺癌，卵巢癌、乳腺癌、膀胱癌等多种。吉西他滨在细胞内经过核苷磷酸化酶的作用下，在5′位结合磷酸基团，形成吉西他滨单磷酸酯，二磷酸酯和三磷酸酯。其中二磷酸酯和三磷酸酯为活性产物。虽然盐酸吉西他滨是治疗胰腺癌优选的标准药物，但治疗效果并非理想。严重的血液毒性限制了剂量的提高，从而影响治疗的效果。肿瘤药理学研究表明，抗肿瘤药物的疗效、毒性与给药方法(方案)密切相关，甚至给药方法决定了药物毒性和疗效。有报道盐酸吉西他滨在病人输液时间分别为0.5、1、3、6、24小时，最大耐受剂量分别为1500、875、450、400、180mg/m2，输液时间越短，毒性小，抗瘤作用强。而且这种差别是以‘分钟’为单位的，例如0.5和1小时，耐受剂量相差近1倍。小鼠实验表明，分别给药1、2、3、4、5天，半数致死量(LD50)是700、200、40、15、5mg/kg。连续给药毒性大，抗瘤效果差。这种药理特性说明，改变给药方法可从根本上改变药物的疗效和毒性，选择最佳的治疗方法，可明显的提高治疗的效果。自1996年以来，临床研究过的治疗方法有4种，(1)输液30分，(2)输液2小时，(3)输液6小时，(4)输液24小时。随着输液时间的延长，疗效降低，毒性增加。因此，输注时间0.5小时是礼来药厂推荐的标准滴注给药时间，也是目前最短输液给药的治疗方案。根据以上资料，再缩短输液给药时间有可能会进一步增加疗效，但目前没有任何临床研究报道。这是因为盐酸吉西他滨注射液最快的给药方法也就是30分钟。因为盐酸吉西他滨注射液的pH3-4,快速注射可引起急性毒性反应和死亡。另一个原因是盐酸吉西他滨注射药物的用量大，溶解度低，注射用量2-4克，注射剂量需要50-100ml，无法在1-2分钟完成。因此，礼来药厂推荐的标准滴注给药时间也只能是30分钟。
本发明发现，在动物身上采用静脉推注注射(1-2钟内给药)比静脉滴注30分钟能提高30-50％的疗效。如果能研发可以快速注射的盐酸吉西他滨制剂或其衍生物制剂，将会提高临床的治疗效果。但目前没有这方面衍生物或制剂技术的报道。本发明经过多种制剂和衍生物研究之后，发现盐酸吉西他滨的代谢物吉西他滨单磷酸酯是理想的快速给药的衍生物。吉西他滨单磷酸酯结构式如下：
Figure PCTCN2021085145-appb-000001
英文名称：Gemcitabine monophosphate；
CAS号116371-67-6
分子式C9H12F2N3O7P
分子量343.17800
吉西他滨单磷酸酯是吉西他滨代谢的第一产物，是一个老的化合物，但关于它的药理和应用研究很少，吉西他滨单磷酸酯抗肿瘤作用如何，特别是能否符合本发明要求的(1)高溶解度(2)无刺激性，进而可以静脉快速注射给药，提高治疗效果等没有现有技术报道。
本发明人首次发现，吉西他滨单磷酸酯与盐酸吉西他滨有很完全不同理化性质。吉西他滨单磷酸酯抗瘤作用强、高溶解度、无刺激性、毒性小、稳定性好。适合于1-2分钟快速静脉注射给药。除了吉西他滨单磷酸酯抗瘤比盐酸吉西他滨作用强以外(表5)，吉西他滨单磷酸酯快速给药又进一步增加抗瘤作用(表4)。据此，本发明完成了一种新的吉西他滨单磷酸酯制剂和新的治疗肿瘤的方案。提高治疗效果，且具有明显的使用价值和新颖性。
发明内容
本发明的目的是提供一种溶解度高，毒性低、性质稳定可供快速(1-2分钟)静脉注射的吉西他滨单磷酸酯制剂。本专利经研究发现，吉西他滨单磷酸酯水溶液配制浓度可达400mg/ml。临床病人每次用量2-4g，可配制在5-10ml的溶剂内，可以1-2分中内静脉注射快速给入。进一步发明的制剂技术是调节西他滨单磷酸酯溶液的pH，西他滨单磷酸酯本身的pH值为4左右，快速注射毒性稍大，用碱性物质吉西他滨单磷酸酯水溶液pH值调节在5.0-6.0时，溶液性质稳定、毒性更小，可以快速注射。由于注射液pH接近中性，对静脉无刺激性，可以避免输入盐酸吉西他滨引起的上肢静脉炎和疼痛。与静脉滴注30分钟相比提高抗瘤作用30-50％(表4)。为此，本发明提供一种400mg/ml浓度的吉西他滨单磷酸酯注射用水溶液制剂，溶液pH值为5.0-6.0。
本发明所述吉西他滨单磷酸酯水溶液制剂，采用pH调节剂调节溶液的酸碱度，其中pH调节剂选自：氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，碳酸氢钾，磷酸盐，缓冲溶液。优选的所述pH调节剂选自：碳酸钠、碳酸氢钠。
本发明进一步提供吉西他滨单磷酸酯水溶液制剂的制备方法，所述方法包括以下步骤：将吉西他滨单磷酸酯溶解在水中，加入碳酸钠或碳酸氢钠，其中碳酸钠(碳酸氢钠)：吉西他滨单磷酸酯为0.05-0.3：1(M/M)。
本发明制剂的制备方法，包括加热步骤，调节pH值的步骤，100-121℃加热灭菌步骤，过滤除菌步骤。
本发明制剂的制备方法，可以包括以下步骤：取一定量的吉西他滨单磷酸酯，先加入0.25％量的碳酸氢钠，加注射用到500mg/ml，溶解后用10％的碳酸氢钠溶液调节pH在5.0-6.0之间，随后补加注射用水到400mg/ml。用0.45微米过滤膜过滤，除去气体，100-121℃灭菌，或用0.22微米滤膜过滤除菌，包装，储存，得到吉西他滨单磷酸酯水溶液制剂。
以下通过实验数据说明本发明的吉西他滨单磷酸酯水溶液制剂的有益效果。
1)吉西他滨单磷酸酯水中溶解性实验(物理稳定性)
用注射用水溶解药物，实验室温20℃。发现吉西他滨单磷酸酯溶解度400mg/ml长期放置无析出，是盐酸吉西他滨40mg/ml的10倍(盐酸吉西他滨说明书最高允许浓度不超过40mg/ml)。临床病人治疗量的吉西他滨单磷酸酯可溶解在10ml左右的溶液中，可在1-2分钟内注射完毕，提高治疗效果。
表1，吉西他滨单磷酸酯和盐酸吉西他滨溶解度(放置时间)
Figure PCTCN2021085145-appb-000002
2)吉西他滨单磷酸酯制剂稳定性实验(化学稳定性)
实验样品含量400mg/ml，100℃30分钟灭菌，观察灭菌前后和45℃放置3个月含量变化，实验前浓度作为100％，结果见下表。结果表明：pH4.0-6.5制剂稳定好。
表2，吉西他滨单磷酸酯制剂处理后含量变化(％)
样品组成 样品pH 100℃加热后 45℃放置
实验样品 4.0 99.8 99.9
样品+碳酸钠 5.5 99.9 99.9
样品+碳酸钠 6.5 99.8 99.8
样品+碳酸钠 7.0 99.1 99.0
盐酸吉西他滨 3.5 91.2 88.2
3)吉西他滨单磷酸酯注射液快速静脉注射毒性反应研究
实验结果见实施例4。吉西他滨单磷酸酯pH4和pH6溶液对小鼠的最大耐受剂量分别为3600和4500mg/kg，盐酸吉西他滨为1000mg/kg。吉西他滨单磷酸酯急性毒性很低，接近无毒性物质。
4)盐酸吉西他滨刺激性的研究
小鼠尾静脉注射盐酸吉西他滨和吉西他滨单磷酸酯，24小时后观察小鼠尾巴红肿情况。给吉西他滨单磷酸酯的小鼠尾巴没有刺激性变化。给盐酸吉西他滨的动物尾巴红肿明显。在临床病人滴注盐酸吉西他滨常引起胳膊疼痛，吉西他滨单磷酸酯可避免这一副作用。
5)吉西他滨单磷酸酯快速静脉注射比静脉输液30分钟有明显增强抗瘤作用，详见实施例5。药代动力学研究表明，静脉注射和静脉输液30分钟的峰浓度分别为405000和72ng/ml(5786倍，图2)
本发明的有益效果：
本发明人发现，吉西他滨单磷酸酯是水溶性极高的化合物，溶解度可达400mg/ml,是盐酸吉西他滨40mg/ml的10倍。临床使用剂量的吉西他滨单磷酸酯可溶解在10ml左右的溶液中，可在1-2分钟内注射完毕，盐酸吉西他滨每次给药剂量需要100ml左右，无法采用1 分钟给药方法。进一步发现，吉西他滨单磷酸酯注射液的刺激小，瞬时毒性低。在小白鼠2分钟快速注射，吉西他滨单磷酸酯注射液的最大耐受剂量达4500mg/kg,盐酸吉西他滨是1000mg/kg。盐酸吉西他滨溶液pH3.5,小鼠尾静脉注射后出现局部刺激性，尾巴红肿。在临床病人输注盐酸吉西他滨引起胳膊的刺激性疼痛。吉西他滨单磷酸酯溶液注射后小鼠尾巴无血管刺激性反应。再进一步实验发现，1分钟注射给药比30分钟输液，提高效果30-50％抗瘤效果。
吉西他滨单磷酸酯制剂工艺简单。盐酸吉西他滨在酸碱情况下均不稳定，因此，需要制成冻干粉。吉西他滨单磷酸酯酯水溶液经100℃高温灭菌后性质稳定。本专利的吉西他滨单磷酸酯不是由吉西他滨经脱氧胞苷激酶在体内转化而来，而是直接供给。在体内吉西他滨转化为吉西他滨单磷酸酯是一个限速过程，吉西他滨在转化为吉西他滨单磷酸酯的同时，一部分吉西他滨转化为无活性的二氟脱氧尿苷。因此，直接注射吉西他滨单磷酸酯，提供了更多的有效药物分子，细胞内可有较高药物浓度。经动物实验表明，在相同的剂量下，比吉西他滨有更好的治疗效果。
附图说明
图1：吉西他滨单磷酸酯静脉注射和静脉输液30分钟的抗肿瘤作用比较图2：吉西他滨单磷酸酯静脉注射和静脉输液30分钟的血药浓度
具体实施方式：
以下通过实施例进一步说明本发明。
实施例1
本发明的药物制剂，其组成为：
吉西他滨单磷酸酯400g
碳酸氢钠1g
注射用水到1000ml
调节pH6.0
取吉西他滨单磷酸酯，加注射用水800ml，将以上成分放入不锈钢容器，拌溶解后，用10％碳酸氢钠调节pH，补足水到1000ml；过滤，除菌，除气。无菌分装到5ml小瓶中，100-121℃灭菌,包装，储存，得到吉西他滨单磷酸酯水溶液制剂。
实施例2吉西他滨单磷酸酯400g，取吉西他滨单磷酸酯，加注射用水800ml，将以上成分放入不锈钢容器，拌溶解后，用10％的碳酸氢钠溶液调节pH5.0，补足水到1000ml；过滤，除菌，除气。0.22微米膜再过滤，得无菌液，分装到5ml小瓶中，得到吉西他滨单磷酸酯水溶液制剂。
实施例3吉西他滨单磷酸酯300g，取吉西他滨单磷酸酯，加注射用水800ml，将以上成分放入不锈钢容器，拌溶解后，调节pH5.5，补足水到1000ml；过滤，除菌，除气。无菌分装到10ml小瓶中，100-121℃灭菌,包装，储存，得到吉西他滨单磷酸酯水溶液制剂。
实施例4吉西他滨单磷酸酯快速静脉注射毒性反应研究
昆明种小白鼠，25克，雄性。尾静脉注射容积0.5ml，注射时间是1和2分钟。吉西他滨单磷酸酯pH4和pH6溶液对小鼠的最大耐受剂量分别为3600和4500mg/kg，盐酸吉西他滨 为1000mg/kg。
表3.吉西他滨单磷酸酯快速静脉注射毒性反应研究
Figure PCTCN2021085145-appb-000003
实施例5快速注射1分钟和输液30分钟的治疗效果
实验方法：昆明种鼠，雄性25克，每组10只，取S180小鼠肉瘤腹水液，用盐水稀释3倍，取0.2ml接种到右前肢皮下，接种2天后给药，药后8天取瘤称重，抑瘤率％＝对照组-实验组/对照组。结果表明见下表4。
表4静脉注射1分钟和输液30分钟的治疗效果比较
  mg/kg 给药方法 抑瘤率％ 体重变化％
吉西他滨单磷酸酯 30 1分钟 76.1 +5
吉西他滨单磷酸酯 30 30分钟 40.1 +4
实施例6比较吉西他滨单磷酸酯和盐酸吉西他滨的抗瘤作用。
实验方法同实施例5，结果如下表5，吉西他滨单磷酸酯比和盐酸吉西他滨有较强的抗瘤作用。
表5吉西他滨单磷酸酯和盐酸吉西他滨的抗瘤作用比较
  mg/kg 给药方法 抑瘤率％ 体重变化％
吉西他滨单磷酸酯 26* 1分钟 68.5 -4
盐酸吉西他滨 20 1分钟 56.8 -4
*等分子用量

Claims (9)

  1. 一种吉西他滨单磷酸酯注射液，其特征在于，其中吉西他滨单磷酸酯在水溶液中的浓度为300-500mg/ml，溶液的pH值为4.5-6.9。
  2. 根据权利要求1所述的制剂，其特征在于，其中吉西他滨单磷酸酯在水溶液中的浓度为400mg/ml。
  3. 根据权利要求1所述的制剂，其特征在于，溶液pH值为：5.0-6.0。
  4. 根据权利要求1所述的制剂，其特征在于，其中所述溶液pH值采用碱性物质进行调节，pH调节剂选自：氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，碳酸氢钾，磷酸盐缓冲溶液。
  5. 根据权利要求4所述的制剂，其特征在于，其中所述pH调节剂选自：碳酸钠，碳酸氢钠。
  6. 权利要求1所述的制剂的制备方法，所述方法包括以下步骤：将吉西他滨单磷酸酯溶解在水中，加入碱性物质，其中碳酸钠(碳酸氢钠)：吉西他滨单磷酸酯的摩尔比为0.05-0.3：1。
  7. 权利要求6所述的制备方法，所述方法必要时还可以包括加热步骤，调节pH值的步骤，100-121℃加热灭菌步骤，过滤除菌步骤。
  8. 权利要求6所述的制备方法，所述方法包括以下步骤：取一定量的吉西他滨单磷酸酯，加入0.25％碳酸氢钠，加注射用水500mg/ml,溶解后用10％碳酸氢钠溶液调节pH在5.0-6.0之间，随后补加注射用水到400mg/ml,，用0.45微米过滤膜过滤，除去气体，100-121℃灭菌,或用0.22微米滤膜再过滤除菌，分装到100-500支包装瓶中，包装，储存，得到吉西他滨单磷酸酯注射液。
  9. 权利要求8的制剂适用于1-2分钟的静脉注射给药。
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