A kind of compound lidocaine gel and preparation method thereof

Abstract

The invention provides a kind of compound lidocaine gel and preparation method thereof, belong to the technical field of pharmaceutical preparations, the compound lidocaine gel, by weight, comprises the following components: 0.02-0.04 parts of prednisolone acetate, 0.08-0.2 parts of lidocaine hydrochloride, 10-25 parts of dimethyl sulfoxide, 0.05-3 parts of cross-linking agent, 0.01-3 parts of pH adjusting agent, 0.02-2 parts of stabilizer, 0.02-0.05 parts of preservative, 0.4-2 parts of penetrant, 0.5-5 parts of tackifier, 5-8 parts of gel skeleton material, 10-20 parts of humectant, 20-50 parts of purified water. The compound lidocaine gel provided by the invention has the characteristics of good bioavailability, fast absorption and onset, stable quality, no irritation to skin, etc., and the preparation process of the compound lidocaine gel is simple, and it is suitable for amplification production application.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a compound lidocaine gel and a preparation method thereof. Background Art

[0002] Musculoskeletal disease is one of the common diseases in veterinary clinics. It is usually caused by structural damage or dysfunction of the bones, muscles and surrounding soft tissues of the affected animal. Common causes include trauma, stress injury, arthritis, developmental bone disease, etc., which can easily cause local inflammation and pain in the animal body, leading to lameness and adverse effects on the health and motor performance of the affected animal. Therefore, it is necessary to have an external gel with both analgesic and anti-inflammatory effects, which can act directly on the affected area of ​​the animal to relieve the body damage and pain caused by such diseases.

[0003] Lidocaine hydrochloride is an amide-type medium-acting local anesthetic with a chemical formula of C 14 H 23 ClN2O, after being absorbed by the blood or administered intravenously, has obvious biphasic effects of excitation and inhibition on the central nervous system, and can be excited without precursors. It has the advantages of strong penetration, rapid action, wide diffusion and stable properties. It is widely used in topical analgesic preparations clinically. It has strong anesthetic strength, rapid onset and strong diffusion. It takes about 2 hours for the drug to be eliminated from the local area. Prednisolone acetate is also known as prednisone, prednisone, prednisolone acetate, etc. Its chemical name is: 11β, 17α, 21-trihydroxypregnane-1,4-diene-3,20-dione-21-acetate. It belongs to the glucocorticoid class and can counteract the stimulation response of bacterial endotoxins to the body, reduce cell damage, and play a role in protecting the body. It is used clinically to treat allergic, non-infectious skin diseases and some proliferative skin diseases.

[0004] my country already has registered veterinary drugs such as lidocaine hydrochloride injection and prednisolone acetate tablets, but there are no related compound veterinary drugs. It is urgent to develop a compound preparation of lidocaine hydrochloride and prednisolone acetate that can synergistically exert the combined effect of these two types of drugs. In combination with clinical practice, in order to solve the related pain and inflammation caused by common local musculoskeletal diseases in animals, it is particularly important to develop an external gel dosage form with good bioavailability, rapid absorption and easy application. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a compound lidocaine gel with good bioavailability, rapid absorption and effect, stable quality and no irritation to the skin. The preparation process of the compound lidocaine gel is simple and suitable for large-scale production and application.

[0006] The first object of the present invention is to provide a compound lidocaine gel, which comprises the following components, measured by weight: 0.02-0.04 parts of prednisolone acetate, 0.08-0.2 parts of lidocaine hydrochloride, 10-25 parts of dimethyl sulfoxide, 0.05-3 parts of a cross-linking agent, 0.01-3 parts of a pH regulator, 0.02-2 parts of a stabilizer, 0.02-0.05 parts of a preservative, 0.4-2 parts of a penetrant, 0.5-5 parts of a viscosity enhancer, 5-8 parts of a gel skeleton material, 10-20 parts of a humectant, and 20-50 parts of purified water.

[0007] Preferably, the cross-linking agent is selected from at least one of aluminum chloride, calcium hydroxide, aluminum hydroxide, aluminum sulfate, and zinc hydroxide.

[0008] Preferably, the pH adjuster is selected from at least one of lactic acid, citric acid and tartaric acid.

[0009] Preferably, the stabilizer is a 10% formic acid aqueous solution.

[0010] Preferably, the preservative is selected from at least one of benzoic acid, p-hydroxybenzoic acid and propylparaben.

[0011] Preferably, the penetrant is selected from at least one of azone, propylene glycol, menthol, salicylic acid and oleic acid.

[0012] Preferably, the viscosity enhancer is selected from at least one of sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin and hydroxyethyl cellulose.

[0013] Preferably, the gel skeleton material is selected from at least one of carbomer (acrylic acid cross-linked resin), ammonium polyacrylate, and diethanolamine polyacrylate.

[0014] Preferably, the moisturizing agent is selected from at least one of sorbitol, polyethylene glycol, glycerin, isopropyl myristate, and isopropyl hexadecanoate.

[0015] The second object of the present invention is to provide a method for preparing a compound lidocaine gel, comprising the following steps:

[0016] (1) Weigh each component in proportion;

[0017] (2) dissolving the thickener in purified water, wherein the mass ratio of the thickener to the purified water is 1:1, the speed of the stirrer is 80-100 rpm, and adding prednisolone acetate, lidocaine hydrochloride, dimethyl sulfoxide, stabilizer, preservative, and penetrant under stirring at room temperature. After the addition is completed, stirring is continued for 20-30 minutes to obtain a mixture A for standby use;

[0018] (3) uniformly mixing the cross-linking agent, gel skeleton material, moisturizing agent and the remaining purified water to obtain a mixture B for later use;

[0019] (4) Turn on the stirrer at a speed of 100-200 rpm, add the mixture A described in step (2) to the mixture B described in step (3) while stirring, add in small amounts and multiple times, add a pH adjuster after mixing evenly, adjust the pH value to 7.5-8.0, and ensure that the system temperature is within the range of 70-90° C., keep the temperature for reaction for 1-2 hours, and then cool to room temperature to obtain the finished product.

[0020] Compared with the prior art, the present invention has the following beneficial effects: lidocaine hydrochloride is an amide medium-acting local anesthetic, which has obvious biphasic effects of excitation and inhibition on the central nervous system after being absorbed by the blood or intravenously administered, and has the advantages of strong penetration, rapid action, wide diffusion and stable properties, but it will produce toxic impurities after degradation in the body. The present invention reduces the amount of lidocaine hydrochloride by combining it with prednisolone acetate and using a specific combination of stabilizers, thereby inhibiting the generation of impurities and making it safer; in addition, the present invention can improve the release of effective ingredients of lidocaine hydrochloride and prednisolone acetate and improve the efficacy by selecting a specific type and ratio of transdermal enhancers; traditional cream administration has the defects of being easy to wipe off and having a short action time, and is not suitable for use in chronic pain, while the gel provided by the present invention can significantly reduce the frequency of administration and has important clinical value. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described clearly and completely below. 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 belong to the scope of protection of the present invention.

[0022] The experimental methods or test methods described in the following examples are conventional methods unless otherwise specified; the raw materials and auxiliary agents are obtained from conventional commercial channels or prepared by conventional methods unless otherwise specified.

[0023] Example 1

[0024] A method for preparing a compound lidocaine gel comprises the following steps:

[0025] (1) Weigh the raw materials: 0.02 parts of prednisolone acetate, 0.08 parts of lidocaine hydrochloride, 10 parts of dimethyl sulfoxide, 0.08 parts of aluminum hydroxide, 1 part of tartaric acid, 2 parts of 10% formic acid aqueous solution, 0.02 parts of benzoic acid, 1 part of salicylic acid, 2 parts of hydroxyethyl cellulose, 6 parts of ammonium polyacrylate, 15 parts of isopropyl myristate, and 35 parts of purified water;

[0026] (2) Dissolve hydroxyethyl cellulose in purified water, wherein the mass ratio of hydroxyethyl cellulose to purified water is 1:1, the speed of the stirrer is 80 rpm, and prednisolone acetate, lidocaine hydrochloride, dimethyl sulfoxide, 10% formic acid aqueous solution, benzoic acid, and salicylic acid are added under stirring at room temperature. After the addition is completed, stirring is continued for 30 minutes to obtain a mixture A for standby use;

[0027] (3) mixing aluminum hydroxide, ammonium polyacrylate, isopropyl myristate and the remaining purified water to obtain a mixture B for later use;

[0028] (4) Turn on the stirrer at a speed of 200 rpm, add the mixture A described in step (2) to the mixture B described in step (3) while stirring, add in small amounts and multiple times, add tartaric acid after mixing evenly, adjust the pH value to 8.0, and ensure that the system temperature is within the range of 80° C., keep the reaction warm for 2 hours, and then cool to room temperature to obtain the finished product.

[0029] Example 2

[0030] The difference from Example 1 is that the formula of the compound lidocaine gel is: 0.04 parts of prednisolone acetate, 0.2 parts of lidocaine hydrochloride, 25 parts of dimethyl sulfoxide, 3 parts of aluminum sulfate, 3 parts of citric acid, 2 parts of 10% formic acid aqueous solution, 0.05 parts of p-hydroxybenzoic acid, 1 part of oleic acid, 3 parts of sodium carboxymethyl cellulose, 8 parts of polyacrylic acid diethanolamine, 20 parts of polyethylene glycol, and 50 parts of purified water.

[0031] Example 3

[0032] The difference from Example 1 is that the formula of the compound lidocaine gel is: 0.03 parts of prednisolone acetate, 0.15 parts of lidocaine hydrochloride, 18 parts of dimethyl sulfoxide, 2 parts of aluminum chloride, 2 parts of lactic acid, 2 parts of 10% formic acid aqueous solution, 0.04 parts of propylparaben, 2 parts of propylene glycol, 4 parts of polyvinyl pyrrolidone, 6 parts of carbomer, 15 parts of sorbitol, and 45 parts of purified water.

[0033] In other embodiments, the cross-linking agent may be selected from one or a mixture of two or more of aluminum chloride, calcium hydroxide, aluminum hydroxide, aluminum sulfate, and zinc hydroxide.

[0034] In other embodiments, the pH adjuster may be selected from lactic acid, citric acid, tartaric acid, or a mixture of two or more thereof.

[0035] In other embodiments, the preservative may be selected from benzoic acid, p-hydroxybenzoic acid, propylparaben, or a mixture of two or more thereof.

[0036] In other embodiments, the penetrant may be selected from one or a mixture of two or more of azone, propylene glycol, menthol, salicylic acid and oleic acid.

[0037] In other embodiments, the viscosity enhancer may be selected from sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin, hydroxyethyl cellulose, or a mixture of two or more thereof.

[0038] In other embodiments, the gel skeleton material can be selected from one or a mixture of two or more of acrylic acid cross-linked resin, ammonium polyacrylate, and poly(diethanolamine) acrylic acid.

[0039] In other embodiments, the moisturizer can be selected from one of sorbitol, polyethylene glycol, glycerin, isopropyl myristate, isopropyl hexadecanoate, or a mixture of two or more thereof.

[0040] Comparative Example 1

[0041] The difference from Example 1 is that prednisolone acetate is not added to the formula of the compound lidocaine gel.

[0042] Comparative Example 2

[0043] The difference from Example 1 is that lidocaine hydrochloride is not added into the formula of the compound lidocaine gel.

[0044] Comparative Example 3

[0045] The difference from Example 1 is that the weight portion of prednisolone acetate added to the formula of the compound lidocaine gel is 0.01 parts.

[0046] Comparative Example 4

[0047] The difference from Example 1 is that the weight portion of prednisolone acetate added to the formula of the compound lidocaine gel is 0.06 parts.

[0048] Comparative Example 5

[0049] The difference from Example 1 is that the weight portion of lidocaine hydrochloride added to the formula of the compound lidocaine gel is 0.05 parts.

[0050] Comparative Example 6

[0051] The difference from Example 1 is that the weight portion of lidocaine hydrochloride added to the formula of the compound lidocaine gel is 0.25 parts.

[0052] The gels prepared in Examples 1-3 and Comparative Examples 1-6 were tested for bioavailability, chemical stability during storage, and skin toxicity and irritation. The results showed that:

[0053] 1) The gel provided in Examples 1-3 can well enhance the absorption of lidocaine hydrochloride and prednisolone acetate by the human body, and has good bioavailability. It is expected that the gel provided in Examples 1-3 will have significant therapeutic effects during clinical use, while the gel prepared in Comparative Examples 1-6 has significantly poorer effects;

[0054] 2) The compound lidocaine gel provided in Examples 1-3 can still maintain good chemical stability when placed at room temperature for a long time;

[0055] 3) The gels provided in Examples 1-3 and Comparative Examples 1-6 were subjected to safety tests. The specific experimental process was as follows: the rats were divided into 9 groups, each group consisting of 50 SD rats of similar age, size, and physiological state. The gels provided in Examples 1-3 and Comparative Examples 1-6 were respectively applied to the skin of the SD rats in their respective groups (the hair on both sides of the spine of the SD rats was removed with a depilatory agent one day before administration, and the rats were fasted but not watered for 12 hours before administration). The results showed that there were no adverse reactions on the skin at the administration site of Examples 1-3, and the effect of Comparative Examples 1-6 was slightly worse. This proves that the compound lidocaine gel provided by the present invention is non-irritating and safe, and that the components and contents in the formula are specific.

[0056] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a compound lidocaine gel, characterized in that: It consists of the following steps: (1) Weigh the raw materials: 0.02 parts of prednisolone acetate, 0.08 parts of lidocaine hydrochloride, 10 parts of dimethyl sulfoxide, 0.08 parts of aluminum hydroxide, 1 part of tartaric acid, 2 parts of 10% formic acid aqueous solution, 0.02 parts of benzoic acid, 1 part of salicylic acid, 2 parts of hydroxyethyl cellulose, 6 parts of ammonium polyacrylate, 15 parts of isopropyl myristate, and 35 parts of purified water; (2) Dissolve hydroxyethyl cellulose in purified water, wherein the mass ratio of hydroxyethyl cellulose to purified water is 1:1, the speed of the stirrer is 80 rpm, and prednisolone acetate, lidocaine hydrochloride, dimethyl sulfoxide, 10% formic acid aqueous solution, benzoic acid, and salicylic acid are added under stirring at room temperature. After the addition is completed, stirring is continued for 30 minutes to obtain a mixture A for standby use; (3) mixing aluminum hydroxide, ammonium polyacrylate, isopropyl myristate and the remaining purified water to obtain a mixture B for later use; (4) Turn on the stirrer at a speed of 200 rpm, add the mixture A described in step (2) to the mixture B described in step (3) while stirring, add in small amounts and multiple times, add tartaric acid after mixing evenly, adjust the pH value to 8.0, and ensure that the system temperature is within the range of 80° C., keep the reaction warm for 2 hours, and then cool to room temperature to obtain the finished product.