A thermosensitive microemulsion gel formulation and its preparation method

Abstract

The present invention belongs to the field of medicine and specifically discloses a heat-sensing microemulsion gel preparation and a preparation process thereof. The preparation comprises a microemulsion, a hydrogel matrix, and a drug-containing fluid extract, which are stirred and mixed. The present invention achieves the stable presence of an oily component in the aqueous gel matrix by preparing the microemulsion, and controls the particle size of the microemulsion to be below 50 nm through the process, thereby further improving the stability of the entire gel system. While resolving the poor compatibility between the oil phase and the aqueous phase, and the unstable and easily delaminated system, the present invention also ensures that the heat sensation is generated quickly and lasts for a long time. Furthermore, the addition of a heat-sensing agent can accelerate microcirculation and significantly improve the local absorption efficiency of the drug-containing fluid extract having the efficacy of promoting blood circulation, removing blood stasis, reducing inflammation, relieving pain, and healing wounds, thereby ensuring that the prepared heat-sensing microemulsion gel has good heat-generating and analgesic efficacy. Furthermore, the heat-sensing microemulsion gel prepared by the method has the characteristics of a refreshing and translucent texture, being non-greasy, and having a good skin feel.

Description

Technical Field

[0001] This invention belongs to the field of medicine, and specifically discloses a thermosensitive microemulsion gel formulation and its preparation method. Background Technology

[0002] More than 300 million people in China suffer from chronic pain, and this number is increasing by approximately 10 to 20 million annually. This makes chronic pain a serious public health problem in China. Among the various causes of chronic pain, there is an urgent need for over-the-counter (OTC) medications and non-pharmacological treatments. These include: muscle tension, fatigue, strains, or minor bruises experienced by sports enthusiasts and professional athletes during training or competition; muscle strain and soreness caused by daily activities such as shopping and hiking; joint, shoulder, cervical spine, and muscle pain resulting from prolonged sitting and heavy workloads in the workplace; and chronic pain such as rheumatic bone pain and joint strain that arise with age.

[0003] Vanillyl butyl ether, chemically named 4-(butoxymethyl)-2-methoxyphenol, is an oil-soluble thermosensitive agent that accelerates microcirculation, stimulates subcutaneous fat metabolism, and promotes capillary blood circulation. When applied topically to the skin, it rapidly produces a mild and long-lasting pyrogenic effect. Its structural formula is as follows:

[0004]

[0005] Currently, there are several heat-generating creams and ointments available both domestically and internationally that use vanillyl butyl ether as the main ingredient. Due to their use of a single base, they all suffer from the drawbacks of short heating time, the need for repeated application, and inability to effectively relieve deep pain. Summary of the Invention

[0006] To address the above problems, this invention discloses a thermosensitive microemulsion gel formulation and its preparation process.

[0007] The technical solutions of the present invention are as follows:

[0008] A thermosensitive microemulsion gel formulation, said formulation comprising a microemulsion, a hydrogel matrix, and a drug-containing fluid extract;

[0009] The microemulsion consists of an oil phase matrix, antioxidants, fragrances, heat-sensitive agents, emulsifiers, co-emulsifiers, and purified water;

[0010] The hydrogel matrix includes carbomer, wetting agent, humectant, pH adjuster, preservative and purified water.

[0011] Furthermore, in the aforementioned thermosensitive microemulsion gel formulation, the components of the microemulsion, by weight, are as follows:

[0012]

[0013] Furthermore, in the aforementioned thermosensitive microemulsion gel formulation, the components in the hydrogel matrix, by weight, are as follows:

[0014]

[0015] Furthermore, in the aforementioned thermosensitive microemulsion gel formulation, the active ingredients in the medicated fluid extract include, but are not limited to, active ingredients of traditional Chinese medicine that have the effects of promoting blood circulation, removing blood stasis, reducing inflammation, relieving pain, or healing wounds.

[0016] Furthermore, in the aforementioned thermosensitive microemulsion gel formulation, the effective components of the traditional Chinese medicine include, but are not limited to, Yunnan Baiyao or ginsenosides.

[0017] This invention also discloses a preparation process for the above-mentioned thermosensitive microemulsion gel formulation, comprising the following steps:

[0018] (1) According to the prescription amount, the oil phase matrix, antioxidant, heat sensitizer, emulsifier, co-emulsifier and purified water 1 are homogenized and emulsified to form a microemulsion. Fragrance is added and stirred evenly to form a microemulsion phase.

[0019] (2) Carbomer was dispersed and swollen with a wetting agent and purified water 2, and then set aside as phase A;

[0020] (3) Mix the preservative and humectant, stir well, and set aside for later use; this is phase B.

[0021] (4) Mix the prescribed amount of drug-containing fluid extract and purified water 3, stir well, and set aside as phase C;

[0022] (5) Mix the prescribed amount of pH adjuster with purified water 4, stir well, and set aside as phase D;

[0023] (6) Mix phases A, B, and C thoroughly and set aside; this is phase E.

[0024] (7) Mix the microemulsion phase with the E phase, stir evenly, and set aside to form the F phase;

[0025] (8) Mix phase D and phase F together and stir until homogeneous to obtain the finished product;

[0026] The total amount of purified water 1, purified water 2, purified water 3 and purified water 4 is the total amount of purified water in the prescription.

[0027] Furthermore, in the preparation process of the above-mentioned thermosensitive microemulsion gel formulation, the droplet size D90 of the microemulsion phase in step (1) is less than 50 nm.

[0028] Furthermore, in the preparation process of the above-mentioned thermosensitive microemulsion gel formulation, step (1) uses purified water to titrate the oil and emulsion mixture to prepare the microemulsion, and controls the system temperature to be 40-70℃.

[0029] Furthermore, in the preparation process of the above-mentioned thermosensitive microemulsion gel formulation, step (1) uses a high-pressure homogenization emulsification method to prepare the microemulsion, controlling the homogenization pressure to be 20,000 to 30,000 PSI and the number of homogenization cycles to be 1 to 4.

[0030] Furthermore, in the preparation process of the above-mentioned thermosensitive microemulsion gel formulation, the pH range of the finished product in step (8) is controlled to be 6.0 to 7.0, and the viscosity is controlled to be 10,000 to 30,000 cP.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] This invention discloses a thermosensitive microemulsion gel formulation and its preparation process. The microemulsion is prepared by titration or high-pressure homogenization emulsification, ensuring a droplet diameter (D90) of less than 50 nm. This allows for the stable dispersion of oil-soluble thermosensitive agents within an aqueous gel matrix. Due to the characteristics of the microemulsion, the thermosensitive agent, after penetrating the skin barrier, can form a reservoir within the skin, achieving a sustained heat release. Furthermore, this invention specifically adds active ingredients from medicinal fluid extracts with effects such as promoting blood circulation, reducing inflammation, relieving pain, and promoting wound healing. Combined with the long-lasting increase in microvascular blood flow brought about by the thermosensitive microemulsion, this significantly improves the local absorption efficiency of drugs such as ginsenosides and Yunnan Baiyao extract, effectively relieving deep pain. In addition, by adjusting the amounts of carbomer, humectants, and pH adjusters, this invention prepares a thermosensitive microemulsion gel with a refreshing, clear, non-greasy texture and a pleasant skin feel. Detailed Implementation

[0033] This invention relates to a thermosensitive microemulsion gel formulation, comprising a microemulsion, a hydrogel matrix, and a drug-containing fluid extract. The microemulsion consists of an oil phase, a thermosensitive agent, an emulsifier, a co-emulsifier, purified water, an antioxidant, and a flavoring agent. The hydrogel matrix includes carbomer, a wetting agent, a humectant, a pH adjuster, a preservative, and purified water. The drug-containing fluid extract includes Yunnan Baiyao extract and rare ginsenosides. The components, calculated by mass parts, are as follows:

[0034]

[0035] The specific components of each part in the thermosensitive microemulsion gel formulation are described in detail below.

[0036] Oil phase matrix: The oil phase matrix used in the embodiments of the present invention is isopropyl myristate. Coconut oil, olive oil or grapeseed oil can also be used. These oils are rich in unsaturated fatty acids and vitamins, have good skin affinity and moisturizing effect, and are preferred choices for the oil phase of topical preparations. They can be used alone or in combination of two or more.

[0037] Antioxidant: The antioxidant used in the embodiments of the present invention is DL-α-tocopherol, or ascorbic acid can also be selected, mainly to prevent the oxidative rancidity of the oil phase components.

[0038] Fragrance: The fragrance used in this embodiment of the invention is rose fragrance.

[0039] Heat sensitizer: The heat sensitizer used in the embodiments of the present invention is vanillyl butyl ether.

[0040] Emulsifier: The emulsifier used in the embodiments of the present invention is Tween 80, but other hydrophilic nonionic surfactants can also be selected. It is generally non-toxic and non-irritating when used externally.

[0041] Co-emulsifier: The co-emulsifier used in the embodiments of the present invention is propylene glycol, or one or more of short-chain alcohols such as glycerol, ethanol, ethylene glycol, and n-butanol can also be selected. The co-emulsifier plays a crucial role in the stability of the microemulsion system in the present invention.

[0042] Carbomer: The main carbomer used in this embodiment of the invention is carbomer 971. Alternatively, one or more of carbomer 940, 980, 1342, U21, and SF-1 can be used in combination. After neutralization with a pH adjuster, the carbomer solution forms a clear and transparent hydrogel with a bright texture, high water content, and is not easy to dry out, making it an excellent topical coating matrix.

[0043] Wetting agent: The wetting agent used in the embodiments of the present invention is propylene glycol, but one or more of glycerol, ethanol, and sodium dodecyl sulfate can also be used. The addition of the wetting agent can effectively reduce the surface tension of purified water, so as to efficiently wet the carbomer powder and ensure that no dust is generated during the stirring process.

[0044] Moisturizer: The moisturizer used in this embodiment of the invention is glycerin, but one or more of propylene glycol, polyethylene glycol, and sorbitol can also be used. The addition of the moisturizer can greatly slow down the drying speed of the gel matrix and ensure the product has a soft and moisturizing feel on the skin.

[0045] pH Adjuster: The pH adjuster used in this embodiment of the invention is triethanolamine, but sodium hydroxide can also be used. The pH adjuster is mainly used to neutralize the carbomer solution, causing the carbomer to crosslink and form a semi-solid transparent gel. The selection of the pH adjuster needs to consider the type of carbomer. For carbomer matrices that are not ion-resistant, sodium hydroxide is not suitable as a pH adjuster. Furthermore, the pH of the finished gel should be consistent with the optimal pH of human skin, specifically within the range of 6.0 to 7.0.

[0046] Preservatives: The main preservatives used in the embodiments of this invention are phenoxyethanol and octyl glycol. Parabens or benzalkonium chloride or one or more of them can also be used. Parabens are the most commonly used preservatives in topical preparations. The combination of methylparaben and propylparaben is the most classic preservative.

[0047] Medicated fluid extract: The medicated fluid extract used in the embodiments of this invention can be any ointment that is pharmaceutically permissible to be added, such as Yunnan Baiyao fluid extract in this embodiment, but this is not a limitation. The Yunnan Baiyao fluid extract of this invention can be added in various forms, such as in this embodiment using a 1:1 compound of Yunnan Baiyao fluid extract and rare ginsenosides provided by Yunnan Baiyao Group to enhance the effects of promoting blood circulation, removing blood stasis, reducing inflammation, relieving pain, and promoting wound healing.

[0048] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0049] Examples 1-5

[0050] Table 1 below shows the formulations of the thermosensitive microemulsion gels used in Examples 1-5.

[0051] Table 1. Formulations (parts by weight) of thermosensitive microemulsion gel formulations

[0052]

[0053] Preparation method: includes the following steps:

[0054] (1) Mix the oil phase matrix, antioxidant, vanillyl butyl ether, emulsifier, and co-emulsifier evenly, preheat at 50°C, and add purified water 1 dropwise to the mixture while stirring. After titration, allow it to cool naturally to room temperature, add fragrance, and mix evenly to form a microemulsion. During titration, the titration rate needs to be controlled to keep the mixed phase clear and transparent. Alternatively, the oil phase matrix, antioxidant, vanillyl butyl ether, emulsifier, co-emulsifier, and purified water 1 can be initially mixed, homogenized and emulsified three times under high pressure at 20000 PSI, and then the fragrance can be added and mixed evenly to form a microemulsion.

[0055] (2) After fully dispersing and swelling the prescribed amount of carbomer with wetting agent and purified water 2, it is set aside as phase A. This swelling process needs to be carried out under vacuum conditions with low-speed continuous stirring to avoid the introduction of air bubbles.

[0056] (3) Mix the preservative and humectant evenly and set aside for later use; this is phase B.

[0057] (4) Mix the prescribed amount of Yunnan Baiyao fluid extract, rare ginsenosides, and purified water 3 evenly and set aside as phase C.

[0058] (5) Mix the prescribed amount of pH adjuster with purified water 4, stir well, and set aside as phase D;

[0059] (6) Mix the three phases A, B and C, stir evenly, and set aside. This is phase E. The mixture is coffee-colored. This step must be carried out under vacuum conditions to avoid entrapment of air bubbles.

[0060] (7) Mix the microemulsion phase with the E phase, stir evenly, and set aside. This is the F phase. This step must be carried out under vacuum conditions to avoid entrapment of air bubbles.

[0061] (8) Add phase D to phase F and stir slowly until the mixture becomes a uniform, clear and transparent orange-yellow gel. Fill the sample into a 100ml vacuum pump bottle to obtain the finished product.

[0062] Test Case

[0063] The thermosensitive microemulsion gel formulations prepared in Examples 1-5 were tested, and the results are shown in Table 2.

[0064] Table 2. Detection results of the thermosensitive microemulsion gels prepared in Examples 1-5

[0065]

[0066] pH test: Dilute the sample 10 times with purified water, stir well, and then use a pH meter to test the pH of the sample.

[0067] Viscosity test: The finished product was placed in a 25℃ water bath for 30 minutes. Then the sample was added to the specified sample cup. The viscosity of the sample was measured using a Bollerfeld DV-E viscometer with a 91# T-type rotor installed and the rotation speed set to 10 rpm.

[0068] Properties and duration of heat sensation: Observation and dermal test: Press one pump of product onto the back of the forearm, apply a thin layer of about 1mm, feel the texture of the application, whether the skin feels warm and the duration of heat sensation. Collect feedback from 10 people for data statistics.

[0069] Example 1 is a standard formulation, and the prepared sample has a good shape, moderate viscosity, and long duration of heat sensation. Compared with Example 1, Example 2 uses benzalkonium chloride preservative, which results in carbomer 971 producing flocculent precipitation and failing to form a gel. Compared with Example 1, Example 3 uses carbomer SF-1 as the gel matrix and parabens as preservatives. The gel prepared in Example 3 has general properties, with a fast onset of heat sensation but a short duration of heat sensation. Compared with Example 1, Example 4 increases the amount of glycerin moisturizer, and the prepared sample has a significantly reduced texture when applied, exhibiting a noticeable stickiness. The rotational viscosity of the sample is higher than that of Example 1. Compared with Example 1, Example 5 reduces the amount of glycerin moisturizer, and the prepared sample has a refreshing texture when applied. The rotational viscosity of the sample is lower than that of Example 1, the sample is thinner, and the jelly-like texture is poor.

[0070] The above experiments revealed the influence of glycerol on gel viscosity and texture: excessive glycerol resulted in higher gel viscosity and a stickier coating texture, while insufficient glycerol resulted in lower gel viscosity, stronger fluidity, and greater difficulty in molding. The experiments also revealed the influence of different carbomer types on the release of active ingredients in the finished product: Carbomer 971 and Carbomer SF-1 are suitable for different applications due to their different degrees of polymerization of polyacrylic acid and group modifications. For example, Carbomer 971 is a long-rheological type with strong cohesion and good suspension properties, making it suitable for sustained-release gels. Carbomer SF-1 is a short-rheological type with strong rigidity but poor cohesion, requiring the addition of thickeners to the formulation to adjust the sample's rheological properties, making it suitable for immediate-release gels.

[0071] The thermally sensitive microemulsion gel obtained in Example 1 was placed in a constant temperature and humidity chamber at a temperature of 25℃±2℃ and a humidity of 60%±10%. Samples were taken in the 0th, 3rd, 6th, 9th and 12th months for testing. The results are shown in Table 3.

[0072] Table 3. Results of long-term stability test of the thermosensitive microemulsion gel in Example 1

[0073]

[0074] Based on the above long-term stability test results, it can be seen that the thermosensitive microemulsion gel prepared in Example 1 of the present invention has high stability. After long-term storage, there are no significant changes in the sample properties, pH, viscosity and thermosensitivity.

[0075] As can be seen from the results of the above embodiments and test examples, this invention discloses a thermosensitive microemulsion gel formulation and its preparation process. This invention prepares the microemulsion using titration or high-pressure homogenization emulsification, ensuring that the droplet diameter (D90) is less than 50 nm. This allows for the stable dispersion of oil-soluble thermosensitive agents in an aqueous gel matrix. Simultaneously, due to the characteristics of the microemulsion, the thermosensitive agent can form a reservoir within the skin after penetrating the skin barrier, achieving a sustained heat release. Furthermore, this invention specifically adds active ingredients from medicinal fluid extracts with effects such as promoting blood circulation, reducing inflammation, relieving pain, and promoting wound healing. Combined with the long-lasting increase in microvascular blood flow brought about by the thermosensitive microemulsion, this significantly improves the local absorption efficiency of drugs such as ginsenosides and Yunnan Baiyao extract, effectively relieving deep pain. In addition, by adjusting the amounts of carbomer, humectants, and pH adjusters, this invention prepares a thermosensitive microemulsion gel with a refreshing, clear, non-greasy texture and a pleasant skin feel.

[0076] The above are merely a few preferred embodiments of the present invention, described in a relatively specific and detailed manner, but they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A thermosensitive microemulsion gel formulation, characterized in that, The formula, by weight, is as follows: The preparation process of the above-mentioned thermosensitive microemulsion gel formulation includes the following steps: (1) According to the prescription amount, homogenize and emulsify isopropyl myristate, DL-α-tocopherol, vanillyl butyl ether, Tween 80, propylene glycol as a co-emulsifier and purified water to form a microemulsion, add rose fragrance, stir evenly to form a microemulsion phase; (2) Carbomer 971 was dispersed and swollen with propylene glycol as a wetting agent and purified water 2, and then set aside as phase A; (3) Mix phenoxyethanol & octyl glycol with glycerin, stir well, and set aside as phase B; (4) Mix the prescribed amount of Yunnan Baiyao fluid extract, rare ginsenosides and purified water 3, stir well and set aside for later use as phase C; (5) Mix the prescribed amount of triethanolamine with purified water 4, stir well, and set aside as phase D; (6) Mix phases A, B, and C thoroughly and set aside; this is phase E. (7) Mix the microemulsion phase with the E phase, stir evenly, and set aside for later use; this is the F phase. (8) Mix the D phase and F phase and stir evenly to obtain the finished product.

2. The thermosensitive microemulsion gel formulation according to claim 1, characterized in that, In step (1), the droplet size D90 of the microemulsion phase is less than 50 nm.

3. The thermosensitive microemulsion gel formulation according to claim 1, characterized in that, In step (1), purified water is used to titrate the oil and emulsion mixture to prepare a microemulsion, and the system temperature is controlled at 40~70℃.

4. The thermosensitive microemulsion gel formulation according to claim 1, characterized in that, In step (1), microemulsions are prepared using high-pressure homogenization emulsification, with the homogenization pressure controlled at 20,000 to 30,000 PSI and the homogenization times being 1 to 4.

5. The thermosensitive microemulsion gel formulation according to claim 1, characterized in that, In step (8), the pH range of the finished product is controlled to be 6.0~7.0, and the viscosity is controlled to be 10000~30000 cP.

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