Immunosuppressant transdermal patch and preparation method thereof
By developing a tacrolimus transdermal patch, the problem of low bioavailability of oral tacrolimus formulations has been solved, achieving efficient local absorption and convenient use, making it suitable for the prevention and treatment of graft rejection after liver or kidney transplantation.
Patent Information
- Application Number
- CN202511761373.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-27
- Publication Date
- 2026-01-16
AI Technical Summary
Existing oral tacrolimus formulations have low bioavailability, significant differences in absorption within the body, and are affected by food, leading to unstable treatment effects.
A transdermal patch containing tacrolimus was developed, using a polyester and ethylene-vinyl acetate copolymer film as the backing layer. The medicated patch is composed of tacrolimus, stabilizer, matrix and pressure-sensitive adhesive. It is prepared by coating and capping to form a transdermal patch with good adhesion and good permeability.
It achieves efficient local absorption of tacrolimus, is easy to use, reduces individual differences, avoids the influence of food, and has good therapeutic effects and safety.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, and more specifically to an immunosuppressant transdermal patch and its preparation method. Background Technology
[0002] Tacrolimus is a fermentation product isolated from Streptomyces spp., and its chemical structure belongs to the 23-membered macrolide antibiotic class. It is a potent novel immunosuppressant, belonging to the calcineurin inhibitor class. It exerts its immunosuppressive effect primarily by inhibiting the release of interleukin-2 (L-2), thus comprehensively suppressing the function of T lymphocytes; it is 100 times more potent than cyclosporine (CsA). In recent years, it has been marketed in 14 countries, including Japan and the United States, as a first-line drug for liver and kidney transplantation. Clinical trials have shown its good efficacy in heart, lung, intestinal, and bone marrow transplants. Tacrolimus also plays a positive role in the treatment of autoimmune diseases such as atopic dermatitis (AD), systemic lupus erythematosus (SLE), and autoimmune eye diseases.
[0003] Currently, the main marketed formulations of tacrolimus include oral formulations such as capsules and tablets (including extended-release formulations); injectable formulations for patients who cannot take oral medication (usually used for a short period immediately after transplantation); and topical ointments, typically at concentrations of 0.03% and 0.1%, for local skin treatment. The recommended starting dose for adults receiving oral tacrolimus post-transplantation is as follows: For liver transplant patients, the initial oral dose should be 0.1-0.2 mg / kg daily, divided into two doses, starting 6 hours post-transplantation. For kidney transplant patients, the initial oral dose should be 0.15-0.3 mg / kg daily, divided into two doses, starting within 24 hours post-transplantation. However, the biggest drawback of currently available oral formulations is their low bioavailability and significant differences in absorption within the body.
[0004] Tacrolimus is not completely absorbed in the gastrointestinal tract after oral administration, and the absorption varies considerably. Food (especially high-fat foods) significantly reduces the rate and extent of absorption. In some patients, absorption is rapid, reaching peak absorption within 0.5 hours. In others, the drug appears to be absorbed continuously over a longer period, exhibiting a plateau effect to varying degrees. The average bioavailability of tacrolimus capsules is approximately 21.8% in liver transplant patients, approximately 20.1% in kidney transplant patients, and 14.4-17.4% in healthy volunteers. Bile does not affect the absorption of this product; therefore, oral administration or early conversion from intravenous to oral administration is feasible for liver transplant patients. However, new tacrolimus formulations are needed to address the issues of bioavailability and significant differences in absorption within the body. Summary of the Invention
[0005] To address the aforementioned issues, this invention provides an immune transdermal patch containing tacrolimus that is effective, has a simple formulation, is easy to manufacture, and is suitable for large-scale industrial production.
[0006] The purpose of this invention is to provide an immunosuppressive agent, specifically for preventing graft rejection after liver or kidney transplantation, and a pharmaceutical composition and its preparation method for treating graft rejection after liver or kidney transplantation when other immunosuppressive drugs cannot control the rejection; as well as for severe rheumatoid arthritis, lupus nephritis, autoimmune hepatitis, certain types of uveitis, nephrotic syndrome (such as minimal change disease, focal segmental glomerulosclerosis) and other immune system diseases.
[0007] This invention discloses an immunosuppressant transdermal patch, which comprises a backing layer, a medicated ointment, and a protective layer. The backing layer is a polyester-ethylene-vinyl acetate copolymer film. The medicated ointment is composed of the active pharmaceutical ingredient tacrolimus, a stabilizer, a matrix, a crosslinking agent, and a pressure-sensitive adhesive. The protective layer is a polyethylene terephthalate film. The medicated ointment is coated onto the protective layer, and then the backing layer is pressed onto the surface of the medicated ointment.
[0008] Preferably, the matrix is a mixture of micronized silica gel, glycerin, hydroxypropyl methylcellulose, a penetration enhancer, and a pressure-sensitive adhesive.
[0009] Preferably, the stabilizer is sodium sulfite, sodium bisulfite, sodium thiosulfate, sodium vitamin C, or a mixture thereof. Preferably, the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, a silicone pressure-sensitive adhesive, or a mixture thereof.
[0010] Preferably, the ointment contains the following components and their parts by weight: 0.5-5 parts tacrolimus, 0.1-0.5 parts stabilizer, 5-20 parts pressure-sensitive adhesive, 0.5-3 parts micronized silica gel, 2-10 parts softener, 6-10 parts glycerin, 1-5 parts hydroxypropyl methylcellulose, and 0.1-0.5 parts penetration enhancer.
[0011] This invention also discloses a method for preparing the above-mentioned transdermal immunosuppressant patch, which includes the following steps: S1. Preparation of drug-containing matrix: Add the pressure-sensitive adhesive to an ethanol solution and liquid paraffin, and heat at 50-60℃ while stirring until a viscous semi-solid fluid is formed. Dissolve tacrolimus in ethanol, then add the antioxidant sodium sulfite and stir until homogeneous. Finally, add the mixture to the semi-solid fluid solution and mix thoroughly. S2. Preparation of the substrate: Mix the formulated amounts of micronized silica gel, glycerin, hydroxypropyl methylcellulose, and penetration enhancer evenly to form a matrix; S3. Preparation of ointment-containing formulation: Add the drug-containing matrix prepared in step S1 to the matrix prepared in step S2, then add an appropriate amount of titanium dioxide, stir for 65-90 min at a speed of 20-35 rpm to form a uniform drug-containing paste. S4. Finished Product Preparation: The medicated ointment obtained in step S3 is coated onto a polyethylene terephthalate film, then covered with a polyester and ethylene-vinyl acetate copolymer film. After being left at room temperature for about 30-36 hours, it is sliced according to specifications and packaged.
[0012] Preferably, in step S3, the rotation speed is 25-30 rpm and the stirring time is 65-75 min.
[0013] Preferably, the room temperature placement time in step S4 is 30 hours.
[0014] Compared with the prior art, the beneficial effects of the present invention are: The transdermal immunosuppressant patch provided by this invention mainly contains tacrolimus, which is scientifically processed and prepared based on its pharmacological properties and effects. It can fully leverage the advantages of external application for easy local absorption, convenient use, and easy acceptance by patients, and has a good effect.
[0015] The immunosuppressant transdermal patch provided by this invention can be applied to the neck, shoulders, chest, arms, and other areas. The duration of use can be adjusted according to the specific condition, and it is safe and free of toxic side effects. Furthermore, the transdermal patch of this invention has good adhesion, excellent permeability, and causes no irritation or allergic reactions, resulting in good patient compliance and long-term use. It also boasts advantages such as low manufacturing cost and a simple and reasonable manufacturing process, and has broad application prospects. Detailed Implementation
[0016] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.
[0017] This invention discloses an immunosuppressant transdermal patch, which comprises a backing layer, a medicated ointment, and a protective layer. The backing layer is a polyester-ethylene-vinyl acetate copolymer film, the medicated ointment is composed of the active pharmaceutical ingredient tacrolimus, a stabilizer, a matrix, a crosslinking agent, and a pressure-sensitive adhesive, and the protective layer is a polyethylene terephthalate film. The medicated ointment is coated onto the protective layer, and then the backing layer is pressed onto the surface of the medicated ointment.
[0018] Example 1 This embodiment discloses an immunosuppressant transdermal patch prepared according to the drug-containing ingredients shown in Table 1.
[0019] Table 1 Preparation method: S1. Preparation of drug-containing matrix: Add the pressure-sensitive adhesive to an ethanol solution and liquid paraffin, and heat at 50-60℃ while stirring until a viscous semi-solid fluid is formed. Dissolve tacrolimus in ethanol, then add the antioxidant sodium sulfite and stir until homogeneous. Finally, add the mixture to the semi-solid fluid solution and mix thoroughly. S2. Preparation of the substrate: Mix the formulated amounts of micronized silica gel, glycerin, hydroxypropyl methylcellulose, and penetration enhancer evenly to form a matrix; S3. Preparation of ointment-containing formulation: Add the drug-containing matrix prepared in step S1 to the matrix prepared in step S2, then add an appropriate amount of titanium dioxide, stir for 90 minutes at a speed of 25 rpm to form a uniform drug-containing paste. S4. Finished Product Preparation: The medicated ointment obtained in step S3 is coated onto a polyethylene terephthalate film, then covered with a polyester and ethylene-vinyl acetate copolymer film. After being left at room temperature for about 30 hours, it is sliced according to specifications and packaged.
[0020] Example 2 This embodiment discloses an immunosuppressant transdermal patch prepared according to the drug-containing ingredients shown in Table 2.
[0021] Table 2 Preparation method: S1. Preparation of drug-containing matrix: Add the pressure-sensitive adhesive to an ethanol solution and liquid paraffin, and heat at 50-60℃ while stirring until a viscous semi-solid fluid is formed. Dissolve tacrolimus in ethanol, then add the antioxidant sodium vitamin C and stir until homogeneous. Finally, add the mixture to the semi-solid fluid solution and mix thoroughly. S2. Preparation of the substrate: Mix the formulated amounts of micronized silica gel, glycerin, hydroxypropyl methylcellulose, and penetration enhancer evenly to form a matrix; S3. Preparation of ointment-containing formulation: Add the drug-containing matrix prepared in step S1 to the matrix prepared in step S2, then add an appropriate amount of titanium dioxide, stir for 90 minutes at a speed of 25 rpm to form a uniform drug-containing paste. S4. Finished Product Preparation: The medicated ointment obtained in step S3 is coated onto a polyethylene terephthalate film, then covered with a polyester and ethylene-vinyl acetate copolymer film. After being left at room temperature for about 30 hours, it is sliced according to specifications and packaged.
[0022] Example 3 This embodiment discloses an immunosuppressant transdermal patch prepared according to the drug-containing ingredients shown in Table 3.
[0023] Table 3 Preparation method: S1. Preparation of drug-containing matrix: Add the pressure-sensitive adhesive to an ethanol solution and liquid paraffin, and heat at 50-60℃ while stirring until a viscous semi-solid fluid is formed. Dissolve tacrolimus in ethanol, then add the antioxidant sodium vitamin C and stir until homogeneous. Finally, add the mixture to the semi-solid fluid solution and mix thoroughly. S2. Preparation of the substrate: Mix the formulated amounts of micronized silica gel, glycerin, hydroxypropyl methylcellulose, and penetration enhancer evenly to form a matrix; S3. Preparation of ointment-containing formulation: Add the drug-containing matrix prepared in step S1 to the matrix prepared in step S2, then add an appropriate amount of titanium dioxide, stir for 90 minutes at a speed of 25 rpm to form a uniform drug-containing paste. S4. Finished Product Preparation: The medicated ointment obtained in step S3 is coated onto a polyethylene terephthalate film, then covered with a polyester and ethylene-vinyl acetate copolymer film. After being left at room temperature for about 30 hours, it is sliced according to specifications and packaged.
[0024] Example 4 Pharmacokinetic studies were conducted on the tacrolimus transdermal patch prepared in Example 1 and commercially available capsules.
[0025] Experimental method: 24 SD rats weighing 180-22g were randomly divided into 2 groups (n=12 in each group).
[0026] One group (control group) received oral administration of commercially available tacrolimus capsules (Fumeixin), with the contents dissolved in saline to form a suspension. Blood samples of 0.5 ml were collected from the posterior ocular venous plexus at 0.25 h before administration and at 0.016, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after injection. Plasma samples were placed in heparinized glass tubes and immediately centrifuged at 3000 rpm for 10 min. The supernatant was carefully collected and stored at -20°C until analysis was initiated.
[0027] Another group (Example 1 group) was given a 5 mg dose of the tacrolimus transdermal patch from Example 1. Before administration, the specific area for hair removal was determined on the back of the rats based on the patch's application area. Hair at the application site was carefully shaved, and the rats were observed for 48 hours. Rats with broken skin or incomplete hair removal were removed. On the day of the experiment, after applying the patch to the skin on the rat's back, it was pressed firmly with a finger for about 1 minute to ensure the patch was securely attached to the skin. Medical tape was then used to fix the patch in place to prevent it from falling off due to the rat's movement during the experiment. 0.5 ml of blood was collected from the posterior ocular venous plexus 0.5 h before administration and at 1, 2, 4, 6, 8, 12, 24, 25, 26, 28, 32, 48, and 72 h after administration (the patch was removed at 24 h). The plasma samples were placed in heparinized glass tubes and immediately centrifuged at 3000 rpm for 10 min. The supernatant was carefully collected and stored at -20°C until analysis was initiated.
[0028] Sample preparation: Take 200 μL of plasma, add 200 μL of acetonitrile, and vortex for 30 seconds. Then add 1 mL of ethyl acetate and shake for 15 min. After centrifugation, take the supernatant and dry it under nitrogen. Just before detection, reconstitute with 400 μL of acetonitrile-water (1:1, v / v), vortex, and inject. Detect the content using LC-MS. The experimental data are recorded in Table 4 below.
[0029] Table 4 In summary, the transdermal immunosuppressant patch provided by this invention mainly contains tacrolimus, which is scientifically processed and prepared based on its pharmacological properties and effects. It can fully leverage the advantages of external application for easy local absorption, convenient use, and easy acceptance by patients, and has a good effect.
[0030] The immunosuppressant transdermal patch provided by this invention can be applied to the neck, shoulders, chest, arms, and other areas. The duration of use can be adjusted according to the specific condition, and it is safe and free of toxic side effects. Furthermore, the transdermal patch of this invention has good adhesion, excellent permeability, and causes no irritation or allergic reactions, resulting in good patient compliance and long-term use. It also boasts advantages such as low manufacturing cost and a simple and reasonable manufacturing process, and has broad application prospects.
[0031] The above descriptions are merely some embodiments of the present invention. It should be noted that those skilled in the art can make other modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.
Claims
1. An immunosuppressant transdermal patch characterized in that, The transdermal patch is provided with a backing layer, a drug-containing ointment body and a protective layer, the backing layer is a polyester and ethylene-vinyl acetate copolymer film, the drug-containing ointment body is mixed by a main drug tacrolimus, a stabilizer, a matrix and a crosslinking agent, and a pressure-sensitive adhesive, and the protective layer is a polyethylene terephthalate film, the drug-containing ointment body is coated on the protective layer, and then the backing layer is pressed on the surface of the drug-containing ointment body.
2. The transdermal patch according to claim 1, wherein The matrix is mixed by micro-powder silica gel, glycerol, hydroxypropyl methyl cellulose, a penetration enhancer and a pressure-sensitive adhesive.
3. The transdermal patch of claim 2, wherein, The stabilizer is sodium sulfite, sodium bisulfite, sodium thiosulfate, sodium ascorbate or a mixture thereof.
4. The transdermal patch of claim 3, wherein, The pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, a silicone pressure-sensitive adhesive or a mixture thereof.
5. The transdermal patch according to claim 4, wherein The drug-containing ointment body is composed of the following components and their weight parts: tacrolimus 0.5-5 parts, stabilizer 0.1-0.5 parts, pressure-sensitive adhesive 5-20 parts, micro-powder silica gel 0.5-3 parts, softener 2-10 parts, glycerol 6-10 parts, hydroxypropyl methyl cellulose 1-5 parts, and penetration enhancer 0.1-0.5 parts.
6. The method of claim 1-5, wherein the transdermal patch is prepared by the steps of, The preparation method comprises the following steps: S1, preparation of a drug-containing matrix: The pressure-sensitive adhesive is added into an ethanol solution and liquid paraffin, heated at 50-60℃, and stirred while adding, until a viscous semi-solid fluid is formed; The tacrolimus is dissolved using ethanol, then the antioxidant sodium sulfite is added and stirred uniformly, and then added into the semi-solid fluid solution and mixed uniformly; S2, preparation of a matrix: The formula amount of micro-powder silica gel, glycerol, hydroxypropyl methyl cellulose and penetration enhancer are stirred uniformly to form a matrix; S3, preparation of a drug-containing ointment body: The drug-containing matrix prepared in step S1 is added to the matrix prepared in step S2, and then an appropriate amount of titanium dioxide is added, stirred for 65-90 min at a speed of 20-35 rpm, to form a uniform drug-containing ointment body; S4, preparation of a finished product: The drug-containing ointment body prepared in step S3 is coated on a polyethylene terephthalate film, and then a polyester and ethylene-vinyl acetate copolymer film is pressed on, and placed at room temperature for about 30-36 h, then cut according to specifications and packaged.
7. The production method according to claim 6, wherein In step S3, the stirring speed is 25-30 rpm, and the stirring time is 65-75 min.
8. The preparation method according to claim 6, characterized in that, In step S4, the room temperature placing time is 30 h.