Trifarotene external preparation and preparation method thereof

Abstract

The invention discloses a trifarotene external preparation and a preparation method thereof, and relates to the technical field of preparation of trifarotene preparations. The trifarotene external preparation is prepared from the following raw materials in percentage by mass: 1.0 to 5.0 percent of trifarotene, 6 to 12 percent of gel base material, 10 to 15 percent of polylactic acid, 5 to 7.5 percent of cellulose, 1 to 2.5 percent of penetration enhancer, 8 to 14 percent of water-retaining agent, 5 to 9 percent of surfactant and the balance of water, the gel base material comprises medium-chain fatty glyceride and polycarbophil, and the mass ratio of the medium-chain fatty glyceride to the polycarbophil is (2.5-4): 1. According to the novel trifarotene external preparation provided by the invention, the raw material formula is coordinated and matched, so that the hardening and setting time of the medicine is reasonably matched with the slow release time of trifarotene capable of ensuring the effective concentration. After the medicament layer is completely hardened, the drug release of the trifarotene is basically completed. The raw materials used by the medicament are mild, the medicament layer is soft and moderate, the skin covering area is small, and the discomfort basically does not exist.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of trifarotene preparations, and particularly to a trifarotene topical agent and a preparation method thereof. Background Art

[0002] Trifarotene (molecular formula C 29 H 33 NO4) is a white, off-white or slightly yellowish powder. It is a γ-retinoic acid receptor (RAR) agonist and is a prescription topical drug for treating diseases such as acne on the skin surface of patients, acne vulgaris, cutaneous T-cell lymphoma, and lamellar ichthyosis. Trifarotene belongs to the retinoid drugs, and its function is to remove dead skin, dredge pores and reduce inflammation. It can also prevent the formation of new acne and acne. The common adverse reactions of trifarotene are itching and irritation at the application site, and in severe cases, there may also be rashes, swelling, allergic rhinitis and erythema.

[0003] Trifarotene is generally prepared into topical dosage forms such as creams. However, because it is poorly soluble or insoluble in water and is easily soluble in organic solvents such as dimethyl sulfoxide (DMSO), the stability of the trifarotene topical preparation is general, and the drug transdermal diffusion efficiency is relatively low, which is not conducive to the long-term and rapid efficacy of the topical dosage form, nor is it conducive to the daily storage of the drug preparation. Summary of the Invention

[0004] Aiming at the above deficiencies of the prior art, the present invention provides a trifarotene topical agent and a preparation method thereof, which are specifically realized through the following technologies.

[0005] A trifarotene topical agent, the raw materials of which by mass fraction include 1.0 - 5.0% of trifarotene, 6 - 12% of gel base material, 10 - 15% of polylactic acid, 5 - 7.5% of cellulose, 1 - 2.5% of penetration enhancer, 8 - 14% of water-retaining agent, 5 - 9% of surfactant, and the rest is water; the gel base material includes medium-chain fatty acid glycerides and polycarbophil, and the mass ratio of the two is (2.5 - 4):1; the weight-average molecular weight of the polylactic acid is 80,000 - 150,000; the diameter of the cellulose is 5 - 10 nm and the length is 2.5 - 10 μm.

[0006] The above-mentioned tretinoin topical agent provided by the present invention is a gel or paste-like medicament; it is generally used for applying on the skin surface, and tretinoin is absorbed by the human body through the skin. After the conventional paste-like medicament is applied, it will gradually lose water, has poor adhesion to the skin, and is easily wiped off accidentally by the patient's hand or clothing, making it difficult to ensure the efficacy of the medicament. Therefore, in order to solve the above problems, improve the adhesion of the medicament on the skin surface, extend the duration of the medicament staying on the skin surface, and achieve the sustained and long-acting release of the tretinoin drug, the present invention selects polylactic acid and cellulose in the medicament. After the medicament is evenly applied, the medicament layer can firmly adhere to the skin surface, and as the surface slowly loses water, it will harden to form a soft protective shell layer, delaying the continuous loss of water. The surface of the protective shell layer has a slightly matte texture and is not easily wiped off by the hand, clothing, or toilet paper, ensuring the retention time of the medicament. Polylactic acid and cellulose can also form an interlaced grid-like structure in the medicament, improving the stability and overall support of the medicament during storage and the medicament layer during the hardening process. As the medicament layer continues to lose water, the entire medicament layer will eventually form a soft sheet material. At this time, the tretinoin drug has completed effective slow release, and the medicament layer can be simply torn off by hand.

[0007] The tretinoin medicament provided by the present invention can be embedded and dispersed by a gel substrate and a surfactant to achieve the slow release of the tretinoin drug and ensure the effective concentration of the medicament. In this process, polylactic acid and cellulose can also play a certain role in assisting slow release.

[0008] Further, the mass ratio of the polylactic acid to the cellulose is (1.8 - 2.7):1.

[0009] Furthermore, the mass ratio of the polylactic acid to the cellulose is 2.5:1.

[0010] Further, the surfactant includes meglumine and at least one of polyethylene glycol glycerol caprylate / caprate and polyoxyethylene hydrogenated castor oil.

[0011] Further, the surfactant consists of meglumine and polyethylene glycol glycerol caprylate / caprate / polyoxyethylene hydrogenated castor oil, and the dosage of meglumine accounts for 55 - 70% of the total mass of the surfactant.

[0012] Furthermore, the dosage of meglumine accounts for 65% of the total mass of the surfactant.

[0013] Further, the water-retaining agent includes at least one of white petrolatum, beeswax, glycerol, and liquid paraffin; the penetration enhancer is at least one of lauryl alcohol, menthol, geraniol, anethole, decyl methyl sulfoxide, and sodium tetradecyl sulfate.

[0014] Further, the raw materials by mass fraction include adapalene 4.5%, gel base material 10%, polylactic acid 13.5%, cellulose 6.5%, penetration enhancer 2%, water retention agent 12%, surfactant 6%, and the rest is water.

[0015] The present invention also provides a preparation method of the above-mentioned adapalene external preparation, comprising the following steps:

[0016] Heat and stir the water retention agent until it becomes liquid, then add the liquid water retention agent, as well as the adapalene, penetration enhancer and polylactic acid to an organic solvent and mix evenly to obtain an oil phase;

[0017] Add the cellulose and surfactant to 40 - 50% of the total water consumption and mix evenly to obtain an aqueous phase;

[0018] Add the oil phase to the aqueous phase, stir at a constant temperature of 50 - 55°C in a closed environment until the organic solvent is removed, and shear and emulsify to obtain a mixture;

[0019] Dissolve the gel base material in the remaining water, add the mixture at a constant temperature of 50 - 55°C and disperse to obtain the finished adapalene external preparation.

[0020] Further, the conditions for shear emulsification are shear at 10000 - 15000 rpm for 20 - 40 min; the conditions for dispersion are dispersion at 500 - 800 rpm for 1 - 1.5 h.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a novel adapalene external preparation. Through the coordinated cooperation of the raw material formula, the hardening and solidification time of the medicine is reasonably matched with the sustained release time of adapalene that can ensure the effective concentration. After the medicine layer is completely hardened, adapalene has basically completed drug release. The raw materials used in the medicine are mild, the medicine layer is soft and moderate, covers a small skin area, and there is basically no discomfort. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the drug release rate curve diagram of the adapalene external preparation prepared in Examples 1 - 4;

[0023] Figure 2 It is the drug release rate curve diagram of the adapalene external preparation prepared in Comparative Examples 1 - 4. DETAILED DESCRIPTION OF THE INVENTION

[0024] The technical solutions of the present invention will be described clearly and completely below. Apparently, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0025] Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment, etc. used in the present invention can be obtained through market purchase or by existing methods.

[0026] The technical means disclosed in the following specific embodiments of the present invention are to solve the above technical problems, and the general idea is as follows:

[0027] A tazarotene topical agent provided by the present invention, the raw materials of which include 1.0 - 5.0% of tazarotene, 6 - 12% of gel base material, 10 - 15% of polylactic acid, 5 - 7.5% of cellulose, 1 - 2.5% of penetration enhancer, 8 - 14% of water retention agent, 5 - 9% of surfactant by mass fraction, and the rest is water; the gel base material includes medium-chain fatty acid glyceride and polycarbophil, and the mass ratio of the two is (2.5 - 4):1; the weight-average molecular weight of the polylactic acid is 80,000 - 150,000; the diameter of the cellulose is 5 - 10 nm, and the length is 2.5 - 10 μm.

[0028] The above components cooperate synergistically to make the storage stability of the medicament better and the release rate more stable. Specifically:

[0029] Selecting 10 - 15% of polylactic acid and 5 - 7.5% of cellulose can promote the hardening of the medicament layer after application, and form an interlaced network structure during the medicament itself and the hardening process of the medicament, improving the storage stability of the drug and the supportability of the medicament layer; polylactic acid and cellulose form a smooth or slightly matte texture on the surface of the hardened medicament layer, preventing the medicament from being easily wiped off and ensuring the retention time of the medicament layer; polylactic acid and cellulose can also play an auxiliary sustained-release role.

[0030] Preferably, the raw materials of the above tazarotene topical agent include 4.5% of tazarotene, 10% of gel base material, 14% of polylactic acid, 5.6% of cellulose, 2% of penetration enhancer, 12% of water retention agent, 6% of surfactant by mass fraction, and the rest is water.

[0031] Among the raw materials of the tazarotene topical agent provided in the following examples and comparative examples, preferably, the mass ratio of polylactic acid to cellulose can be selected as (1.8 - 2.7):1; optimally, the mass ratio of the polylactic acid to the cellulose is 2.5:1.

[0032] The surfactant used includes meglumine, and also includes at least one of polyethylene glycol glycerol caprylate / caprate and polyoxyethylene hydrogenated castor oil. And, the dosage of meglumine accounts for 55 - 70% of the total mass of the surfactant. For the convenience of comparison in the following examples and comparative examples, the dosage of meglumine accounts for 65% of the total mass of the surfactant.

[0033] Among the raw materials of the tretinoin topical agent provided in the following examples and comparative examples, the water retention agents used include at least one of white petrolatum, beeswax, glycerol, and liquid paraffin. The penetration enhancers used are at least one of lauryl alcohol, menthol, geraniol, anethole, decyl methyl sulfoxide, and sodium lauryl sulfate.

[0034] For the convenience of comparison in the following examples and comparative examples, white petrolatum and liquid paraffin (mass ratio 1:1) are selected as the water retention agents; lauryl alcohol and menthol (mass ratio 1:1) are selected as the penetration enhancers.

[0035] Among the raw materials of the tretinoin topical agent provided in the following examples and comparative examples, the weight-average molecular weight of polylactic acid can be selected to be 80,000 - 150,000. The weight-average molecular weight of the polylactic acid purchased in the following examples and comparative examples is 100,000 - 150,000.

[0036] The cellulose selected in the present invention, in addition to directly purchasing finished products that meet the requirements in the market, can also be obtained by the following self-preparation method:

[0037] (1) Wash, remove impurities, and dry wood, straw, and cotton and linen fibers to a moisture content ≤ 2%, and then mechanically crush them into fragments ≤ 3 mm.

[0038] (2) Add a mixed solution of sodium hydroxide and dimethyl sulfoxide with a volume ratio of 1:10, stir at room temperature for 1 h, and the mass ratio of the fiber to the mixed solution is 1:10.

[0039] (3) Filter and separate to obtain fibers, wash them, add water to prepare a suspension with a mass fraction of 5%, and grind with a colloid mill until the diameter ≤ 1 μm; then homogenize 3 times under a pressure of 1400 MPa.

[0040] (4) Centrifuge to remove the supernatant, dry the product to a water content ≤ 1%, and obtain cellulose with a diameter of 5 - 10 nm and a length of 2.5 - 10 μm.

[0041] The following examples and comparative examples also provide a preparation method for a tretinoin topical agent, and the steps include:

[0042] (1) Heat and stir the water retention agent until it becomes liquid (if it is already liquid, heating and stirring are not required), and then add the liquid water retention agent, as well as the tretinoin, penetration enhancer, and polylactic acid to an organic solvent and mix evenly to obtain an oil phase.

[0043] In the above step (1), it is only necessary to mix the raw materials evenly. Generally, the mixing conditions are stirring at 300 - 500 rpm for 5 min; for the convenience of comparison in the following examples and comparative examples, the mixing conditions of stirring at 300 rpm for 5 min are selected.

[0044] (2) Add the cellulose and surfactant to water accounting for 40 - 50% of the total water consumption and mix evenly to obtain an aqueous phase;

[0045] For the above step (2), it only needs to mix the raw materials evenly. Generally, the mixing conditions for the above step (2) are stirring at 200 - 300 rpm for 2 - 5 min; for the convenience of comparison in the following examples and comparative examples, the mixing conditions are selected as stirring at 200 rpm for 5 min.

[0046] (3) Add the oil phase to the aqueous phase, and stir at a constant temperature of 50 - 55°C in a closed environment until the organic solvent is removed, and shear and emulsify to obtain a mixture;

[0047] Generally, the conditions for shear emulsification in the above step (3) are shearing at 10000 - 15000 rpm for 20 - 40 min.

[0048] For the convenience of comparison in the following examples and comparative examples, preferably, the conditions for the above shear emulsification can be selected as shearing at 15000 rpm for 30 min;

[0049] (4) Dissolve the gel substrate in the remaining water, and add the mixture at a constant temperature of 50 - 55°C for dispersion to obtain the finished product of tretinoin topical agent.

[0050] Generally, the conditions for dispersion in the above step (4) are dispersing at 500 - 800 rpm for 1 - 1.5 h.

[0051] For the convenience of comparison in the following examples and comparative examples, preferably, the conditions for the above dispersion are dispersing at 800 rpm for 1 h.

[0052] Next, a tretinoin topical agent of the present application will be described in detail in combination with examples, comparative examples and experimental data.

[0053] Example 1

[0054] For the tretinoin topical agent provided in this example, its raw materials include tretinoin 4.5% by mass fraction, gel substrate (saturated caprylic triglyceride and polycarbophil) 10%, polylactic acid (weight average molecular weight 100,000 - 150,000) 14%, cellulose (prepared by the above mechanical grinding, diameter 5 - 8 nm, length 5 - 10 μm) 5.6%, penetration enhancer 2%, water retention agent 12%, surfactant (N - methyl - D - glucamine and polyoxyethylene hydrogenated castor oil) 6%, and the rest is water;

[0055] In the gel substrate, the mass ratio of medium - chain fatty acid triglyceride (saturated caprylic triglyceride) to polycarbophil is 3.5:1. The mass ratio of polylactic acid to cellulose is 2.5:1.

[0056] Example 2

[0057] The tazarotene topical agent provided by this example contains, by mass fraction, 5% of tazarotene, 6% of a gel base material (saturated caprylic triglyceride and polycarbophil), 10% of polylactic acid (weight-average molecular weight 100,000 - 150,000), 7.5% of cellulose (prepared by the above-mentioned mechanical grinding, with a diameter of 5 - 8 nm and a length of 5 - 10 μm), 1% of a penetration enhancer, 14% of a water retention agent, 5% of a surfactant (N-methyl-D-glucamine and polyoxyethylene hydrogenated castor oil), and the balance being water;

[0058] In the gel base material, the mass ratio of medium-chain fatty acid triglyceride (saturated caprylic triglyceride) to polycarbophil is 4:1. The mass ratio of polylactic acid to cellulose is 1.33:1.

[0059] Example 3

[0060] The tazarotene topical agent provided by this example contains, by mass fraction, 1% of tazarotene, 12% of a gel base material (saturated caprylic triglyceride and polycarbophil), 15% of polylactic acid (weight-average molecular weight 100,000 - 150,000), 5.56% of cellulose (prepared by the above-mentioned mechanical grinding, with a diameter of 5 - 8 nm and a length of 5 - 10 μm), 2.5% of a penetration enhancer, 8% of a water retention agent, 9% of a surfactant (N-methyl-D-glucamine and polyoxyethylene hydrogenated castor oil), and the balance being water;

[0061] In the gel base material, the mass ratio of medium-chain fatty acid triglyceride (saturated caprylic triglyceride) to polycarbophil is 2.5:1. The mass ratio of polylactic acid to cellulose is 2.7:1.

[0062] Example 4

[0063] The tazarotene topical agent provided by this example contains, by mass fraction, 4.5% of tazarotene, 10% of a gel base material (saturated caprylic triglyceride and polycarbophil), 10% of polylactic acid (weight-average molecular weight 100,000 - 150,000), 5.6% of cellulose (prepared by the above-mentioned mechanical grinding, with a diameter of 5 - 8 nm and a length of 5 - 10 μm), 2% of a penetration enhancer, 12% of a water retention agent, 6% of a surfactant (N-methyl-D-glucamine and polyoxyethylene hydrogenated castor oil), and the balance being water;

[0064] In the gel base material, the mass ratio of medium-chain fatty acid triglyceride (saturated caprylic triglyceride) to polycarbophil is 3.5:1. The mass ratio of polylactic acid to cellulose is approximately 1.8:1.

[0065] Comparative Example 1

[0066] The difference between the tazarotene topical agent provided by this example and that of Example 1 lies in that: in the gel base material, the mass ratio of medium-chain fatty acid triglyceride (saturated caprylic triglyceride) to polycarbophil is 2:1.

[0067] Comparative Example 2

[0068] The tazarotene topical agent provided in this example is different from that in Example 1 in terms of raw materials: in the gel base material, the mass ratio of medium-chain fatty acid glyceride (saturated caprylic triglyceride) to polycarbophil is 5:1.

[0069] Comparative Example 3

[0070] The tazarotene topical agent provided in this example is different from that in Example 1 in terms of raw materials: polylactic acid or other substitutes for polylactic acid are not selected in its raw materials. During preparation, polylactic acid or other substitutes for polylactic acid are not added in the corresponding steps either.

[0071] Comparative Example 4

[0072] The tazarotene topical agent provided in this example is different from that in Example 1 in terms of raw materials: cellulose or other substitutes for cellulose are not selected in its raw materials. During preparation, cellulose or other substitutes for cellulose are not added in the corresponding steps either.

[0073] Test Example: Performance Evaluation of Tazarotene Topical Agent

[0074] 1. Stability Test and Accelerated Stability Test

[0075] (1) Coating Test: Take an appropriate amount of the finished tazarotene topical agent of each example and comparative example, apply it on the arm with a coating thickness of not less than 2 mm; evaluate the ease of application and check the state of the topical agent 10 min, 1 h, 2 h, 4 h, and 6 h after application.

[0076] (2) Cold Resistance Test: Take 10 g of the finished tazarotene topical agent of each example and comparative example, fill it into a 10-ml ampoule, seal it, and let it stand in an environment of -18 °C for 24 h, and observe the layering situation.

[0077] (3) Heat Resistance Test: Take 10 g of the finished tazarotene topical agent of each example and comparative example, fill it into a 10-ml ampoule, seal it, and place it in an environment of 55 ± 2 °C for 10 days, and take samples on the 3rd, 5th, and 10th days after the start of the test to observe the layering situation.

[0078] (4) Accelerated Stability Test: To further investigate the stability of the tazarotene topical agent of the present invention, according to the relevant regulations in the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Pharmaceutical Products" in Appendix XIX C of the Chinese Pharmacopoeia 2010 Edition, take the tazarotene topical agents prepared in each example and comparative example, and place them under the conditions of temperature 30 ± 2 °C and relative humidity 65 ± 5% for 6 months. Take samples at 1, 2, 3, and 6 months respectively, and detect the properties and layering phenomena of each sample according to the quality standards, and repeat the determination 3 times.

[0079] The test results of the stability test and the accelerated stability test and the accelerated stability test are shown in Table 1 below.

[0080] Table 1 Test results of stability and accelerated stability

[0081]

[0082] As can be seen from Table 1, the trefarotene external preparations prepared in the above Examples 1-4 and Comparative Examples 1-2, after being applied on the arm, are initially in a viscous, translucent gel-like form, and a suitable amount of the agent can be adhered to the surface of the gel by touching the surface with a finger, which indicates that the agent has good adhesion to the skin.

[0083] 4-5 minutes after the application of the trefarotene topical preparation of Example 1, a visible film layer begins to appear on the surface of each topical preparation. This is due to the synergistic effect of the dehydration of the preparation and the grid structure gradually formed by polylactic acid and cellulose. In some embodiments and comparative examples, the film layer has a frosted texture when touched by hand, and the fingers will no longer stick to the preparation, and the preparation will deform when lightly pressed. During the application period of 2-2.5 hours, the film layer on the surface of the preparation becomes harder, and the fingers can obviously feel the film layer thickening, but the preparation under the film layer still deforms after light pressure. When applied for 4-5 hours, the film layer on the surface of the preparation continues to thicken, and there is basically no obvious deformation when the gel is lightly pressed; if the preparation is peeled off at this time, only the thick film on the outside can be peeled off, and part of the preparation inside is still adhered to the skin. 7.5-8 hours after application, the entire topical agent has basically hardened, and there is no obvious deformation when the agent is pressed lightly, but the agent is still relatively firmly adhered to the skin surface; 10 hours after application, the edge of the agent layer is slightly warped, and it is easy to pick it off or peel it off directly with your hands.

[0084] The trefarotene topical preparations prepared in comparative examples 1-4 had slight stratification and delamination problems in the stability and accelerated stability tests. The trefarotene topical preparations prepared in comparative examples 3-4 had a slow appearance of the film layer on the surface of the preparation and were easily deformed by pressing with fingers. After analysis, this may be due to the inappropriate proportion of the gel substrate in the raw materials, or the lack of polylactic acid or cellulose affecting the formation of the network structure, which in turn led to stratification; the lack of polylactic acid or cellulose also affected the formation of the network structure, thereby affecting the support of the drug layer.

[0085] 2. In vitro release test

[0086] The trefarotene external preparations prepared in Examples 1-4 and Comparative Examples 1-4 were subjected to an in vitro release test. A drug release test was performed using a diffusion cell. A 5 μm artificial fiber membrane was used as the permeation material, a 25% ethanol solution was used as the receiving medium, the dosage in the supply chamber was 0.2 ml, the volume of the receiving cell was 7 mL, and the effective permeation area was 3.14 cm 2The diffusion cell was placed in a thermostatic water bath (37°C ± 0.5°C), and the magnetic stirrer was placed under the thermostatic water bath with a stirring speed of 300 r / min. At 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 10 h respectively, 5 mL of the receiving solution was taken out, and at the same time, the same volume of blank receiving solution was supplemented. The obtained samples were centrifuged, and the supernatant was taken. The receiving solution was analyzed by liquid chromatography, and the drug release rate was obtained by dividing the drug release amount by the drug release time.

[0087] The specific calculation method of the drug release rate is as follows: Assume that the total amount of the drug is w, the drug release amount at 10 min is w0, and the cumulative drug release amount at 30 min is w1. Then the drug release rate at 10 min is (w0 / w) / (1 / 6), and the drug release rate at 30 min is (w1 - w0) / (1 / 3). It should be noted that 1 / 6 in (w0 / w) / 0.25 refers to 10 min, that is, (1 / 6) h, that is, 0.25 h; 1 / 3 in (w1 - w0) / 0.25 is 30 min - 10 min = 20 min, that is, (1 / 3) h. The drug release curves of the tazarotene topical agents of Examples 1-4 and Comparative Examples 1-4 were plotted respectively, as shown in Figure 1 , 2 respectively.

[0088] From Figure 1 it can be seen that for the tazarotene topical agents prepared in Examples 1-4, the drug release rate increased significantly after administration; the drug release rate peak appeared at about 2 h, and then began to decline slowly and steadily. However, until the 10th h of sampling, the drug release rate was still relatively high.

[0089] From Figure 2 it can be seen that the drug release rates of Comparative Examples 1 and 2 increased gently, and reached the highest drug release rate 4 h after administration respectively. However, the drug release rate decreased relatively quickly afterwards, and the drug release rate had dropped to about 2% at the 10th h. This indicates that changing the dosage of the gel substrate has a certain impact on the sustained release of tazarotene drug. Only by using the dosage ratio of medium-chain fatty acid glyceride (saturated caprylic triglyceride) and polycarbophil of the present invention can the drug release concentration be ensured for a long time.

[0090] From Figure 2 it can be seen that the drug release rates of the tazarotene topical agents prepared in Comparative Examples 3 and 4 increased rapidly, and the drug release rate had reached the peak at the 1st h. Then it decreased rapidly, and the drug release rate had dropped to about 1% at the 10th h. This indicates that the drug release rates of the topical agents in both groups of comparative examples cannot be effectively controlled, indicating that the lack of polylactic acid or cellulose has a significant impact on the release rate of tazarotene drug, which will significantly accelerate the drug release, thus failing to achieve the purpose of long-term sustained release.

[0091] In summary, the tazarotene topical agent provided by the present invention has good adhesion performance, avoiding accidental wiping off of the gel; by selecting polylactic acid and cellulose in the raw materials, it can provide a certain degree of grid-like support for the topical agent during the solidification process and form a gradually thickening film layer on the surface of the topical agent, delaying the evaporation of water in the medicament; polylactic acid and cellulose also have a certain auxiliary sustained-release effect, cooperating synergistically with the gel substrate and the surfactant, ensuring a reasonable adaptation of the drug release rate and the water loss hardening process of the topical agent, and it is convenient to use by visually and tactilely confirming whether the medicament can be peeled off with the naked eye and fingers.

[0092] The above specific embodiments have described the implementation of the present invention in detail. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple variations all belong to the protection scope of the present invention.

Claims

1. A topical tretinoin agent, characterized in that, Its raw materials by mass fraction include tretinoin 1.0 - 5.0%, gel base material 6 - 12%, polylactic acid 10 - 15%, cellulose 5 - 7.5%, penetration enhancer 1 - 2.5%, water retention agent 8 - 14%, surfactant 5 - 9%, and the balance is water; the gel base material includes medium-chain fatty acid glyceride and polycarbophil, and the mass ratio of the two is (2.5 - 4):1; the weight-average molecular weight of the polylactic acid is 80,000 - 150,000; the diameter of the cellulose is 5 - 10 nm and the length is 2.5 - 10 μm.

2. The tazarotene topical agent according to claim 1, wherein The mass ratio of the polylactic acid to the cellulose is (1.8 - 2.7):

1.

3. The tazarotene topical agent according to claim 2, wherein The mass ratio of the polylactic acid to the cellulose is 2.5:

1.

4. The tazarotene topical agent according to claim 1, wherein The surfactant includes meglumine, and also includes at least one of polyethylene glycol glycerol caprylate / caprate and polyoxyl 40 hydrogenated castor oil; the dosage of meglumine accounts for 55 - 70% of the total mass of the surfactant.

5. The tazarotene topical agent according to claim 4, wherein The dosage of meglumine accounts for 65% of the total mass of the surfactant.

6. The tazarotene topical agent according to claim 1, wherein The water retention agent includes at least one of white petrolatum, beeswax, glycerol, and liquid paraffin; the penetration enhancer is at least one of lauryl alcohol, menthol, geraniol, anethole, decyl methyl sulfoxide, and sodium tetradecyl sulfate.

7. The tazarotene topical agent according to any one of claims 1-6, characterized in that Its raw materials by mass fraction include tretinoin 4.5%, gel base material 10%, polylactic acid 14%, cellulose 5.6%, penetration enhancer 2%, water retention agent 12%, surfactant 6%, and the balance is water.

8. A method for preparing the tretinoin topical agent according to any one of claims 1-6, characterized in that, It includes the following steps: Heat and stir the water retention agent until it becomes liquid, then add the liquid water retention agent, as well as the tretinoin, penetration enhancer, and polylactic acid to an organic solvent and mix evenly to obtain an oil phase; Add the cellulose and surfactant to water accounting for 40 - 50% of the total water consumption and mix evenly to obtain an aqueous phase; Add the oil phase to the aqueous phase, stir at a constant temperature of 50 - 55°C in a closed environment until the organic solvent is removed, and shear and emulsify to obtain a mixture; Dissolve the gel base material in the remaining water, add the mixture at a constant temperature of 50 - 55°C and disperse to obtain the finished tretinoin topical agent.

9. The preparation method according to claim 8, characterized in that, The conditions for the shear emulsification are shearing at 10,000 - 15,000 rpm for 20 - 40 min; the conditions for the dispersion are dispersing at 500 - 800 rpm for 1 - 1.5 h.

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