阅读说明：本技术 遮光剂及其组合物 (Sunscreen and compositions thereof ) 是由 冯杰 张甡午 刘永波 陈桔英 于 2019-10-16 设计创作，主要内容包括：本发明揭示了一种遮光剂,该遮光剂为氨茴酸尿囊素复合盐。本发明还揭示了一种光稳定性较高的甲氨蝶呤制剂/组合物,该制剂/组合物包括甲氨蝶呤、氨茴酸尿囊素复合盐。(The invention discloses a sunscreen agent which is an allantoin anthranilate composite salt. The invention also discloses a methotrexate preparation/composition with higher light stability, which comprises methotrexate and allantoin anthranilate complex salt.)

1. A sunscreen agent is anthranilic allantoin composite salt.

2. A methotrexate preparation/composition with high light stability comprises methotrexate and opacifier allantoin anthranilate complex salt.

3. A methotrexate preparation/composition with high light stability comprises a physical mixture of methotrexate and opacifier allantoin anthranilate complex salt, or a solid solution of the methotrexate and opacifier allantoin anthranilate complex salt.

4. The formulation/composition according to claim 3, said physical mixture or solid solution being further processed into granules, tablets, capsules.

5. The formulation/composition according to claim 3, said physical mixture being prepared by: preparing a solution containing anthranilic acid and allantoin (or adding other carrier components or additives at once, mixing uniformly), volatilizing the solvent of the solution to form an anisic acid-urocystine compound salt, and mixing the compound salt with methotrexate (or other carrier components or additives) to obtain the preparation/composition (physical mixture), wherein the solvent is water or alcohol or a mixture thereof; or

The preparation method of the solid solution comprises the following steps: preparing solution containing methotrexate, anthranilic acid and allantoin (or further adding other carrier components or additives, mixing well), and volatilizing solvent of the above solution to obtain preparation/composition (solid solution) containing methotrexate, anthranilic acid and allantoin composite salt, wherein the above solvent is water or alcohol or mixture thereof.

6. The formulation/composition according to claim 2 or 3, wherein the mass ratio of the allantoin anthranilate complex salt to the methotrexate is 1:0.01-1:100 (wt/wt).

7. A methotrexate preparation/composition with high light stability is a preparation/composition of a solid solution of mesoporous silica-loaded methotrexate and allantoin anthranilate complex salt.

8. The formulation/composition according to claim 7, wherein the mesoporous silica has a pore size of 3-300 nm.

9. The formulation/composition according to claim 7, wherein the mesoporous silica has a pore size of 3-30 nm.

10. A formulation/composition according to claim 2 or 3, which comprises further carrier ingredients or additives.

Technical Field

The invention relates to a light screening agent, a composition thereof and a preparation method thereof.

Background

Rheumatoid Arthritis (RA) is an autoimmune disease that involves joint synovial inflammation as the main component and the whole body. Methotrexate (MTX) is used as a first-choice core drug for treating rheumatoid arthritis at present, can regulate abnormal immunity of patients, remarkably reduce cartilage destruction and bone erosion, control aggravation of bone diseases, prevent or delay joint destruction, reduce disability and play an important role in treatment for controlling disease course progression.

However, methotrexate (insoluble in water, ethanol, etc., but soluble in acidic or basic solutions) is unstable to light, and causes a decrease in the amount of methotrexate and the formation of analogs in the case of large exposure, thereby increasing harmful analogs, decreasing the efficacy as an active substance, causing adverse reactions in patients due to long-term large-scale administration, and decreasing the compliance of patients with drugs.

Due to the light instability of the methotrexate, the methotrexate needs to be protected from light in the preparation and storage processes, so that the stability of the methotrexate preparation is improved, the toxic and side effects of the medicine are reduced, and the patient adaptability in the clinical application process is improved.

For the formulation of such a photo-labile drug, several methods are known for improving its stability, such as:

patent CN109475557 discloses a method for ensuring photostability in which decrease in the content of methotrexate as an active ingredient due to light and the formation of the like are suppressed by film-coating with an iron oxide in the film-coated layer and uncoated tablets. However, the method introduces an iron oxide component which can form iron ions under the action of acid or alkali, and the iron ions have an accelerating catalysis effect on the conventional chemical reaction and can greatly influence the quality and the curative effect of the product.

In order to solve the problem of photostability of a methotrexate preparation, the patent CN109985248A discloses that polydopamine or polymethyl dopa formed by polymerizing dopamine or methyldopa under an alkaline condition is wrapped on the surface of a mesoporous material to block the release of methotrexate, so that the photostability of the methotrexate is improved, the toxic and side effects of the methotrexate are reduced, and the patient adaptability is improved.

CN102164606 in order to solve the problem of photostability of methotrexate formulations, a photostabilizer is added to a pharmaceutical composition containing hyaluronic acid-methotrexate conjugate. The term "light stabilizer" refers to a substance having an extinction effect of absorbing energy from a molecule in an excited state by light irradiation, a radical trapping effect of trapping radicals, or both of these effects. The matting agent is preferably a substance having an effect of suppressing the generation of fluorescence emitted from the HA-MTX conjugate excited by irradiation with light of 320 to 430nm (matting effect). Examples of the light stabilizer having a matting effect and/or a radical trapping effect which can be suitably used in the present invention include the following compounds (a) to (c).

(a) Sulfur-containing inorganic or organic acids and their salts

This group of compounds includes, for example, sodium thiosulfate, thioglycolic acid, ammonium thioglycolate, sodium thioglycolate, potassium thioglycolate, ethyl thioglycolate, thiomalic acid, ammonium thiomalate, sodium thiomalate, potassium thiomalate, mercaptopropionic acid, ammonium mercaptopropionate, sodium mercaptopropionate and potassium mercaptopropionate.

Preferred compounds are thiosulphuric acid, sodium thiosulphate, thioglycolic acid, ammonium thioglycolate, sodium thioglycolate, potassium thioglycolate and ethyl thioglycolate.

Particularly preferred compounds are thiosulphuric acid, sodium thiosulphate and sodium thioglycolate.

(b) Aromatic amino acid derivative and salt thereof

This group of compounds includes, for example, N-acetyl tryptophan, tryptophan methyl ester, tryptophan ethyl ester, tyrosine and phenylalanine and salts thereof.

Preferred compounds are N-acetyl tryptophan and tryptophan.

A particularly preferred compound is N-acetyl tryptophan.

Salts of these amino acid derivatives are not particularly limited and include, for example, acid addition salts such as hydrochloride, nitrate, sulfate, phosphate, etc.; and base addition salts such as sodium salt, potassium salt, calcium salt, aluminum salt, zinc salt, iron salt, ammonium salt, tetrabutylammonium salt, and the like.

(c) Hydroxybenzoic acids and salts thereof

This group of compounds includes, for example, salicylic acid, sodium salicylate, methyl salicylate, ethyl salicylate, phenyl salicylate, benzyl salicylate, isoamyl salicylate, methyl paraben (methyl paraben), ethyl paraben, propyl paraben, n-butyl paraben, isobutyl paraben, 4-hydroxybenzoic acid, sodium 4-hydroxybenzoate, 3-hydroxybenzoic acid and sodium 3-hydroxybenzoate.

Preferred compounds are salicylic acid, sodium salicylate, methyl paraben and propyl paraben.

Particularly preferred compounds are salicylic acid, sodium salicylate and methyl paraben.

The main drawbacks of the above-mentioned techniques are: the absorption and interception abilities of ultraviolet UVA wave band and UVB wave band with strong penetrating power are relatively weak, the content of methotrexate is reduced, analogs are generated, more harmful analogs are added, and the efficacy of active substances is reduced.

According to the biological effect, the ultraviolet rays are divided into four bands according to the wavelength:

UVA wave band

The wavelength is 320-400 nm, also called long-wave black spot effect ultraviolet ray. It has strong penetrating power and can penetrate most transparent glass and plastics. More than 98% of long-wave ultraviolet rays contained in sunlight can penetrate through an ozone layer and a cloud layer to reach the earth surface, UVA can directly reach the dermis layer of the skin, elastic fibers and collagen fibers are damaged, and the skin is tanned.

UVB band

The wavelength is 290-320 nm, also known as medium wave erythema effect ultraviolet. The medium penetrating power, the shorter wavelength part of which is absorbed by the transparent glass, the most part of the medium ultraviolet rays contained in sunlight are absorbed by the ozone layer, less than 2% of which can reach the earth's surface, and the medium penetrating power is particularly strong in summer and afternoon. UVB ultraviolet rays have erythema effect on human body, and can promote mineral metabolism and vitamin D formation in vivo, but long-term or excessive irradiation can make skin tan and cause red swelling and desquamation.

UVC wave band

The wavelength is 200-275 nm, also called short wave sterilization ultraviolet. It has the weakest penetrating power and can not penetrate most transparent glass and plastics. The short-wave ultraviolet rays contained in sunlight are almost completely absorbed by the ozone layer. The short wave ultraviolet ray has great harm to human body, can burn skin after short time irradiation, and can cause skin cancer after long time or high intensity irradiation. The ultraviolet germicidal lamp emits UVC short-wave ultraviolet rays.

UVD wave band

Wavelength of 100-200 nm, also known as vacuum ultraviolet.

Therefore, the problem of photostability of methotrexate preparations still needs to be improved, and a methotrexate preparation with higher photostability is still needed in reality.

Disclosure of Invention

The invention aims to provide a methotrexate preparation/composition with higher photostability.

The inventor finds that adding the allantoin anthranilate complex salt to the methotrexate preparation/composition can better solve the problem of photostability of the methotrexate preparation/composition. On the basis, the above purpose is achieved.

The invention relates to a sunscreen agent which is an anthranilic allantoin composite salt.

The invention relates to a methotrexate preparation/composition with high light stability, which comprises methotrexate and allantoin anthranilate complex salt.

The sunscreen compound of the anthranilic acid and the allantoin overcomes the defects that the absorption of the anthranilic acid (anthranilic acid) or the ester thereof on UVB is weak, and the absorption of UVA near 34Onm is mainly weak, the compound of the anthranilic acid and the allantoin is compatible with the double effects of absorbing UVA and UVB, so that broad-spectrum protection can be obtained, the protection on methotrexate is better than the effect of using the anthranilic acid and the ester thereof or the allantoin alone, and is also better than the physical mixture of the anthranilic acid and the allantoin, because the physical mixture of the anthranilic acid and the allantoin is difficult to be uniformly mixed with the methotrexate on a microscopic scale (complete UVA and UVB double protection cannot be obtained), and the compound of the anthranilic acid and the allantoin is easier to achieve, so that more complete UVA and UVB double protection can be obtained.

The methotrexate preparation/composition with high photostability can be a physical mixture containing methotrexate and allantoin anthranilate complex salt or a solid solution containing methotrexate and allantoin anthranilate complex salt, and the physical mixture or the solid solution can be prepared into preparations such as granules, tablets and capsules.

The preparation method of the solid solution containing the methotrexate and allantoin compound salt comprises preparing a solution containing methotrexate, anthranilic acid and allantoin (or adding other carrier components or additives at once, mixing uniformly), and volatilizing the solvent of the solution (such as spray drying) to obtain a preparation/composition (solid solution) containing the methotrexate and allantoin compound salt; the solvent is water or alcohol (such as ethanol, propanol, butanol) or mixture thereof.

The physical mixture of methotrexate and allantoin anthranilate complex salt is prepared by preparing a solution containing anthranilic acid and allantoin (or adding other carrier components or additives thereto at once, mixing them well), volatilizing the solvent of the above solution (such as spray drying) to form an ascorbyl anisate complex salt, and mixing the complex salt with methotrexate (or other carrier components or additives) to obtain the preparation/composition (physical mixture); the solvent is water or alcohol (such as ethanol, propanol, butanol) or mixture thereof.

The invention relates to a methotrexate preparation/composition with high light stability, which comprises methotrexate, an allantoin anthranilate complex salt (and other carrier components or additives), wherein the mass ratio of the allantoin anthranilate complex salt to the methotrexate is usually 1:0.01-1:100(wt/wt), preferably 1:0.1-1:10(wt/wt), more preferably 1:0.2-1:5(wt/wt), and most preferably 1:0.3-1:3 (wt/wt).

The methotrexate preparation/composition having high photostability according to the present invention is preferably a preparation/composition in which methotrexate and an allantoin complex salt (solid solutions of both) are supported on mesoporous silica. The mesoporous silica is mSiO2 with the pore diameter of 3-300 (preferably, 3-100, more preferably, 3-30, most preferably, 5-10, such as 7) nm, the drug loading rate is 10-80%, and the mass ratio of methotrexate to silica is 1:1-1: 10. The preferable preparation/composition is prepared by dispersing methotrexate and mesoporous silica in an anthranilic acid solution (or allantoin), adding allantoin (or anthranilic acid), mixing them uniformly, volatilizing the solvent (e.g., spray drying) to form an allantoin anthranilate complex salt, and adsorbing the methotrexate and allantoin complex salt in the pores of the mesoporous silica to obtain a preparation/composition of the methotrexate and allantoin complex salt with good light stability. The adopted mesoporous silica has good biocompatibility, uniform structure and high drug loading rate and loading rate.

The formulation/composition of the present invention may contain other conventional carrier components or additives therein as long as the effects of the present invention are not impaired. As carrier components or additives, there may be exemplified: excipient, disintegrating agent, binder, lubricant, antioxidant, preservative, cosolvent, surfactant, fluidizing agent, plasticizer, pH regulator, colorant, correctant, sweetener, flavoring agent, adsorbent, antiseptic, humectant, etc. These carrier components or additives may be used alone or in combination of two or more.

Examples of the excipient include: sugar alcohols (e.g., D-sorbitol, pentaerythritol, xylitol, and powdered reduced maltose), saccharides (e.g., lactose, glucose, fructose, and white sugar), and hydrates thereof, crystalline cellulose, powdered cellulose, starches (e.g., potato starch, corn starch, and wheat starch), dextrin, β -cyclodextrin, sodium carboxymethylcellulose, light anhydrous silicic acid, hydrous silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminum magnesium metasilicate, synthetic hydrotalcite, talc, and kaolin.

As the disintegrant, for example, there can be exemplified: carboxymethylcellulose (e.g., carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crystalline cellulose sodium carboxymethylcellulose, etc.), carboxymethyl starch (e.g., sodium carboxymethyl starch, etc.), crospovidone, low-substitution hydroxypropyl cellulose, low-substitution sodium hydroxymethyl starch, starch (e.g., corn starch, etc.), alginic acid, bentonite, and the like. Preferable examples can be given: croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crystalline cellulose sodium carboxymethyl cellulose, and low-substitution sodium hydroxy methyl starch. It may be more preferably exemplified that: low-substitution hydroxypropyl cellulose, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch. These disintegrants may be used singly or in any combination of two or more.

As the lubricant, there can be exemplified: stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hardened oil, polyethylene glycol, polydimethylsiloxane, carnauba wax, sodium lauryl sulfate, beeswax, white beeswax, and the like. These lubricants may be used singly or in combination of two or more. Among these lubricants, stearate such as magnesium stearate is commonly used.

As the fluidizing agent, there can be exemplified: light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like.

[ examples ] A method for producing a compound

The present invention is explained in more detail below with reference to examples, but the present invention should not be construed as being limited to only the following examples.