Self-emulsifying external liniment containing clindamycin phosphate and application

Abstract

The invention provides a self-emulsifying external liniment containing clindamycin phosphate and application thereof, and the self-emulsifying external liniment comprises the following components by weight: 0.5%-2.0% of clindamycin phosphate, 10%-40% of an oil phase, 30%-60% of a surfactant, 10%-30% of a cosurfactant, and the balance of purified water. After the self-emulsifying external liniment is in contact with moisture, sweat and the like on the surface of skin, nano-scale emulsion droplets with extremely small particle sizes and uniform distribution can be spontaneously formed. The nano-emulsion droplet can smoothly pass through a skin microstructure, carries the drug and goes deep into hair follicles and sebaceous glands, and realizes precise delivery of propionibacterium acnes, so that the local bioavailability and the treatment effect of the drug are remarkably improved. As clindamycin phosphate is mainly dissolved in a hydrophobic microenvironment composed of the oil phase and the surfactant in a molecular state, direct contact between clindamycin phosphate and water molecules is greatly reduced, the hydrolytic degradation reaction of drugs can be effectively inhibited, and the validity period and shelf life of the product are remarkably prolonged.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparations, and in particular to a self-emulsifying external liniment containing clindamycin phosphate and its application. Background Art

[0002] Clindamycin phosphate is an antibiotic commonly used to treat acne, exerting its therapeutic effects by inhibiting Propionibacterium acnes. Currently, most commercially available topical clindamycin phosphate preparations are in traditional formulations, such as aqueous solutions, gels, or alcohols, and are widely used in dermatology.

[0003] However, existing topical clindamycin phosphate formulations face numerous technical bottlenecks. For example, the drug struggles to effectively penetrate the skin's stratum corneum, resulting in low transdermal absorption and impacting efficacy. The drug is susceptible to hydrolysis and degradation in aqueous environments, resulting in insufficient chemical stability. Some formulations contain high concentrations of organic solvents, such as alcohol, which can cause skin irritation and dryness, impacting patient compliance. Furthermore, the dosage form is highly fluid, prone to dripping during use, compromising dosing accuracy and convenience.

[0004] Self-emulsifying drug delivery systems (SEDDS) are mixtures composed of an oil phase, a surfactant, and a cosurfactant. Their characteristic characteristic is that they spontaneously form oil-in-water (O / W) microemulsions or nanoemulsions upon contact with water under gentle stirring. This system can significantly enhance the solubility of poorly soluble drugs and, due to its extremely small droplet size and large specific surface area, greatly promotes drug absorption (widely used in oral administration). However, the application of this technology in topical liniments, particularly clindamycin phosphate liniments, has not been reported.

[0005] The present invention aims to innovatively apply SEDDS technology to local skin drug delivery to solve the above technical difficulties. Summary of the Invention

[0006] In order to solve the technical problems of low transdermal absorption efficiency, poor stability, high irritation and poor user experience of clindamycin phosphate topical preparations, the present application provides a self-emulsifying topical ointment containing clindamycin phosphate and its application.

[0007] In a first aspect, the present application provides a self-emulsifying topical liniment containing clindamycin phosphate, comprising the following components in weight percentage: 0.5% to 2.0% clindamycin phosphate, 10% to 40% oil phase, 30% to 60% surfactant, 10% to 30% co-surfactant, and purified water to 100%.

[0008] Upon contact with moisture, sweat, and other substances on the skin surface, this self-emulsifying topical liniment spontaneously forms nanoscale droplets with extremely small particle sizes and uniform distribution. These tiny droplets significantly increase the drug's solubility and specific surface area on the skin surface, enabling clindamycin phosphate to be released and diffused more efficiently into the skin's surface layer, effectively promoting its penetration through the stratum corneum barrier. Nanoemulsions can smoothly penetrate the skin's microstructure, carrying the drug deep into the hair follicles and sebaceous glands, achieving precise delivery to Propionibacterium acnes, thereby significantly improving the drug's local bioavailability and therapeutic efficacy. Because clindamycin phosphate primarily dissolves in a molecular state in the hydrophobic microenvironment composed of the oil phase and surfactant, its direct contact with water molecules is greatly reduced, effectively inhibiting the drug's hydrolytic degradation reaction and significantly extending the product's shelf life. The resulting nanoemulsion has a refreshing texture, moderate fluidity, and is non-sticky. It is easy to apply evenly to the skin surface and is not prone to dripping, helping to enhance the patient's medication experience. The design of a self-emulsifying system significantly reduces the amount of traditional irritating solvents, such as alcohol, added, minimizing the risk of skin dryness and irritation, and improving skin tolerance and safety. Furthermore, the system maintains uniformity and stability during storage and use, making it less susceptible to stratification or drug precipitation. This ensures accurate and consistent dosing for each dose, further enhancing the convenience and compliance of the formulation.

[0009] Furthermore, the oil phase is selected from one or more of medium-chain triglycerides, isopropyl myristate, ethyl oleate, and caprylic / capric triglyceride. By optimizing the type and ratio of the oil phase, the emulsification performance and drug solubility can be further optimized, thereby improving the transdermal efficiency and stability of the preparation. Specifically, the oil phase can be isopropyl myristate, medium-chain triglycerides, ethyl oleate, or caprylic / capric triglyceride.

[0010] Furthermore, the surfactant is selected from one or more of polysorbate 80, polysorbate 20, polyoxyethylene castor oil, and Solutol HS 15. Preferably, the surfactant helps form nanoemulsion droplets with smaller particle size and more uniform distribution, thereby improving the stability of the system and drug release performance. Specifically, the surfactant can be polysorbate 80, polysorbate 20, polyoxyethylene castor oil, or Solutol HS 15.

[0011] Furthermore, the co-surfactant is selected from one or more of anhydrous ethanol, propylene glycol, polyethylene glycol 400, glycerol, and diethylene glycol monoethyl ether. Reasonable selection and proportion of the co-surfactant helps to stabilize the emulsion droplets with the surfactant, improving drug solubility and skin perception. Specifically, the co-surfactant can be anhydrous ethanol, propylene glycol, polyethylene glycol 400, glycerol, and diethylene glycol monoethyl ether.

[0012] Furthermore, the composition may contain 0% to 0.5% of a stabilizer or antioxidant selected from disodium edetate or sodium metabisulfite. This component can further improve the chemical stability of the drug, reduce the formation of degradation products, and extend the shelf life of the product.

[0013] A second aspect of the present application provides a method for preparing the self-emulsifying external liniment as described above, comprising the following steps: (1) Mix the oil phase, surfactant and co-surfactant evenly; (2) Add clindamycin phosphate and stir until it is completely dissolved to form a clear, transparent oily solution; (3) Optionally add a stabilizer or antioxidant and stir evenly; (4) Add purified water to the full amount and stir evenly to obtain a self-emulsifying topical ointment.

[0014] The method is simple to operate and easy to industrialize for production. The resulting preparation has good uniformity and excellent emulsification properties, which helps to achieve efficient drug delivery.

[0015] Furthermore, the oil phase is a mixture of isopropyl myristate and medium-chain triglycerides. This combination can further improve the stability of the emulsion system and the solubility of the drug.

[0016] Furthermore, the surfactant is polysorbate 80. This surfactant has strong emulsifying ability and high safety, and is suitable for external skin preparations.

[0017] Furthermore, the cosurfactant is Transcutol P. This cosurfactant can significantly improve the solubility and transdermal efficiency of drugs.

[0018] A third aspect of the present application provides a use of the self-emulsifying topical liniment described above for the treatment of acne. The self-emulsifying topical liniment can effectively deliver clindamycin phosphate to the hair follicles and sebaceous glands, significantly increasing the local bioavailability of the drug, improving the therapeutic effect of acne, and reducing skin irritation. DETAILED DESCRIPTION

[0019] For ease of understanding of the present application, the present application will be described more fully below. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0020] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of this application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0022] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0023] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0024] Unless otherwise specified, the percentage contents mentioned in this application refer to mass percentage for solid-liquid mixture and solid-solid mixture, and refer to volume percentage for liquid-liquid mixture.

[0025] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0026] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0027] The "particles" referred to in this application, or materials with a defined average particle size distribution, are not necessarily spherical in shape but may be irregular, primary or secondary. The average particle size of irregular particles is the average of their maximum and minimum diameters.

[0028] Example 1 This example provides a clindamycin phosphate self-emulsifying liniment (1%).

[0029] 1. Weigh the prescribed amount of polysorbate 80, Transcutol P, isopropyl myristate and medium-chain triglycerides into a beaker and mix them evenly using magnetic stirring to serve as the oil phase matrix.

[0030] 2. Add clindamycin phosphate to the above matrix and continue stirring until it is completely dissolved to obtain a clear solution.

[0031] 3. Dissolve EDTA-2Na in a small amount of purified water and add it to the above clear solution.

[0032] 4. Finally, add the remaining purified water and continue stirring for 15-20 minutes until a homogeneous, clear, transparent solution is formed.

[0033] 5. Take samples for inspection and repack them into high-density polyethylene (HDPE) plastic bottles if they pass the inspection.

[0034] Example 2 This example provides a clindamycin phosphate self-emulsifying liniment (1.2%).

[0035] 1. Weigh the prescribed amount of ethyl oleate, Solutol HS 15, polyethylene glycol 400 and anhydrous ethanol in a beaker and mix them evenly using magnetic stirring to form the oil phase matrix.

[0036] 2. Add clindamycin phosphate to the above matrix and continue stirring until it is completely dissolved to obtain a clear solution.

[0037] 3. Finally, add the remaining purified water and continue stirring for 15-20 minutes until a homogeneous, clear, transparent solution is formed.

[0038] 4. Take samples for inspection and repack them into high-density polyethylene (HDPE) plastic bottles if they pass the inspection.

[0039] Example 3 This example provides a clindamycin phosphate self-emulsifying liniment (1.5%).

[0040] 1. Weigh the prescribed amount of polyoxyethylene castor oil, propylene glycol, isopropyl myristate and medium-chain triglycerides into a beaker and mix them evenly with magnetic stirring to serve as the oil phase matrix.

[0041] 2. Add clindamycin phosphate to the above matrix and continue stirring until it is completely dissolved to obtain a clear solution.

[0042] 3. Dissolve sodium metabisulfite in a small amount of purified water and add it to the above clear solution.

[0043] 4. Finally, add the remaining purified water and continue stirring for 15-20 minutes until a homogeneous, clear, transparent solution is formed.

[0044] 5. Take samples for inspection and repack them into high-density polyethylene (HDPE) plastic bottles if they pass the inspection.

[0045] Test Example 1: Self-emulsification performance verification and droplet size determination Slowly add 1 mL of the sample prepared in Example 1 to a beaker containing 100 mL of purified water and gently stir (50 rpm) for 5 minutes. Visual observation reveals that the solution immediately changes from clear to milky white and becomes uniformly translucent, with no oil droplets floating or settling, indicating good self-emulsification properties. An appropriate amount of this emulsion is diluted appropriately and its particle size is measured using a laser particle size analyzer. The experiment is repeated three times. The results show that the average particle size of the formed emulsion droplets ranges from 258.0 nm to 339.3 nm, and the polydispersity index (PDI) ranges from 0.047 to 0.135, indicating that the droplets are small and uniformly distributed.

[0046] Test Example 2 In vitro transdermal diffusion test A Franz diffusion cell with a synthetic membrane as a barrier was used. The receiving cell was filled with pH 5.5 phosphate buffer and maintained at 37°C. 1.0 g of the sample from Example 1 and a commercially available 1% aqueous solution of clindamycin phosphate (as a control) were evenly coated on the membrane surface of the donor cell. The release rate was measured at 37°C for 6 hours. The results are shown in the table below.

[0047] The results showed that after 6 hours, the release rate of the sample of Example 1 of the present invention was 52.457%, which was 1.41 times the release rate of the commercial sample of 37.150%. This means that the transdermal efficiency of the present invention is significantly better than that of the commercial product.

[0048] Test Example 3 The sample from Example 1 of the present invention and a commercially available reference substance were placed under accelerated test conditions (40°C ± 2°C, 75% ± 5% relative humidity) for 6 months. Samples were collected at the end of 0, 1, 2, 3, and 6 months, and the content of clindamycin phosphate and related impurities were determined by HPLC. The changes in appearance were observed.

[0049] result: Appearance: The sample of the present invention remained clear and transparent throughout the entire test period without any change; the commercially available reference product began to show a slight yellow color at the end of the sixth month.

[0050] Content and related impurities: Within 6 months of storage, the increasing trend of related impurities in the sample of Example 1 of the present invention was lower than that of the commercial sample. The results show that the self-emulsifying system of the present invention can significantly improve the chemical stability of drugs.

[0051] Test Example 3: Effectiveness and skin irritation test Using rats as a model, 30-50 μL of a culture of Propionibacterium acnes in its logarithmic growth phase was injected into one ear of the rat, followed by application of 0.2-0.5 mL of coal tar or oleic acid for 14 consecutive days to induce an acne model with granulomatous inflammation. The sample of Example 1 of the present invention was applied to the left ear, while a commercially available control product was applied to the right ear. Administration was continued for 7 consecutive days, with six parallel groups undergoing the experiment. After the final administration, acne treatment phenomena, skin erythema, and edema were observed. (Acne severity scoring: The acne severity after successful model establishment is scored on a 10-point scale, with milder symptoms resulting in lower scores, and complete acne being scored as 0. Skin irritation scoring: No skin irritation is scored as 0, with scoring based on the degree of erythema and edema.) Results: Compared with the commercially available example, the example had a significant advantage in the treatment effect on acne during the 7-day treatment period; no obvious erythema and edema were observed on the skin after application of the example, and the irritation score was significantly lower than that of the commercially available control group, indicating that the preparation of the present invention has better skin safety.

[0052] The above experimental results demonstrate that the self-emulsifying topical liniment spontaneously forms extremely small, evenly distributed nano-sized droplets upon contact with moisture, sweat, and other substances on the skin surface. These tiny droplets significantly increase the drug's solubility and specific surface area on the skin surface, enabling more efficient release and diffusion of clindamycin phosphate into the skin's surface layers, effectively promoting its penetration through the stratum corneum barrier. The nano-emulsions can smoothly penetrate the skin's microstructure, carrying the drug deep into the hair follicles and sebaceous glands, achieving precise delivery to Propionibacterium acnes and significantly improving the drug's local bioavailability and therapeutic efficacy. Because clindamycin phosphate primarily dissolves molecularly in the hydrophobic microenvironment composed of the oil phase and surfactant, direct contact with water molecules is greatly reduced, effectively inhibiting the drug's hydrolytic degradation, significantly extending the product's shelf life. The resulting nanoemulsion exhibits a light texture, moderate fluidity, and a non-sticky feel. It is easy to apply evenly to the skin surface and is non-drip-resistant, enhancing the patient's medication experience. The design of a self-emulsifying system significantly reduces the amount of traditional irritating solvents, such as alcohol, added, minimizing the risk of skin dryness and irritation, and improving skin tolerance and safety. Furthermore, the system maintains uniformity and stability during storage and use, making it less susceptible to stratification or drug precipitation. This ensures accurate and consistent dosing for each dose, further enhancing the convenience and compliance of the formulation.

[0053] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0054] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A self-emulsifying external liniment containing clindamycin phosphate, characterized in that: The invention comprises the following components in percentage by weight: 0.5% to 2.0% of clindamycin phosphate, 10% to 40% of oil phase, 30% to 60% of surfactant, 10% to 30% of co-surfactant, and purified water to 100%.

2. The self-emulsifying external liniment according to claim 1, wherein The oil phase is selected from one or more of medium chain triglycerides, isopropyl myristate, ethyl oleate, and caprylic / capric triglyceride.

3. The self-emulsifying external liniment according to claim 1, wherein The surfactant is selected from one or more of polysorbate 80, polysorbate 20, polyoxyethylene castor oil, and Solutol HS 15.

4. The self-emulsifying external liniment according to claim 1, wherein The co-surfactant is selected from one or more of anhydrous ethanol, propylene glycol, polyethylene glycol 400, glycerol, and diethylene glycol monoethyl ether.

5. The self-emulsifying external liniment according to claim 1, wherein The invention also contains 0% to 0.5% of a stabilizer or an antioxidant, wherein the stabilizer or the antioxidant is selected from disodium edetate or sodium metabisulfite.

6. The method for preparing the self-emulsifying external liniment according to any one of claims 1 to 5, characterized in that: The method comprises the following steps: (1) uniformly mixing an oil phase, a surfactant, and a co-surfactant; (2) adding clindamycin phosphate and stirring until the clindamycin phosphate is completely dissolved to form a clear and transparent oily solution; (3) adding a stabilizer or an antioxidant and stirring evenly; and (4) adding purified water to the full amount and stirring evenly to obtain a self-emulsifying topical ointment.

7. The preparation method according to claim 6, characterized in that The oil phase is a mixture of isopropyl myristate and medium chain triglycerides.

8. The preparation method according to claim 6, characterized in that The surfactant is polysorbate 80.

9. The preparation method according to claim 6, characterized in that The co-surfactant is Transcutol P.

10. Use of the self-emulsifying external liniment according to any one of claims 1 to 5 in treating acne.

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