CN117815399A - Composition for treating atopic dermatitis, preparation method and application thereof - Google Patents
Composition for treating atopic dermatitis, preparation method and application thereof Download PDFInfo
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Abstract
Disclosed herein is a composition for treating atopic dermatitis, which comprises hyaluronic acid or a salt thereof, osthole extract, cryptotanshinone extract. The application also provides a hydrogel patch and a method for preparing the hydrogel patch. The present application also provides a use of hyaluronic acid or a salt thereof for improving transdermal absorption of osthole extract and/or cryptotanshinone extract. The composition for treating atopic dermatitis provided by the application comprises hyaluronic acid or salt thereof, osthole extract and cryptotanshinone extract with specific components, so that the composition can effectively release the osthole extract and the cryptotanshinone extract in the hydrogel patch, and has better effect of treating atopic dermatitis.
Description
Technical Field
The application relates to the field of medicines, in particular to a composition for treating atopic dermatitis, a preparation method and application thereof.
Background
Atopic dermatitis (atopic dermatitis, AD), also known as atopic dermatitis, is a chronic, recurrent, inflammatory skin disease, with prevalence of up to 18% and 7% for children and adults, respectively, and showing a year-by-year rising trend, and is mainly clinically manifested by severe itching, recurrent attacks and longer course of disease, dry skin, chronic eczematoid skin lesions, severely affecting the quality of life of the patient.
The external drug treatment mainly comprises local external glucocorticoid, calcineurin inhibitor, antimicrobial agent, physiological sodium chloride solution, black soya bean distillate oil ointment and the like, but skin and system adverse reactions such as local burning, irritation and the like are easy to occur when the hormone is used for a long time in a large area, so that the compliance of patients is poor; the systemic treatment modes such as an antihistamine, an anti-inflammatory mediator, a systemic anti-infective drug, an immunosuppressant and the like are mainly suitable for patients with serious illness and difficult control of conventional therapy, and the indications and contraindications of related drugs are needed to be paid attention to during use, so that adverse reactions are closely monitored. Compared with western medicine treatment with great side effect, poor patient compliance and the like, the traditional Chinese medicine has certain advantages in the aspects of improving the clinical symptoms of patients with mild-moderate atopic dermatitis, reducing the recurrence rate and the like, and has higher safety.
Osthole (Osthole, ost) also known as methoxy Parslephenol or Parsley methyl ether, has chemical name of 7-methoxy-8-isopentenyl coumarin, can be used for treating skin itch by antiallergic reaction, and has certain analgesic and antiinflammatory effects. Cryptotanshinone (CTS) is a monomer compound extracted from radix salviae miltiorrhizae, has antioxidant, anti-inflammatory and anticancer effects, and researches show that the application of cryptotanshinone on the back of mice has a certain effect on treating atopic dermatitis of mice. Thus, it is contemplated that osthole and cryptotanshinone may be used in combination for the treatment of atopic dermatitis.
At present, osthole and cryptotanshinone are often applied as oral administration preparations, traditional Chinese medicine bath preparations or ointment preparations, and other traditional Chinese medicine-derived atopic dermatitis preparations in the prior art are also mostly oral administration preparations or ointment preparations, for example, CN112870286A discloses an oral traditional Chinese medicine preparation for treating atopic dermatitis, and CN113041296A discloses an ointment for treating atopic dermatitis. However, oral formulations have certain toxic and side effects on the irritation of the gastrointestinal tract; multiple administrations are required in order to maintain a stable blood concentration; is not suitable for infants, the elderly and patients with coma. The ointment has poor spreadability, often causes uneven spreading and is greasy, the atopic dermatitis is mainly characterized by skin itch, the affected part is spread on the antecubital fossa, the popliteal fossa, the wrist flexor side, the eyelid, the face and the neck, the spreading range is wider, the ointment is easy to pollute clothes in the use process, and the defects cause the reduced compliance of patients on the dosage forms, thus also greatly limiting the clinical application of the ointment.
The hydrogel patch has large drug-loading capacity, can avoid adverse reactions of oral preparations and paste, can keep moisture in hydrogel to moisten skin, can effectively improve symptoms such as skin dryness and skin peeling, can improve skin itch, can be used for treating atopic dermatitis, but can effectively release medicine components in the hydrogel patch, particularly fat-soluble medicine components, which is an important factor for limiting the application of the hydrogel patch.
Disclosure of Invention
In order to solve the above problems, the present application provides a composition for treating atopic dermatitis, which comprises hyaluronic acid or a salt thereof, osthole extract and cryptotanshinone extract of a specific composition, so that the composition can effectively release osthole extract and cryptotanshinone extract in the composition, and has a better effect of treating atopic dermatitis.
The application provides a composition for treating atopic dermatitis, which comprises hyaluronic acid or salt thereof, osthole extract and cryptotanshinone extract.
Further, the mass ratio of the hyaluronic acid or the salt thereof to the osthole extract and the cryptotanshinone extract is as follows: 0.05 to 1:0.6 to 14:0.3 to 8.
Further, the molecular weight of the hyaluronic acid or the salt thereof is 40 ten thousand to 200 ten thousand daltons, preferably 80 ten thousand to 150 ten thousand daltons.
The present application provides a hydrogel patch comprising the aforementioned composition.
Further, the hydrogel patch also comprises a cross-linked framework, a cross-linking agent and a polyol.
Further, in the hydrogel patch, the adhesive layer,
the content of the hyaluronic acid or the salt thereof is 0.05 to 1 part by weight,
The content of the osthole extract is 0.6 to 14 weight parts,
The content of the cryptotanshinone extract is 0.3 to 8 weight parts,
The content of the cross-linked framework is 0.1 to 10 parts by weight,
The content of the cross-linking agent is 0.01 to 0.5 part by weight,
The content of the polyol is 5-30 parts by weight.
Further, the polyhydric alcohol is one or more selected from glycerol, 1, 3-propylene glycol, 1, 2-propylene glycol, butylene glycol, dipropylene glycol, sorbitol, isosorbide and 1, 2-pentanediol.
Further, the cross-linked backbone comprises sodium polyacrylate, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, or carbomer.
Further, the crosslinking agent comprises aluminum glycinate, aluminum chloride, aluminum starch, alum or aluminum hydroxide.
The application provides a method for preparing the hydrogel patch, which comprises the following steps:
adding osthole extract and cryptotanshinone extract into polyalcohol, and dispersing to obtain solution A;
adding hyaluronic acid or salt thereof into water for injection, and stirring uniformly to obtain solution B;
adding the solution A into the solution B, and stirring to obtain a colloid C;
and coating and cutting the colloid C to obtain the hydrogel patch.
Further, a crosslinking skeleton and a crosslinking agent are added to the solution A.
The present application provides the use of hyaluronic acid or a salt thereof for improving transdermal absorption of osthole extract and/or cryptotanshinone extract.
The present application provides a use of hyaluronic acid or a salt thereof to facilitate release of osthole extract and/or cryptotanshinone extract from a transdermal formulation.
The present application provides a use of hyaluronic acid or a salt thereof to facilitate release of osthole extract and/or cryptotanshinone extract from a hydrogel patch.
The composition for treating atopic dermatitis has the advantages of simple components and high safety, the prepared hydrogel patch is convenient to use, has good comfort, does not feel greasy, is free from washing, does not hinder the normal physiological action of skin, has a certain water-retaining effect, can promote the release of medicines from the hydrogel patch, is beneficial to the transdermal absorption of the medicines, and has obvious improvement and treatment effects on atopic dermatitis.
The composition for treating atopic dermatitis provided by the application can be prepared into gel patches, has large drug loading, does not need to add percutaneous absorption promoters, can improve the release of osthole extracts and cryptotanshinone extracts in the gel patches, promotes the penetration of the osthole extracts and cryptotanshinone extracts into the stratum corneum, and has the effect of treating atopic dermatitis.
Detailed Description
Exemplary embodiments of the present application are described below, including various details of embodiments of the present application to facilitate understanding, which should be considered as merely exemplary. Accordingly, one of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.
Osthole (Osthole, ost) is also known as methoxy Parslephenol or Parsley methyl ether, and has chemical name of 7-methoxy-8-isopentenyl coumarin, and has analgesic and antiinflammatory effects.
Cryptotanshinone (CTS) is a monomer compound extracted from Saviae Miltiorrhizae radix, is orange needle crystal, and has natural antioxidant, atherosclerosis resisting, myocardial oxygen consumption reducing, and other cardiovascular effects, and antibacterial, antiinflammatory, and antitumor effects.
The inventor finds that the osthole extract and the cryptotanshinone extract have the effect of treating atopic dermatitis after being combined. However, osthole and cryptotanshinone are often applied as oral administration preparations, traditional Chinese medicine bath preparations or ointment preparations, and have certain toxic and side effects on the irritation to gastrointestinal tracts; multiple administrations are required in order to maintain a stable blood concentration; is not suitable for infants, the elderly and patients with coma.
If the osthole extract and the cryptotanshinone extract are prepared into paste, the coating property is poor, the phenomenon of uneven coating is easy to occur, and the paste is greasy.
Based on the above, the present application provides a composition for treating atopic dermatitis, which comprises hyaluronic acid or a salt thereof, osthole extract, cryptotanshinone extract, wherein the mass ratio of hyaluronic acid or a salt thereof, osthole extract, cryptotanshinone extract is: 0.05 to 1:0.6 to 14:0.3 to 8, preferably 0.1 to 0.3: 4-12: 2 to 6.
When the mass of the hyaluronic acid or salt thereof is 0.05,
the osthole extract may have a mass of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9.2, 9.4, 9.6, 9.8, 10, 10.2, 10.4, 10.6, 10.8, 11.2, 11.11.2, 11.11.11.11, 11.12, 13.12.
The mass of the cryptotanshinone extract may be 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 7, 8.
When the mass of the hyaluronic acid or salt thereof is 0.1,
the osthole extract may have a mass of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9.2, 9.4, 9.6, 9.8, 10, 10.2, 10.4, 10.6, 10.8, 11.2, 11.11.2, 11.11.11.11, 11.12, 13.12.
The mass of the cryptotanshinone extract may be 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 7, 8.
When the mass of the hyaluronic acid or salt thereof is 0.2,
the osthole extract may have a mass of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9.2, 9.4, 9.6, 9.8, 10, 10.2, 10.4, 10.6, 10.8, 11.2, 11.11.2, 11.11.11.11, 11.12, 13.12.
The mass of the cryptotanshinone extract may be 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 7, 8.
When the mass of the hyaluronic acid or salt thereof is 0.3,
the osthole extract may have a mass of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9.2, 9.4, 9.6, 9.8, 10, 10.2, 10.4, 10.6, 10.8, 11.2, 11.11.2, 11.11.11.11, 11.12, 13.12.
The mass of the cryptotanshinone extract may be 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 7, 8.
When the mass of the hyaluronic acid or salt thereof is 1.0,
the osthole extract may have a mass of 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9.2, 9.4, 9.6, 9.8, 10, 10.2, 10.4, 10.6, 10.8, 11.2, 11.11.2, 11.11.11.11, 11.12, 13.12.
The mass of the cryptotanshinone extract may be 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 7, 8.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.05:6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.1:6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.3:6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 1:6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:6:0.3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:6:2.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:6:6.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:0.6:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:4:3.
In some embodiments, the mass ratio of hyaluronic acid or salt thereof, osthole extract, cryptotanshinone extract is 0.2:12:3.
In the present application, the molecular weight of the hyaluronic acid or salt thereof is 40 to 200 kilodaltons, preferably 80 to 150 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-150 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-160 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-170 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-180 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-190 kilodaltons.
In some embodiments, the hyaluronic acid or salt thereof has a molecular weight of 80-200 kilodaltons.
Specifically, the molecular weight of the hyaluronic acid or the salt thereof may be 40 ten thousand daltons, 50 ten thousand daltons, 60 ten thousand daltons, 70 ten thousand daltons, 80 ten thousand daltons, 90 ten thousand daltons, 100 ten thousand daltons, 110 ten thousand daltons, 120 ten thousand daltons, 130 ten thousand daltons, 140 ten thousand daltons, 150 ten thousand daltons, 160 ten thousand daltons, 170 ten thousand daltons, 180 ten thousand daltons, 190 ten thousand daltons, 200 ten thousand daltons.
In the present application, the hyaluronic acid or a salt thereof is selected from one of hyaluronic acid, sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, magnesium hyaluronate, and calcium hyaluronate, preferably sodium hyaluronate.
Sodium Hyaluronate (HA) is used as a physiological necessary substance of a human body, widely exists in a cell matrix in a living body, HAs no species difference, no immunogenicity, is safe and nontoxic, and HAs good biodegradability and biocompatibility. The water solubility of the water-soluble paint has viscosity, water retention and lubricity. HA HAs good moisturizing effect and is known as an ideal natural moisturizing factor. The skin care product added with HA is compatible with skin, and can quickly permeate into deep skin; a hydration film is formed on the skin surface, so that the moisture of the horny layer is effectively maintained.
Clinically, in order to improve the drug release in the transdermal drug delivery preparation and improve the permeation rate of the transdermal drug delivery preparation into the stratum corneum, a transdermal absorption promoter is mainly added into the preparation. The following requirements should be satisfied by the ideal percutaneous absorption enhancer: (1) non-toxic, non-irritating, non-allergic; (2) The effect is rapid, the effect time and the effect part are controllable; (3) no pharmacological activity; (4) Only reduces the barrier function of skin to the drug without causing loss of endogenous substances; (5) reversible changes to the stratum corneum; (6) no incompatibility with medicines. The first clinically used transdermal enhancers were chemical transdermal enhancers such as dimethyl sulfoxide, ethanol, propylene glycol, oleic acid, azone, etc., however, they all have far away from the ideal properties of the above-mentioned transdermal enhancers, thus greatly limiting their clinical application.
The application finds that after hyaluronic acid or salt thereof is combined with osthole extract and cryptotanshinone extract, the release of the osthole extract and the cryptotanshinone extract from the hydrogel patch can be promoted without adding a percutaneous absorption promoter, so that the efficiency of treating atopic dermatitis by the osthole extract and the cryptotanshinone extract is improved, and simultaneously, the curative effect of the combined hyaluronic acid or salt thereof, the osthole extract and the cryptotanshinone extract on the atopic dermatitis is better than that of the osthole extract and/or the cryptotanshinone extract.
The application also provides a hydrogel patch comprising the composition.
In the present application, the hydrogel patch further comprises a polyol, a cross-linked backbone, and a cross-linking agent.
In this application, the hydrogel patch further includes a pH adjuster.
In some embodiments, the hydrogel patch is composed of hyaluronic acid or a salt thereof, osthole extract, cryptotanshinone extract, polyol, cross-linked backbone, cross-linking agent, pH adjuster, and water.
In some embodiments, in the hydrogel patch,
the content of the hyaluronic acid or the salt thereof is 0.05 to 1 weight part;
the content of the osthole extract is 0.6-14 parts by weight;
the content of the cryptotanshinone extract is 0.3-8 parts by weight;
the content of the cross-linked framework is 0.1-10 parts by weight;
the content of the cross-linking agent is 0.01-0.5 weight part;
the content of the polyol is 5-30 parts by weight.
The content of the pH regulator is 0.01-2.0 parts by weight.
The balance being water.
In some embodiments, in the hydrogel patch,
the content of the hyaluronic acid or the salt thereof is 0.1-0.3 weight part;
the content of the osthole extract is 4-12 parts by weight;
the content of the cryptotanshinone extract is 2-6 parts by weight;
the content of the cross-linked framework is 0.1-10 parts by weight;
the content of the cross-linking agent is 0.01-0.5 weight part;
the content of the polyol is 5-30 parts by weight.
The content of the pH regulator is 0.01-2.0 parts by weight.
The balance being water.
Specifically, in the hydrogel patch, the content of the hyaluronic acid or the salt thereof may be 0.05 part by weight, 0.06 part by weight, 0.07 part by weight, 0.08 part by weight, 0.09 part by weight, 0.1 part by weight, 0.11 part by weight, 0.12 part by weight, 0.13 part by weight, 0.14 part by weight, 0.15 part by weight, 0.16 part by weight, 0.17 part by weight, 0.18 part by weight, 0.19 part by weight, 0.2 part by weight, 0.21 part by weight, 0.22 part by weight, 0.23 part by weight, 0.24 part by weight, 0.25 part by weight, 0.26 part by weight, 0.27 part by weight, 0.28 part by weight, 0.29 part by weight, 0.3 part by weight, 0.35 part by weight, 0.4 part by weight, 0.45 part by weight, 0.50 part by weight, 0.55 part by weight, 0.6 part by weight, 0.65 part by weight, 0.7 part by weight, 0.75 part by weight, 0.85 part by weight, 0.95, 0.1 part by weight, or 0.21 part by weight.
In the hydrogel patch, the content of the osthole extract is 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, 5.5 parts by weight, 6 parts by weight, 6.5 parts by weight, 7 parts by weight, 7.5 parts by weight, 8 parts by weight, 8.5 parts by weight, 9 parts by weight, 9.5 parts by weight, 10 parts by weight, 10.5 parts by weight, 11 parts by weight, 11.5 parts by weight, 12 parts by weight, 12.5 parts by weight, 13 parts by weight, 13.5 parts by weight or 14 parts by weight.
In the hydrogel patch, the content of the cryptotanshinone extract may be 0.3 part by weight, 0.4 part by weight, 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1 part by weight, 1.5 part by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, 5.5 parts by weight, 6 parts by weight, 6.5 parts by weight, 7 parts by weight, 7.5 parts by weight, or 8 parts by weight.
In the hydrogel patch, the content of the crosslinked skeleton may be 0.1 part by weight, 0.2 part by weight, 0.3 part by weight, 0.4 part by weight, 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, 5.5 parts by weight, 6 parts by weight, 6.5 parts by weight, 7 parts by weight, 7.5 parts by weight, 8 parts by weight, 8.5 parts by weight, 9 parts by weight, 9.5 parts by weight, or 10 parts by weight.
In the hydrogel patch, the crosslinking agent may be contained in an amount of 0.01 part by weight, 0.02 part by weight, 0.03 part by weight, 0.04 part by weight, 0.05 part by weight, 0.06 part by weight, 0.07 part by weight, 0.08 part by weight, 0.09 part by weight, 0.1 part by weight, 0.11 part by weight, 0.12 part by weight, 0.13 part by weight, 0.14 part by weight, 0.15 part by weight, 0.16 part by weight, 0.17 part by weight, 0.18 part by weight, 0.19 part by weight, 0.2 part by weight, 0.21 part by weight, 0.22 part by weight, 0.23 part by weight, 0.24 part by weight, 0.25 part by weight, 0.26 part by weight, 0.27 part by weight, 0.28 part by weight, 0.29 part by weight, 0.3 part by weight, 0.31 part by weight, 0.32 part by weight, 0.33 part by weight, 0.34 part by weight, 0.35 part by weight, 0.36 part by weight, 0.37 part by weight, 0.38 part by weight, 0.44 part by weight, 0.45 part by weight, 0.44 part by weight, 0.45.
In the hydrogel patch, the content of the polyhydric alcohol may be 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight, 15 parts by weight, 16 parts by weight, 17 parts by weight, 18 parts by weight, 19 parts by weight, 20 parts by weight, 21 parts by weight, 22 parts by weight, 23 parts by weight, 24 parts by weight, 25 parts by weight, 26 parts by weight, 27 parts by weight, 28 parts by weight, 29 parts by weight, or 30 parts by weight.
In the present application, the polyol is one selected from glycerol, 1, 3-propanediol, 1, 2-propanediol, butanediol, dipropylene glycol, sorbitol, isosorbide, and 1, 2-pentanediol, preferably glycerol.
In the present application, the cross-linked backbone is selected from one of sodium polyacrylate, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, and carbomer, preferably sodium polyacrylate.
In the present application, the crosslinking agent is selected from one of aluminum glycinate, aluminum chloride, aluminum starch, alum and aluminum hydroxide, preferably aluminum glycinate.
In this application, the pH adjuster is disodium edentate and/or tartaric acid.
The application provides a method for preparing the hydrogel patch, which comprises the following steps:
step one: adding osthole extract and cryptotanshinone extract into polyalcohol, and dispersing to obtain solution A;
step two: adding hyaluronic acid or salt thereof into water for injection, and stirring uniformly to obtain solution B;
step three: adding the solution A into the solution B, and starting stirring to obtain a colloid C;
step four: and coating and cutting the colloid C to obtain the hydrogel patch.
In the first step, the osthole and the cryptotanshinone are prepared by adopting an ethanol extraction method. In view of the fact that the patch acts by diffusion, in order to make the active ingredient more easily released from the patch, the present application dissolves osthole ethanol extract and cryptotanshinone ethanol extract in the polyhydric alcohol, which can further promote the absorption of the active ingredient by the skin.
In the present application, both the osthole extract and the cryptotanshinone extract can be obtained by commercial means.
In some embodiments, the osthole extract is obtained by organic solvent extraction, for example, by ethanol extraction.
In some embodiments, the osthole extract is prepared by:
weighing appropriate amount of fructus Cnidii, pulverizing, sieving, adding ethanol solution, reflux extracting, filtering, collecting medicinal liquid, and concentrating under reduced pressure to obtain osthole extract.
In some embodiments, the cryptotanshinone extract is obtained by organic solvent extraction, e.g., by ethanol extraction.
In some embodiments, the cryptotanshinone extract is prepared by the steps of:
weighing appropriate amount of Saviae Miltiorrhizae radix, pulverizing, sieving, adding ethanol solution, ultrasonic extracting, filtering, collecting medicinal liquid, and concentrating under reduced pressure to obtain cryptotanshinone extract.
Further, the osthole extract is prepared by the following steps:
weighing and crushing an appropriate amount of fructus cnidii, sieving with a 30-80 mesh sieve, adding an ethanol solution with concentration of 75% which is 10-30 times of the weight of the medicinal materials, carrying out reflux extraction for 30-90 min at 50-80 ℃, filtering, reserving medicinal liquid, and carrying out reduced pressure concentration to obtain the osthole extract.
In some embodiments, the cryptotanshinone extract is prepared by the steps of:
weighing appropriate amount of Saviae Miltiorrhizae radix, pulverizing, sieving, adding ethanol solution, ultrasonic extracting, filtering, collecting medicinal liquid, and concentrating under reduced pressure to obtain cryptotanshinone extract.
Further, the cryptotanshinone extract is prepared by the following steps:
weighing a proper amount of the red sage root medicinal material, crushing, sieving with a 50-100 mesh sieve, adding an ethanol solution with the concentration of 95% and the weight of 8-20 times of the medicinal material, performing ultrasonic extraction for 20-60 min, filtering, reserving medicinal liquid, and performing reduced pressure concentration to obtain the cryptotanshinone extract.
And a cross-linking framework and a cross-linking agent are also added into the solution A.
In the second step, a pH adjuster is also added to the solution B.
The pH value of the hydrogel patch is 4.0-7.5, and can be, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0 and 7.5. Because the product is in direct contact with the surface of human skin, the pH value should be close to the pH value of the surface of human skin. Studies have shown that the pH of the skin surface ranges from 4.0 to 7.5. The skin can be in the best state of absorbing nutrition only in the normal pH value range, and the skin is in the best state of resisting external erosion, elasticity, luster, moisture and the like.
The gel patch has large drug-loading capacity, can avoid adverse reactions of oral preparations and paste, can keep skin moist by water in hydrogel, can effectively improve symptoms such as skin dryness and skin peeling, can also improve the condition of skin itch, and can effectively release osthole extract and cryptotanshinone extract in the gel patch for treating atopic dermatitis.
The preparation method of the gel patch comprises the following steps:
step one: adding osthole extract, cryptotanshinone extract, crosslinked skeleton and crosslinking agent into polyalcohol, and dispersing to obtain solution A;
step two: adding hyaluronic acid or salt thereof into water for injection, and stirring uniformly to obtain solution B;
step three: adding the solution A into the solution B, and starting stirring to obtain a colloid C;
step four: coating, slitting, curing and packaging the colloid C;
step five: and (5) carrying out terminal sterilization on the packaged product to obtain the gel patch.
In the first step, both the osthole and the cryptotanshinone can be prepared by adopting an ethanol extraction method or are commercially available. Considering that the gel composition can be subsequently prepared into a patch, the patch acts by diffusion, and in order to make the active ingredient easier to release from the patch, the application dissolves osthole ethanol extract and cryptotanshinone ethanol extract in polyalcohol, so that the active ingredient can be absorbed by skin better.
In the present application, the pH of the gel patch is 4.0 to 7.5, and may be, for example, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5. Because the product is in direct contact with the surface of human skin, the pH value should be close to the pH value of the surface of human skin. Studies have shown that the pH of the skin surface ranges from 4.0 to 7.5. The skin can be in the best state of absorbing nutrition only in the normal pH value range, and the skin is in the best state of resisting external erosion, elasticity, luster, moisture and the like.
In the first step, the osthole extract is 0.6-14 parts by weight, the cryptotanshinone extract is 0.3-8 parts by weight, the crosslinking skeleton is 0.1-10 parts by weight, the crosslinking agent is 0.01-0.5 parts by weight, and the polyol is 5-30 parts by weight.
In the second step, a pH regulator and hyaluronic acid or a salt thereof are also added to form a solution B for injection. The hyaluronic acid or the salt thereof is 0.05 to 1 weight part, and the pH regulator is 0.01 to 2.0 weight parts.
In the fifth step, the terminal sterilization adopts ionization radiation sterilization, and the sterilization dosage is 10-20 kGy.
Examples
The experimental methods used in the following examples are conventional methods, if no special requirements are imposed.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Preparation of composition for treating atopic dermatitis
Preparation of osthole extract: weighing and crushing an appropriate amount of fructus cnidii, sieving with a 40-mesh sieve, adding an ethanol solution with concentration of 75% which is 20 times of the weight of the medicinal material, carrying out reflux extraction at 65 ℃ for 45min, filtering, collecting a medicinal liquid, and carrying out reduced pressure concentration under the conditions of 60 ℃ and minus 0.06 to minus 0.09MPa to obtain the osthole extract.
Preparation of cryptotanshinone extract: weighing and crushing a proper amount of the red sage root medicinal material, sieving with a 80-mesh sieve, adding ethanol solution with the concentration of 95% which is 12 times of the weight of the medicinal material, performing ultrasonic extraction for 30min, filtering, reserving medicinal liquid, and performing reduced pressure concentration under the conditions of 60 ℃ and minus 0.06 to minus 0.09MPa to obtain the cryptotanshinone extract.
Example 1-1
The composition for treating atopic dermatitis of this example contains 0.2g of sodium hyaluronate (molecular weight of 100 kilodaltons), 6g of osthole extract, and 3g of cryptotanshinone extract.
Examples 1-2 to 1-5 differ from example 1 in the molecular weight of sodium hyaluronate.
Examples 1-6 to 1-9 differ from example 1 in the amount of sodium hyaluronate added.
Examples 1-10 to 1-12 differ from example 1 in the amount of cryptotanshinone extract added.
Examples 1-13 to 1-15 differ from example 1 in the amount of osthole extract added.
Comparative examples 1 to 1
A composition for treating atopic dermatitis comprises 6g of osthole extract and 3g of cryptotanshinone extract.
Comparative examples 1 to 2
A composition for the treatment of atopic dermatitis comprising 0.2g sodium hyaluronate (molecular weight 100 kilodaltons).
Comparative examples 1 to 3
A composition for treating atopic dermatitis comprises 6g of osthole extract and 0.3g of cryptotanshinone extract.
Comparative examples 1 to 4
A composition for treating atopic dermatitis comprises 6g of osthole extract and 2g of cryptotanshinone extract.
Comparative examples 1 to 5
A composition for treating atopic dermatitis comprises 6g of osthole extract and 6g of cryptotanshinone extract.
Comparative examples 1 to 6
A composition for treating atopic dermatitis comprises osthole extract 0.6g and cryptotanshinone extract 3g.
Comparative examples 1 to 7
A composition for treating atopic dermatitis comprises 4g osthole extract and 3g cryptotanshinone extract.
Comparative examples 1 to 8
A composition for treating atopic dermatitis comprises osthole extract 12g and cryptotanshinone extract 3g.
Example 2 hydrogel patch
Adding osthole extract, cryptotanshinone extract, crosslinking skeleton, crosslinking agent and edetate disodium in the compositions of the examples 1-15 or the comparative examples 1-8 into polyalcohol, and dispersing uniformly to obtain solution A; adding sodium hyaluronate and tartaric acid in the composition of the example or the comparative example into water for injection, and uniformly stirring to obtain a solution B; adding the solution A into the solution B, starting stirring at a rotating speed of 50+/-2 r/min, and stirring until a viscous colloid C is formed; transferring the colloid C to a hydrogel coating machine for coating and cutting, and packaging when no colloid substance remains when the isolating layer is solidified and removed; and (3) carrying out terminal sterilization on the packaged product to obtain the gel patches of examples 2-1 to 2-15 or comparative examples 2-1 to 2-8. The components of this example are shown in tables 1 and 2.
Table 1 shows the contents of sodium hyaluronate, osthole extract and cryptotanshinone in each example
Table 2 shows the compositions of the hydrogel patches of the examples
Experimental example effect test
First), in vitro transdermal diffusion test
The test method comprises the following steps: (1) preparation of isolated mouse skin: SD rats were sacrificed by cervical scission, the abdominal skin of the rats was immediately peeled off, dehaired with 8% sodium sulfide solution, and the excess subcutaneous tissue carefully removed, cleaned with normal saline, and stored at 4deg.C for later use, and used up within one week. The integrity of the skin was checked before testing to avoid breakage. (2) transdermal diffusion test method: the treated skin was held between a Franz diffusion cell supply cell and a receiving cell, with the stratum corneum facing the supply cell, the receiving cell filled with saline and purged of air bubbles. Taking a test sample, cutting the test sample into test samples with the size of about 25mm multiplied by 25mm, sealing and fixing the test samples (gel patches prepared in examples 2-1 to 2-15 and comparative examples 2-1 to 2-8) on mouse skin, keeping the temperature at 37 ℃ for starting timing, taking out all the received liquid at 24h, concentrating to 1.5mL, and measuring the content of osthole and cryptotanshinone. Wherein the receiving tank volume is 15mL.
And (3) calculating the accumulated permeability:
wherein Q is the accumulated permeability, C is the concentration of osthole and cryptotanshinone in the receiving liquid for 24 hours, V is the volume of the receiving liquid, and m is the mass of the initial osthole and cryptotanshinone contained in the gel.
TABLE 3 cumulative permeability comparison
| Sample of | Osthole cumulative permeability (%) | Cumulative permeation rate of cryptotanshinone (%) |
| Example 2-1 | 96.26 | 95.47 |
| Example 2-2 | 92.81 | 90.15 |
| Examples 2 to 3 | 96.27 | 95.41 |
| Examples 2 to 4 | 96.25 | 95.47 |
| Examples 2 to 5 | 96.29 | 95.50 |
| Examples 2 to 6 | 91.76 | 89.03 |
| Examples 2 to 7 | 96.24 | 95.45 |
| Examples 2 to 8 | 96.29 | 95.50 |
| Examples 2 to 9 | 96.35 | 95.54 |
| Examples 2 to 10 | 96.23 | 9.62 |
| Examples 2 to 11 | 96.24 | 81.03 |
| Examples 2 to 12 | 96.26 | 95.51 |
| Examples 2 to 13 | 9.83 | 95.48 |
| Examples 2 to 14 | 82.63 | 95.50 |
| Examples 2 to 15 | 96.32 | 95.46 |
| Comparative example 2-1 | 59.24 | 51.72 |
| Comparative examples 2 to 2 | —— | —— |
| Comparative examples 2 to 3 | 59.23 | 3.01 |
| Comparative examples 2 to 4 | 59.25 | 41.28 |
| Comparative examples 2 to 5 | 59.25 | 51.76 |
| Comparative examples 2 to 6 | 3.24 | 51.74 |
| Comparative examples 2 to 7 | 42.91 | 51.70 |
| Comparative examples 2 to 8 | 59.29 | 51.73 |
As can be seen from table 3, when the experiment comparative examples 2-1, 2-3 to 2-8 are not added with hyaluronic acid, the cumulative permeability of osthole and cryptotanshinone is lower, which indicates that osthole and cryptotanshinone in the hydrogel patch are not easy to release from the gel patch, thereby affecting the transdermal absorption effect; experimental examples 2-1 to 2-15 after adding hyaluronic acid, the cumulative permeability of osthole and cryptotanshinone is obviously improved, which shows that the hyaluronic acid can promote the release of osthole and cryptotanshinone from the gel patch, and the transdermal absorption effect of osthole and cryptotanshinone is improved.
Second, mouse ear swelling experiment
Experiments were performed using an ear swelling model as an animal model of atopic dermatitis. The 20 male Balb/c mice were randomly divided into five groups of 4, which were blank group, model group, control group 1 (example 2-1), control group 2 (comparative example 2-1), and control group 3 (comparative example 2-2), respectively.
The abdomen of the mice was dehaired about 2X 2cm 24h before the experiment 2 Treatment, 50 μl of 0.5% dnfb (acetone: olive oil=4:1) solution was applied to the back of mice except for the blank group at 1d, 20 μl of 0.2% dnfb (acetone: olive oil=4:1) solution was applied to the right ear of mice at 5d instead, 50 μl was applied to the back of mice, and the stimulation was repeated at 8, 11, and 14 days. The blank served as a control and was not stimulated at all. The skin lesions such as hypertrophy, red swelling and the like of the right ear of the 11 d-th mouse are regarded as successful modeling.
Test samples of example 2-1 and comparative examples 2-1 to 2-2 were closed and fixed to the right ears of mice in the morning and evening except for the blank group and the model group from 11d, and 7d was continuously administered, and 0.9% physiological saline was administered to the blank group and model group mice. After the treatment, the thickness of the right ear (the same position) of the mouse was measured by a vernier caliper.
Table 4 comparison table of ear swelling degree of mice
| Group of | Ear swelling degree/thickness (mm) |
| Blank group | 0.376 |
| Model group | 0.904a |
| Control group 1 (example 2-1) | 0.712b |
| Control group 2 (comparative example 2-1) | 0.862 |
| Control group 3 (comparative examples 2-2) | 0.871 |
( a represents that P is less than 0.05 and has difference significance compared with a blank group; b represents that P is less than 0.05 and has difference significance compared with the model group )
The small knot: compared with a blank group, the ears of the mice in the model group are obviously swollen and thickened (P is less than 0.05), and the difference has statistical significance, so that the model is successfully modeled; compared with the model group, the ear swelling of the control group 1 is obviously reduced (P is less than 0.05), and the difference has statistical significance, so that the hydrogel patch has good inhibition effect on the ear swelling.
Third), performance detection and effect evaluation
Test object: example 2-1 (treatment group), aloe vera gel (control group).
The test method comprises the following steps:
1. the scheme is as follows: a randomized controlled trial study was performed with the treatment group and the control group.
2. Grouping: the patients are received 120 times, the ages are 2-70 years, 50 times are female, 70 times are male, the total disease course is half a year at the shortest and 3 years at the longest. The patients have no statistical significance in comparison of differences in age, sex and disease severity, and have comparability. 60 cases of the treatment group and the control group were tested.
Williams diagnostic criteria were used:
(1) The main standard is as follows: it is necessary to have skin itch.
(2) Secondary standard: (1) pre-2 years old onset (for patients over 4 years old); (2) history of eczema of flexor dermatitis including fossa, anterior malleoli, neck (children under 10 years old including cheeks); (3) there has been a history of systemic skin dryness in recent years; (4) other allergic diseases such as asthma or pollinosis are in the personal history, or allergic diseases in the first-class relatives; (5) eczema is visible on the flexor side (or on the cheek/forehead and limb extension side for children under 4 years old).
(3) Determining a standard: major standard +3 or more minor standards.
Treatment criteria:
the calculation formula (nimodipine method) is evaluated according to the four-level efficacy standard: treatment efficiency = (pre-treatment score-post-treatment score)/(pre-treatment score) ×100%;
basic cure: the skin damage completely subsides, the itching symptom completely disappears, and the total curative effect rate is not less than 90%;
the effect is shown: most of skin damage is resolved, pruritus symptom is obviously reduced, total therapeutic efficiency is more than or equal to 60% and less than or equal to 90%;
the method is effective: the skin damage part is resolved, the pruritus symptom is improved, the total therapeutic efficiency is more than or equal to 20% and less than or equal to 60%;
invalidation: the skin damage has no obvious change, the pruritus symptom is not improved or even aggravated, and the total therapeutic efficiency is less than 20 percent.
3. The treatment method comprises the following steps: the test subjects apply or smear (the smear amount is just enough to see the smear layer) on the affected part in the morning and evening every day, and the test subjects need to use continuously. No other medicines are used during the treatment period, the treatment course is 1 day, and the curative effect is evaluated after 12 treatment courses.
4. Analysis of results:
(1) the therapeutic effect is shown in Table 5.
Table 5 comparison of the efficacy of two groups of cases
The small knot: the treatment group has obvious effect after 12 treatment courses, and the total effective rate is 96.7%, which shows that the invention can effectively improve and treat atopic dermatitis.
(2) Security analysis
No adverse reactions were seen in the treatment groups during the treatment period.
In conclusion, the gel patch has good effect of improving and treating atopic dermatitis, has no irritation to skin, and is safe and effective.
Although embodiments of the present application have been described above, the present application is not limited to the specific embodiments and fields of application described above, which are merely illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may make numerous forms, and equivalents thereof, without departing from the scope of the invention as defined by the claims.
Claims (10)
1. A composition for treating atopic dermatitis comprises hyaluronic acid or its salt, osthole extract, and cryptotanshinone extract.
2. The composition according to claim 1, wherein the mass ratio of hyaluronic acid or its salt, osthole extract, cryptotanshinone extract is: 0.05 to 1:0.6 to 14:0.3 to 8.
3. The composition of claim 1 or 2, wherein the hyaluronic acid or salt thereof has a molecular weight of 40-200 kilodaltons.
4. A hydrogel patch comprising the composition of any one of claims 1-3.
5. The hydrogel patch of claim 4, wherein the hydrogel patch further comprises a cross-linked backbone, a cross-linking agent, and a polyol.
6. The hydrogel patch according to claim 4 or 5, wherein, in the hydrogel patch,
the content of the hyaluronic acid or the salt thereof is 0.05 to 1 part by weight,
The content of the osthole extract is 0.6 to 14 weight parts,
The content of the cryptotanshinone extract is 0.3 to 8 weight parts,
The content of the cross-linked framework is 0.1 to 10 parts by weight,
The content of the cross-linking agent is 0.01 to 0.5 part by weight,
The content of the polyol is 5-30 parts by weight.
7. The hydrogel patch according to claim 5 or 6, wherein,
the polyalcohol is one or more than two selected from glycerol, 1, 3-propylene glycol, 1, 2-propylene glycol, butanediol, dipropylene glycol, sorbitol, isosorbide and 1, 2-pentanediol;
the cross-linked framework comprises sodium polyacrylate, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch or carbomer;
the cross-linking agent comprises aluminum glycinate, aluminum chloride, aluminum starch, alum or aluminum hydroxide.
8. A method of preparing the hydrogel patch of any one of claims 4-7, comprising the steps of:
adding osthole extract and cryptotanshinone extract into polyalcohol, and dispersing to obtain solution A;
adding hyaluronic acid or salt thereof into water for injection, and stirring uniformly to obtain solution B;
adding the solution A into the solution B, and stirring to obtain a colloid C;
and coating and cutting the colloid C to obtain the hydrogel patch.
9. The method according to claim 8, wherein a crosslinking skeleton and a crosslinking agent are further added to the solution a.
10. Use of hyaluronic acid or a salt thereof for improving transdermal absorption of osthole extract and/or cryptotanshinone extract.
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