阅读说明：本技术 一种含有芳基丙酸类化合物的药物组合物 (Pharmaceutical composition containing aryl propionic acid compounds ) 是由 闵涛 徐烨 胡情姣 宿连征 陈晨 曹卫 李瑜 于 2019-04-23 设计创作，主要内容包括：本发明提供了一种包含式Ⅰ化合物即(S)-2-(4-(((1R,2S)-2-羟基环戊基)甲基)苯基)丙酸的药物组合物,该药物组合物可以是多种制剂形式,包括注射剂、口服固体制剂、外用半固体制剂等。本发明还提供了上述药物组合物的制备方法,以及这些药物组合物在制备用于解热、镇痛、消炎药物中的用途。本发明药物组合物具有用药剂量较小、药效发挥较快、毒副作用较小的优点,在镇痛、解热、消炎的临床治疗领域具有广阔前景。(The invention provides a pharmaceutical composition containing a compound of formula I, namely (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, which can be in various preparation forms, including injections, oral solid preparations, external semi-solid preparations and the like. The invention also provides a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in preparing antipyretic, analgesic and anti-inflammatory drugs. The pharmaceutical composition has the advantages of small dosage, quick drug effect and small toxic and side effects, and has wide prospects in the clinical treatment fields of analgesia, antipyresis and inflammation diminishing.)

1. The chemical name of the compound of the formula I is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, the structural formula is shown as follows,

。

2. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula i according to claim 1 in combination with a pharmaceutically acceptable excipient in the form of tablets, capsules, granules, powders, dry suspensions, lyophilized powders, injections, suspensions, emulsions for injections, drops for suspensions, syrups, oral solutions, eye drops, nasal drops, ointments, creams, gels, patches, cataplasms, gel patches, gels, suppositories, sprays.

3. The pharmaceutical composition according to claim 2, which is an injection, preferably an injection solution, comprising a main drug, a cosolvent, a pH regulator, preferably, but not limited to, an osmotic pressure regulator, an antioxidant, a metal ion chelating agent; wherein the cosolvent is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide, L-arginine, L-lysine and meglumine; the pH regulator is one or more selected from dilute hydrochloric acid, sodium hydroxide solution, sodium bicarbonate solution, tromethamine solution, L-arginine solution, L-lysine solution, phosphate buffer solution and citrate buffer solution; the osmotic pressure regulator is selected from sodium chloride or glucose; the metal ion chelating agent is selected from disodium edetate or calcium disodium edetate; the antioxidant is selected from sodium pyrosulfite, sodium bisulfite, ascorbic acid or sodium thiosulfate.

4. The composition of claim 3, which is a freeze-dried powder injection and comprises a main drug, a cosolvent, a pH regulator and a freeze-drying protective agent, wherein the freeze-drying protective agent is selected from mannitol or dextran; the lyophilized powder for injection is reconstituted with water for injection or normal saline before use, and is used for intravenous injection or intramuscular injection.

5. The composition of claim 2, which is an ointment comprising: main medicine, white vaseline and one or more of the following auxiliary materials: liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, antiseptic, skin penetration enhancer, and aromatic; among them, the hardened oil is preferably hydrogenated peanut oil or hydrogenated castor oil; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the skin penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, urea, and Borneolum Syntheticum; the types and the dosage of the auxiliary materials are in the conventional range of ointment preparation and pharmaceutically acceptable;

or the pharmaceutical composition is a cream, and the cream comprises a main drug, an oil phase matrix, water, an emulsifier and one or more of the following auxiliary materials: humectant, penetration enhancer, antiseptic, and thickener, wherein the oil phase matrix is selected from one or more of white vaseline, liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, cetyl alcohol, and stearyl alcohol; the emulsifier is one or more selected from tween, span, sodium dodecyl sulfate, polyoxyethylene alkyl ether, polyoxyethylene nonyl phenyl ether, cetostearyl alcohol and macrogol glyceride; the humectant is selected from one or more of propylene glycol, glycerol, sorbitol, and polyethylene glycol; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, diisopropyl adipate, laurocapram, and cocoyl caprylocaprate; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the thickener is one or more of xanthan gum, carbomer and sodium carboxymethylcellulose; and the types and the dosage of the auxiliary materials are in the conventional range of cream preparation and pharmaceutically acceptable.

6. The composition of claim 2, which is an aqueous gel comprising a main drug, a gel matrix, a solvent, and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant;

or the medicine composition is latex type gel (emulsion), which comprises main medicine, gel matrix, oily matrix, emulsifier, solvent and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant;

wherein, the components in the water-based gel agent or emulsion agent are selected as follows: the gel matrix is selected from carboxyvinyl polymer, more preferably one or more of carbomer, hydroxypropyl methylcellulose, sodium hyaluronate, hydroxyethyl cellulose and hydroxypropyl cellulose; the solvent is one or more selected from water, ethanol, isopropanol and propylene carbonate; the neutralizer is one or more selected from triethanolamine, diisopropanolamine, concentrated ammonia solution, diethylamine and sodium hydroxide; the humectant is one or more selected from glycerol, 1, 3-butanediol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, and sorbitol; the perfume is selected from one or more of neroli oil, orange essence, banana essence, peppermint oil and lavender oil; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, polyethylene glycol monoethyl ether, cocoyl caprylocaprate, water-soluble azone, L-menthol, laurocapram, octyl decyl myristate and isopropyl myristate; the antiseptic is selected from one or more of sodium benzoate, benzyl alcohol, butyl p-hydroxybenzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, and propyl hydroxybenzoate; the antioxidant is selected from one or more of dibutyl hydroxy toluene BHT, sodium bisulfite, sodium metabisulfite, propyl gallate and DL-alpha-tocopherol; the emulsifier is selected from one or more of polyoxyethylene (35) castor oil, polyoxyethylene (20) hexadecyl octadecyl ether, hexadecyl octadecyl alcohol, oleyl alcohol, tween, span, polyoxyethylene polyoxypropylene hexadecyl ether and polyethylene glycol glyceride; the cross-linking agent is one or more selected from edetate disodium, lactic acid, citric acid, and tartaric acid; the oily matrix is selected from one or more of liquid paraffin, mineral oil, castor oil, and coconut oil; and the types and the dosage of the auxiliary materials are in the conventional range of gel preparation and pharmaceutically acceptable.

7. The composition according to claim 2, which is a patch, and the patch is a pressure-sensitive adhesive type patch comprising a backing, a plaster-containing layer and an anti-adhesive film; the material of the pressure-sensitive adhesive is selected from ethylene/acrylate copolymer, polyisobutylene, polypentadiene, polyacrylate, silicone copolymer, styrene-isoprene-styrene triblock copolymer (SIS), ethylene-butadiene-styrene triblock copolymer (SBS), hydrogenated SBS (SEBS), polyurethane; the patch comprises a backing, a patch-containing layer and an anti-sticking film, wherein the patch-containing layer comprises 10-50 wt% of styrene-isoprene-styrene block copolymer (SIS), 5-30 wt% of tackifying resin, 19.9-59.9 wt% of plasticizer and 1-5 wt% of main drug; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.

8. The pharmaceutical composition according to claim 7, wherein the main drug is preferably 1 to 3 wt%, the styrene-isoprene-styrene block copolymer (SIS) is preferably 20 to 40 wt%, the tackifying resin is preferably 15 to 25 wt%, the plasticizer is preferably 29.9 to 59.9 wt%, and the plaster-containing layer may further contain a dissolution enhancer, an antioxidant, a filler, a tackifier and other pharmaceutically acceptable excipients; wherein the tackifying resin is selected from one or more of saturated cyclic hydrocarbon resin, hydrogenated rosin glyceride and terpene resin; the plasticizer is selected from one or more of liquid paraffin and hardened oil; the tackifier is selected from one or more of polybutylene and polyisobutylene; the dissolution penetration enhancer is selected from one or more of L-menthol, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, isopropyl myristate, laurocapram and azone; the antioxidant is selected from one or more of Butyl Hydroxy Anisol (BHA), dibutyl hydroxy toluene (BHT), Propyl Gallate (PG), and tert-butyl hydroquinone (TBHQ), preferably dibutyl hydroxy toluene (BHT); the filler is selected from one or more of titanium dioxide, silicon dioxide and kaolin; the back lining is non-woven fabric or woven fabric, preferably non-woven fabric; the backing substrate material is selected from one or more of polyester, cotton, polyamide, polyolefin, polyurethane, silk and hemp, preferably polyolefin or polyester, the polyolefin is selected from one or more of polyethylene, polypropylene and polyvinyl chloride, and more preferably polypropylene; the polyester is selected from polyethylene terephthalate (PET), or polybutylene terephthalate (PBT), and is preferably PET; the anti-sticking film material is selected from one or more of polyethylene, polypropylene, vinyl acetate, ethylene polymer and polyvinyl chloride, and more preferably, the surface layer of the anti-sticking film is treated by silica gel and the like; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.

9. The pharmaceutical composition of claim 2, which is a cataplasm, also known as a gel patch; the cataplasm comprises a backing, a plaster-containing layer and an anti-sticking film; wherein, the ointment-containing layer comprises a humectant, a hydrophilic framework material, a cross-linking agent, a pH regulator, a surfactant, a filling agent, a tackifier, a dissolution penetration enhancer, a preservative and purified water; wherein the humectant is one or more selected from glycerol, propylene glycol, D-sorbitol solution, and polyethylene glycol 300; the hydrophilic skeleton material is selected from one or more of partially neutralized sodium polyacrylate, polyacrylic acid, sodium carboxymethylcellulose, polyvinyl alcohol (partially saponified), carboxyvinyl polymer (carbomer), and methylcellulose; the cross-linking agent is selected from one or more of aluminum hydroxide dry gel and sodium ethylene diamine tetracetate hydrate; the pH regulator is selected from one of tartaric acid, citric acid and malic acid, more preferably tartaric acid; the surfactant is selected from one or more of polyoxyethylene hydrogenated castor oil, polysorbate 80, sorbitan sesquioleate, polyoxyethylene nonyl phenyl ether, sodium dodecyl sulfate, polyoxyethylene alkyl ether, cetostearyl alcohol and polyethylene glycol glyceride; one or more of titanium dioxide as filler, light anhydrous silicic acid, talcum powder and kaolin; tackifier methyl acrylate/acrylic acid-2-ethylhexyl copolymer emulsion, and/or gelatin; the dissolution penetration enhancer is selected from one or more of L-menthol, isopropyl myristate, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, laurocapram and azone; the preservative is selected from one or more of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and ethyl p-hydroxybenzoate; and the types and the dosage of the auxiliary materials are in the conventional range of the preparation of the cataplasm and the pharmacy acceptance.

10. The pharmaceutical composition according to claim 9, wherein the weight percentage of each component is in the following range: 10-50% of a humectant, 2-25% of a hydrophilic framework material, 0-1% of a cross-linking agent, 0-1% of a cross-linking regulator, 0-2% of a surfactant, 0-8% of a filler, 0-10% of a tackifier, 1-20% of a dissolving penetration enhancer, 0.01-0.5% of a preservative and 0.1-1% of a pH regulator; preferably, 25-40% of humectant, 0.2-0.8% of cross-linking agent, 0.3-1% of cross-linking regulator and 10-18% of dissolution penetration enhancer.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a pharmaceutical composition containing an aryl propionic acid compound, wherein the aryl propionic acid compound is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, and application of the pharmaceutical composition in preparation of antipyretic, analgesic and anti-inflammatory drugs.

Background

Loxoprofen sodium with chemical name of 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl]Sodium propionate dihydrate, the English name Loxoprofen Sodium, of the formula C₁₅H₁₇O₃Na·2H₂O, molecular weight 304.32, CAS number 80382-23-6. The loxoprofen sodium belongs to aryl propionic acid non-steroidal anti-inflammatory drugs, and has an action mechanism of inhibiting synthesis of prostaglandin by inhibiting cyclooxygenase. When orally taken, loxoprofen sodium is absorbed by the digestive tract in a precursor state with weak gastric mucosa stimulation effect and then quickly converted into an active metabolite for strongly inhibiting the biosynthesis of prostaglandin, namely the compound of the formula I, the structure is shown as follows,thereby playing the roles of analgesia, anti-inflammation and antipyresis. The analgesic effect of the loxoprofen sodium is 20 times that of indometacin, and the mouse paw carrageenin edema experiment shows that the antiphlogistic effect of the loxoprofen sodium is 2 times that of the indometacin, and the loxoprofen sodium has strong and lasting analgesic, antiphlogistic and antipyretic effects. Compared with the similar medicines in clinic, the medicine has the characteristics that: stronger (good clinical effect), quicker (the peak value can be reached after the oral administration for 30 minutes), safer (little side effect); indications for loxoprofen sodiumIt can be widely used for anti-inflammatory and analgesic treatment of rheumatoid arthritis, lumbago, scapulohumeral periarthritis, neck, shoulder and wrist syndrome, analgesic and anti-inflammatory treatment after operation, trauma and tooth extraction, and antipyretic and analgesic treatment of acute upper respiratory inflammation. The preparation forms used clinically at present are tablets, granules, capsules, external patches, gels, cataplasma and the like.

Currently, loxoprofen sodium related drugs are not available on the market in injection form, because loxoprofen itself belongs to precursor drugs, and the loxoprofen sodium needs to enter the liver to be metabolized into an active substance, namely, a compound of formula I, so as to exert the drug effect. It is difficult to satisfy the clinical requirement of quick analgesia, antipyresis and anti-inflammation. Currently, the clinical need for non-steroidal anti-inflammatory drugs that are safer, less irritating, and at the same time, fast acting is still pressing.

Disclosure of Invention

The invention provides a compound of formula I, the chemical name is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, the structural formula is shown as follows,

the invention provides a pharmaceutical composition, which comprises a main drug compound shown in formula I and pharmaceutic adjuvants, wherein the main drug compound is in a therapeutically effective dose, and the preparation forms comprise tablets, capsules, granules, powder, dry suspension, freeze-dried powder injection, injection liquid, suspension, injection emulsion, suspension drops, syrup, oral solution, eye drops, nose drops, ointment, cream, gel, patch, cataplasm, gel plaster, gel paste, suppository and spray.

The pharmaceutical compositions of the present invention may be prepared according to methods known in the art. If desired, the active ingredient may be combined with one or more adjuvants for solid or liquid medicaments in suitable administration forms or dosage forms for human administration. The pharmaceutical compositions of the present invention may be administered in unit dosage form, either enterally or parenterally, for example orally, intramuscularly, subcutaneously, nasally, oromucosally, dermally, peritoneally or rectally, and the like. The route of administration of the pharmaceutical composition of the present invention may be administration by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc. The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc. The composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.

According to the technical scheme of the invention, the pharmaceutical composition is any clinically or pharmaceutically acceptable dosage form, preferably an injection, an external preparation or an oral preparation. According to the clinical treatment requirement, the compound contains 20mg to 180mg of the compound shown in the formula I with a therapeutically effective dose, and can be 20mg, 30mg, 40mg, 50mg, 60mg, 80mg, 100mg, 120mg, 150mg, 180mg and the like, and can be applied to a patient needing the treatment by oral administration or parenteral administration and the like.

When used for parenteral administration, it can be prepared into injections. The injection is a sterile preparation of solution, emulsion or suspension for injection into the body and powder or concentrated solution for preparation or dilution into solution or suspension before use, and can be divided into injection, sterile powder for injection and concentrated solution for injection. The injection is sterile solution type injection, emulsion type injection or suspension type injection prepared from the medicine for injection into human body, and can be used for intramuscular injection, intravenous drip, etc.; the standard of the injection is 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml and the like, wherein the large-volume (generally not less than 100ml) injection for intravenous drip is also called intravenous infusion. The sterile powder for injection is sterile powder or sterile block which is prepared by proper sterile solution to be prepared into clear solution or uniform suspension before use, can be prepared by proper solvent for injection and then injected, and can also be prepared by intravenous infusion and then is subjected to intravenous drip; the sterile powder is prepared by solvent crystallization, spray drying or freeze drying. Concentrated solution for injection refers to sterile concentrated solution of the drug for dilution before use for intravenous drip. In order to prepare the administration unit into the composition of the present invention into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder injection, the preparation may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants.

The injection can be prepared by conventional method in pharmaceutical field, and can be aqueous solvent or non-aqueous solvent. The most commonly used aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solution can also be used; the common non-aqueous solvent is vegetable oil, which is mainly soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol and the like. When preparing the injection, the additive can be not added, and the proper additives can be added according to the property of the medicine, such as osmotic pressure regulator, pH value regulator, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending agent and the like. Commonly used osmo-regulators include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; common pH regulator includes acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate, sodium carbonate, etc.; commonly used solubilizers include polysorbate 80, propylene glycol, lecithin, polyoxyethylene castor oil, and the like; common fillers include lactose, mannitol, sorbitol, dextran, and the like; common antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, and the like; common bacteriostatic agents are chlorobutanol and the like. The common containers for injections include glass ampoules, glass bottles, plastic ampoules, plastic bottles and the like.

When used for oral administration, the composition can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. The tablet is a round or special-shaped tablet solid preparation prepared by uniformly mixing and pressing the medicament and proper auxiliary materials, mainly takes an oral common tablet as a main part, and also comprises a buccal tablet, a sublingual tablet, an oral patch, a chewable tablet, a dispersible tablet, a soluble tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet, an enteric-coated tablet and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. The capsule refers to a solid preparation prepared by filling a drug or an adjuvant into an empty capsule or sealing in a soft capsule material, and can be divided into hard capsules (generally called capsules), soft capsules (capsules), sustained-release capsules, controlled-release capsules, enteric capsules and the like according to the dissolution and release characteristics of the solid preparation. The pill refers to a spherical or spheroidal solid preparation prepared by mixing the medicine and proper materials uniformly and preparing the mixture by a proper method, and comprises a dropping pill, a sugar pill, a pellet and the like. The granules refer to dry granular preparations with certain granularity prepared by the medicines and proper auxiliary materials, and can be divided into soluble granules (generally called granules), suspension granules, effervescent granules, enteric granules, sustained-release granules, controlled-release granules and the like. Oral solution means that the drug is dissolved in a suitable solvent to make into a clear liquid preparation for oral administration. Oral suspensions refer to poorly soluble solid drugs dispersed in a liquid medium to form a suspension formulation for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to a concentrated aqueous solution of sucrose containing the drug.

When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. Common fillers include starch, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, lactose, mannitol, sucrose, sodium chloride, glucose, calcium carbonate, microcrystalline cellulose, aluminum silicate, and the like; common binders include sodium carboxymethylcellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, gelatinized starch, acacia slurry, gelatin slurry, polyvinylpyrrolidone, polyethylene glycol, etc.; common disintegrating agents include dry starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.; common lubricants include talc, sodium lauryl sulfate, colloidal silica, silica dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. In addition, according to the formulation requirements, a disintegration inhibitor such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil, etc. may be optionally added; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like;

for making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of vectors are as follows: diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, and the like; binding agents, such as acacia, tragacanth, gelatin, ethanol, honey, rice paste, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. For making the administration unit into a suppository, various carriers well known in the art can be widely used. Examples of vectors are as follows: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like. To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection. In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparations, if desired.

The pharmaceutical composition provided by the invention comprises the following preparation forms: tablet, capsule, granule, powder, dry suspension, lyophilized powder for injection, suspension drop, syrup, oral solution, eye drop, nose drop, ointment, cream, gel, patch, cataplasma, suppository, and spray. Wherein the tablet also comprises sustained release tablet, double release tablet and enteric coated tablet; the capsule includes hard capsule, soft capsule, delayed release capsule, and enteric capsule.

As an embodiment of the present invention, preferably, the pharmaceutical composition is an injection, and comprises a main drug compound of formula i, a cosolvent, and a pH adjusting agent, and preferably, may further include but is not limited to: osmotic pressure regulator, antioxidant, metal ion chelating agent; wherein the cosolvent is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide, L-arginine, L-lysine and meglumine; the pH regulator is one or more selected from dilute hydrochloric acid, sodium hydroxide solution, sodium bicarbonate solution, tromethamine solution, L-arginine solution, L-lysine solution, phosphate buffer solution and citrate buffer solution; the osmotic pressure regulator is selected from sodium chloride or glucose; the metal ion chelating agent is selected from disodium edetate or calcium disodium edetate; the antioxidant is selected from one or more of sodium pyrosulfite, sodium bisulfite, ascorbic acid or sodium thiosulfate.

Preferably, the pharmaceutical composition is a freeze-dried powder injection and comprises a main drug compound shown as a formula I, a cosolvent, a pH regulator and a freeze-drying protective agent, wherein the freeze-drying protective agent is selected from mannitol or dextran; the lyophilized powder for injection is reconstituted with water for injection or normal saline before use, and is used for intravenous injection or intramuscular injection; .

Preferably, the pharmaceutical composition is an ointment comprising: main medicine, white vaseline and one or more of the following auxiliary materials: liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, antiseptic, skin penetration enhancer, and aromatic; wherein the hardened oil is selected from hydrogenated peanut oil or hydrogenated castor oil; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the skin penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, urea, and Borneolum Syntheticum; and the types and the dosage of the auxiliary materials are in the conventional range of ointment preparation and pharmaceutically acceptable.

Preferably, the pharmaceutical composition is a cream, and the cream comprises a main drug, an oil phase matrix, water, an emulsifier, and one or more of the following auxiliary materials: humectant, penetration enhancer, antiseptic, and thickener, wherein the oil phase matrix is selected from one or more of white vaseline, liquid paraffin, hardened oil, lanolin, glyceryl monostearate, stearic acid, cetyl alcohol, and stearyl alcohol; the emulsifier is preferably one or more of tween, span, sodium dodecyl sulfate, polyoxyethylene alkyl ether, polyoxyethylene nonyl phenyl ether, cetostearyl alcohol and macrogol glyceride; the humectant is selected from one or more of propylene glycol, glycerol, sorbitol, and polyethylene glycol; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, L-menthol, isopropyl myristate, azone, diisopropyl adipate, laurocapram, and cocoyl caprylocaprate; the preservative is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate and propyl hydroxybenzoate; the thickener is one or more of xanthan gum, carbomer and sodium carboxymethylcellulose; and the types and the dosage of the auxiliary materials are in the conventional range of cream preparation and pharmaceutically acceptable.

Preferably, the pharmaceutical composition is an aqueous gel, and comprises a main drug, a gel matrix, a solvent and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant; or the pharmaceutical composition is a latex type gel (emulsion), and comprises a main drug, a gel matrix, an oily matrix, an emulsifier, a solvent and one or more of the following auxiliary materials: neutralizer, perfume, penetration enhancer, antiseptic, antioxidant, cross-linking agent, and humectant;

wherein, the components in the water-based gel agent or emulsion agent are selected as follows: the gel matrix is selected from carboxyvinyl polymer, more preferably one or more of carbomer, hydroxypropyl methylcellulose, sodium hyaluronate, hydroxyethyl cellulose and hydroxypropyl cellulose; the solvent is one or more selected from water, ethanol, isopropanol and propylene carbonate; the neutralizer is one or more selected from triethanolamine, diisopropanolamine, concentrated ammonia solution, diethylamine and sodium hydroxide; the humectant is one or more selected from glycerol, 1, 3-butanediol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, and sorbitol; the perfume is selected from one or more of neroli oil, orange essence, banana essence, peppermint oil and lavender oil; the penetration enhancer is one or more selected from N-methyl-2-pyrrolidone, diisopropyl adipate, polyethylene glycol monoethyl ether, cocoyl caprylocaprate, water-soluble azone, L-menthol, laurocapram, octyl decyl myristate and isopropyl myristate; the antiseptic is selected from one or more of sodium benzoate, benzyl alcohol, butyl p-hydroxybenzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, and propyl hydroxybenzoate; the antioxidant is selected from one or more of dibutyl hydroxy toluene BHT, sodium bisulfite, sodium metabisulfite, propyl gallate, vitamin E, and tocopherol; the emulsifier is selected from one or more of polyoxyethylene (35) castor oil, polyoxyethylene (20) hexadecyl octadecyl ether, hexadecyl octadecyl alcohol, oleyl alcohol, tween, span, polyoxyethylene polyoxypropylene hexadecyl ether and polyethylene glycol glyceride; the cross-linking agent is one or more selected from edetate disodium, lactic acid, citric acid, and tartaric acid; the oily matrix is selected from one or more of liquid paraffin, mineral oil, castor oil, and coconut oil; and the types and the dosage of the auxiliary materials are in the conventional range of gel preparation and pharmaceutically acceptable.

Preferably, the pharmaceutical composition is a patch, which is a pressure-sensitive adhesive type patch comprising a backing, a plaster-containing layer and an anti-adhesive film; the material of the pressure-sensitive adhesive is selected from ethylene/acrylate copolymer, polyisobutylene, polypentadiene, polyacrylate, silicone copolymer, styrene-isoprene-styrene triblock copolymer (SIS), ethylene-butadiene-styrene triblock copolymer (SBS), hydrogenated SBS (SEBS), polyurethane; the patch comprises a backing, a patch-containing layer and an anti-sticking film, wherein the patch-containing layer comprises 10-50 wt% of styrene-isoprene-styrene block copolymer (SIS), 5-30 wt% of tackifying resin, 19.9-59.9 wt% of plasticizer and 1-5 wt% of main drug; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.

More preferably, the main drug in the patch is preferably 1-3 wt%, the styrene-isoprene-styrene block copolymer (SIS) is preferably 20-40 wt%, the tackifying resin is preferably 15-25 wt%, and the plasticizer is preferably 29.9-59.9 wt%, wherein the layer containing the patch can be added with a dissolved permeation enhancer, an antioxidant, a filler, a tackifier and other pharmaceutically acceptable excipients; wherein the tackifying resin is selected from one or more of saturated cyclic hydrocarbon resin, hydrogenated rosin glyceride and terpene resin; the plasticizer is selected from one or more of liquid paraffin and hardened oil; the tackifier is selected from one or more of polybutylene and polyisobutylene; the dissolution penetration enhancer is selected from one or more of L-menthol, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, isopropyl myristate, laurocapram and azone; the antioxidant is selected from one or more of Butyl Hydroxy Anisol (BHA), dibutyl hydroxy toluene (BHT), Propyl Gallate (PG), and tert-butyl hydroquinone (TBHQ), preferably dibutyl hydroxy toluene (BHT); the filler is selected from one or more of titanium dioxide, silicon dioxide and kaolin; the backing is a non-woven fabric or a woven fabric, and is preferably a non-woven fabric; the substrate material of the backing is selected from one or more of polyester, cotton, polyamide, polyolefin, polyurethane, silk and hemp, and is preferably polyolefin or polyester; the polyolefin is selected from one or more of polyethylene, polypropylene and polyvinyl chloride, and is more preferably polypropylene; the polyester is selected from polyethylene terephthalate (PET), or polybutylene terephthalate (PBT), and is preferably PET; the anti-sticking film material is selected from one or more of polyethylene, polypropylene, vinyl acetate, ethylene polymer and polyvinyl chloride, and more preferably, the surface layer of the anti-sticking film is treated by silica gel and the like; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.

Preferably, the pharmaceutical composition is a cataplasm, also known as a gel patch; the cataplasm comprises a backing, a plaster-containing layer and an anti-sticking film; wherein, the ointment-containing layer comprises a humectant, a hydrophilic framework material, a cross-linking agent, a pH regulator, a surfactant, a filling agent, a tackifier, a dissolution penetration enhancer, a preservative and purified water; the humectant is one or more selected from glycerol, propylene glycol, D-sorbitol solution, and polyethylene glycol 300; the hydrophilic skeleton material is selected from one or more of partially neutralized sodium polyacrylate, polyacrylic acid, sodium carboxymethylcellulose, polyvinyl alcohol (partially saponified), carboxyvinyl polymer (carbomer), and methylcellulose; the cross-linking agent is selected from one or more of aluminum hydroxide dry gel and sodium ethylene diamine tetracetate hydrate; the pH regulator is selected from one of tartaric acid, citric acid and malic acid, more preferably tartaric acid; the surfactant is selected from one or more of polyoxyethylene hydrogenated castor oil, polysorbate 80, sorbitan sesquioleate, polyoxyethylene nonyl phenyl ether, sodium dodecyl sulfate, polyoxyethylene alkyl ether, cetostearyl alcohol and polyethylene glycol glyceride; one or more of titanium dioxide as filler, light anhydrous silicic acid, talcum powder and kaolin; tackifier methyl acrylate/acrylic acid-2-ethylhexyl copolymer emulsion, and/or gelatin; the dissolution penetration enhancer is selected from one or more of L-menthol, isopropyl myristate, isostearic acid, polyethylene glycol, N-methyl-2-pyrrolidone, medium chain fatty acid triglyceride, laurocapram and azone; the preservative is selected from one or more of methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and ethyl p-hydroxybenzoate; and the types and the dosage of the auxiliary materials are in the conventional range of patch preparation and pharmaceutically acceptable.

Further preferably, the weight percentage ranges of the components in the cataplasm are as follows: 10-50% of a humectant, 2-25% of a hydrophilic framework material, 0-1% of a cross-linking agent, 0-1% of a cross-linking regulator, 0-2% of a surfactant, 0-8% of a filler, 0-10% of a tackifier, 1-20% of a dissolving penetration enhancer, 0.01-0.5% of a preservative and 0.1-1% of a pH regulator; further preferably, the humectant accounts for 25-40%, the cross-linking agent accounts for 0.2-0.8%, the cross-linking regulator accounts for 0.3-1%, and the dissolution penetration enhancer accounts for 10-18%.

According to the technical scheme of the invention, the pharmaceutical composition is used for the administration of 20mg to 180mg of the salt of the compound of the formula I calculated by the compound of the formula I in the daily dosage. The specific dosage can be adjusted according to the preparation form, administration route and treatment effect on the basis of the medication safety.

The salt of the compound shown in the formula I belongs to a non-steroidal anti-inflammatory drug molecule, and plays roles of relieving fever, easing pain and resisting inflammation mainly by inhibiting the biosynthesis of prostaglandin. Therefore, one of the objects of the present invention is to provide a use of the pharmaceutical composition comprising the compound of formula i in the present invention for preparing a medicament for preventing or treating pain, inflammation and fever.

The pharmaceutical composition containing the compound of the formula I can be used for diminishing inflammation, and the inflammation which can be used for treating is non-infectious inflammation comprising trauma, inflammation after operation or tooth extraction, chronic rheumatoid arthritis, osteoarthritis, lumbago, scapulohumeral periarthritis, neck-shoulder-wrist syndrome, periodontitis and ocular inflammatory diseases.

The pharmaceutical compositions provided by the present invention comprising a compound of formula I are useful for antipyretic purposes.

The pharmaceutical composition containing the compound of formula I provided by the invention can be used for analgesia, and can be used for symptomatic treatment of mild to moderate acute pain, such as musculoskeletal pain, dysmenorrhea and toothache; can be used for treating moderate pain, and can be used as adjuvant of opioid analgesic for treating moderate to severe pain.

The salts of the compounds of formula I provided by the invention can also be used as one of the pharmaceutical ingredients of compound preparations or combination drugs to improve the treatment effect on pain symptoms. For example, the compounds of formula i may be administered in combination with opioid analgesics, or to form a compound formulation, to exert a synergistic effect of peripheral and central analgesia, enabling the required dose of each active agent to be reduced, thereby reducing the risk of adverse reactions; wherein the opioid analgesics include, but are not limited to: codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl, meperidine, and tramadol.

The invention achieves the following beneficial technical effects

1) The main drug of the pharmaceutical composition prepared by the invention is the active metabolite, namely the compound shown in the formula I, derived from loxoprofen, and the main drug is used, so that the dosage is reduced, the toxic and side effects are reduced, the irritation during injection is reduced, and the medication compliance of patients is improved.

2) The invention provides an injection containing a compound shown in the formula I, which can be an injection or a freeze-dried powder injection, can play a role in quickly relieving pain in clinical application, quickly relieves the pain of a patient, reduces the dosage and improves the safety.

3) The invention provides an external preparation containing a compound shown in a formula I, which comprises ointment, cream, gel, emulsion, patch, cataplasm, gel plaster and the like, and active effective components are expected to be directly absorbed through skin, so that the purposes of quickly exerting local analgesia and anti-inflammation are achieved, and the effective time of the medicine is shortened.

4) The pharmaceutical composition containing the compound shown in the formula I can be used for injection, solid preparation and external semi-solid preparation, and has important application in preparing fast antipyretic, analgesic and anti-inflammatory drugs.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the compound of formula 1.

FIG. 2 is a mass spectrum of the compound of formula 1.

FIG. 3 is a two-dimensional nuclear magnetic NOE spectrum of the compound of formula 1.

Detailed Description

The invention will be further elucidated with reference to the following description of an embodiment in conjunction with the accompanying drawing. It is to be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, which is to be given the full breadth of the appended claims and any and all equivalent modifications thereof which may occur to those skilled in the art upon reading the present specification.