Ceftiofur compound injection and preparation method thereof

Abstract

The present invention discloses a ceftiofur compound injection and a preparation method thereof, belonging to the field of pharmaceutical preparations. The compound is characterized by being prepared from the following raw materials in weight percentage: 5-10% of a ceftiofur raw material, 5-10% of ketoprofen, 10-20% of an aqueous compounding agent, 2-8% of an antioxidant, and the balance being water for injection. The present invention has the beneficial effects of: ketoprofen not only serving as a pH regulator but also increasing the solubility of ceftiofur; glycine not only serving as an antioxidant but also serving as a pH regulator and a nutritional supplement, fully utilizing the functions of pharmaceutical excipients; and forming a unique aqueous compounding agent through the specific ratio of the components for the specific purpose of dissolving ceftiofur free acid or ceftiofur hydrochloride in a water-soluble system. This solves the problem of ceftiofur free acid or ceftiofur hydrochloride being insoluble in a water-soluble system and the problem that ceftiofur drugs can only be used in fresh preparation or suspension form or cannot be solved by sedimentation.

Description

Technical field:

[0001] The present invention belongs to the field of pharmaceutical preparations, and more particularly relates to a ceftiofur compound injection and a preparation method thereof. Background technology:

[0002] Ceftiofur, also known as Ceftiofur, is used to treat animal diseases. Ceftiofur is rapidly absorbed and has high bioavailability. Its high protein binding rate in the body creates a reservoir of bactericidal potential, resulting in a long half-life and sustained efficacy. Compared to other antibiotics, this drug is unique in that its concentration in infected tissues is 2-4 times higher than in uninfected tissues, resulting in a targeted, concentrated distribution and a bactericidal effect.

[0003] Currently, approved formulations in my country include ceftiofur soluble powder and suspension injection, both of which have demonstrated promising results in treating animal diseases. However, since these formulations typically maintain effective blood concentrations for only 24-32 hours, clinical treatment requires daily injections, which can be inconvenient for veterinarians and can also lead to animal discomfort.

[0004] Ceftiofur is available in various forms, including ceftiofur crystals, ceftiofur hydrochloride, and ceftiofur sodium salt. Ceftiofur sodium salt is readily soluble in water but has poor stability after dissolution, requiring immediate preparation for injection. It also has a short half-life after injection and requires frequent dosing. Ceftiofur crystals and ceftiofur hydrochloride are poorly soluble in water. Currently, there are no reports on aqueous injections of ceftiofur crystals or ceftiofur hydrochloride.

[0005] Patent CN102341125A discloses formulations containing ceftiofur and ketoprofen or ceftiofur and benzyl alcohol, including a wetting agent or dispersant, a preservative, a flocculant, a suspendability enhancer, and / or a biocompatible oil vehicle. The formulations further provide methods for increasing the resuspendability of oily formulations. The formulations are primarily composed of oily excipients, resulting in high viscosity and high cost.

[0006] Patent CN103191057B, an aqueous suspension injection of ceftiofur and its preparation method, provides an aqueous suspension of ceftiofur. The suspension comprises micronized ceftiofur starting material, a water-soluble excipient, a suspending agent, a suspending aid, and water for injection. While this solution addresses the high viscosity and inconvenience of ceftiofur oily suspensions, it does not address the sedimentation characteristics of the suspension. Summary of the invention:

[0007] To solve the above problems and overcome the deficiencies of the prior art, the present invention provides a ceftiofur compound injection and a preparation method thereof, which can effectively:

[0008] Solve the problem that ceftiofur sodium salt is easily soluble in water, has poor stability after dissolution, needs to be prepared immediately after injection, and has a short half-life after injection, requiring frequent administration;

[0009] Solve the problems of high viscosity or sedimentation of aqueous suspension of ceftiofur and oily excipients.

[0010] The specific technical solution of the present invention for solving the above technical problems is: a ceftiofur compound injection, characterized in that it is prepared from the following raw materials in weight percentage: 5-10% ceftiofur raw material, 5-10% ketoprofen, 10-20% aqueous compounding agent, 2-8% antioxidant, and the balance being water for injection.

[0011] Furthermore, the ceftiofur raw material is ceftiofur free acid or ceftiofur hydrochloride.

[0012] Furthermore, the aqueous compounding agent is a combination of glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate.

[0013] Furthermore, the mass ratio of the glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate is (5-1): (3-1): (2-1).

[0014] Furthermore, the antioxidant is glycine.

[0015] A method for preparing a ceftiofur compound injection, using the components of the ceftiofur compound injection, is characterized by comprising the following steps:

[0016] a. Prepare an aqueous compound according to the component ratio;

[0017] b. The ceftiofur drug substance is added to the above solution, heated and stirred to dissolve completely, and continued to heat and stir for a certain period of time after the compound is cooled to room temperature;

[0018] c. Inject the above solution into an appropriate amount of water for injection;

[0019] d. Add the antioxidant to the above solution and stir until completely dissolved;

[0020] e. Add ketoprofen to the above solution, stir to dissolve, pH value 6.5 ~ 7.0, add the remaining amount of water for injection, stir to obtain the compound injection of ceftiofur and ketoprofen.

[0021] Furthermore, the compounding time is 30 min to 90 min.

[0022] Furthermore, the compounding temperature is 60-80°C.

[0023] The beneficial effects of the present invention are:

[0024] The present invention provides a compound injection of ceftiofur and ketoprofen, comprising a ceftiofur API, ketoprofen, an aqueous compounding agent, an antioxidant, and water for injection. The compound has a wide range of excipients and is inexpensive, significantly saving costs. The compound has low viscosity, making it easy to draw and inject. It also has low irritation, minimizing pain for livestock.

[0025] Unlike other ceftiofur suspensions, the present invention provides a water-soluble compound injection of ceftiofur and ketoprofen, offering stable efficacy and requiring no pre-preparation, thus filling a gap in aqueous injection solutions. Ketoprofen not only serves as a pH regulator but also increases the solubility of ceftiofur; while glycine not only acts as an antioxidant, but also as a pH regulator and nutritional supplement, fully utilizing the functions of pharmaceutical excipients.

[0026] The present invention provides a method for preparing a compound injection of ceftiofur and ketoprofen. A unique aqueous compound is formed by proportioning specific components, and is used for the specific purpose of dissolving ceftiofur free acid or ceftiofur hydrochloride in a water-soluble system. The method solves the problem that ceftiofur free acid or ceftiofur hydrochloride is insoluble in a water-soluble system, promotes the improvement of water-soluble ceftiofur compound injection, and solves the problem that ceftiofur drugs can only be used in fresh preparation or suspension or cannot be settled. Description of the drawings:

[0027] Attachment Figure 1 1 is a state diagram of the sample configurations of Example 1 and Comparative Example 2 of the present invention;

[0028] Attachment Figure 2 This is a state diagram of the sample configuration of Comparative Example 3 of the present invention;

[0029] Attachment Figure 3 This is a state diagram of the sample configuration of Comparative Example 4 of the present invention;

[0030] Attachment Figure 4 This is a state diagram of the sample configuration of Comparative Example 5 of the present invention; Specific implementation method:

[0031] In the description of the present invention, specific details are provided solely to facilitate a thorough understanding of the embodiments of the present invention. However, those skilled in the art will appreciate that the present invention is not limited to these details. Furthermore, well-known structures and functions have not been described or illustrated in detail to avoid obscuring the key points of the embodiments of the present invention. Those skilled in the art will appreciate the specific meanings of the above terms as used in the present invention.

[0032] Specific implementation of the present invention:

[0033] In order to better understand the present invention, a specific embodiment is used for illustration. It is worth emphasizing that the effects of this embodiment are not substantially different from those of various embodiments within the scope of protection of the present invention, including the respective reagents and the content ratios of the reagents. All of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here.

[0034] Example 1:

[0035] Ceftiofur free acid 75g

[0036] Ketoprofen 75g

[0037] 150g glycerol acetone acetal

[0038] Pea maltodextrin 90g

[0039] Propylene glycol monolaurate 60g

[0040] Glycine 50g

[0041] Add water for injection to 1000mL;

[0042] Preparation method: Step 1, compounding glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate according to the component ratio to prepare an aqueous compounding agent;

[0043] Step 2: Add the prescribed amount of ceftiofur free acid to the above aqueous compound, heat to 80°C, stir and dissolve the ceftiofur free acid, continue heating and stirring for 30 minutes, and then cool to room temperature;

[0044] Step 3: inject the above solution into an appropriate amount of water for injection;

[0045] Step 4: Add glycine to the above solution and stir until completely dissolved;

[0046] Step 5: adding ketoprofen to the above solution, stirring to dissolve, pH value 6.5-7.0, adding the remaining amount of water for injection, stirring evenly to obtain the compound injection of ceftiofur and ketoprofen.

[0047] Example 2:

[0048] Ceftiofur free acid 75g

[0049] Ketoprofen 75g

[0050] 120g acetone acetal

[0051] 120g pea maltodextrin

[0052] Propylene glycol monolaurate 60g

[0053] Glycine 50g

[0054] Add water for injection to 1000mL

[0055] The preparation method is the same as that of Example 1.

[0056] Example 3:

[0057] Ceftiofur Hydrochloride 75g

[0058] Ketoprofen 75g

[0059] 100g acetone acetal

[0060] Pea maltodextrin 100g

[0061] Propylene glycol monolaurate 100g

[0062] Glycine 50g

[0063] Add water for injection to 1000mL

[0064] The preparation method is the same as that of Example 1.

[0065] The test results of the sample under strong light irradiation of 5000±500Lux are shown in Table 1 below:

[0066] Table 1. Sample illumination test results

[0067]

[0068] As can be seen from the experimental results in Table 1, the ceftiofur ketoprofen injections prepared using the components and proportions provided in Examples 1-3 of the present invention exhibited stable sample quality under strong light irradiation. Furthermore, the related substances, pH value, ketoprofen content, and ceftiofur content in Example 2 varied less than those in Examples 1 and 3. Therefore, when the component proportions were the same as in Example 2, the sample quality was more stable.

[0069] In particular, the results of the accelerated test of the samples in the embodiment at 40±2°C and RH75±5% are shown in Table 2 below:

[0070] Table 2. Sample accelerated test results

[0071]

[0072] From the experimental results in Table 2, it can be seen that the sample of Example 2 was placed under accelerated conditions for 6 months, and the quality indicators such as pH value, related substances, ketoprofen and ceftiofur content were all qualified, and the fluctuation of each quality indicator of the sample was small, indicating that the compound injection of ceftiofur and ketoprofen prepared by this prescription process is stable and feasible.

[0073] In order to more intuitively demonstrate the process advantages of the present invention, the present invention uses the same process and the replacement method for comparison.

[0074] Comparative Example 1:

[0075] The preparation method is the same as that in Example 1, except that in the preparation process of this comparative example, the ceftiofur raw material is replaced with ceftiofur sodium;

[0076] After the samples were placed at room temperature (25±2°C) for 24 hours, the sample results are shown in Table 3 below:

[0077] Table 3. Test results of samples placed for 24 hours

[0078]

[0079] From the experimental results in Table 3, it can be seen that for the compound injection of ceftiofur and ketoprofen prepared using ceftiofur crystals as the raw material, there is no change in the related substances, content, and pH value after the sample is placed at room temperature (25±2℃) for 24 hours; for the compound injection of ceftiofur and ketoprofen prepared using ceftiofur sodium as the raw material, there is a significant increase in the related substances, a significant decrease in the ceftiofur content, and a significant decrease in the pH value after the sample is placed at room temperature (25±2℃) for 24 hours.

[0080] Comparative Example 2:

[0081] The preparation method is the same as that of Example 1, except that ketoprofen is removed during the preparation of this comparative example; and a hydrochloric acid aqueous solution is used to adjust the pH value to 6.5-7.0;

[0082] The details are as follows:

[0083] Ceftiofur free acid 75g

[0084] 150g glycerol acetone acetal

[0085] Pea maltodextrin 90g

[0086] Propylene glycol monolaurate 60g

[0087] Glycine 50g

[0088] Appropriate amount of hydrochloric acid aqueous solution

[0089] Add water for injection to 1000mL

[0090] Preparation method: Step 1, compounding glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate according to the component ratio to prepare an aqueous compounding agent;

[0091] Step 2: Add the prescribed amount of ceftiofur free acid to the above aqueous compound, heat to 80°C, stir and dissolve the ceftiofur free acid, continue heating and stirring for 30 minutes, and then cool to room temperature;

[0092] Step 3: inject the above solution into an appropriate amount of water for injection;

[0093] Step 4: Add glycine to the above solution and stir until completely dissolved;

[0094] Step 5: using hydrochloric acid aqueous solution to adjust the pH value to 6.5-7.0, adding the remaining amount of water for injection, and stirring evenly to obtain the compound injection of ceftiofur and ketoprofen.

[0095] According to the test phenomena, we can know that:

[0096] During the preparation process of Comparative Example 2, in step 3, after the above solution was injected into an appropriate amount of water for injection, part of the ceftiofur raw material was precipitated, and some of the raw material was not completely dissolved until the final preparation was completed; while during the preparation process of Example 1, in step 3, after the above solution was injected into an appropriate amount of water for injection, part of the ceftiofur raw material was also precipitated, but ketoprofen was added until the final preparation was completed, and the raw material was completely dissolved. Figure 1 .

[0097] Comparative Example 3:

[0098] The preparation method is the same as that in Example 1, except that in the preparation process of this comparative example, the ceftiofur raw material is replaced with cefixime;

[0099] In the preparation process of Comparative Example 3, in step 3, after the above solution was injected into an appropriate amount of water for injection, cefixime was partially precipitated, and some of the raw materials were not completely dissolved until the final preparation was completed. Figure 2 .

[0100] Combined with Example 1, Comparative Example 2 and Comparative Example 3, it can be proved that ketoprofen can not only serve as a pH regulator, but also increase the solubility of ceftiofur free acid or ceftiofur hydrochloride in glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate;

[0101] In order to more intuitively demonstrate the advantages of the aqueous compound of the present invention, the present invention is compared with the replacement method using the same process.

[0102] Comparative Example 4:

[0103] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the acetone acetal in the aqueous compounding agent is replaced with glycerol;

[0104] During the preparation of Comparative Example 4, in step 5, ketoprofen was added to the above solution and could not be completely dissolved. The prepared sample is shown below. Figure 3 ,

[0105] In combination with Example 1, it can be seen that the aqueous compound prepared by the present invention has a specific dissolving effect and can synergize with ketoprofen to increase the solubility of ceftiofur.

[0106] Comparative Example 5:

[0107] The preparation method is the same as that of Example 1, except that in the preparation process of this comparative example, the water for injection is replaced with propylene glycol;

[0108] Preparation method: Step 1, compounding glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate according to the component ratio to prepare an aqueous compounding agent;

[0109] Step 2: Add the prescribed amount of ceftiofur free acid to the above aqueous compound, heat to 80°C, stir and dissolve the ceftiofur free acid, continue heating and stirring for 30 minutes, and then cool to room temperature;

[0110] Step 3, injecting the above solution into an appropriate amount of propylene glycol;

[0111] Step 4: glycine was added to the above solution, but the glycine was not completely dissolved;

[0112] Step 5: add ketoprofen to the above solution. If ketoprofen is not completely dissolved, adjust the pH value to 6.5-7.0, add the remaining amount of propylene glycol, and stir evenly to obtain a suspension injection of ceftiofur and ketoprofen. Figure 4 .

[0113] It can be seen from Comparative Example 5 and Example 1 that when propylene glycol is used instead of the water for injection in the present invention, a clear compound injection of ceftiofur and ketoprofen cannot be obtained, but only a suspension injection of ceftiofur and ketoprofen can be obtained.

[0114] Comparative Example 6:

[0115] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the antioxidant glycine is not added;

[0116] Table 4. Sample high temperature test results

[0117]

[0118] As can be seen from the experimental results in Table 4, the sample of Comparative Example 6 without the addition of the antioxidant glycine, after being stored at 60°C for 10 days, showed significantly increased levels of both single and total impurities, while significantly decreased levels of ketoprofen and ceftiofur, compared to Example 1. The sample of Example 1 with the addition of the antioxidant showed relatively stable quality, with no significant changes.

[0119] In order to more intuitively demonstrate the advantages of the compounding conditions of the present invention, the present invention is compared with the replacement method using the same process.

[0120] Example 4

[0121] Ceftiofur free acid 75g

[0122] Ketoprofen 75g

[0123] 120g acetone acetal

[0124] 120g pea maltodextrin

[0125] Propylene glycol monolaurate 60g

[0126] Glycine 50g

[0127] Add water for injection to 1000mL

[0128] Preparation method: Step 1, compounding glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate according to the component ratio to prepare an aqueous compounding agent;

[0129] Step 2: Add the prescribed amount of ceftiofur free acid to the above aqueous compound, heat to 80°C, stir and dissolve the ceftiofur free acid, continue heating and stirring for 60 minutes, and then cool to room temperature;

[0130] Step 3: inject the above solution into an appropriate amount of water for injection;

[0131] Step 4: Add glycine to the above solution and stir until completely dissolved;

[0132] Step 5: adding ketoprofen to the above solution, stirring to dissolve, pH value 6.5-7.0, adding the remaining amount of water for injection, stirring evenly to obtain the compound injection of ceftiofur and ketoprofen.

[0133] Example 5

[0134] Ceftiofur free acid 75g

[0135] Ketoprofen 75g

[0136] 120g acetone acetal

[0137] 120g pea maltodextrin

[0138] Propylene glycol monolaurate 60g

[0139] Glycine 50g

[0140] Add water for injection to 1000mL

[0141] Preparation method: Step 1, compounding glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate according to the component ratio to prepare an aqueous compounding agent;

[0142] Step 2: Add the prescribed amount of ceftiofur free acid to the above aqueous compound, heat to 70°C, stir and dissolve the ceftiofur free acid, continue heating and stirring for 60 minutes, and then cool to room temperature;

[0143] Step 3: inject the above solution into an appropriate amount of water for injection;

[0144] Step 4: Add glycine to the above solution and stir until completely dissolved;

[0145] Step 5: adding ketoprofen to the above solution, stirring to dissolve, pH value 6.5-7.0, adding the remaining amount of water for injection, stirring evenly to obtain the compound injection of ceftiofur and ketoprofen.

[0146] The test results of the sample under strong light irradiation of 5000±500Lux are shown in Table 5 below:

[0147] Table 5. Sample illumination test results

[0148]

[0149] As can be seen from the experimental results of Table 5, when the heating temperature of Example 4 was 80°C and the heating and remixing time was 60min, and when the heating temperature of Example 5 was 70°C and the heating and remixing time was 60min, the sample quality changed greatly compared with Example 2 when the heating temperature was 80°C and the heating and remixing time was 30min. Single impurities and total impurities were significantly increased, and the ketoprofen content and ceftiofur content were significantly reduced. Moreover, the experimental data of 10 days of illumination showed that Example 4 was the most sensitive under illumination conditions, followed by Example 5, and Example 2 was the most stable. Therefore, the heating time was set to 80°C and the remixing time was set to 30min.

[0150] In summary:

[0151] The present invention provides a compound injection of ceftiofur and ketoprofen, comprising a ceftiofur API, ketoprofen, an aqueous compounding agent, an antioxidant, and water for injection. The compound has a wide range of excipients and is inexpensive, significantly saving costs. The compound has low viscosity, making it easy to draw and inject. It also has low irritation, minimizing pain for livestock.

[0152] Unlike other ceftiofur suspensions, the present invention provides a water-soluble compound injection of ceftiofur and ketoprofen, offering stable efficacy and requiring no pre-preparation, thus filling a gap in aqueous injection solutions. Ketoprofen not only serves as a pH regulator but also increases the solubility of ceftiofur; while glycine not only acts as an antioxidant, but also as a pH regulator and nutritional supplement, fully utilizing the functions of pharmaceutical excipients.

[0153] The present invention provides a method for preparing a compound injection of ceftiofur and ketoprofen. A unique aqueous compound is formed by proportioning specific components, and is used for the specific purpose of dissolving ceftiofur free acid or ceftiofur hydrochloride in a water-soluble system. The method solves the problem that ceftiofur free acid or ceftiofur hydrochloride is insoluble in a water-soluble system, promotes the improvement of water-soluble ceftiofur compound injection, and solves the problem that ceftiofur drugs can only be used in fresh preparation or suspension or cannot be settled.

Claims

1. A ceftiofur compound injection, characterized in that: The preparation is prepared from the following raw materials in the following weight percentages: 5-10% of ceftiofur raw material, 5-10% of ketoprofen, 10-20% of aqueous compounding agent, 2-8% of antioxidant, and the balance is water for injection; The ceftiofur API is ceftiofur free acid or ceftiofur hydrochloride; The aqueous compounding agent is a combination of glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate.

2. The ceftiofur compound injection according to claim 1, characterized in that The mass ratio of the glycerol acetone acetal, pea maltodextrin and propylene glycol monolaurate is (5-1): (3-1): (2-1).

3. The ceftiofur compound injection according to claim 1, characterized in that The antioxidant is glycine.

4. The method for preparing the ceftiofur compound injection according to any one of claims 1 to 3, wherein: The following steps are involved: a. Prepare an aqueous compound according to the component ratio; b. The ceftiofur drug substance is added to the above solution, heated and stirred until completely dissolved, and continued to heat to the compounding temperature, stirred and compounded for a certain period of time and then cooled to room temperature; c. Inject the above solution into an appropriate amount of water for injection; d. Add the antioxidant to the above solution and stir until completely dissolved; e. Add ketoprofen to the above solution, stir to dissolve, pH value 6.5-7.0, add the remaining amount of water for injection, stir evenly to obtain the compound injection of ceftiofur and ketoprofen.

5. The method for preparing the ceftiofur compound injection according to claim 4, characterized in that The compounding time is 30 to 90 minutes.

6. The method for preparing the ceftiofur compound injection according to claim 4, characterized in that The compounding temperature is 60-80°C.

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