Amorolfine hydrochloride liniment and production process thereof

Abstract

The invention discloses an amorolfine hydrochloride liniment and a production process. The formula of the amorolfine hydrochloride liniment comprises amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, glyceryl triacetate, ethyl acetate and butyl acetate. The preparation method comprises the following steps: 1, selecting a solvent material; step 2, generation of an amorolfine raw material; step 3, synthesizing amorolfine hydrochloride; step 4, preparation of the liniment; step 5, quality control; and step 6, packaging and storing. The amorolfine hydrochloride liniment based on the acrylic resin RL100 as the coating and framework material is designed, the specific release requirement of the medicine can be effectively met, ultraviolet rays can be absorbed, erosion of the ultraviolet rays can be effectively resisted, and the service life of the medicine is prolonged; meanwhile, the propylene glycol component is added, so that the stability and solubility of the medicine and the permeability of the medicine are improved; the polyethylene glycol component is also added, so that the smearing property and the use experience of the medicine can be improved.

Description

Technical Field

[0001] The invention relates to the technical field of infection treatment drugs, in particular to an amorolfine hydrochloride liniment and a production process. Background Art

[0002] Amorolfine hydrochloride is an antifungal drug that can kill various fungi that can cause nail infections. It is used for nail infections caused by fungi. Before use, use the nail file in the medicine box to file the infected nail as smooth as possible, including the surface of the nail. Do not use the nail file that has been in contact with the diseased nail to file the healthy nail to avoid the spread of infection. At the same time, be careful not to share a nail file with other people to prevent cross infection. After filing the infected nail, use the swab in the medicine box to clean the surface of the nail. Repeat the above steps for each diseased nail, then use the medicine spatula to take out the ointment, avoid the ointment touching the bottle mouth to prevent it from leaking, and then apply the ointment evenly. Apply to the entire nail, repeat the application for each diseased nail, and finally let the nail coated with the ointment dry for 3 minutes. Before the second use, remove the old ointment with a swab, file it again if necessary, and then reapply the solution. Since the dry ointment is not affected by water and soap, the patient can wash his hands or feet normally, but when in contact with chemicals, rubber or impermeable gloves should be worn to protect the ointment. It is necessary to continue using this product before the infection is cleared and normal nails have grown. For nail medication, it usually takes 6 months, and toenails need to continue for 9-12 months. It is usually necessary to observe the progress of treatment every three months.

[0003] However, the traditional amorolfine hydrochloride ointment and production process cannot meet people's needs, and it has the following defects: first, the coating and skeleton materials used in the existing amorolfine hydrochloride ointment cannot effectively meet the specific release requirements of the drug, and have certain requirements for the environment, and cannot effectively resist the erosion of outdoor ultraviolet rays, so that the service life of the drug is reduced to a certain extent; second, the existing amorolfine hydrochloride ointment does not contain a certain component of cosolvent, and a certain amount of time is required for mixing during the production and preparation of the drug, which increases the consumption of preparation time and increases the preparation cost of the drug; third, the existing amorolfine hydrochloride ointment does not contain a certain component of thickener or lubricant, and the spreadability of the drug cannot be guaranteed during the use of the drug, which reduces the user experience. Summary of the invention

[0004] The object of the present invention is to provide an amorolfine hydrochloride ointment and a production process to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical scheme: an amorolfine hydrochloride liniment, the formula of which includes: amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, triacetin, ethyl acetate and butyl acetate, characterized in that the mass percentages of the components are: 2% to 15% of amorolfine hydrochloride, 35% to 50% of ethanol, 8% to 15% of propylene glycol, 1% to 3% of polyethylene glycol, 18% to 27% of acrylic resin RL100, 5% to 10% of triacetin, 6% to 8% of ethyl acetate and 6% to 8% of butyl acetate.

[0006] As a further technical solution of the present invention, the mass percentages of the components are: 5% amorolfine hydrochloride, 40% ethanol, 10% propylene glycol, 2% polyethylene glycol, 23% acrylic resin RL100, 7% triacetin, 6% ethyl acetate and 7% butyl acetate.

[0007] The production process of amorolfine hydrochloride liniment comprises the following steps: first, selecting a solvent material; second, generating amorolfine raw material; third, synthesizing amorolfine hydrochloride; fourth, preparing the liniment; fifth, quality control; and sixth, packaging and storage.

[0008] In the above step 1, each component of the solvent is confirmed;

[0009] In the above step 2, a chemical reagent is selected to synthesize the amorolfine raw material according to its chemical preparation route;

[0010] In the above step 3, the amorolfine raw material is dissolved in alcohol or ether, and a hydrochloric acid solution is added dropwise to react and produce amorolfine hydrochloride;

[0011] In the above step 4, the obtained amorolfine hydrochloride is mixed with other excipients to prepare a liniment;

[0012] In the above step 5, the quality control of the drug is strictly carried out during the preparation process;

[0013] In the above step six, the prepared qualified amorolfine hydrochloride ointment is packaged and stored in accordance with regulations.

[0014] As a further technical solution of the present invention, in the step 1, the components of the solvent are confirmed, acrylic resin RL100 is selected as the coating and skeleton material of the drug, propylene glycol is selected as the cosolvent and stabilizer of the drug, polyethylene glycol is selected as the thickener or lubricant of the drug, and ethanol, triacetin, ethyl acetate and butyl acetate are selected as solvents for the drug, which helps to improve the solubility and stability of the drug.

[0015] As a further technical solution of the present invention, in the step 2, commonly used chemical raw materials benzene and tert-amyl alcohol are selected as starting materials, tert-amylbenzene is obtained by Friedel-Crafts alkylation reaction, propionyl chloride is selected to carry out Friedel-Crafts acylation reaction with tert-amylbenzene to generate tert-amylpropiophenone, 2,6-dimethylmorpholine and paraformaldehyde are selected to carry out Mannich reaction with tert-amylpropiophenone to produce 4-tert-amyl-1-(2-methyl-1-oxy-3-(2,6-dimethylmorpholine-4-)propyl)benzene, and finally palladium carbon is selected for catalytic oxidation to generate amorolfine.

[0016] As a further technical solution of the present invention, in the step three, the generated amorolfine raw material is dissolved in alcohol or ether, released according to a specified ratio, and an appropriate amount of hydrochloric acid solution is added dropwise to the solution, and a suitable time is waited for the solution to react after mixing, and the reaction produces amorolfine hydrochloride.

[0017] As a further technical solution of the present invention, in the step 4, the obtained amorolfine hydrochloride is mixed with an appropriate amount of ethanol, propylene glycol and other auxiliary materials, dissolved and uniformly mixed to ensure the stability and uniformity of the drug, and the components are added according to the specified ratio so that the amorolfine hydrochloride is dissolved in a sufficient solvent and kept uniformly mixed in the solvent, and the pH value of the obtained drug reagent is adjusted so that the pH value of the solution is within the specification range to ensure comfort and stability during drug use.

[0018] As a further technical solution of the present invention, in the step 4, the preparation is homogenized by a homogenizing device, and the preparation is treated by a high-pressure homogenizer so that the drug particles are crushed to an average diameter of less than 1 μm, thereby breaking the drug cell wall, enhancing the drug's penetration ability and absorption efficiency, helping to improve the drug's distribution accuracy, maintain a constant active ingredient content, and improve production efficiency.

[0019] As a further technical solution of the present invention, in the step 5, after the drug selection is determined, amorolfine hydrochloride and all auxiliary materials are strictly inspected, including physical and chemical properties, to ensure that the materials meet the quality standards. During the preparation process, key intermediates are tested and different detection methods are used for their special properties to ensure the quality and purity of the intermediates. Finally, the prepared amorolfine hydrochloride ointment is tested for appearance, content, related substances, microbial limits and other items to ensure that all parameters meet the quality standards. After the test, the material preparation can be adjusted according to the test results to ensure the qualified rate of the drug.

[0020] As a further technical solution of the present invention, in step six, the qualified amorolfine hydrochloride ointment is packaged in a sealed container to prevent drug volatilization and contamination, and the product name, specifications, production date, expiration date, usage and dosage, precautions and other information are indicated on the package, and a detailed instruction manual is provided to let users know how to use it correctly, and the packaged amorolfine hydrochloride ointment is stored in a cool, dry, well-ventilated place to avoid direct sunlight and high temperature.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention is designed with an amorolfine hydrochloride ointment based on acrylic resin RL100 as a coating and skeleton material, which can effectively achieve the specific release requirements of the drug, the acrylic resin RL100 has a large number of carbon-carbon double bonds, can absorb ultraviolet rays, effectively resist the erosion of ultraviolet rays, and improve the service life of the drug, due to its high molecular weight characteristics, the interaction between molecular chains is strong, and it has good wear resistance and corrosion resistance, and the acrylic resin RL100 is 100% biodegradable, which increases the environmental performance of the drug; at the same time, the addition of propylene glycol components helps to increase the stability and solubility of the drug, as well as the permeability of the drug, which can effectively improve the solubility and bioavailability of the drug, improve the physical properties of the drug, reduce the consumption of preparation time, reduce the preparation cost of the drug, and effectively improve the absorption and distribution of the drug on the skin; a polyethylene glycol component is also added, which can be used as a thickener and lubricant for the drug, and the polyethylene glycol has good water solubility and lubricity, which can effectively improve the spreadability and use experience of the drug, and the material has stable chemical properties, and is safe and non-toxic. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The figure is a flow chart of the method of the present invention. DETAILED DESCRIPTION

[0023] 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.

[0024] Please see attached Figure 1 , a technical solution provided by the present invention:

[0025] Example 1

[0026] The invention discloses an amorolfine hydrochloride ointment, wherein the formula includes: amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, triacetin, ethyl acetate and butyl acetate, and the mass percentages of the components are: 5% amorolfine hydrochloride, 40% ethanol, 10% propylene glycol, 2% polyethylene glycol, 23% acrylic resin RL100, 7% triacetin, 6% ethyl acetate and 7% butyl acetate.

[0027] The production process of amorolfine hydrochloride liniment comprises the following steps: first, selecting a solvent material; second, generating amorolfine raw material; third, synthesizing amorolfine hydrochloride; fourth, preparing the liniment; fifth, quality control; and sixth, packaging and storage.

[0028] In the above step 1, the components of the solvent are confirmed, acrylic resin RL100 is selected as the coating and skeleton material of the drug, propylene glycol is selected as the cosolvent and stabilizer of the drug, polyethylene glycol is selected as the thickener or lubricant of the drug, and ethanol, triacetin, ethyl acetate and butyl acetate are selected as the solvent of the drug, which is helpful to improve the solubility and stability of the drug;

[0029] wherein in the above step 2, a chemical reagent is selected to synthesize amorolfine raw material according to its chemical preparation route, common chemical raw materials benzene and tert-amyl alcohol are selected as starting materials, tert-amylbenzene is obtained by Friedel-Crafts alkylation reaction, propionyl chloride is selected to react with tert-amylbenzene for Friedel-Crafts acylation reaction to generate tert-amylpropiophenone, 2,6-dimethylmorpholine and paraformaldehyde are selected to react with tert-amylpropiophenone for Mannich reaction to produce 4-tert-amyl-1-(2-methyl-1-oxy-3-(2,6-dimethylmorpholine-4-)propyl)benzene, and palladium carbon is selected for catalytic oxidation to generate amorolfine;

[0030] Wherein in the above step 3, the amorolfine raw material is dissolved in alcohol or ether, hydrochloric acid solution is added dropwise, and amorolfine hydrochloride is produced by reaction, the generated amorolfine raw material is dissolved in alcohol or ether, released according to a specified ratio, and an appropriate amount of hydrochloric acid solution is added dropwise to the solution, and a suitable time is waited for the solution to react after mixing, and the reaction produces amorolfine hydrochloride;

[0031] wherein in the above step 4, the obtained amorolfine hydrochloride is mixed with other excipients to prepare an ointment, the obtained amorolfine hydrochloride is mixed with an appropriate amount of ethanol, propylene glycol and other excipients, dissolved and uniformly mixed to ensure the stability and uniformity of the drug, the components are added according to the specified ratio, the amorolfine hydrochloride is dissolved in a sufficient solvent, and uniformly mixed in the solvent, and the pH value of the obtained drug reagent is adjusted to ensure that the pH value of the solution is within the specification range to ensure comfort and stability during drug use, the preparation is homogenized by a homogenizing device, and the preparation is treated by a high-pressure homogenizer so that the drug particles are crushed to an average diameter of less than 1 μm, thereby breaking the drug cell wall, enhancing the penetration ability and absorption efficiency of the drug, helping to improve the distribution accuracy of the drug, maintaining a constant active ingredient content, and improving production efficiency;

[0032] In the above step 5, the quality control of the drug is strictly carried out during the preparation process. After the drug is selected and determined, amorolfine hydrochloride and all excipients are strictly inspected, including physical and chemical properties, to ensure that the materials meet the quality standards. During the preparation process, key intermediates are tested and tested by different detection methods for their special properties to ensure the quality and purity of the intermediates. Finally, the prepared amorolfine hydrochloride ointment is tested for appearance, content, related substances, microbial limits and other items to ensure that all parameters meet the quality standards. After the test, the material preparation can be adjusted according to the test results to ensure the qualified rate of the drug.

[0033] In the above step six, the prepared qualified amorolfine hydrochloride ointment is packaged and stored in accordance with regulations, the qualified amorolfine hydrochloride ointment is packaged in a sealed container to prevent drug volatilization and contamination, the product name, specifications, production date, expiration date, usage and dosage, precautions and other information are indicated on the package, and a detailed instruction manual is provided to let users know how to use it correctly, and the packaged amorolfine hydrochloride ointment is stored in a cool, dry and well-ventilated place to avoid direct sunlight and high temperature.

[0034] Example 2

[0035] The amorolfine hydrochloride ointment comprises: amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, triacetin, ethyl acetate and butyl acetate, and the mass percentages of the components are: 2% amorolfine hydrochloride, 45% ethanol, 12% propylene glycol, 1% polyethylene glycol, 20% acrylic resin RL100, 5% triacetin, 7% ethyl acetate and 8% butyl acetate. The preparation method is the same as that of Example 1.

[0036] Example 3

[0037] The amorolfine hydrochloride ointment comprises: amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, triacetin, ethyl acetate and butyl acetate, and the mass percentages of the components are: 10% amorolfine hydrochloride, 39% ethanol, 9% propylene glycol, 3% polyethylene glycol, 19% acrylic resin RL100, 8% triacetin, 6% ethyl acetate and 6% butyl acetate. The preparation method is the same as that of Example 1.

[0038] The specific composition ratios of each embodiment are shown in the following table:

[0039]

[0040] Based on the above, the advantages of the present invention are: the present invention is designed with an amorolfine hydrochloride ointment based on acrylic resin RL100 as a coating and skeleton material, which can effectively achieve the specific release requirements of the drug. The acrylic resin RL100 has a large number of carbon-carbon double bonds, can absorb ultraviolet rays, effectively resist the erosion of ultraviolet rays, and improve the service life of the drug. Due to its high molecular weight characteristics, the interaction between molecular chains is strong, and it has good wear resistance and corrosion resistance. The acrylic resin RL100 is 100% biodegradable, which increases the environmental performance of the drug. At the same time, a propylene glycol component is added. Propylene glycol has good solubility and can make some drugs with poor water solubility and good oil solubility better dissolve in the solvent, thereby improving the solubility of the drug. Its good stability can prevent the drug from being damaged by chemical reactions or physical effects. It can prevent the deterioration of drug efficacy, help increase the stability and solubility of drugs, as well as the permeability of drugs, effectively improve the solubility and bioavailability of drugs, improve the physical properties of drugs, reduce the consumption of preparation time, reduce the preparation cost of drugs, and effectively improve the absorption and distribution of drugs on the skin; polyethylene glycol is also added. Polyethylene glycol has good lubricity, can reduce friction, facilitate application, reduce skin irritation, and can be used as a thickener and lubricant for drugs. Polyethylene glycol has good water solubility and lubricity. Due to its hydrophilicity, polyethylene glycol can absorb and retain moisture to help maintain the moist state of the skin or mucous membranes. Polyethylene glycol has good compatibility with human tissues and is not easy to cause immune response. It can effectively improve the applicability and usage experience of drugs, and the material has stable chemical properties, safe and non-toxic.

[0041] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

Claims

1. Amorolfine hydrochloride liniment, the formula comprising: Amorolfine hydrochloride, ethanol, propylene glycol, polyethylene glycol, acrylic resin RL100, triacetin, ethyl acetate and butyl acetate, characterized in that the mass percentages of the components are respectively: 2% to 15% of amorolfine hydrochloride, 35% to 50% of ethanol, 8% to 15% of propylene glycol, 1% to 3% of polyethylene glycol, 18% to 27% of acrylic resin RL100, 5% to 10% of triacetin, 6% to 8% of ethyl acetate and 6% to 8% of butyl acetate.

2. The amorolfine hydrochloride liniment according to claim 1, characterized in that: The mass percentages of the components are: 5% amorolfine hydrochloride, 40% ethanol, 10% propylene glycol, 2% polyethylene glycol, 23% acrylic resin RL100, 7% triacetin, 6% ethyl acetate and 7% butyl acetate.

3. The production process of amorolfine hydrochloride liniment comprises step 1, selection of solvent material; step 2, generation of amorolfine raw material; step 3, synthesis of amorolfine hydrochloride; step 4, preparation of liniment; step 5, quality control; step 6, packaging and storage; characterized in that: In the above step 1, each component of the solvent is confirmed; In the above step 2, a chemical reagent is selected to synthesize the amorolfine raw material according to its chemical preparation route; In the above step 3, the amorolfine raw material is dissolved in alcohol or ether, and a hydrochloric acid solution is added dropwise to react and produce amorolfine hydrochloride; In the above step 4, the obtained amorolfine hydrochloride is mixed with other excipients to prepare a liniment; In the above step 5, the quality control of the drug is strictly carried out during the preparation process; In the above step six, the prepared qualified amorolfine hydrochloride ointment is packaged and stored in accordance with regulations.

4. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 1, the components of the solvent are confirmed, acrylic resin RL100 is selected as the coating and skeleton material of the drug, propylene glycol is selected as the cosolvent and stabilizer of the drug, polyethylene glycol is selected as the thickener or lubricant of the drug, and ethanol, triacetin, ethyl acetate and butyl acetate are selected as the solvents of the drug, which helps to improve the solubility and stability of the drug.

5. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 2, commonly used chemical raw materials benzene and tert-amyl alcohol are selected as starting materials, tert-amylbenzene is obtained by Friedel-Crafts alkylation reaction, propionyl chloride is selected to carry out Friedel-Crafts acylation reaction with tert-amylbenzene to generate tert-amylpropiophenone, 2,6-dimethylmorpholine and paraformaldehyde are selected to carry out Mannich reaction with tert-amylpropiophenone to produce 4-tert-amyl-1-(2-methyl-1-oxy-3-(2,6-dimethylmorpholine-4-)propyl)benzene, and finally palladium carbon is selected to carry out catalytic oxidation to generate amorolfine.

6. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 3, the generated amorolfine raw material is dissolved in alcohol or ether, released according to the specified ratio, and a proper amount of hydrochloric acid solution is added dropwise to the solution, and a suitable time is waited for the solution to react after mixing, and the reaction produces amorolfine hydrochloride.

7. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 4, the obtained amorolfine hydrochloride is mixed with an appropriate amount of ethanol, propylene glycol and other auxiliary materials, dissolved and uniformly mixed to ensure the stability and uniformity of the drug, and the components are added according to the specified ratio so that the amorolfine hydrochloride is dissolved in a sufficient solvent and kept uniformly mixed in the solvent, and the pH value of the obtained drug reagent is adjusted so that the pH value of the solution is within the specification range to ensure comfort and stability during drug use.

8. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 4, the preparation is homogenized by a homogenizing device, and the preparation is treated by a high-pressure homogenizer, so that the drug particles are crushed to an average diameter of less than 1 μm, thereby breaking the drug cell wall, enhancing the drug's penetration ability and absorption efficiency, helping to improve the drug's distribution accuracy, maintain a constant active ingredient content, and improve production efficiency.

9. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step 5, after the drug selection is determined, amorolfine hydrochloride and all excipients are strictly inspected, including physical and chemical properties, to ensure that the materials meet the quality standards. During the preparation process, key intermediates are tested and different detection methods are used for their special properties to ensure the quality and purity of the intermediates. Finally, the prepared amorolfine hydrochloride ointment is tested for appearance, content, related substances, microbial limits and other items to ensure that all parameters meet the quality standards. After the test, the material preparation can be adjusted according to the test results to ensure the qualified rate of the drug.

10. The production process of amorolfine hydrochloride liniment according to claim 3, characterized in that: In the step six, the qualified amorolfine hydrochloride ointment is packaged in a sealed container to prevent drug volatilization and contamination, and the product name, specifications, production date, expiration date, usage and dosage, precautions and other information are indicated on the package, and a detailed instruction manual is provided to let users know how to use it correctly. The packaged amorolfine hydrochloride ointment is stored in a cool, dry and well-ventilated place to avoid direct sunlight and high temperature.

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