Upatinib cream and preparation method thereof

Abstract

The invention discloses an upatinib emulsifiable paste and a preparation method thereof, the emulsifiable paste is directly smeared on an affected part, administration and use are convenient, diseases are rapidly relieved, the number of treatment times is reduced, the influence of a gastrointestinal tract absorption way on a medicine is reduced, toxic and side effects of gastrointestinal tract administration are reduced, the upatinib emulsifiable paste fills the market blank, administration of a patient is facilitated, and the curative effect of the upatinib emulsifiable paste is improved. And the market prospect is wide.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to an utpatinib cream, and also to a method for preparing the cream. Background Technology

[0002] Upadacitinib is a second-generation JAK inhibitor that selectively inhibits the JAK1 target. JAKs are intracellular enzymes that transmit signals generated by the interaction of cytokines or growth factor receptors on the cell membrane, thereby affecting cellular processes of hematopoiesis and immune cell function. The main difference between different generations of JAK inhibitors lies in the degree of selectivity for signaling pathways in the body. First-generation JAK inhibitors comprehensively inhibit the JAK family, targeting multiple JAK subtypes, and can treat a wider range of diseases. However, due to their poor target selectivity, they can affect normal sites in addition to their effects on diseases, leading to various side effects, including cardiovascular, tumor, thrombotic, and death risks. The US FDA has issued black box warnings for all first-generation JAK inhibitors. Second-generation JAK inhibitors selectively inhibit members of the JAK family, reducing the toxic side effects of JAK inhibitors.

[0003] Upadacitinib, an effective JAK1 inhibitor, has shown good efficacy in clinical trials for the treatment of various autoimmune and inflammatory diseases. It has been approved for seven indications: atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, spondyloarthritis (radiographically negative axial spondyloarthritis), moderate to severe active ulcerative colitis, and moderate to severe active Crohn's disease, making it suitable for a wide range of patients.

[0004] The original formulation of utpatinib marketed in China is utpatinib extended-release tablets manufactured by AbbVie Deutschland GmbH & Co KG, available in 15mg, 30mg, and 45mg strengths. Chinese patent CN119385940A mentions that utpatinib extended-release tablets have a large first-pass effect, thus limiting bioavailability. Its solubility in different buffer media is pH-dependent; as pH increases, the solubility of utpatinib decreases significantly. Therefore, the dissolution of utpatinib varies considerably under different pH conditions. Based on these reasons, utpatinib may have low bioavailability due to intestinal precipitation or poor dissolution.

[0005] Currently, there are no studies on topical formulations of utpatinib. Topical formulations can act directly on the affected area, reducing the impact of gastrointestinal absorption on the drug and minimizing toxic side effects from gastrointestinal administration. Furthermore, skin administration is convenient. This provides better treatment options for patients with psoriasis and arthritis. Summary of the Invention

[0006] In view of this, one objective of the present invention is to provide an utpatinib cream; another objective of the present invention is to provide a method for preparing the utpatinib cream.

[0007] To achieve the above objectives, the present invention provides the following technical solution: An utpatinib cream, by mass fraction, comprises the following components: utpatinib 0.5%~2%, emulsifier 1%~10%, preservative 0.1%~2%, stabilizer 0.05%~5%, oil component 5%~30%, moisturizer 5%~15%, transdermal penetration enhancer 2%~10%, and solvent 35%~70%.

[0008] Preferably, the emulsifier is selected from one or more of glyceryl stearate, polysorbate 20, stearic acid, sodium lauryl sulfate, polyethylene glycol fatty acid ester, and sodium oleate; the preservative is selected from one or more of methylparaben, propylparaben, and phenoxyethanol; the stabilizer is selected from one or more of xanthan gum, α-cyclodextrin, sodium carboxymethyl cellulose, guar gum, and carbomer; the oil is selected from one or more of volatile oil, stearyl alcohol, cetyl alcohol, mineral oil, cocoa butter, beeswax, and dimethylsiloxane; the humectant is selected from one or more of propylene glycol, glycerin, and hyaluronic acid; the transdermal penetration enhancer is selected from one or more of dimethyl sulfoxide, menthol, eucalyptus oil, limonene, and laurocapram; and the solvent is selected from water or propylene glycol.

[0009] Preferably, the present invention comprises, by mass fraction, the following components: 2% utpatinib, 15% propylene glycol, 20% polysorbate, 10% glycerin, 6% petrolatum, 10% mineral oil, 5% cetyl alcohol, 0.1% methylparaben, 0.1% propylparaben, 2% phenoxyethanol, 1.5% xanthan gum, 2% laurocapram, 3% menthol, and 38.3% water.

[0010] Preferably, the present invention comprises, by mass fraction, the following components: 2% utpatinib, 15% propylene glycol, 20% polysorbate, 2% glyceryl stearate, 10% glycerin, 5% petrolatum, 8% mineral oil, 5% cetyl alcohol, 0.4% methylparaben, 0.2% propylparaben, 2% phenoxyethanol, 1.2% xanthan gum, 2% laurocapram, 5% menthol, and 37.2% water.

[0011] The preparation method of the utpatinib cream includes the following steps: (1) The petrolatum, mineral oil, cetyl alcohol, polysorbate 20 and glyceryl stearate were heated to 75°C and melted, and stirred evenly to obtain system ①; (2) Glycerin, methylparaben, propylparaben, phenoxyethanol and xanthan gum were heated to 75°C and dissolved in pure water, and stirred evenly to obtain system ②; Upatinib was dissolved in propylene glycol to form a solution; At 75°C, add system ② to system ①, start stirring at 400 rpm for 30 min, then add utpatinib solution from (3), laurocapram, and menthol, stir at 5500 r / min for 20 min, and cool to below 25°C to obtain the final product.

[0012] The beneficial effects of this invention are as follows: This invention provides an utpatinib cream, which is convenient to use by applying the cream directly to the affected area, quickly relieving symptoms, reducing the number of visits to the doctor, and reducing the impact of gastrointestinal absorption on the drug, thus reducing the toxic side effects of gastrointestinal administration. Upatinib cream fills a market gap, facilitates medication for patients, and has broad market prospects. Attached Figure Description

[0013] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration: Figure 1 The cumulative transdermal permeation of utpatinib in Examples 1-4; Figure 2 The amount retained intradermally in Examples 1-4. Detailed Implementation

[0014] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0015] Example 1 An utpatinib cream comprises the following substances in weight percentage: effect Components Percentage of total (% w / w) active ingredients Upadacitinib 1 solvent Propylene glycol 10 emulsifier Polysorbate 20 3 Moisturizer glycerin 5 Oil component Vaseline 6 Stearyl alcohol 5 preservative Methylparaben 0.1 propylparaben 0.1 stabilizer Xanthan Gum 1.5 Transdermal penetration enhancer Lauryl diazepine 2 solvent Purified water 66.3 The preparation method is as follows: Petrolatum, stearyl alcohol and polysorbate 20 were heated to 73°C and melted, and stirred evenly to obtain system ①; Glycerin, methylparaben, propylparaben, and xanthan gum were heated to 75°C and dissolved in pure water, and stirred until homogeneous to obtain system ②; Upatinib was dissolved in propylene glycol to form a solution; At 73°C, system ② is added to system ①, and stirring is started at 300 rpm for 30 min. Then, utpatinib solution and laurocapram from (3) are added, and shear stirring is started at 5000 r / min for 10 min. The mixture is then cooled to below 25°C to obtain the final product.

[0016] Example 2 An utpatinib cream comprises the following substances in weight percentage: effect Components Percentage of total (% w / w) active ingredients Upadacitinib 2 solvent Propylene glycol 15 emulsifier Polysorbate 20 5 Moisturizer glycerin 10 Oil component Vaseline 6 mineral oil 10 cetyl alcohol 5 preservative Methylparaben 0.1 propylparaben 0.1 Phenoxyethanol 2 stabilizer Xanthan Gum 1.5 Transdermal penetration enhancer Lauryl diazepine 2 Menthol 3 solvent Purified water 38.3 The preparation method is as follows: (1) The petrolatum, mineral oil, cetyl alcohol and polysorbate 20 were heated to 75°C and melted, and stirred evenly to obtain system ①; (2) Glycerin, methylparaben, propylparaben, phenoxyethanol and xanthan gum were heated to 75°C and dissolved in pure water, and stirred evenly to obtain system ②; (3) Dissolve utpatinib in propylene glycol to form a solution; (4) At 75°C, add system ② to system ①, start stirring at 400 rpm for 30 min, then add utpatinib solution, laurocapram, and menthol from (3), start shear stirring (6000 r / min), shear for 15 min, and cool to below 25°C to obtain the final product.

[0017] Example 3 An utpatinib cream comprises the following substances in weight percentage: effect Components Percentage of total (% w / w) active ingredients Upadacitinib 1.5 solvent Propylene glycol 12 emulsifier Polysorbate 20 5 Glyceryl stearate 2 Moisturizer glycerin 8 Oil component Vaseline 6 mineral oil 10 cetyl alcohol 5 preservative Methylparaben 0.4 propylparaben 0.2 Phenoxyethanol 2 stabilizer Xanthan Gum 1.5 Transdermal penetration enhancer Lauryl diazepine 2 Menthol 3 solvent Purified water 41.4 The preparation method is as follows: (1) The petrolatum, mineral oil, cetyl alcohol, polysorbate 20 and glyceryl stearate were heated to 70°C and melted, and stirred evenly to obtain system ①; (2) Glycerin, methylparaben, propylparaben, phenoxyethanol and xanthan gum were heated to 75°C and dissolved in pure water, and stirred evenly to obtain system ②; (3) Dissolve utpatinib in propylene glycol to form a solution; (4) At 7°C, add system ② to system ①, start stirring at 350 rpm for 30 min, then add utpatinib solution, laurocapram, and menthol from (3), start shear stirring (6000 r / min), shear for 20 min, and cool to below 25°C to obtain the final product.

[0018] Example 4 An utpatinib cream comprises the following substances in weight percentage: effect composition Percentage of total (% w / w) active ingredients Upadacitinib 2 solvent Propylene glycol 15 emulsifier Polysorbate 20 5 Glyceryl stearate 2 Moisturizer glycerin 10 Oil Vaseline 5 mineral oil 8 cetyl alcohol 5 preservative Methylparaben 0.4 propylparaben 0.2 Phenoxyethanol 2 stabilizer Xanthan Gum 1.2 Transdermal penetration enhancer Lauryl diazepine 2 Menthol 5 solvent Purified water 37.2 The preparation method is as follows: (1) The petrolatum, mineral oil, cetyl alcohol, polysorbate 20 and glyceryl stearate were heated to 75°C and melted, and stirred evenly to obtain system ①; (2) Glycerin, methylparaben, propylparaben, phenoxyethanol and xanthan gum were heated to 75°C and dissolved in pure water, and stirred evenly to obtain system ②; (3) Dissolve utpatinib in propylene glycol to form a solution; (4) At 75°C, add system ② to system ①, start stirring at 400 rpm for 30 min, then add utpatinib solution from (3), laurocapram and menthol, start shear stirring (5500 r / min), shear for 20 min, and cool to below 25°C to obtain the final product.

[0019] Example 5 The performance of utpatinib cream was tested in Examples 1-4: (1) High temperature stability test The prepared utpatinib cream was placed at 60°C, and samples were taken on days 0, 5, 10, and 30 for high-performance liquid chromatography (HPLC) to detect the utpatinib content and related impurities. Changes in the appearance and viscosity of the cream were recorded, and the stability of the prepared formulation was tested, as shown in Tables 1-4. The results showed that after 30 days at 60°C, the total impurities in Examples 1-4 were all <0.75%. Example 1, with its higher water content, changed from a smooth white paste to a white emulsion after 30 days at 60°C. Examples 2-4 remained smooth white pastes, indicating good cream stability.

[0020] Table 1. Stability results of Example 1 Test items 0d 60℃-5d 60℃-10d 60℃-30d Impurities 2 (%) 0.05 0.09 0.12 0.23 Impurities 3 (%) 0.01 0.06 0.08 0.21 Impurities 5% 0.03 0.07 0.10 0.25 Impurities 6% Not detected Not detected Not detected Not detected Total miscellaneous items (%) 0.09 0.22 0.30 0.69 Upatinib content (%) 100.5 99.2 98.3 96.7 Appearance Smooth white paste White emulsion White emulsion White emulsion Viscosity (cps) 33000 20000 15000 12000 Table 2. Stability results of Example 2 Test items 0d 60℃-5d 60℃-10d 60℃-30d Impurities 2 (%) 0.04 0.08 0.11 0.18 Impurities 3 (%) 0.02 0.14 0.22 0.26 Impurities 5% 0.05 0.10 0.16 0.20 Impurities 6% Not detected Not detected Not detected Not detected Total miscellaneous items (%) 0.11 0.32 0.49 0.64 Upatinib content (%) 101.9 101.4 100.1 98.9 Appearance Smooth white paste Smooth white paste Smooth white paste Smooth white paste Viscosity (cps) 67500 42100 40000 33100 Table 3. Stability results of Example 3 Test items 0d 60℃-5d 60℃-10d 60℃-30d Impurities 2 (%) 0.05 0.09 0.16 0.18 Impurities 3 (%) 0.03 0.08 0.14 0.27 Impurities 5% 0.01 0.05 0.08 0.10 Impurities 6% Not detected Not detected Not detected Not detected Total miscellaneous items (%) 0.09 0.22 0.38 0.55 Upatinib content (%) 99.9 100.1 99.2 98.6 Appearance Smooth white paste Smooth white paste Smooth white paste Smooth white paste Viscosity (cps) 62500 40200 35000 33100 Table 4. Stability results of Example 4 Test items 0d 60℃-5d 60℃-10d 60℃-30d Impurities 2 (%) 0.02 0.04 0.09 0.19 Impurities 3 (%) 0.01 0.03 0.08 0.10 Impurities 5% 0.03 0.07 0.10 0.13 Impurities 6% Not detected Not detected Not detected Not detected Total miscellaneous items (%) 0.06 0.14 0.27 0.42 Upatinib content (%) 101.8 100.6 99.9 99.6 Appearance Smooth white paste Smooth white paste Smooth white paste Smooth white paste Viscosity (cps) 69800 57700 53100 46800 (2) Low-temperature freeze-thaw stability study of utpatinib cream The creams prepared in Examples 1-4 were dispensed into vials and sealed. Each freeze-thaw test cycle was performed by first placing the cream at -20 to -10°C for 2 days, then placing it at 40°C for 2 days. Samples were taken for testing after 3 freeze-thaw cycles. The test results are shown in Table 5.

[0021] Table 5. Results of the freeze-thaw stability study of utpatinib cream name Example 1 Example 2 Example 3 Example 4 Upatinib content (%) 97.6 100.5 98.7 100.2 Appearance White emulsion Smooth white paste Smooth white paste Smooth white paste (3) In vitro transdermal test The formulations described in Examples 1-4 above were used in transdermal tests.

[0022] The TP-6 ​​intelligent transdermal testing instrument (effective area 1.13 cm²) was used. 2 (Receiver volume 15 ml). Piglet skin was cut to a suitable size and fixed between the supply and receiving pools, with the dermis facing the receiving pool and the stratum corneum facing the supply pool. 1 g of the preparation was added to the skin surface (supply pool), and the upper end of the supply pool connected to the atmosphere was sealed with plastic wrap. 15 ml of receiving medium was added to the receiving pool, and air bubbles under the skin were removed. The diffusion pool was placed in a thermostatic magnetic stirrer at 32±0.5°C and a stirring speed of 300 rpm / min. The receiving medium was 20% ethanol saline. At 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 30 h, 1 ml samples were taken from the receiving pool (with an equal volume of fresh receiving liquid added simultaneously). After filtration through a 0.45 μm microporous membrane, the samples were injected according to the established HPLC method to determine the utpatinib content. The cumulative permeation per unit area (Q) was calculated. n ).

[0023] Cumulative infiltration per unit area (Q) n )=(C n ×V0+ C i ×V i ) / A, where C n V represents the sample concentration at the nth sampling, V0 represents the total volume of the receiving liquid in the receiving cell, V represents the sampling volume, and A represents the effective surface area of ​​the diffuser.

[0024] After the transdermal test, the skin was washed three times with physiological saline to remove any residual utpatinib cream from the skin surface. The washed skin was then patted dry with filter paper. The skin was then cut into small pieces with scissors, and 5 ml of anhydrous ethanol was added. The mixture was then sonicated in a water bath for 30 minutes, centrifuged, and the supernatant was collected. This supernatant was used as the test solution for intradermal retention.

[0025] Compared with Examples 1-4, when laurocapram and menthol are used together as penetration enhancers, the transdermal penetration is higher. In Example 1, which uses 2% laurocapram alone as a penetration enhancer, the transdermal penetration effect is the worst.

[0026] The cumulative transdermal penetration results of utpatinib in Examples 1-4 are as follows: Figure 1 Intradermal retention amount such as Figure 2 .

[0027] According to Tables 1-5, Figure 1 and Figure 2 Experimental results showed that when 2% laurocapram and 5% menthol were used together as penetration enhancers, the cumulative transdermal penetration Q over 30 hours could exceed 1400 μg / cm³. 2In Example 1, the formulation with a solvent purity of 66.3% water had poor stability and easily changed from a cream to an emulsion when stored at high temperatures. The formulations in Examples 2-4 were all relatively stable.

[0028] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. An utpatinib cream, characterized in that, By mass fraction, it includes the following components: 0.5%~2% utpatinib, 1%~10% emulsifier, 0.1%~2% preservative, 0.05%~5% stabilizer, 5%~30% oil component, 5%~15% moisturizer, 2%~10% transdermal penetration enhancer, and 35%~70% solvent.

2. The utpatinib cream according to claim 1, characterized in that: The emulsifier is selected from one or more of glyceryl stearate, polysorbate 20, stearic acid, sodium lauryl sulfate, polyethylene glycol fatty acid ester, and sodium oleate; the preservative is selected from one or more of methylparaben, propylparaben, and phenoxyethanol; the stabilizer is selected from one or more of xanthan gum, α-cyclodextrin, sodium carboxymethyl cellulose, guar gum, and carbomer; the oil is selected from one or more of volatile oil, stearyl alcohol, cetyl alcohol, mineral oil, cocoa butter, beeswax, and dimethylsiloxane; the moisturizer is selected from one or more of propylene glycol, glycerin, and hyaluronic acid; the transdermal penetration enhancer is selected from one or more of dimethyl sulfoxide, menthol, eucalyptus oil, limonene, and laurocapram; and the solvent is selected from water or propylene glycol.

3. The utpatinib cream according to claim 1, characterized in that: By mass fraction, it comprises the following components: 2% utpatinib, 15% propylene glycol, 5% polysorbate, 10% glycerin, 6% petrolatum, 10% mineral oil, 5% cetyl alcohol, 0.1% methylparaben, 0.1% propylparaben, 2% phenoxyethanol, 1.5% xanthan gum, 2% laurocapram, 3% menthol, and 38.3% water.

4. The utpatinib cream according to claim 1, characterized in that, By mass fraction, it comprises the following components: 2% utpatinib, 15% propylene glycol, 20% polysorbate, 2% glyceryl stearate, 10% glycerin, 5% petrolatum, 8% mineral oil, 5% cetyl alcohol, 0.4% methylparaben, 0.2% propylparaben, 2% phenoxyethanol, 1.2% xanthan gum, 2% laurocapram, 5% menthol, and 37.2% water.

5. The method for preparing utpatinib cream according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) The petrolatum, mineral oil, cetyl alcohol, polysorbate 20 and glyceryl stearate were heated to 75°C and melted, and stirred evenly to obtain system ①; (2) Glycerin, methylparaben, propylparaben, phenoxyethanol and xanthan gum were heated to 75°C and dissolved in pure water, and stirred evenly to obtain system ②; Upatinib was dissolved in propylene glycol to form a solution; At 75°C, add system ② to system ①, start stirring at 400 rpm for 30 min, then add utpatinib solution from (3), laurocapram, and menthol, stir at 5500 r / min for 20 min, and cool to below 25°C to obtain the final product.

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