Gel composition as well as preparation method and application thereof

Abstract

The EG017 gel composition provided by the invention is moderate in viscosity, high in in-vitro release rate and high in stability, and can be used for remarkably improving the use compliance and the treatment effect of androgen alopecia patients. The gel provided by the invention is free from thick, heavy, sticky and greasy feelings and good in refreshing degree; the medicine can be kept for a long time at a medicine application part, medicine absorption is enhanced, and the medicine utilization degree is improved; and a patient can easily insist on taking the medicine.

Description

[0001] This application claims the right of priority from the following prior patent applications:

[0002] A prior application filed by the applicant with the State Intellectual Property Office of China on March 19, 2024, with the patent application number 202410315859.5 and the title "A Gel Composition, Its Preparation Method and Application";

[0003] The entire text of the above prior patent applications is incorporated into this application by reference. Technical Field

[0004] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a gel composition, its preparation method and application. Background Art

[0005] EG017, as a new ester - containing aromatic propanamide compound, is a selective androgen receptor modulator (SARM). Its chemical name is (S)-1-((4 - cyano - 3-(trifluoromethyl)phenyl)amino)-3-(4 - cyanophenoxy)-2 - methyl - 1 - oxopropan - 2 - yl nicotinate.

[0006] The structural formula is:

[0007]

[0008] EG017 binds to the androgen receptor (AR) and regulates its activity, and at the same time has significant selectivity for AR in different tissue cells. Currently, SARMs have been studied as possible treatment methods for various diseases, including stress urinary incontinence (SUI), benign prostatic hyperplasia (BPH), breast cancer, muscle atrophy, etc. The applicant found in previous research work (CN202311779797.5) that EG017 has a good therapeutic effect on androgenetic alopecia.

[0009] Most of the currently commercially available hair loss treatment preparations are solutions (liniments, tinctures, sprays), foams. Solutions are mostly used by spraying, and have disadvantages such as being unable to be quantified (the liquid has strong fluidity and the dosage is difficult to control), unable to be targeted (spraying to other parts of the body, and if not cleaned in time, it will cause hirsutism), and greasy hair (it is easy to wet the hair and cause greasy hair). Although foams are easy to apply, they have certain requirements for temperature. When the temperature is too high, they will become liquid, which affects the use effect, and foams are flammable and explosive products, which are inconvenient to carry. Summary of the Invention

[0010] The purpose of the present invention is to provide an external semi - solid gel agent that can ensure the stability of EG017 in the preparation, enhance the therapeutic effect, while improving the compliance and drug efficacy of androgenetic alopecia patients, and its preparation method.

[0011] The present invention provides an EG017 gel composition, which comprises EG017 or a pharmaceutically acceptable salt thereof as an active substance and a gel matrix;

[0012] Wherein, the structural formula of EG017 is as follows:

[0013]

[0014] According to an embodiment of the present invention, the content (weight percentage) of EG017 is 0.1% - 20%, preferably 1% - 10%, and more preferably 3% - 9%, such as 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%.

[0015] According to an embodiment of the present invention, the gel matrix is selected from one, two or more of carbomer, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose; preferably, the gel matrix is selected from one, two or more of carbomer type A homopolymer, carbomer type B homopolymer, and carbomer type C homopolymer.

[0016] According to an embodiment of the present invention, the content of the gel matrix is 0.01% - 5%, preferably 0.05% - 4%, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%.

[0017] According to an embodiment of the present invention, the gel composition optionally further comprises a humectant.

[0018] According to an embodiment of the present invention, the humectant is selected from one, two or more of glycerol, sorbitol, and liquid paraffin.

[0019] According to an embodiment of the present invention, the content of the humectant is 1% - 10%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.

[0020] According to an embodiment of the present invention, the gel composition optionally further comprises an antibacterial agent.

[0021] According to an embodiment of the present invention, the antibacterial agent is selected from one, two or more of benzalkonium chloride, methylparaben (methyl hydroxybenzoate), ethylparaben (ethyl hydroxybenzoate), propylparaben (propyl hydroxybenzoate), butylparaben (butyl hydroxybenzoate), benzyl alcohol, chlorobutanol, and sorbic acid.

[0022] According to an embodiment of the present invention, the content of the bacteriostatic agent is 0 to 1%, preferably 0.005% to 0.5%, such as 0.01%, 0.02%, 0.05%, 0.09%, 0.10%, 0.14%, 0.15%, 0.18%, 0.20%, 0.30%, 0.40%.

[0023] According to an embodiment of the present invention, the bacteriostatic agent comprises methylparaben and / or propylparaben; preferably, the content of methylparaben is 0.02% - 0.20%, such as 0.18%; preferably, the content of propylparaben is 0.005% - 0.05%, such as 0.01%, 0.02%, 0.03%. According to an embodiment of the present invention, the bacteriostatic agent comprises sorbic acid and / or butylparaben; preferably, the content of sorbic acid is 0.05% - 0.20%, such as 0.08%, 0.09%, 0.1%; preferably, the content of butylparaben is 0.05% - 0.20%, such as 0.08%, 0.09%, 0.1%.

[0024] According to an embodiment of the present invention, the gel composition optionally further comprises an antioxidant.

[0025] According to an embodiment of the present invention, the antioxidant is selected from one, two or more of butylated hydroxytoluene (BHT), sodium metabisulfite, sodium sulfite, cysteine, L-ascorbic acid or disodium ethylenediaminetetraacetate (EDTA-2Na).

[0026] According to an embodiment of the present invention, the content of the antioxidant is 0 to 1%, such as 0%, 0.01%, 0.03%, 0.05%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.5%.

[0027] According to an embodiment of the present invention, the gel composition optionally further comprises a pH regulator.

[0028] According to an embodiment of the present invention, the pH regulator is selected from one, two or more of organic bases or inorganic bases; preferably, selected from one, two or more of triethanolamine, sodium hydroxide, sodium citrate.

[0029] According to an embodiment of the present invention, the pH of the gel composition is less than 7.0, preferably 5.0 - 6.8, such as 5.1, 5.3, 5.5, 5.8, 6.0, 6.3, 6.5, 6.8.

[0030] According to an embodiment of the present invention, the gel composition optionally further comprises a suspending agent.

[0031] According to an embodiment of the present invention, the suspending agent is selected from one, two or more of hydroxypropyl cellulose (HPC), methylcellulose, hydroxypropyl methylcellulose (HPMC), gum arabic, tragacanth, and sodium alginate.

[0032] According to an embodiment of the present invention, the content of the suspending agent is 0% to 4%, preferably 0.5% to 3%, such as 1%, 1.5%, 2%, 2.5%.

[0033] According to an embodiment of the present invention, the gel composition optionally further comprises a transdermal absorption enhancer.

[0034] According to an embodiment of the present invention, the transdermal absorption enhancer is selected from one, two or more of isopropyl myristate, isooctyl salicylate, laurocapram, and myristic acid.

[0035] According to an embodiment of the present invention, the content of the transdermal absorption enhancer is 0% to 5%, such as 0%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%.

[0036] According to an embodiment of the present invention, the gel composition optionally further comprises a solvent.

[0037] According to an embodiment of the present invention, the solvent is selected from water.

[0038] According to an embodiment of the present invention, the gel composition comprises the following components:

[0039] 0.1% - 20% (preferably 1% - 10%, 3% - 9%) of EG017, 0.05% - 5% (preferably 0.01% - 4%) of a gel matrix, 1% - 10% of a humectant, 0 - 1% (preferably 0.005% - 0.5%) of an antibacterial agent, an appropriate amount of a pH regulator, and the balance being water;

[0040] Preferably, the gel composition comprises the following components:

[0041] 3% (or 9%) of EG017, 0.5% (or 0.2%, 1.0%) of a gel matrix, 5% of a humectant, 0.14% (or 0.20%, 0.18%, 0.09%, 0.02%) of an antibacterial agent, adjusting the pH value to about 5.0 - 6.5 with a pH regulator, and the balance being water;

[0042] Preferably, the gel matrix is a carbomer B-type homopolymer;

[0043] Preferably, the humectant is sorbitol;

[0044] Preferably, the bacteriostatic agent is selected from one, two or more of butylparaben, methylparaben, propylparaben;

[0045] Preferably, the pH regulator is triethanolamine;

[0046] Preferably, the pH value is adjusted to about 5.5.

[0047] According to an embodiment of the present invention, the gel composition comprises the following components:

[0048] 0.1%-20% (preferably 1%-10%, 3%-9%) of EG017, 0.05%-5% (preferably 0.01%-4%) of gel matrix, 1%-10% of humectant, 0%-4% (preferably 0.5%-3%) of suspending agent, appropriate amount of pH regulator, and the balance is water;

[0049] Preferably, the gel composition comprises the following components:

[0050] 3% (or 9%) of EG017, 0.5% of gel matrix, 5% of humectant, 1% (or 2%) of suspending agent, adjust the pH value to about 5.0 - 6.5 with pH regulator, and the balance is water;

[0051] Preferably, the gel matrix is carbomer B type homopolymer;

[0052] Preferably, the humectant is sorbitol;

[0053] Preferably, the suspending agent is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC);

[0054] Preferably, the pH regulator is triethanolamine;

[0055] Preferably, the pH value is adjusted to about 5.5.

[0056] According to an embodiment of the present invention, the gel composition comprises the following components:

[0057] 0.1%-20% (preferably 1%-10%, 3%-9%) of EG017, 0.05%-5% (preferably 0.01%-4%) of gel matrix, 1%-10% of humectant, 0-1% (preferably 0.005%-0.5%) of bacteriostatic agent, 0-1% of antioxidant, 0%-5% of transdermal enhancer, appropriate amount of pH regulator, and the balance is water;

[0058] Preferably, the gel composition comprises the following components:

[0059] 3% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, the pH value is adjusted to about 5.0 - 6.5 with a pH regulator, and the balance is water;

[0060] Preferably, the gel composition comprises the following components:

[0061] 3% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, 2% of transdermal enhancer, the pH value is adjusted to about 5.0 - 6.5 with a pH regulator, and the balance is water;

[0062] Preferably, the gel composition comprises the following components:

[0063] 9% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, the pH value is adjusted to about 5.0 - 6.5 with a pH regulator, and the balance is water;

[0064] Preferably, the gel matrix is selected from Carbomer B type homopolymers;

[0065] Preferably, the transdermal enhancer is selected from isopropyl myristate;

[0066] Preferably, the humectant is selected from sorbitol;

[0067] Preferably, the bacteriostat is selected from one or two of sorbic acid and butylparaben;

[0068] Preferably, the antioxidant is selected from butylated hydroxytoluene;

[0069] Preferably, the pH regulator is selected from triethanolamine;

[0070] Preferably, the pH value is adjusted to about 5.5.

[0071] According to the embodiments of the present invention, the viscosity of the gel composition at a shear rate of 1.02 (1 / S) is 1 Pa·s - 100 Pa·s, preferably 5 Pa·s - 100 Pa·s, such as 7 Pa·s, 10 Pa·s, 20 Pa·s, 30 Pa·s, 40 Pa·s, 50 Pa·s, 60 Pa·s, 65 Pa·s, 70 Pa·s, 75 Pa·s, 78 Pa·s, 80 Pa·s.

[0072] According to an embodiment of the present invention, the maximum particle size of the gel composition is less than 300 μm, preferably less than 250 μm or 200 μm or 180 μm or 150 μm or 120 μm, and more preferably less than 100 μm, such as 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm.

[0073] In this text, when referring to the percentage content (%) of a component, it means weight percentage (wt% or weight %). Those skilled in the art can understand that when formulating a composition or preparation, and / or expressing the composition of a composition or preparation, it is conventional to use weight percentage for components in different aggregation states.

[0074] The present invention also provides a method for preparing the above-mentioned EG017 gel composition, which is characterized in that the preparation method includes: mixing EG017 or its pharmaceutically acceptable salt, a gel matrix, and optionally added excipients to obtain the EG017 gel composition.

[0075] According to an embodiment of the present invention, the preparation method includes the following steps:

[0076] (1) Prepare a solution containing a humectant (and optionally added antioxidant);

[0077] (2) Swelling: Add the gel matrix to (1), stir and disperse evenly;

[0078] (3) Add EG017 (and optionally added bacteriostatic agent, optionally added transdermal enhancer) to the dispersion in (2), and homogenize (optionally, add an appropriate amount of pH regulator and mix).

[0079] According to an embodiment of the present invention, the preparation method optionally further includes the preparation process of a suspending agent solution. According to an embodiment of the present invention, the preparation method optionally further includes the following steps: Add EG017 to the suspending agent solution and perform homogenization treatment. According to an embodiment of the present invention, the preparation method optionally further includes: adding the solution containing the suspending agent and EG017 after homogenization treatment (and optionally added bacteriostatic agent, optionally added transdermal enhancer) to the dispersion in (2), and homogenize (optionally, add an appropriate amount of pH regulator and mix).

[0080] The present invention also provides the application of the above-mentioned EG017 gel composition in the preparation of a drug for treating androgenetic alopecia.

[0081] According to an embodiment of the present invention, the dosage range of the drug is 0.01 - 9 mg / cm 2 , preferably 0.1 - 0.9 mg / cm 2 , such as 0.05 mg / cm2 , 0.1 mg / cm 2 , 0.15 mg / cm 2 , 0.2 mg / cm 2 , 0.25 mg / cm 2 , 0.3 mg / cm 2 , 0.5 mg / cm 2 , 0.6 mg / cm 2 , 0.7 mg / cm 2 , 0.8 mg / cm 2 , 0.9 mg / cm 2 , 1.0 mg / cm 2 , 2.0 mg / cm 2 , 3.0 mg / cm 2 , 5.0 mg / cm 2 .

[0082] The present invention also provides a method for preventing and / or treating androgenetic alopecia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned EG017 gel composition.

[0083] Beneficial effects

[0084] The present invention provides an EG017 gel composition, which has a moderate viscosity, a high in vitro release rate and high stability, and can significantly improve the compliance and treatment effect of patients with androgenetic alopecia. The gel agent provided by the present invention has no heavy and sticky feeling and good freshness; it can stay at the application site for a long time, enhance drug absorption and improve drug utilization; it is convenient to carry and patients are more likely to adhere to the medication. Brief description of the drawings

[0085] Figure 1 : Schematic diagram of the rheometer viscosity results of EG017 gel compositions prepared with carbomers of different models and dosages and commercially available minoxidil gel.

[0086] Figure 2 : Schematic diagram of the results of in vitro release studies of EG017 gel compositions prepared with carbomers of different models and dosages.

[0087] Figure 3 : Schematic diagram of the results of in vitro release studies of EG017 gel compositions at different pH values.

[0088] Figure 4 : Schematic diagram of the results of in vitro transdermal studies of EG017 gel composition and control ointment and control solution.

[0089] Figure 5 : Schematic diagram of the scoring of the dorsal hair growth in the depilated area of androgenetic alopecia mice in different groups.

[0090] Figure 6 : Schematic diagram of the time required for the skin in the depilated area of androgenetic alopecia mice to change from pink to gray and from pink to black in different groups.

[0091] Figure 7 : Schematic diagram of the results of the effects of different groups on the hair weight and hair length of the dorsal hair in the depilated area of androgenetic alopecia mice.

[0092] Figure 8 : Schematic diagram of the expression of AR protein around the hair follicles in the skin of the depilated area of mice in different groups after 17 days of drug administration. Note: The arrow indicates the positive staining of androgen receptor (AR) around the hair follicles in the skin of the depilated area of mice (A: normal control group; B: model control group; C: EG017 ointment group; D: EG017 solution group; E: EG017 gel composition group (prescription 17); F: EG017 gel composition group (prescription 18); G: EG017 gel composition group (prescription 19).

[0093] Term definitions

[0094] As used herein, "treatment" includes alleviating, reducing or improving the symptoms of a disease or disorder, preventing additional symptoms, delaying or preventing the underlying metabolic causes of symptoms, inhibiting a disease or disorder, preventing the development of a disease or disorder, alleviating a disease or disorder, causing the regression of a disease or disorder, resolving the conditions caused by a disease or disorder, or stopping the symptoms of a disease or disorder, and is intended to include prevention.

[0095] As used herein, "effective amount" means any amount necessary or sufficient for achieving or facilitating a desired result. In some cases, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application may vary depending on factors such as the disease or disorder being treated, the specific agent being administered, the size of the subject, or the severity of the disease or disorder. Detailed implementation manners

[0096] For ease of understanding, the present application will be described more comprehensively below, and preferred embodiments of the present application will be given. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0097] Test method for viscosity: Use a rotational viscometer and test according to the method for determining viscosity (Method 3 of General Rule 0633 in Chinese Pharmacopoeia 2020).

[0098] Test method for in vitro release rate: Using a flow-through cell, it is determined according to the dissolution and release determination method (Method VI in General Chapter 0931 of Chinese Pharmacopoeia 2020).

[0099] Test method for stability: It is detected by high performance liquid chromatography. The content is detected with 0.01mol / L potassium dihydrogen phosphate aqueous solution - acetonitrile (35:65) as the mobile phase, and the related substances are detected with 0.01mol / L potassium dihydrogen phosphate aqueous solution - methanol as the mobile phase. The pH is detected using a multi-parameter analyzer.

[0100] Test method for maximum particle size: Take an appropriate amount of the test sample, place it on a glass slide, spread it into a thin layer, and the area of the thin layer is equivalent to the area of the cover glass. A total of 3 slides are coated and determined according to the particle size and particle size distribution determination method (Method I in General Chapter 0982 of Chinese Pharmacopoeia 2020).

[0101] Example 1 EG017 gel compositions prepared using different gel matrices

[0102] 1.1 Prepare EG017 gel compositions using carbomer matrices of different models and dosages, and investigate their effects on the viscosity and in vitro release of the gel compositions.

[0103] Table 1. Prescription ratios of gel compositions of Formulations 1 - 7

[0104]

[0105] The preparation method of the EG017 gel compositions of Formulations 1 - 7 in Table 1 includes the following steps:

[0106] (1) Preparation of dispersion: Weigh the humectant sorbitol into water and stir until evenly dispersed at room temperature;

[0107] (2) Swelling: Weigh the carbomer homopolymer into the dispersion solution, stir with a overhead magnetic stirrer until the carbomer is completely and evenly dispersed to form a blank gel matrix;

[0108] (3) Accurately weigh the prescribed amount of EG017 and the bacteriostatic agent butylparaben into another beaker, add the blank gel matrix; homogenize to fully suspend the API EG017 at the bottom of the bottle; add the pH regulator triethanolamine to adjust the pH to about 5.5, and continue to stir and mix.

[0109] Measure the viscosities of Formulations 1 - 7 at different shear rates. The results show that the viscosities of Formulations 1 and 2 containing carbomer A-type homopolymers are too low. The rheometer viscosity results of Formulations 3 - 7 with carbomer B-type and C-type are as Figure 1 , shown in Table 2.

[0110] Table 2. Viscosity characterization of gel compositions of Formulations 3 - 7

[0111]

[0112] Determine the in vitro release rates of Formulations 3 to 7 at each time point, as Figure 2 shown in Table 3. The release rates of Formulations 3, 4, and 6 at 16 h were all above 30%.

[0113] Table 3. In vitro release rates of the gel compositions of Formulations 3 to 7 at each time point

[0114]

[0115]

[0116] 1.2 Prepare the EG017 gel composition by using hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and Carbopol B homopolymer as the gel matrix respectively

[0117] Formulations 8 to 10 are shown in Table 4.

[0118] The preparation method of the EG017 gel composition of Formulations 8 to 10 includes the following steps:

[0119] (1) Preparation of the dispersion: Weigh the humectant sorbitol into water and stir until uniformly dispersed at room temperature;

[0120] (2) Swelling: Weigh the gel matrix (Carbopol B homopolymer, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose) into the dispersion solution, stir with a overhead magnetic stirrer until the gel matrix is completely and uniformly dispersed to form a blank gel matrix;

[0121] (3) Weigh accurately the prescribed amount of EG017 and other excipients except the pH regulator into another beaker, add the blank gel matrix; homogenize to fully suspend the API EG017 at the bottom of the bottle; add the pH regulator to adjust the pH to about 5.5 (there is no pH adjustment step for Formulations 9 - 10), and continue to stir and mix.

[0122] The results showed that the appearance of the EG017 gel composition of Formulation 8 was white, and its purity and content met the requirements. The content of Formulation 9 did not meet the requirements, and the EG017 of Formulation 10 underwent crystal transformation.

[0123] Table 4. Prescription ratios and characterizations of the gel compositions of Formulations 8 to 10

[0124]

[0125]

[0126] Example 2. EG017 gel compositions with different pH values

[0127] Adjust the dosage of the pH regulator to regulate the pH value of the EG017 gel composition. The prescription ratios of the gel compositions with different pH values are shown in Table 5. Specifically, the pH values of the gel compositions in Formulations 11 to 14 are approximately 5.5, 6.0, 6.5, and 7.0, respectively.

[0128] The preparation method of the EG017 gel compositions of Formulations 11 to 14 refers to Example 1.

[0129] Table 5. Ratios of the gel compositions of Formulations 11 to 14

[0130]

[0131] Determine the stability of the gel compositions of Formulations 11 to 14. The results are shown in Table 6. The amounts of related substances of the gel compositions of Formulations 11 - 14 placed at 40 °C for 1 M (1 month) are all within the controllable range.

[0132] Determine the viscosities of the gel compositions of Formulations 11 to 14. The results are shown in Table 7. The viscosities of the gel compositions of Formulations 11 to 13 measured using a rotational viscometer are all between 60 and 80 Pa·s (shear rate = 1.02 (1 / S)), and the viscosity of Formulation 14 exceeds the measurement range.

[0133] Determine the in vitro release rates of the gel compositions of Formulations 11 to 14 at each time point, as Figure 3 and shown in Table 8. The release rates of the gel compositions of Formulations 11, 12, and 13 are all above 29% at 16 h.

[0134] Table 6. Stability of the gel compositions of Formulations 11 to 14

[0135]

[0136]

[0137] Table 7 Viscosity characterization of the gel compositions of Formulations 11 to 14

[0138]

[0139] Table 8. In vitro release rate conditions of the gel compositions of Formulations 11 - 14 at each time point

[0140] Group Prescription 11 Prescription 12 Prescription 13 Prescription 14 pH 5.5 6.0 6.5 7.0 Release rate at 1h (%) 0.8 0.676 0.76 0.86 Release rate at 2h (%) 2.4 2.25 2.49 2.55 Release rate at 3h (%) 4.14 4.0 4.29 4.37 Release rate at 4h (%) 5.87 5.71 5.98 6.15 Release rate at 6h (%) 9.1 8.64 9.01 8.89 Release rate at 8h (%) 13.2 12.2 12.8 11.4 Release rate at 12h (%) 21.8 19.8 21.2 16.4 Release rate at 16h (%) 32.1 29.6 31.1 23.1

[0141] The EG017 gel composition prepared in Example 3 by dispersing API using different suspending agents

[0142] Using hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) as a suspending agent, the EG017 gel compositions of Formulations 15 to 16 were prepared, and the formulation ratios are shown in Table 9.

[0143] The preparation method of the EG017 gel compositions of Formulations 15 to 16 includes the following steps:

[0144] (1) Preparation of the suspending agent solution: First, weigh 20% of the volume of the suspending agent solution of purified water and preheat it to 80°C. While it is hot, add the suspending agent (HPC or HPMC) and suspend it, then add 80% of the normal-temperature purified water of the volume of the suspending agent solution, and stir at room temperature until completely dissolved;

[0145] (2) Preparation of the blank gel matrix: Weigh the humectant and an appropriate amount of purified water, and stir magnetically at room temperature until completely dissolved to obtain an aqueous solution of the humectant; Weigh the Carbomer B-type homopolymer, and slowly add it to the aqueous solution of the humectant under stirring at room temperature. After the addition is complete, continue to stir until completely dispersed and uniform to obtain a blank gel matrix containing the humectant;

[0146] (3) Preparation of the API dispersion: Weigh the prescribed amount of EG017 and add it to the suspending agent solution, and homogenize it in an ice bath for 5 - 10 minutes to avoid overheating;

[0147] (4) Preparation of the drug-loaded gel: Weigh the prescribed amount of the blank gel matrix containing the humectant, add it to the API dispersion, and stir at room temperature to fully suspend the API at the bottom of the bottle; Add a pH regulator to adjust the pH value to about 5.5, and continue to stir and mix.

[0148] Measure the maximum particle size of Formulations 15 to 16, and the results are shown in Table 10.

[0149] Table 9. Formulation ratios of the gel compositions of Formulations 15 to 16

[0150]

[0151] Table 10. Maximum particle size of the gel compositions of Formulations 15 to 16

[0152]

[0153] Example 4 In vitro transdermal and in vivo pharmacodynamic effects

[0154] The ratios of the gel compositions of Formulations 17 to 19 are shown in Table 11. Among them, the gel composition of Formulation 17 uses a transdermal penetration enhancer, and the proportion of EG017 in the gel composition of Formulation 19 is 9%. The EG017 ointment formulation (Table 12) and the EG017 solution formulation (Table 13) are both comparative preparations with a mass ratio of EG017 of 3%.

[0155] The preparation method of the EG017 gel composition of Prescriptions 17 - 19 comprises the following steps:

[0156] (1) Weigh the humectant sorbitol, bacteriostat 1 sorbic acid, bacteriostat 2 butylparaben, and antioxidant dibutylhydroxytoluene (BHT) according to the prescription ratios in Table 11 into an appropriate amount of water, and stir until evenly dispersed.

[0157] (2) Weigh Carbomer B type homopolymer according to the prescription ratio into the above solution, stir for 30 min (800 rpm) until the Carbomer is completely dispersed and swollen to form a blank gel matrix.

[0158] (3) Precisely weigh the prescribed amount of EG017 into another beaker, add the blank gel matrix and optionally added transdermal enhancer isopropyl myristate; homogenize to fully suspend the API at the bottom of the bottle; add triethanolamine to adjust the pH to about 5.5, and continue to stir and mix to obtain the product.

[0159] The preparation method of Comparative Preparation 1 (EG017 ointment):

[0160] (1) Melt the excipient matrix white petrolatum, light liquid paraffin, wool fat, and butylparaben in the prescribed amounts, stir well and then cool down.

[0161] (2) Precisely weigh EG017 and add it to the matrix, homogenize and then cool to room temperature to obtain the product.

[0162] The preparation method of Comparative Preparation 2 (EG017 solution):

[0163] Precisely weigh the prescribed amount of EG017 raw material into a Schott bottle, add the prescribed amount of ethyl acetate, shake to dissolve, and then add medium-chain triglyceride, isopropyl myristate, and butylparaben in sequence, and stir well.

[0164] Table 11. Prescription ratios of the gel composition of Prescriptions 17 - 19

[0165]

[0166] In vitro transdermal test:

[0167] The method of alternately administering each preparation on a continuous diffusion cell was adopted to control the consistency of experimental conditions between groups and ensure the balance of the influence of experimental factors on the results. Four groups with a mass ratio of EG017 of 3% were set up respectively: Comparative Preparation 1 - EG017 ointment (prescription shown in Table 12), Comparative Preparation 2 - EG017 solution (prescription shown in Table 13), the gel composition of Prescription 17, and the gel composition of Prescription 18, with 6 cups in each group. After terminating the experiment at 24 h, the skin was taken out, the residual drug on the skin surface was washed, and the residual solvent on the skin surface was blotted dry with filter paper. The skin around the periphery that did not directly contact the preparation was cut off with scissors, and only the skin with an area equivalent to the cell mouth was retained. The treated skin was weighed and stored sealed in an EP tube. The skin was cut into pieces and placed in a cryogenic grinding cup. The cryogenic grinding cup was placed in liquid nitrogen and frozen for at least 1 h. After taking it out, it was ground into powder in a cryogenic grinder, extracted with an extraction solution, and ultrasonicated. The LC-MS / MS method was used to measure the EG017 content in the skin extract.

[0168] Table 12. Prescription of Comparative Preparation 1 - EG017 Ointment

[0169] Ingredient Percentage in prescription (%) EG017 3.00 White petrolatum 90.00 Light liquid paraffin 5.94 Lanolin 1.00 Butylparaben 0.06 Total 100.00

[0170] Table 13. Prescription of Comparative Preparation 2 - EG017 Solution

[0171] Ingredient Percentage in prescription (%) EG017 3.00 Ethyl acetate 30.00 Medium-chain triglyceride 50.00 Isopropyl myristate 16.98 Butylparaben 0.02 Total 100.00

[0172] Table 14. Results of Skin Retention per Unit Mass of the Gel Compositions of Prescriptions 17 - 18 and Comparative Preparations

[0173] Prescription Skin retention per unit mass (μg / g) Prescription 17 31.04 Prescription 18 15.23 Reference preparation 1 - Ointment 19.12 Reference preparation 2 - Solution 18.56

[0174] The results are as Figure 4 shown in Table 14. According to the analysis of the results of skin retention per unit mass, the trend of EG017 retention amount is Gel Composition of Example 17 > EG017 Ointment > EG017 Solution > Gel Composition of Example 18.

[0175] In vivo Pharmacodynamic Experiment:

[0176] Fifty-six male C57BL / 6J mice were selected, and intraperitoneal injection of testosterone propionate was used to establish a pharmacodynamic model of androgenetic alopecia in the model control group and the test article administration group. The mice were randomly divided into 7 groups, with 8 mice in each group, namely the blank control group, the model control group (6 animals were actually used for the experiment), and the test article administration groups (comparative preparation 1 - EG017 ointment group, comparative preparation 2 - EG017 solution group, EG017 gel composition prescriptions 17 - 19). Before administration, their backs were shaved and then depilated. The blank control group and the model control group were smeared with the blank matrix, and the test article administration groups were smeared with EG017 ointment, EG017 solution, and EG017 gel composition of prescriptions 17 - 19 respectively. The drug was administered once a day for 17 consecutive days. The skin discoloration time and hair growth time were observed and recorded once a day, and the hair growth status in the depilated area was scored. On the 17th day, the hair length and weight of the mice were measured.

[0177] The experimental results of the effects of different groups on the dorsal hair growth in the depilated area of androgenetic alopecia mice showed ( Figures 5 - 6 ), compared with the normal control group, on the 8th, 11th, and 15th days of administration, the dorsal hair scores of the mice in the model control group were significantly reduced, and the time required for the skin to change from pink to gray and from pink to black was significantly prolonged, indicating that the dorsal hair growth of the mice was significantly slowed down. For the EG017 gel compositions of prescriptions 17 and 19, the time required for the skin in the depilated area to change from pink to black after depilation of the mice was significantly shortened (P≤0.05, P≤0.01).

[0178] The experimental results of the effects of different groups on the dorsal hair weight and hair length in the depilated area of androgenetic alopecia mice showed ( Figure 7 , Table 15), compared with the model control group, in the EG017 gel composition groups of prescriptions 17 - 19, the dorsal hair weight of the mice in the depilated area was significantly increased (P≤0.01), and the hair length was significantly increased (P≤0.01).

[0179] Table 15. Effects of different dosage forms of EG017 on dorsal hair weight and hair length in the depilated area of androgenetic alopecia mice induced by testosterone propionate (Mean±SEM, n)

[0180]

[0181] Note: Compared with the normal control group, ## P≤0.01; compared with the model control group, * P≤0.05, ** P≤0.01; n = animal number

[0182] The test results of the effects of different groups on the hair follicle growth cycle of the hair follicle tissue in the depilated area of androgenetic alopecia mice are shown (Table 16). After 17 days of administration, no obvious abnormalities were observed in the epidermis and dermal hair follicles of the skin in the normal control group, and the hair follicles were all in the growth phase (late stage). Compared with the normal control group, the hair bulbs and hair roots of the hair follicles in the skin of the model control group and each administration group were reduced, the melanin was reduced, and the hair follicles were all in the telogen phase, growth phase (early stage) or growth phase (late stage). Compared with the model control group, the hair follicles in the skin of each administration group were in the growth phase (early stage) or growth phase (late stage), and the degree of skin lesions showed a slight tendency to decrease. At the same time, it was shown that the interval from the telogen phase to the growth phase in the administration group became shorter, and the EG017 gel compositions of Prescription 17 and Prescription 19 had better effects.

[0183] Table 16. Effects of different groups on the hair follicle growth cycle of the hair follicle tissue in the depilated area of androgenetic alopecia mice

[0184]

[0185] Note: — No lesion; ± Slight lesion; + Mild lesion; ++ Moderate lesion; +++ Severe lesion

[0186] The test results of the effects of different groups on the expression level of androgen receptor in the skin hair follicles of the depilated area of androgenetic alopecia mice are shown ( Figure 8 ). Compared with the normal control group, the positive staining intensity in the skin of the depilated area of the model control group mice was significantly enhanced, and the AR expression around the hair follicles was significantly increased (P≤0.01). Compared with the model control group, the positive staining intensity in the skin of the depilated area of the EG017 ointment and EG017 gel composition groups of Prescription 17-19 mice was significantly weakened, and the protein expression around the hair follicles was significantly reduced. Among them, the effects of Prescription 17 and Prescription 19 were better.

[0187] In the androgenetic alopecia mouse model, each dosage form of EG017 can accelerate the hair follicles to enter the growth phase from the telogen phase, increase the hair length and hair weight, and improve the lesions of the hair follicles and hair roots, showing an obvious therapeutic effect on androgenetic alopecia. Compared with other dosage forms, the EG017 gel composition has a better effect.

[0188] The above has given an exemplary description of the implementation manner of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manner. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. An EG017 gel composition, which comprises EG017 as an active substance and a gel matrix; Among them, The structural formula of EG017 is shown as follows: Preferably, the content of EG017 is 0.1%-20%, preferably 1%-10%.

2. The gel composition according to claim 1, wherein The gel matrix is selected from one, two or more of carbomer, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; preferably, the gel matrix is selected from one, two or more of carbomer type A homopolymer, carbomer type B homopolymer, carbomer type C homopolymer; preferably, the content of the gel matrix is 0.01%-5%, preferably 0.05%-4%; Preferably, the gel composition optionally further comprises a humectant; preferably, the humectant is selected from one, two or more of glycerol, sorbitol, liquid paraffin; preferably, the content of the humectant is 1%-10%.

3. The gel composition according to claim 1 or 2, characterized in that, The gel composition optionally further comprises an antibacterial agent; Preferably, the antibacterial agent is selected from one, two or more of benzalkonium chloride, methyl paraben (methyl hydroxybenzoate), ethyl paraben (ethyl hydroxybenzoate), propyl paraben (propyl hydroxybenzoate), butyl paraben (butyl hydroxybenzoate), benzyl alcohol, chlorobutanol, sorbic acid; preferably, the content of the antibacterial agent is 0%-1%, preferably 0.005%-0.5%; Preferably, the antibacterial agent comprises methyl paraben and / or propyl paraben; preferably, the content of methyl paraben is 0.02%-0.20%; preferably, the content of propyl paraben is 0.005%-0.05%; Preferably, the antibacterial agent comprises sorbic acid and / or butyl paraben; preferably, the content of sorbic acid is 0.05%-0.20%; preferably, the content of butyl paraben is 0.05%-0.20%.

4. The gel composition according to any one of claims 1-3, characterized in that The gel composition optionally further comprises an antioxidant; preferably, the antioxidant is selected from one, two or more of dibutylhydroxytoluene, sodium metabisulfite, sodium sulfite, cysteine, L-ascorbic acid or disodium ethylenediaminetetraacetate; preferably, the content of the antioxidant is 0%-1%; Preferably, the gel composition optionally further comprises a pH regulator; preferably, the pH regulator is selected from one, two or more of organic bases or inorganic bases; preferably, selected from one, two or more of triethanolamine, sodium hydroxide, sodium citrate; preferably, the pH of the gel composition is less than 7.0, preferably 5.0-6.8; Preferably, the gel composition optionally further comprises a suspending agent; preferably, the suspending agent is selected from one, two or more of hydroxypropyl cellulose (HPC), methylcellulose, hydroxypropyl methylcellulose (HPMC), gum arabic, tragacanth, sodium alginate; preferably, the content of the suspending agent is 0%-4%, preferably 0.5%-3%; Preferably, the gel composition optionally further comprises a transdermal absorption enhancer; preferably, the transdermal absorption enhancer is selected from one, two or more of isopropyl myristate, isooctyl salicylate, laurocapram, and myristic acid; preferably, the content of the transdermal absorption enhancer is 0% to 5%; Preferably, the gel composition optionally further comprises a solvent; preferably, the solvent is selected from water.

5. The gel composition according to any one of claims 1-4, characterized in that, The gel composition comprises the following components: 0.1% - 20% (preferably 1% - 10%, 3% - 9%) of EG017, 0.05% - 5% (preferably 0.01% - 4%) of a gel matrix, 1% - 10% of a humectant, 0 - 1% (preferably 0.005% - 0.5%) of an antibacterial agent, an appropriate amount of a pH regulator, and the balance being water; Preferably, the gel composition comprises the following components: 3% (or 9%) of EG017, 0.5% (or 0.2%, 1.0%) of a gel matrix, 5% of a humectant, 0.14% (or 0.20%, 0.18%, 0.09%, 0.02%) of an antibacterial agent, and the pH value is adjusted to about 5.0 - 6.5 with a pH regulator, and the balance is water; Preferably, the gel matrix is a carbomer B-type homopolymer; Preferably, the humectant is sorbitol; Preferably, the antibacterial agent is selected from one, two or more of butylparaben, methylparaben, and propylparaben; Preferably, the pH regulator is triethanolamine; Preferably, the pH value is adjusted to about 5.

5.

6. The gel composition according to any one of claims 1-4, characterized in that, The gel composition comprises the following components: 0.1% - 20% (preferably 1% - 10%, 3% - 9%) of EG017, 0.05% - 5% (preferably 0.01% - 4%) of a gel matrix, 1% - 10% of a humectant, 0% - 4% (preferably 0.5% - 3%) of a suspending agent, an appropriate amount of a pH regulator, and the balance is water; Preferably, the gel composition comprises the following components: 3% (or 9%) of EG017, 0.5% of a gel matrix, 5% of a humectant, 1% (or 2%) of a suspending agent, and the pH value is adjusted to about 5.0 - 6.5 with a pH regulator, and the balance is water; Preferably, the gel matrix is a carbomer B-type homopolymer; Preferably, the humectant is sorbitol; Preferably, the suspending agent is selected from hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC); Preferably, the pH regulator is triethanolamine; Preferably, the pH value is adjusted to about 5.

5.

7. The gel composition according to any one of claims 1-4, characterized in that, The gel composition comprises the following components: 0.1% - 20% (preferably 1% - 10%, 3% - 9%) of EG017, 0.05% - 5% (preferably 0.01% - 4%) of a gel matrix, 1% - 10% of a humectant, 0 - 1% (preferably 0.005% - 0.5%) of an antibacterial agent, 0 - 1% of an antioxidant, 0% - 5% of a transdermal enhancer, an appropriate amount of a pH regulator, and the balance is water; Preferably, the gel composition comprises the following components: 3% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, adjusting the pH value to about 5.0 - 6.5 with a pH regulator, and the balance being water; Preferably, the gel composition comprises the following components: 3% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, 2% of transdermal enhancer, adjusting the pH value to about 5.0 - 6.5 with a pH regulator, and the balance being water; Preferably, the gel composition comprises the following components: 9% of EG017, 0.5% of gel matrix, 5% of humectant, 0.18% (or 0.20%, 0.14%, 0.09%, 0.02%) of bacteriostat, 0.05% of antioxidant, adjusting the pH value to about 5.0 - 6.5 with a pH regulator, and the balance being water; Preferably, the gel matrix is selected from carbomer B-type homopolymers; Preferably, the transdermal enhancer is selected from isopropyl myristate; Preferably, the humectant is selected from sorbitol; Preferably, the bacteriostat is selected from one or two of sorbic acid and butylparaben; Preferably, the antioxidant is selected from dibutylhydroxytoluene; Preferably, the pH regulator is selected from triethanolamine; Preferably, the pH value is adjusted to about 5.

5.

8. A method for preparing the EG017 gel composition according to any one of claims 1-7, characterized in that, Comprising the following steps: (1) Prepare a solution containing a humectant and optionally added antioxidant; (2) Swelling: Add the gel matrix to (1), stir and disperse evenly; (3) Add EG017 and optionally added bacteriostat and optionally added transdermal enhancer to the dispersion in (2) and homogenize.

9. Use of the EG017 gel composition according to any one of claims 1 - 7 in the preparation of a medicament for treating androgenetic alopecia; Preferably, the dosage range of the drug is 0.01 - 9 mg / cm 2 .

10. A method for preventing and / or treating androgenetic alopecia, the method comprising administering to a subject in need a therapeutically effective amount of the EG017 gel composition according to any one of claims 1 - 7.

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