A long-acting sustained-release film for improving external liquid preparation, and a preparation method and application thereof

Abstract

This invention relates to a modified long-acting sustained-release coating agent for topical liquid formulations, its preparation method, and its application, belonging to the field of pharmaceutical preparations. The modified long-acting sustained-release coating agent for topical liquid formulations comprises a carrier and a topical liquid formulation in a mass ratio of 1:1 to 3:2. The carrier includes PVA, glycerin, liquid paraffin, β-hydroxyethyl urea, glyceryl stearate, PEG stearate, and purified water. The topical liquid formulation includes one or more of the following: tincture, liniment, solution, lotion, ointment, oil, and rinse. This invention's long-acting sustained-release coating agent is a universal coating agent, safe to use, non-irritating, and has no incompatibility with topical liquid formulations. It facilitates film formation, has a short film-forming time, and produces a flexible film that is not easily detached.

Description

Technical Field

[0001] This invention relates to a long-acting sustained-release coating agent for improved topical liquid formulations, its preparation method, and its application, belonging to the field of pharmaceutical preparations. Background Technology

[0002] Topical liquid preparations are commonly used in dermatology, orthopedics, and sports medicine, offering advantages such as rapid onset of action and ease of use. However, they also face several technical bottlenecks: the preparations are prone to volatility and loss, resulting in short skin retention time, requiring frequent administration and leading to poor patient compliance; they lack sustained-release capabilities, making it difficult to maintain effective concentrations at the lesion site for extended periods, thus failing to meet the needs of chronic disease treatment; relying solely on penetration enhancers to improve transdermal efficiency can easily cause skin irritation; and they cannot form a physical barrier, making them unsuitable for broken wounds.

[0003] While existing film-forming technologies are attempting to address these issues, they still have significant drawbacks: slow film formation, with the formulation typically requiring more than 20 minutes to fully dry; brittle films that are prone to cracking and detachment at joints and other active sites; the need to add irritating penetration enhancers to ensure transdermal efficacy; and the fact that most are custom-designed for specific drugs, resulting in poor formulation versatility and making them unsuitable for directly modifying commercially available topical liquid formulations.

[0004] Therefore, developing a universal film-forming agent carrier that can be directly combined with commercially available tinctures, liniments, solutions, and other topical liquid formulations to achieve rapid film formation, flexible film, sustained drug release, and low irritation is of great practical significance and clinical application value for improving existing dosage forms, meeting clinical needs, and improving patients' quality of life. Summary of the Invention

[0005] This invention addresses the problems of short skin surface retention time, frequent application, low transdermal efficiency, and high irritation associated with existing topical liquid formulations. It provides an improved long-acting sustained-release film-forming agent for topical liquid formulations, its preparation method, and its application. This invention uses two different types of PVA blended in a specific ratio as a film-forming matrix, combined with the synergistic effect of various functional excipients, to prepare a universal film-forming agent carrier. This carrier can be blended with various drug-containing topical liquid formulations to prepare improved film-forming agents with excellent film-forming properties, controllable drug release, and good skin compatibility without the addition of traditional potent penetration enhancers.

[0006] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: a long-acting sustained-release coating agent for improved topical liquid preparation, comprising a carrier and a topical liquid preparation in a mass ratio of 1:1 to 3:2, wherein the carrier comprises PVA, glycerin, liquid paraffin, β-hydroxyethyl urea, glyceryl stearate, PEG stearate and purified water, and the topical liquid preparation comprises one or more of tinctures, liniments, solutions, lotions, ointments, oils and rinses;

[0007] The improved topical liquid formulation with long-acting sustained-release coating comprises the following raw materials by weight percentage:

[0008] PVA 8.0%–20.0%, glycerin 2.0%–10.0%, liquid paraffin 0.2%–2.0%, β-hydroxyethyl urea 2.0%–10.0%, glyceryl stearate 1.0%–5.0%, PEG stearate 1.0%–5.0%, topical liquid preparation 10.0%–50.0%, balance being pure water;

[0009] The PVA is composed of PVA-1 and PVA-2 in a mass ratio of 3:1 to 5:1, wherein PVA-1 is polyvinyl alcohol type 117 and PVA-2 is polyvinyl alcohol type 1799.

[0010] This invention constructs a fully functional film-forming agent carrier system through the precise proportioning and synergistic combination of various raw material components, with each component acting in a complementary manner. The PVA used in this invention is a blend of two different grades of polyvinyl alcohol, which synergistically construct a high-performance film carrier system. The low-viscosity, high-hydrolysis-degree polyvinyl alcohol component can rapidly and orderly arrange itself during water evaporation, quickly forming a continuous and dense network structure, endowing the carrier with excellent rapid film-forming performance. The high-viscosity, high-hydrolysis-degree polyvinyl alcohol component, due to its longer molecular chains and higher content of hydroxyl active groups, can form tight molecular chain entanglement and strong hydrogen bonds with the network structure formed by the former. This interaction not only effectively enhances the mechanical strength and flexibility of the film but also precisely adjusts the rheological properties of the carrier, significantly improving its spreadability and surface adhesion during application. Through the scientific blending of these two polyvinyl alcohols, key indicators such as porosity, swelling rate, mechanical strength, and moisture permeability of the final film material can be precisely and flexibly controlled, laying a solid and diverse material foundation for achieving efficient and controllable drug release.

[0011] Glycerin, as a small-molecule plasticizer, can insert itself between PVA molecular chains, weakening intermolecular hydrogen bonding, increasing molecular chain mobility, reducing membrane brittleness, and improving elongation at break. β-hydroxyethyl urea, a highly effective moisturizer, can penetrate deep into the stratum corneum of the skin, bind to intercellular lipids, replenish and lock in moisture, relieve skin dryness, and prevent the membrane from becoming brittle due to excessive dryness. These three components work synergistically to achieve the dual benefits of membrane flexibility and skin comfort.

[0012] Glyceryl stearate and PEG stearate are nonionic surfactants that effectively reduce the surface tension at the oil-water interface, ensuring uniform dispersion of the oil and water phases to form a stable O / W emulsion and preventing stratification and precipitation during carrier storage. Liquid paraffin, as an oil phase component, participates in the emulsion system construction, while improving the lubricity and spreadability of the carrier during application, reducing the pulling and tightness of the skin caused by moisture evaporation during film drying, and enhancing the user experience.

[0013] The emulsion system formed by the carrier has a pH value between 5.0 and 7.0, which is close to the physiological pH of the skin. This will not cause pH shock to drug-containing topical liquid preparations, leading to drug precipitation or degradation. The emulsion system can effectively accommodate drug components of different polarities, achieving good compatibility with various dosage forms such as tinctures, liniments, and solutions, and has broad formulation compatibility.

[0014] All topical liquid preparations used in this invention are commercially available, or they may be uncommercial topical liquid preparations awaiting improvement, such as the swelling-reducing and analgesic tincture sold by Guangxi Zhuang Autonomous Region Huahong Pharmaceutical Group Co., Ltd., the musk analgesic liniment sold by Beijing Jindian Hanfang Pharmaceutical Co., Ltd., and the red fragrance analgesic tincture sold by Guangxi Baoruitan Pharmaceutical Co., Ltd.

[0015] Based on the above technical solution, the present invention can be further improved as follows.

[0016] Furthermore, the improved topical liquid formulation with long-acting sustained-release film-forming properties comprises the following raw materials in weight percentages:

[0017] The composition includes PVA 12.0%–18.0%, glycerin 5.0%–8.0%, liquid paraffin 0.3%–1.0%, β-hydroxyethyl urea 3.0%–6.0%, glyceryl stearate 1.5%–3.0%, PEG stearate 1.5%–3.0%, topical liquid preparation 35.0%–45.0%, and the balance being pure water; wherein the PVA is composed of PVA-1 and PVA-2 in a mass ratio of 3.5:1 to 4.5:1.

[0018] Furthermore, the improved topical liquid formulation with long-acting sustained-release film-forming properties comprises the following raw materials by weight percentage:

[0019] The composition is as follows: PVA 15.0%, glycerin 6.0%, liquid paraffin 0.5%, β-hydroxyethyl urea 4.0%, glyceryl stearate 2.0%, PEG stearate 2.0%, topical liquid preparation 40.0%, and the balance being pure water; wherein the PVA is composed of PVA-1 and PVA-2 in a mass ratio of 4:1.

[0020] The preferred raw material composition and dosage of the long-acting sustained-release coating agent of this invention are shown in Table 1:

[0021] Table 1. Optimal composition of long-acting sustained-release coating agent formulation (by mass percentage)

[0022]

[0023] This invention also provides a method for preparing a long-acting sustained-release coating agent of the improved topical liquid formulation as described above, comprising:

[0024] 1) Take PVA, add pure water to swell it, and obtain a PVA solution;

[0025] 2) Take liquid paraffin, glyceryl stearate and PEG stearate, and stir at 80-90℃ until all components are completely melted and mixed evenly to obtain a clear and transparent oil phase mixture;

[0026] 3) Take glycerin, β-hydroxyethylurea, topical liquid preparation and the PVA solution obtained in 1), stir and dissolve at 60-70℃ until a homogeneous solution is formed, and obtain a homogeneous aqueous mixture;

[0027] 4) Under constant stirring conditions at 60-70℃, the aqueous phase mixture obtained in 3) and the oil phase mixture obtained in 2) are stirred and mixed for 15-30 min to obtain a brownish-brown emulsion;

[0028] 5) Transfer the brown emulsion obtained in 4) to room temperature and continue to stir slowly for 30-60 minutes to form a uniform, fine, semi-fluid emulsion gel, which is the long-acting sustained-release coating agent for improving topical liquid formulations.

[0029] Based on the above technical solution, the present invention can be further improved as follows.

[0030] Furthermore, in steps 2) to 4), the stirring rate is 500 to 700 r / min.

[0031] Furthermore, in step 5), the stirring rate is 200-300 r / min, and the stirring time is 40-50 min.

[0032] The beneficial effects of this step are: stirring at 500-700 r / min during the heating and emulsification stage can provide strong shear force, promote the full emulsification and dispersion of the oil and water phases, and form a uniform and stable emulsion system; stirring at 200-300 r / min after transferring to room temperature can reduce the generation of bubbles, avoid damaging the already formed droplet structure and polymer network, facilitate uniform cooling and solidification of the system, and ensure the stability of the system and the quality of film forming.

[0033] The present invention also provides a long-acting sustained-release coating agent as described above for shortening the film-forming time of topical liquid formulations, increasing film flexibility, increasing the continuous release time of topical liquid formulations, and reducing skin irritation.

[0034] Based on the above technical solution, the present invention can be further improved as follows.

[0035] Furthermore, the topical liquid preparation is one or more of the following: tinctures, liniments, solutions, lotions, ointments, oils, and rinses for treating arthritis, sports injuries, burns, and skin diseases.

[0036] The beneficial effects of this invention are:

[0037] Excellent film-forming properties: Addressing the problem of slow film-forming speed in existing coating technologies, where complete drying of the formulation typically takes more than 20 minutes, this invention, through the compounding of two different types of PVA, produces a coating that forms a continuous, dense, and transparent film within 8–10 minutes after application, significantly faster than traditional coatings.

[0038] Excellent membrane flexibility: Addressing the problem that membranes prepared by existing coating agents are prone to brittleness, especially cracking and falling off in active areas such as joints, the membrane of this invention has a breaking elongation of over 200% and a tensile strength of over 5 MPa. It can stretch with the flexion and extension of the joint skin. After 50 repeated folding tests, there was no cracking or falling off. It is especially suitable for frequently moving areas such as the knee and elbow joints.

[0039] Significant long-lasting sustained-release effect: Addressing the issues of traditional topical liquid formulations being prone to evaporation and loss, having short skin retention time, and requiring frequent administration. In vitro transdermal experiments show that the film-forming agent modified with the carrier of this invention can continuously release the drug for more than 12 hours, with a cumulative transdermal volume more than 2.4 times that of the original tincture / liniment, achieving a therapeutic effect of "one application, effective all day".

[0040] Extremely low skin irritation: Existing topical liquid formulations and film-forming agents rely on penetration enhancers to ensure transdermal efficiency, often leading to skin irritation. This invention eliminates the need for traditional, potent penetration enhancers like azone; efficient transdermal penetration is achieved through synergistic formulation. Skin irritation tests show that after 7 days of continuous administration, the film-forming agent of this invention exhibited zero erythema and edema scores, demonstrating high safety and suitability for long-term topical use.

[0041] Excellent patient compliance: Addressing the issue of poor patient compliance with existing topical liquid formulations, this invention's film-forming agent has a fine texture, applies smoothly without greasiness, and causes no tightness or pulling sensation during film formation. The addition of β-hydroxyethyl urea provides long-lasting moisturizing effects, making it especially suitable for dry skin and elderly patients.

[0042] Excellent versatility and compatibility: Addressing the problem that existing film-forming agents are mostly custom-designed for specific drugs, resulting in poor formulation versatility and inability to be directly used to improve various commercially available topical liquid formulations, this invention's carrier can be directly mixed with most commercially available water-containing tinctures, liniments, solutions, and other topical liquid formulations in a mass ratio of 1:1 to 3:2, exhibiting good compatibility and stability with various topical liquid formulations.

[0043] Good stability: Accelerated and long-term experimental results show that the key quality indicators of the coating agent of this invention, such as appearance, pH value, film-forming time, and drug content, do not change significantly, and it has good storage stability. Attached Figure Description

[0044] Figure 1 The image shows the appearance of the blank coating agent prepared in Example 1 of this invention; where A is the coating agent just applied, B is the coating agent after drying, C is the coating agent being peeled off, and D is the coating agent after peeling off. Detailed Implementation

[0045] The principles and features of the present invention are described below with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0046] The sources of raw materials used in the following examples and comparative examples are shown below:

[0047] ①The swelling-reducing and pain-relieving tincture was purchased from Guangxi Zhuang Autonomous Region Huahong Pharmaceutical Group Co., Ltd., and the specification is 60mL / bottle.

[0048] ②Musk Pain Relief Liniment was purchased from Beijing Jindian Hanfang Pharmaceutical Co., Ltd., and the specification is 56 mL / bottle.

[0049] ③ Hongxiang Analgesic Tincture was purchased from Guangxi Baoruitan Pharmaceutical Co., Ltd., and the specification is 40 mL / bottle.

[0050] ④ PVA-1 was purchased from Shanghai Yi'en Chemical Technology Co., Ltd., and the product name is polyvinyl alcohol 117.

[0051] ⑤PVA-2 was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., and its product name is polyvinyl alcohol 1799.

[0052] Example 1

[0053] In this embodiment, 50% ethanol (by volume) was used to replace the topical liquid formulation to prepare a blank coating agent. The raw materials are shown in Table 2.

[0054] Table 2 Raw materials and dosage of blank coating agent

[0055]

[0056] The method for preparing the blank coating agent in this embodiment includes:

[0057] 1) Weigh the prescribed amount of PVA and dissolve it in pure water to obtain a PVA solution.

[0058] 2) Weigh the prescribed amounts of liquid paraffin, glyceryl stearate, and PEG stearate, and heat them in a water bath at 85°C at 600 r / min until they are melted and mixed evenly to obtain a clear and transparent oil phase mixture.

[0059] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and 50% ethanol, and mix them evenly in a water bath at 65℃ and 600 r / min to obtain a homogeneous aqueous mixture.

[0060] 4) At 65℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a milky white emulsion.

[0061] 5) Place the obtained milky white emulsion at room temperature and stir slowly at 250 r / min for 40 min to form a uniform, fine, semi-fluid emulsion gel, which is the blank coating agent.

[0062] Example 2

[0063] The raw materials for the improved long-acting sustained-release coating agent for topical liquid formulations in this embodiment are shown in Table 3:

[0064] Table 3. Raw materials and dosage of long-acting sustained-release coating agents for improved topical liquid formulations.

[0065]

[0066] This embodiment describes an improved method for preparing a long-acting sustained-release coating for topical liquid formulations, including:

[0067] 1) Weigh the prescribed amount of PVA and dissolve it in pure water to obtain a PVA solution.

[0068] 2) Weigh the prescribed amounts of liquid paraffin, glyceryl stearate, and PEG stearate, and heat them in a water bath at 85°C at 600 r / min until they are melted and mixed evenly to obtain a clear and transparent oil phase mixture.

[0069] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and anti-inflammatory and analgesic tincture, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0070] 4) At 65℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a brown emulsion.

[0071] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir slowly at 250 r / min for 40 min to form a uniform, delicate, semi-fluid emulsion gel, which is the long-acting sustained-release coating agent for improving topical liquid formulations.

[0072] Example 3

[0073] The raw materials for the improved long-acting sustained-release coating agent for topical liquid formulations in this embodiment are shown in Table 4:

[0074] Table 4. Raw materials and dosage of long-acting sustained-release coating agents for improved topical liquid formulations.

[0075]

[0076] This embodiment describes an improved method for preparing a long-acting sustained-release coating for topical liquid formulations, including:

[0077] 1) Weigh the prescribed amount of PVA and dissolve it in pure water to obtain a PVA solution.

[0078] 2) Weigh the prescribed amounts of liquid paraffin, glyceryl stearate, and PEG stearate, and heat them in a water bath at 85°C at 600 r / min until they are melted and mixed evenly to obtain a clear and transparent oil phase mixture.

[0079] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and musk analgesic liniment, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0080] 4) At 65 ℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a brown emulsion.

[0081] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir slowly at 250 r / min for 40 min to form a uniform, delicate, semi-fluid emulsion gel, which is the long-acting sustained-release coating agent for improving topical liquid formulations.

[0082] Example 4

[0083] The raw materials for the improved long-acting sustained-release coating agent for topical liquid formulations in this embodiment are shown in Table 5:

[0084] Table 5. Raw materials and dosage of long-acting sustained-release coating agents for improved topical liquid formulations.

[0085]

[0086] This embodiment describes an improved method for preparing a long-acting sustained-release coating for topical liquid formulations, including:

[0087] 1) Weigh the prescribed amount of PVA and dissolve it in pure water to obtain a PVA solution.

[0088] 2) Weigh the prescribed amounts of liquid paraffin, glyceryl stearate, and PEG stearate, and heat them in a water bath at 85°C at 600 r / min until they are melted and mixed evenly to obtain a clear and transparent oil phase mixture.

[0089] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and red spice analgesic tincture, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0090] 4) At 65℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a brown emulsion.

[0091] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir slowly at 250 r / min for 40 min to form a uniform, delicate, semi-fluid emulsion gel, which is the long-acting sustained-release coating agent for improving topical liquid formulations.

[0092] Comparative Example 1

[0093] This comparative example is based on Example 2, without the addition of emulsifiers (glyceryl stearate and PEG stearate). The specific raw material composition and dosage are shown in Table 6.

[0094] Table 6 Raw materials and dosage of coating agents

[0095]

[0096] The preparation method of this comparative coating agent includes:

[0097] 1) Weigh out the prescribed amount of PVA and dissolve it in the prescribed amount of pure water to obtain a PVA solution.

[0098] 2) Weigh the prescribed amount of liquid paraffin, place it in an 85°C water bath and stir to preheat it, as the oil phase.

[0099] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and anti-inflammatory and analgesic tincture, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0100] 4) Under stirring conditions of 65℃ and 600 r / min, the obtained aqueous phase mixture was slowly added to the oil phase, and stirring was continued for 20 min to obtain a brownish-brown uniform emulsion.

[0101] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir it slowly at 250 r / min for 40 min to form a uniform, fine, semi-fluid brown emulsion gel, which is the coating agent.

[0102] Comparative Example 2

[0103] This comparative example is based on Example 2, with the addition of 0.2 g of the penetration enhancer azone. The specific raw material composition and dosage are shown in Table 7.

[0104] Table 7 Raw materials and dosage of coating agents

[0105]

[0106] The preparation method of this comparative coating agent includes:

[0107] 1) Weigh out PVA and dissolve it in the prescribed amount of pure water to obtain a PVA solution.

[0108] 2) Weigh out the prescribed amounts of glyceryl stearate, PEG stearate, liquid paraffin and azone, and melt them in an 85°C water bath at 600 r / min with stirring. Stir until homogeneous to obtain an oil phase mixture.

[0109] 3) Weigh out the prescribed amounts of glycerin, β-hydroxyethylurea, PVA solution and anti-inflammatory and analgesic tincture, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0110] 4) At 65℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a brown emulsion.

[0111] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir it slowly at 250 r / min for 40 min to form a uniform, fine, semi-fluid emulsion gel, which is the coating agent.

[0112] Comparative Example 3

[0113] This comparative example is based on Example 2, without the addition of β-hydroxyethyl urea. The specific raw material composition and dosage are shown in Table 8:

[0114] Table 8 Raw materials and dosage of coating agents

[0115]

[0116] The preparation method of this comparative coating agent includes:

[0117] 1) Weigh out PVA and dissolve it in the prescribed amount of pure water to obtain a PVA solution.

[0118] 2) Weigh out the prescribed amounts of glyceryl stearate, PEG stearate and liquid paraffin, heat and melt them in an 85°C water bath at 600 r / min, and stir until homogeneous to obtain an oil phase mixture.

[0119] 3) Weigh the prescribed amounts of glycerin, anti-inflammatory and analgesic tincture and PVA solution, and mix them evenly in a 65°C water bath at 600 r / min to obtain a homogeneous aqueous mixture.

[0120] 4) At 65℃ and 600 r / min, the aqueous phase mixture was slowly poured into the oil phase mixture and stirred for 20 min to obtain a brown emulsion.

[0121] 5) Take the brown emulsion obtained in 4) and place it at room temperature. Stir it slowly at 250 r / min for 40 min to form a uniform, fine, semi-fluid emulsion gel, which is the coating agent.

[0122] Comparative Example 4

[0123] Sample: Purchased the swelling-reducing and pain-relieving tincture (specification: 60mL / bottle) commercially available from Guangxi Zhuang Autonomous Region Huahong Pharmaceutical Group Co., Ltd. as the reference preparation for the original dosage form to be improved.

[0124] Experimental Example 1: Quality Evaluation of Coating Agent (Appearance and pH Value)

[0125] Methods: Observe the color, texture, and uniformity of the sample. Measure the pH value of the sample directly using a pH meter.

[0126] The results showed that the blank coating agent prepared in Example 1 was milky white, while the coating agents prepared in Examples 2 to 4 were all brownish-yellow, uniform, fine, semi-fluid emulsion gels with no grainy texture or layering. The pH value was between 5.0 and 7.0, close to the physiological pH value of the skin.

[0127] Comparative Example 1, lacking emulsifiers (glyceryl stearate and PEG stearate), showed obvious stratification after 24 hours of standing, demonstrating the necessity of the emulsification system.

[0128] Comparative Example 2 showed no significant change in appearance due to the addition of azone, but the skin irritation test showed that its irritation was significantly higher than that of Example 2.

[0129] The coating agent prepared in Comparative Example 3 lacked the moisturizing agent β-hydroxyethyl urea, resulting in a slight tightness on the skin after application.

[0130] Table 9. Evaluation results of the film-forming properties of the coatings prepared in Examples 1-4 on the skin.

[0131]

[0132] Experiment Example 2: In vitro transdermal experiment

[0133] Methods: The cumulative transdermal drug transdermal amount within 12 h was determined by HPLC using the Franz diffusion cell method with isolated porcine skin as the permeation barrier.

[0134] Results: See Table 10 for details. The cumulative transdermal dose of Example 2 over 12 h was 285.6 ± 15.3 μg / cm², which was 2.4 times that of Comparative Example 4 (anti-inflammatory and analgesic tincture).

[0135] Table 10 Comparison of cumulative transdermal release in vitro between Example 2 and Comparative Example 4 (12 h)

[0136]

[0137] Experiment Example 3: Skin Irritation Test

[0138] Methods: Healthy rabbits were selected, and samples were applied to their backs for 7 consecutive days after hair removal. The erythema and edema were observed and recorded.

[0139] Scoring criteria:

[0140] 1) Erythema score: 0 points for no erythema, 1 point for mild erythema, 2 points for clearly visible light red erythema, 3 points for moderate to severe bright red erythema, and 4 points for severe purplish-red erythema, with or without crust formation.

[0141] 2) Edema score: 0 points for no edema, 1 point for mild edema, 2 points for mild edema with clear borders and slight skin elevation, 3 points for moderate edema with obvious skin elevation and localized area, and 4 points for severe edema with significant skin elevation.

[0142] Results: See Table 11 for details. The coating agent prepared in Example 2 showed no erythema or edema on the skin throughout the entire experimental period, and the total irritation score was 0, which was significantly better than that of Comparative Example 2, which added azone, indicating that it has excellent skin compatibility.

[0143] Table 11 Comparison of skin irritation scores between Example 2 and Comparative Example 2 (with 2% azone added)

[0144]

[0145] Experiment Example 4: Film Formation Time Determination

[0146] Film formation time determination method: Take about 0.5 g of sample and evenly coat it on the surface of a clean glass plate. Place it in a constant temperature environment of 37±2℃. Gently touch the film surface with your finger until it no longer feels sticky, and record the time required. This is the film formation time. Perform three parallel measurements and take the average value. Results: See Table 12 for details.

[0147] Table 12 Comparison of film-forming times for different types of modified topical liquid formulations in Examples 1-4

[0148]

[0149] Example 1 is a 50% ethanol aqueous solution, containing no drugs or other solid components; the system consists only of ethanol and water, with a solid content of 0. Examples 2-4 replace the 50% ethanol aqueous solution with a topical liquid formulation, significantly increasing the solid content of the system. During film formation, a higher solid content allows the remaining solids to form a continuous film layer more quickly after solvent evaporation, reducing the continuous evaporation time of the solvent, especially water. In contrast, the pure solvent system in Example 1 lacks a solid framework and requires the complete evaporation of ethanol and water before film formation, thus resulting in a longer film formation time.

[0150] Experimental Example 5: Evaluation of Membrane Flexibility

[0151] Method: Peel off the film after it has been formed, cut it into strips, and conduct folding and tensile tests.

[0152] Results: See Table 13 for details.

[0153] Table 13 Results of membrane flexibility test of coatings in Examples 1-4 under simulated joint activity conditions.

[0154]

[0155] Experiment Example 6: Stability Experiment

[0156] Methods: Samples from Examples 2 to 4 were subjected to accelerated testing (40 °C, RH 25%, 6 months) and long-term testing (25 °C, RH 40%, 12 months) to examine changes in various indicators.

[0157] Results: After 6 months of accelerated treatment and 12 months of long-term treatment, there were no significant changes in any of the sample indicators, and the drug content retention rate was >98%, indicating that the coating agent of the present invention has good stability.

[0158] Experiment Example 7: Universality and Adaptability Experiment

[0159] Methods: The carrier without 50% ethanol in Example 1 was mixed with topical liquid preparations containing different proportions of ethanol, such as anti-inflammatory and analgesic tincture (containing 47% to 57% ethanol) and musk analgesic liniment (containing 47% to 57% ethanol). The appearance, film-forming properties and stability of the mixture were examined.

[0160] Results: The carrier of the present invention has good compatibility with various topical liquid formulations containing 40% to 60% ethanol, and can achieve stable film formation within the range of carrier to topical liquid formulation mass ratio of 1:1 to 3:2, demonstrating excellent versatility.

[0161] In summary, this invention provides a long-acting sustained-release coating agent for improving topical liquid formulations. By carefully selecting PVA-1 and PVA-2 and compounding them in a specific ratio as a film-forming matrix, and combining the synergistic effects of excipients such as glycerin, liquid paraffin, β-hydroxyethyl urea, glyceryl stearate, and PEG stearate, a fully functional and high-performance coating agent carrier system is successfully constructed.

[0162] When the carrier of this invention is combined with various commercially available topical liquid preparations such as tinctures, liniments, and solutions, it can significantly improve their pharmaceutical properties, giving them outstanding advantages such as rapid film formation (≤10 min), flexible film (elongation at break >200%), sustained release and long-lasting effect (transdermal absorption increased by more than 2.4 times in 24 h), high safety (irritation score of 0), and comfortable use. It successfully solves the key technical problems of existing topical liquid preparations, such as short residence time, need for frequent administration, easy film breakage, and high irritation.

[0163] Meanwhile, the carrier of this invention has excellent versatility and adaptability, and can be directly mixed with commercially available topical liquid formulations with different solvent systems and drug components without adjusting the carrier formulation, providing a convenient, efficient and reliable platform technology for the dosage form upgrade of traditional topical liquid formulations.

[0164] This invention has broad clinical application prospects and huge industrialization value in improving traditional tinctures, liniments and solutions for arthritis, sports injuries, burns, scalds and skin diseases, and is expected to become a platform technology for improving traditional topical liquid preparations.

[0165] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A long-acting sustained-release coating agent for improved topical liquid formulations, characterized in that, The product includes a carrier and a topical liquid preparation in a mass ratio of 1:1 to 3:

2. The carrier includes PVA, glycerin, liquid paraffin, β-hydroxyethyl urea, glyceryl stearate, PEG stearate and purified water. The topical liquid preparation includes one or more of the following: tincture, liniment, solution, lotion, ointment, oil and rinse. The improved topical liquid formulation with long-acting sustained-release coating comprises the following raw materials by weight percentage: PVA 8.0%–20.0%, glycerin 2.0%–10.0%, liquid paraffin 0.2%–2.0%, β-hydroxyethyl urea 2.0%–10.0%, glyceryl stearate 1.0%–5.0%, PEG stearate 1.0%–5.0%, topical liquid preparation 10.0%–50.0%, balance being pure water; The PVA is composed of PVA-1 and PVA-2 in a mass ratio of 3:1 to 5:1, wherein PVA-1 is polyvinyl alcohol type 117 and PVA-2 is polyvinyl alcohol type 1799.

2. The long-acting sustained-release coating agent according to claim 1, characterized in that, Including the following percentages by weight of raw materials: The composition includes PVA 12.0%–18.0%, glycerin 5.0%–8.0%, liquid paraffin 0.3%–1.0%, β-hydroxyethyl urea 3.0%–6.0%, glyceryl stearate 1.5%–3.0%, PEG stearate 1.5%–3.0%, topical liquid preparation 35.0%–45.00%, and the balance being pure water; wherein the PVA is composed of PVA-1 and PVA-2 in a mass ratio of 3.5:1 to 4.5:

1.

3. The long-acting sustained-release coating agent according to claim 1, characterized in that, Including the following percentages by weight of raw materials: The composition is as follows: PVA 15.0%, glycerin 6.0%, liquid paraffin 0.5%, β-hydroxyethyl urea 4.0%, glyceryl stearate 2.0%, PEG stearate 2.0%, topical liquid preparation 40.0%, and the balance being pure water; wherein the PVA is composed of PVA-1 and PVA-2 in a mass ratio of 4:

1.

4. A method for preparing a long-acting sustained-release coating agent as described in any one of claims 1 to 3, characterized in that, include: 1) Take PVA, add pure water to swell it, and obtain a PVA solution; 2) Take liquid paraffin, glyceryl stearate and PEG stearate, and stir at 80-90℃ until all components are completely melted and mixed evenly to obtain a clear and transparent oil phase mixture; 3) Take glycerin, β-hydroxyethylurea, topical liquid preparation and the PVA solution obtained in 1), stir and dissolve at 60-70℃ until a homogeneous solution is formed, and obtain a homogeneous aqueous mixture; 4) Under constant stirring conditions at 60-70℃, the aqueous phase mixture obtained in 3) and the oil phase mixture obtained in 2) are stirred and mixed for 15-30 min to obtain a brownish-brown emulsion; 5) Transfer the brown emulsion obtained in 4) to room temperature and continue to stir slowly for 30-60 minutes to form a uniform, fine, semi-fluid emulsion gel, which is the long-acting sustained-release coating agent for improving topical liquid formulations.

5. The preparation method according to claim 4, characterized in that, In steps 2) to 4), the stirring rate is 500 to 700 r / min.

6. The preparation method according to claim 4, characterized in that, In step 5), the stirring rate is 200-300 r / min and the stirring time is 40-50 min.

7. A long-acting sustained-release film-forming agent as described in any one of claims 1 to 3, used to shorten the film-forming time of topical liquid formulations, increase film flexibility, increase the continuous release time of topical liquid formulations, and reduce skin irritation.

8. The application according to claim 7, characterized in that, The topical liquid preparation is one or more of the following: tincture, liniment, solution, lotion, ointment, oil, and rinse for treating arthritis, sports injuries, burns, and skin diseases.

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