A 32p external use scar-removing patch and a preparation method thereof

Abstract

The application discloses a phosphorus 32 external use scar-removing plaster and a preparation method thereof. The plaster comprises, from outside to inside, a backing layer, a medicine adhesive plaster layer, a sticking prevention isolation layer and an outer protective layer. The medicine adhesive plaster layer contains an acrylic pressure-sensitive adhesive framework and Na2H 32 PO4, pH=6.5-7.5, activity of 0.0001-100 millie per cm2; 80-90 g of acrylic pressure-sensitive adhesive, 4-6 g of PEG400, 2-4 g of glycerol, 1-2 g of laurocapram, 0.2-0.4 g of disodium hydrogen phosphate and 4-6 g of anhydrous ethanol are contained in 100 g of the adhesive plaster. The application realizes pH control and disodium hydrogen phosphate cooperation stability 32 P ion form, migration rate <0.5%; laurocapram penetration, 12 h penetration rate 32.5%-38.7%; no solvent residue, self-adhesion comfort, load activity controllable. The plaster can be used for treating keloid, hemangioma and neurodermatitis, and is suitable for industrialized production.

Description

Technical Field

[0001] This application belongs to the field of radiopharmaceutical preparation technology, specifically relating to a phosphorus-32 external scar removal patch and its preparation method, which is suitable for radioactive patch treatment of skin diseases such as keloids, hemangiomas, and neurodermatitis. Background Technology

[0002] Radionuclide application therapy is one of the effective methods in dermatology for treating proliferative skin diseases such as keloids, hemangiomas, and neurodermatitis. Phosphorus-32 ( 32 P) is a pure beta-ray emitter with a maximum energy of 1.71 MeV. Its maximum penetration depth in tissue is about 8 mm, and its average penetration depth is about 3.5 mm. It has good advantages in local treatment and can effectively inhibit the abnormal proliferation of diseased tissue without damaging deep normal tissue. 32 P has a half-life of 14.3 days, and the therapeutic dose is easy to control, making it one of the most commonly used radioactive patch therapy nuclides in clinical practice.

[0003] at present, 32 The P-radioactive dressing device mainly involves the following technical approaches: (a) Hydrogel-based applicators. For example, Chinese patent CN116983464A discloses a PVA-based... 32 P-radiotherapy hydrogel patch, Na3 32 After mixing PO4 solution and polyvinyl alcohol solution, a hydrogel is formed through freeze-thaw cycles and encapsulated between two layers of transparent adhesive. Although this type of hydrogel applicator has good biocompatibility, it has the following shortcomings: (1) The hydrogel has poor mechanical strength and is easily damaged, leading to leakage of radioactive materials and posing a safety hazard; (2) It lacks self-adhesion and needs to be fixed with external tape, which is inconvenient to use and easy to shift; (3) The preparation process is complicated (requiring freeze-thaw cycles or light curing), resulting in low production efficiency and making it unsuitable for industrial production; (4) The uniformity of drug loading is difficult to control precisely, affecting the uniformity of the treatment effect.

[0004] (ii) Silicone body-shaped applicator. In existing technologies, phosphorus […] 32 The sodium phosphate oral solution and the addition-type silicone component are mixed and emulsified under the action of an emulsifier, and then solidified. Although this type of applicator has a certain degree of flexibility, it has the following shortcomings: (1) The silicone system is a hydrophobic matrix, which is incompatible with water-based... 32 The P-material solution has poor compatibility and requires emulsifiers to barely disperse it, resulting in uneven distribution of radionuclides and affecting the consistency of treatment effects; (2) the exothermic curing process may affect the chemical stability of the nuclides, leading to a decrease in the activity of the radiopharmaceutical; (3) there is a lack of systematic transdermal permeation enhancement design. 32P has low local transdermal absorption efficiency, which affects bioavailability; (4) The cost of silica matrix is ​​high, which is not conducive to large-scale promotion and application.

[0005] (iii) Layered sealing type patch. For example, Chinese patent CN116196541A discloses a phosphorus isotope patch, in which the phosphorus isotope layer is sealed between the first and second base layers, the adhesive layer surrounds the phosphorus isotope layer, and the radiation shielding layer is made of lead-aluminum alloy. Although this type of patch has a simple structure, it has the following shortcomings: (1) 32 P is concentrated in an independent isotope layer rather than dispersed in the matrix. Once the sealing layer is damaged, a large amount of radioactive material will leak out, resulting in poor safety; (2) lack of control over the radioactive material. 32 Protective measures for P chemical form: after hydrolysis or precipitation, the nuclide may be transformed into other chemical forms and lose its therapeutic activity; (3) No excipient system such as permeation enhancer is involved, and the transdermal absorption effect needs to be improved; (4) The selection of radiation protection materials is limited and lacks flexible selection schemes for different clinical scenarios.

[0006] Therefore, developing a method that can maintain 32 P ions are stable in form, do not migrate radioactively, leave no organic solvent residue, are self-adhesive and comfortable, and have quantifiable activity carrying capacity. 32 P-radioactive external dressings have significant clinical application value and broad market prospects. Summary of the Invention

[0007] This invention provides a phosphorus 32 external scar removal patch and its preparation method, which solves the technical problems existing in the prior art.

[0008] To achieve the above objectives, the present invention provides a phosphorus 32 external scar removal dressing, comprising, from the outside to the inside, a backing layer, a medicated adhesive layer, an anti-adhesion isolation layer, and an outer protective layer, wherein: The drug adhesive layer comprises an acrylic pressure-sensitive adhesive matrix and a radioactive active ingredient dispersed therein, wherein the radioactive active ingredient is Na2H. 32 The sterile aqueous solution of PO4, the pH value of the drug gelatin layer is 6.5-7.5, and the concentration of PO4 per square centimeter in the drug gelatin layer is... 32 P activity ranges from 0.0001 mCu to 100 mCu; The backing layer is a medical non-woven fabric layer or a polyester radiation-proof film layer, and the backing layer is used for barrier purposes. 32 To prevent P-ray leakage and drug seepage, the backing layer is soft and conforms to the skin. The anti-stick release layer is a silicone release paper layer. The anti-stick release layer is used to prevent the adhesive from sticking together, so that it can be easily peeled off during use. The outer protective layer is a radiation-proof material layer. The outer protective layer is used to shield against light, radiation and seal, and prolong the stability of the formulation.

[0009] As a preferred embodiment, the drug ointment layer comprises the following components per 100g of ointment base: Acrylic pressure-sensitive adhesive 80.0~90.0g; Polyethylene glycol 400 4.0~6.0g; Glycerin 2.0–4.0 g; Lauryl diazepine 1.0–2.0 g; Disodium hydrogen phosphate 0.2–0.4 g; Anhydrous ethanol 4.0–6.0 g; The total amount of each of the above components is 100g.

[0010] In this invention, acrylic pressure-sensitive adhesive serves as the matrix, carrying both the radioactive drug and excipients while providing self-adhesive properties, allowing the patch to be directly applied to the affected skin without additional fixation. When the amount of acrylic pressure-sensitive adhesive is 80.0–90.0 g / 100 g of the adhesive matrix, it simultaneously satisfies good film-forming properties, moderate pressure-sensitive adhesion, and sufficient drug carrying capacity. When the amount of acrylic pressure-sensitive adhesive is less than 80.0 g, the mechanical strength of the adhesive layer is insufficient, making it prone to cold flow; when the amount of acrylic pressure-sensitive adhesive is greater than 90.0 g, the adhesive layer becomes too hard, resulting in poor skin adherence and affecting application comfort.

[0011] More preferably, the acrylic pressure-sensitive adhesive is DURO-TAK 87-4098, which has moderate pressure sensitivity, no skin irritation, good compatibility with various excipients, and is suitable as a matrix material for radiopharmaceuticals.

[0012] In this invention, polyethylene glycol 400 (PEG400) is used as a solubilizer and softener, which can increase Na2H 32 The solubility of PO4 in the pressure-sensitive adhesive matrix improves the flexibility and skin adherence of the adhesive layer, while also helping to promote transdermal drug absorption. The dosage is 4.0-6.0g / 100g of adhesive matrix. If the dosage is too low, the solubilizing effect is not obvious, and if the dosage is too high, it may affect the adhesive properties of the pressure-sensitive adhesive.

[0013] In this invention, glycerin is used as a moisturizer and skin feel improver, which can reduce the skin irritation of the patch and improve the comfort of long-term application. Its dosage is 2.0-4.0g / 100g of adhesive base.

[0014] In this invention, laurocapram (azone) serves as a highly efficient transdermal penetration enhancer, capable of reversibly altering the lipid structure of the stratum corneum and effectively promoting... 32 P can be absorbed locally through the skin to increase the effective drug concentration at the lesion site. The dosage is 1.0 to 2.0 g / 100 g of ointment base. When the dosage of laurocapram is less than 1.0 g, the penetration-enhancing effect is not obvious, and when it is more than 2.0 g, it may cause local skin irritation.

[0015] In this invention, disodium hydrogen phosphate is used as... 32 P is a chemical stabilizer and carrier, which, on the one hand, can provide a phosphate ion environment and inhibit Na2H. 32 Hydrolysis of PO4 ensures 32 P maintains a stable ionic form in the formulation; on the other hand, as a carrier, it can reduce the impact of the backing layer on the formulation. 32 The adsorption of phosphorus (P) prevents the radioactive main drug from migrating or leaking during storage and use. The dosage of disodium hydrogen phosphate is 0.2–0.4 g / 100 g of the paste base.

[0016] In this invention, anhydrous ethanol is used as a viscosity modifier to adjust the viscosity of the adhesive paste during application, facilitating uniform application. It is completely evaporated through a low-temperature drying process in the later stage, leaving no organic solvent residue in the finished product. The dosage is 4.0-6.0g / 100g of adhesive paste matrix.

[0017] It should be noted that, in this invention, the Na2H 32 The radiochemical purity of the sterile aqueous solution of PO4 is ≥99%, and the single-layer activity is 3.7–7.4 MBq (adjustable according to clinical needs). When adding the material, follow the instructions for Na2H2O. 32 The volume required to calculate the actual activity concentration of the PO4 stock solution is added to the gel system without altering the above matrix ratio.

[0018] The medicated gel layer per square centimeter 32 The P activity ranges from 0.0001 mCv to 100 mCv. When the activity is below 0.0001 mCv per square centimeter, the radiation dose per unit area is insufficient, making it difficult to achieve an effective therapeutic concentration. When it is above 100 mCv, the radiation dose is too high and may cause damage to normal tissues. This range ensures flexible dose adjustment for different lesion areas and treatment needs.

[0019] As a further preferred embodiment, a controlled-release microporous membrane is further disposed between the backing layer and the drug gel layer. The controlled-release microporous membrane has a microporous structure for regulating the release of drugs. 32 The transdermal release rate of P is optimized to avoid skin irritation caused by excessively high local concentrations, thus achieving a stable and continuous release of the drug.

[0020] In this invention, the radiation-shielding material of the outer protective layer is selected from any one or a combination of the following materials: (1) Metallic or alloy materials: lead, lead-aluminum alloy, aluminum, copper, stainless steel, tungsten, bismuth; (2) Polymer-based composite materials: lead-containing PVC composite film, lead-containing PE composite film, tungsten-containing flexible composite material, bismuth-containing flexible composite material, metal / polymer laminated composite film; (3) Multi-layer composite shielding structure: aluminum foil composite film, metal foil / polymer multi-layer film, lead / polymer / aluminum multi-layer composite film, silver / aluminum / polymer composite film; (4) Inorganic non-metallic filler materials: barium sulfate filler material, bismuth oxide filler material, tungsten oxide filler material, barite composite material; (5) Medical radiation protection materials: medical radiation protection blankets and medical non-woven fabrics with shielding layers.

[0021] The aforementioned radiation protection materials cover five major categories: metal / alloy materials, polymer-based composite materials, multi-layer composite structures, inorganic non-metallic filler materials, and medical radiation protection materials. The appropriate material can be flexibly selected based on the specific application scenario, shielding requirements, and cost considerations. For example: for scenarios with high shielding requirements, tungsten-containing flexible composite materials or lead / polymer / aluminum multi-layer composite films can be used; for scenarios with environmental protection requirements, bismuth-containing flexible composite materials or bismuth oxide filler materials can be used; for lightweight and portable scenarios, medical non-woven fabrics or medical radiation protection blankets with shielding layers can be used; and for economical scenarios, barite composite materials or lead-containing PVC composite films can be used.

[0022] More preferably, the patch is in the shape of a round or square sheet, and the appropriate size can be selected according to the shape and area of ​​the lesion.

[0023] This invention also provides a method for preparing a phosphorus-32 topical scar-removing patch, comprising the following steps: S100: Mix acrylic pressure-sensitive adhesive, polyethylene glycol 400, glycerin, laurocapramone, disodium hydrogen phosphate and anhydrous ethanol in the specified ratio to form a paste matrix. S200, according to Na2H 32 The volume required to convert the actual activity concentration of sterile PO4 aqueous solution into the calculated amount of Na2H+ is used. 32 A sterile aqueous solution of PO4 was added to the adhesive base and stirred until homogeneous, while controlling the pH of the system to be 6.5–7.5. S300. Apply the adhesive paste containing the radioactive main drug onto the backing layer; S400, low-temperature drying to evaporate anhydrous ethanol; S500, with a non-stick protective layer; S600, cut into patches of the required specifications; The S700 is encapsulated with an outer protective layer.

[0024] In step S200, the pH of the system is controlled to be between 6.5 and 7.5, within which Na2H... 32 PO4 can exist stably in ionic form without hydrolysis or precipitation. When the pH of the system is below 6.5, the equilibrium will shift towards the formation of H2PO4. - The directional movement weakened it. 32The binding stability between phosphorus and the carrier increases the risk of adsorption by the backing layer or migration with moisture; when the pH of the system is higher than 7.5, free Na in the system... + A relatively high concentration may promote the formation of insoluble phosphate microcrystals. Therefore, a pH range of 6.5–7.5 is necessary to ensure... 32 Key process parameters for stabilizing the P ion state.

[0025] In step S400, a low-temperature drying process is used, with the temperature controlled between 40 and 60°C. This ensures that the anhydrous ethanol evaporates fully while avoiding the adverse effects of high temperatures on the performance of the radiopharmaceutical and pressure-sensitive adhesive.

[0026] This invention provides a topical scar-removing patch with phosphorus 32, which has the following significant advantages over existing technologies: This invention effectively preserves the Na₂H₂O content by precisely controlling the pH of the drug gel layer to 6.5–7.5 and adding disodium hydrogen phosphate as a carrier. 32 The stable ionic form of PO4 prevents hydrolysis or precipitation, ensuring radiochemical purity ≥99%, while also solving... 32 The problem of P migrating to or being adsorbed into the backing layer during storage and use is addressed with a migration rate of <0.5%, resulting in significantly improved formulation safety and stability. (2) The present invention uses acrylic pressure-sensitive adhesive (80-90g / 100g adhesive matrix) as the skeleton matrix, which has the dual functions of drug carrying and self-adhesion. No additional fixation is required. Combined with the moisturizing effect of glycerin (2-4g) and the softening effect of PEG400 (4-6g), the skin is comfortable to adhere to, with low irritation and good patient compliance. (3) The present invention uses laurocapram (1-2g) as a highly efficient transdermal penetration enhancer, and combines it with a low-temperature drying process to achieve no organic solvent residue. The cumulative transdermal penetration rate after 12 hours reaches 32.5%-38.7%, which is significantly better than the prior art (<16%). (4) In this invention, the single-patch activity can be precisely controlled (3.7~7.4 MBq / piece), per square centimeter 32 P activity can be flexibly adjusted within the range of 0.0001 to 100 mCu, to meet the individualized needs of different lesion areas and treatment doses; (5) The present invention adopts a five-layer composite structure. The controlled-release microporous membrane can be selected to regulate the release rate. The outer protective layer radiation protection material covers five categories: metal / alloy, polymer composite material, multi-layer composite shielding structure, inorganic non-metallic filling material and medical radiation protection material. It can be flexibly selected according to clinical scenarios. The preparation process is simple and suitable for industrial production. Attached Figure Description

[0027] Figure 1 This is a schematic diagram of the structure of the phosphorus 32 external scar removal patch of the present invention; Figure 2 This is a schematic diagram of the structure of the phosphorus 32 external scar removal patch of the present invention; Figure 3 This is a flowchart illustrating the preparation method of the phosphorus 32 external scar removal patch of the present invention.

[0028] In the picture: 1. Outer protective layer (radiation shielding material layer); 2. Anti-stick release layer (silicified release paper); 3. Drug plaster layer (pressure-sensitive adhesive skeleton layer containing ³²P); 4. Backing layer (medical non-woven fabric / polyester non-irradiation membrane); 5. Controlled-release microporous membrane (optional). Detailed Implementation

[0029] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way.

[0030] Example 1 like Figure 1 As shown, this embodiment provides a phosphorus 32 topical scar removal patch, which comprises, from the outside to the inside: Outer protective layer 1 is made of aluminum foil composite film and is used for light protection, radiation protection and sealing; The anti-stick release layer 2 is made of silicone release paper and is used to prevent the adhesive from sticking and to make it easy to peel off during use. Drug plaster layer 3 includes an acrylic pressure-sensitive adhesive matrix layer and a radioactive active ingredient dispersed therein, the radioactive active ingredient being Na2H. 32 The sterile aqueous solution of PO4, the pH value of the drug gelatin layer is 6.5, and the concentration of the drug gelatin layer per square centimeter is... 32 The P activity was 0.0001 mCurry; Backing layer 4 is made of medical non-woven fabric and is used to block radiation leakage and prevent drug leakage.

[0031] The drug ointment layer, per 100g of ointment base, comprises the following components: Acrylic pressure-sensitive adhesive (DURO-TAK 87-4098) 80.0g Polyethylene glycol 400 (PEG400) 4.0g Glycerin 2.0g Lauryl azone (azone) 1.0g Disodium hydrogen phosphate 0.2g 12.8g of anhydrous ethanol The total amount of the above components is 100.0g.

[0032] Radioactive main drug Na2H 32 The radiochemical purity of the sterile PO4 aqueous solution is ≥99%. Add the solution according to the required volume calculated based on the actual activity concentration of the original solution. The target single-patch activity is 3.7 MBq / patch. The drug gel layer contains [amount missing] per square centimeter. 32 The P activity was 0.0001 millicuries.

[0033] like Figure 3 As shown, this embodiment provides a method for preparing a phosphorus 32 topical scar-reducing patch, which specifically includes the following steps: S100: Add 80.0g DURO-TAK 87-4098 acrylic pressure-sensitive adhesive, 4.0g PEG400, 2.0g glycerin, 1.0g laurocapram, 0.2g disodium hydrogen phosphate and 12.8g anhydrous ethanol into a mixing container according to the specified ratio, stir evenly to form an adhesive paste matrix; S200, determination of Na2H 32 The actual activity concentration of sterile PO4 aqueous solution, calculated based on the target single-patch activity of 3.7 MBq / sheet, requires a corresponding volume of Na2H. 32 Add sterile aqueous solution of PO4 to the adhesive base, stir thoroughly, and measure and adjust the pH of the system to 6.5; S300. Apply the adhesive paste containing the radioactive main drug evenly to the medical non-woven fabric backing layer. S400 is dried at a low temperature of 45℃ to completely evaporate the anhydrous ethanol; S500, with siliconized release paper as an anti-sticking isolation layer; S600, cut into round or square patches according to clinical needs; S700 is externally packaged with an aluminum foil composite film.

[0034] The performance of the phosphorus 32 topical scar-reducing patch prepared in Example 1 was tested, and the results showed that: In the drug gel layer 32 P is uniformly dispersed, pH value is 6.5, Na2H 32 PO4 remains in ionic form; Organic solvent residues: Not detected (gas chromatography, detection limit 10 ppm). Radioactive migration rate: <0.5% (determination of backing layer adsorption rate); Adhesion: Initial tack (rolling ball method) meets pharmacopoeia requirements, holding power > 4 hours; Skin irritation: Primary irritation index (PII) is 0.2; Transdermal penetration rate: The cumulative penetration rate reached 32.5% after 12 hours (ex vivo porcine skin test).

[0035] This embodiment verifies that even when the dosage of all formulation components is minimized and the loading activity is low, good formulation performance and basic therapeutic effect can still be achieved, making it suitable for the initial treatment of small-area keloids.

[0036] Example 2 like Figure 2 As shown, this embodiment provides a phosphorus 32 topical scar removal patch, which comprises, from the outside to the inside: The outer protective layer 1 is made of tungsten-containing flexible composite material (which has high shielding performance and is environmentally friendly and lead-free) and is used for light protection, radiation protection and sealing. The anti-stick release layer 2 is made of silicone release paper and is used to prevent the adhesive from sticking and to make it easy to peel off during use. Drug plaster layer 3 includes an acrylic pressure-sensitive adhesive matrix layer and a radioactive active ingredient dispersed therein, the radioactive active ingredient being Na2H. 32 The sterile aqueous solution of PO4, the pH value of the drug gelatin layer is 7.0, and the concentration of the drug gelatin layer per square centimeter is... 32 The activity of P is 0.5 millicuries; Controlled-release microporous membrane 5: Located between the backing layer 4 and the drug gel layer 3, with a pore size of 0.22 μm, used for regulating release. 32 The transdermal release rate of P should be optimized to avoid excessively high local concentrations. Backing layer 4 is made of polyester non-radiation film and is used to block radiation leakage and prevent drug leakage.

[0037] The drug ointment layer, per 100g of ointment base, comprises the following components: Acrylic pressure-sensitive adhesive (DURO-TAK 87-4098) 85.0g Polyethylene glycol 400 (PEG400) 5.0g 3.0g of glycerin Lauryl azelazone (azelazone) 1.5g Disodium hydrogen phosphate 0.3g 5.2g of anhydrous ethanol The total amount of the above components is 100.0g.

[0038] Radioactive main drug Na2H 32 The radiochemical purity of the sterile PO4 aqueous solution is ≥99%. Add the solution according to the required volume calculated based on the actual activity concentration of the original solution. The target single-patch activity is 5.5 MBq / patch. The drug gel layer contains [amount missing] per square centimeter. 32 The activity of P is 0.5 millicuries.

[0039] This embodiment also provides a method for preparing a phosphorus 32 topical scar removal patch, which specifically includes the following steps: S100: Add 85.0g DURO-TAK 87-4098 acrylic pressure-sensitive adhesive, 5.0g PEG400, 3.0g glycerin, 1.5g laurocapram, 0.3g disodium hydrogen phosphate and 5.2g anhydrous ethanol to a mixing container according to the specified ratio, stir well to form an adhesive base; S200, determination of Na2H 32 The actual activity concentration of sterile PO4 aqueous solution, calculated based on a target single-patch activity of 5.5 MBq / sheet, requires a corresponding volume of Na2H. 32 Add sterile aqueous solution of PO4 to the adhesive base, stir thoroughly, and measure and adjust the pH of the system to 7.0; S300, First, attach the controlled-release microporous membrane to the polyester non-irradiable membrane backing layer; S400. Apply the gel containing the radioactive drug evenly to the controlled-release microporous membrane. S500 is dried at a low temperature of 50℃ to completely evaporate the anhydrous ethanol; S600, with siliconized release paper as an anti-sticking isolation layer; S700, cut into round or square patches according to clinical needs; S800 is externally packaged with a tungsten-containing flexible composite material.

[0040] The performance of the phosphorus 32 topical scar-reducing patch prepared in Example 2 was tested, and the results showed that: In the drug gel layer 32 P is uniformly dispersed, pH value is 7.0, Na2H 32 PO4 remains in ionic form; Organic solvent residue: Not detected (same detection method as in Example 1); Radioactive migration rate: <0.3% (determination of adsorption rate of backing layer); Adhesion: Initial tack (rolling ball method) meets pharmacopoeia requirements, holding power > 6 hours; Skin irritation: Primary irritation index (PII) is 0.1; Transdermal penetration rate: The cumulative penetration rate after 12 hours reached 38.7% (ex vivo porcine skin test). Release rate stability: Controlled-release microporous membranes enable 32 The P release curve was more stable, and the peak concentration was reduced by about 30% compared with the control group without membrane, thus avoiding excessively high local concentrations.

[0041] This embodiment verifies that, under the optimal formulation conditions, all performance indicators reach their best, making it particularly suitable for indications such as hemangioma and neurodermatitis that require prolonged application treatment.

[0042] Example 3 like Figure 1As shown, this embodiment provides a phosphorus 32 topical scar removal patch, which comprises, from the outside to the inside: Outer protective layer 1 is made of a lead / polymer / aluminum multilayer composite film and is used for light protection, radiation protection and sealing; The anti-stick release layer 2 is made of silicone release paper and is used to prevent the adhesive from sticking and to make it easy to peel off during use. Drug plaster layer 3 includes an acrylic pressure-sensitive adhesive matrix layer and a radioactive active ingredient dispersed therein, the radioactive active ingredient being Na2H. 32 The sterile aqueous solution of PO4, the pH value of the drug gelatin layer is 7.5, and the concentration of the drug gelatin layer per square centimeter is... 32 The P activity is 100 millicuries; Backing layer 4 is made of medical non-woven fabric and is used to block radiation leakage and prevent drug leakage.

[0043] The drug ointment layer, per 100g of ointment base, comprises the following components: Acrylic pressure-sensitive adhesive (DURO-TAK 87-4098) 86.0g Polyethylene glycol 400 (PEG400) 5.5g 3.5g of glycerin Lauryl azelazone (azone) 1.8g Disodium hydrogen phosphate 0.4g 2.8g of anhydrous ethanol The total amount of the above components is 100.0g.

[0044] Radioactive main drug Na2H 32 The radiochemical purity of the sterile PO4 aqueous solution is ≥99%. Add the solution according to the required volume calculated based on the actual activity concentration of the original solution. The target single-patch activity is 7.4 MBq / patch. The drug gel layer contains [amount missing] per square centimeter. 32 The P activity is 100 millicuries.

[0045] This embodiment also provides a method for preparing a phosphorus 32 topical scar removal patch, which specifically includes the following steps: S100: Add 86.0g DURO-TAK 87-4098 acrylic pressure-sensitive adhesive, 5.5g PEG400, 3.5g glycerin, 1.8g laurocapram, 0.4g disodium hydrogen phosphate and 2.8g anhydrous ethanol to a mixing container according to the specified ratio, stir well to form an adhesive base. S200, determination of Na2H 32 The actual activity concentration of the sterile PO4 aqueous solution, calculated based on the target single-patch activity of 7.4 MBq / sheet, requires a corresponding volume of Na2H. 32Add sterile aqueous solution of PO4 to the adhesive base, stir thoroughly, and measure and adjust the pH of the system to 7.5; S300. Apply the adhesive paste containing the radioactive main drug evenly to the medical non-woven fabric backing layer. S400 is dried at a low temperature of 55℃ to completely evaporate the anhydrous ethanol; S500, with siliconized release paper as an anti-sticking isolation layer; S600, cut into round or square patches according to clinical needs; The S700 is externally encapsulated with a lead / polymer / aluminum multilayer composite film.

[0046] The performance of the phosphorus 32 topical scar-reducing patch prepared in Example 3 was tested, and the results showed that: In the drug gel layer 32 P is uniformly dispersed, pH value is 7.5, Na2H 32 PO4 remains in ionic form; Organic solvent residue: Not detected (same detection method as in Example 1); Radioactive migration rate: <0.4% (determination of adsorption rate of backing layer). Adhesion: Initial tack (rolling ball method) meets pharmacopoeia requirements, holding power > 5 hours; Skin irritation: Primary irritation index (PII) is 0.3; Transdermal penetration rate: The cumulative penetration rate reached 35.2% after 12 hours (ex vivo porcine skin test); Radiation shielding efficiency: The lead / polymer / aluminum multilayer composite film has a shielding efficiency of >99.9% against ³²Pβ rays, and the dose rate on the outer surface is close to the background level.

[0047] This embodiment verifies that when the dosage of all formulation components is taken at the maximum value and the activity is taken at a high value, the present invention can still achieve good formulation performance and excellent radiation shielding effect. It is particularly suitable for large-area keloids or stubborn lesions that require high-dose treatment. The high activity combined with the high shielding performance of the outer protective layer ensures the unity of treatment effectiveness and safety of use.

[0048] Example 4

[0049] The only difference between this embodiment and Embodiment 2 is the choice of radiation-shielding material for the outer protective layer, in order to demonstrate the diversity and flexibility of the radiation-shielding material selection in this invention.

[0050] Example 4A In this embodiment, the outer protective layer uses a bismuth-based flexible composite material instead of a tungsten-based flexible composite material. Bismuth-based materials have radiation shielding properties similar to lead, and are non-toxic and environmentally friendly, making them particularly suitable for scenarios with high environmental and biosafety requirements, such as topical treatments for pediatric patients. Testing has shown that it...32 The shielding efficiency of Pβ rays is >99.5%, and the external surface dose rate meets the requirements of GBZ 133-2009 "Sanitary Protection Management of Medical Radioactive Waste".

[0051] Example 4B In this embodiment, the outer protective layer uses a medical radiation shielding blanket (an ultra-thin, flexible, lead-free shielding material), which is particularly suitable for application scenarios that require conforming to irregular body surface areas (such as joints, auricles, etc.). This material is soft and can be freely bent to conform to the shape of the body surface while maintaining excellent radiation shielding performance.

[0052] Example 4C In this embodiment, the outer protective layer uses an aluminum foil composite film (an economical solution), which is low in cost and easy to process. It is suitable for scenarios with relatively low shielding requirements and low therapeutic activity, and can be used as an economical option for disposable dressings.

[0053] Example D In this embodiment, the outer protective layer is made of bismuth oxide (Bi2O3) filled polymer composite material, which has the advantages of high shielding performance and lead-free environmental protection. The atomic number of bismuth (Z=83) is higher than that of lead (Z=82), which has an excellent shielding effect on bremsstrahlung radiation generated by β rays, and is particularly suitable for radiation protection of high activity³²P patches.

[0054] Comparative Example To verify the technical effect of the present invention, the application methods of Embodiments 1 to 3 of the present invention are compared with the following prior art solutions: Comparative Example 1: Preparation of phosphorus isotope patches according to the method of CN116196541A ( 32 P is concentrated in an independent isotope layer, a lead-aluminum alloy radiation shielding layer.

[0055] Comparative Example 2: Preparation of PVA-based materials according to the method in CN116983464A 32 P hydrogel applicator (PVA hydrogel matrix, ³²P dispersed in hydrogel, encapsulated with two layers of transparent adhesive).

[0056] Comparative Example 3: Preparation according to the method of silicone body radionuclide applicator ( 32 P emulsifies and cures with addition-type silicone components.

[0057]

[0058] Note: In Comparative Example 1 32 P is concentrated in separate isotopic layers, making mobility measurements unsuitable.

[0059] As can be seen from Table 1, Embodiments 1-3 of the present invention are significantly superior to Comparative Embodiments 1-3 of the prior art in all key performance indicators, especially in...32 It exhibits outstanding substantive features and significant technological advancements in terms of P ion preserving form, non-migrating radioactivity, enhanced transdermal penetration, precise control of quantitative activity loading, and selectivity of radiation protection materials.

[0060] Example 5 To further verify the rationality and criticality of the pH range (6.5–7.5) of the present invention, five groups of samples with pH values ​​of 6.0, 6.5, 7.0, 7.5, and 8.0 were prepared (formulations same as in Example 2), and the results were investigated. 32 Stability of the ionic form of P.

[0061] Test method: Na₂H₂O in each sample was determined by radioactive thin-layer chromatography. 32 The chemical form of PO4 is considered stable and qualified when the radiochemical purity is >95%. The test results are shown in Table 2.

[0062]

[0063] As can be seen from Table 2, when the pH value is controlled within the range of 6.5 to 7.5, Na2H 32 PO4 maintained a radiochemical purity of >95% for 14 days. 32 Phosphate (P) ions are stable in their form. Outside this range (pH ≤ 6.0 or pH ≥ 8.0), the radiochemical purity decreases significantly. 32 The chemical form of phosphorus (P) undergoes a significant change. This verifies the rationality and necessity of precisely controlling the pH value between 6.5 and 7.5 in this invention.

[0064] Example 6 To verify the rationality and criticality of the laurocapram dosage range (1.0-2.0g / 100g ointment base) of the present invention, five groups of samples with laurocapram dosages of 0.5g, 1.0g, 1.5g, 2.0g, and 2.5g were prepared (other components of the formulation are the same as in Example 2) to investigate transdermal penetration and skin irritation.

[0065] Test methods: Ex vivo porcine skin was used for transdermal permeation experiments in a Franz diffusion cell to determine the cumulative permeability over 12 hours; simultaneously, rabbit skin was used to determine the primary irritation index (PII). The test results are shown in Table 3.

[0066]

[0067] As shown in Table 3, when the dosage of laurocapram is within the range of 1.0–2.0 g / 100 g of the gel base, the cumulative penetration rate after 12 hours is >30%, and the skin irritation is non-irritating to mildly irritating (PII ≤ 0.3), which is acceptable for use. When the dosage is below 1.0 g, the penetration-enhancing effect is insufficient (penetration rate < 30%); when the dosage is above 2.0 g, the skin irritation increases significantly (PII > 0.5, showing mild irritation), which is unacceptable. This verifies the rationality and necessity of setting the dosage range of laurocapram to 1.0–2.0 g / 100 g of the gel base in this invention.

[0068] In summary, the phosphorus-32 topical scar-reducing patch and its preparation method provided by this invention not only have widely available raw materials and a simple preparation process, but are also suitable for industrial production and can be widely used in the radioactive patch treatment of skin diseases such as keloids, hemangiomas, and neurodermatitis. This invention, through systematic prescription design and structural optimization, solves the problems existing in the prior art. 32 Despite technical challenges such as unstable P-ion form, easy radioactive migration, organic solvent residue, lack of transdermal penetration enhancement design, and limited selection of radiation protection materials, it has promising clinical application prospects and market economic benefits.

[0069] The foregoing has provided a detailed description of a phosphorus-32 external scar-removing dressing and its preparation method. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the embodiments above are merely for the purpose of helping to understand the core ideas of this application. It should be noted that those skilled in the art can make various improvements and modifications to this application without departing from its principles, and these improvements and modifications also fall within the protection scope of the claims of this application.

Claims

1. A topical scar-removing patch for phosphorus 32, characterized in that, It includes, from the outside to the inside, a backing layer, a medicated adhesive layer, an anti-sticking barrier layer, and an outer protective layer, wherein: The drug adhesive layer comprises an acrylic pressure-sensitive adhesive matrix and a radioactive active ingredient dispersed therein, wherein the radioactive active ingredient is Na2H. 32 The sterile aqueous solution of PO4, the pH value of the drug gelatin layer is 6.5-7.5, and the concentration of PO4 per square centimeter in the drug gelatin layer is... 32 P activity ranges from 0.0001 mCu to 100 mCu; The backing layer is a medical non-woven fabric layer or a polyester non-radiation-proof film layer; The anti-stick release layer is a siliconized release paper layer; The outer protective layer is a radiation-shielding material layer.

2. The phosphorus 32 external scar removal patch according to claim 1, characterized in that, The drug ointment layer contains the following components per 100g of ointment base: Acrylic pressure-sensitive adhesive 80.0~90.0g; Polyethylene glycol 400 4.0~6.0g; Glycerin 2.0–4.0 g; Lauryl diazepine 1.0–2.0 g; Disodium hydrogen phosphate 0.2–0.4 g; Anhydrous ethanol 4.0–6.0 g; The total amount of each of the above components is 100g.

3. The phosphorus 32 external scar removal patch according to claim 2, characterized in that, The acrylic pressure-sensitive adhesive is DURO-TAK87-4098.

4. The phosphorus 32 external scar removal patch according to claim 1, characterized in that, The Na2H 32 The radiochemical purity of the sterile aqueous solution of PO4 is ≥99%.

5. The phosphorus 32 external scar removal patch according to claim 1, characterized in that, The activity of each patch is 3.7–7.4 MBq.

6. The phosphorus 32 external scar-removing patch according to claim 1, characterized in that, A controlled-release microporous membrane is also provided between the backing layer and the drug gel layer, and the controlled-release microporous membrane is used to regulate the transdermal release rate of ³²P.

7. The phosphorus 32 external scar removal patch according to claim 1, characterized in that, The radiation shielding material of the outer protective layer is selected from any one or a combination of the following materials: (1) Metallic or alloy materials: lead, lead-aluminum alloy, aluminum, copper, stainless steel, tungsten, bismuth; (2) Polymer-based composite materials: lead-containing PVC composite film, lead-containing PE composite film, tungsten-containing flexible composite material, bismuth-containing flexible composite material, metal / polymer laminated composite film; (3) Multi-layer composite shielding structure: aluminum foil composite film, metal foil / polymer multi-layer film, lead / polymer / aluminum multi-layer composite film, silver / aluminum / polymer composite film; (4) Inorganic non-metallic filler materials: barium sulfate filler material, bismuth oxide filler material, tungsten oxide filler material, barite composite material; (5) Medical radiation protection materials: medical radiation protection blankets and medical non-woven fabrics with shielding layers.

8. The phosphorus 32 external scar removal patch according to claim 1, characterized in that, The patch is in the form of a round or square sheet.

9. The preparation method of the phosphorus 32 external scar-reducing patch according to any one of claims 1 to 8, characterized in that, Includes the following steps: S100: Mix acrylic pressure-sensitive adhesive, polyethylene glycol 400, glycerin, laurocapramone, disodium hydrogen phosphate and anhydrous ethanol in the specified ratio to form a paste matrix. S200, according to Na2H 32 The volume required to convert the actual activity concentration of sterile PO4 aqueous solution into the calculated amount of Na2H+ is used. 32 A sterile aqueous solution of PO4 was added to the adhesive base and stirred until homogeneous, with the pH of the system controlled at 6.5–7.

5. S300. Apply the adhesive paste containing the radioactive main drug onto the backing layer; S400, low-temperature drying to evaporate anhydrous ethanol; S500, with a non-stick protective layer; S600, cut into patches of the required specifications; The S700 is encapsulated with an outer protective layer.

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