20% ceftiofur hydrochloride long-acting slow-release injection for dairy cow and preparation method thereof
By preparing a long-acting sustained-release injection containing ceftiofur hydrochloride, the problems of production complexity and high cost in the existing technology have been solved, and the stability and release effect of the drug have been improved, making it suitable for industrial production and clinical application.
Patent Information
- Application Number
- CN202511830756.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-06
- Publication Date
- 2026-02-10
AI Technical Summary
The existing 20% ceftiofur crystal injection has a complex production process, high quality control requirements, long-acting sustained-release effect depends on crystal morphology and is expensive, and has low solubility, which affects release behavior and the ability to quickly achieve high blood drug concentrations.
This long-acting sustained-release injection, composed of ceftiofur hydrochloride, dispersant, suspending agent, emulsifier, antioxidant, and sustained-release material, is prepared using a high-speed shear disperser to ensure the physical and chemical stability of the drug solution, resulting in a narrow particle size distribution and improved release effect.
It significantly improves the stability and release effect of the injection solution, reduces the probability of needle blockage, prolongs the drug action time, reduces the frequency of administration, is suitable for industrial production, and has broad application prospects.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of veterinary injectable drug technology, and relates to a long-acting sustained-release injection of 20% ceftiofur hydrochloride for dairy cows and its preparation method. Background Technology
[0002] Treating and preventing bovine respiratory diseases (such as pneumonia and transport fever) caused by Pasteurella multocida, Pasteurella multocida, and Haemophilus dorsi are crucial for ensuring herd health and profitability. These pathogens are transmitted through the respiratory tract, digestive tract, or by contact, and are prone to outbreaks under stressful conditions such as transportation and cold, leading to high mortality rates. Mixed infections can further exacerbate the disease. Strengthening prevention and control measures not only ensures food safety and market stability but also enhances the industry's resilience and supports the sustainable development of cattle farming, a pillar of agriculture. Therefore, treating and preventing bovine respiratory diseases (pneumonia and transport fever) caused by Pasteurella multocida, Pasteurella multocida, and Haemophilus dorsi are key to protecting herd health, public health, industry stability, and policy compliance.
[0003] Zoetis's Easily Target (20% Ceftiofur Crystal Injection) offers significant advantages as a veterinary drug for cattle. Its core ingredient exhibits strong antibacterial activity against key pathogens causing bovine respiratory diseases, and its sustained-release formulation technology achieves long-lasting efficacy. The effective blood concentration remains high after a single subcutaneous injection, significantly reducing injection frequency and lowering operational costs. When used on lactating dairy cows, it eliminates the milk loss period, ensuring both efficient market entry and reduced milk production. Its indications cover a variety of common bovine diseases, including respiratory diseases and metritis, simplifying treatment regimens and improving disease control efficiency. Furthermore, it boasts good safety profiles, with few side effects and mild, reversible reactions at normal doses. It is an important disease control drug that balances antibacterial efficacy, farming efficiency, and animal safety, particularly suitable for large-scale farms seeking cost reduction and efficiency improvement. However, the production process and quality control requirements for 20% Ceftiofur Crystal Injection are high. Its long-lasting effect depends on the specific morphology and uniform particle size distribution of ceftiofur crystals. The production process must control crystal morphology and avoid forming excessively large particles, which could affect release behavior or clog needles. Meanwhile, the low solubility of the crystalline form, while prolonging the duration of action, also limits its ability to rapidly achieve high blood concentrations. Furthermore, the price of Easily Released Ceftiofur is significantly higher than similar ordinary ceftiofur products on the market. Therefore, developing a clinically effective, easily industrially produced 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows, for the treatment and prevention of bovine respiratory diseases caused by hemolytic Pasteurella multocida, Pasteurella multocida, and Haemophilus neonatorum infections, is of great significance in livestock production practices. Summary of the Invention
[0004] This invention addresses the technical problems existing in the prior art by providing a long-acting sustained-release injection of 20% ceftiofur hydrochloride for dairy cows and its preparation method. The injection can effectively maintain the physical and chemical stability of the drug solution during long-term storage, and is not prone to sedimentation, clumping, or discoloration. Furthermore, it has a suitable viscosity, exhibiting excellent flowability and needle-passing performance.
[0005] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows, wherein each 100 ml of the injection contains the following components: 20 g of ceftiofur hydrochloride, 0.1-3 g of dispersant, 0.1-5 g of suspending agent, 0.1-5 g of emulsifier, 0.01-1 g of antioxidant, 0.1-5 g of sustained-release material, and the balance being an injection solvent.
[0006] Preferably, the dispersant is selected from one or more of sulfobutyl-β-cyclodextrin, propylene glycol laurate, propylene glycol glycerol, nanocellulose, distearate phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC), dilinoleyl dimethyl methacrylate (DLin-MC3-DMA), glyceryl oleate (GMO), and dioleyl glycerol (GDO).
[0007] Preferably, the suspending agent is selected from one or more of epoxidized soybean oil (ESO), cashew phenolic acetate (CA), and methyl methacrylate (MEMAA).
[0008] Preferably, the emulsifier is selected from one or more of sucrose fatty acid esters, cyclopentyl methyl ether, sophorolipid, polyoxyethylene fatty acid esters, hydrogenated soybean phosphatidylcholine, distearate phosphatidylcholine, sorbitan sesquioleate, methyl glucoside ester, lauroyl polyoxyethylene glycerol ester (Gelucire 44 / 14), and glycerol monooleate (GMO).
[0009] Preferably, the antioxidant is selected from one or more of the following: rosemary extract, tea polyphenols, sage extract, licorice antioxidants, grapefruit seed extract, sesamol, oryzanol, ellagic acid, and tocotrienols.
[0010] The sustained-release material is selected from one or more of sucrose isobutyrate acetate (SAIB), polycaprolactone (PCL), polyglycerol polyricinoleate (PGPR), and triethyl citrate (TEC).
[0011] Preferably, the solvent for injection is selected from one or more of tiger nut oil, high oleic sunflower seed oil, low erucic acid rapeseed oil, and algal oil.
[0012] This invention also provides a 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows, comprising the following steps: Step 1: Weigh the raw materials according to the amount needed to prepare 100 ml of injection solution; Step 2: Dry heat sterilize the injection solvent at 150 °C for 1 hour, then cool to room temperature; add the dispersant, suspending agent, emulsifier, antioxidant, sustained-release material, and ceftiofur hydrochloride to the injection solvent and stir until homogeneous; Step 3: Disperse evenly using a high-speed shear disperser at a speed of 18,000 to 28,000 rpm for 10 to 30 minutes to obtain long-acting ceftiofur hydrochloride injection; Step 4: After passing the inspection, the product can be filled, labeled, and packed.
[0013] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention utilizes ceftiofur hydrochloride, dispersants, suspending agents, emulsifiers, antioxidants, and sustained-release materials to form a 20% ceftiofur hydrochloride long-acting sustained-release injection. The concentration of active ingredients is higher than that of commercially available ceftiofur injections. Compared to 20% ceftiofur hydrochloride crystal injections (Excede), the probability of needle clogging is significantly reduced. Furthermore, over 96% of the powder particles in the suspension are <15μm, exhibiting a narrow particle size distribution, which enhances the release effect and significantly improves the overall performance of the injection. While ceftiofur raw material is sensitive to light and heat, the formulation of this invention, through process improvements, significantly enhances its stability to light and heat. This formulation effectively maintains the physical and chemical stability of the drug solution during long-term storage, is not prone to sedimentation, clumping, or discoloration, and has suitable viscosity, exhibiting excellent flowability and needle-clearing performance. Before use, the drug solution can be quickly restored to a uniform suspension state by simple shaking, ensuring the accuracy and convenience of dosage.
[0014] This invention achieves a significant long-acting sustained-release effect in vivo, enabling a stable and continuous release of the drug, effectively prolonging its duration of action in infected tissues, thereby significantly reducing the frequency of administration. Simultaneously, this formulation process helps ensure the bioavailability of the drug, allowing it to exert its broad-spectrum antibacterial activity efficiently.
[0015] The preparation process of this invention employs key technologies such as high-speed shearing, which has relatively relaxed requirements for equipment conditions and a simple and reliable process flow. It is very suitable for large-scale industrial production, demonstrating significant advantages of strong practicality and controllable cost, and has broad application prospects. Attached Figure Description
[0016] Figure 1 Concentration-time curves of ceftiofur in plasma after injecting dairy cows with the injection solution prepared in Example 1 and Excede. Detailed Implementation
[0017] The following examples are used to illustrate the present invention, but are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Unless otherwise specified, the experimental methods in the following examples are conventional methods. All reagents used are commercially available.
[0018] Example 1 This embodiment of the 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows contains the following components per 100 ml of injection: The preparation method of the above-mentioned 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows includes the following steps: Step 1: Weigh the raw materials according to the amount needed to prepare 100 ml of injection solution; Step 2: Dry heat sterilize the injection solvent at 150 °C for 1 hour, then cool to room temperature; add the dispersant, suspending agent, emulsifier, antioxidant, sustained-release material, and ceftiofur hydrochloride to the injection solvent and stir until homogeneous; Step 3: Disperse evenly using a high-speed shear disperser at a speed of 22,000 rpm for 15 minutes to obtain long-acting ceftiofur hydrochloride injection; Step 4: After passing the inspection, proceed with filling (three sizes: 50 ml, 100 ml, 250 ml), labeling, and packing.
[0019] Example 2 This embodiment of the 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows contains the following components per 100 ml of injection: The preparation method in this embodiment is the same as in Embodiment 1.
[0020] Example 3 This embodiment of the 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows contains the following components per 100 ml of injection: The preparation method in this embodiment is the same as in Embodiment 1.
[0021] Example 4 This embodiment of the 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows contains the following components per 100 ml of injection: The preparation method in this embodiment is the same as in Embodiment 1.
[0022] Comparative Example 1 This comparative example is basically the same as Example 1, except that the dispersant sulfobutyl-β-cyclodextrin is reduced from 0.2 g to 0.05 g.
[0023] Comparative Example 2 This comparative example is basically the same as Example 1, except that the suspending agent epoxidized soybean oil (ESO) is reduced from 0.5 g to 0.05 g.
[0024] Comparative Example 3 This comparative example is basically the same as Example 1, except that the emulsifier sucrose fatty acid ester is reduced from 0.5 g to 0.05 g.
[0025] Comparative Example 4 This comparative example is basically the same as Example 1, except that the sustained-release material sucrose isobutyrate acetate (SAIB) is reduced from 0.2 g to 0.05 g.
[0026] Comparative Example 5 This comparative example is basically the same as Example 1, except that the sustained-release material was changed from 0.2 g of sucrose isobutyrate acetate (SAIB) to 0.2 g of Tween 80.
[0027] Comparative Example 6 This comparative example is basically the same as Example 1, except that the sustained-release material sucrose isobutyrate acetate (SAIB) is removed.
[0028] Comparative Example 7 This comparative example is basically the same as Example 1, except that the dispersant sulfobutyl-β-cyclodextrin is replaced with sorbitan oleate.
[0029] Comparative Example 8 This comparative example is basically the same as Example 1, except that the suspending agent epoxidized soybean oil (ESO) is replaced with lecithin.
[0030] Comparative Example 9 This comparative example is basically the same as Example 1, except that the emulsifier sucrose fatty acid ester is replaced with poloxamer 188.
[0031] Application Example 1: Pharmacodynamic Test Thirty healthy dairy cows of uniform age and weight were selected from a dairy farm and randomly divided into three groups of 10 cows each. Administered medication before long-distance transport. The control group received saline injection, control group A received the sample from Example 1, and control group B received Excede. A single subcutaneous injection of ceftiofur crystals was administered near the base of the ear (at the ear root) to lactating cows: 6.6 mg per kg body weight (i.e., 3.3 ml per 100 kg body weight). In the second week after arrival, the prevalence of respiratory diseases (pneumonia, transport fever) in each group was calculated, and the results are shown in Table 1.
[0032] Health: No symptoms of infection, all physiological indicators are normal.
[0033] Mild to moderate infection: depression, loss of appetite, fever of about 40-41°C, shallow and rapid breathing (up to 40-100 breaths / minute), accompanied by cough and serous or mucous nasal discharge, rales can be heard on lung auscultation, but overall physiological function has not completely failed.
[0034] Severe infection: persistent high fever (above 41°C), difficulty breathing (abdominal breathing with gurgling sounds), cyanosis of mucous membranes, inability to stand or loss of appetite, decreased breath sounds or pleural friction rub on lung auscultation, may be accompanied by systemic symptoms such as sepsis, pulmonary consolidation or pleurisy, poor prognosis.
[0035] Table 1. Statistical results of the prevalence of respiratory diseases (pneumonia, transport fever) in dairy cows in different groups. The results showed that the control group A, which received the sample from Example 1, was significantly better than the blank group in terms of the incidence of respiratory diseases (pneumonia, transport fever) in dairy cows, and was not inferior to the control group B, which received Excede.
[0036] Application Example 2: Adverse Reaction Rate Test Thirty healthy dairy cows of uniform age and weight were selected from a dairy farm and randomly divided into three groups of 10 cows each. The control group was injected with saline, control group A was injected with the sample from Example 1, and control group B was injected with Excede. Ceftiofur crystals were administered via single subcutaneous injection near the base of the ear (ear root): 6.6 mg per kg body weight for lactating cows (i.e., 3.3 ml per 100 kg body weight). Local swelling at the injection site was observed 12 hours after injection, and the results are shown in Table 2.
[0037] Table 2. Statistical results of the incidence of adverse reactions in dairy cows in each group. The results showed that the adverse reactions of the injection prepared by this invention were lower than those of Zoetis's Excede.
[0038] Application Example 3: Accelerated Testing The product quality was checked and accelerated testing (temperature 40℃±2℃, relative humidity 75%±5%) was conducted according to the quality standards of ceftiofur crystal injection in the "Compilation of Veterinary Drug Quality Standards 2006-2011" and the appendix standards of the "Chinese Veterinary Pharmacopoeia 2010 Edition". The experimental results after 6 months are shown in Table 3 below.
[0039] Table 3 Accelerated test data The results showed that all test items in Example 1 met the standards; however, all test items in Comparative Examples 1-9 had varying degrees of non-compliance. Therefore, in this invention, adjusting the excipient ratios or omitting the sustained-release material (such as dispersants, suspending agents, emulsifiers, and sustained-release materials) has a significant impact on product performance. In particular, when dispersants, suspending agents, emulsifiers, and sustained-release materials are replaced with conventional excipients, the product performance also fails to meet standards. This may be because when the concentration of ceftiofur in the injection solution is high, ordinary excipients cannot achieve the corresponding effect.
[0040] Application Example 4: Bioequivalence Test Twenty healthy dairy cows of uniform age and weight were selected from a dairy farm and randomly divided into two groups of 10 cows each. One group was injected with the sample from Example 1, and the other with Excede. A single subcutaneous injection of ceftiofur crystals was administered near the base of the ear (at the ear root): 6.6 mg per kg body weight for lactating cows (i.e., 3.3 ml per 100 kg body weight). The concentration of ceftiofur in the plasma after injection was measured, and a concentration-time curve was plotted. Figure 1 As shown.
[0041] from Figure 1 It can be seen that the pharmacokinetic processes of the two ceftiofur injection products in dairy cows are similar, indicating that the 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows prepared in this invention is bioequivalent to Zoetis's Excede in dairy cows.
[0042] The embodiments described above are merely preferred embodiments of the present invention and are only used to explain the present invention. They are not intended to limit the scope of the present invention. For those skilled in the art, other implementation methods can be easily made by substitution or modification based on the technical content disclosed in this specification. Therefore, all changes and improvements made on the principle of the present invention should be included within the scope of the patent application of the present invention.
Claims
1. A long-acting sustained-release injection of 20% ceftiofur hydrochloride for dairy cows, characterized in that, Each 100 ml of injection solution contains the following components: based on ceftiofur, 20 g of ceftiofur hydrochloride, 0.1-3 g of dispersant, 0.1-5 g of suspending agent, 0.1-5 g of emulsifier, 0.01-1 g of antioxidant, 0.1-5 g of sustained-release material, and the balance being solvent for injection.
2. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The dispersant is selected from one or more of the following: sulfobutyl-β-cyclodextrin, propylene glycol laurate, propylene glycol glycerol, nanocellulose, distearate, 1,2-dioleoyl-sn-glycerol-3-phosphate choline, dilinoleyl dimethyl methacrylate, glyceryl oleate, and dioleyl glycerol.
3. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The suspending agent is selected from one or more of epoxidized soybean oil, cashew phenolic acetate, and tung oil anhydride.
4. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The emulsifier is selected from one or more of the following: sucrose fatty acid ester, cyclopentyl methyl ether, sophorolipid, polyoxyethylene fatty acid ester, hydrogenated soybean phosphatidylcholine, distearate phosphatidylcholine, sorbitan sesquioleate, methyl glucoside ester, lauroyl polyoxyethylene glycerol ester, and monooleate glycerol ester.
5. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The antioxidant is selected from one or more of the following: rosemary extract, tea polyphenols, sage extract, licorice antioxidants, grapefruit seed extract, sesamol, oryzanol, ellagic acid, and tocotrienols.
6. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The sustained-release material is selected from one or more of the following: sucrose isobutyrate acetate, polycaprolactone, polyglycerol polyricinoleate, and triethyl citrate.
7. The 20% ceftiofur hydrochloride long-acting sustained-release injection for dairy cows according to claim 1, characterized in that, The solvent for injection is selected from one or more of tiger nut oil, high oleic sunflower seed oil, low erucic acid rapeseed oil, and algal oil.
8. A long-acting sustained-release injection of 20% ceftiofur hydrochloride for dairy cows according to any one of claims 1 to 7, characterized in that, Includes the following steps: Step 1: Weigh the raw materials according to the amount needed to prepare 100 ml of injection solution; Step 2: Dry heat sterilize the injection solvent at 150 °C for 1 hour, then cool to room temperature; add the dispersant, suspending agent, emulsifier, antioxidant, sustained-release material, and ceftiofur hydrochloride to the injection solvent and stir until homogeneous; Step 3: Disperse evenly using a high-speed shear disperser at a speed of 18,000 to 28,000 rpm for 10 to 30 minutes to obtain long-acting ceftiofur hydrochloride injection; Step 4: After passing the inspection, the product can be filled, labeled, and packed.