A shihua extract external use effervescent tablet and effervescent patch preparation thereof

Abstract

This invention discloses an effervescent tablet and its effervescent patch formulation for external use, belonging to the field of medical dressing technology. The formulation comprises 5%–20% agaric extract, 15%–30% acid source, 10%–25% alkali source, 20%–40% filler, 2%–8% binder, 1%–5% disintegrant, 0.5%–2% lubricant, 0.1%–1% stabilizer, and 0.5%–3% adhesive. This invention effectively avoids acid-base degradation of the active ingredients of agaric during effervescence by optimizing the acid source (citric acid and tartaric acid in a 2:1 ratio), the alkali source (sodium bicarbonate and sodium carbonate in a 4:1 ratio), and the stabilizer system (vitamin E and EDTA-2Na), resulting in high tablet storage stability. The pH of the solution after disintegration is close to that of the skin, making it mild and non-irritating. The pH of the solution formed after the effervescent tablet disintegrates in water is precisely controlled between 6.5 and 7.0, close to the physiological pH of normal skin, synergistically enhancing permeability and adhesion.

Description

Technical Field

[0001] This invention relates to the field of medical dressing technology, and in particular to a topical effervescent tablet of Lithospermum erythrorhizon extract and its effervescent patch formulation. Background Technology

[0002] Psoriasis is a chronic, relapsing skin disease characterized by excessive proliferation of keratinocytes and abnormal immune inflammatory responses. Topical medications are the preferred treatment for mild to moderate psoriasis because they act directly on the lesions and have few systemic side effects. Commonly used topical formulations include ointments, gels, lotions, and wet compresses. Among these, wet compresses soften thickened keratin and provide continuous medication, showing particularly outstanding effects in improving thick-skinned psoriasis lesions.

[0003] However, existing topical psoriasis preparations have significant drawbacks: (1) Traditional aqueous solutions and lotions have poor stability and the active ingredients are easily degraded, resulting in a decrease in efficacy; ointments and gels are easy to stick to clothing after application and are difficult to penetrate the thickened stratum corneum of psoriasis lesions.

[0004] (2) Conventional wet dressings need to be prepared and used immediately, which is cumbersome and results in low patient compliance.

[0005] (3) Some formulations lack a pH buffer system, which can easily irritate broken skin lesions and aggravate skin discomfort.

[0006] (4) Most existing skin patches are made of hydrogel or non-woven fabric substrates, which have high water content and are easy to dry and harden. They are not compatible with effervescent systems and it is difficult to achieve the synergistic effect of effervescent penetration and long-lasting application.

[0007] As a traditional medicinal fungus, *Gynostemma pentaphyllum* (also known as agaric fungus) is rich in calciferic acid, polysaccharides, and flavonoids in its extracts. These compounds have been proven to have significant anti-inflammatory, immunomodulatory, keratin-softening, and skin barrier-repairing effects, making it an ideal natural active ingredient for topical treatment of psoriasis. There are folk remedies that grind rapeseed oil and *Gynostemma pentaphyllum* together and apply it to the affected area to treat psoriasis. While there are existing studies on topical gels and ointments made from *Gynostemma pentaphyllum* extract, there are no reports on effervescent tablets made from it. Preparing *Gynostemma pentaphyllum* extract into effervescent tablets requires addressing key issues such as the susceptibility of the active ingredients to degradation by the effervescent acid-base system, insufficient adhesiveness of the solution after disintegration, and excessive irritation to broken skin.

[0008] Therefore, developing a novel topical formulation of Lithops extract with good stability, strong permeability, convenient use, and both effervescent and patching functions has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0009] The purpose of this invention is to solve the problems of poor stability, insufficient permeability, inconvenience of use, and poor adhesion of traditional patches in the prior art of topical preparations of agarwood. The invention proposes a topical effervescent tablet of agarwood extract and its effervescent patch formulation. By optimizing the acid source (citric acid and tartaric acid in a 2:1 ratio), the alkali source (sodium bicarbonate and sodium carbonate in a 4:1 ratio), and the stabilizer system (vitamin E and EDTA-2Na), the acid-base degradation of the active ingredients of agarwood during effervescence is effectively avoided. The tablet has high storage stability, and the pH of the solution after disintegration is close to that of the skin, making it mild and non-irritating.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: A topical effervescent tablet containing agaric extract, comprising the following components by weight percentage: The composition includes: 5%–20% Lithops extract, 15%–30% acid source, 10%–25% alkali source, 20%–40% filler, 2%–8% binder, 1%–5% disintegrant, 0.5%–2% lubricant, 0.1%–1% stabilizer, and 0.5%–3% adhesive. The content of black tea extract in the agar-agar extract is ≥50%.

[0011] As a preferred embodiment, the acid source is a complex of organic acid and polybasic acid, and the base source is a complex of carbonate and bicarbonate. The weight ratio of citric acid to tartaric acid in the acid source is 2:1, and the weight ratio of sodium bicarbonate to sodium carbonate in the alkali source is 4:1.

[0012] As a preferred embodiment, the stabilizer is a compound of vitamin E and EDTA-2Na, and the adhesive is sodium hyaluronate.

[0013] As a preferred embodiment, the effervescent tablet completely disintegrates within 1 to 3 minutes after contact with water, and the pH of the resulting solution is 6.5 to 7.0.

[0014] A method for preparing an effervescent tablet for external use of agaric extract includes the steps of pretreatment, wet granulation, drying and granulation, total mixing, tableting, and nitrogen filling packaging. The wet granulation process uses a 5% povidone K30 ethanol solution as a binder, and the drying is vacuum drying at a temperature of 50℃~70℃.

[0015] An effervescent skin adhesive patch for use in conjunction with topical effervescent tablets of agaric extract, wherein the base of the patch is composed of a copolymer, wherein the copolymer contains components A and C as essential polymeric units, and the moisture content of the patch is less than 10% by mass. Among them, component A is a polysiloxane macromonomer with a number average molecular weight ≥6000, and component C is an alkyl methacrylate. The surface adhesion of the patch is 10-90 g / 10 mm, and the tensile elastic modulus is 0.01-5 MPa.

[0016] As a preferred embodiment, the copolymer further comprises at least one of a fluorinated alkyl polymerizable monomer component B and a monofunctional linear siloxane monomer component M.

[0017] A topical effervescent tablet formulation, comprising the aforementioned agaric extract topical effervescent tablet and an effervescent skin adhesive patch; The effervescent tablet is dissolved and the resulting effervescent solution is loaded onto the surface of the patch and dried until the moisture content is <5%; or, the formulation components of the effervescent tablet are directly loaded onto the surface of the patch and dried; the preparation foams upon contact with water and is applied to the affected area of ​​the skin.

[0018] As a preferred embodiment, the effervescent disintegration time of the formulation after application is 1 to 3 minutes, and the pH of the disintegrated solution is 6.5 to 7.0; The patch maintains a moisture content of <5% for more than 6 hours while in the applied state.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention effectively avoids the acid-base degradation of the active ingredients of agar-agar during effervescence by optimizing the acid source (citric acid and tartaric acid in a 2:1 ratio), the alkali source (sodium bicarbonate and sodium carbonate in a 4:1 ratio), and the stabilizer system (vitamin E and EDTA-2Na). The tablets have high storage stability, and the pH of the liquid after disintegration is close to that of the skin, making them mild and non-irritating.

[0020] 2. The pH value of the effervescent tablets designed in this invention after disintegration in water is precisely controlled at 6.5-7.0, which is close to the normal physiological pH of skin, and the permeability and adhesion are synergistically enhanced: Sodium hyaluronate is added as an adhesive, combined with the physical penetration promotion of effervescent microbubbles, which significantly improves the retention rate of active ingredients in the stratum corneum. In vitro experiments show that the skin retention rate is ≥75%.

[0021] 3. This invention is the first to use a low-moisture polysiloxane-based patch that is compatible with effervescent medications. After application, it is soft and adheres well, does not dry out for a long time, and has a shrinkage rate of <1%, thus solving the problems of traditional patches being easy to fall off and not durable. It is also convenient to use and has high compliance: it can be directly dissolved for wet compresses or used as a patch for immediate application after soaking, simplifying the operation. It is especially suitable for the treatment of psoriasis in active joint areas. Attached Figure Description

[0022] Figure 1 This is a schematic diagram of the layer structure of the effervescent skin adhesive patch in this invention; Figure 2 This is a schematic diagram illustrating the disintegration of the effervescent tablet formulation upon contact with water and its application in this invention. Detailed Implementation

[0023] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0024] It should be understood that, when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components and / or collections thereof.

[0025] It should also be understood that the terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0026] It should also be further understood that the term "and / or" as used in this specification and the appended claims refers to any combination of one or more of the associated listed items and all possible combinations, and includes such combinations.

[0027] Example, refer to Figures 1 to 2 A topical effervescent tablet containing agarwood extract, comprising the following components by weight percentage: 5%–20% agarwood extract, 15%–30% acid source, 10%–25% alkali source, 20%–40% filler, 2%–8% binder, 1%–5% disintegrant, 0.5%–2% lubricant, 0.1%–1% stabilizer, and 0.5%–3% adhesive; the agarwood extract contains ≥50% black tea extract.

[0028] It is worth noting that the acid source is a complex of organic acid and polybasic acid, and the base source is a complex of carbonate and bicarbonate; the weight ratio of citric acid to tartaric acid in the acid source is 2:1, and the weight ratio of sodium bicarbonate to sodium carbonate in the base source is 4:1.

[0029] The stabilizer is a compound of vitamin E and EDTA-2Na; the adhesive is sodium hyaluronate.

[0030] Effervescent tablets completely disintegrate within 1 to 3 minutes after contact with water, and the pH of the resulting solution is 6.5 to 7.0.

[0031] A method for preparing topical effervescent tablets of agaric extract: The process includes pretreatment, wet granulation, drying and granulation, total mixing, tableting, and nitrogen-filled packaging. The wet granulation uses a 5% povidone K30 ethanol solution as a binder, and the drying is done under vacuum at a temperature of 50℃ to 70℃.

[0032] An effervescent skin adhesive patch for use with effervescent tablets: The substrate of the patch is composed of a copolymer, which contains components A and C as essential polymerization units, and the moisture content of the patch is less than 10% by mass; wherein, component A is a polysiloxane macromonomer with a number average molecular weight ≥6000, and component C is (meth)acrylate alkyl ester; the surface adhesion of the patch is 10-90 g / 10 mm, and the tensile elastic modulus is 0.01-5 MPa.

[0033] The copolymer also includes a fluorinated alkyl polymerizable monomer component B and / or a monofunctional linear siloxane monomer component M.

[0034] A topical effervescent tablet formulation: The preparation is made by combining the above-mentioned effervescent tablets containing the extract of Lithops with the above-mentioned effervescent skin adhesive patch. The effervescent liquid formed after the effervescent tablets are dissolved is loaded onto the surface of the patch and dried until the water content is <5%. Alternatively, the formulation components of the effervescent tablets are directly loaded onto the surface of the patch and dried. The preparation foams upon contact with water and is applied to the affected area of ​​the skin.

[0035] Furthermore, the effervescent disintegration time of the formulation after application is 1 to 3 minutes, and the pH of the disintegrated drug solution is 6.5 to 7.0; the patch maintains a moisture content of <5% for more than 6 hours while in the applied state.

[0036] The above-mentioned effervescent tablets or effervescent tablet preparations of Lithops extract are used in the preparation of topical medications for treating psoriasis. The effervescent tablets are dissolved in warm water and then applied as a wet compress, or the effervescent tablet preparations are directly applied to the psoriatic lesions, once or twice a day.

[0037] Examples 1-6: Preparation of effervescent tablets for external use of agaric extract: The effervescent tablet formulations of Examples 1-6 are shown in Table 1 (by weight percentage). Preparation method: The agar extract (containing ≥55% black tea extract) was mixed evenly with the filler and partial disintegrant. A binder (5% povidone K30 ethanol solution) was added, and the mixture was wet-granulated. The granules were then vacuum-dried at 60°C. After granulation, the remaining disintegrant, acid source, alkali source, stabilizer, adhesive, and lubricant were added and mixed together. The mixture was then compressed into tablets to obtain the final product.

[0038] Table 1. Composition of effervescent tablet formulations in each embodiment (by weight %) The effervescent tablets prepared in Examples 1-6 were subjected to sensory characteristics, hardness and friability; disintegration time, pH value, adhesion and in vitro drug release determination. The results are shown in Tables 2-3.

[0039] Table 2 Performance Indicators of Effervescent Tablets from Different Embodiments Table 3 Performance Indicators of Effervescent Tablets in Different Embodiments (II) Example 7: Preparation of effervescent skin adhesive patch substrate: According to the specified weight, 35 parts of dimethacryloyl polydimethylsiloxane (component A, number average molecular weight 8000), 58 parts of trifluoroethyl acrylate (component B), and 7 parts of 2-ethylhexyl acrylate (component C) were mixed with a photoinitiator and solvent, injected into a glass mold, and photocured. After extraction with isopropanol, the mixture was dried at room temperature to obtain a low-moisture effervescent patch substrate (moisture content <1%). Testing showed a surface adhesion of 52 g / 10 mm, a tensile modulus of elasticity of 1.2 MPa, and a drying shrinkage rate of 0.5%.

[0040] After dissolving the effervescent tablets of Example 1 in an appropriate amount of purified water, the effervescent solution was evenly sprayed onto the surface of the patch substrate, vacuum dried at 40°C until the moisture content was <5%, and then sealed and packaged to obtain an external effervescent tablet formulation (Sample A). Similarly, Sample B and Sample C were prepared by loading the effervescent solutions of Examples 3 and 6, respectively.

[0041] Example 8: Comparative preparation: Comparative Example 1: Effervescent tablets were prepared using the same formulation as in Example 1, but with only citric acid (18%) as the acid source and only sodium bicarbonate (15%) as the alkali source. Stabilizers and adhesives were not used.

[0042] Comparative Example 2: A commercially available ointment containing 10% agaric extract.

[0043] Comparative Example 3: Refer to the patch substrate of Example 7, but the substrate is ordinary polyurethane hydrogel (water content 35%), loaded with the same effervescent drug solution.

[0044] Performance testing and results: 1. Disintegration characteristics and pH of effervescent tablets: Examples 1-6: disintegration time 1.4-2.5 min, pH of solution 6.5-6.9; Comparative Example 1: disintegration time 0.8 min, pH of solution 5.2, with obvious irritation.

[0045] 2. In vitro drug release and skin retention rate: The cumulative release over 30 minutes was determined using the Franz diffusion cell method, and the results for all examples were >90%; the skin retention rate (24 hours) for Examples 1-6 was 72.5%–81.3%, for Comparative Example 1 it was 53.2%, and for Comparative Example 2 it was 41.6%, indicating that the effervescent tablets of the present invention significantly enhance penetration and retention.

[0046] 3. Effervescent Patch Adhesion and Durability: Samples A, B, C, and Comparative Example 3 were applied to the human forearm for 8 hours. Samples A and C did not fall off or show any signs of drying and edge lifting, while Comparative Example 3 showed edge lifting and hardening after 4 hours. The adhesion test results for Sample A were 51 g / 10 mm, and for Comparative Example 3, they were 28 g / 10 mm.

[0047] 4. Skin irritation test: The hairless areas on the backs of guinea pigs were treated with the effervescent tablets of Example 1, Comparative Example 1, and physiological saline for 7 consecutive days. No erythema or edema was observed in the Example 1 group, while mild erythema appeared in the Comparative Example 1 group. This indicates that the effervescent tablets of the present invention are mild and non-irritating.

[0048] Stability test: The effervescent tablets of Examples 1-6 were packaged in aluminum-plastic packaging and placed under accelerated conditions (40±2℃, RH 75%±5%) for 6 months and under long-term conditions (25±2℃, RH 60%±5%) for 12 months. Content, dissolution, and related substances were examined. Results showed that after 6 months of accelerated storage, the content of the agaric extract was between 95% and 105% of the labeled amount, the dissolution rate was ≥85%, and the total impurities were <3%, meeting the requirements. There was no significant change in quality after 12 months of long-term storage. In Comparative Example 1, the content decreased to 82% and the dissolution rate was only 71% after 6 months of accelerated storage.

[0049] Animal pharmacodynamic studies: A mouse model of psoriasis induced by imiquimod was used, and mice were randomly divided into four groups: model group, positive control group (tazarotene gel), Example 1 effervescent tablet wet compress group, and Sample A effervescent patch group. Treatment was administered continuously for 14 days, and the skin area and severity index (PASI), epidermal thickness, and inflammatory factor levels were evaluated. Results showed that the PASI scores of the Example 1 group and Sample A group were significantly lower than those of the model group (P < 0.01), epidermal thickness was reduced by more than 50%, and IL-17 and TNF-α levels decreased by 60%–70%. The therapeutic effect was superior to that of the positive control group, and the Sample A group showed higher patient compliance.

[0050] Industrial applicability: The topical effervescent tablets and effervescent patch formulations of Lithops extract provided by this invention have a mature preparation process, readily available raw materials, stable and controllable quality, and are convenient to use. They are suitable for the local treatment of psoriasis (especially plaque psoriasis and oyster shell psoriasis) and have clear industrial practical value and good market prospects.

[0051] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A stone flower extract external use effervescent tablet, characterized by, By weight percentage, it includes the following components: The composition includes: 5%–20% Lithops extract, 15%–30% acid source, 10%–25% alkali source, 20%–40% filler, 2%–8% binder, 1%–5% disintegrant, 0.5%–2% lubricant, 0.1%–1% stabilizer, and 0.5%–3% adhesive. The content of black tea extract in the agar-agar extract is ≥50%.

2. The external use effervescent tablet of Hana extract according to claim 1, characterized by, The acid source is a complex of organic acid and polybasic acid, and the base source is a complex of carbonate and bicarbonate. The weight ratio of citric acid to tartaric acid in the acid source is 2:1, and the weight ratio of sodium bicarbonate to sodium carbonate in the alkali source is 4:

1.

3. The external use effervescent tablet of Hana extract according to claim 1, characterized by, The stabilizer is a compound of vitamin E and EDTA-2Na, and the adhesive is sodium hyaluronate.

4. The external use effervescent tablet of Hana extract according to claim 1, characterized by, The effervescent tablets completely disintegrate within 1 to 3 minutes after contact with water, and the pH of the resulting solution is 6.5 to 7.

0.

5. A method for preparing an effervescent tablet for external use of agaric extract as described in any one of claims 1-4, characterized in that, The process includes pretreatment, wet granulation, drying and sizing, total mixing, tableting, and nitrogen-filled packaging. The wet granulation process uses a 5% povidone K30 ethanol solution as a binder, and the drying is vacuum drying at a temperature of 50℃~70℃.

6. An effervescent skin adhesive patch for use in conjunction with the effervescent tablet of Lithops extract as described in claim 1, characterized in that, The substrate of the patch is composed of a copolymer, wherein component A and component C are essential polymeric units, and the patch has a moisture content of less than 10% by mass. Among them, component A is a polysiloxane macromonomer with a number average molecular weight ≥6000, and component C is an alkyl methacrylate. The surface adhesion of the patch is 10-90 g / 10 mm, and the tensile elastic modulus is 0.01-5 MPa.

7. The effervescent skin adhesive patch according to claim 6, characterized in that, The copolymer further comprises at least one of a fluorinated alkyl polymerizable monomer component B and a monofunctional linear siloxane monomer component M.

8. A topical effervescent tablet formulation, characterized in that, The product is composed of an effervescent tablet for external use of the extract of Glehnia littoralis as described in any one of claims 1-4, and an effervescent skin adhesive patch as described in claim 6 or 7. The effervescent tablet is dissolved and the resulting effervescent solution is loaded onto the surface of the patch and dried until the moisture content is <5%; or, the formulation components of the effervescent tablet are directly loaded onto the surface of the patch and dried; the preparation foams upon contact with water and is applied to the affected area of ​​the skin.

9. A topical effervescent tablet formulation according to claim 8, characterized in that, The formulation has an effervescent disintegration time of 1–3 minutes after application, and the pH of the disintegrated solution is 6.5–7.

0. The patch maintains a moisture content of <5% for more than 6 hours while in the applied state.

10. The use of the topical effervescent tablet of the *Gynostemma pentaphyllum* extract according to any one of claims 1-4 or the topical effervescent tablet formulation according to any one of claims 8-9 in the preparation of a topical treatment for psoriasis, characterized in that, The effervescent tablets can be dissolved in warm water and then used as a wet compress, or the effervescent tablet preparation can be directly applied to the psoriatic lesions, 1 to 2 times daily.

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