Upatinib gel plaster and preparation method thereof

Abstract

The invention discloses an upatinib gel plaster and a preparation method thereof, the gel plaster can improve the skin transmittance, absorptivity and stability of an upatinib gel composition through the combination of sorbitol and propylene glycol and the compounding of other components such as a penetration enhancer. The traditional Chinese medicine composition is used for treating psoriasis and arthritis, can be directly adhered to an affected part for administration, is convenient to use, reduces the influence of a gastrointestinal tract absorption way on the medicine, reduces toxic and side effects of gastrointestinal tract administration, is large in medicine loading capacity and long in acting time, and does not pollute clothes. The developed Upatinib gel plaster fills up the market blank, is convenient for patients to take, and has a wide market prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a gel patch of upadacitinib, and to a preparation method of the gel patch. BACKGROUND

[0002] Upadacitinib belongs to the second generation of JAK inhibitors and selectively inhibits the JAK1 target. JAK is an intracellular enzyme that transmits signals generated by the interaction of cytokine or growth factor receptors on the cell membrane, thereby affecting the cellular processes of hematopoiesis and immune cell function. The difference between JAK inhibitors of different generations mainly lies in the selectivity of the signal pathway in the body. The first generation of JAK inhibitors comprehensively inhibits the JAK family and targets multiple JAK subtypes, which can treat more types of diseases. However, due to the poor selectivity of the target, the target has an impact on normal sites in addition to the disease, resulting in various side effects, including cardiovascular, tumor, thrombosis, and the risk of death. The second generation of JAK inhibitors selectively inhibits members of the JAK family, reducing the toxic side effects of JAK inhibitors.

[0003] Upadacitinib, as an effective JAK1 inhibitor, has shown good efficacy in the treatment of various autoimmune diseases and inflammatory diseases in clinical trials. It has been approved for 7 indications, including atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, axial spondyloarthritis (radiographic negative axial spondyloarthritis), moderate to severe active ulcerative colitis, and moderate to severe active Crohn's disease, with a wide range of suitable populations.

[0004] The original research preparation of upadacitinib for domestic listing is upadacitinib sustained-release tablets produced by AbbVie Deutschland GmbH&Co KG, which are divided into three specifications of 15mg, 30mg and 45mg. In Chinese patent CN119385940A, it is mentioned that the first-pass effect of upadacitinib sustained-release tablets is large, thereby limiting the bioavailability, and the solubility in different buffer media is pH-dependent, and the solubility of upadacitinib decreases significantly with the increase of pH. Therefore, the dissolution of upadacitinib is greatly different under different pH environments. Based on the above reasons, upadacitinib may have low bioavailability due to precipitation or difficulty in dissolution in the intestinal tract.

[0005] There is no study on the upatin gel patch at present. Compared with cream, patch, traditional rubber ointment and black ointment, the gel patch has the following advantages: 1) convenient administration, suitable for patients with difficulty in oral administration or injection; 2) the drug is directly absorbed into the systemic circulation after transdermal absorption, avoiding the damage of the gastrointestinal tract to the drug and the first-pass effect of the liver; 3) long-acting and stable blood drug concentration, avoiding the phenomenon of high peak concentration and low concentration; 4) high drug loading, reducing the frequency of drug administration and avoiding clothing contamination; 5) improving the safety of drug treatment, and easily stopping drug administration immediately if side effects are found. SUMMARY

[0006] Therefore, one of the purposes of the present application is to provide an upatin gel patch, and the second purpose of the present application is to provide a preparation method of the upatin gel patch.

[0007] To achieve the above-mentioned purposes, the present application provides the following technical solutions:

[0008] 1. An upatin gel patch, the gel patch comprising a backing layer, a drug storage layer and a protective layer, the drug storage layer being located between the backing layer and the protective layer; the weight parts of each component of the drug storage layer are as follows:

[0009]

[0010] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0011]

[0012] Preferably, the polyol is one or more of sorbitol, xylitol, propylene glycol and butylene glycol; the gel matrix material is any one of sodium polyphenylacrylate, carbomer, polyvinyl alcohol, gelatin and gum arabic; the pH regulator is any one of citric acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid and malic acid; the penetration enhancer is one or a combination of at least two of menthol, eucalyptus oil, laurocapram and diethylene glycol monoethyl ether; the adhesive is any one or a combination of at least two of sodium carboxymethyl cellulose, povidone, methyl cellulose, polyacrylic acid and starch; the crosslinking agent is any one or a combination of at least two of aluminum chloride, aluminum hydroxide, aluminum hydroxymagnesium glycerophosphate and potassium aluminum sulfate; and the humectant is any one or a combination of at least two of glycerol, propylene glycol, polyethylene glycol and sodium hyaluronate.

[0013] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0014]

[0015] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0016]

[0017] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0018]

[0019]

[0020] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0021]

[0022] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0023]

[0024]

[0025] Preferably, the weight parts of each component of the drug storage layer are as follows:

[0026]

[0027] 2. The preparation method of the upatin gel patch, comprising the following steps:

[0028] (1) uniformly mixing upatin, polyol and penetration enhancer to obtain a phase A mixture;

[0029] (2) uniformly mixing gel base, pH regulator, adhesive, crosslinking agent, crosslinking regulator, humectant and solvent to obtain a phase B mixture;

[0030] (3) uniformly mixing the phase A mixture and the phase B mixture to obtain an upatin gel composition;

[0031] (4) coating the upatin gel composition obtained in step (3) on a backing layer by using a gel patch coater to form a drug storage layer; and then combining a protective layer, cutting to obtain an upatin gel patch.

[0032] The present application has the beneficial effects that the present application provides an upatin gel patch, the gel patch formula is reasonable, the combination of sorbitol and propylene glycol and the compounding of other components such as penetration enhancer can improve the skin permeability, absorption and stability of the upatin gel composition. It is used for treating psoriasis and arthritis, can be directly pasted on the affected part for convenient use, reduces the influence of gastrointestinal absorption on the drug, reduces the toxic and side effects of gastrointestinal administration, has large drug loading amount, long action time and does not pollute clothes. The developed upatin gel patch fills the market gap, facilitates patient medication and has a broad market prospect. DETAILED DESCRIPTION

[0033] The present application will be further described below in conjunction with specific examples, so that those skilled in the art can better understand the present application and implement it, but the examples are not as a limitation on the present application.

[0034] Example 1

[0035] An upatin gel patch, the difference between each embodiment is that the formula of the upatin gel patch is different, as shown in Table 1; wherein the amount of each component is "parts by mass".

[0036] Table 1, the formula of the upatin gel patch of different embodiments

[0037]

[0038] The preparation method of the upatin gel patch comprises the following steps:

[0039] (1) mixing upatin, polyol and penetration enhancer uniformly to obtain a phase A mixture;

[0040] (2) mixing gel base, pH adjuster, adhesive, crosslinking agent, crosslinking regulator, humectant and solvent uniformly to obtain a phase B mixture;

[0041] (3) mixing the phase A mixture and the phase B mixture uniformly to obtain an upatin gel composition;

[0042] (4) coating the upatin gel composition obtained in step (2) on the backing layer by using a gel patch coater to form a drug storage layer; and then compounding a protective layer, cutting to obtain an upatin gel patch.

[0043] Comparative example

[0044] In order to study the influence of different components on the upatin gel patch, sorbitol, propylene glycol, menthol and laurocapram are not added respectively, and the addition amount of other adjuvants is adjusted, and the comparative examples are set, as shown in Table 2.

[0045] Table 2, Comparative Examples of Different Component Addition Amounts

[0046]

[0047] The upatinib gel compositions, upatinib gel patches provided by Examples 1-6, Comparative Examples 1-6 were subjected to performance testing, according to the following specific methods:

[0048] (1) Stability test: impurity content before and after high-temperature storage

[0049] The upatinib gel patch to be tested was stored in a high-temperature environment at 50°C, and the total impurity content before storage (0 days) and after 30 days of storage was tested by high-performance liquid chromatography (HPLC). The chromatographic conditions were as follows: Waters XBridge Peptide BEH column (100 x 4.6 mm, 2.5 μm), mobile phase A was a buffer aqueous solution of formic acid and ammonium formate with pH = 4.0, the mass fraction of ammonium formate in mobile phase A was 0.2 wt%, mobile phase B was methanol, the column temperature was 40°C, the detection wavelength was 340 nm, the flow rate was 1.0 ml / min, and gradient elution was performed.

[0050] The gradient elution program was as follows: within 0-15 min, the volume fraction of mobile phase A gradually changed from 80% to 15%; within 15-18 min, the volume fraction of mobile phase A remained at 15%; within 18-25 min, the volume fraction of mobile phase A gradually changed from 15% to 80%.

[0051] (2) In vitro transdermal experiment

[0052] A TP-6 intelligent transdermal test instrument (effective area 1.13 cm 2 , receiving liquid volume 15 mL) was used. The pigskin was cut to the appropriate size and fixed between the supply pool and the receiving pool, with the dermis layer facing the receiving pool and the stratum corneum layer facing the supply pool. The upatinib gel patch to be tested was cut into a 1.1 cm 2 diameter disc using a mold and attached to the surface of the pigskin (supply pool). 15 ml of receiving medium was added to the receiving pool, and the air bubbles under the skin were exhausted. The diffusion pool was placed in a constant-temperature magnetic stirrer, with a temperature of 32 ± 0.5°C and a stirring speed of 300 rpm / min, and the receiving medium was 20% ethanol physiological saline. At 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h, 1 mL of sample was taken from the receiving pool (while adding an equal volume of fresh receiving liquid), filtered through a 0.45 μm microporous filter, and injected according to the established HPLC method to determine the upatinib content. The cumulative permeation amount per unit area (Q n ) was calculated.

[0053] Cumulative permeation amount per unit area wherein, C nCn is the concentration of the sample at the nth sampling, V0 is the total volume of the receiving liquid in the receiving pool, V is the sampling volume, and S is the effective surface area of the diffusion body.

[0054] The skin after the transdermal test was washed with normal saline three times to remove the residual upatinib on the surface of the skin, and the washed skin was dried with filter paper to remove water on the skin. The skin was cut into pieces with scissors, 5ml of anhydrous ethanol was added for water bath ultrasonic for 30min, centrifuged, and the supernatant was taken as the intradermal retention amount of the test sample solution (Table 3).

[0055] (3) Appearance stability

[0056] The upatinib gel patch to be tested was packaged and sealed with a paper aluminum bag, and placed at room temperature. After 30 days, the appearance of the patch (drug storage layer) was observed (Table 3).

[0057] (4) Test of gel patch excipients

[0058] According to the test method of the excipients in Chinese Pharmacopoeia 2020 Edition Volume IV General Chapter 0122 Patch, the following test method was used:

[0059] Take one piece of gel patch test sample, place it in a constant temperature and humidity chamber at 37℃ and 64% relative humidity for 30 minutes, take it out, and fix it on a flat steel plate with a clamp. The angle between the steel plate and the horizontal plane is 60°. Place for 24 hours. The paste surface should not show any signs of running (Table 4).

[0060] Table 3, in vitro transdermal test, intradermal retention amount and appearance test results

[0061]

[0062] Table 4, test results of gel patch excipients

[0063] Group Gel patch excipient test results Example 1 No oozing phenomenon on the paste surface Example 2 No oozing phenomenon on the paste surface Example 3 No oozing phenomenon on the paste surface Example 4 No oozing phenomenon on the paste surface Example 5 No oozing phenomenon on the paste surface Example 6 No oozing phenomenon on the paste surface Comparative Example 1 No oozing phenomenon on the paste surface Comparative Example 2 No oozing phenomenon on the paste surface Comparative Example 3 No oozing phenomenon on the paste surface Comparative Example 4 Oozing phenomenon on the paste surface Comparative Example 5 No oozing phenomenon on the paste surface Comparative Example 6 Oozing phenomenon on the paste surface

[0064] According to the data in the foregoing table, the combination of sorbitol and propylene glycol and the compounding of other components such as penetration enhancers in the upatinib gel composition provided by the application can improve the skin permeability, absorption and stability of the upatinib gel composition. The cumulative permeation amount of the upatinib gel patch provided in Examples 1-6 is 987-1536μg / cm 2 After 30 days of storage at 50℃, the total impurity content is 0.11-0.36%, and after 30 days of storage at room temperature, it still maintains an excellent white appearance and does not change to yellow, which improves the room temperature and high temperature storage performance and treatment effect of the upatinib gel patch.

[0065] The impurity increase was obvious and the 24h cumulative permeation rate was relatively low after 30 days of storage at 50°C in Comparative Example 1, Comparative Example 4 and Comparative Example 6, and the transdermal absorption and storage stability decreased. The 24h cumulative permeation amount increased with the increase of penetration enhancer in Comparative Example 4 and Example 5.

[0066] The above examples are only preferred examples for fully illustrating the present application, and the protection scope of the present application is not limited thereto. Any equivalent replacement or transformation made by the person skilled in the art on the basis of the present application is within the protection scope of the present application. The protection scope of the present application is subject to the claims.

Claims

1. An upadacitinib gel patch characterized in that: The gel patch comprises a backing layer, a drug storage layer and a protective layer, the drug storage layer is located between the backing layer and the protective layer; the weight parts of each component of the drug storage layer are as follows:

2. The upadacitinib gel patch of claim 1, wherein: The weight parts of each component of the drug storage layer are as follows:

3. The upadacitinib gel patch of claim 1 or 2, wherein: The polyol is one or several of sorbitol, xylitol, propylene glycol, butylene glycol; the gel matrix material is any one of sodium polyphenylacrylate, carbomer, polyvinyl alcohol, gelatin, acacia gum; the pH regulator is any one of citric acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, malic acid; the penetration enhancer is one or a combination of at least two of menthol, eucalyptus oil, laurocapram, diethylene glycol monoethyl ether; the adhesive is any one or a combination of at least two of sodium carboxymethyl cellulose, povidone, methyl cellulose, polyacrylic acid, starch; the crosslinking agent is any one or a combination of at least two of aluminum chloride, aluminum hydroxide, aluminum hydroxychloride, potassium aluminum sulfate; the humectant is any one or a combination of at least two of glycerol, propylene glycol, polyethylene glycol, sodium hyaluronate.

4. The gel patch of upadacitinib according to claim 1, characterized in that: The weight parts of each component of the drug storage layer are as follows:

5. The gel patch of upadacitinib according to claim 1, characterized in that: The weight parts of each component of the drug storage layer are as follows:

6. The upadacitinib gel patch of claim 1, wherein: The weight parts of each component of the drug storage layer are as follows:

7. The upadacitinib gel patch of claim 1, wherein: The weight parts of each component of the drug storage layer are as follows:

8. The upadacitinib gel patch of claim 1, wherein: The weight parts of each component of the drug storage layer are as follows:

9. The upadacitinib gel patch of claim 1, wherein: The weight parts of each component of the drug storage layer are as follows: The weight parts of each component of the drug storage layer are as follows:

10. A preparation method of the upatin gel patch according to any one of claims 1-9, characterized in that: (1) uniformly mixing upatin, a polyol and a penetration enhancer to obtain a phase A mixture; (2) uniformly mixing a gel matrix, a pH regulator, an adhesive, a crosslinking agent, a crosslinking regulator, a humectant and a solvent to obtain a phase B mixture; (3) uniformly mixing the phase A mixture and the phase B mixture to obtain an upatin gel composition; (4) coating the upatin gel composition obtained in step (3) on a backing layer by using a gel patch coater to form a drug storage layer; and then combining a protective layer, cutting to obtain an upatin gel patch.

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