阅读说明：本技术 抗真菌用氟曲马唑洗发香波制剂及其制备工艺 (Antifungal flutramazole shampoo preparation and preparation process thereof ) 是由 金牮 马冬冬 陈寅 郝超 张桂森 于 2021-01-18 设计创作，主要内容包括：本发明提供了一种抗真菌用氟曲马唑洗发香波制剂及其制备工艺。该洗发香波制剂包括以下重量份的组分：0.1％-3.0％的氟曲马唑、10％-80％的表面活性剂、1％-10％的增溶剂、0％-8％的助溶剂、1％-8％的调理剂、0.5％-4％的流变调节剂、0.05％-0.1％的螯合剂、0.05％-1％的防腐剂、0％-1％的pH调节剂、0％-0.5％的香精、余量为纯化水。本发明可为患者提供新的药用洗发香波,用于局部治疗头皮糠疹(头皮屑)、脂溢性皮炎。同时,解决了氟曲马唑溶解性差、稳定性差的技术难题,并具有良好的柔顺、调理及洁发效果。本发明还提供了该抗真菌用氟曲马唑洗发香波制剂的制备工艺,该制备工艺简单可行,可控性强,易于工业化生产。(The invention provides an antifungal flutramazole shampoo preparation and a preparation process thereof. The shampoo preparation comprises the following components in parts by weight: 0.1 to 3.0 percent of flutramazole, 10 to 80 percent of surfactant, 1 to 10 percent of solubilizer, 0 to 8 percent of cosolvent, 1 to 8 percent of conditioner, 0.5 to 4 percent of rheology regulator, 0.05 to 0.1 percent of chelating agent, 0.05 to 1 percent of preservative, 0 to 1 percent of pH regulator, 0 to 0.5 percent of essence and the balance of purified water. The invention can provide a new medicinal shampoo for patients, which is used for locally treating pityriasis capitis (dandruff) and seborrheic dermatitis. Meanwhile, the technical problems of poor solubility and poor stability of the flutramadol are solved, and the effects of softening, conditioning and cleaning hair are good. The invention also provides a preparation process of the antifungal flutramadol shampoo preparation, and the preparation process is simple and feasible, strong in controllability and easy for industrial production.)

1. An antifungal flutramazole shampoo preparation, which is characterized in that: the paint comprises the following components in parts by weight:

and (3) flutramazole: 0.1 to 3.0 percent

Surfactant (b): 10 to 80 percent

Solubilizer: 1 to 10 percent

Cosolvent: 0 to 8 percent of

Conditioner: 1 to 8 percent

Rheology modifier: 0.5 to 4 percent

Chelating agent: 0.05 to 0.1 percent

Preservative: 0.05 to 1 percent

pH regulator: 0 to 1 percent

Essence: 0 to 0.5 percent

The balance being water.

2. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the paint comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 32 to 76.35 percent

Solubilizer: 2 to 10 percent

Cosolvent: 3 to 7 percent of

Conditioner: 1.9 to 4.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.1 to 0.3 percent

pH regulator: 0.5 percent

Essence: 0 to 0.5 percent

The balance being purified water.

3. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the paint comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 35 to 47 percent of

Solubilizer: 2 to 7 percent of

Cosolvent: 3 to 7 percent of

Conditioner: 2 to 4.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.1 to 0.3 percent

pH regulator: 0.5 percent

Essence: 0 to 0.5 percent

The balance being purified water.

4. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the composition comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 76.35 percent

Solubilizer: 10 percent of

Cosolvent: 3 percent of

Conditioner: 1.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.2 percent of

pH regulator: 0.5 percent

The balance being purified water.

5. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the surfactant is at least one selected from fatty alcohol sulfate, fatty alcohol-polyoxyethylene ether sulfate, alkenyl sulfonate, fatty acid methyl ester sodium sulfonate, amino acids, alkyl glycoside, alkylolamide, betaine, imidazoline and phosphate; preferably at least one of sodium fatty alcohol-polyoxyethylene ether sulfate, alkyl glycoside or cocamidopropyl betaine; or, the solubilizer is selected from at least one of tween 20, ethanol, modified castor oil or benzyl alcohol, preferably tween 20, modified castor oil or any combination thereof; or the cosolvent is selected from at least one of propylene glycol, butanediol or glycerol; preferably propylene glycol, glycerol or any combination thereof.

6. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the conditioning agent is selected from polyquaternium-7, polyquaternium-10, polyquaternium-22, polyquaternium-47, polyquaternium-54, guar gum, PEG-75 lanolin, water-soluble olive oil, PPG-3 octyl ether, polydimethylsiloxane propyl PG-betaine, emulsified silicone oil or any combination thereof; preferably polydimethylsiloxane propyl PG-betaine, silicone emulsion or any combination thereof.

7. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the rheology modifier is selected from di (hydrogenated tallow) phthalic acid amide, acrylic acid copolymer, acrylic acid/steareth-20 methacrylate copolymer, PEG-150 distearate, cocamide MEA, PEG-120 methyl glucose dioleate, sodium chloride, ammonium chloride or any combination thereof, preferably acrylic acid copolymer, acrylic acid/steareth-20 methacrylate copolymer, sodium chloride or any combination thereof.

8. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the chelating agent is selected from edetic acid and derivatives or salts thereof; alternatively, the preservative is selected from dimethylol dimethyl hydantoin, methyl isothiazolinone, diazoimidazolidinyl urea, sodium benzoate, potassium sorbate, phenoxyethanol, methylparaben, or any combination thereof.

9. The antifungal flutramadol shampoo formulation according to claim 1, characterized in that: the pH regulator is selected from citric acid, lactic acid, hydrochloric acid, sodium hydroxide or any combination thereof.

10. A process for the preparation of an antifungal flutramazole shampoo preparation for use in the preparation of an antifungal flutramazole shampoo preparation according to any one of claims 1 to 9, comprising the steps of:

s1, dissolving of raw material medicines: dispersing the flutriazole in a mixed solvent of a solubilizer and a cosolvent, heating the mixture to be dissolved under the condition of oil bath at the temperature of 70-160 ℃, and cooling the mixture for later use;

s2, preparing the antifungal flumetrazole shampoo preparation by adopting a cold mixing method or a hot mixing method according to the components in the formula.

Technical Field

The invention belongs to the technical field of medicinal preparations, relates to medicinal shampoo, and particularly relates to an antifungal flutramadol shampoo preparation and a preparation process thereof.

Background

Pityriasis capitis (dandruff) and seborrheic dermatitis are common diseases and frequently encountered diseases of dermatology, can be caused at various age stages and are mainly caused by fungal infection. With the wide application of high-efficiency broad-spectrum antibiotics, adrenocortical hormones and immunosuppressants in recent years, the gradual increase of organ and tissue transplantation and surgical intervention of human bodies and the breeding and spread of a plurality of viruses, fungal infection has an increasingly serious trend, the incidence rate of the fungal infection is obviously increased in some areas, and the emergence of some drug-resistant strains also provides challenges for the treatment of the fungal disease.

The research shows that the medicinal shampoos on the market in the United states, Japan, Europe and China are relatively single, and mainly focus on ketoconazole, clobetasol propionate, selenium disulfide, benzalkonium chloride and ciclopirox olamine. At present, the ketoconazole lotion and the compound ketoconazole lotion for hair are sold in the market at home, the product is single, the drug selection of patients is not facilitated, and meanwhile, the drug resistance is easy to occur. Therefore, there is an urgent need in the domestic world for a new medicinal shampoo for topical treatment of pityriasis capitis (dandruff), seborrheic dermatitis.

The flutramazole is a typical imidazole antifungal drug, not only inhibits lanosterol 14 alpha-demethylase, but also can generate membrane permeability disorder through interaction with membrane lipid so as to achieve an antibacterial effect. The antifungal drug is a local antifungal drug with broad-spectrum activity, good tolerance, low toxicity and good in-vivo and in-vitro activity proved by research.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a novel medicinal shampoo which is used for locally treating pityriasis capitis (dandruff) and seborrheic dermatitis; the antifungal flutramazole shampoo preparation solves the technical problems of poor solubility and poor stability of the raw material medicines, and has good effects of softening, conditioning and cleaning hair.

In order to achieve the aim, the invention provides an antifungal flutramazole shampoo preparation which comprises the following components in parts by weight:

and (3) flutramazole: 0.1 to 3.0 percent

Surfactant (b): 10 to 80 percent

Solubilizer: 1 to 10 percent

Cosolvent: 0 to 8 percent of

Conditioner: 1 to 8 percent

Rheology modifier: 0.5 to 4 percent

Chelating agent: 0.05 to 0.1 percent

Preservative: 0.05 to 1 percent

pH regulator: 0 to 1 percent

Essence: 0 to 0.5 percent

The balance being water.

Preferably, the antifungal flutramazole shampoo preparation comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 32 to 76.35 percent

Solubilizer: 2 to 10 percent

Cosolvent: 3 to 7 percent of

Conditioner: 1.9 to 4.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.1 to 0.3 percent

pH regulator: 0.5 percent

Essence: 0 to 0.5 percent

The balance being purified water.

Preferably, the antifungal flutramazole shampoo preparation comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 35 to 47 percent of

Solubilizer: 2 to 7 percent of

Cosolvent: 3 to 7 percent of

Conditioner: 2 to 4.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.1 to 0.3 percent

pH regulator: 0.5 percent

Essence: 0 to 0.5 percent

The balance being purified water.

Preferably, the antifungal flutramazole shampoo preparation comprises the following components in parts by weight:

and (3) flutramazole: 1.0 percent

Surfactant (b): 76.35 percent

Solubilizer: 10 percent of

Cosolvent: 3 percent of

Conditioner: 1.9 percent

Rheology modifier: 7 percent of

Chelating agent: 0.05 percent

Preservative: 0.2 percent of

pH regulator: 0.5 percent

The balance being purified water.

Wherein the surfactant is selected from fatty alcohol sulfate, fatty alcohol polyoxyethylene ether sulfate, alkenyl sulfonate, sodium fatty acid methyl ester sulfonate, amino acids (such as N-acyl sarcosinate, N-acyl glutamate, etc.), alkyl glycosides (such as alkyl glycoside APG, etc.), alkylolamides (such as cocamide DEA, cocamide MEA, etc.), betaines (such as dodecyl dimethyl betaine, cocamidopropyl betaine, etc.), imidazolines (such as acetic acid type imidazoline, propionic acid type imidazoline, etc.), phosphate esters (such as phosphatidyl choline, etc.), or any combination thereof, preferably fatty alcohol polyoxyethylene ether sodium sulfate AES, alkyl glycoside APG, cocamidopropyl betaine CAB, or any combination thereof.

The solubilizer is selected from tween 20, ethanol, modified castor oil, benzyl alcohol or any combination thereof, preferably tween 20, modified castor oil or any combination thereof.

The cosolvent is selected from propylene glycol, butylene glycol, glycerol or any combination thereof, preferably propylene glycol, glycerol or any combination thereof.

The conditioning agent is selected from polyquaternium-7, polyquaternium-10, polyquaternium-22, polyquaternium-47, polyquaternium-54, guar gum, PEG-75 lanolin, water soluble olive oil, PPG-3 octyl ether, polydimethylsiloxane propyl PG-betaine, emulsified silicone oil or any combination thereof, preferably polydimethylsiloxane propyl PG-betaine, emulsified silicone oil or any combination thereof.

The rheology modifier is selected from di (hydrogenated tallow) phthalic acid amide, acrylic acid copolymer, acrylic acid/steareth-20 methacrylate copolymer, PEG-150 distearate, cocamide MEA, PEG-120 methyl glucose dioleate, sodium chloride, ammonium chloride or any combination thereof, preferably acrylic acid copolymer, acrylic acid/steareth-20 methacrylate copolymer, sodium chloride or any combination thereof.

The chelating agent is selected from edetic acid and derivatives or salts thereof.

The preservative is selected from dimethylol dimethyl hydantoin, methyl isothiazolinone, diazo imidazolidinyl urea, sodium benzoate, potassium sorbate, phenoxyethanol, methylparaben or any combination thereof.

The pH regulator is selected from citric acid, lactic acid, hydrochloric acid, sodium hydroxide or any combination thereof.

In order to achieve the above object, the present invention further provides a process for preparing an antifungal flutramadol shampoo preparation, which is used for preparing the antifungal flutramadol shampoo preparation according to any of the preceding technical schemes, comprising the steps of:

s1, dissolving of raw material medicines: dispersing the flutriazole in a mixed solvent of a solubilizer and a cosolvent, heating the mixture to be dissolved under the condition of oil bath at the temperature of 70-160 ℃, and cooling the mixture for later use;

s2, preparing the antifungal flumetrazole shampoo preparation by adopting a cold mixing method or a hot mixing method according to the components in the formula.

The invention has the beneficial effects that:

(1) the invention can provide a new medicinal shampoo for patients, which is used for locally treating pityriasis capitis (dandruff) and seborrheic dermatitis.

(2) The antifungal flumetrazol shampoo preparation solves the technical problems of poor dissolubility and stability of the flumetrazol, and has good effects of softening, conditioning and cleaning hair.

Detailed Description

For better understanding, a plurality of preferred embodiments of the present invention will be described in detail, and the technical solutions of the embodiments of the present invention will be clearly and completely described below. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.

Example 1

Example 1 provides an antifungal flutramazole shampoo formulation having the composition shown in the following table:

the preparation process of the antifungal flutramadol shampoo preparation comprises the following steps:

s1, preparing a flutramadol solution: dispersing flutramazole in Tween 20, propylene glycol and glycerol, heating to dissolve in 100 deg.C oil bath, and cooling;

s2, sequentially adding water, EDTA2Na, AES, PEG-75 lanolin and a flutrimazole solution into a batching pot under a water bath of 80 ℃, stirring until the materials are dissolved and uniformly mixed, and cooling to 50 ℃;

s3, uniformly mixing water-soluble olive oil, cocamide DEA, essence and PPG-3 octyl ether for later use;

s4, sequentially adding CAB35, the solution obtained in the step S3, the acrylic acid (ester) copolymer (SF-1) water solution, 10% sodium hydroxide solution, emulsified silicone oil 7137, emulsified silicone oil 1785 and phenoxyethanol into the batching kettle in a water bath at 50 ℃, and stirring until the materials are dissolved and mixed uniformly;

s5, slowly adding sodium chloride into the batching pan to adjust the viscosity, and supplementing water to full dose; cooling and defoaming to obtain the antifungal flutramadol shampoo preparation.

Example 2

Example 2 provides an antifungal flutramazole shampoo formulation having the composition shown in the following table:

the preparation process of the antifungal flutramadol shampoo preparation comprises the following steps:

s1, preparing a flutramadol solution: dispersing the flutramazole in Tween 20 and propylene glycol, heating to dissolve in oil bath at 100 ℃, and cooling for later use;

s2, sequentially adding water, EDTA2Na, APG0810, CAB35 and a flutrimazole solution into a batching pot in a water bath at 50 ℃, and stirring until the materials are dissolved and uniformly mixed;

s3, sequentially adding polydimethylsiloxane propyl PG-betaine, diazo imidazolidinyl urea, Aculyn22 aqueous solution and sodium hydroxide solution into the batching pot, and stirring until the components are dissolved and uniformly mixed;

s4, slowly adding sodium chloride into the batching pan to adjust the viscosity, and supplementing water to full dose; cooling and defoaming to obtain the antifungal flutramadol shampoo preparation.

Example 3

Example 3 provides an antifungal flutramazole shampoo formulation having the composition shown in the following table:

the preparation process of the antifungal flutramadol shampoo preparation comprises the following steps:

s1, preparing a flutramadol solution: dispersing flutramazole in Tween 20, propylene glycol and glycerol, heating to dissolve in 100 deg.C oil bath, and cooling;

s2, sequentially adding water, EDTA2Na, AES, APG0810, PEG-75 lanolin and a flutrimazole solution into a batching pot under a water bath of 80 ℃, stirring until the materials are dissolved and uniformly mixed, and cooling to 50 ℃;

s3, uniformly mixing water-soluble olive oil, cocamide DEA, essence and PPG-3 octyl ether for later use;

s4, sequentially adding CAB35, the solution obtained in the step S3, the acrylic acid (ester) copolymer (SF-1) water solution, 10% sodium hydroxide solution, emulsified silicone oil 7137, emulsified silicone oil 1785 and phenoxyethanol into the batching kettle in a water bath at 50 ℃, and stirring until the materials are dissolved and mixed uniformly;

s5, slowly adding sodium chloride into the batching pan to adjust the viscosity, and supplementing water to full dose; cooling and defoaming to obtain the antifungal flutramadol shampoo preparation.

Examples 4 to 8

Examples 4-8 provide antifungal flutramazole shampoo formulations having the compositions shown in the following table:

the preparation process of the antifungal flutramadol shampoo preparation comprises the following steps:

s1, preparing a flutramadol solution: dispersing the flutramazole in Tween 20 and propylene glycol, heating to dissolve in oil bath at 100 ℃, and cooling for later use;

s2, sequentially adding water, EDTA2Na, AES, APG0814, PEG-75 lanolin and a flutrimazole solution into a batching pot under a water bath of 80 ℃, stirring until the materials are dissolved and uniformly mixed, and cooling to 50 ℃;

s3, sequentially adding CAB35, water-soluble olive oil, cocamide DEA, PPG-3 octyl ether, SF-1 aqueous solution, 10% sodium hydroxide solution and phenoxyethanol into the batching pot under a water bath of 50 ℃, and stirring until the materials are dissolved and mixed uniformly;

s4, slowly adding sodium chloride into the batching pan to adjust the viscosity, and supplementing water to full dose; cooling and defoaming to obtain the antifungal flutramadol shampoo preparation.

Example 9 product stability study

The antifungal flutramadol shampoo formulations of examples 1-8 were subjected to product stability studies.

And (3) accelerated test: the antifungal flutramadol shampoo formulations of examples 1-8 were placed at 30 ℃. + -. 2 ℃ and 65%. + -. 5% relative humidity for 6 months and sampled for 0, 1, 2, 3, 6 months. The results of the examination are shown in the following table.

The experimental results show that: the antifungal flumetrazol shampoo preparation of example 1 has unsatisfactory content in 1 and 2 months of acceleration and poor stability, and it was analyzed that the flumetrazol is liable to be hydrolyzed and the formulation contains a large amount of water, and the amount of the flumetrazol decreases due to the generation of a hydrolysate during the accelerated stability test; the antifungal flumetrazol shampoo preparations of examples 4, 5, 6 and 7 have unsatisfactory properties and poor stability for 2 or 3 months, mainly because the flumetrazol is difficult to dissolve in water, and in the surfactant system and the solubilizing cosolvent system of examples 4, 5, 6 and 7, the flumetrazol exceeds the saturated solubility in the process of accelerating stability investigation, so that the raw material drug is separated out, and the properties are not qualified; the antifungal flutrimazole shampoo preparations of examples 2, 3, and 8 had good stability, and it was analyzed that flutrimazole was not easily hydrolyzed and precipitated during the accelerated stability test in the surfactant system and solubilizing cosolvent system of examples 2, 3, and 8.

Example 10 evaluation of safety-skin irritation test

Safety evaluation-skin irritation test method: selecting 30 healthy rabbits with half male and female parts, shearing two sides of the spine of the back of the rabbit with surgical scissors 24 hours before the test without damaging the skin, and removing the hair with the area of 15 multiplied by 10cm²After unhairing, animals were randomized into 3 groups, each group tested separately for the antifungal flutrimazole shampoo formulations of examples 2, 3, 8. Applying the antifungal flutrimazole shampoo preparation of example 2, example 3 or example 8 to the left depilatory area of the rabbit, massaging for 5 minutes, and cleaning with 2 g; the right side is sprayed with pure water and massaged for 5 minutes, the dosage is also 2 g. After drying and knotting, covering the test area with a layer of sterilized oilpaper and two layers of sterilized gauze, and fixing with adhesive tapes. After 12 hours, the cover was removed, and the presence of erythema and edema at the administration site was observed and recorded 1, 24 and 48 hours later, respectively.

And (3) test results: the antifungal flutrimazole shampoo preparations of examples 2, 3, and 8 showed no irritation and safety in all of the antifungal flutrimazole shampoo preparations of examples 2, 3, and 8, since they were 0 in the score of the normal skin irritation response of rabbits, and no erythema or edema was observed in the administration site after 1, 24, and 48 hours.

Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the spirit and scope of the present invention.