Methylprednisolone acetate injection for inhibiting inflammation and preparation method thereof

Abstract

The invention discloses a methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof, and relates to the technical field of medicine preparation, each milliliter of the methylprednisolone acetate injection comprises 45mg of methylprednisolone acetate, 2mg of mixed medicament, 15mg of surfactant, 15mg of cosurfactant and 5mg of solubilizer, the mixed medicament comprises 20mg of povidone and 15mg of polyethylene glycol, and the surfactant comprises 5mg of cosurfactant and 5mg of solubilizer. The preparation method comprises the following steps: adjusting the raw materials to be isotonic by using a sodium chloride solution, adjusting the pH value to be 4.5-7.0 by using sodium hydroxide and the balance of water, wherein the raw materials comprise 2mg of sodium carboxymethyl cellulose, 1.5 mg of polysorbate, 7.2 mg of sodium dihydrogen phosphate, 1.8 mg of disodium hydrogen phosphate, 8.9 mg of benzyl alcohol and the balance of water; compared with the traditional methylprednisolone acetate injection, the methylprednisolone acetate injection provided by the invention has the advantages that the solubility is improved, the preparation stability is high, the absorption capacity of people on the methylprednisolone acetate injection can be improved, the methylprednisolone acetate injection can be applied to intravenous injection, and the application range of the methylprednisolone acetate injection is widened.

Description

Technical Field

[0001] The invention relates to the technical field of medicine preparation, in particular to a methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof. Background Art

[0002] Prednisolone acetate injection, the indication is mainly used for allergic and autoimmune inflammatory diseases. It is now mostly used for active rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, nephrotic syndrome, thrombocytopenic purpura, granulocytopenia, various adrenal insufficiency, severe dermatitis, acute leukemia, etc., and is also used for the comprehensive treatment of certain infections; the main ingredient of prednisolone acetate injection is prednisolone acetate, which is a medium-acting glucocorticoid, and prednisolone acetate mainly works by inhibiting immune response and reducing inflammatory factors. Prednisolone acetate injection can alleviate the clinical manifestations of many diseases, such as fever, joint swelling, etc. For different indications, the patient can be given the corresponding dose of prednisolone acetate injection by oral or intravenous injection according to the doctor's advice. However, long-term and large-scale use of this product may cause side effects such as lower limb edema and weight gain, so it is necessary to monitor and seek medical treatment in time.

[0003] Methylprednisolone acetate injection suspension is a sterile preparation, so sterilization is required in the preparation process. Terminal sterilization has a great influence on the particle size of the preparation, which in turn affects the quality of the preparation. Therefore, the use of sterile methylprednisolone acetate API is of great significance to improving the stability of the preparation. A new type of methylprednisolone acetate injection for inhibiting inflammation is needed.

[0004] After searching, Chinese patent publication number CN113461762A discloses methylprednisolone acetate of specific particle size and its preparation method and application;

[0005] The above patent has the following deficiencies: Since methylprednisolone acetate injection is a poorly soluble drug, it has problems such as low utilization and slow onset of action, and the stability of the preparation of sterile methylprednisolone acetate raw materials is poor. Therefore, the solubilization problem of methylprednisolone acetate injection is an important problem in medical applications. In order to improve people's absorption capacity of methylprednisolone acetate injection, the existing technology is to prepare it into a suspension injection, but the problem is that the drug solubility is still very low, decomposes slowly, and is not suitable for intravenous injection, which reduces the scope of use of methylprednisolone acetate injection.

[0006] In view of the above problems, a methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof are proposed. Summary of the invention

[0007] The object of the present invention is to provide a methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof. The device is used to work, thereby solving the problems that the methylprednisolone acetate injection is a poorly soluble drug, has low utilization, slow onset, and the like, and the preparation stability of the sterile methylprednisolone acetate raw material is poor, so the solubilization problem of the methylprednisolone acetate injection is an important problem in medical applications, thereby improving people's absorption capacity of the methylprednisolone acetate injection. The prior art is to prepare it into a suspension injection, but the problem that the drug solubility is still very low, decomposes slowly, is not suitable for intravenous injection, and reduces the scope of use of the methylprednisolone acetate injection.

[0008] To achieve the above object, the present invention provides the following technical solutions: a methylprednisolone acetate injection for inhibiting inflammation, wherein each milliliter of the injection comprises methylprednisolone acetate, a mixed agent, a surfactant, a co-surfactant and a solubilizing agent;

[0009] Preferably, 45 mg of methylprednisolone acetate, the mixed drug comprises 2 mg of povidone, 15 mg of polyethylene glycol, 2 mg of sodium carboxymethyl cellulose, 1.5 mg of polysorbate, 7.2 mg of sodium dihydrogen phosphate, 1.8 mg of disodium hydrogen phosphate, 8.9 mg of benzyl alcohol, adjusted to isotonicity with sodium chloride solution, adjusted to pH 4.5-7.0 with sodium hydroxide, and the balance is composed of water;

[0010] Preferably, the co-surfactant is one or a mixture of injection-grade polyethylene glycol 3.2 mg, polyethylene glycol 1.56 mg, glycerol, anhydrous ethanol and propylene glycol;

[0011] Preferably, the solubilizer is one or more selected from pharmaceutical excipients such as injection-grade polysorbate 1.32 mg, injection-grade polysorbate 1.86 mg, injection-grade oleic acid 1.5 mg, injection-grade beta-cyclodextrin sodium sulfobutyl for use.

[0012] Preferably, the solubilizer accounts for 5%-20% of the mass percentage of the methylprednisolone acetate injection.

[0013] Preferably, the surfactant accounts for 45%-80% of the mass percentage of the methylprednisolone acetate injection.

[0014] Preferably, the surfactant is one or a mixture of 2 mg of injection-grade polyethylene glycol, 1.52 mg of hydroxystearate, 1.82 mg of polyoxyethylene ether, 2.32 mg of hydrogenated castor oil, and 2.54 mg of poloxamer.

[0015] Preferably, a method for preparing methylprednisolone acetate injection for inhibiting inflammation comprises the following steps:

[0016] Step 1, firstly mixing the bulk drug solution of methylprednisolone acetate with the auxiliary anti-solvent in a chemical reactor, and performing recrystallization to obtain methylprednisolone acetate;

[0017] Step 2, the raw material drug solution and the anti-solvent are simultaneously introduced into the microreactor at their respective flow rates, the two are mixed in the microreactor and recrystallized to obtain methylprednisolone acetate; the methylprednisolone acetate obtained in step 1 and step 2 is dissolved in an organic solvent to prepare a raw material drug solution;

[0018] Step 3, the organic solvent is selected from one or a combination of acetonitrile or tetrahydrofuran; the anti-solvent is selected from one or a combination of isopropyl ether or methyl tert-butyl ether;

[0019] Step 4, adding the surfactant, the co-surfactant and the solubilizer to the methylprednisolone acetate bulk drug solution, stirring and mixing evenly, and stirring until clear, to obtain the methylprednisolone acetate injection for inhibiting inflammation;

[0020] Step 5, adjust to isotonicity with sodium chloride, adjust the pH value, add water for injection to the total amount, and then sterilize the methylprednisolone acetate injection with medical disinfection equipment for 15 minutes, and the temperature can be adjusted to between 120 degrees and 135 degrees;

[0021] Step six, finally filter and sterilize with a 0.18 μm microporous filter membrane, aseptically fill, and wait for the subsequent use of the injection solution.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. A methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof proposed by the present invention. The methylprednisolone acetate injection of the present invention is an adrenocortical hormone drug, which has multiple pharmacological effects such as anti-inflammatory, anti-allergic and immunosuppressive, and is mainly used to inhibit inflammation, including anti-inflammatory effect, glucocorticoids reduce and prevent tissue response to inflammation, thereby reducing the manifestation of inflammation; immunosuppressive effect: prevent or inhibit cell-mediated immune response, delayed allergic reaction, and reduce the expansion of primary immune response; anti-toxic and anti-shock effect: glucocorticoids can resist the stimulation reaction of bacterial endotoxins to the body, reduce cell damage, and play a role in protecting the body; in the blood, most of this product is bound to plasma proteins, and free and bound metabolites are excreted from urine, part of which is excreted in its original form, and a small part can be excreted through breast milk. Compared with traditional methylprednisolone acetate injection, the methylprednisolone acetate injection of the present invention has improved solubility and high preparation stability, which can improve people's absorption capacity of methylprednisolone acetate injection, and can be used for intravenous injection, thereby improving the scope of use of methylprednisolone acetate injection;

[0024] 2. The present invention provides a method for preparing methylprednisolone acetate. The raw material drug solution containing methylprednisolone acetate and other solvents are fully and uniformly contacted in a microreactor to achieve good microscopic mixing and realize recrystallization. Compared with the traditional methylprednisolone acetate injection, the method has a narrow particle size distribution, good fluidity and is not easy to agglomerate. No bacteria grows during the preparation process, which is beneficial to the stability of the preparation. The method is suitable for preparing sterile methylprednisolone acetate suspension injection and meets the requirements of sterile pharmaceutical preparations. The methylprednisolone acetate prepared from the methylprednisolone acetate of a specific particle size provided by the present invention is sterile and has a uniform particle size, which eliminates the sterilization step in the preparation of the suspension injection and simplifies the process steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The present invention is a flow chart of the method for preparing methylprednisolone acetate injection. DETAILED DESCRIPTION

[0026] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] In order to further understand the content of the present invention, the present invention is described in detail in conjunction with the accompanying drawings.

[0028] Implementation Cases

[0029] A methylprednisolone acetate injection for inhibiting inflammation, wherein each milliliter of the injection comprises methylprednisolone acetate, a mixed agent, a surfactant, a co-surfactant and a solubilizer;

[0030] Methylprednisolone acetate 45 mg, a mixed drug comprising povidone 2 mg, polyethylene glycol 15 mg, sodium carboxymethylcellulose 2 mg, polysorbate 1.5 mg, sodium dihydrogen phosphate 7.2 mg, sodium dihydrogen phosphate 1.8 mg, benzyl alcohol 8.9 mg, adjusted to isotonicity with sodium chloride solution, adjusted to pH 4.5-7.0 with sodium hydroxide, and the balance water;

[0031] The co-surfactant is one or a mixture of injection-grade polyethylene glycol 3.2 mg, polyethylene glycol 1.56 mg, glycerol, anhydrous ethanol and propylene glycol;

[0032] The solubilizer is selected from one or more pharmaceutical excipients such as injection-grade polysorbate 1.32 mg, injection-grade polysorbate 1.86 mg, injection-grade oleic acid 1.5 mg, injection-grade sulfobutyl beta-cyclodextrin sodium, etc. and used in combination.

[0033] The mass percentage of the solubilizer in the methylprednisolone acetate injection is 5%-20%.

[0034] The surfactant accounts for 45%-80% of the mass percentage of the methylprednisolone acetate injection.

[0035] The surfactant is one or a mixture of 2 mg of injection-grade polyethylene glycol, 1.52 mg of hydroxystearate, 1.82 mg of polyoxyethylene ether, 2.32 mg of hydrogenated castor oil, and 2.54 mg of poloxamer.

[0036] A method for preparing methylprednisolone acetate injection for inhibiting inflammation comprises the following steps:

[0037] Combination Figure 1 , step 1, firstly mixing the bulk drug solution of methylprednisolone acetate with the auxiliary anti-solvent in a chemical reactor, and performing recrystallization to obtain methylprednisolone acetate;

[0038] Step 2, the raw material drug solution and the anti-solvent are simultaneously introduced into the microreactor at their respective flow rates, the two are mixed in the microreactor and recrystallized to obtain methylprednisolone acetate; the methylprednisolone acetate obtained in step 1 and step 2 is dissolved in an organic solvent to prepare a raw material drug solution;

[0039] Step 3, the organic solvent is selected from one or a combination of acetonitrile or tetrahydrofuran; the anti-solvent is selected from one or a combination of isopropyl ether or methyl tert-butyl ether;

[0040] Step 4, adding the surfactant, the co-surfactant and the solubilizer to the methylprednisolone acetate bulk drug solution, stirring and mixing evenly, and stirring until clear, to obtain the methylprednisolone acetate injection for inhibiting inflammation;

[0041] Step 5, adjust to isotonicity with sodium chloride, adjust the pH value, add water for injection to the total amount, and then sterilize the methylprednisolone acetate injection with medical disinfection equipment for 15 minutes, and the temperature can be adjusted to between 120 degrees and 135 degrees;

[0042] Step six, finally filter and sterilize with a 0.18 μm microporous filter membrane, aseptically fill, and wait for the subsequent use of the injection solution.

[0043] In summary, the present invention provides a methylprednisolone acetate injection for inhibiting inflammation and a preparation method thereof. The methylprednisolone acetate injection of the present invention is an adrenocortical hormone drug, which has multiple pharmacological effects such as anti-inflammatory, anti-allergic and immunosuppressive, and is mainly used to inhibit inflammation, including anti-inflammatory effect, glucocorticoids reduce and prevent tissue response to inflammation, thereby reducing the manifestation of inflammation; immunosuppressive effect: prevent or inhibit cell-mediated immune response, delayed allergic reaction, and reduce the expansion of primary immune response; anti-toxic and anti-shock effect: glucocorticoids can resist the stimulation reaction of bacterial endotoxins to the body, reduce cell damage, and play a role in protecting the body; in the blood, most of this product is bound to plasma proteins, free and bound metabolites are excreted from urine, part is excreted in the original form, and a small part can be excreted through breast milk, and the methylprednisolone acetate injection of the present invention has improved solubility and high preparation stability compared with the traditional methylprednisolone acetate injection, which can improve people's absorption capacity of methylprednisolone acetate injection, can be used for intravenous injection, and improve the scope of use of methylprednisolone acetate injection;

[0044] The invention provides a preparation method of methylprednisolone acetate. A raw material drug solution containing methylprednisolone acetate and other solvents are fully and evenly contacted in a microreactor to achieve good microscopic mixing and realize recrystallization. Compared with a traditional methylprednisolone acetate injection, the methylprednisolone acetate has a narrow particle size distribution, good fluidity and is not easy to agglomerate. No bacteria grows during the preparation process, which is beneficial to the stability of the preparation. The methylprednisolone acetate is suitable for preparing a sterile methylprednisolone acetate suspension injection and meets the requirements of a sterile pharmaceutical preparation. The methylprednisolone acetate prepared by the methylprednisolone acetate with a specific particle size provided by the invention is sterile and has a uniform particle size, so the sterilization step in preparing the suspension injection is omitted, thereby simplifying the process steps.

[0045] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0046] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A methylprednisolone acetate injection for inhibiting inflammation, characterized in that Each milliliter of injection solution includes methylprednisolone acetate, a mixed agent, a surfactant, a co-surfactant, and a solubilizer; 45 mg of methylprednisolone acetate, the mixed drug comprises 2 mg of povidone, 15 mg of polyethylene glycol, 2 mg of sodium carboxymethyl cellulose, 1.5 mg of polysorbate, 7.2 mg of sodium dihydrogen phosphate, 1.8 mg of disodium hydrogen phosphate, 8.9 mg of benzyl alcohol, adjusted to isotonicity with sodium chloride solution, adjusted to pH 4.5-7.0 with sodium hydroxide, and the balance is water; The co-surfactant is one or a mixture of injection-grade polyethylene glycol 3.2 mg, polyethylene glycol 1.56 mg, glycerol, anhydrous ethanol and propylene glycol; The solubilizer is selected from one or more pharmaceutical excipients such as injection-grade polysorbate 1.32 mg, injection-grade polysorbate 1.86 mg, injection-grade oleic acid 1.5 mg, injection-grade sulfobutyl beta-cyclodextrin sodium, etc. and used in combination.

2. A methylprednisolone acetate injection for inhibiting inflammation according to claim 1, characterized in that: The solubilizer accounts for 5%-20% of the mass percentage of the methylprednisolone acetate injection.

3. A methylprednisolone acetate injection for inhibiting inflammation according to claim 2, characterized in that: The surfactant accounts for 45%-80% of the mass percentage of the methylprednisolone acetate injection.

4. The methylprednisolone acetate injection for inhibiting inflammation according to claim 3, characterized in that: The surfactant is one or a mixture of 2 mg of injection-grade polyethylene glycol, 1.52 mg of hydroxystearate, 1.82 mg of polyoxyethylene ether, 2.32 mg of hydrogenated castor oil, and 2.54 mg of poloxamer.

5. A method for preparing a methylprednisolone acetate injection for inhibiting inflammation according to any one of claims 1 to 4, characterized in that: The following steps are involved: Step 1, firstly mixing the bulk drug solution of methylprednisolone acetate with the auxiliary anti-solvent in a chemical reactor, and performing recrystallization to obtain methylprednisolone acetate; Step 2, the raw material drug solution and the anti-solvent are simultaneously introduced into the microreactor at their respective flow rates, the two are mixed in the microreactor and recrystallized to obtain methylprednisolone acetate; the methylprednisolone acetate obtained in step 1 and step 2 is dissolved in an organic solvent to prepare a raw material drug solution; In step 3, the organic solvent is selected from acetonitrile or tetrahydrofuran or a combination thereof; the anti-solvent is selected from isopropyl ether or methyl tert-butyl ether or a combination thereof.

6. The method for preparing a methylprednisolone acetate injection for inhibiting inflammation according to claim 5, characterized in that: The following steps are also included: Step 4: Add the surfactant, co-surfactant and solubilizer to the methylprednisolone acetate bulk drug solution, stir and mix evenly, and stir until clear to obtain the methylprednisolone acetate injection for inhibiting inflammation.

7. The methylprednisolone acetate injection for inhibiting inflammation and the preparation method thereof according to claim 6, characterized in that: Step 5, adjust to isotonicity with sodium chloride, adjust the pH value, add water for injection to the total amount, and then sterilize the methylprednisolone acetate injection with medical disinfection equipment for 15 minutes, and the temperature can be adjusted to between 120 degrees and 135 degrees; Step six, finally filter and sterilize with a 0.18 μm microporous filter membrane, aseptically fill, and wait for the subsequent use of the injection solution.

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