WO2012013116A1 - Composition pharmaceutique de témozolomide comprenant un stabilisateur d'acides aminés et son procédé d'élaboration - Google Patents

Composition pharmaceutique de témozolomide comprenant un stabilisateur d'acides aminés et son procédé d'élaboration Download PDF

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Publication number
WO2012013116A1
WO2012013116A1 PCT/CN2011/077093 CN2011077093W WO2012013116A1 WO 2012013116 A1 WO2012013116 A1 WO 2012013116A1 CN 2011077093 W CN2011077093 W CN 2011077093W WO 2012013116 A1 WO2012013116 A1 WO 2012013116A1
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WO
WIPO (PCT)
Prior art keywords
temozolomide
pharmaceutical composition
cysteine
amino acid
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2011/077093
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English (en)
Chinese (zh)
Inventor
孙飘扬
张辉
吴玉霞
Original Assignee
江苏恒瑞医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201180003766.XA priority Critical patent/CN102481288B/zh
Priority to TW100141216A priority patent/TWI561526B/zh
Publication of WO2012013116A1 publication Critical patent/WO2012013116A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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

Definitions

  • Temozolomide pharmaceutical composition containing amino acid stabilizer and preparation method thereof
  • the present invention relates to a stable temozolomide pharmaceutical composition
  • a stable temozolomide pharmaceutical composition comprising an antitumor drug temozolomide or a pharmaceutically acceptable salt thereof, at least one amino acid stabilizer.
  • the domestic temozolomide market preparation is a hard capsule.
  • the oral preparation is convenient to use, and can be completely absorbed after oral administration.
  • the bioavailability is as high as 98%.
  • the main side effects are nausea, vomiting, fatigue, constipation and mild myelosuppression, among which severe nausea, Side effects such as vomiting are common. This often causes fluctuations in drug absorption, which affects bioavailability.
  • Some patients have nausea and vomiting reactions that are too severe to be administered orally, and many patients in the clinic have difficulty swallowing and cannot be administered orally.
  • temozolomide preparations that can be administered intravenously.
  • temozolomide is stable at pH ⁇ 7, and easily decomposes at pH>7.
  • Temozolomide is a prodrug and is easily degraded into an active product in aqueous solution. Preparation of a conventional intravenous solution does not guarantee long-term stability.
  • a temozolomide formulation administered in a micronized suspension is disclosed in U.S. Patent No. 6,251,886, however, suspension formulations are not preferred and can cause vascular occlusion.
  • suspension formulations are not preferred and can cause vascular occlusion.
  • temozolomide in aqueous solution it is prepared by freeze-drying and solidification to prepare a sterile lyophilized powder. It is reconstituted with an aqueous diluent for injection before use to obtain a temozolomide injection which can be administered parenterally. , will be a good strategy.
  • 6,987,108 discloses a lyophilized powder injection of temozolomide for intravenous administration of temozolomide.
  • the lyophilized powder of the above temozolomide can change from white to pale pink under long-term and accelerated conditions, which indicates that there may be some problems in its quality or stability.
  • the change in the color of the lyophilized powder tends to make the patient suspect the quality of the drug and reduce the patient's compliance and acceptance. Therefore, it is necessary to study and develop a technique and a preparation thereof which can ensure the parenteral administration of temozolomide, which is stable and suitable for long-term preservation. Summary of the invention
  • a primary object of the present invention is to provide a stable temozolomide pharmaceutical composition, and a process for its preparation.
  • the inventors discovered through research that some amino acids have an effect of increasing the stability of temozolomide.
  • the present invention provides a pharmaceutical composition
  • temozolomide or a pharmaceutically acceptable salt thereof and at least one amino acid stabilizer, wherein the amino acid stabilizer is selected from one or more L-alanines An L-glycine, a cysteine analog or a pharmaceutically acceptable salt thereof, wherein the cysteine analog is an amino acid having a cysteine main structure.
  • the pharmaceutical composition further comprises at least one aqueous diluent.
  • cysteine is as follows:
  • cysteine analog can be structurally modified on the structure of cysteine, and the modification sites are a thiol group, a carboxyl group and an amino group. That is, cysteine analogs have the following cysteine main structure:
  • Specific cysteine analogs are selected from the group consisting of L-cysteine, L-cysteine hydrochloride, acetylcysteine, S-carboxymethyl-L-cysteine, L-cysteine One or more of ethyl acetate and L-cysteine methyl ester, preferably the analog is L-cysteine, L-cysteine hydrochloride or acetylcysteine, more preferably L-cysteine or L-cysteine hydrochloride, wherein L-cysteine hydrochloride includes anhydrate thereof and a hydrate such as L-cysteine hydrochloride monohydrate.
  • the invention can be made by using the pharmaceutical composition of temozolomide and amino acid stabilizer provided by the invention.
  • An injectable parenteral pharmaceutical preparation especially a pharmaceutical preparation in the form of a lyophilized powder.
  • the amino acid stabilizer based on the present invention has a stabilizing effect on temozolomide, and those skilled in the art will recognize that the addition of the amino acid stabilizer of the present invention will stabilize temozolomide.
  • a preferred embodiment is that the weight ratio between temozolomide or a pharmaceutically acceptable salt thereof and an amino acid stabilizer is the following relationship in terms of temozolomide:
  • Amino acid stabilizer the weight ratio of temozolomide or a pharmaceutically acceptable salt thereof is greater than
  • the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof has a weight ratio greater than 0.8:1;
  • the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof is present in a weight ratio greater than 1.2:1;
  • the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof has a weight ratio of more than 1.6:1.
  • the pharmaceutical composition may comprise one or more of an excipient, a wetting agent, a pH adjuster or a buffer, preferably the excipient is mannitol; the wetting agent is a polysorbate;
  • the pH adjusting agent is hydrochloric acid; the buffering agent is selected from the group consisting of sodium citrate, acetic acid or acetate.
  • Temozolomide or its salt in terms of temozolomide 2.5 parts
  • Temozolomide or its salt in terms of temozolomide 2.5 parts
  • the present invention also provides a process for preparing a pharmaceutical composition.
  • the method of preparation comprises the step of uniformly mixing temozolomide or a pharmaceutically acceptable salt thereof with at least one amino acid stabilizer. 1) dissolving at least one amino acid stabilizer in an aqueous diluent to form a solution, preferably the solution temperature is controlled at 0-60 ° C;
  • Temozolomide or a pharmaceutically acceptable salt thereof is added to the above solution to dissolve.
  • the above preparation method specifically includes the following steps:
  • the pH is from 2.0 to 6.0, more preferably from 2.5 to 4.5, most preferably from 3.5 to 4.0;
  • the aqueous diluent used in the above preparation method is selected from the group consisting of water, physiological saline, 5% dextrose solution or a mixture thereof.
  • the pharmaceutical composition of the present invention can be further prepared into a lyophilized powder preparation, and a mixed solution of temozolomide or a pharmaceutically acceptable salt thereof and a stabilizer is freeze-dried.
  • the present invention provides a pharmaceutical composition capable of ensuring the stability of temozolomide by the addition of an amino acid stabilizer.
  • the amino acid stabilizer represented by cysteine monohydrate hydrochloride enhances the stability of temozolomide, which is not only guaranteed to ensure temozolomide The content and related substances were stable, and the color of the temozolomide composition which showed cysteine hydrochloride as a stabilizer under long-term and accelerated conditions did not change.
  • the prepared temozolomide lyophilized powder injection maintains the appearance of white to off-white lyophilized powder, and the color of lyophilized powder becomes pale pink, and the change of color of temozolomide is an insurmountable difficulty in the use of medicines.
  • the change in the color appearance of the drug will greatly reduce the credibility and compliance of the doctor and the patient.
  • cysteine has similar structural properties. : L-cysteine, L-cysteine hydrochloride anhydrate, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine Amino acid, L-cysteine ethyl ester hydrochloride, L-cysteine methyl ester hydrochloride, and amino acids having the same main structure and small difference in substituent groups can achieve a similar effect of stabilizing temozolomide.
  • the stabilizer is selected from the group consisting of L-cysteine, L-cysteine hydrochloride anhydrate, L-cysteine hydrochloride monohydrate, and acetyl half. Cystine or a mixture thereof. L-cysteine hydrochloride monohydrate is preferred.
  • the pharmaceutical composition of the present invention wherein the content of the stabilizer is theoretically higher as possible, but for the preparation of the composition, various properties such as lyophilization process and molding are also considered, and various factors for the preparation of the composite composition are
  • the total weight stabilizer is present in an amount ranging from 2% by weight to 60% by weight. Preferably, it is 5 wt% to 30 wt%; the pharmaceutical composition of the present invention, wherein the temozolomide or a pharmaceutically acceptable salt thereof is contained in an amount of 2 wt% to 60 wt% based on the total weight of the composition. It is preferably 5 wt% to 20 wt%.
  • aqueous diluent is added, and the aqueous diluent is selected from the group consisting of water for injection, physiological saline, 5% dextrose solution or a mixture thereof.
  • Excipients which can be used in the present invention are selected from the group consisting of sodium chloride, glucose, lactose, mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hydroxyethyl starch, cyclodextrin, glycine Or a mixture thereof, preferably mannitol;
  • the wetting agent is selected from the group consisting of polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salt, lecithin, polyethylene glycol or a mixture thereof, preferably selected From polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-80 or mixtures thereof, most preferably polysorbate-80; buffer selected from tannic acid Salt, lactate, acetate, tartrate, succinate, phosphate or mixtures thereof, preferably selected from the group consisting of citrates, acetates, phosphates or mixtures thereof, most preferably
  • buffers For excipients, buffers, conventional pH adjusting agents, buffers, those skilled in the art will be able to make selections and adjustments based on the lyophilized formulation preparation requirements.
  • the excipient is preferably mannitol; the wetting agent is preferably polysorbate-80; and the conventional pH adjuster is preferably hydrochloric acid.
  • the buffering agent is preferably sodium citrate, acetic acid and acetate.
  • percent by weight (wt%) used in the present invention is calculated on the basis of the total weight of the pharmaceutical composition.
  • the invention improves the temozolomide because of poor water solubility by the addition of a wetting agent, and is difficult to be
  • the characteristics of water wetting and dissolution increase the dissolution rate of temozolomide, reduce the preparation time of the whole solution, reduce the time of temozolomide degradation in the solution, and thus reduce the degradation of temozolomide.
  • the final formability of the temozolomide freeze-dried powder injection is ensured by the addition of the excipient, and the protective support of the excipient is ensured, and the temozolomide freeze-dried powder injection is reconstituted into a suitable patient.
  • the time of preparation is greatly reduced.
  • the excipient is used in a pharmaceutical composition, its wt% may be from 20 wt% to 80 wt% based on the total weight of the pharmaceutical composition.
  • a buffering agent and a conventional pH adjusting agent in the present invention ensures that temozolomide reduces its degradation rate in a relatively low pH environment and a certain buffer system in a solution state.
  • its wt% may be from 5 wt% to 60 wt% based on the total weight of the pharmaceutical composition.
  • its wt% may be from 0.1 wt% to 20 wt% based on the total weight of the pharmaceutical composition.
  • the invention can reduce the degradation rate of temozolomide in the dissolution process and the solution state, thereby ensuring that temozolomide can be kept stable in a solution state for a long time, thereby facilitating the whole process of preparation, filling, freeze-drying, etc., and is easy to realize. Industrial production.
  • the temperature should be appropriately controlled during the preparation of the chemical solution to reduce the degradation of temozolomide.
  • compositions of the invention are typically prepared by the following steps:
  • the prescribed amount of temozolomide is weighed, dissolved in the above solution, dissolved, and the pH of the solution is measured. The pH of the solution is adjusted to 3.5-4.5 as needed.
  • Example 6 Weigh 3.00 g polysorbate-80, 4.00 g L-alanine, 10.00 g mannitol, 5.67 g acetic acid, 5.03 g sodium acetate, add 900 mL water for injection, stir and dissolve in a water bath at 40 °C, add 2.50 g Temozolomide, dissolved by stirring, added with water to 1000 mL, filtered through a 0.22 ⁇ microporous membrane, dispensed, and lyophilized to obtain temozolomide lyophilized powder. Comparative Example 1 (conventional freeze-drying prescription)
  • a solution of temozolomide was prepared according to Example 2 and Comparative Example 3 (U.S. Patent No. 6,987,108, Example 2), and the prepared solution was freeze-dried to prepare a temozolomide freeze-dried powder injection.
  • the solution stability of the solutions of Example 2 and Comparative Example 3 before lyophilization and the stability of the solution after reconstitution after lyophilization were respectively determined by reverse high performance liquid chromatography (HPLC). The results are shown in Table 1.
  • the corresponding temozolomide solution was prepared according to the prescriptions of Examples 1, 2, 4 and Comparative Examples 1, 2, and 3, and lyophilized powder was prepared by freeze-drying. The prepared lyophilized powder was taken at 40 ° C for examination. The appearance and related substances of the samples after 5 days of storage were examined, and the relevant substances were determined by reversed-phase high performance liquid chromatography (HPLC). The results are shown in Table 2.
  • Example 4 White Loose Mass 0.18 Comparative Example 1 Light Pink Loose Mass 1.09 Comparative Example 2 White Loose Mass 0.11 Comparative Example 3 White Loose Mass 0.23 Example 1 White Loose Mass 0.10 Example 2 White Loose block 0.09 Example 4 White loose block 0.18
  • Comparative Example 1 Light pink loose mass 1.32 Comparative Example 2 Light pink loose mass 0.11 Comparative Example 3 Light pink loose mass 0.25
  • the freeze-dried powder obtained by the present invention has better stability.
  • the lyophilized powder samples of Examples 1, 2, and 4 were surprisingly found to have no change in appearance and more excellent stability; while the lyophilized powders of Comparative Examples 1, 2, and 3 all showed significant color. Changes in appearance, changes in the color of the lyophilized powder indicate that the sample may have undergone significant changes, and changes in the appearance of the sample may reduce the compliance of the patient's medication, or even this indicates a poor stability of the sample.
  • the amino acid having a cysteine main structure has an effect of improving the stability of temozolomide, and L-cysteine or a salt thereof has the best effect. Stability comparison experiment three
  • Example 2 The lyophilized powder prepared according to Example 2 and Comparative Example 3 (U.S. Patent No. 6,987,108, Example 2) was subjected to changes in related substances at 2-8 ° C, 25 ° C and 40 ° C, respectively. For stability investigation, the results are shown in Table 3, 4. Stability

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Abstract

La présente invention concerne une composition pharmaceutique de témozolomide comprenant un stabilisateur d'acides aminés et l'un de ses procédés d'élaboration. La composition pharmaceutique comprend du témozolomide ou l'un de ses sels de qualité pharmaceutique et au moins un type de stabilisateur d'acides aminés. Le stabilisateur d'acides aminés est choisi parmi un ou plusieurs analogues de L-alanine, de L-glycine et de L-cystéine, ou leurs sels de qualité pharmaceutique. Le procédé d'élaboration de la composition pharmaceutique comprend une étape de mélangeage en parts égales du témozolomide ou de son sel de qualité pharmaceutique avec au moins un stabilisateur d'acides aminés.
PCT/CN2011/077093 2010-07-29 2011-07-13 Composition pharmaceutique de témozolomide comprenant un stabilisateur d'acides aminés et son procédé d'élaboration WO2012013116A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201180003766.XA CN102481288B (zh) 2010-07-29 2011-07-13 含氨基酸稳定剂的替莫唑胺药物组合物及其制备方法
TW100141216A TWI561526B (en) 2011-07-13 2011-11-11 Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010244080.7A CN102342931B (zh) 2010-07-29 2010-07-29 替莫唑胺的可注射的胃肠外用药物制剂及其制备方法
CN201010244080.7 2010-07-29

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PCT/CN2011/077093 WO2012013116A1 (fr) 2010-07-29 2011-07-13 Composition pharmaceutique de témozolomide comprenant un stabilisateur d'acides aminés et son procédé d'élaboration

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Cited By (1)

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US10337501B2 (en) 2014-11-26 2019-07-02 Saitec Offshore Technologies S.L.U. Floating platform for harnessing wind energy

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CN103705446A (zh) * 2012-10-08 2014-04-09 正大天晴药业集团股份有限公司 一种多烯磷脂酰胆碱注射液及其制备方法
US9033949B2 (en) * 2012-11-27 2015-05-19 Bang & Olufsen Medicom A/S Needle protection device
CN104274412A (zh) * 2013-07-01 2015-01-14 北京恒瑞康达医药科技发展有限公司 一种含有替莫唑胺、其药学上可接受的盐或其他衍生物的药物制剂
BR112020005703A2 (pt) * 2017-09-27 2020-10-20 Novartis Ag formulação parentérica compreendendo siponimod

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CN101869551A (zh) * 2010-06-28 2010-10-27 江苏奥赛康药业有限公司 一种替莫唑胺冻干制剂
CN101984968A (zh) * 2010-10-29 2011-03-16 北京润德康医药技术有限公司 抗肿瘤剂替莫唑胺的药物制剂制备方法

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CN101869551A (zh) * 2010-06-28 2010-10-27 江苏奥赛康药业有限公司 一种替莫唑胺冻干制剂
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Publication number Priority date Publication date Assignee Title
US10337501B2 (en) 2014-11-26 2019-07-02 Saitec Offshore Technologies S.L.U. Floating platform for harnessing wind energy

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CN102342931A (zh) 2012-02-08
CN102481288A (zh) 2012-05-30
CN102481287A (zh) 2012-05-30
CN102481288B (zh) 2014-02-19
CN102342931B (zh) 2014-04-23
WO2012013117A1 (fr) 2012-02-02
CN102481287B (zh) 2013-09-18

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