CN114073669A

CN114073669A - Gel containing aryl propionic acid compound

Info

Publication number: CN114073669A
Application number: CN202110922762.7A
Authority: CN
Inventors: 周文亮; 闵涛; 王佳琳; 苗娜娜; 陶莉
Original assignee: Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Current assignee: Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Priority date: 2020-08-13
Filing date: 2021-08-12
Publication date: 2022-02-22

Abstract

The invention relates to a gel containing an aryl propionic acid compound, belonging to the field of pharmaceutical preparations. The gel is suitable for relieving inflammation and pain caused by osteoarthritis, myalgia, and trauma. The preparation greatly reduces the specification of active medicine and the dosage of the medicine for patients, and improves the compliance of the patients.

Description

Gel containing aryl propionic acid compound

Cross Reference to Related Applications

The present application claims priority to a prior application entitled "a gel containing an arylpropionic acid-based compound" filed on 8/13/2020 by the applicant to the intellectual property office of the chinese country, patent application No. 202010809786.7. The entire content of this prior application is incorporated by reference into this application.

Technical Field

The invention relates to an external transdermal preparation containing an aryl propionic acid compound, in particular to a gel containing the aryl propionic acid compound, belonging to the field of pharmaceutical preparations.

Background

Loxoprofen sodium is an aryl propionic acid non-steroidal anti-inflammatory drug developed by the first three co-companies in japan, is a non-selective cyclooxygenase inhibitor, and achieves the purpose of anti-inflammatory and analgesic effects by inhibiting the synthesis of prostaglandins and unsaturated fatty acids catalyzed by arachidonic acid to produce a drug effect. At present, the medicine is mainly prepared into two dosage forms of oral administration and external application in clinic. Oral administration is not tolerated by patients who need to take the medicine for a long time or patients with gastric ulcer because of the short half-life, 3-4 times a day, gastrointestinal damage and cardiovascular disease risks.

In order to avoid the side effects associated with oral administration, non-oral administration routes of NSAIDs have been widely studied in recent years, and external preparations including loxoprofen sodium transdermal patches, gels, cataplasms and the like are continuously marketed at home and abroad and are widely used for treating diseases such as arthralgia and arthritis. The transdermal drug delivery preparation does not pass through the digestive tract and the liver, avoids the first pass effect of passing through the liver, reduces the direct stimulation to the gastrointestinal tract, greatly reduces the whole body exposure of the drug, reduces the toxic and side effects related to oral drug delivery, and improves the compliance of patients.

However, loxoprofen sodium is a precursor drug, and is required to be subjected to the action of carbonyl reductase in a human body to perform stereoselective reduction on a cyclopentanone group, and only (2' S,1' R,2' S) -trans-OH of eight metabolites has anti-inflammatory activity. The loxoprofen transdermal administration preparations in the prior patents are all prepared by taking loxoprofen sodium salt as a main drug, such as the following patents: CN110946846A, CN105106180A, CN102940618A, CN 102525875A. Although the literature shows that topical administration can deliver drugs to local skeletal muscle tissues where arthritic conditions occur, loxoprofen sodium still needs to enter the systemic circulation through capillaries due to the limited carbonyl reductase in skin and skeletal muscle, and after being metabolized to active metabolites which act, it returns to the target site with the blood to play a role. Therefore, the existing loxoprofen sodium external preparation has the defects of low bioavailability, large specification and large dosage, taking the first common LOXONIN GEL in Japan as an example: the gel contains loxoprofen sodium anhydrous substance with the specification of 1 wt%, and is applied to affected parts 3-4 times a day, and 8cm (about 2g) of loxoprofen sodium anhydrous substance is extruded each time. Therefore, there is still much room for improvement in the existing loxoprofen sodium external preparation.

Disclosure of Invention

Loxoprofen is a prodrug of liver metabolism that is biotransformed in vivo into a hydroxyl metabolite having 3 chiral centers, theoretically yielding 8 stereoisomers, of which the 2' S,1' R,2' S-trans hydroxyl active metabolite that exerts the major biological activity, is of the formula i:

during the drug development stage, the loxoprofen active metabolite is found to be white or off-white solid in appearance, has low solubility in pure water and is dissolved in a slightly alkaline aqueous solution. The physical and chemical stability is poor, the tendency of the solid to become sticky and yellow under the conditions of high temperature, high humidity, cold white fluorescent lamp and ultraviolet lamp is realized, and the solid is easy to absorb moisture and adhere, so that the difficulty in preparing the solid preparation is caused. It is therefore of great interest to further optimize the potency of the loxoprofen active, i.e. the compound of formula i.

The invention aims to further optimize the drug forming property of the loxoprofen active substance, namely the compound shown in the formula I, on the basis of the prepared compound shown in the formula I, try to develop a proper salt form of the loxoprofen active substance and prepare a proper external preparation, and achieve the purposes of quick response and reduction of the drug taking times.

The technical scheme for realizing the aim of the invention is as follows:

one of the objects of the present invention is to provide a gel containing an aryl propionic acid compound, comprising:

a. a compound of formula I or a pharmaceutically acceptable salt thereof;

b. a pharmaceutically acceptable base;

the salt of the compound shown in the formula I is a base addition salt formed by reacting the compound shown in the formula I with a base; wherein the chemical name of the compound in the formula I is (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, the structure is shown as follows,

the base is selected from the group consisting of alkali metals, alkylamines, heterocyclic amines, basic amino acids, aminosugars; the alkali metal comprises sodium, potassium, magnesium and calcium; the alkylamine comprises diethylamine, triethylamine, ethylenediamine, 2-diethylaminoethanol, N-dimethylethanolamine, tromethamine, ethanolamine, diethanolamine, triethanolamine, choline and trimethylglycine; said heterocyclic amines include piperazine, pyrrolidine, morpholine, 1- (2-hydroxyethyl) -pyrrolidine, 4- (2-hydroxyethyl) -morpholine, 1- (2-hydroxyethyl) piperidine; the basic amino acids comprise arginine and lysine; the amino sugar comprises glucosamine, N-methylglucamine and N-ethylglucosamine; the above salts include crystalline forms and amorphous forms.

Preferably, in the present invention, the salt is selected from the salts shown by the following structural formula, including:

a sodium salt of a compound of formula I represented by formula II;

a compound of formula I, diethylamine salt, of formula III;

tromethamine salt of a compound of formula I as shown in formula IV;

a compound of formula I, formula V, ethanolamine salt;

a compound of formula I, L-lysine salt, represented by formula VI;

a compound of formula I, L-arginine salt, represented by formula VII;

a triethanolamine salt of a compound of formula I represented by formula VIII;

a compound of formula i, formula IX, N-methylglucamine salt;

an epolamine salt of a compound of formula I represented by formula X;

a magnesium salt of a compound of formula I, represented by formula XI;

calcium salts of compounds of formula I as shown in formula XII;

a compound of formula I, represented by formula XIII;

a piperazine salt of a compound of formula I represented by formula XIV:

preferably, in the present invention, the salt is selected from the following forms, including:

a compound of formula I, diethylamine salt, of formula III;

tromethamine salt of a compound of formula I as shown in formula IV;

a compound of formula I, formula V, ethanolamine salt;

an epolamine salt of a compound of formula I represented by formula X.

According to the embodiment of the invention, the content of the active ingredient compound shown in the formula I or the pharmaceutically acceptable salt thereof in the gel is 0.01-5.0 wt%; preferably 0.1 to 3.0 wt%.

According to an embodiment of the invention, the acceptable matrix in the gel comprises: at least one gel matrix, at least one humectant, at least one penetration enhancer, at least one pH regulator.

The gel matrix is selected fromFrom carbomer, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, SEPINEO^TMP600, starch gelatinized gel matrix, xanthan gum, sodium alginate, gum tragacanth, guar gum, and carob gum; the content is 0.05 to 20 wt%.

The humectant is one or more selected from glycerol, urea, propylene glycol, butanediol, sodium hyaluronate, trehalose, dextran, jojoba free, ceramide, and water-soluble lanolin; the content is 0.05-20 wt%;

the penetration enhancer is one or more selected from ethanol, butanol, propylene glycol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether and urea; the content is 0.01 to 5 wt%.

The pH regulator is selected from one or more of sodium hydroxide, triethanolamine, diethanolamine, citric acid, tartaric acid, disodium hydrogen phosphate and sodium dihydrogen phosphate, and the content of the pH regulator is 0.5-5 wt%.

According to an embodiment of the present invention, the acceptable matrix in the gel further comprises a preservative selected from one or more of benzyl alcohol, sodium benzoate, methylparaben, ethylparaben, propylparaben, phenol, chlorocresol, phenoxyethanol, diazolidinyl urea, dichlorobenzyl alcohol, benzalkonium chloride, benzalkonium bromide, preferably benzyl alcohol, sodium benzoate; the content is 0.01-2 wt%.

The invention also aims to provide a preparation method of the gel containing the aryl propionic acid compound, which comprises the following steps:

1) adding water into the gel matrix according to the formula amount, stirring and swelling, and adding a pH regulator to regulate the pH to 6.0-7.5;

2) adding water into the pharmaceutically acceptable salt of the compound shown in the formula I, the humectant, the antioxidant, the preservative and the penetration enhancer in the formula I according to the prescription amount, stirring and dispersing uniformly, adding the mixture into the gel matrix obtained in the step 1), and adding water and stirring uniformly to obtain the gel.

The invention also aims to provide application of the gel containing the aryl propionic acid compound in preparing the non-steroidal anti-inflammatory drugs.

According to the invention, the medicament can be used for treating rheumatoid arthritis, lumbago, migraine, neuralgia, scapulohumeral periarthritis, osteoarthritis, inflammation and/or pain relief of neck-shoulder-wrist syndrome, pain and/or inflammation relief after operation, trauma or tooth extraction, and acute upper respiratory tract inflammation fever and/or pain relief.

The invention has the following beneficial effects:

1. the aqueous gel has the advantages of beautiful appearance, high bioavailability, good stability, no greasiness, no pollution to clothes and the like, so compared with patches, ointments and the like, the external preparation has better medication compliance for patients;

2. the various salt forms of the compound of the formula I prepared by the invention overcome the defects of small water solubility, poor physicochemical stability, easy moisture absorption and stickiness, poor fluidity and the like of the compound of the formula I in the prior art. The new salt form has good physicochemical properties, is convenient for smooth operation in the preparation process, so as to obtain a preparation form with good quality, is particularly suitable for preparing an external gel, and expands the application of the loxoprofen active metabolite in the preparation of the non-steroidal anti-inflammatory drugs;

3. the free acid of the compound shown in the formula I has poor physical and chemical properties, and tends to become sticky and yellow under the conditions of high temperature, high humidity, cold white fluorescent lamps and ultraviolet lamps, so that solids are easy to absorb moisture and adhere, and the preparation process is difficult. However, the salt of the compound of the formula I does not affect the chemical stability of the compound under the conditions of strong acid, strong alkali, strong oxidation, high temperature and strong light; in the target pH range of 5.8-8.0 of the external preparation, the compound keeps good physical and optical stability and has high solubility (>10 mg/mL); the compound has no obvious impurity change under the condition of keeping a sample for the compatibility of binary raw and auxiliary materials; 4. in the gel preparation containing the aryl propionic acid compound, the active ingredient is the active metabolite of loxoprofen in a human body, namely, (S) -2- (4- (((1R, 2S) -2-hydroxycyclopentyl) methyl) phenyl) propionic acid, and the loxoprofen reaches the skeletal muscle part through skin penetration to immediately exert the drug effect. The invention greatly reduces the pharmaceutical specification of the gel and the dosage used by patients, and improves the compliance of the patients.

Drawings

FIG. 1 is a flow chart of the gel of example 1.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

The main detection methods involved in the invention are as follows:

first, High Performance Liquid Chromatography (HPLC):

1. determination of related substances

Taking a proper amount of the product, precisely weighing, adding a diluent [ methanol-water (3:7) ] to shake and dissolve, and quantitatively diluting to prepare a solution containing about 1mg of the compound in each 1 ml. Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition general regulation 0512), using octadecylsilane chemically bonded silica as filler (Welch Xtimate C18, 4.6mm × 250mm, 5 μm); performing linear gradient elution according to the following table by using 0.01mol/L ammonium acetate solution (pH value is adjusted to 4.5 by phosphoric acid) -acetonitrile (95:5) as a mobile phase A and acetonitrile as a mobile phase B, wherein the flow rate is 1.0ml per minute; the column temperature was 40 ℃; the detection wavelength is 221 nm; injecting sample amount of 20 μ L into liquid chromatograph, recording chromatogram, and counting the result according to area normalization method.

2. Isomer assay

Taking a proper amount of the product, adding a diluent [ n-hexane-absolute ethyl alcohol-trifluoroacetic acid (70:30:2) ] and shaking to dilute the product to prepare a solution containing about 0.5mg of the compound in every 1 mL. Performing high performance liquid chromatography (China pharmacopoeia 2020 edition general rule 0512) with amylose-tris (3, 5-dimethylphenyl carbamate) silica gel as filler (Chiralpak AD-H, 250 × 4.6mm, 5 μm); n-hexane-methanol-isopropanol (88:8:4) was used as the mobile phase at a flow rate of 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 220 nm; and (4) injecting the sample with the volume of 20 mu L into a liquid chromatograph, recording a chromatogram, and counting the result according to an area normalization method.

3. The content measurement is performed by high performance liquid chromatography (China pharmacopoeia 2020 edition general regulation 0512).

Chromatographic conditions systematic suitability test using octadecylsilane chemically bonded silica as a filler (Welch Xtimate C18, 4.6 mm. times.250 mm, 5 μm) with water-methanol-triethylamine-glacial acetic acid (400:600:1:1) as the mobile phase; the flow rate was 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 221 nm; the sample volume is 20 mu L; the duration of the test was 15 minutes per needle. II, pH measurement: the pH value is measured according to a pH value measuring method (China pharmacopoeia 2020 edition general rule 0631).

Thirdly, rheological measurement:

1. and (3) viscosity measurement: the viscosity values of the examples were measured by setting the height of the parallel plate and the bottom to 1mm, keeping the temperature at the measurement temperature for 180s, the shear rate to 0-20/s, and the scanning time to 60 s.

Test example 1 solubility in water of salts of the Compound of formula I

Weighing 20mg of free acid of a compound shown in a formula I, sodium salt of the compound shown in the formula I, diethylamine salt, tromethamine salt, ethanolamine salt, L-lysine salt, L-arginine salt, triethanolamine salt, N-methylglucamine salt, epolamine salt, magnesium salt, calcium salt and tert-butylamine salt respectively, adding a sample into a proper amount of water with the temperature of 25 ℃ respectively by using a solubility test method of 2020 edition of Chinese pharmacopoeia, shaking strongly for 30 seconds every 5 minutes, and observing the dissolution condition within 30 minutes; to the point where no visible solute particles are present, it is considered to be completely dissolved. Very soluble means that 1g (ml) of solute can be dissolved in less than 1ml of solvent; soluble means that 1g (ml) of solute can be dissolved in 1-less than 10ml of solvent; the dissolving means that 1g (ml) of solute can be dissolved in 10 to less than 30ml of solvent; slightly soluble means that 1g (ml) of solute can be dissolved in 30-less than 100ml of solvent; slightly soluble means that solute lg (ml) can be dissolved in 100-less than 1000ml of solvent; the minimal dissolution means that 1g (ml) of solute can be dissolved in 1000-less than 10000ml of solvent; by almost insoluble or insoluble is meant that 1g (ml) of solute is not completely soluble in 10000ml of solvent. The results are given in the following table:

TABLE 1 solubility determination

Name (R)	Solubility (in free acid)	Solubility in water
			Free acid	About 1.00mg/mL	Slightly soluble
Sodium salt	Greater than 92.78mg/mL	Is easy to dissolve
			Diethylamine salt	Greater than 78.02mg/mL	Is easy to dissolve
Tromethamine salt	Greater than 67.88mg/mL	Is easy to dissolve
			Ethanolamine salts	Greater than 81.06mg/mL	Is easy to dissolve
L-lysine salt	Greater than 63.57mg/mL	Is easy to dissolve
			L-arginine salt	Greater than 59.53mg/mL	Is easy to dissolve
Triethanolamine salt	Greater than 63.09mg/mL	Is easy to dissolve
			N-methylglucamine salt	Greater than 56.55mg/mL	Is easy to dissolve
Epolamine salts	Greater than 69.00mg/mL	Is easy to dissolve
			Magnesium salt	Greater than 96.72mg/mL	Is easy to dissolve
Calcium salt	Greater than 93.82mg/mL	Is easy to dissolve
			Tert-butylamine salt	Greater than 78.02mg/mL	Is easy to dissolve

From the above, after the loxoprofen active metabolite (i.e., free acid) is prepared into a new salt form, the solubility is improved by about 60-100 times, and the improvement of the physicochemical properties is beneficial to the preparation of an external transdermal preparation and the adjustment of the permeation rate of the external preparation.

Test example 2 salt strong degradation test of Compound of formula I

The following table shows the results of strong degradation tests carried out on the respective diethylamine, ethanolamine, tromethamine and epolamine compounds of formula i:

TABLE 2 determination of the strong degradation test of diethylamine salts of the compounds of formula I

TABLE 3 determination of the formula I Compound ethanolamine salt by the strong degradation test

TABLE 4 determination of the compound of formula I tromethamine salt by strong degradation test

TABLE 5 determination of the compound of formula I by the Epinamide salt strong degradation test

The above results show that: the chemical stability of the compound is not affected by strong acid, strong alkali, strong oxidation, high temperature and strong light conditions.

Test example 3

The solubility of the compound of formula I, namely, diethylamine salt, ethanolamine salt, tromethamine salt and epolamine in buffer solutions with various pH values is respectively examined, and the results are shown in the following table:

TABLE 6 solubility assay of diethylamine salt of the compound of formula I at 37 deg.C for 24 hours

TABLE 7 determination of the solubility of ethanolamine salt of the compound of formula I at 37 ℃ for 24 hours

Target pH	pH before sample retention	pH after sample retention	Average solubility (mg/mL)
				3.00	3.25	3.30	0.021
4.00	4.43	4.28	0.027
				5.00	5.33	5.49	0.054
6.00	6.18	6.30	>10
				7.00	7.20	7.41	>10
8.00	8.01	7.99	>10

TABLE 8 determination of the solubility of the compound of the formula I tromethamine salt at 37 ℃ for 24 hours

Target pH	pH before sample retention	pH after sample retention	Average solubility (mg/mL)
				3.00	3.09	3.16	0.019
4.00	3.87	4.05	0.025
				5.00	4.98	4.96	>10mg/mL
6.00	6.12	6.00	>10mg/mL
				7.00	7.06	7.18	>10mg/mL
8.00	8.09	7.90	>10mg/mL

TABLE 9 determination of the solubility of the compounds of the formula I in epolamine at 37 ℃ for 24 hours

The results show that the compounds have high solubility (>10mg/mL) in the target pH range of 5.0-8.0 of the external preparation.

Examples 1 to 11

The formulation composition of each example is as follows (wt%):

TABLE 10 gel formulations

Note: API refers to the active ingredient in the gel formulation of the present invention, i.e. the pharmaceutically acceptable salt of the compound of formula i.

Example 1:

1) weighing carbomer Tr-1 and sodium hyaluronate into a proper amount of purified water, fully swelling, and then dropwise adding a sodium hydroxide aqueous solution to neutralize the gel phase to pH6.5;

2) weighing API and benzyl alcohol in the formula amount into ethanol, fully dissolving, mixing the API and the benzyl alcohol with the gel prepared in the step 1), and uniformly stirring to obtain the gel.

Example 2:

1) weighing carbomer Tr-1 into a proper amount of purified water, fully swelling, and dropwise adding a sodium hydroxide aqueous solution to neutralize the gel phase to pH6.5;

2) weighing API and benzyl alcohol in the amount of the prescription into ethanol, fully dissolving, mixing the gel phase prepared in the step 1) and jojoba seed oil in the amount of the prescription, and uniformly stirring to obtain the product.

Example 3:

1) weighing carbomer Tr-1 into a proper amount of purified water, fully swelling, and dropwise adding triethanolamine aqueous solution to neutralize the gel phase to pH6.5;

2) weighing API and benzyl alcohol in the amount of the prescription into diethylene glycol monoethyl ether, fully dissolving, mixing the obtained product with the gel phase prepared in the step 1) and urea in the amount of the prescription, and uniformly stirring to obtain the product.

Example 4:

2) weighing API, dichlorobenzyl alcohol, glycerol and diethylene glycol monoethyl ether according to the prescription amount, fully mixing, and then mixing with the step 1)

Mixing the obtained gel phase, and stirring.

Example 5:

1) weighing the prescribed amount of SEPINEO^TMUniformly stirring the P600 and the glycerol with the prescription amount, adding purified water, and uniformly mixing to obtain a gel phase;

2) dissolving API in a proper amount of water, adding the prescription amount of diazolidinyl urea and butanediol, uniformly mixing, mixing with the gel prepared in the step 1), and uniformly stirring to obtain the product.

Example 6:

1) taking the sodium carboxymethylcellulose and the glycerol with the prescription amount, and uniformly grinding in a mortar;

2) taking API, butyl paraben sodium salt and propylene glycol in the prescription amount into a proper amount of purified water, and stirring in a water bath at 70 ℃ to uniformly disperse the materials;

3) and (3) adding the 70 ℃ auxiliary material mixture obtained in the step (2) into the sodium carboxymethylcellulose glycerol mixture obtained in the step (1), quickly stirring to uniformly mix the mixture, dropwise adding a saturated solution of disodium hydrogen phosphate, adjusting the pH to 6.5, supplementing purified water to the prescription amount, and uniformly stirring to obtain the sodium carboxymethylcellulose glycerol mixture.

Example 7:

1) taking a mixture of sesbania gum, API, propylene glycol, glycerin and potassium sorbate according to the prescription amount, putting the mixture into a proper amount of purified water, and stirring to uniformly mix the mixture;

2) adding triethanolamine dropwise, adjusting pH to 7.0, adding purified water to 70g, and stirring.

Example 8:

1) taking a mixture of xanthan gum, API, propylene glycol, trehalose and potassium sorbate according to the prescription amount, putting the mixture into a proper amount of purified water, and stirring to uniformly mix the mixture;

2) adding triethanolamine dropwise, adjusting pH to 6.5, adding purified water to the prescribed amount, and stirring.

Example 9:

1) taking a mixture of guar gum, API, propylene glycol, glycerin and potassium sorbate according to the prescription amount, putting the mixture into a proper amount of purified water, and stirring to uniformly mix the mixture;

2) adding triethanolamine dropwise, adjusting pH to 6.0, adding purified water to the prescribed amount, and stirring.

Example 10:

3) taking a mixture of the formula amount of carob bean gum, API, propylene glycol, butyl paraben sodium salt and water-soluble lanolin in a proper amount of purified water, stirring to uniformly mix the mixture, and adding a plurality of drops of saturated solution of sodium tetraborate to form thick gel;

4) adding triethanolamine dropwise, adjusting pH to 6.0, and stirring.

Example 11:

1) taking the prescription amount of methylcellulose and glycerol, and uniformly grinding in a mortar;

2) taking API, sodium benzoate and diethylene glycol monoethyl ether in the formula amount to a beaker, adding a proper amount of purified water after completely dissolving, and stirring to uniformly disperse the materials;

3) adding the auxiliary material mixture obtained in the step 2 into the methyl cellulose glycerol mixture obtained in the step 1), quickly stirring to uniformly mix the mixture, adding a plurality of drops of 1M sodium dihydrogen phosphate solution, adjusting the pH value to 6.5, supplementing purified water to the total weight, and uniformly stirring to obtain the sodium hydrogen phosphate.

Test example 4

The gels prepared in examples 1 to 4 were subjected to in vitro transdermal test at 15mg/cm²The application method comprises uniformly spreading the ointment on pig skin, measuring the content of the receptor solution at 0.5h, 1h, 2h, 4h, 6h, 8h, and 12h, taking out all the receptor solution, rapidly supplementing fresh receptor solution, and collecting the cumulative release amount (μ g/cm) per unit area at each sampling time²) The results are shown in Table 11:

TABLE 11 cumulative release per unit area (. mu.g/cm) for the different examples²)

The results show that when the gel matrix is the same, the transdermal rate of the diethylamine salt gel of the compound in the formula I is the largest, and the transdermal rate of the ethanolamine salt gel of the compound in the formula I is the smallest.

Test example 5

The gels prepared in the above examples were kept at 5 ℃, 25 ℃ and 40 ℃, and appearance scores, acidity values and rheology measurements were performed on samples kept for 0 days, 5 days, 10 days, 20 days and 30 days to examine the physicochemical stability of the examples.

Wherein the scoring criteria for the appearance score are shown in the following table:

the above results show that: example 10 is less preferred than the other examples because it has inferior gloss, spreadability, uniformity, delamination, odor at 40 ℃ and is more stable than the other examples.

TABLE 13 pH values of the examples at different stock conditions

The above results show that: the above examples have good physical stability with pH fluctuations within a reasonable range under accelerated conditions.

TABLE 14 viscosity values η (unit: Pa. s) at a shear rate γ of 20(1/s) for the examples

The above results show that: when the shear rate is under the condition of 20 (1/s): when the gel viscosity value is within the range of 0-2.5 Pa · s, the gel is expressed in a low-viscosity fluid form, is extruded on the skin to be amorphous and has fluidity, and the compliance of a patient is poor; when the viscosity value is more than 5 pas, the coating is high-viscosity semisolid, has no fluidity, and is not easy to apply, so that the patient compliance is poor. The preferred embodiment should maintain better physical stability during storage and less viscosity change, and examples 9, 10, 11 have greater viscosity change under accelerated conditions than the other examples, so guar gum, carob bean gum, methyl cellulose are less stable as the gel phase. The flow profile of the gel prepared in example 1 is shown in FIG. 1, where it can be seen that the gel has shear thinning flow behavior.

Claims

1. A gel containing an aryl propionic compound, comprising:

a. a compound of formula I or a pharmaceutically acceptable salt thereof;

b. a pharmaceutically acceptable base;

wherein the compound of formula I has the following structure:

2. the gel formulation of claim 1, wherein the aryl propionic acid compound,

the salt is selected from the following forms:

a sodium salt of a compound of formula I represented by formula II;

a compound of formula I, diethylamine salt, of formula III;

tromethamine salt of a compound of formula I as shown in formula IV;

a compound of formula I, formula V, ethanolamine salt;

a compound of formula I, L-lysine salt, represented by formula VI;

a compound of formula I, L-arginine salt, represented by formula VII;

a triethanolamine salt of a compound of formula I represented by formula VIII;

a compound of formula i, formula IX, N-methylglucamine salt;

an epolamine salt of a compound of formula I represented by formula X;

a magnesium salt of a compound of formula I, represented by formula XI;

calcium salts of compounds of formula I as shown in formula XII;

a compound of formula I, represented by formula XIII;

a piperazine salt of a compound of formula I represented by formula XIV:

3. the gel of claim 2, wherein the salt is selected from the following forms:

a compound of formula I, diethylamine salt, of formula III;

tromethamine salt of a compound of formula I as shown in formula IV;

a compound of formula I, formula V, ethanolamine salt;

an epolamine salt of a compound of formula I represented by formula X.

4. The gel containing the arylpropionic acid compound according to claim 1, wherein the content of the compound of formula I or the pharmaceutically acceptable salt thereof as an active ingredient in the gel is 0.01 to 5.0 wt%.

5. The gel containing the arylpropionic acid compound according to claim 4, wherein the content of the compound of formula I or the pharmaceutically acceptable salt thereof as an active ingredient in the gel is 0.01 to 3.0 wt%.

6. The gel of claim 1, wherein the acceptable base in the gel comprises: at least one gel matrix, at least one humectant, at least one penetration enhancer, at least one pH regulator.

7. The aryl propionic acid compound-containing gel according to claim 6, wherein the gel base is selected from one or more of carbomer, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, SEPINETMP 600, starch gelling gel base, xanthan gum, sodium alginate, gum tragacanth, guar gum, carob gum; the content is 0.05-20 wt%;

the penetration enhancer is selected from one or more of ethanol, butanol, propylene glycol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether and urea; the content is 0.01-5 wt%;

8. The gel of claim 6, wherein the acceptable base of the gel further comprises a preservative selected from one or more of benzyl alcohol, diazolidinyl urea, dichlorobenzyl alcohol, sodium benzoate, methylparaben, ethylparaben, propylparaben, phenol, chlorocresol, phenoxyethanol, benzalkonium chloride, benzalkonium bromide, preferably benzyl alcohol, sodium benzoate; the content is 0.01-2 wt%.

9. A method of preparing a gel containing an arylpropionic acid compound of claim 8, comprising the steps of:

10. Use of a gel containing an arylpropionic acid compound according to any one of claims 1 to 8 in the manufacture of a non-steroidal anti-inflammatory drug;

the medicine is preferably used for treating rheumatoid arthritis, lumbago, migraine, neuralgia, scapulohumeral periarthritis, osteoarthritis, inflammation and/or pain relief of neck-shoulder-wrist syndrome, pain and/or inflammation relief after operation, trauma or tooth extraction, and fever and/or pain relief of acute upper respiratory tract inflammation.