A method for preparing a high drug loading adapalene gel

Abstract

The application is a preparation method of high drug loading adalapin gel, which adopts micro sponge technology to wrap adalapin in porous microspherical material, so as to improve the drug loading of adalapin preparation without increasing irritation, improve the effectiveness and safety of the drug, meet the basic theory of pharmacoeconomics, and improve the clinical value of the product. The obtained adalapin micro sponge can be used to prepare a series of external preparations, including cream, gel, ointment, lotion and the like. The capsule material used in the micro sponge is preferably dermacryl 79, which has film-forming sunscreen properties, so that the active ingredient can be prevented from contacting ultraviolet light, thereby reducing the risk of drug light irritation.

Description

Technical Field

[0001] This invention relates to a method for preparing adapalene gel with high drug loading, specifically to a method for preparing an adapalene microsponge and an adapalene gel with a drug loading of up to 1%. Background Technology

[0002] Adapalene, its chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, and its structural formula is:

[0003] As a third-generation retinoid, it is primarily used to treat acne vulgaris, a skin condition characterized by comedones, papules, and pustules. Compared to other retinoids, this drug has a stronger effect in regulating epidermal cell differentiation, inhibiting keratinocyte proliferation and keratinization at the follicular opening, inhibiting sebaceous gland cell proliferation, and dissolving keratin plugs and comedones. It also possesses a strong anti-inflammatory effect. Its unique stability makes it superior to other retinoids in terms of efficacy and tolerability.

[0004] However, due to the acidic nature of its molecule, adapalene can cause some irritation when used on the face, limiting its clinical application and dosage. Specifically, patients often experience skin redness, swelling, and stinging sensations when using adapalene gel. This not only limits the product's use but also restricts the strength of the adapalene gel. Currently, most adapalene formulations marketed in China are 0.1% strength. While lower strength formulations reduce irritation, they also limit the product's effectiveness. Since efficacy and safety are the most fundamental attributes of a drug, current adapalene gel technology cannot effectively meet these requirements.

[0005] Currently, the commercially available dosage of adapalene is Galderma International's Differin, a 0.1% gel. However, in recent years, domestic and international literature and case reports have indicated that the use of Differin can cause skin irritation, which limits its clinical application (Harris B, Bitner B, Thomas L. Differin® and depilation, a word of warning. J Cosmet Dermatol. 2019 Aug;18(4):1081-1082. doi:10.1111 / jocd.12799. Epub 2018 Oct 29. PMID:30375157.).

[0006] Increasing the drug loading of adapalene and reducing its irritation can effectively improve its efficacy.

[0007] With the rapid advancements in pharmaceutical technology, drug research has entered an era of formulation innovation. Novel drug delivery systems, such as sustained-release and controlled-release formulations, are increasingly favored, and their enormous market potential and broad development prospects are driving the rapid development of my country's pharmaceutical industry. Controlling the release rate of drugs at specific sites in the human body remains a major challenge and is an area that researchers both domestically and internationally have been focusing on in recent years.

[0008] Microsponges are a novel drug delivery system proposed in recent years for controlled-release drug delivery. They have shown significant advantages in controlling the rate and site of drug release, improving drug stability, reducing toxicity, and increasing bioavailability, and have been successfully applied in the pharmaceutical and cosmetic fields. Microsponges are a formulation intermediate product, defined as fine, highly cross-linked, porous, spherical particles with a particle size ranging from approximately 5-300 μm (see [link to product description]). Figure 1 ).

[0009] Generally, microsponge drug delivery systems are considered to have the following advantages: 1. They can extend the shelf life of products with little or no preservatives because bacteria are too large relative to the pore size of the microsponge to enter the channels and react with the drug; 2. The highly porous physical structure allows microsponges to have a very high drug loading capacity; 3. For drugs with irritating or unpleasant odors, microsponges can adsorb them into the channels, thereby masking the odor and reducing irritation; 4. Liquid drugs can be solidified through microsponges; 5. Microsponges can adsorb a large amount of drug into the channels and achieve equilibrium with the medium, thus achieving a sustained-release effect; 6. By adsorbing the drug into the channels, the contact between the active ingredient and the external environment can be reduced, thereby increasing the chemical stability of the drug.

[0010] In the existing technology, microsponge technology is mostly used in skin preparations, but there is no record of its use in adapalene preparations. Furthermore, the encapsulation material used in existing microsponge technology cannot resist ultraviolet light, which may lead to the risk of drug photoirritation and affect the efficacy. Summary of the Invention

[0011] This invention proposes a method for preparing adapalene gel with high drug loading capacity. Its purpose is to overcome the above-mentioned shortcomings of the existing technology and to increase the drug loading capacity to 1% while ensuring the low irritation of adapalene gel.

[0012] The technical solution of this invention: Adapalene is encapsulated in porous microspheres using microsponge technology, increasing the drug loading capacity of the adapalene formulation without increasing irritation. A high dose of adapalene is encapsulated in the microsponge and reaches equilibrium with the adapalene in the medium. The adapalene in the medium then continues to diffuse through the skin, creating a dynamic equilibrium. This can be understood as a controlled-release technology for skin formulations.

[0013] Specifically, a method for preparing adapalene microsponge includes the following steps: Adapalene and acrylamide / octylacrylamide copolymer were dissolved in dichloromethane to prepare an internal phase for later use. Then, polyvinyl alcohol is dissolved in water to prepare the external phase, namely, a polyvinyl alcohol solution; The internal phase is gradually added dropwise to the external phase, and the emulsification is achieved by shearing and dispersing using a high-shear emulsifier. The emulsion was then heated in a water bath using a rotary evaporator with continuous stirring, and dried under reduced pressure to evaporate the dichloromethane. The solution is then filtered through a membrane, and the remaining solid spherical particles are dried in a vacuum drying oven to produce adapalene microsponge.

[0014] Preferably, the weight ratio of adapalene, acrylate / octylacrylamide copolymer and dichloromethane is 1:9:20.

[0015] Preferably, the acrylate / octylacrylamide copolymer is dermacryl79.

[0016] Preferably, the polyvinyl alcohol solution has a concentration of 2% w / w.

[0017] Preferably, the high-shear emulsifier has a shearing speed of 10,000 rpm, shearing dispersion for 10 min, and the droplet size is controlled to be 10-100 μm after emulsification.

[0018] Preferably, the rotary evaporator heats the emulsion in a water bath at 60°C and stirs continuously at 100 rpm.

[0019] Preferably, the filter membrane is a 0.45 μm filter membrane.

[0020] Use of an adapalene microsponge for the preparation of adapalene gels, creams, lotions, or ointments.

[0021] A method for preparing a high-drug-loading adapalene gel, comprising: Weigh the raw materials and auxiliary materials according to the following weight ratio: Adapalene micro sponge: purified water: thickener: preservative: emulsifier: sodium hydroxide = 1-20: 50-90: 0.1-5: 0.01-0.2: 0-10: 0-1, and set aside. Sodium hydroxide was dissolved in purified water to prepare a 25% w / w sodium hydroxide aqueous solution; Add the remaining amount of purified water and preservative to a container, heat to 60-80℃, and stir to dissolve. After cooling, add the thickener and let it swell completely overnight; Add the emulsifier and stir well; Add the adapalene micro sponge and continue stirring until well combined; Add the sodium hydroxide aqueous solution and stir until homogeneous to obtain adapalene microsponge gel.

[0022] Preferably, the thickener is carbomer.

[0023] Preferably, the carbomer is one of carbomer 940, carbomer 941, carbomer 934, carbomer 1342, carbomer 980, carbomer ETD 2020, carbomer SF-1, and carbomer Ultraz.

[0024] Preferably, the preservative is ethylparaben.

[0025] Preferably, the emulsifier is propylene glycol and Tween 80 in a weight ratio of 20:0.35.

[0026] The advantages of this invention are: the method is rationally designed, and by pretreating adapalene into microsponges without altering the drug's molecular structure, the drug loading capacity of adapalene can be increased without increasing its irritation. This improves the drug's efficacy and safety, aligns with basic pharmacoeconomic principles, and enhances the product's clinical value. The resulting adapalene microsponges can be used to prepare a series of topical formulations, including creams, gels, ointments, and lotions. Furthermore, the encapsulating material used in the microsponges is preferably dermacryl 79, which, due to its film-forming and sun-protective properties, prevents the active ingredient from being exposed to ultraviolet light, reducing the risk of photoirritation. Attached Figure Description

[0027] Figure 1 This is an electron microscope image of a microsponge embodiment.

[0028] Figure 2 This is an electron microscope image of the adapalene microsponge from Example 1.

[0029] Figure 3 This is the particle size distribution diagram of adapalene microsponge in Example 1.

[0030] Figure 4 These are comparison photos of the experimental results of the experimental subjects in Example 3. Detailed Implementation

[0031] The present invention will be further described in detail below with reference to embodiments and specific implementation methods.

[0032] Example 1: Preparation of Adapalene Microsponge

[0033] Adapalene microsponges were prepared using an emulsion-like solvent diffusion method.

[0034] First, 1g of adapalene and 9g of dermacryl79 were dissolved in 20g of dichloromethane to prepare an internal phase for later use. Then, dissolve an appropriate amount of polyvinyl alcohol in an appropriate amount of water to prepare an external phase (a 2% w / w polyvinyl alcohol solution). The internal phase is slowly added (drop by drop) to the external phase, and the mixture is dispersed by shearing using a high-shear emulsifier (shear speed of 10000 rpm) for 10 min. Once emulsification is complete, the droplet size is controlled to be between 10-100 μm. The emulsion was then heated in a rotary evaporator at 60°C in a water bath and stirred continuously at 100 rpm. The emulsion was then dried under reduced pressure to evaporate the dichloromethane. The solution is then filtered through a 0.45 μm filter membrane, and the solid spherical particles retained (such as...) Figure 2 (As shown) After drying in a vacuum drying oven, it becomes adapalene microsponge, with a particle size distribution as shown. Figure 3 And as shown in the table below.

[0035]

[0036] Example 2 and Comparative Example

[0037] Example 2 describes the preparation of adapalene microsponge gel, while the comparative example describes the preparation of ordinary adapalene gel.

[0038]

[0039] Weigh the raw and auxiliary materials according to the prescription in the table above and set aside; Sodium hydroxide was dissolved in purified water to prepare an aqueous solution of sodium hydroxide (25% w / w). Add the prescribed amount of water to a container, add ethylparaben, heat to 60-80℃, and stir to dissolve; After cooling, add Carbomer 980 and let it swell completely overnight; Add the prescribed amounts of propylene glycol and Tween 80, and stir well. Add adapalene microsponge or adapalene and continue stirring until well combined; Add an aqueous solution of sodium hydroxide and stir until homogeneous to obtain 1% adapalene microsponge gel or adapalene gel.

[0040] Adapalene pretreated with microsponges can also be prepared into different dosage forms, including but not limited to creams, gels, lotions, ointments, and other topical preparations, all of which fall within the scope of protection of this invention. Example 3

[0041] Skin irritation tests were conducted on the adapalene microsponge gel of Example 2 and the comparative adapalene gel. The irritation was evaluated for single and multiple administrations in accordance with the NMPA guidelines (National Food and Drug Administration, Technical Guidelines for Drug Irritation, Allergy and Hemolysis Studies, 2014).

[0042] Take 6 New Zealand white rabbits. Figure 4 As shown, 3 microsponge gels (ABC) were used in Example 2 with 1% adapalene microsponge gel, and 3 microsponge gels (DEF) were used in the comparative example with 1% adapalene gel. Using the same in vivo left-right control method, the hair along the spine on the rabbit's back was trimmed with a razor and scissors. Depilatory cream was then evenly applied to the skin on the back, and after approximately 10 seconds, it was washed off with warm water and the skin was wiped clean. A cross was then drawn with a black pen to divide the skin into four areas. The left side was treated with the drug-free formulation as a negative control, and the right side was treated with the drug-containing formulation as a positive control. The upper side was intact skin, and the lower side was treated with a sterilized scalpel to create a broken skin area.

[0043] Weigh 0.5g of adapalene microsponge gel and adapalene gel (0.5g of drug-free gel was used for the negative control area); apply the gels separately to cut gauze (cut the gauze into 2×2cm square pieces and stack the gauze in 3 layers before use). Then quickly apply the medication to hairless skin and secure the gauze with two layers of adhesive tape. Administer once daily for 7 consecutive days.

[0044] The results showed that after applying the adapalene microsponge gel of Example 2 to intact or damaged skin for 7 consecutive days, there were no significant changes in the skin. After 7 days, the skin on the back of the rabbits remained intact, without rashes, lumps, erythema, etc. (see figures A, B, and C). However, after applying the comparative adapalene gel to intact or damaged skin for 7 consecutive days, obvious skin damage was observed. Lumps and erythema appeared in D, obvious wound ulceration appeared in E, and wound ulceration also appeared in F.

[0045] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. An adapalene gel, characterized in that, Includes 10% adapalene microsponge, 0.6% carbomer 980, 20% propylene glycol, 0.35% Tween 80, 0.07% sodium hydroxide, 0.01% ethylparaben, and purified water to make up to the total volume. The method for preparing the adapalene microsponge includes the following steps: (1) Dissolve 1g of adapalene and 9g of dermacryl79 in 20g of dichloromethane to prepare an internal phase for later use; (2) Dissolve an appropriate amount of polyvinyl alcohol in an appropriate amount of water to prepare an external phase. The concentration of the polyvinyl alcohol solution is 2% w / w. (3) Slowly add the inner phase to the outer phase and use a high-shear emulsifier with a shear rate of 10,000 rpm to shear and disperse for 10 min. After emulsification, control the droplet size to be 10-100 μm. (4) Use a rotary evaporator to heat the emulsion in a water bath at 60°C and stir continuously at 100 rpm. Dry under reduced pressure to evaporate the dichloromethane. (5) The solution is filtered through a 0.45 μm filter membrane, and the solid spherical particles that are retained are dried in a vacuum drying oven to obtain adapalene micro sponges.

2. The method for preparing the adapalene gel according to claim 1, characterized in that, Includes the following steps: (1) Weigh the raw and auxiliary materials according to the prescription and set aside; (2) Dissolve sodium hydroxide in purified water to prepare a 25% w / w sodium hydroxide aqueous solution; (3) Add the prescribed amount of water to a container, add ethylparaben, heat to 60-80℃, stir to dissolve, let cool, add carbomer 980, and let it swell fully overnight; (4) Add the prescribed amount of propylene glycol and Tween 80, stir well, then add the adapalene micro sponge and continue stirring until well mixed; (5) Finally, add an aqueous solution of sodium hydroxide and stir until homogeneous to obtain adapalene microsponge gel.

3. Adapalene gel prepared by the method of claim 2.

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