Coenzyme Q10 anti-inflammatory and pain-relieving gel and preparation method thereof

Abstract

The invention belongs to the technical field of biological medicine manufacturing, and particularly relates to coenzyme Q10 anti-inflammatory and pain-relieving gel and a preparation method thereof. The coenzyme Q10 is taken as a pharmaceutical activity API, prescription auxiliary materials and dosage are optimized and screened, and specific cationic lipid and a high-molecular polymer carrier are added into the auxiliary materials, so that the uniformity and the stability of the gel are improved, the skin penetrability is also remarkably improved, and a synergistic interaction effect is achieved in the aspects of diminishing inflammation and relieving pain. By adopting a combined process of'oil phase dissolution, emulsification dispersion and high-pressure homogenization ', the pain points of low water solubility and non-uniform dispersion of the coenzyme Q10 are solved, the uniform distribution of active ingredients is ensured, and the method has important significance in promoting the clinical application of an external anti-inflammatory and analgesic preparation.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical manufacturing technology, specifically to a coenzyme Q10 anti-inflammatory and analgesic gel and its preparation method. Background Technology

[0002] Inflammation and pain are common and inseparable symptoms in clinical and daily life, widely seen in various conditions such as traumatic bruising, muscle strain, arthritis, postoperative recovery, and skin inflammation. They not only cause direct physical discomfort but can also affect limb function and quality of life. Topical anti-inflammatory and analgesic preparations have become one of the preferred methods for relieving these symptoms because they act directly on the affected area, avoid systemic side effects such as gastrointestinal irritation associated with oral medications, and are convenient to use and have a direct onset of action. Market demand remains strong.

[0003] Coenzyme Q10, a naturally occurring fat-soluble antioxidant found in human cells, has seen its application value in anti-inflammatory and analgesic fields widely explored in recent years. It not only reduces oxidative stress damage at inflamed sites by scavenging excess free radicals and inhibiting lipid peroxidation, but also regulates the release of inflammatory factors (such as TNF-α and IL-6), blocking the cascade transmission of inflammatory responses. Simultaneously, it improves energy metabolism in local tissues, alleviating pain signal transmission at its source. With its synergistic anti-inflammatory, antioxidant, and analgesic effects, it possesses unique advantages over traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and local anesthetics, including good biocompatibility, fewer side effects, and a wider range of applicable populations, making it one of the ideal active ingredients for topical anti-inflammatory and analgesic preparations.

[0004] Existing topical gel products and related technologies centered on coenzyme Q10 still face numerous unresolved technical bottlenecks, severely limiting their clinical application and market promotion. Firstly, coenzyme Q10 is highly lipid-soluble and extremely poorly water-soluble. Traditional gel matrices are mostly water-soluble or hydrophilic systems, making it difficult for coenzyme Q10 to disperse evenly within the matrix. This leads to aggregation and precipitation, affecting the gel's appearance uniformity and stability, and hindering the effective release of active ingredients. Secondly, the stratum corneum, as a natural physical barrier, offers significant resistance to the penetration of lipid-soluble components. Traditional gels lack effective penetration-enhancing mechanisms, causing most dispersed coenzyme Q10 to remain only in the epidermis, failing to penetrate the stratum corneum to reach the dermis and subcutaneous inflammatory and pain-targeting tissues. This results in weak anti-inflammatory and analgesic effects, requiring repeated and extensive application to achieve the desired effect, reducing ease of use and... The accumulation of local ingredients may cause discomfort such as stickiness and clogged pores. Secondly, some existing technologies, in order to improve permeability, blindly add a high proportion of penetration enhancers. Although this can damage the stratum corneum structure and improve the penetration effect to a certain extent, it is often accompanied by obvious side effects. On the one hand, organic solvents can easily disrupt the hydrophilic-hydrophobic balance of the gel system, leading to abnormal rheological properties of the gel and the release of components, reducing the stability and shelf life of the product. On the other hand, chemical penetration enhancers can irritate the skin and mucous membranes, especially sensitive or broken skin, which can easily cause allergic or irritating reactions such as redness, swelling, itching, and stinging, seriously affecting the safety of medication. In addition, existing products generally have the problems of uneven release rate of active ingredients and short duration of effect. The effect usually decreases significantly 1-2 hours after application, requiring frequent reapplication, which cannot meet the core needs of patients for "rapid onset and long-lasting anti-inflammatory and analgesic effects".

[0005] Therefore, given the numerous shortcomings of existing technologies, such as uneven dispersion of coenzyme Q10, poor skin penetration, insufficient efficacy, poor stability, and the need to improve safety, developing a gel product with a reasonable formulation, scientific preparation process, and the ability to achieve uniform dispersion and efficient transdermal delivery of coenzyme Q10, while also possessing excellent anti-inflammatory and analgesic effects, stability, and safety, has become a technical challenge that urgently needs to be overcome by those skilled in the art. This is of great significance for promoting the clinical application of topical anti-inflammatory and analgesic preparations. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to overcome the shortcomings of the prior art and provide a coenzyme Q10 anti-inflammatory and analgesic gel and its preparation method. By selecting and adding appropriate excipients, the skin penetration, stability and uniformity of the coenzyme Q10 gel are increased, thereby improving the anti-inflammatory and analgesic effect of coenzyme Q10.

[0007] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a coenzyme Q10 anti-inflammatory and analgesic gel, which is composed of the following raw materials: coenzyme Q10, hydrogel matrix, humectant, penetration enhancer, polymer carrier, cationic lipid and surfactant.

[0008] Furthermore, the hydrogel matrix is ​​selected from one or more of the following: astragalus gum, gelatin, xanthan gum, carrageenan, hyaluronic acid, chitosan, hyaluronic acid, alginate, gum arabic, carbomer, dextran, cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, methylcellulose, and ethylcellulose.

[0009] More preferably, the hydrogel matrix is ​​selected from one or more of carrageenan, hyaluronic acid, carbomer, and sodium carboxymethyl cellulose.

[0010] Furthermore, the moisturizer is selected from one or more of glycerin, sorbitol, trehalose, hyaluronic acid, urea, propylene glycol, and polyethylene glycol.

[0011] More preferably, the moisturizer is selected from one or more of glycerin, sorbitol, hyaluronic acid and propylene glycol.

[0012] Furthermore, the penetration enhancer is selected from one or more of peppermint oil, glycerin, azone, turpentine oil, borneol, eucalyptus oil, laurocapram, squalane, benzyl nicotinate, polysorbate, poloxamer, and polyoxyethylene castor oil.

[0013] More preferably, the penetration enhancer is selected from one or more of peppermint oil, borneol, lauryl azelastone, poloxamer, and polyoxyethylene castor oil.

[0014] Furthermore, the polymer carrier is selected from at least one of hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose phthalate, acrylic resin, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethyl methacrylate, polyacrylic acid, and copovidone.

[0015] More preferably, the polymer carrier is selected from one or more of hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose succinate, polyvinylpyrrolidone, and polymethyl methacrylate.

[0016] Further, the cationic lipid is selected from one or more of dioleoyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, trimethyl-2,3-diolenooxypropylammonium chloride, trimethyl-2,3-diolenooxypropylammonium bromide, dimethyl-2,3-diolenooxypropyl-2-(2-sperminecarbamoylamino)ethylammonium trifluoroacetate, dimethyl-2-hydroxyethyl-2,3-diolenooxypropylammonium bromide, dimethyl-2-hydroxyethyl-2,3-diolenooxypropylammonium bromide, dimethyl-3-hydroxypropyl-2,3-diolenooxypropylammonium bromide, dimethyl-4-hydroxybutyl-2,3-diolenooxypropylammonium bromide, and dimethyl-5-hydroxypentyl-2,3-diolenooxypropylammonium bromide.

[0017] More preferably, the cationic lipid is selected from one or more of hexadecyltrimethylammonium bromide and trimethyl-2,3-dioleoyloxypropylammonium bromide; More preferably, the cationic lipid is composed of hexadecyltrimethylammonium bromide and trimethyl-2,3-dioleoyloxypropylammonium bromide in a mass ratio of 1:(2-4).

[0018] Furthermore, the surfactant is selected from one or more of polyethylene glycol 400, polyoxyethylene 40 hydrogenated castor oil, Tween-80, Tween-20, Span-80, and polyethylene glycol glycerol octanoate-capric acid.

[0019] Further, it is composed of the following raw materials in parts by weight: 2-10 parts coenzyme Q10, 10-20 parts hydrogel matrix, 2-6 parts humectant, 0.5-3 parts penetration enhancer, 2-6 parts polymer carrier, 4-8 parts cationic lipid and 0.01-0.5 parts surfactant.

[0020] Furthermore, the gel also includes 0.01-0.05 parts of preservative.

[0021] Furthermore, the preservative is selected from one or more of chlorhexidine acetate, ethylparaben, propylparaben, butylparaben, sodium benzoate, glyceryl monostearate, glyceryl monolaurate, glyceryl monooleate, methylparaben, propylparaben, sorbic acid, ethylparaben, potassium sorbate, propylparaben, and benzyl alcohol.

[0022] The present invention also provides the use of the gel in the preparation of therapeutic anti-inflammatory and analgesic drugs.

[0023] This invention also provides a method for preparing a coenzyme Q10 anti-inflammatory and analgesic gel, comprising the following steps: Step 1, Pretreatment: Raw material dispersion and dissolution Take Coenzyme Q10, add all the penetration enhancer and surfactant, place it in a 50-55℃ constant temperature water bath, stir magnetically for 15-20 minutes to form a uniform oil phase dispersion, and keep it warm for later use (avoid low temperature precipitation). Add 5 times the mass of the cationic lipid to purified water and stir at room temperature until completely dissolved to form a cationic aqueous solution for later use.

[0024] Step 2, Aqueous Phase Preparation: Dissolving the Gel Matrix and Carrier Take an appropriate amount of purified water and place it in a high-speed disperser. Slowly sprinkle the hydrogel matrix and polymer carrier into the system while stirring at low speed (200-300 r / min). Continue stirring for 30 min and then let it stand to swell for 2 h. Add a humectant to the swollen system and turn on high-speed stirring (800-1000 r / min) for 10 min. After mixing evenly, add the cationic aqueous solution prepared in step 1 and continue stirring for 5 min to form a homogeneous aqueous phase.

[0025] Step 3, Emulsification and Mixing: Oil Phase and Water Phase Fusion Slowly and uniformly add the oil phase dispersion after heat preservation in step 1 to the homogeneous aqueous phase in step 2, and keep stirring at high speed (1000-1200 r / min) for 20-30 min until the gel viscosity is uniformly increased and there is no particle feel, thus forming a colostrum gel system.

[0026] Step 4: Homogenization: Improves gel smoothness and stability The initial gel system was transferred to a high-pressure homogenizer and homogenized 2-3 times at 20-30 MPa, with each cycle lasting 5 minutes, to break up any remaining tiny oil droplets and particles, ensuring that coenzyme Q10 is uniformly dispersed in the gel (particle size controlled at 100-500 nm). The homogenized gel was then placed in a vacuum degassing machine and degassed for 15 minutes at a vacuum of -0.06 to -0.08 MPa to remove air bubbles. The gel was then allowed to stand at room temperature for 24 hours until the viscosity stabilized, at which point the anti-inflammatory and analgesic gel was obtained.

[0027] Compared with the prior art, the present invention has the following beneficial effects: This invention develops an anti-inflammatory and analgesic gel using coenzyme Q10 as the drug API. By optimizing the selection and dosage of excipients, and adding specific cationic lipids and polymer carriers to the excipients, the uniformity and stability of the gel are improved, and skin penetration is significantly enhanced, thus achieving a synergistic effect in anti-inflammatory and analgesic properties. The combined process of "oil-phase dissolution, emulsification dispersion, and high-pressure homogenization" addresses the challenges of low water solubility and uneven dispersion of coenzyme Q10, ensuring uniform distribution of the active ingredient. This is of great significance for promoting the clinical application of topical anti-inflammatory and analgesic preparations. Detailed Implementation

[0028] The following detailed description of the embodiments of the present invention provided in the examples is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0029] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0030] Example 1: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below: Raw material components Components Each component by mass Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier Hydroxypropyl methylcellulose succinate 4 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:2. 6 surfactants Polyethylene glycol 400 0.25 water Appropriate amount The preparation process is as follows: Step 1, Pretreatment: Raw material dispersion and dissolution Take the proportions of coenzyme Q10 shown in the table above, add all the penetration enhancer and surfactant, place in a 50℃ constant temperature water bath, stir magnetically for 20 minutes to form a uniform oil phase dispersion, and keep warm for later use (avoid low temperature precipitation). Add 5 times the mass of the cationic lipid to purified water and stir at room temperature until completely dissolved to form a cationic aqueous solution for later use.

[0031] Step 2, Aqueous Phase Preparation: Dissolving the Gel Matrix and Carrier Take an appropriate amount of purified water and place it in a high-speed disperser. Slowly sprinkle the hydrogel matrix and polymer carrier into the system while stirring at low speed (200 r / min). Continue stirring for 30 min and then let it stand to swell for 2 h. Add a humectant to the swollen system and turn on high-speed stirring (1000 r / min) for 10 min. After mixing evenly, add the cationic aqueous solution prepared in step 1 and continue stirring for 5 min to form a homogeneous aqueous phase.

[0032] Step 3, Emulsification and Mixing: Oil Phase and Water Phase Fusion Slowly and uniformly add the oil phase dispersion after heat preservation in step 1 to the homogeneous aqueous phase in step 2, and keep stirring at high speed (1000 r / min) for 30 min until the gel viscosity is uniformly increased and there is no particle feel, thus forming a colostrum gel system.

[0033] Step 4: Homogenization: Improves gel smoothness and stability The initial gel system was transferred to a high-pressure homogenizer and homogenized 2-3 times at 30 MPa, with each cycle lasting 5 minutes, to break up any remaining tiny oil droplets and particles, ensuring that coenzyme Q10 is uniformly dispersed in the gel (particle size controlled at 100-200 nm). The homogenized gel was then placed in a vacuum degassing machine and degassed at a vacuum of -0.06 to -0.08 MPa for 15 minutes to remove air bubbles. The gel was then allowed to stand at room temperature for 24 hours until the viscosity stabilized, at which point the anti-inflammatory and analgesic gel was obtained.

[0034] Example 2: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1.

[0035] Raw material components Components Each component is expressed in parts by mass. Drug API Coenzyme Q10 2 hydrogel matrix Hyaluronic acid 10 Moisturizer Hyaluronic acid 2 Penetration enhancer Borneol 0.5 Polymer carrier Hydroxyethyl methyl cellulose 2 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:3. 4 surfactants Twain-80 0.01 water Appropriate amount Example 3: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1.

[0036] Raw material components Components Each component by mass Drug API Coenzyme Q10 10 hydrogel matrix Carbomer 20 Moisturizer Propylene glycol 6 Penetration enhancer Lauryl diazepine 3 Polymer carrier Hydroxypropyl methylcellulose 6 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:3. 8 surfactants Span-80 0.05 water Appropriate amount Example 4: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1.

[0037] Raw material components Components Each component by mass Drug API Coenzyme Q10 8 hydrogel matrix Sodium carboxymethyl cellulose 14 Moisturizer Sorbitol 3 Penetration enhancer Polyoxyethylene castor oil 2 Polymer carrier Polyvinylpyrrolidone 5 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:4. 5 surfactants Caprylic / Capric ... 0.3 water Appropriate amount Comparative Example 1: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. The mass fractions of each component differ compared to Example 1.

[0038] Raw material components Components Each component by mass Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 8 Moisturizer glycerin 8 Penetration enhancer peppermint 0.2 Polymer carrier Hydroxypropyl methylcellulose succinate 8 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:2. 2 surfactants Polyethylene glycol 400 0.25 water Appropriate amount Comparative Example 2: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. Compared with Example 1, no polymer carrier was added, and the amount of cationic lipids was increased.

[0039] Raw material components Components Each component is expressed in parts by mass. Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:2. 10 surfactants Polyethylene glycol 400 0.25 water Appropriate amount Comparative Example 3: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. Compared with Example 1, no cationic lipids were added, and the amount of polymer carrier was increased.

[0040] Raw material components Components Each component by mass Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier Hydroxypropyl methylcellulose succinate 10 cationic lipids surfactants Polyethylene glycol 400 0.25 water Appropriate amount Comparative Example 4: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. Compared with Example 1, the mass ratio of each component of the cationic lipid is 1:5.

[0041] Raw material components Components Each component is expressed in parts by mass. Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier Hydroxypropyl methylcellulose succinate 4 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:5. 6 surfactants Polyethylene glycol 400 0.25 water Appropriate amount Comparative Example 5: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. Compared with Example 1, the cationic component contains only hexadecyltrimethylammonium bromide.

[0042] Raw material components Components Each component is expressed in parts by mass. Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier Hydroxypropyl methylcellulose succinate 4 cationic lipids cetyltrimethylammonium bromide 6 surfactants Polyethylene glycol 400 0.25 water Appropriate amount Comparative Example 6: A Coenzyme Q10 Anti-inflammatory and Analgesic Gel The components of the anti-inflammatory and analgesic gel are shown in the table below, and the preparation process is the same as in Example 1. Compared with Example 1, in the cationic lipid, dimethyl-2-hydroxyethyl-2,3-dioleoyloxypropylammonium bromide is used instead of trimethyl-2,3-dioleoyloxypropylammonium bromide.

[0043] Raw material components Components Each component is expressed in parts by mass. Drug API Coenzyme Q10 6 hydrogel matrix Carrageenan 15 Moisturizer glycerin 4 Penetration enhancer peppermint 2 Polymer carrier Hydroxypropyl methylcellulose succinate 4 cationic lipids The mass ratio of hexadecyltrimethylammonium bromide to trimethyl-2,3-dioleoyloxypropylammonium bromide is 1:2. 6 surfactants Polyethylene glycol 400 0.25 water Appropriate amount Example 1: Gel content uniformity test According to the content uniformity test method (General Rule 0941) of Part IV of the 2025 edition of the Chinese Pharmacopoeia, the gel uniformity of Examples 1-4 and Comparative Examples 1-6 was tested.

[0044] Ten test samples were taken from each group, and the relative content xi of each single agent with a labeled amount of 100 was determined. The mean value was calculated. and standard deviation And the absolute value A of the difference between the indicated quantity and the mean (A = |100- ) |).

[0045] If A+2.2S≤L, the uniformity of the content of the test sample meets the requirements; if A+S>L, it does not meet the requirements; if A+2.2S>L and A+S≤L, 20 more test samples should be taken for retesting.

[0046] Based on the results of the preliminary and final tests, the mean of the 30 single doses was calculated. The standard deviation S and the absolute value A of the difference between the indicated quantity and the mean are then calculated and determined using the following formula.

[0047] When A ≤ 0.25L, if A 2 +S 2 ≤0.25L 2 If A, then the uniformity of the content of the test sample meets the requirements; if A 2 +S 2 >0.25L 2 If A > 0.25L, and A + 1.7S ≤ L, then the uniformity of the sample content meets the requirements; if A + 1.7S > L, then it does not meet the requirements. In the above formula, L is the specified value, L = 15.0.

[0048] Refer to the above method to determine the content uniformity of the gels prepared in Examples 1-4 and Comparative Examples 1-6, and the results are shown in Table 1.

[0049] Table 1 Content Uniformity experimental group Content uniformity Example 1 8.4 Example 2 7.6 Example 3 8.2 Example 4 8.5 Comparative Example 1 13.5 Comparative Example 2 18.2 Comparative Example 3 16.8 Comparative Example 4 13.5 Comparative Example 5 15.5 Comparative Example 6 14.7 As can be seen from Table 1 above, the content uniformity of the coenzyme Q10 anti-inflammatory and analgesic gel provided by the present invention is less than 10, which meets the requirements of the pharmacopoeia and is far less than that of Comparative Examples 1-6. The gels prepared in the examples of the present invention have good content uniformity, and the composition and content of the polymer carrier and cationic lipid have a great impact on the content uniformity of the final gel.

[0050] Effect Example 2: Gel Stability Test According to the requirements of the guiding principles for the stability test of raw drugs and preparations (the guiding principles for the stability test of raw drugs and preparations in Part IV of the Chinese Pharmacopoeia 2025 Edition, Drug Preparations), the test samples (gels prepared in Examples 1-4 and Comparative Examples 1-6) were placed at 30°C ± 2°C and a relative humidity of 65% ± 5% for 6 months for accelerated test investigation, and their related substances (total impurities, %) were determined. The results are shown in Table 2: Table 2 Stability Determination Results

[0051] As can be seen from the stability determination results in Table 2, for the gels of Examples 1-4, after 6 months of accelerated test, the change range of related substances is not large (compared with day 0), indicating high long-term stability. The related substances of Comparative Examples 1-6 were significantly higher than those of the examples of the present invention starting from the 3rd month, indicating that the composition and content of the drug excipients, such as the polymer carrier and cationic lipid, have a great impact on the stability of the gel, and the composition of the excipients plays a crucial role in the stability of the entire drug system.

[0052] Effect Example 3: Gel Transdermal Permeability Test Take 60 SPF-grade rats, with 30 males and 30 females, weighing 220 ± 20 g. Randomly divide them into 10 groups evenly, with 6 rats in each group. The animal production license number is SCXK(Ji)-2020-0002, and the SPF rat maintenance feed is provided by Changchun Yisi Experimental Animal Technology Co., Ltd. Abdominal hair removal of the rats was performed with an 80 g / L sodium sulfide solution, the skin was washed with physiological saline, and they were raised naturally for 24 h. On the next day before the experiment, they were anesthetized with 10% chloral hydrate and then sacrificed. Immediately, the abdominal skin was dissected and the subcutaneous fat and tissues were separated. Those without damage were selected and soaked in physiological saline, and then stored in the refrigerator at 12 h for later use.

[0053] Mount the rat skin on a Franz diffusion cell (the effective permeation area is 3 cm2 The gels (approximately 600 μm thick) were placed with the stratum corneum facing the supply chamber and the dermis facing the receiving chamber, fixed in a transdermal experimental apparatus. The receiving solution was 30 mL of methanol-physiological saline (1:1), and the apparatus was kept in a constant temperature water bath at (37±1) ℃ with a magnetic stirrer speed of 100 rpm. The gels prepared in Examples 1-4 and Comparative Examples 1-6 were reconstituted with methanol / chloroform (V / V=1:1) to prepare a solution containing 2 mg of coenzyme Q10. The solution was evenly coated on the surface of the stratum corneum. 24 h after administration, 1 mL of sample was taken from the receiving chamber (with 1 mL of receiving solution at the same temperature added simultaneously). The sample was filtered through a 0.22 μm microporous membrane, and the concentration of coenzyme Q10 was determined by high performance liquid chromatography. The cumulative transdermal volume was calculated, and the results are shown in Table 3.

[0054] The HPLC analysis used a C18 column with a mobile phase of methanol:anhydrous ethanol = 70:30 (v / v), a flow rate of 1.0 mL / min, a detection wavelength of 275 nm, a column temperature of 30 ℃, and an injection volume of 10 μL.

[0055] Cumulative transdermal dose ; Among them: Q n The cumulative release per unit area (μg / cm²) of a certain component during the nth sampling. 2 ), C n Let C be the concentration (μg / mL) of a certain component in the receiving liquid of the nth sampling. i Let V be the mass concentration (μg / mL) of coenzyme Q10 in the receiving solution of the i-th (i < n-1) sampling, V be the volume of the receiving chamber (15 mL), V0 be the sampling volume (1 mL), and S be the effective permeation area (cm²) during drug diffusion. 2 ).

[0056] Table 3. Transdermal effect of gel in vitro ( ±S, n=6) experimental group <![CDATA[Cumulative transdermal amount (μg·cm -2 ).]]> Example 1 32.58±1.68 Example 2 30.54±2.03 Example 3 29.71±1.80 Example 4 31.46±2.15 Comparative Example 1 22.53±1.86* Comparative Example 2 16.54±1.97** Comparative Example 3 18.07±2.04** Comparative Example 4 17.65±1.71** Comparative Example 5 22.48±1.78* Comparative Example 6 19.75±1.65** Note: Compared with Example 1, *P<0.05, **P<0.01.

[0057] As can be seen from the transdermal effect data in Table 3, the transdermal amount of coenzyme Q10 in the gels of Comparative Examples 1-6 was significantly lower than that in Examples 1-4. This indicates that the cationic lipid and polymer carrier of the present invention can significantly and synergistically improve the transdermal effect of the active drug API, thereby promoting the transdermal absorption of coenzyme Q10 and facilitating the accumulation of the gel drug in the epidermis and dermis.

[0058] Example 4: Evaluation of anti-inflammatory and analgesic effects (1) Torsion test Sixty SPF-grade rats, with 30 males and 30 females, weighing 220±20 g, were randomly and evenly divided into 12 groups, with 5 rats in each group. The animal production license number is SCXK(Ji)-2020-0002. The maintenance feed for SPF rats was provided by Changchun Yisi Laboratory Animal Technology Co., Ltd. The 12 groups included a blank control group, a model control group, and groups of Examples 1-4 and Comparative Examples 1-6 respectively.

[0059] Treatment of each group: Blank control group: No treatment was performed, and the writhing times of the rats within 10 minutes were observed and the average value was recorded; Model control group: No drug application treatment was performed, and an intraperitoneal injection was carried out with an acetic acid solution (20 mL / kg) with a mass concentration of 0.6%. The twisting times of the mice within 10 minutes were observed, and the average value of the twisting times was recorded; Groups of Examples 1-4 and Comparative Examples 1-6: After fixing the limbs of the mice on a flat plate and shaving the abdominal hair, the shaving area was 2×2 cm, and 5 mg of gel was applied to the abdomen of the mice. The drug was administered continuously for 7 days, once a day. After 1 hour of the last drug administration, an intraperitoneal injection was carried out with an acetic acid solution (20 mL / kg) with a mass concentration of 0.6%; Within 10 minutes, the twisting times of the mice were observed, and the average value of the twisting times was recorded. The differences in the writhing times of each group were compared for statistical analysis.

[0060] (2)Swelling experiment Fifty-five SPF-grade rats, with 27 males and 28 females, were randomly and evenly divided into 11 groups, with 5 rats in each group. The 12 groups included a blank control group, groups of Examples 1-4 and Comparative Examples 1-6. The abdominal hair was removed with hair removal cream, and the area was 2 cm×2 cm. First, the circumference of the right hind paw of the rats was measured. Then, 5 mg of the anti-inflammatory and analgesic gel of Examples 1-4 and Comparative Examples 1-6 or an equal amount of normal saline was applied to the abdomen of the rats in the blank control group. Then, the rats were fixed on a wooden board to prevent them from scratching off the drug. 0.1 mL of 0.1 wt% carrageenan was subcutaneously injected into the right hind paw of the rats 30 minutes after drug administration. One hour after inflammation induction, the circumference of the right hind paw of the rats was measured respectively, and the difference before and after inflammation induction was used as the average swelling degree. The differences in the swelling degrees of each group were compared for statistical analysis.

[0061] Table 4 Evaluation of the anti-inflammatory and analgesic test of the gel ( ±S, n = 5) experimental group Average number of twists Average swelling degree / cm Blank control group 1.5±0.2 0.68±0.11 Model control group <![CDATA[42.5±3.3 ** ]]> — Example 1 <![CDATA[16.8±1.3 **## ]]> <![CDATA[0.35±0.12 ** ]]> Example 2 <![CDATA[15.5±1.4 **## ]]> <![CDATA[0.32±0.10 ** ]]> Example 3 <![CDATA[16.4±0.9 **## ]]> <![CDATA[0.28±0.11 ** ]]> Example 4 <![CDATA[17.5±1.4 **## ]]> <![CDATA[0.33±0.16 ** ]]> Comparative Example 1 <![CDATA[25.4±2.1 **# ]]> <![CDATA[0.48±0.11 * ]]> Comparative Example 2 <![CDATA[31.5±1.8 ** ]]> 0.51±0.13 Comparative Example 3 <![CDATA[29.7±2.4 ** ]]> 0.49±0.15 Comparative Example 4 <![CDATA[32.5±2.5 ** ]]> 0.56±0.15 Comparative Example 5 <![CDATA[36.4±2.2 ** ]]> 0.58±0.20 Comparative Example 6 <![CDATA[27.1±1.8 **# ]]> 0.51±0.18 Note: Compared with the blank control group, *P < 0.05, **P < 0.01; compared with the model control group, #P < 0.05, ##P < 0.01.

[0062] The anti-inflammatory and analgesic test results in Table 4 show that the number of writhing movements in the model control group, the example groups, and the comparative groups was significantly higher (p<0.01) than that in the blank control group, indicating that intraperitoneal injection of 0.6% acetic acid solution successfully induced pain response in rats, and the model was successfully established. However, the number of writhing movements in the example groups 1-4 was significantly lower than that in the comparative groups 1-6, indicating that the gels in the example groups 1-4 of this invention, with better permeability, can more significantly reduce the pain response in rats and have a significant analgesic effect. In addition, according to the swelling data, the gels in the example groups 1-4 of this invention can significantly reduce the swelling of the right hind paw of rats in a short time, indicating that the gels of this invention have a significant anti-inflammatory effect. In summary, the gels prepared by the unique excipient components in the example groups 1-4 of this invention have anti-inflammatory and analgesic effects, and the cationic lipids and polymer carriers can significantly synergistically improve the transdermal effect of the active drug API, thereby exerting a synergistic effect in anti-inflammatory and analgesic properties.

[0063] Based on the foregoing description, those skilled in the art will understand that this disclosure can be implemented in different specific forms without altering its technical spirit and essential features. Therefore, it should be understood that the above embodiments are not restrictive in any respect but rather illustrative. The scope of this disclosure is limited by the appended claims, not by the preceding description, and thus all changes and modifications fall within the boundaries and scope of the claims, or equivalents of such boundaries and scope are therefore intended to be covered by the claims.

Claims

1. A coenzyme Q10 anti-inflammatory and analgesic gel, characterized in that, It is composed of the following raw materials: coenzyme Q10, hydrogel matrix, humectant, penetration enhancer, polymer carrier, cationic lipids, and surfactant; among which, The polymer carrier is selected from one or more of hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose succinate, and polyvinylpyrrolidone; The cationic lipid is selected from one or more of hexadecyltrimethylammonium bromide and trimethyl-2,3-dioleoyloxypropylammonium bromide; the cationic lipid is formed by mixing hexadecyltrimethylammonium bromide and trimethyl-2,3-dioleoyloxypropylammonium bromide in a mass ratio of 1:(2-4).

2. The gel according to claim 1, characterized in that, The hydrogel matrix is ​​selected from one or more of the following: astragalus gum, gelatin, xanthan gum, carrageenan, hyaluronic acid, chitosan, hyaluronic acid, alginate, gum arabic, carbomer, dextran, cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, methylcellulose, and ethylcellulose.

3. The gel according to claim 2, characterized in that, The hydrogel matrix is ​​selected from one or more of carrageenan, hyaluronic acid, carbomer, and sodium carboxymethyl cellulose.

4. The gel according to claim 1, characterized in that, The moisturizer is selected from one or more of glycerin, sorbitol, trehalose, hyaluronic acid, urea, propylene glycol, and polyethylene glycol.

5. The gel according to claim 4, characterized in that, The moisturizer is selected from one or more of glycerin, sorbitol, hyaluronic acid, and propylene glycol.

6. The gel according to claim 1, characterized in that, The penetration enhancer is selected from one or more of peppermint oil, glycerin, azone, turpentine oil, borneol, eucalyptus oil, laurocapram, squalane, benzyl nicotinate, polysorbate, poloxamer, and polyoxyethylene castor oil.

7. The gel according to claim 6, characterized in that, The penetration enhancer is selected from one or more of peppermint oil, borneol, laurocapram, poloxamer, and polyoxyethylene castor oil.

8. The gel according to claim 1, characterized in that, The surfactant is selected from one or more of polyethylene glycol 400, polyoxyethylene 40 hydrogenated castor oil, Tween-80, Tween-20, Span-80, and polyethylene glycol glycerol octanoate-capric acid.

9. The gel according to any one of claims 1-8, characterized in that, It is composed of the following raw materials in parts by weight: 2-10 parts coenzyme Q10, 10-20 parts hydrogel matrix, 2-6 parts moisturizer, 0.5-3 parts penetration enhancer, 2-6 parts high molecular weight polymer carrier, 4-8 parts cationic lipid and 0.01-0.5 parts surfactant.

10. Use of the gel according to any one of claims 1-9 in the preparation of a therapeutic anti-inflammatory and analgesic medicament.

Images