A kind of gabexate mesylate lyophilized preparation and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparation preparation, and specifically discloses a lyophilized preparation of gabexate mesylate and a preparation method thereof. The preparation method of the lyophilized preparation of gabexate mesylate provided by the present invention improves the pre-freezing process by optimizing the preparation method of the lyophilized preparation of gabexate mesylate without adding any lyophilizing excipient, so that the prepared lyophilized preparation of gabexate mesylate has a larger and uniform crystal form, and improves the appearance of the lyophilized preparation; it is also beneficial to further increase the number of channels for sublimation drying, so that the lyophilized preparation of gabexate mesylate maintains a good appearance consistent with the product with added excipients. The lyophilized preparation of gabexate mesylate prepared by the preparation method provided by the present invention only needs one main ingredient to achieve the effect that the indicators in terms of product shape, drying loss detection and related substance detection are better than the original research drug, the quality stability is good, the drug safety is high, and it is suitable for factory production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation preparation, in particular to a lyophilized gabexate mesylate preparation and a preparation method thereof. Background Art

[0002] As a non-peptide protease inhibitor, Gabexate mesylate can inhibit the activity of proteases such as trypsin, kallikrein, plasmin, and thrombin, thereby inhibiting the pathophysiological changes caused by these enzymes. Therefore, Gabexate mesylate is widely used in the clinic as a drug for the treatment of acute mild (edema type) pancreatitis and as an adjuvant therapy for acute hemorrhagic necrotizing pancreatitis.

[0003] However, gabexate mesylate is unstable in water and is easily hydrolyzed into ethyl paraben, and the ester bond of gabexate mesylate is broken and ring-opened in strong acid and alkaline aqueous solutions, causing adverse drug reactions in patients. Therefore, gabexate mesylate is currently mostly in the form of lyophilized preparations.

[0004] At present, for the lyophilized preparation of gabexate mesylate, the general preparation method is to add mannitol and acetic acid-sodium acetate buffer salt and other auxiliary materials to gabexate mesylate; or to add organic solvents such as ethanol, methanol, etc. to gabexate mesylate, and then freeze-dry to shorten the freeze-drying time. However, the introduction of organic solvents may have safety issues, and the use of auxiliary materials will complicate the liquid preparation process, and may also increase quality risks, greatly increasing the risk of clinical drug safety. Therefore, it is of great significance to provide a new lyophilized preparation of gabexate mesylate and a preparation method thereof. Summary of the invention

[0005] In view of this, the present invention provides a lyophilized preparation of gabexate mesylate and a preparation method thereof. The lyophilized preparation of gabexate mesylate provided by the present invention only requires one main ingredient and can achieve the effect of being superior to the original drug in terms of product shape, drying loss detection and related substance detection without adding other auxiliary materials, has good quality stability, high drug safety, and is suitable for factory production.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] The first aspect of the present invention provides a method for preparing a lyophilized preparation of gabexate mesylate, comprising the following steps:

[0008] S1, mixing gabexate mesylate and water evenly, cooling to -45°C to -35°C for freezing, and then heating to -10°C to -8°C to obtain freeze-dried gabexate mesylate;

[0009] S2, keeping the freeze-dried gabexate mesylate at 0°C to 5°C to obtain a primary freeze-dried gabexate mesylate preparation;

[0010] S3, raising the temperature of the primary gabexate mesylate lyophilized preparation to 20° C. to 30° C. to obtain the gabexate mesylate lyophilized preparation.

[0011] Compared with the prior art, the gabexate mesylate lyophilized preparation provided by the present invention first freezes the gabexate mesylate at a specific temperature to form lyophilized crystals of the gabexate mesylate, and then heats the temperature to a specific temperature to re-crystallize the lyophilized gabexate mesylate, which is beneficial for small-molecule ice crystal molecules to migrate to large ice crystal molecules, so that they form a larger and more uniform crystal form, and can also form more sublimation channels to improve the sublimation efficiency; further, the present invention performs sublimation drying and analytical drying at a specific temperature, respectively, which can ensure that the water in the gabexate mesylate lyophilized preparation is removed smoothly, and can further improve the stability and effectiveness of the lyophilized preparation without causing damage to the drug components.

[0012] The invention abandons the conventional research method, optimizes the preparation method of the gabexate mesylate lyophilized preparation on the basis of not adding a lyophilized excipient, improves the pre-freezing process, so that the prepared gabexate mesylate lyophilized preparation has a larger and uniform crystal form, and improves the appearance of the lyophilized preparation; it is also beneficial to further increase the number of channels for sublimation drying, so that the lyophilized gabexate mesylate lyophilized preparation after lyophilization maintains a good appearance consistent with the product with added excipients; the gabexate mesylate lyophilized preparation prepared by the preparation method provided by the invention is superior to the original drug in terms of product shape, drying loss detection, related substance detection and other indicators.

[0013] Preferably, in S1, the mass volume ratio of gabexate mesylate to water is 1 g:(9-11) mL.

[0014] The preferred ratio is beneficial to improving the quality of the lyophilized preparation of gabexate mesylate.

[0015] Preferably, in S1, the cooling rate is 1°C / min to 2°C / min.

[0016] Preferably, in S1, the freezing time is 30 min to 35 min.

[0017] Preferably, in S1, the heating rate is 0.5°C / min to 0.7°C / min.

[0018] The preferred heating rate is beneficial to further improve the quality of the lyophilized preparation of gabexate mesylate.

[0019] Preferably, in S1, the temperature is raised to -10°C to -8°C and then kept warm for 120min to 130min.

[0020] The optimal insulation time is conducive to forming more sublimation channels, improving the subsequent sublimation efficiency, and thus improving the comprehensive indicators of the gabexate mesylate lyophilized preparation.

[0021] Preferably, in S2, the insulation time is 6h to 8h, and the insulation vacuum degree is 15Pa to 20Pa.

[0022] The preferred sublimation drying conditions can ensure the removal of water in the product, increase the content of gabexate mesylate in the gabexate mesylate lyophilized preparation, and reduce the impurity content in the product.

[0023] Preferably, in S3, the heating rate is 1°C / min to 2°C / min.

[0024] Preferably, in S3, the temperature is raised to 20°C to 30°C and a predetermined time of insulation is required.

[0025] Further preferably, in S3, the insulation time is 1 h to 3 h, and the insulation vacuum degree is 15 Pa to 20 Pa.

[0026] The preferred analytical drying process is beneficial to improving the stability and effectiveness of the product and improving the quality of the gabexate mesylate lyophilized preparation.

[0027] The second aspect of the present invention provides the above-mentioned gabexate mesylate lyophilized preparation, which is prepared by the preparation method of the above-mentioned gabexate mesylate lyophilized preparation.

[0028] The gabexate mesylate lyophilized preparation provided by the present invention requires only one main ingredient and can achieve the effect that the indicators in product shape, drying loss detection and related substance detection, etc. are better than those of the original drug without adding other auxiliary materials, has good quality stability, high drug safety, and is suitable for factory production. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0030] In order to better illustrate the present invention, further examples are given below.

[0031] Example 1

[0032] This embodiment provides a method for preparing a lyophilized preparation of gabexate mesylate, comprising the following steps:

[0033] S1. Mix 0.1 g of gabexate mesylate and 1 mL of water for injection, cool to -45°C at a rate of 1°C / min, freeze for 30 min, then heat to -8°C at a rate of 0.7°C / min, and keep warm for 120 min to obtain freeze-dried gabexate mesylate;

[0034] S2, raising the temperature of the lyophilized gabexate mesylate to 5° C., and keeping the temperature for 6 hours under a vacuum degree of 15 Pa to obtain a primary lyophilized gabexate mesylate preparation;

[0035] S3. The primary lyophilized gabexate mesylate preparation is heated to 30° C. at a rate of 1° C. / min, and kept warm for 1 h under a vacuum degree of 15 Pa to obtain the lyophilized gabexate mesylate preparation.

[0036] Example 2

[0037] This embodiment provides a method for preparing a lyophilized preparation of gabexate mesylate, comprising the following steps:

[0038] S1. Mix 0.1 g of gabexate mesylate and 1 mL of water for injection, cool to -35°C at a rate of 2°C / min, freeze for 35 min, then heat to -8°C at a rate of 0.5°C / min, and keep warm for 130 min to obtain freeze-dried gabexate mesylate;

[0039] S2, raising the temperature of the lyophilized gabexate mesylate to 0° C., and keeping the temperature for 8 hours under a vacuum degree of 20 Pa to obtain a primary lyophilized gabexate mesylate preparation;

[0040] S3. Raise the temperature of the primary gabexate mesylate lyophilized preparation to 30° C. at a rate of 2° C. / min, and keep the temperature for 3 h under a vacuum degree of 20 Pa to obtain the gabexate mesylate lyophilized preparation.

[0041] Example 3

[0042] This embodiment provides a method for preparing a lyophilized preparation of gabexate mesylate, comprising the following steps:

[0043] S1. Mix 0.1 g of gabexate mesylate and 1 mL of water for injection, cool to -40°C at a rate of 1.5°C / min, freeze for 32 minutes, then heat to -9°C at a rate of 0.6°C / min, and keep warm for 125 minutes to obtain freeze-dried gabexate mesylate;

[0044] S2, raising the temperature of the lyophilized gabexate mesylate to 3° C., and keeping the temperature under a vacuum degree of 18 Pa for 7 hours to obtain a primary lyophilized gabexate mesylate preparation;

[0045] S3. The primary lyophilized gabexate mesylate preparation is heated to 25° C. at a rate of 1.5° C. / min, and kept warm for 2 h under a vacuum degree of 17 Pa to obtain the lyophilized gabexate mesylate preparation.

[0046] Comparative Example 1

[0047] This comparative example provides a method for preparing a lyophilized preparation of gabexate mesylate, which is different from Example 1 in that: S1, 0.1 g of gabexate mesylate and 1 mL of water for injection are mixed evenly, cooled to -45°C at a rate of 1°C / min, frozen for 30 minutes, then heated to -3°C at a rate of 0.7°C / min, and then kept warm for 120 minutes to obtain lyophilized gabexate mesylate;

[0048] The other operations are the same as those in Example 1.

[0049] Comparative Example 2

[0050] This comparative example provides a method for preparing a lyophilized preparation of gabexate mesylate, which is different from Example 1 in that: S1, 0.1 g of gabexate mesylate and 1 mL of water for injection are mixed evenly, cooled to -45°C at a rate of 1°C / min, frozen for 30 minutes, then heated to -15°C at a rate of 0.7°C / min, and then kept warm for 120 minutes to obtain lyophilized gabexate mesylate;

[0051] The other operations are the same as those in Example 1.

[0052] Comparative Example 3

[0053] This comparative example provides a preparation method of a lyophilized preparation of gabexate mesylate, which is different from Example 1 in that: S1, 0.1 g of gabexate mesylate and 1 mL of water for injection are uniformly mixed, cooled to -45°C at a rate of 1°C / min, and frozen for 30 minutes to obtain lyophilized gabexate mesylate;

[0054] The other operations are the same as those in Example 1.

[0055] Comparative Example 4

[0056] This comparative example provides a method for preparing a lyophilized gabexate mesylate preparation, which is different from Example 1 in that: S2, heating the lyophilized gabexate mesylate to 10° C. and keeping the temperature for 6 hours under a vacuum degree of 15 Pa to obtain a primary lyophilized gabexate mesylate preparation;

[0057] The other operations are the same as those in Example 1.

[0058] Comparative Example 5

[0059] This comparative example provides a method for preparing a lyophilized preparation of gabexate mesylate.

[0060] S1. Evenly mix 0.1 g of gabexate mesylate, 0.1 g of mannitol and 1 mL of water for injection, cool to -15°C at a rate of 1°C / min, freeze for 30 min, then quickly cool to below -40°C, and keep warm for 3 h to obtain freeze-dried gabexate mesylate;

[0061] S2, raising the temperature of the lyophilized gabexate mesylate to -15°C, and keeping the temperature for 12 hours under a vacuum degree of 30Pa to obtain a primary lyophilized gabexate mesylate preparation;

[0062] S3. Raise the temperature of the primary lyophilized gabexate mesylate preparation to 35° C. and keep it warm for 4-5.5 hours under a vacuum degree of 30 Pa to obtain the lyophilized gabexate mesylate preparation.

[0063] The gabexate mesylate lyophilized preparations prepared in Examples 1 to 3 and Comparative Examples 1 to 5 and the reference preparations were tested according to Part II of the 2020 edition of the Chinese Pharmacopoeia, wherein the manufacturer of the reference preparation is Maruishi Pharmaceutical Co., Ltd. / Ono Pharmaceutical Industry Co., Ltd., batch number: 033021;

[0064] The specific test results are shown in Table 1:

[0065] Table 1

[0066]

[0067]

[0068] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a lyophilized preparation of gabexate mesylate, characterized in that: The steps include: S1. Evenly mix gabexate mesylate and water, cool to -45°C~-35°C for freezing, and then heat to -10°C~-8°C to obtain freeze-dried gabexate mesylate; S2, keeping the freeze-dried gabexate mesylate at 0°C to 5°C to obtain a primary freeze-dried gabexate mesylate preparation; S3. Raising the temperature of the primary gabexate mesylate lyophilized preparation to 20° C. to 30° C. to obtain the gabexate mesylate lyophilized preparation.

2. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, wherein In S1, the mass volume ratio of gabexate mesylate and water is 1 g: (9-11) mL.

3. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, characterized in that: In S1, the cooling rate is 1°C / min to 2°C / min.

4. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, wherein In S1, the freezing time is 30 min to 35 min.

5. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, characterized in that: In S1, the heating rate is 0.5°C / min to 0.7°C / min; and / or In S1, after the temperature is raised to -10°C to -8°C, it is necessary to keep the temperature for 120min to 130min.

6. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, characterized in that: In S2, the insulation time is 6h~8h, and the insulation vacuum degree is 15Pa~20Pa.

7. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, characterized in that: In S3, the heating rate is 1°C / min to 2°C / min.

8. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 1, characterized in that: In S3, the temperature is raised to 20°C-30°C and a predetermined time of insulation is required.

9. The method for preparing the lyophilized preparation of gabexate mesylate according to claim 8, characterized in that: In S3, the insulation time is 1h~3h, and the insulation vacuum degree is 15Pa~20Pa.

10. A lyophilized preparation of gabexate mesylate, characterized in that: The gabexate mesylate lyophilized preparation is prepared by the preparation method of any one of claims 1 to 9.

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