阅读说明：本技术 曲尼司特的盐 (Salt of tranilast ) 是由 刘飞 吴刚 郭见桥 尹德燕 赵鑫鑫 于 2020-04-09 设计创作，主要内容包括：曲尼司特的盐。本发明涉及N-(3,4-二甲氧基肉桂酰)邻氨基苯甲酸的盐,尤其是氨丁三醇盐,包含所述盐的药物制剂,及其在制备针对过敏性疾病的药物中的应用。(A salt of tranilast. The invention relates to salts of N- (3, 4-dimethoxycinnamoyl) anthranilic acid, in particular tromethamine salts, pharmaceutical preparations containing said salts, and the use thereof for producing medicaments against allergic diseases.)

Tromethamine salt of N- (3, 4-dimethoxycinnamoyl) anthranilic acid.

2. A pharmaceutical formulation comprising a therapeutic amount of the salt of claim 1 and one or more pharmaceutically acceptable carriers.

3. The pharmaceutical formulation of claim 2, which is a topical formulation.

4. The pharmaceutical formulation of claim 3, wherein the topical formulation is a lotion, cream, gel, ointment, spray or patch.

5. A pharmaceutical formulation according to claim 3, comprising a therapeutic amount of a salt according to claim 1, a penetration enhancer, a thickening agent.

6. The pharmaceutical formulation of claim 5, wherein the penetration enhancer is selected from one or more of pyrrolidones, terpenes, water, amides, amines, cyclodextrins, amino acids and esters thereof, macrocyclic compounds, curdlins, fatty acids, fatty alcohols, esters, sulfoxides, surfactants, polyols, polysorbates, hyaluronidase.

7. The pharmaceutical formulation according to claim 6, wherein the penetration enhancer is selected from the group consisting of saturated or cis-unsaturated fatty acids, saturated or cis-unsaturated fatty alcohols.

8. The pharmaceutical formulation of claim 7, wherein the penetration enhancer is selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, arachidic acid, stearic acid, palmitoleic acid, oleic acid, caprylic acid, linoleic acid, cis-octadecenoic acid, linolenic acid, arachidonic acid, ethanol, isopropanol, propylene glycol, oleyl alcohol, linoleyl alcohol, decanol, lauryl alcohol, stearyl alcohol, and myristyl alcohol.

9. The pharmaceutical formulation of claim 6, wherein the penetration enhancer is selected from the group consisting of povidone, dioctyl sodium sulfosuccinate, isopropyl myristate, monoglyceride, diglyceride, dimethyl sulfoxide, decyl methyl sulfoxide, sodium lauryl sulfate, sodium laurate, sodium lauryl sulfate, polysorbate 80, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium caprate, glycerin, and polyethylene glycol.

10. The pharmaceutical formulation of claim 5, wherein the penetration enhancer is selected from the group consisting of ethanol, isopropanol, propylene glycol, and dimethylsulfoxide.

11. The pharmaceutical formulation of claim 5, wherein the thickening agent is selected from one or more of cellulose, cellulose polymers, cellulose ethers, carbomer polymers, carbomer derivatives, cellulose derivatives, polyethylene glycols, poloxamers, polysaccharides.

12. The pharmaceutical formulation according to claim 5, wherein said thickening agent is selected from one or more of carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol 200-.

13. The pharmaceutical formulation of claim 5, further comprising a solubilizing agent.

14. The pharmaceutical formulation of claim 13, wherein the solubilizing agent is selected from one or more of polysorbates and polyoxyethylene fatty acid esters.

15. The pharmaceutical formulation of claim 14, wherein the solubilizing agent is selected from polysorbate 80.

16. The pharmaceutical formulation of claim 5, further comprising a dissolution medium.

17. The pharmaceutical formulation of claim 16, wherein the dissolution medium is selected from one or more of water, alcohol, sulfoxide; preferably one or more selected from water, ethanol, ethylene glycol, propanol, propylene glycol, isopropanol, butanol and dimethyl sulfoxide.

Technical Field

The invention relates to a medicinal salt of N- (3, 4-dimethoxy cinnamoyl) anthranilic acid, and a medicinal preparation containing the medicinal salt of N- (3, 4-dimethoxy cinnamoyl) anthranilic acid as an effective component, in particular to a local preparation.

Background

Tranilast is a compound other than H₁，H₂Novel receptor competitive antihistaminesThe anti-allergic reaction medicament has a chemical name of N- (3, 4-dimethoxy cinnamoyl) anthranilic acid, and has a structure shown in the following formula (I):

tranilast has the function of stabilizing the cell membrane of mast cells and basophils and preventing degranulation of the mast cells and the basophils. Thereby inhibiting the release of anaphylactic reaction substances such as histamine, 5-hydroxytryptamine and the like, having remarkable inhibiting effect on rat skin anaphylactic reaction and experimental asthma caused by lgE antibody, and being a therapeutic drug aiming at the causes of anaphylactic disease occurrence mechanisms. The traditional Chinese medicine composition is mainly used for treating bronchial asthma, allergic rhinitis, atopic dermatitis, keloids or hypertrophic scars in clinic.

Known dosage forms of tranilast include oral solid preparations such as tablets, capsules, granules and the like. After oral tranilast is absorbed into the liver from the digestive tract through the portal vein, the drug is metabolized and only a portion of the drug is delivered to the local site, reducing bioavailability. In order to maintain effective blood concentration, a large amount of medicine needs to be taken, and side effects are easily caused. The external preparation can be directly applied to local skin, can control the concentration of the drugs in blood, reduces the probability of side effects, and is favorable for treating atopic dermatitis, keloid or hypertrophic scars.

The resistance to the invasion of foreign substances from the outside of the body into the body is an inherent property of the skin, and in order to obtain an effective blood concentration of the drug, it is important to improve the transdermal absorption degree of the drug. The degree of transdermal absorption of a drug depends on the characteristics of the molecule, which greatly limits the preparation of drugs that can achieve effective transdermal absorption.

Tranilast is extremely difficult to dissolve in water, methanol, ethanol and ethyl acetate, and because the solubility of tranilast is not high, the tranilast cannot be well dispersed in a preparation, so that the transdermal absorbability of a medicament is influenced, and an external preparation is difficult to form. Therefore, there is a need to develop a tranilast salt form having improved physical properties, which is suitable for preparation into an external preparation and is easily permeable through the skin.

No specific tranilast salt is disclosed in US3940422, nor is any particular property of the salt mentioned. The present inventors have long made efforts to find that the preparation of tranilast as a pharmaceutically acceptable salt of the present invention can solve the above problems.

Disclosure of Invention

Aiming at the problems of low solubility, strong hygroscopicity, poor bioavailability, poor transdermal absorbability and the like of tranilast, the inventor finds that the problem can be solved by preparing the tranilast into the medicinal salt of the invention through long-term efforts. Compared with tranilast free acid or tranilast sodium salt, the medicinal salt provided by the invention has unexpected excellent properties and is more suitable for further development.

The invention provides a medicinal salt of tranilast, preferably the medicinal salt is tromethamine salt.

The invention also provides a pharmaceutical preparation comprising a therapeutic amount of a pharmaceutically acceptable salt of tranilast and optionally one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable salt is selected from diethylamine salt, diethanolamine salt and tromethamine salt.

In one embodiment, the pharmaceutical formulation of the invention is a topical formulation, preferably a self-lotion, cream, gel, ointment, spray or patch.

In one embodiment, the pharmaceutical formulation of the invention comprises a therapeutic amount of tranilast diethanolamine salt, tromethamine salt or diethylamine salt, a penetration enhancer and a thickening agent.

In another embodiment, the penetration enhancer in the pharmaceutical formulation of the present invention is selected from one or more of pyrrolidones, terpenes, water, amides, amines, cyclodextrins, amino acids and esters thereof, macrocyclic compounds, curdlins, fatty acids, fatty alcohols, esters, sulfoxides, surfactants, polyols, polysorbates, hyaluronidase.

In a preferred embodiment, the penetration enhancer in the pharmaceutical formulation of the present invention is selected from the group consisting of saturated or cis-unsaturated fatty acids, saturated or cis-unsaturated fatty alcohols.

In a more preferred embodiment, the penetration enhancer in the pharmaceutical formulation of the present invention is selected from one or more of capric acid, lauric acid, myristic acid, palmitic acid, arachidic acid, stearic acid, palmitoleic acid, oleic acid, caprylic acid, linoleic acid, cis-octadecenoic acid, linolenic acid, arachidonic acid, ethanol, isopropanol, propylene glycol, oleyl alcohol, linoleyl alcohol, decanol, lauryl alcohol, stearyl alcohol, and myristyl alcohol.

In a preferred embodiment, the penetration enhancer in the pharmaceutical formulation of the present invention is selected from one or more of povidone, dioctyl sodium sulfosuccinate, isopropyl myristate, monoglyceride, diglyceride, dimethyl sulfoxide, decyl methyl sulfoxide, sodium lauryl sulfate, sodium laurate, sodium lauryl sulfate, polysorbate 80, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium caprate, glycerin, and polyethylene glycol.

In another embodiment, the penetration enhancer in the pharmaceutical formulation of the present invention is selected from one or more of ethanol, isopropanol, propylene glycol, and dimethylsulfoxide.

In another embodiment, the thickening agent in the pharmaceutical formulation of the present invention is selected from one or more of cellulose, cellulose polymers, cellulose ethers, carbomer polymers, carbomer derivatives, cellulose derivatives, polyethylene glycols, poloxamers, polysaccharides.

In a preferred embodiment, the thickening agent in the pharmaceutical formulation of the present invention is selected from one or more of carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol 200-.

In another embodiment, the pharmaceutical formulation of the present invention further comprises a solubilizing agent.

In a preferred embodiment, the solubilizing agent in the pharmaceutical formulation of the present invention is selected from polysorbates and polyoxyethylene fatty acid esters

In another embodiment, the pharmaceutical formulation of the present invention further comprises a dissolution medium.

In a preferred embodiment, the dissolution medium in the pharmaceutical formulation of the present invention is selected from one or more of water, alcohol, sulfoxide; preferably one or more selected from water, ethanol, ethylene glycol, propanol, propylene glycol, isopropanol, butanol and dimethyl sulfoxide.

The invention further provides a topical pharmaceutical preparation, which comprises 1-20% w/w of tranilast diethanolamine salt, tromethamine salt or diethylamine salt, 10-90% w/w of a penetration enhancer, 0.5-15% w/w of a thickening agent, and 1-85% w/w of a dissolving medium.

In one embodiment, the topical pharmaceutical formulation of the invention comprises 1-10% w/w tranilast diethanolamine salt, tromethamine salt or diethylamine salt, preferably selected from 2-9% w/w, 3-8% w/w, 4-6% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w tranilast tromethamine salt or diethylamine salt.

In one embodiment, the topical pharmaceutical formulation of the invention comprises 20-75% w/w of a penetration enhancer, preferably 25-60% w/w, 30-55% w/w, 30-50% w/w, 30-45% w/w, 30-40% w/w, 30-35% w/w of a penetration enhancer, more preferably from 20% w/w, 21% w/w, 22% w/w, 23% w/w, 24% w/w, 25% w/w, 26% w/w, 27% w/w, 28% w/w, 29% w/w, 30% w/w, 31% w/w, 32% w/w, 33% w/w, 34% w/w, 35% w/w, 36% w/w, 37% w/w, 38% w/w, 39% w/w, 40% w/w, 41% w/w, 42% w/w, 43% w/w, 44% w/w, 45% w/w, 46% w/w, 47% w/w, 48% w/w, 49% w/w, 50% w/w, 51% w/w, 52% w/w, 53% w/w, 54% w/w, 55% w/w, 56% w/w, 57% w/w, 58% w/w, 59% w/w, 60% w/w of the penetration enhancer.

In one embodiment, the topical pharmaceutical formulation of the present invention comprises 0.5-10% w/w, 0.5-9% w/w, 0.5-8% w/w, 0.5-7% w/w, 0.5-6% w/w, 0.5-5% w/w, 0.5-4% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1% w/w; preferably a thickener selected from the group consisting of 0.5% w/w, 1% w/w, 1.5% w/w, 2% w/w, 2.5% w/w, 3% w/w, 3.5% w/w, 4% w/w, 4.5% w/w, 5% w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 7.5% w/w, 8% w/w, 8.5% w/w, 9% w/w, 9.5% w/w, 10% w/w.

In one embodiment, the penetration enhancer in the topical pharmaceutical formulation of the present invention is selected from one or more of pyrrolidones, terpenes, water, amides, amines, cyclodextrins, amino acids and esters thereof, macrocyclic compounds, curdlins, fatty acids, fatty alcohols, esters, sulfoxides, surfactants, polyols, polysorbates, hyaluronidase.

In another embodiment, the penetration enhancer in the topical pharmaceutical formulation of the present invention is selected from the group consisting of saturated or cis-unsaturated fatty acids, saturated or cis-unsaturated fatty alcohols.

In a preferred embodiment, the penetration enhancer in the topical pharmaceutical formulation of the invention is selected from one or more of capric acid, lauric acid, myristic acid, palmitic acid, arachidic acid, stearic acid, palmitoleic acid, oleic acid, caprylic acid, linoleic acid, cis-octadecenoic acid, linolenic acid, arachidonic acid, ethanol, isopropanol, propylene glycol, oleyl alcohol, linoleyl alcohol, decyl alcohol, lauryl alcohol, stearyl alcohol, myristyl alcohol.

In another embodiment, the penetration enhancer in the topical pharmaceutical formulation of the present invention is selected from one or more of povidone, dioctyl sodium sulfosuccinate, isopropyl myristate, monoglyceride, diglyceride, dimethyl sulfoxide, decyl methyl sulfoxide, sodium lauryl sulfate, sodium laurate, sodium lauryl sulfate, polysorbate 80, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium caprate, glycerin, polyethylene glycol.

In another embodiment, the penetration enhancer in the topical pharmaceutical formulation of the present invention is selected from one or more of ethanol, isopropanol, propylene glycol, dimethylsulfoxide.

In another embodiment, the thickening agent in the topical pharmaceutical formulation of the present invention is selected from one or more of cellulose, cellulose polymers, cellulose ethers, carbomer polymers, carbomer derivatives, cellulose derivatives, polyethylene glycols, poloxamers, polysaccharides.

In a preferred embodiment, the thickening agent in the topical pharmaceutical formulation of the invention is selected from one or more of carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol 200-.

In one embodiment, the topical pharmaceutical formulation of the invention further comprises 0.1-5% w/w, 0.1-4% w/w, 0.1-3% w/w, 0.1-2% w/w, 0.1-1% w/w, 0.1-0.5% w/w of a solubilizing agent, preferably 0.1% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w, 1% w/w, 1.1% w/w, 1.2% w/w, 1.3% w/w, 1.4% w/w, 1.5% w/w, 1.6% w/w, 1.7% w/w, 1.8% w/w, 1.9% w/w, 1.2% w/w, 1.3% w/w, 1.4% w/w, 1.5% w, 2% w/w, 2.3% w/w, 2.4% w/w, 2.5% w/w, 2.6% w/w, 2.7% w/w, 2.8% w/w, 2.9% w/w, 3% w/w, 3.1% w/w, 3.2% w/w, 3.3% w/w, 3.4% w/w, 3.5% w/w, 3.6% w/w, 3.7% w/w, 3.8% w/w, 3.9% w/w, 4% w/w, 4.1% w/w, 4.2% w/w, 4.3% w/w, 4.4% w/w, 4.5% w/w, 4.6% w/w, 4.7% w/w, 4.8% w/w, 4.9% w/w, 5% w/w of a solubilizer.

In another embodiment, the solubilizing agent in the topical pharmaceutical formulation of the present invention is selected from one or more of polysorbates and polyoxyethylene fatty acid esters; preferably polysorbate 80.

In one embodiment, the topical pharmaceutical formulation of the present invention the dissolution medium is selected from one or more of water, alcohol, sulfoxide; preferably one or more selected from water, ethanol, ethylene glycol, propanol, propylene glycol, isopropanol, butanol and dimethyl sulfoxide.

The invention also provides a local medicinal preparation, which comprises 1-20% w/w of tranilast diethanolamine salt, tromethamine salt or diethylamine salt, 10-90% w/w of a penetration enhancer, 0.5-15% w/w of a thickening agent, 0.1-5% w/w of a solubilizer and 1-85% w/w of a dissolving medium; wherein the penetration enhancer is selected from one or a mixture of isopropanol and propylene glycol, the thickener is selected from carbomer 980, the solubilizer is selected from polysorbate 80, and the dissolving medium is selected from water.

The invention also provides a local medicinal preparation, which comprises 1-20% w/w of tranilast diethanolamide salt, tromethamine salt or diethylamine salt, 10-90% w/w of a mixture of isopropanol and propylene glycol, 0.5-15% w/w of carbomer 980, 0.1-5% w/w of polysorbate 80, and 1-85% w/w of water.

In one embodiment, the topical pharmaceutical formulation preferably comprises 5% w/w tranilast diethanolamine, tromethamine or diethylamine salt.

In one embodiment, the topical pharmaceutical formulation preferably comprises a 30% w/w mixture of isopropyl alcohol and propylene glycol.

In one embodiment, the topical pharmaceutical formulation preferably comprises 1% w/w carbomer 980.

In one embodiment, the topical pharmaceutical formulation preferably comprises 0.5% w/w polysorbate 80.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w tranilast diethanolamine salt, tromethamine salt or diethylamine salt, 30% w/w isopropanol and propylene glycol in admixture, 1% w/w carbomer 980, 0.5% w/w polysorbate 80, 63.5% w/w water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w tranilast tromethamine salt, 30% w/w isopropanol and propylene glycol in admixture, 1% w/w carbomer 980, 0.5% w/w polysorbate 80, 63.5% w/w water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w of tranilast diethanolamine salt, 30% w/w of a mixture of isopropanol and propylene glycol, 1% w/w of carbomer 980, 0.5% w/w of polysorbate 80, 63.5% w/w of water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w of tranilast diethylamine salt, 30% w/w of a mixture of isopropanol and propylene glycol, 1% w/w of carbomer 980, 0.5% w/w of polysorbate 80, 63.5% w/w of water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w tranilast tromethamine salt, 10% w/w isopropanol, 20% w/w propylene glycol, 1% w/w carbomer 980, 0.5% w/w polysorbate 80, 63.5% w/w water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w tranilast diethanolamine salt, 10% w/w isopropanol, 20% w/w propylene glycol, 1% w/w carbomer 980, 0.5% w/w polysorbate 80, 63.5% w/w water.

The invention also provides a topical pharmaceutical formulation comprising 5% w/w of tranilast diethylamine salt, 10% w/w isopropanol, 20% w/w propylene glycol, 1% w/w carbomer 980, 0.5% w/w polysorbate 80, 63.5% w/w water.

The invention also provides an application of the medicinal salt of tranilast or a medicinal preparation containing the medicinal salt of tranilast in preparing a medicament for treating allergic diseases. The allergic disease includes bronchial asthma, allergic rhinitis, atopic dermatitis, keloids or hypertrophic scars.

The term "therapeutic amount" as used herein refers to an amount that results in an improvement in any parameter or clinical symptom. The actual dosage may vary from patient to patient and does not necessarily refer to the total amount that eliminates all disease symptoms.

The term "transdermal" as used herein generally includes processes through the skin.

The term "topical pharmaceutical formulation" as used herein generally includes formulations which can be applied to the skin or mucous membranes. Topical pharmaceutical formulations are useful for topical and transdermal administration of substances.

The term "permeation enhancer" as used herein generally includes agents that are capable of enhancing the transport of molecules (e.g., drugs) such as active agents into or through the skin. Various conditions may occur at different locations in the body, whether the skin or beneath the skin, and thus there is a need for targeted delivery of compounds. "penetration enhancers" may be used to help deliver the active agent directly to the skin or underlying tissue or indirectly to the site of disease through systemic distribution. The penetration enhancer may be a pure substance or may comprise a mixture of different chemical substances.

Tranilast of the present invention can be purchased commercially or can be prepared according to known methods.

Detailed Description

The invention discloses a compound medicinal salt, a medicinal preparation containing the medicinal salt, a medicinal salt and application of the medicinal salt and the medicinal preparation, and a person skilled in the art can realize the compound medicinal salt by appropriately improving process parameters according to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The invention is further illustrated by the following examples:

preparation of medicinal salt of tranilast