A maropitant citrate injection and a method of preparing the same

Abstract

This invention discloses a maripitan citrate injection and its preparation method, relating to the field of pharmaceutical formulation technology. It addresses the technical problems of existing maripitan citrate injections, such as low bioavailability, poor stability, and susceptibility to adverse reactions during injection. The maripitan citrate injection comprises maripitan citrate, TPGS-SO3H, zinc sodium EDTA, and water for injection. The mass ratio of maripitan citrate (calculated as maripitan) to TPGS-SO3H is 1:(1-2), and the mass ratio of TPGS-SO3H to zinc sodium EDTA is (100-200):(1-2). The maripitan citrate injection provided by this invention can effectively improve the bioavailability and stability of the product, while reducing adverse reactions such as injection pain.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a maripitan citrate injection and its preparation method. Background Technology

[0002] Maropitan citrate is a potent and selective type 1 NK-1 receptor antagonist that acts on the central nervous system by inhibiting substance P (a key neurotransmitter that induces vomiting), thus suppressing both peripheral and central vomiting. It was the first drug approved for the prevention and treatment of severe vomiting and motion sickness in dogs, and also the first drug approved for the treatment of canine motion sickness, demonstrating significant clinical value and market potential.

[0003] The main component of maropistan citrate injection is maropistan citrate. Because maropistan citrate is almost insoluble in water, this characteristic greatly reduces the bioavailability of maropistan citrate injection and increases the dosage. At the same time, the existing maropistan citrate injection has poor stability and causes pain during injection, resulting in poor animal compliance during treatment and failing to meet the needs of clinical use. Summary of the Invention

[0004] This invention aims to address the technical problems of existing maropistan citrate injections, such as low bioavailability, poor stability, and easy adverse reactions during injection. The purpose is to provide a maropistan citrate injection and its preparation method, which can effectively improve the bioavailability and stability of the product, while reducing adverse reactions such as injection pain.

[0005] This invention is achieved through the following technical solution:

[0006] The first objective of this invention is to provide a maropistan citrate injection, comprising TPGS-SO3H (weight-average molecular weight: 1590~1600) and sodium zinc ethylenediaminetetraacetate.

[0007] This invention incorporates a combination of TPGS-SO3H and sodium zinc ethylenediaminetetraacetate (EDTA) into maropistamate injection. TPGS-SO3H comprises three parts: vitamin E (hydrophobic end), polyethylene glycol (PEG, hydrophilic bridge), and terminal sulfonic acid groups (–SO3H). It is amphiphilic and can self-assemble into nanomicelles, effectively encapsulating the drug and thus improving its stability. The addition of sulfonic acid groups to TPGS significantly enhances the solubility of the material, shortens the preparation time, and significantly improves the water solubility and encapsulation efficiency of the drug, further enhancing its solubility and stability. The zinc element in sodium zinc ethylenediaminetetraacetate (EDTA zinc sodium) has antioxidant properties, which can improve the product's stability.

[0008] Extensive experiments and research have revealed a synergistic effect between TPGS-SO3H and EDTA sodium zinc. The combination of TPGS-SO3H and EDTA sodium zinc can significantly improve product stability and reduce adverse reactions when administered to animals. This results in a significant improvement in the safety and efficacy of the maripitan citrate injection prepared in this invention, enhanced stability, and reduced injection pain, greatly improving comfort during treatment.

[0009] Furthermore, the mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is (100-200):(1-2).

[0010] Furthermore, the mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is 100:1.

[0011] Furthermore, the maropistan citrate injection comprises maropistan citrate, TPGS-SO3H, sodium zinc ethylenediaminetetraacetate, and water for injection.

[0012] Furthermore, the mass ratio of the malopistan citrate (calculated as malopistan) to TPGS-SO3H is 1:(1-2).

[0013] Furthermore, the mass ratio of the malopistan citrate (calculated as malopistan) to TPGS-SO3H is 1:1 or 1:2.

[0014] Furthermore, each 20ml of injection solution contains the following components:

[0015] Maropitan citrate (calculated as maropitan) 200mg;

[0016] TPGS-SO3H 200-400mg;

[0017] 2-4 mg of zinc sodium ethylenediaminetetraacetate;

[0018] 20ml of water for injection.

[0019] The second objective of this invention is to provide a method for preparing maripitan citrate injection, comprising the following steps:

[0020] Weigh TPGS-SO3H and sodium zinc ethylenediaminetetraacetate, add them to water for injection, and stir to dissolve.

[0021] Add malopistan citrate, stir to dissolve, then add water for injection to the final volume to obtain a mixed solution;

[0022] Filter the mixed solution until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0023] Sterilize to obtain malopistan citrate injection.

[0024] Furthermore, the filtration uses a 0.22~0.45μm microporous filter membrane.

[0025] Furthermore, the sterilization is performed using moist heat steam sterilization.

[0026] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0027] 1. This invention incorporates a combination of TPGS-SO3H and sodium zinc ethylenediaminetetraacetate (EDTA) into maropistamyl citrate injection. TPGS-SO3H comprises three parts: vitamin E (hydrophobic end), polyethylene glycol (PEG, hydrophilic bridge), and terminal sulfonic acid groups (–SO3H). It is amphiphilic and can self-assemble into nanomicelles, effectively encapsulating the drug and thus improving its stability. The addition of sulfonic acid groups to TPGS significantly enhances the solubility of the material, shortens the preparation time, and significantly improves the water solubility and encapsulation efficiency of the drug, further enhancing its solubility and stability. The zinc element in sodium zinc ethylenediaminetetraacetate (EDTA zinc sodium) has antioxidant properties, which can improve the product's stability.

[0028] 2. Through extensive experiments and research, this invention has discovered that TPGS-SO3H and EDTA sodium zinc can produce a synergistic effect. The combination of TPGS-SO3H and EDTA sodium zinc can significantly improve product stability and significantly reduce adverse reactions caused by injection in animals. This results in a significant improvement in the safety and efficacy of the maripitan citrate injection prepared by this invention, better stability, and effective reduction of injection pain, greatly enhancing the comfort during treatment. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0030] The embodiments of the present invention will be described in detail below. However, unnecessary details may be omitted. For example, detailed descriptions of well-known matters and repeated descriptions may be omitted. This is to avoid making the following description unnecessarily lengthy and to facilitate understanding by those skilled in the art.

[0031] The "scope" disclosed in this invention is defined in the form of a lower limit and an upper limit. A given scope is defined by selecting a lower limit and an upper limit, which define the boundaries of the specific scope. The scope defined in this way can include or exclude end values, and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a scope.

[0032] Unless otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form new technical solutions.

[0033] Unless otherwise specified, all technical features and optional technical features of this invention can be combined to form new technical solutions.

[0034] Unless otherwise specified, the terms "comprising" and "including" as used in this invention can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other substances not listed may also be included, or that only the listed substances may be included.

[0035] Unless otherwise specified, all steps of the present invention may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0036] To address the technical problems of existing maropistan citrate injections, such as low bioavailability, poor stability, and susceptibility to adverse reactions during injection, this invention provides a maropistan citrate injection comprising maropistan citrate, TPGS-SO3H, sodium zinc ethylenediaminetetraacetate, and water for injection.

[0037] In one or more specific embodiments, the mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is (100-200):(1-2).

[0038] Preferably, the mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is 100:1.

[0039] In one or more specific embodiments, the mass ratio of maropistan citrate to TPGS-SO3H is 1:(1-2).

[0040] Preferably, the mass ratio of maropistan citrate to TPGS-SO3H is 1:1 or 1:2.

[0041] In one or more specific embodiments, each 20 ml of injection solution contains the following components:

[0042] Maropitan citrate (calculated as maropitan) 200mg;

[0043] TPGS-SO3H 200-400mg;

[0044] 2-4 mg of zinc sodium ethylenediaminetetraacetate;

[0045] 20ml of water for injection.

[0046] The preparation method of maripitan citrate injection provided by the present invention includes the following steps:

[0047] Weigh TPGS-SO3H and sodium zinc ethylenediaminetetraacetate, add them to water for injection, and stir to dissolve.

[0048] Add malopistan citrate, stir to dissolve, then add water for injection to the final volume to obtain a mixed solution;

[0049] Filter the mixed solution until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0050] Sterilize to obtain malopistan citrate injection.

[0051] In one or more specific embodiments, the filtration uses a 0.22~0.45μm microporous membrane.

[0052] In one or more specific embodiments, the sterilization is performed using moist heat steam sterilization.

[0053] The technical solution of the present invention will be further described in detail below with reference to the embodiments.

[0054] It should be noted that, unless otherwise specified, the experimental methods used in the embodiments are conventional methods. The materials, reagents, methods, and instruments used, unless otherwise specified, are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0055] Example 1

[0056] Each unit dose of malopistan citrate injection is made from the following materials:

[0057] Maropitan citrate (calculated as maropitan): 200mg

[0058] TPGS-SO3H (weight average molecular weight: 1594): 200mg

[0059] Sodium zinc ethylenediaminetetraacetate: 2 mg

[0060] Add water for injection to a final volume of 20 ml.

[0061] Its preparation method is carried out according to the following steps:

[0062] 1. Weigh out TPGS-SO3H and sodium zinc ethylenediaminetetraacetate according to the prescription, add water for injection, and stir to dissolve;

[0063] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0064] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0065] 4. The sample filled into ampoules is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0066] Example 2

[0067] Each unit dose of malopistan citrate injection is made from the following materials:

[0068] Maropitan citrate (calculated as maropitan): 200mg

[0069] TPGS-SO3H (weight average molecular weight: 1594): 400mg

[0070] Sodium zinc ethylenediaminetetraacetate: 4 mg

[0071] Add water for injection to a final volume of 20 ml.

[0072] Its preparation method is carried out according to the following steps:

[0073] 1. Weigh out TPGS-SO3H and sodium zinc ethylenediaminetetraacetate according to the prescription, add water for injection, and stir to dissolve;

[0074] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0075] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0076] 4. The sample filled into ampoules is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0077] Example 3

[0078] Each unit dose of malopistan citrate injection is made from the following materials:

[0079] Maropitan citrate (calculated as maropitan): 200mg

[0080] TPGS-SO3H (weight average molecular weight: 1594): 300mg

[0081] Sodium zinc ethylenediaminetetraacetate: 3mg

[0082] Add water for injection to a final volume of 20 ml.

[0083] Its preparation method is carried out according to the following steps:

[0084] 1. Weigh out TPGS-SO3H and sodium zinc ethylenediaminetetraacetate according to the prescription, add water for injection, and stir to dissolve;

[0085] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0086] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0087] 4. The sample filled into ampoules is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0088] Comparative Example 1

[0089] Each unit dose of malopistan citrate injection is made from the following materials:

[0090] Maropitan citrate (calculated as maropitan): 200mg

[0091] TPGS-SO3H (weight average molecular weight: 1594): 200mg

[0092] Add water for injection to a final volume of 20 ml.

[0093] Its preparation method is carried out according to the following steps:

[0094] 1. Weigh out the prescribed amount of TPGS-SO3H and add it to water for injection, stirring to dissolve it;

[0095] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0096] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0097] 4. The sample filled into ampoules is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0098] Comparative Example 2

[0099] Maropitane citrate injection (trade name: Cerrin) sold on the market uses sodium sulfobutyl betacyclodextrin as a solubilizer, and a batch of samples is prepared according to the product's formula.

[0100] Each unit dose of malopistan citrate injection is made from the following materials:

[0101] Maropitan citrate (calculated as maropitan): 200mg

[0102] Sodium sulfobutyl betacyclodextrin: 0.5g

[0103] Add water for injection to a final volume of 20 ml.

[0104] Its preparation method is carried out according to the following steps:

[0105] 1. Weigh out the prescribed amount of sodium sulfobutyl betacyclodextrin and add it to water for injection, stirring until dissolved;

[0106] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0107] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0108] 4. The sample, which is filled into an ampoule, is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0109] Comparative Example 3

[0110] This comparative example increases the amount of sodium sulfobutyl betacyclodextrin in comparative example 2 to prepare a batch of maropistane citrate injection samples.

[0111] Each unit dose of malopistan citrate injection is made from the following materials:

[0112] Maropitan citrate (calculated as maropitan): 200mg

[0113] Sodium sulfobutyl betacyclodextrin: 3g

[0114] Add water for injection to a final volume of 20 ml.

[0115] Its preparation method is carried out according to the following steps:

[0116] 1. Weigh out the prescribed amount of sodium sulfobutyl betacyclodextrin and add it to water for injection, stirring until dissolved;

[0117] 2. Add malopistan citrate, stir constantly to dissolve, then add water for injection to the total volume, and stir to mix thoroughly;

[0118] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0119] 4. The sample, which is filled into an ampoule, is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0120] Comparative Example 4

[0121] Each unit dose of malopistan citrate injection is made from the following materials:

[0122] Maropitan citrate (calculated as maropitan): 200mg

[0123] Tween 80: 300mg

[0124] Add water for injection to a final volume of 20 ml.

[0125] Its preparation method is carried out according to the following steps:

[0126] 1. Add water for injection. Add Tween 80 to water for injection according to the prescription and stir to dissolve.

[0127] 2. Add malopistan citrate and stir continuously until dissolved. Then add water for injection to the total volume and stir until well mixed.

[0128] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0129] 4. The sample, which is filled into an ampoule, is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0130] Comparative Example 5:

[0131] Each unit dose of malopistan citrate injection is made from the following materials:

[0132] Maropitan citrate (calculated as maropitan): 200mg

[0133] TPGS-SO3H (weight average molecular weight: 1594): 200mg

[0134] Ethylenediaminetetraacetic acid (EDTA): 2mg

[0135] Add water for injection to a final volume of 20 ml.

[0136] Its preparation method is carried out according to the following steps:

[0137] 1. Weigh out the prescribed amounts of TPGS-SO3H and EDTA and add them to water for injection, stirring to dissolve them;

[0138] 2. Add malopistan citrate and stir continuously until dissolved. Then add water for injection to the total volume and stir until well mixed.

[0139] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0140] 4. The sample, which is filled into an ampoule, is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0141] Comparative Example 6

[0142] Each unit dose of malopistan citrate injection is made from the following materials:

[0143] Maropitan citrate (calculated as maropitan): 200mg

[0144] TPGS-SO3H (weight average molecular weight: 1594): 200mg

[0145] Disodium EDTA: 2mg

[0146] Add water for injection to a final volume of 20 ml.

[0147] Its preparation method is carried out according to the following steps:

[0148] 1. Weigh out TPGS-SO3H and disodium ethylenediaminetetraacetate according to the prescription and add them to water for injection, stirring to dissolve them;

[0149] 2. Add malopistan citrate and stir continuously until dissolved. Then add water for injection to the total volume and stir until well mixed.

[0150] 3. Filter the obtained solution through a 0.45μm microporous membrane until the filtrate is clear, test it, dispense it, and seal it into ampoules;

[0151] 4. The sample, which is filled into an ampoule, is sterilized by moist heat steam to obtain the maropistam citrate injection sample.

[0152] Experimental Example

[0153] 1. Stability Testing

[0154] The stability of the samples prepared in Example 1 and Comparative Examples 1, 5, and 6 was investigated. The stability test method was as follows: the samples were placed at 40°C and 75% humidity for 6 months, and samples were taken at 0, 1, 3, and 6 months. The samples were detected by high performance liquid chromatography according to the quality standard of maropistant injection. The results are shown in Table 1.

[0155] Table 1. Stability test data of samples prepared in Example 1 and Comparative Examples 1, 5, and 6.

[0156]

[0157] As can be seen from the data in Table 1:

[0158] The effect of adding only TPGS-SO3H in Comparative Example 1 was not as good as that of adding the combination of TPGS-SO3H and sodium zinc ethylenediaminetetraacetate in Example 1. After 6 months of acceleration, the single impurity content of Comparative Example 1 was 2.5 times that of Example 1, and the total impurity content was 2.6 times that of Example 1, which proves that the combination of TPGS-SO3H and sodium zinc ethylenediaminetetraacetate of the present invention can effectively improve product stability.

[0159] Comparative Example 5 used ethylenediaminetetraacetic acid (EDTA) instead of sodium zinc EDTA, and Comparative Example 6 used disodium EDTA instead of sodium zinc EDTA. After 6 months of acceleration, the content of single impurities and total impurities also increased significantly, proving that the sodium zinc EDTA of the present invention has better effects than EDTA and disodium EDTA, and can better synergistically improve product stability with TPGS-SO3H.

[0160] 2. Solubility Test

[0161] The solubility of the samples from Example 1 and Comparative Examples 1-4 was tested by adding excess maripitan citrate to the solutions formed by each solubilizer, shaking for a period of time to form a supersaturated solution, filtering, and determining the content (concentration) of maripitan citrate by high performance liquid chromatography.

[0162] Table 2. Solubility test data of samples from Example 1 and Comparative Examples 1-4

[0163]

[0164] As can be seen from the data in Table 2, the combination of TPGS-SO3H and zinc sodium ethylenediaminetetraacetate in the embodiments of the present invention can effectively improve the solubility of the product, and the effect is significantly better than that of sodium sulfobutyl betacyclodextrin used in the prior art. As a result, the maropistam citrate injection prepared by the present invention has better water solubility and higher bioavailability. Moreover, the combination of TPGS-SO3H and zinc sodium ethylenediaminetetraacetate in the formulation has a better solubilizing effect than the formulation with only TPGS-SO3H.

[0165] 3. Adverse reaction testing

[0166] The injection pain, wound healing time, and post-injection infection status of the samples prepared in Examples 1-3 and Comparative Examples 1-6 were further compared. The injection pain test method was the pain behavior observation method, which judged the degree of pain by observing the animals' facial expressions, limb movements, respiratory changes, and whether they made any noises during injection. The results are shown in Table 3.

[0167] Table 3. Results of injection pain sensation in samples prepared in Examples 1-3 and Comparative Examples 1-6

[0168]

[0169] As can be seen from the data in Table 3, the combination of TPGS-SO3H and sodium zinc EDTA prepared by the present invention for maropitane citrate injection can effectively reduce adverse reactions caused by injection, greatly improve the comfort of pets during treatment, accelerate wound healing after injection, and significantly reduce infection events caused by injection.

[0170] Finally, it should be noted that the above specific embodiments are only used to describe the purpose, technical solution, and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation of the present invention and is not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the foregoing specific embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions or improvements can be made to some or all of the technical features. These modifications, equivalent substitutions, and improvements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A maripitan citrate injection, characterized in that, Including TPGS-SO3H and sodium zinc ethylenediaminetetraacetate.

2. The maripitan citrate injection according to claim 1, characterized in that, The mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is (100-200):(1-2).

3. The maripitan citrate injection according to claim 1, characterized in that, The mass ratio of TPGS-SO3H to sodium zinc ethylenediaminetetraacetate is 100:

1.

4. The maripitan citrate injection according to claim 1, characterized in that, The maropistan citrate injection solution comprises maropistan citrate, TPGS-SO3H, sodium zinc ethylenediaminetetraacetate, and water for injection.

5. The malopistan citrate injection according to claim 4, characterized in that, The mass ratio of the malopitant citrate to TPGS-SO3H is 1:(1-2).

6. The maripitan citrate injection according to claim 5, characterized in that, The mass ratio of malopitant citrate to TPGS-SO3H is 1:1 or 1:

2.

7. The maripitan citrate injection according to claim 1, characterized in that, Each 20ml of injection solution contains the following components: Maropitan citrate: 200mg; TPGS-SO3H 200-400mg; 2-4 mg of zinc sodium ethylenediaminetetraacetate; 20ml of water for injection.

8. The method for preparing malopistan citrate injection according to any one of claims 4-7, characterized in that, Includes the following steps: Weigh TPGS-SO3H and sodium zinc ethylenediaminetetraacetate, add them to water for injection, and stir to dissolve. Add malopistan citrate, stir to dissolve, then add water for injection to the final volume to obtain a mixed solution; Filter the mixed solution until the filtrate is clear, test it, dispense it, and seal it into ampoules; Sterilize to obtain malopistan citrate injection.

9. The method for preparing a maripitan citrate injection according to claim 8, characterized in that, The filtration uses a 0.22~0.45μm microporous membrane.

10. The method for preparing a maripitan citrate injection according to claim 8, characterized in that, The sterilization process employs moist heat steam sterilization.

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