Multi-carrier penetration enhancer and preparation method thereof

Abstract

The preparation method comprises the following steps: firstly, weighing natural borneol and menthol, adding 95% ethanol, stirring until the natural borneol and the menthol are completely dissolved, then weighing hydroxypropyl-beta-cyclodextrin, adding water for dissolving, stirring until the solution is clear and transparent, adding ethanol, stirring until the solution is completely dissolved, adding ethanol, stirring until the solution is completely dissolved, adding ethanol, and stirring until the solution is completely dissolved; and finally, adding an ethanol solution of natural borneol and menthol into the hydroxypropyl-beta-cyclodextrin aqueous solution while stirring, and grinding for 5-30 minutes by using a colloid mill to obtain a multielement carrier penetration enhancer solution. The multielement carrier penetration enhancer prepared by the invention is good in synergistic penetration enhancing effect, suitable for hydrophilic and lipophilic drug delivery, good in solubility, high in stability, low in skin irritation and high in safety.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of skin penetration enhancer, in particular to a multi-component carrier penetration enhancer and a preparation method thereof. BACKGROUND

[0002] Transdermal drug delivery system refers to a kind of preparation that drug penetrates through skin, is absorbed by capillary blood vessels and then enters blood circulation to achieve effective blood concentration to produce drug effect. However, the stratum corneum, the outermost layer of the skin, will produce a barrier effect on most exogenous substances, including drugs. The rate of drug penetration through the skin is slow or the amount of penetration is not enough to reach a sufficient concentration, so the best therapeutic effect cannot be achieved. Penetration enhancer refers to a substance that can increase or enhance the rate or amount of drug penetration. The ideal penetration enhancer should have no damage or irritation to the skin, no pharmacological activity and allergy, and stable physicochemical properties, and good compatibility with drugs and excipients. In fact, there is almost no penetration enhancer that completely meets the above requirements. Therefore, the development of new formulations with better penetration enhancing effect has become the focus of enterprises.

[0003] The commonly used single penetration enhancer includes chemical penetration enhancer and natural penetration enhancer. The use of a single penetration enhancer can increase the amount of drug penetration, but the penetration rate is relatively small, and the amount of penetration often does not meet the treatment requirements. Patent CN111803469B discloses a transdermal absorption and sustained-release patch containing estradiol and a preparation method thereof. The estradiol patch combines fatty acid esters and polyhydric alcohol penetration enhancers as a composite penetration enhancer, which has a significantly better penetration enhancing effect than single component penetration enhancer, and the penetration effect is better when combined with terpene penetration enhancer. How to combine 2 or more penetration enhancers, or some natural penetration enhancers with chemical penetration enhancers to further improve the penetration effect is the main research direction. SUMMARY

[0004] The present application aims to overcome the shortcomings of the prior art and provide a multi-component carrier penetration enhancer and a preparation method thereof to solve the problems of high content of single penetration enhancer and poor penetration effect in the prior art.

[0005] The object of the present application is achieved by the following technical solution: a multi-component carrier penetration enhancer, comprising the following components in terms of mass fraction: natural borneol 0.3-3 parts, menthol 0-6 parts, 95% or more ethanol 1-5 parts, hydroxypropyl betadex 8-80 parts, and water 50-1000 parts.

[0006] Preferably, the natural borneol is 1.5 parts, the menthol is 2.4 parts, the 95% or more ethanol is 2.4 parts, the hydroxypropyl betadex is 36 parts, and the water is 360 parts in terms of mass fraction.

[0007] A preparation method of a multi-component carrier penetration enhancer, comprising the following steps: S1. Take natural borneol and menthol and add 95% ethanol to stir until completely dissolved; S2. Take hydroxypropyl betacyclodextrin and dissolve in water, and stir until the solution is clear and transparent; S3. While stirring, add the ethanol solution of natural borneol and menthol to the hydroxypropyl betacyclodextrin water solution, and grind with a colloid mill for 5-30 min to obtain a multi-component carrier penetration enhancer solution.

[0008] The present application has the following advantages: 1. The present application provides a multi-component penetration enhancer, which is prepared from four components, and the components are complementary to each other. Natural borneol and menthol are both natural penetration enhancers of terpenes, which can disrupt the ordered arrangement of the lipid bilayer of the stratum corneum, increase the lipid fluidity, and expand the intercellular space. Ethanol can strengthen the lipid solubility, and its dehydration effect can denature the keratin protein, further weakening the barrier function. The three components can form more drug penetration channels, breaking through the limitations of single components. The hydrophobic cavity of hydroxypropyl betacyclodextrin can include the lipid-soluble drugs natural borneol and menthol to form water-soluble inclusion compounds, which can greatly improve the solubility of the drugs in the carrier. The inclusion compounds are complementary to ethanol as a polar solvent, further enhancing the solubility of water-soluble drugs. The inclusion compounds do not precipitate during storage at room temperature (10-30℃). Hydroxypropyl betacyclodextrin also has a sustained-release effect. Menthol has a fast effect (instant cooling sensation), natural borneol maintains the medium-term penetration, and ethanol evaporates, and the hydroxypropyl betacyclodextrin continuously releases the drugs, forming a "fast-medium-slow" three-level delivery system. Natural borneol and menthol are natural penetration enhancers, which have lower irritation than azone. Hydroxypropyl betacyclodextrin can include ethanol and menthol, reducing the problems of erythema and itching, and is suitable for hydrophilic and lipophilic drugs. 2. The excellent penetration effect of the multi-component penetration enhancer is not a simple superposition of the components. Instead, hydroxypropyl betacyclodextrin is the main component, and natural borneol, menthol, and ethanol are added in small amounts for assistance. The addition of hydroxypropyl betacyclodextrin has a better effect than the combination of azone, natural borneol, menthol, and ethanol in the penetration experiment on mouse skin. BRIEF DESCRIPTION OF DRAWINGS

[0009] Figure 1 is the HE-stained section of hydroxypropyl betacyclodextrin of the present application; Figure 2 is the HE-stained section of the control group azone of the present application. DETAILED DESCRIPTION

[0010] To make the purpose, technical solutions, and advantages of the embodiments of the present application clearer, the technical solutions of the present application will be described clearly and completely below with reference to specific examples of the present application.

[0011] Example 1 A multi-component carrier penetration enhancer is prepared by the following method comprising the steps of, S1. Weigh natural borneol 3g, menthol 6g and 95% ethanol 5g, stir until completely dissolved; S2. Weigh hydroxypropyl betacyclodextrin 80g and add water 1000g to dissolve, stir until the solution is clear and transparent; S3. While stirring, add the ethanol solution of natural borneol and menthol to the hydroxypropyl betacyclodextrin aqueous solution, and grind with a colloid mill for 5-30 minutes to obtain a multi-component carrier penetration enhancer solution.

[0012] Example 2 A multi-component carrier penetration enhancer comprises natural borneol 3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 40g, and water 1000g, and is prepared by the same method as in Example 1.

[0013] Example 3 A multi-component carrier penetration enhancer comprises natural borneol 3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 8g, and water 1000g, and is prepared by the same method as in Example 1.

[0014] Example 4 A multi-component carrier penetration enhancer comprises natural borneol 3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 45g, and water 400g, and is prepared by the same method as in Example 1.

[0015] Example 5 A multi-component carrier penetration enhancer comprises natural borneol 3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 36g, and water 360g, and is prepared by the same method as in Example 1.

[0016] Example 6 A multi-component carrier penetration enhancer comprises natural borneol 3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 4g, and water 50g, and is prepared by the same method as in Example 1.

[0017] Example 7 A multi-component carrier penetration enhancer comprises natural borneol 1.5g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 36g, and water 360g, and is prepared by the same method as in Example 1.

[0018] Example 8 A multi-component carrier penetration enhancer comprises natural borneol 0.3g, menthol 6g, 95% ethanol 5g, hydroxypropyl betacyclodextrin 36g, and water 360g, and is prepared by the same method as in Example 1.

[0019] Example 9 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 4.2 g, 95% ethanol 5 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0020] Example 10 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 5 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0021] Example 11 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 0.6 g, 95% ethanol 5 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0022] Example 12 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 4 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0023] Example 13 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 3 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0024] Example 14 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 2 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0025] Example 15 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 1 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0026] Example 16 A multi-component carrier penetration enhancer comprising natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 2.4 g, hydroxypropyl betacyclodextrin 36 g, and water 360 g, prepared in the same manner as in Example 1.

[0027] Comparative Example 1 A penetration enhancer was prepared by dissolving natural borneol 3 g in 95% ethanol 5 g to form a solution, and dissolving hydroxypropyl betacyclodextrin 80 g in 1000 g water to form a clear and transparent solution. The hydroxypropyl betacyclodextrin solution was added to the natural borneol ethanol solution while stirring, and the mixture was ground for 5-30 min using a colloid mill to obtain a multi-component carrier penetration enhancer solution.

[0028] Comparative Example 2 A penetration enhancer, natural borneol 3 g, azone 80 g, menthol 6 g, 95% ethanol 5 g, and 1000 g of water were mixed and stirred to prepare a penetration enhancer solution.

[0029] Comparative Example 3 A multi-component carrier penetration enhancer, natural borneol 1.5 g, menthol 2.4 g, 95% ethanol 2.4 g, and 1000 g of water were mixed to prepare a penetration enhancer solution.

[0030] The prepared penetration enhancer was used for transdermal testing of mice with chlorogenic acid Drugs and reagents: Chlorogenic acid standard, provided by China Institute for Food and Drug Control, batch number: 110753-202119 Experimental animals: SPF KM mice, ♂, 19-22 g, provided by Shandong Jinan Pengyue Experimental Animal Breeding Co., Ltd. (License: SCXK (Lu) 20220006), animal qualification certificate number: 370726231100985873. Experimental animal use license: SYXK (Yi) 2021-0015. Animal experiment on duty training number: NO00826 Main instruments: Electronic balance (FA (N) / JA (N)): Shanghai Minqiao Precision Instruments Co., Ltd.; analytical balance (METTLER AL204): Mettler-Toledo Instruments (Shanghai) Co., Ltd.; high-speed refrigerated centrifuge (Multifuge X3R): Thermo Fisher Scientific; automatic sample rapid grinder (XFSTPRP-48): Shanghai Jingxin Experimental Development Co., Ltd.; high performance liquid chromatograph (Ultimate 3000): Thermo Fisher Scientific Experimental method 1.1 Determination of chlorogenic acid content (high performance liquid chromatography) Chromatographic conditions: Venusil XBP C18 column (4.6 mm x 250 mm, 5 μm) was used, mobile phase A was acetonitrile, mobile phase B was 0.4% phosphoric acid, gradient elution (0-15 min, 10%-20% A, 15-30 min, 20% A, 30-40 min, 20%-30% A, 40-41 min, 30%-10% A, 41-45 min, 10% A), injection volume 10 μL, detection wavelength 350 nm, flow rate 0.9 mL·min-1, column temperature 35℃.

[0031] Preparation of reference solution: an appropriate amount of chlorogenic acid standard was accurately weighed, and 30% ethanol was added to prepare a 5 μg·mL-1 reference solution.

[0032] Preparation of test solution: about 1 ml sample solution was filtered to obtain the test solution.

[0033] Determination: 10 μl of the above-mentioned control solution and test solution was precisely taken and injected into the high performance liquid chromatograph for determination.

[0034] 1.2 Penetration enhancer - the effect of new and old process on chlorogenic acid transdermal KM mice 57, SPF, ♂, 19 ~ 22 g, adaptive feeding 3 days, were randomly divided into 19 groups, 3 in each group, respectively, experimental group (chlorogenic acid penetration enhancer - new process inclusion complex group), control group (chlorogenic acid penetration enhancer - old process inclusion complex group). The experimental mice were depilated on the abdomen, and the transdermal experiment was carried out after 6 h. The control group and experimental group mice were applied with chlorogenic acid penetration enhancer on the depilated area, and the skin was cut off after 2 h. A part of mice in each group were taken for skin homogenate, centrifuged, and the supernatant was filtered for determination of chlorogenic acid content by high performance liquid chromatography; a part of mice were taken for complete skin tissue, fixed with 10% formaldehyde for 24 h, embedded and sectioned, HE stained, and the pathological changes of skin were observed under optical microscope.

[0035] Control solution: an appropriate amount of chlorogenic acid reference substance was precisely weighed and dissolved in 30% ethanol to prepare a 5 μg·mL-1 control solution.

[0036] Test solution: about 1 ml of supernatant after homogenate centrifugation was filtered to obtain the test solution.

[0037] Detection index: chlorogenic acid content of penetration enhancer - experimental group / control group inclusion complex, chlorogenic acid penetration amount Drug preparation: all drugs were prepared into the required concentration with organic solvent as solvent The experimental results are as follows From the HE-stained section images of Figure 1 , Figure 2 , Figure 1 the effect is relatively good, there is no obvious change in muscle layer, and there is no obvious difference in the number and size of hair follicles, Figure 2 the squamous epithelial cells are slightly atrophic, and the keratin layer is slightly fluffy, indicating that the effect on skin tissue morphology is not obvious.

[0038] Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement to part of the technical features, and any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A multi-carrier penetration enhancer, characterized in that, The invention comprises the following components in parts by mass: 0.3-3 parts of natural borneol, 0-6 parts of menthol, 1-5 parts of 95% or more ethanol, 8-80 parts of hydroxypropyl beta-cyclodextrin, and 50-1000 parts of water.

2. A multi-carrier penetration enhancer according to claim 1, characterized in that: The composition includes the following components in parts by mass: 1.5 parts of natural borneol, 2.4 parts of menthol, 2.4 parts of 95% or more ethanol, 36 parts of hydroxypropyl beta-cyclodextrin, and 360 parts of water.

3. The method for preparing a multi-carrier penetration enhancer according to any one of claims 1 and 2, wherein: The following steps are included: S1. Weigh natural borneol and menthol and add 95% ethanol and stir until completely dissolved; S2. Weigh hydroxypropyl beta-cyclodextrin and dissolve in water, stirring until the solution is clear and transparent; S3. Add the ethanol solution of natural borneol and menthol to the aqueous solution of hydroxypropyl beta-cyclodextrin while stirring, and grind it in a colloid mill for 5-30 minutes to obtain a multi-carrier penetration enhancer solution.

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