A temperature-sensitive gel loaded with a poorly soluble drug, and a preparation method and application thereof

Abstract

The application provides a temperature-sensitive gel for carrying poorly soluble drugs and a preparation method and application thereof, which comprises a poorly soluble drug, a solubilizer, isopropyl myristate and white beeswax, a gel matrix is formed between the isopropyl myristate and the white beeswax, and the poorly soluble drug is carried after the solubilizer is added. The preparation method is as follows: the isopropyl myristate and the white beeswax are mixed and dissolved by ultrasonic and then placed in a magnetic stirrer for stirring; the solubilizer and the poorly soluble drug are mixed by ultrasonic, and then heated in a water bath after being added into the prepared gel matrix. The raw materials of the drug-loaded gel are widely sourced, low in price, low in preparation cost, and high in biological safety; 95% ethanol is used as the solubilizer, which is non-toxic and harmless to human bodies, low in cost, easy to obtain and easy to prepare; the drug loading capacity of the gel can reach 2.5%, the drug loading capacity is large, and the drug-loaded gel has good temperature sensitivity and film-forming property.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a thermosensitive gel carrying a poorly soluble drug, its preparation method, and its application. Background Technology

[0002] Dihydrotestosterone (DHT) is a naturally occurring male hormone widely distributed throughout the bloodstream and plays a positive role in the appearance and maintenance of secondary sexual characteristics. It is an important steroid hormone irreversibly catalyzed by testosterone (T) under the conditions of 5α-reductases (5α-red1 and 5α-red2). It has a higher affinity for androgen receptors (AR) and is therefore considered a more potent androgen than T. In pediatric clinical practice, DHT is used to treat male pseudohermaphroditism caused by congenital 5α-reductase deficiency in children, such as micropenis. 2.5% DHT hydrogel (trade name Andractim) is available in France and is urgently needed in pediatric clinical practice. Currently, DHT gel formulations are not approved for import into my country and cannot be purchased domestically; they can only be obtained through overseas purchases or by purchasing agents. Compared to currently marketed testosterone and its derivatives, dihydrotestosterone (DHT) has the following advantages: 1. Stronger pharmacological activity: DHT is the most potent naturally occurring male hormone, with six times the biological activity of testosterone in the body; 2. Fewer side effects: Unlike ketones and their derivatives, DHT cannot be converted into estradiol in the body, thus avoiding the side effect of gynecomastia in men and women. However, it also has some drawbacks: the application method is unhygienic and inconvenient, and the amount and speed of drug penetration through the skin are limited, which is not conducive to the full absorption of the drug and the speed of its onset of action. Furthermore, the gel is relatively expensive, increasing the economic burden on patients and making long-term use difficult for many.

[0003] Thermosensitive gels are a special type of hydrogel that can transform from a flowing liquid (sol phase) to a non-flowing hydrogel (gel phase) depending on a certain temperature. Due to these properties, they have wide applications in biomedicine and pharmaceuticals, such as drug delivery, cell culture, and tissue engineering. However, because gels are mostly hydrophilic, preparing thermosensitive gels for poorly soluble drugs can easily lead to insufficient drug loading, or some drug remaining in suspension within the gel, resulting in uneven drug dispersion, difficulty in controlling the release rate, and impaired drug efficacy. Although surfactants can be added to increase drug loading, their addition may introduce new problems such as toxic side effects. Moreover, surfactants cannot solve, and may even exacerbate, the problem of rapid drug release in existing pharmaceutical thermosensitive gels. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention first provides a thermosensitive gel carrying a poorly soluble drug, comprising the poorly soluble drug, a solubilizer, isopropyl myristate, and beeswax, wherein the isopropyl myristate and beeswax form a gel matrix, and the solubilizer is mixed with the poorly soluble drug and then added to the gel matrix.

[0005] Preferably, the mass ratio of isopropyl myristate, beeswax, ethanol and the poorly soluble drug is 79.5:8:10:2.5.

[0006] Preferably, the solubilizer is 95% ethanol.

[0007] Preferably, the poorly soluble drug is dihydrotestosterone.

[0008] Based on a general inventive concept, the present invention also provides a method for preparing a thermosensitive gel carrying a poorly soluble drug, comprising the following steps:

[0009] S1. The solubilizer and the poorly soluble drug are ultrasonically mixed to dissolve the drug;

[0010] S2. Mix isopropyl myristate and beeswax and dissolve by ultrasonication. Then stir with a magnetic stirrer. Add the dissolved drug prepared in S1. Heat in a water bath to dissolve. Cool at room temperature and let it solidify to obtain a thermosensitive gel loaded with poorly soluble drugs.

[0011] Preferably, the water bath heating temperature in step S2 is 75°C.

[0012] Based on a general inventive concept, the present invention also provides the application of a thermosensitive gel carrying a poorly soluble drug in the preparation of a gel carrying a poorly soluble drug matrix.

[0013] Compared with the prior art, the present invention has the following beneficial effects:

[0014] 1. This invention provides a gel matrix prepared from isopropyl myristate and beeswax to carry poorly soluble drugs. The raw materials are widely available, inexpensive, have low preparation costs, and are highly biosafety-free.

[0015] 2. The drug-loaded gel provided by this invention has good temperature sensitivity. It can maintain the stability of the gel at room temperature, but it quickly turns into a liquid when it comes into contact with the human skin surface. It has good extensibility and is easily absorbed.

[0016] 3. This invention uses 95% ethanol as a solubilizer, which is non-toxic and harmless to the human body, and is inexpensive, readily available and easy to prepare.

[0017] 4. The gel provided by the present invention has a drug loading capacity of up to 2.5%, which is large, and it has good temperature sensitivity and film-forming properties after drug loading. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 For Experiment 2, the effects of different solubilizers on drug solubility are shown. A represents the effect of β-cyclodextrin and ethanol on DHT solubility; B represents the effect of ethanol, glycerol, IPM, 1,2-propanediol, and N,N-dimethylacetamide on DHT solubility.

[0020] Figure 2 The modeling properties of four groups of DHT-loaded thermosensitive gels in Experiment Example 4 are shown in Figure 1. ① is Experiment Group 1, ② is Experiment Group 2, ③ is Experiment Group 2, and ④ is Experiment Group 4.

[0021] Figure 3 For Experiment 5, the thermosensitivity of two groups of DHT-loaded thermosensitive gels at 25℃ is shown. A is experimental group (1) and B is experimental group (2).

[0022] Figure 4 The thermosensitivity of four groups of DHT-loaded thermosensitive gels at 37℃ is shown in Experiment 5. ① is experimental group (1), ② is experimental group (2), ③ is experimental group (3), and ④ is experimental group (4). Detailed Implementation

[0023] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0024] The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the invention. Any modifications or substitutions made to the methods, steps, or conditions of the present invention without departing from the spirit and essence of the invention are within the scope of the invention.

[0025] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art; unless otherwise specified, the reagents used in the embodiments are all commercially available.

[0026] Experimental Example 1

[0027] Investigating the viscosity of temperature-sensitive gel matrices with different ratios

[0028] Weigh out 100 mg of white beeswax into 2 ml EP tubes, and add 800 μL, 1000 μL, and 1200 μL of IPM respectively. Stir in a 75°C water bath to dissolve the beeswax, then cool to room temperature and allow it to solidify. Measure the viscosity using a DHR-1 rheometer at 25°C and a shear rate of 5.

[0029] The results are shown in Table 1. The viscosity of the gel matrix formed by isopropyl myristate and white beeswax can reach 7.65-30.60 Pa·s. When the ratio is 10:1, the low molecular weight organic gel matrix has good rheological properties. The average viscosity n (Pa·s) measured by the DHR-1 rheometer is 30.5970. In addition, the matrix has good spreadability and is not greasy. Therefore, 10:1 is selected as the gel matrix ratio.

[0030] Table 1 Viscosities of gel matrices with different ratios

[0031]

[0032] Experimental Example 2

[0033] Investigating the effect of different solubilizers on the solubility of dihydrotestosterone.

[0034] This experiment used a single-factor investigation to examine the solubility of DHT in β-cyclodextrin (β-CD), ethanol (95%), 1,2,3-propanetriol (glycerol), IPM, 1,2-propanediol, and N,N-dimethylacetamide to determine the optimal solubilizer. The β-cyclodextrin aqueous solution was prepared by dissolving solid β-CDs in distilled water at a 40% concentration. The experimental groups are as follows:

[0035] Group A: 63 mg of β-cyclodextrin and 250 mg of DHT were added to 177 μL of distilled water and ultrasonically mixed.

[0036] Group B: 125 mg of β-cyclodextrin and 250 mg of DHT were added to 375 μL of distilled water and ultrasonically mixed.

[0037] Group C: Add 250mg of DHT to 1ml of ethanol and mix by sonication;

[0038] Group D: DHT 25mg was added to 100μL of ethanol and ultrasonically mixed / Group E: DHT 25mg was added to 1000μL of ethanol and ultrasonically mixed.

[0039] Group F: DHT 25mg was added to 100μL of glycerol and sonicated for mixing / Group G: DHT 25mg was added to 1000μL of glycerol and sonicated for mixing.

[0040] Group H: DHT 25mg was added to 100μL IPM and ultrasonically mixed / Group I: DHT 25mg was added to 1000μL IPM and ultrasonically mixed.

[0041] Group J: DHT 25mg was added to 100μL of 1,2-propanediol and sonicated. Group K: DHT 25mg was added to 1000μL of 1,2-propanediol and sonicated.

[0042] Group L: DHT 25mg was added to 100μL of N,N-dimethylacetamide and ultrasonically mixed. Group M: DHT 25mg was added to 1000μL of N,N-dimethylacetamide and ultrasonically mixed.

[0043] The results are as follows Figure 1 As shown, according to Figure 1 Observation A revealed that the solutions containing cyclodextrin were either pale yellow or milky white and oily, exhibiting significant layering and poor solubility. In contrast, dihydrotestosterone dissolved completely and rapidly in ethanol, resulting in a clear and transparent solution. Figure 1 Observation B revealed that: in ethanol, DHT partially dissolved at 25 mg / 100 μL and completely dissolved at 25 mg / 1 ml; glycerol was too viscous, and DHT showed no solubility in either concentration, agglomerating and settling to the bottom; in IPM, the active pharmaceutical ingredient dispersed into tiny particles in both concentrations, but was almost insoluble; although propylene glycol was slightly less viscous than glycerol, it still resulted in the active pharmaceutical ingredient forming small clumps and being almost insoluble; N,N-dimethylacetamide only required 25 mg / 100 μL to completely dissolve the active pharmaceutical ingredient, and the dissolution rate was relatively fast, even without stirring. Therefore, DHT exhibits good solubility in ethanol and N,N-dimethylacetamide.

[0044] The above experiments provide some reference for the selection of solubilizers for DHT. However, after reviewing the literature, it was found that N,N-dimethylacetamide is a slightly toxic compound that is highly irritating to the eyes, skin, and mucous membranes. From a safety perspective, it is not suitable as an ingredient in topical preparations.

[0045] Therefore, ethanol is a more suitable solubilizer for DHT.

[0046] Experimental Example 3

[0047] Investigating the effect of drug loading on gel viscosity

[0048] Single-factor experiments were conducted with three groups of different drug loadings: 1.25%, 2.5%, and 5%. A cone-plate rheometer was used to analyze the viscosity to investigate the upper and lower limits of the drug loading. The experimental groups are as follows:

[0049] Drug loading 1.25%: Dissolve 25 mg in 100 μL of ethanol, add to a mixture of 1.704 mL IPM and 171 mg beeswax, stir in a water bath at 75 °C, heat to dissolve, cool at room temperature, and solidify to obtain DHT-loaded thermosensitive gel. The viscosity was measured using a DHR-1 rheometer at 25 °C and a shear rate of 5.

[0050] Drug loading 2.5%: Dissolve 50 mg in 200 μL of ethanol, add to a mixture of 1.591 mL IPM and 159 mg beeswax, stir in a water bath at 75 °C, heat to dissolve, cool at room temperature, and solidify to obtain DHT-loaded thermosensitive gel. The viscosity was measured using a DHR-1 rheometer at 25 °C and a shear rate of 5.

[0051] Drug loading of 5%: Dissolve 100 mg in 400 μL of ethanol, add to a mixture of 1.364 mL of IPM and 136 mg of beeswax, stir in a water bath at 75 °C, heat to dissolve, cool at room temperature, and after solidification, obtain DHT-loaded thermosensitive gel. The viscosity was measured using a DHR-1 rheometer at 25 °C and a shear rate of 5.

[0052] The results are shown in Table 2.

[0053] Table 2 Viscosities of gels with different drug loading capacities

[0054] Viscosity (Pa·s) (average) 15.8284 22.7519 8.1099

[0055] As shown in the table, dihydrotestosterone low molecular weight organic gels can form gels with drug loading of 1.25%, 2.5%, and 5%, respectively, and the average viscosities are 15.8284, 22.7519, and 8.1099 n (Pa·s), respectively.

[0056] Example 1

[0057] Different DHT-loaded thermosensitive gels were prepared, with reaction temperatures designed at 75℃ and 85℃; and 95% ethanol / DHT ratios designed at 200μl / 50mg and 400μl / 50mg. The four experimental groups are designed as follows:

[0058] (1): Dissolve 50 mg in 200 μL of ethanol, add it to a mixture of 1591 μL of IPM and 159 mg of beeswax, stir in a water bath at 75 °C, heat to dissolve, cool at room temperature, and after solidification, DHT-loaded thermosensitive gel A is obtained.

[0059] (2): Dissolve 50 mg in 400 μL of ethanol, add it to a mixture of 1409 μL of IPM and 141 mg of beeswax, stir in a water bath at 75 °C, heat to dissolve, cool at room temperature, and after solidification, DHT-loaded thermosensitive gel B is obtained.

[0060] (3): Dissolve 50 mg in 200 μL of ethanol, add it to a mixture of 1409 μL of IPM and 141 mg of beeswax, stir in a water bath at 85 °C, heat to dissolve, cool at room temperature, and after solidification, DHT-loaded thermosensitive gel C is obtained.

[0061] (4) Dissolve 50 mg in 400 μL of ethanol, add it to a mixture of 1409 μL of IPM and 141 mg of beeswax, stir in a water bath at 85 °C, heat to dissolve, cool at room temperature, and after solidification, you will get DHT-loaded thermosensitive gel D.

[0062] Experiment Example 4

[0063] The film-forming properties of four groups of DHT-loaded thermosensitive gels in Example 1 were investigated.

[0064] Small amounts of dihydrotestosterone organic gel from the four groups (1), (2), (3), and (4) of Example 1 were spread evenly on cell culture dishes and dried in an oven at 37°C. The surface of the cell culture dishes was observed to see if a thin film was formed. If a film was formed, it proved that the prepared dihydrotestosterone low molecular weight organic gel had film-forming properties.

[0065] The results are as follows Figure 2 As shown, all four groups can form a white film on the surface of the cell culture dish, proving that the prepared dihydrotestosterone low molecular weight organic gels all have film-forming properties, and the DHT-loaded thermosensitive gels in groups (1) and (2) are more evenly coated.

[0066] Experimental Example 5

[0067] Thermosensitive properties of four groups of DHT-loaded thermosensitive gels in Example 1 were investigated.

[0068] (1) Take a small amount of dihydrotestosterone organic gel from groups (1) and (2) in Example 1 into a 50ml beaker, place the beaker in a 25℃ constant temperature water bath, and observe the solid-liquid state of the organic gel.

[0069] (2) Take a small amount of dihydrotestosterone organic gel from each of the four groups (1), (2), (3) and (4) in Example 1 into a 50ml beaker, place the beaker in a 37℃ constant temperature water bath, and observe the solid-liquid state of the organic gel.

[0070] The results are as follows Figure 3 As shown, by observing the solid-liquid state of the gels, it can be found that both groups of gels at 25℃ are in a semi-solid state. Figure 4 The results show that, in an environment close to human body temperature (37°C), all four gels rapidly transform from their original semi-solid gel state into a liquid, with a rapid phase transition time. Therefore, the prepared dihydrotestosterone low-molecular-weight organic gels all exhibit good thermosensitivity and are easily absorbed after being applied to the skin surface. In actual application to the skin, the milky white, semi-transparent gel quickly liquefies upon contact with the skin, exhibiting a uniform and delicate consistency, good spreadability, and excellent thermosensitivity.

[0071] Experimental Example 6

[0072] The viscosity of the four groups of DHT-loaded thermosensitive gels in Example 1 was examined.

[0073] This experiment used a DHR-1 rheometer to study the rheological properties of four groups of DHT thermosensitive gels in orthogonal experiments under oscillation mode in order to screen the optimal formulation and conditions. Under the conditions of 25℃ and shear rate 5, the viscosity of the four groups of dihydrotestosterone low molecular weight organic gels in Example 1 was measured by the DHR-1 rheometer.

[0074] The results are shown in Table 3.

[0075] Table 3 Viscosities of the four groups of DHT-loaded thermosensitive gels

[0076]

[0077]

[0078] As shown in the table above, although all four groups of dihydrotestosterone exhibit thermosensitivity and film-forming properties, the rheological properties of group (1) are better than those of experimental groups (2), (3), and (4). Pairwise comparisons reveal that increased ethanol content affects the rheological viscosity of the low-molecular-weight organic gel. The reaction temperature of 75 degrees Celsius is the phase transition point of this low-molecular-weight organic gel; below this temperature, beeswax is difficult to completely dissolve in the organic solvent IPM, while above this temperature, it also has a certain impact on the gel viscosity.

[0079] Experimental Example 7

[0080] The heat resistance, cold resistance, film-forming properties, and moisturizing properties of the DHT-loaded thermosensitive gel (1) in Example 1 were investigated.

[0081] Heat resistance: After being kept at a constant temperature of 37±1℃ for 24 hours and then allowed to return to room temperature, no oil-water separation was observed in the colloid.

[0082] Cold resistance: After being kept at (-8±1℃) for 24 hours and then allowed to return to room temperature, it was tested whether there was any significant difference in shape compared to before the test;

[0083] Film-forming properties: Take a small amount of gel, spread it evenly in a petri dish, dry it in an oven at 37°C, and test whether a film is formed;

[0084] Moisturizing properties: The product was placed at 37±1℃ for 24 hours, and the weight loss was measured.

[0085] The results are shown in Table 4:

[0086] Table 4. Heat resistance, cold resistance, film-forming properties, and moisturizing properties of DHT-loaded thermosensitive gel (1).

[0087]

[0088] Experimental results show that the DHT-loaded thermosensitive gel (1) has no problems in use and coating, and still has good stability in cold and dry environments. However, under high heat, the product exhibits a certain degree of oil-water separation. This is because the product has thermosensitive properties. Under high heat, the spatial structure of the low molecular weight organic gel is destroyed, causing the water that cross-links into the spatial structure to leak out, resulting in oil-water separation.

[0089] The above-described embodiments are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the technical scope of the present invention, based on the technical solution and concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A thermosensitive gel carrying a poorly soluble drug, characterized in that, It is composed of a poorly soluble drug, a solubilizer, isopropyl myristate, and beeswax. The isopropyl myristate and beeswax form a gel matrix. The solubilizer is mixed with the poorly soluble drug and then added to the gel matrix. The solubilizer is ethanol.

2. The temperature-sensitive gel according to claim 1, characterized in that, The mass ratio of isopropyl myristate, beeswax, ethanol, and the poorly soluble drug is 79.5:8:10:2.

5.

3. The temperature-sensitive gel according to claim 1, characterized in that, The solubilizer is 95% ethanol.

4. The temperature-sensitive gel according to claim 1, characterized in that, The poorly soluble drug is dihydrotestosterone.

5. A method for preparing a thermosensitive gel carrying a poorly soluble drug as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. The solubilizer is ultrasonically mixed with the poorly soluble drug to dissolve the drug; S2. Mix isopropyl myristate and white beeswax, dissolve by sonication, and then stir with a magnetic stirrer. Add the dissolved drug prepared in S1, heat in a water bath to dissolve, and then cool at room temperature. After solidification, a thermosensitive gel loaded with poorly soluble drugs is obtained.

6. The preparation method according to claim 5, characterized in that, The water bath heating temperature in step S2 is 75°C.

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