Metronidazole external gel without p-hydroxybenzoate

Abstract

The metronidazole external gel without p-hydroxybenzoate is prepared from benzyl alcohol serving as a preservative, and the mass fraction of the benzyl alcohol is 1.0%-3.5%. The gel further comprises a humectant, a gel-forming polymer, a pH regulator, a chelating agent and a solvent. The metronidazole gel has the advantages that the formula and the preparation method are reasonable in design, p-hydroxybenzoate harmful to skin and human bodies is prevented from being unnecessarily used in the metronidazole gel formula, and microbial limit test and specific microbial test can be met in the whole shelf life. The problem of accidental inoculation of bacteria, fungi, yeast and mould can be solved. The use safety of the metronidazole external gel can be effectively improved.

Description

Technical Field

[0001] The invention relates to a metronidazole external gel, in particular to a metronidazole external gel which does not contain parahydroxybenzoate. Background Art

[0002] Metronidazole is widely used to treat skin diseases and vaginal infections, specifically acne and bacterial vaginosis, in the form of gels, creams, and lotions. and ) generally contain a main preservative, namely methylparaben, propylparaben or ethylparaben (alone or in combination with other parabens).

[0003] Prior art metronidazole gel formulations generally contain the preservative parabens. Parabens are aliphatic esters of parahydroxybenzoic acid and are widely used as preservatives in cosmetics, pharmaceuticals, and foods. The most commonly used parabens are methylparaben, ethylparaben, propylparaben, and butylparaben. Typically, more than one paraben is added to a product, and parabens are often used in conjunction with other preservatives to better protect against a variety of microorganisms.

[0004] The safety of parabens is controversial, and most regions restrict their use to low concentrations, as evidenced by numerous studies. Longer chain parabens, such as propylparaben or isobutylparaben, are generally considered more likely to interfere with the body.

[0005] The following are the main adverse reactions caused by the use of high concentrations of parabens and their causes.

[0006] Contact Dermatitis: Parabens are more likely to cause delayed contact dermatitis when applied topically, but this has also been reported following oral administration.

[0007] Hypersensitivity reactions: Propylparaben has also been linked to reported hypersensitivity reactions. Some studies have found that parabens can cause skin irritation, hives, swelling, and redness, usually around the eyes, cheeks, or lips, especially in people with repeated exposure. Some people seem to be more sensitive to parabens and therefore more likely to have skin reactions. The CDC notes that certain studies have found that sensitive people may experience skin reactions to these chemicals, including urticaria (red, itchy welts) and angioedema (severe hives and swelling of the skin). While parabens are generally not considered to cause allergies, some people have experienced severe allergic reactions to them.

[0008] Reduced immunity: Parabens can reduce the number of healthy bacteria on the skin and weaken the skin's immune system.

[0009] Hormone disruption: Parabens have a weak estrogenic effect in mice. This means that studies have shown that parabens are able to bind to estrogen receptors, which may interfere with hormone production. This is particularly concerning when considering hormone-related cancers, such as certain types of breast cancer. Hormone disruption can affect reproductive activities in the body, such as pregnancy and menstruation.

[0010] Breast cancer: Using creams and lotions containing paraben preservatives under the arms and breasts may increase the incidence of breast cancer in women. Analysis of breast tumor tissue revealed that methylparaben was present at the highest level among the tissue samples analyzed (ethyl, propyl, butyl, and isobutyl parabens).

[0011] Skin cancer: Use of personal care products containing parabens, especially methylparaben, can lead to UV-induced skin cell damage and disruption of cell proliferation (cell growth rate). Daily use, in particular, can lead to increased concentrations of methylparaben, which cannot be completely metabolized. Methylparaben, in combination with other estrogenic chemicals, may influence the development of malignant melanoma (a type of skin cancer) through its estrogenic and genotoxic effects.

[0012] Irritation: Parabens are used because they are gentle and non-irritating. However, like any ingredient, some people may be more susceptible to irritation than others. For example, Healthline notes that some people are allergic to methyl paraben. It is generally recommended that people with overly sensitive skin types, such as those prone to eczema, dermatitis, or broken skin, avoid parabens if they find them irritating. Parabens are also more likely to irritate broken skin, such as those with cuts or ulcers. If you have broken skin, it is best to avoid using parabens in that area.

[0013] Developmental and Reproductive Toxicity: Propylparaben and butylparaben appear to reduce sperm production and cause lower testosterone levels, while methylparaben and ethylparaben do not affect sperm production. These effects appear to be dose-related. In addition, one study found that maternal exposure to butylparaben during pregnancy and lactation altered the development of reproductive organs and sperm production. Overall, propylparaben and butylparaben in particular appear to disrupt the male reproductive system and affect reproductive organs. This is consistent with the estrogenic activity mentioned above.

[0014] In order to avoid unnecessary use of parabens, which are harmful to the skin and human body, in the metronidazole gel formulation, the use of paraben-free formulation ingredients and production processes should be considered, provided that they pass microbial limit tests and specific microbial tests throughout the shelf life.

[0015] CN105769754A discloses a preservative-free metronidazole gel and a preparation method thereof. Although the components thereof do not contain preservatives and have been terminally sterilized, the problem of accidental inoculation of bacteria, fungi, yeasts and molds cannot be solved. Generally, the preservatives in the preparation can neutralize the microorganisms accidentally inoculated in the preparation, but if there is no preservative in the preparation, it will cause serious damage to the target organs. In this case, the eyes are very critical and sensitive organs. In addition, the preparation method thereof is heated at a temperature of 120°C for 30 minutes, and the moist heat generated during the high-pressure sterilization process may degrade the metronidazole or the excipients in the formulation. In addition, the termination sterilization at a semi-solid temperature of 120°C for 30 minutes will irreversibly destroy the structure. The patent document also does not study or evaluate the research on accidental inoculation of microorganisms and microbial growth in the formulation. Therefore, the patent document cannot solve the above-mentioned technical problems existing in the prior art, and the patent cannot solve the practical problems related to the formulation. Summary of the invention

[0016] The present invention provides a metronidazole topical gel that does not contain parabens, and aims to overcome the above-mentioned shortcomings of the prior art and provide a metronidazole topical gel that does not contain parabens to improve the safety of use while ensuring the antibacterial effect.

[0017] The technical solution of the present invention is a paraben-free metronidazole gel for external use, which includes benzyl alcohol as a preservative, and the mass fraction of benzyl alcohol is 1.0%-3.5%. The content and type of preservative can improve the safety of use while ensuring the antibacterial effect.

[0018] Preferably, it also includes a humectant, a gel-forming polymer, a pH adjuster, a chelating agent and a solvent.

[0019] Preferably, the gel-forming polymer is a specific grade of carbomer or a combination of multiple carbomers, the moisturizer is propylene glycol [1-3 propanediol], glycerol, propylene glycol or butylene glycol, the pH regulator is sodium hydroxide, ammonia, triethanolamine or a mixture thereof, the chelating agent is disodium ethylenediaminetetraacetate or dicalcium ethylenediaminetetraacetate, and the solvent is purified water.

[0020] Preferably, for intravaginal application, the pH value is 3.5-4.5.

[0021] Alternatively, preferably, for skin application, the pH is 4.0 to 6.0.

[0022] Preferably, the chelating agent is disodium ethylenediaminetetraacetic acid, the moisturizing agent is propylene glycol [1-3 propanediol], the gel-forming polymer is carbomer, and the pH regulator is sodium hydroxide.

[0023] Preferably, the mass fractions of the components are: metronidazole 0.5%-1.5%, carbomer 0.75%-1.75%, propylene glycol [1-3 propanediol] 2.5%-7.5%, benzyl alcohol 1.0%-3.5%, sodium hydroxide 0.05%-0.2%, disodium ethylenediaminetetraacetate 0.01%-0.1%, and the balance is purified water.

[0024] A method for preparing a paraben-free metronidazole topical gel comprises the following steps:

[0025] 1) Prepare the solution: add metronidazole to a mixture of propylene glycol [1-3 propanediol] and benzyl alcohol under stirring at 1000±500 RPM;

[0026] 2) Preparation of carbomer dispersion: dispersing carbomer in a mixture of metronidazole and propylene glycol [1-3 propanediol] and benzyl alcohol, stirring at a rotation speed of 1000±500 RPM for 10 minutes, and then homogenizing at a rotation speed of 2000±500 RPM for 10 minutes to obtain a polymer dispersion;

[0027] 3) Preparation of aqueous phase: Add disodium ethylenediaminetetraacetate to purified water and dissolve under stirring, and add the aqueous phase to the polymer dispersion;

[0028] 4) Polymer hydration: The polymer dispersion was hydrated for 50 minutes under stirring at 1000±500 RPM, and then homogenized at 2000±500 RPM for 10 minutes;

[0029] 5) pH adjustment: Use 10% sodium hydroxide aqueous solution to adjust the pH value of the solution to 4.5±0.2, and the stirring speed is 50±5RPM;

[0030] 6) Mixing: Mix the pH adjusted mixture for more than 30 minutes under anchor stirring at 50±5 RPM and recirculation stirring at 100±10 RPM.

[0031] The advantages of the present invention are as follows: the formula and preparation method are reasonably designed, and unnecessary use of parabens harmful to the skin and human body is avoided in the metronidazole gel formula, and the microbial limit test and specific microbial test can be met throughout the shelf life. The problem of accidental inoculation of bacteria, fungi, yeasts and molds can be solved. The safety of metronidazole topical gel can be effectively improved. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0033] A paraben-free metronidazole topical gel, which instead uses benzyl alcohol as a preservative (which also acts as a solvent), and also includes a humectant, a gel-forming polymer, a pH adjuster, a chelating agent, and a solvent.

[0034] As an embodiment, the gel-forming polymer is selected from a specific grade of carbomer or a combination of suitable carbomers; the moisturizer is selected from propylene glycol [1-3 propanediol], glycerol, propylene glycol, butylene glycol, the pH adjuster is selected from sodium hydroxide, ammonia water, triethanolamine or a mixture thereof; the chelating agent is selected from disodium ethylenediaminetetraacetic acid, dicalcium ethylenediaminetetraacetic acid; the solvent is selected from purified water.

[0035] As another example, the gel-forming polymer is an acrylic acid cross-linked polymer, such as carbomer or polycarbophil, and / or a cellulosic polymer. Suitable cellulosic polymers include, but are not limited to, carboxymethyl cellulose (CMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose (NEC or HHX), hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC). Suitable carbomers include, but are not limited to, cellulose acetate, cellulose glycol, cellulose ether, cellulose glycol succinate ... Various polymers sold under the trade name include, for example Homopolymers (acrylic acid polymers crosslinked with allyl sucrose or pentaerythritol allyl ether), such as NF, NF, NF, NF and NF; Copolymers (polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with pentaerythritol allyl ether), such as PEMULEN TM TR-1NF and PEMULEN TM TR-2 NF; Interpolymers (carbomer homopolymers or copolymers containing polyethylene glycol and long chain alkyl acid ester block copolymers), such as 2020 NF and 10NF; "traditional" carbomer, such as Carbomer 934 ( 934NF), Carbomer 934P ( NF), Carbomer 940( 940NF), Carbomer 941( NF) and Carbomer 1342 ( NF); and polycarbophil ( USP).

[0036] As another example, a gel for intravaginal mucosal application should have a certain degree of adhesion to prevent leakage of the gel during use. Gels made using cellulosic and / or acrylic adhesive gelling polymers with a viscosity that meets the requirements should have appropriate adhesion. Different gelling polymers have different degrees of adhesion. Gelling polymers that produce high-dose adhesive metronidazole water-based gels with adhesion within about ±10% of the exemplary gel can be appropriately used. As a further example, the mucus adhesive polymer is selected from the group consisting of hydroxyalkyl cellulose, carbomer, polycarbophil and mixtures thereof. In another specific exemplary embodiment, the mucus adhesive polymer is polycarbophil, for example, available from Lubrizol Corporation under the trade name Polycarbophil. Polycarbophil is sold under the trade name Polycarbophil.

[0037] As another example, the pH of the gel should generally match the pH of the intended application site, for example, for intravaginal application, the pH of a healthy vagina is less than 4.5, while for skin application, the pH range is 4-7. Thus, for a gel for intravaginal application, the pH should generally be in the range of about 3.5 to about 4.5, for example, a pH of about 4, while a gel for skin application has a pH of about 4.0 to 6.0. The pH can be adjusted and / or maintained with the aid of acid, base buffers and other pH adjusters, as is well known in the art.

[0038] As a further embodiment, disodium ethylenediaminetetraacetic acid is used as a chelating agent, propylene glycol [1-3 propanediol] is used as a moisturizer, carbomer is used as a gel-forming polymer, sodium hydroxide is used as a pH regulator, and purified water is used as a solvent for external application on the skin or mucous membrane. Compared with the prior art, this formula has a significant effect on the change of the active substance of the metronidazole topical gel, and has better safety and stability in terms of microbial contamination.

[0039] As an effective substance (active ingredient), metronidazole is present in the gel in a therapeutically effective amount. The content may vary depending on the use of the gel, and is preferably 0.5%-1.5% of the total mass of the aqueous gel, and more preferably 0.7%-1.3%.

[0040] As an embodiment, the mass fractions of the components are: metronidazole 0.5%-1.5%, carbomer 0.75%-1.75%, propylene glycol [1-3 propanediol] 2.5%-7.5%, benzyl alcohol 1.0%-3.5%, sodium hydroxide 0.05%-0.2%, disodium ethylenediaminetetraacetate 0.01%-0.1%, and the balance is purified water.

[0041] Example 1: Preservative-free formulation

[0042]

[0043]

[0044] Preparation method:

[0045] 1) Prepare the solution: Add metronidazole to propylene glycol [1-3 propanediol] under stirring at 1000±500 RPM.

[0046] 2) Preparation of carbomer dispersion: Carbomer was dispersed in a mixture of metronidazole and propylene glycol [1-3 propanediol], stirred at a rotation speed of 1000±500 RPM for 10 minutes, and then homogenized at a rotation speed of 2000±500 RPM for 10 minutes to obtain a polymer dispersion.

[0047] 3) Preparation of aqueous phase: Add disodium ethylenediaminetetraacetate to purified water and dissolve under stirring. Add the aqueous phase to the polymer dispersion.

[0048] 4) Polymer hydration: The polymer dispersion was hydrated under stirring at 1000±500 RPM for 50 minutes, and then homogenized at 2000±500 RPM for 10 minutes.

[0049] 5) pH adjustment: Use 10% sodium hydroxide aqueous solution to adjust the pH value of the solution to 4.5±0.2, and the stirring speed is 50±5 RPM.

[0050] 6) Mixing: Mix the pH adjusted mixture for more than 30 minutes under anchor stirring at 50±5 RPM and recirculation stirring at 100±10 RPM.

[0051] Example 2: Paraben-free formulation

[0052] The formula differs from Example 1 in that it also contains 2.0% w / w benzyl alcohol as a preservative and solvent.

[0053] The preparation method is different from that of Example 1 in that in step 1), metronidazole is added to a mixture of propylene glycol [1-3 propanediol] and benzyl alcohol.

[0054] Example 3: Microbial Limit Test

[0055] Microbial limit testing was performed in accordance with USP Chapters 60, 61, and 62. Samples were prepared in such a way that the metronidazole gel solution was homogeneous and consistent. Since microbial contamination will not be uniformly dispersed throughout a batch or sample of a product, the sample was rigorously checked for homogeneous solution. Conventional mechanical shaking was used without altering the original number and type of microorganisms in the product. Samples were analyzed immediately upon completion of the study. Visually inspect the integrity of the primary container of each unit and note any irregularities. Aseptically wipe the outer surface of the sample container with a validated and effective antimicrobial agent and place it on a sterilized tray or surface in a properly sterilized laminar flow hood or biosafety cabinet. Allow the container to dry. Aseptically open the container and perform the weighing procedure in a laminar flow hood or biosafety cabinet whenever possible. Use appropriate environmental controls such as air exposure plates in accordance with local quality procedures. Use appropriate negative controls and run them simultaneously with the samples.

[0056] The results are shown in the following table.

[0057]

[0058] According to the above results, the formula of Example 1 without any preservatives has microbial growth, and the growth is random, which may be caused by accidental inoculation or the presence of microbial growth in the sample. The sample of Example 2 without parabens but using benzyl alcohol as a safe preservative did not show microorganisms under accelerated and room temperature storage conditions. Therefore, the metronidazole gel of Example 2 without parabens is safer than the preservative-free one of Example 1.

[0059] Example 4: Antibacterial effect test

[0060] The test is performed according to Chapter 51 of the United States Pharmacopeia General Chapters. The standard test microbial group used in most methods includes three bacterial strains (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), one mold strain (Aspergillus brasiliensis), and one yeast strain (Candida albicans). These standardized strains all meet the standards of the American Type Culture Collection (ATCC). The standard microbial group is added to the product formulation, containing 100,000 to 1,000,000 microorganisms per gram or milliliter, and then incubated at controlled room temperature (20-25°C) for 28 days. After the 28th day, the formulation is re-inoculated with the same microorganisms and tested a second time. During the incubation process, the growth (or lack of growth) of the microorganisms is counted at specific time intervals of 2, 7, 14, 28, and 56 days. The results are shown in the table below.

[0061]

[0062]

[0063] Based on the above results, Example 2, which does not contain parabens, showed excellent results in the antimicrobial efficacy test, which indicates that the product has the ability to neutralize accidentally inoculated microorganisms, while Example 1 does not have the ability to neutralize accidentally inoculated microorganisms in the formulation because its log reduction value increased from the initial value.

[0064] Conclusion: Compared with the gel containing paraben preservatives and the preservative-free gel of Example 1, the paraben-free formulation of Example 2 has better safety and efficacy.

[0065] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A metronidazole topical gel free of parabens, characterized in that: It includes using benzyl alcohol as a preservative, and the mass fraction of benzyl alcohol is 1.0%-3.5%.

2. The paraben-free metronidazole topical gel according to claim 1, characterized in that: Also included are humectants, gel-forming polymers, pH adjusters, chelating agents and solvents.

3. The paraben-free metronidazole topical gel according to claim 2, characterized in that: The gel-forming polymer is a specific grade of carbomer or a combination of multiple carbomers, the moisturizer is propylene glycol [1-3 propanediol], glycerol, propylene glycol or butylene glycol, the pH regulator is sodium hydroxide, ammonia water, triethanolamine or a mixture thereof, the chelating agent is disodium ethylenediaminetetraacetate or dicalcium ethylenediaminetetraacetate, and the solvent is purified water.

4. The paraben-free metronidazole topical gel according to claim 3, characterized in that: The chelating agent is disodium ethylenediaminetetraacetate, the moisturizing agent is propylene glycol [1-3 propanediol], the gel-forming polymer is carbomer, and the pH regulator is sodium hydroxide.

5. The paraben-free metronidazole topical gel according to claim 4, characterized in that: The mass fractions of each component are: metronidazole 0.5%-1.5%, carbomer 0.75%-1.75%, propylene glycol [1-3 propanediol] 2.5%-7.5%, benzyl alcohol 1.0%-3.5%, sodium hydroxide 0.05%-0.2%, disodium ethylenediaminetetraacetic acid 0.01%-0.1%, and the balance is purified water.

6. The method for preparing a paraben-free metronidazole topical gel according to claim 5, characterized in that: The following steps are involved: 1) Prepare the solution: Add metronidazole to a mixture of propylene glycol [1-3 propanediol] and benzyl alcohol under stirring at 1000±500 RPM; 2) Preparation of carbomer dispersion: dispersing carbomer in a mixture of metronidazole and propylene glycol [1-3 propanediol] and benzyl alcohol, stirring at a speed of 1000±500 RPM for 10 minutes, and then homogenizing at a speed of 2000±500 RPM for 10 minutes to obtain a polymer dispersion; 3) Preparation of aqueous phase: Add disodium ethylenediaminetetraacetate to purified water and dissolve under stirring, then add the aqueous phase to the polymer dispersion; 4) Polymer hydration: The polymer dispersion was hydrated for 50 minutes under stirring at 1000±500RPM, and then homogenized at 2000±500RPM for 10 minutes; 5) pH adjustment: Use 10% sodium hydroxide aqueous solution to adjust the pH value of the solution to 4.5±0.2, and the stirring speed is 50±5RPM; 6) Mixing: Mix the pH adjusted mixture for more than 30 minutes under anchor stirring at 50±5RPM and recirculation stirring at 100±10RPM.

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