CN115702936A

CN115702936A - Lucotinib composition and application thereof

Info

Publication number: CN115702936A
Application number: CN202210962395.8A
Authority: CN
Inventors: 喻进; 罗艳华; 戚卫蕊; 严婷婷; 吴笑笑; 王剑
Original assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Current assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Priority date: 2021-08-13
Filing date: 2022-08-11
Publication date: 2023-02-17
Also published as: WO2023016583A1; CN117813117A

Abstract

The invention relates to an iridocotinib composition and application thereof, wherein the iridocotinib composition comprises an active ingredient iridocotinib or a pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol, and has good stability and permeability promotion. Further provided is an ecteinascidin gel comprising an ecteinascidin composition and a gel matrix. The effects of the composition and the gel of the luccotinib are obviously better than those of the commercial preparations when the composition and the gel of the luccotinib are used for treating diseases, wherein the diseases comprise one or more of dermatitis, psoriasis, leucoderma, hidradenitis, urticaria and alopecia areata.

Description

Luketinib composition and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition of luccotinib and/or pharmaceutically acceptable salts thereof and application thereof.

Background

The compound can be used as a JAK1 and JAK2 tyrosine kinase inhibitor for middle-risk or high-risk Primary Myelofibrosis (PMF) (also called chronic idiopathic Myelofibrosis), myelofibrosis secondary to polycythemia vera (Myelosis secondary to polycythemia vera, PPV-MF) or Myelofibrosis secondary to primary thrombocytosis (PET-MF), and can treat the swollen or other symptoms related to the diseases.

The lucentinib cream was approved by FDA in us 09 menses in 2021 for marketing under the trade name Opzelura, and was used for short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis.

CN103002875B discloses a cream formed from an oil-in-water emulsion containing rucatinib or a pharmaceutically acceptable salt thereof, which comprises water, an oil component, an emulsifier component and a solvent component.

Penetration enhancers can be classified into hydrophilic penetration enhancers, lipophilic penetration enhancers, and amphiphilic penetration enhancers according to the physicochemical properties of penetration enhancers. Common hydrophilic penetration enhancers are carvone, menthol; common lipophilic permeation-promoting agents are lemon essential oil; the amphiphilic penetration enhancer mainly comprises azone, pyrrolidone, terpenoids, fatty acids and the like, wherein the azone, pyrrolidone, unsaturated fatty acid and the like have relatively good penetration enhancing effect on water-soluble medicines. Further, the penetration enhancer may be classified into sulfoxides, fatty acids, terpenes, hydrocarbons, amides, alcohols, amines, and the like according to its structure.

Diethylene glycol monoethyl ether, which was first approved by the FDA for use in topical formulations in 2005, is under the trade name Transcutol, abbreviated as DEGEE, and can be used as a solubilizer, a permeation enhancer, a surfactant, and the like.

Disclosure of Invention

The first aspect of the invention provides an incrustation composition, which comprises an active ingredient of incrustation or a pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol.

"diethylene glycol monoalkyl ether" is to be understood as meaning more than one diethylene glycol substituted by a C1 to C6 alkyl ether. The diethylene glycol monoalkyl ether is one or both of Diethylene Glycol Monoethyl Ether (DGME) and diethylene glycol monomethyl ether (DGMM).

The Transcutol in the embodiment of the invention refers to diethylene glycol monoalkyl ether, and further refers to diethylene glycol monoethyl ether.

In alternative embodiments, the diethylene glycol monoalkyl ether content may be 10 to 50%, based on the total weight of the pharmaceutical composition, 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 20 to 50%, more preferably 20 to 45%.

In alternative embodiments, the ethanol and/or propylene glycol content may be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 50%, more preferably 5 to 40% by weight of the total pharmaceutical composition.

Further, the present invention provides an orchitinib composition further comprises water, wherein the content of the water is up to 100% of the total weight of the pharmaceutical composition, may be 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, 45.0%, 45.5%, 46.0%, 46.5%, 47.0%, 47.5%, 48.0%, 48.5%, 49.0%, 49.5%, 50.0%, 50.5%, 51.0%, 51.5%, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.5% 64.0%, 64.5%, 65.0%, 65.5%, 66.0%, 66.5%, 67.0%, 67.5%, 68.0%, 68.5%, 69.0%, 69.5%, 70.0%, 70.5%, 71.0%, 71.5%, 72.0%, 72.5%, 73.0%, 73.5%, 74.0%, 74.5%, 75.0%, 75.5%, 76.0%, 76.5%, 77.0%, 77.5%, 78.0%, 78.5%, 79.0%, 79.5%, 80.0%, 80.5%, 81.0%, 81.5%, 82.0%, 82.5%, 83.0%, 83.5%, 84.0%, 84.5%, 85.0%, 85.5%, 86.0%, 86.5%, 87.0%, 87.5%, 88.0%, 88.5%, 89.0%, 89.5%, or 90.0%.

The provided compositions of ruckerib may further comprise one or more additional dermatologically acceptable excipients. Exemplary additional dermatologically acceptable excipients include, but are not limited to, pH adjusting agents, chelating agents, preservatives, humectants, thickening or viscosity building agents, fragrances, colorants, and mixtures thereof.

The composition of the present invention may further comprise a pH adjusting agent.

In one embodiment, the pH adjusting agent is an acid, an acid salt, or a mixture thereof. Suitably, the acid is selected from lactic acid, acetic acid, maleic acid, succinic acid, citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid, edetic acid (edetic acid), phosphoric acid, nitric acid, sulphuric acid and hydrochloric acid, and mixtures thereof.

In another embodiment, the pH adjusting agent is a buffering agent. Suitably, the buffer is selected from triethanolamine, citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, propionate/propionic acid, lactate/lactic acid, ammonium salt/ammonia, and edetate/edetic acid. In one embodiment, the pH adjusting agent is a buffer, which is citrate/citric acid.

The provided composition of the present invention may further comprise a chelating agent. In one embodiment, the chelating agent is a mixture of two or more chelating agents. As described herein, the compositions of the present invention may comprise a mixture of a chelating agent and an antioxidant, wherein both excipients serve to prevent or minimize oxidative degradation reactions in the composition.

Exemplary chelating agents include, but are not limited to, citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA), phosphonates, salts thereof, and mixtures thereof. Ethylenediaminetetraacetic acid is also known as edetic acid.

In one embodiment, the chelating agent is EDTA or a salt thereof, such as the potassium, sodium or calcium salt of EDTA. In one embodiment, the EDTA or salt thereof is disodium EDTA. In another embodiment, the chelating agent is citric acid. In yet another embodiment, the composition of the invention comprises a mixture of a chelating agent and an antioxidant, which is a mixture of EDTA or a salt thereof and propyl gallate. In a further embodiment, the composition of the invention comprises a mixture of a chelating agent and an antioxidant, which is a mixture of EDTA or a salt thereof and BHT. In one embodiment, the composition of the present invention comprises a mixture of a chelating agent and an antioxidant, which is a mixture of disodium EDTA and BHT.

In another embodiment, the composition comprises a mixture of a chelating agent and an antioxidant, which is a mixture of citric acid and propyl gallate. In one embodiment, the composition of the present invention comprises a mixture of a chelating agent and an antioxidant, which is a mixture of citric acid and BHT.

The provided composition of the present invention may further comprise a preservative. In one embodiment, the preservative is a mixture of two or more preservatives.

Exemplary preservatives include, but are not limited to, benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol, chloroxylenol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, phenoxyethanol, sorbic acid, benzoic acid, salts thereof, and mixtures thereof.

In one embodiment, the preservative is selected from benzyl alcohol, phenoxyethanol, and benzoic acid, and mixtures thereof.

The orchitinib composition provided by the present invention may further comprise an antioxidant selected from the group consisting of butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, 2,4, 5-trihydroxybutanone, 4-hydroxymethyl-2, 6-di-tert-butylphenol, erythorbic acid, guaiac resin, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butyl hydroquinone, and tocopherol, or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

In some embodiments, the luccotinib composition of the present invention comprises, based on the total weight of the composition:

reed canatinib, or a pharmaceutically acceptable salt thereof: 0.1 to 20 percent

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

And to 100wt% water;

preferably, in some embodiments, the luccotinib composition of the present invention comprises, based on the total weight of the composition:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 10 percent

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

And to 100wt% water;

more preferably, in some embodiments, the luccotinib composition of the present invention comprises, based on the total weight of the composition:

reed canatinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

And to 100wt% water;

the composition provided by the invention has good stability, or the stability of the lucentinib or the pharmaceutically acceptable salt thereof in the composition of diethylene glycol monoalkyl ether, ethanol and/or propylene glycol is good.

Another aspect of the present invention is to provide an external preparation based on the composition of the present invention, which may be a cream, an ointment, a gel, a lotion, a spray, an aerosol, a foam or a suspension.

Further, the invention provides an iridoid gel which comprises an active ingredient iridoid or pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol and a gel matrix.

Further, the invention provides a rucotinib gel, which comprises active ingredients of rucotinib or pharmaceutically acceptable salts thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol, and a gel matrix, wherein the gel matrix is one or more of carbomer, cellulose derivatives, xanthan gum, acacia gum, tragacanth gum, carrageenan, gelatin, sodium alginate and poloxamer, preferably carbomer, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate and poloxamer.

In alternative embodiments, the diethylene glycol monoalkyl ether content may be 10 to 50%, based on the total weight of the ruckerib gel, 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 20 to 50%, more preferably 20 to 45%.

In alternative embodiments, the ethanol and/or propylene glycol content may be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 50%, more preferably 5 to 40% by weight of the total weight of the luctinib gel.

In alternative embodiments, the gel matrix is a poloxamer at a level of 1 to 50%, which may be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 40%, more preferably 10 to 30% based on the total weight of the rucatinib gel.

Further, the luccotinib gel provided by the present invention further comprises water, wherein the content of the water is up to 100% by weight of the total weight of the pharmaceutical composition, may be 20.0%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%, 43.5%, 44.0%, 44.5%, 45.0%, 45.5%, 46.0%, 46.5%, 47.0%, 47.5%, 48.0%, 48.5%, 49.0%, 49.5%, 50.0%, 50.5%, 51.0%, 51.5%, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.5% 64.0%, 64.5%, 65.0%, 65.5%, 66.0%, 66.5%, 67.0%, 67.5%, 68.0%, 68.5%, 69.0%, 69.5%, 70.0%, 70.5%, 71.0%, 71.5%, 72.0%, 72.5%, 73.0%, 73.5%, 74.0%, 74.5%, 75.0%, 75.5%, 76.0%, 76.5%, 77.0%, 77.5%, 78.0%, 78.5%, 79.0%, 79.5%, 80.0%, 80.5%, 81.0%, 81.5%, 82.0%, 82.5%, 83.0%, 83.5%, 84.0%, 84.5%, 85.0%, 85.5%, 86.0%, 86.5%, 87.0%, 87.5%, 88.0%, 88.5%, 89.0%, 89.5%, or 90.0%.

In some embodiments, the reed canatinib gel comprises, based on the total weight of the gel:

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

Carbomer: 0.1 to 20 percent

And to 100wt% water;

preferably, in some embodiments, the luccotinib gel comprises, based on the total weight of the gel:

reed canatinib, or a pharmaceutically acceptable salt thereof: 0.1 to 10 percent

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

Carbomer: 0.1 to 10 percent

And to 100wt% water;

more preferably, in some embodiments, the reed canatinib gel comprises, based on the total weight of the gel:

reed canatinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

Carbomer: 0.1 to 10 percent

And to 100wt% water;

in some embodiments, the luccotinib gel comprises, based on the total weight of the gel:

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

Poloxamer: 1 to 50 percent

And to 100wt% water;

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 10 percent

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

Poloxamer: 5 to 40 percent

And to 100wt% water;

more preferably, in some embodiments, the luccotinib gel comprises, based on the total weight of the gel:

reed canatinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

Poloxamer: 10 to 30 percent

And to 100wt% water;

it is a further aspect of the present invention to provide a use of the composition of reecotinib and reecotinib gel as described above for the treatment of one or more of dermatitis, psoriasis, vitiligo, hidradenitis, urticaria, alopecia areata.

Drawings

FIG. 1: PASI score 7 days after dosing

P <0.05, p <0.01; (ii) a Compared to blank gels, # p <0.05, # p <0.01; θ p <0.05, θ p <0.01; in comparison to the original ground cream,% p <0.05,%% p <0.01; (ii) compared to positive calcipotriol, <0.05; compared with positive phenyl vitamin mode, p is less than 0.05.

FIG. 2: PASI appearance score curve graph

FIG. 3: skin tissue section map of different sample sets

Detailed Description

Example 1: investigation of impurity stability

The impurity stability of the luccotinib phosphate in Transcutol, transcutol + ethanol, transcutol + propylene glycol, transcutol + water, and Transcutol + propylene glycol + ethanol was examined.

The impurity detection method used in this embodiment is:

preparing a test solution: taking about 1g of an incarnib phosphate sample, precisely weighing the sample to a 10ml volumetric flask, adding a diluent (methanol: water = 80) to dilute the sample to a scale mark, shaking up, filtering, and taking a subsequent filtrate for detection.

Detection conditions are as follows: the above-mentioned components are subjected to liquid phase analysis, and measured by high performance liquid chromatography (0512, the four-part general rule of the 2015 edition of Chinese pharmacopoeia). Octadecylsilane bonded silica gel was used as a filler (Waters Symmetry C18, 250mm. Times.4.6 mm,5 μm); the detection wavelength is 220nm, and the sample injection amount is 5 mu L by using methanol/water =60, the column temperature is 25 ℃, the flow rate is 1 mL/min.

Table 1: impurity stability of the Lucotinib phosphate in different compositions

As can be seen from table 1, under the acceleration condition, the change of the ruccotinib phosphate in Transcutol, transcutol + water is obvious, namely the change of the impurity RRT0.53 and the impurity RRT0.86 are obvious, wherein the change of the impurity RRT0.86 is especially obvious; after ethanol and/or propylene glycol are added into Transcutol, the contents of the impurities RRT0.53 and RRT0.86 are obviously reduced.

The stability of the lucokitiob phosphate in the composition of Transcutol + ethanol and/or propylene glycol + water and Transcutol + glycerol + water was further examined.

Table 2: impurity stability of the Lucotinib phosphate in different compositions

As can be seen from table 2, under the acceleration condition, the stability of impurities of the incarnib phosphate in Transcutol + ethanol and/or propylene glycol + water is still good, and when the ethanol and/or propylene glycol is replaced by glycerin, the impurity reduction effect is not obtained.

Example 2: study on content stability of composition

Stability in different concentrations of Transcutol + ethanol and/or propylene glycol was examined from the perspective of changes in the content of incarnib phosphate. The stability is good when the content of the reed cotinib phosphate in the sample solution is 100 +/-5% of 0 day under the acceleration condition by taking the percentage of the content of the reed cotinib phosphate in the sample solution as a reference.

Preparing a sample: weighing 0.1g (1%) of rucotinib phosphate based on 10g, adding corresponding penetration enhancer and/or water, ultrasonically dissolving to obtain sample solution, subpackaging in penicillin bottles, and sealing for storage.

Sampling points are as follows: sampling and detecting at 25 deg.C for 0 day, 25 deg.C for 1 month, 25 deg.C for 2 months, 40 deg.C for 14 days, and 40 deg.C for 2 months;

preparing a test solution: a sample of about 1g is taken, precisely weighed and then added to a 10ml volumetric flask, diluted to the mark with a diluent (methanol: water = 80) and shaken up, filtered and the filtrate is taken for detection.

Detection conditions are as follows: the above-mentioned components are subjected to liquid phase analysis, and measured by high performance liquid chromatography (0512, the four-part general rule of the 2015 edition of Chinese pharmacopoeia). Octadecylsilane chemically bonded silica was used as a filler (Waters Symmetry C18,250mm x 4.6mm,5 μm); the detection wavelength is 220nm, and the sample injection amount is 5 mu L by using methanol/water =60, the column temperature is 25 ℃, the flow rate is 1 mL/min. The detection results are as follows:

table 3: stability of the Lucotinib phosphate

As can be seen from table 3, the stability of the incarnib phosphate is still better in Transcutol + ethanol + water, transcutol + propylene glycol + water, and Transcutol + propylene glycol + ethanol + water at different concentrations.

Example 3: gel formulation composition

This example illustrates the preparation of 18 lucentitinib gels, and the formulation compositions are shown in tables 5-7.

This example is illustratively prepared by the following steps:

1) Weighing 0.1g or 0.15g of rucotinib free alkali by taking 10g as a reference, and adding a prescription amount of Transcutol, ethanol, propylene glycol or the combination thereof to completely dissolve the rucotinib to obtain a medicine phase;

2) Weighing a certain amount of carbomer, adding water, stirring for swelling, preparing into a carbomer aqueous solution with the concentration of 3%, and adjusting the pH value to about 5.5 to obtain a carbomer gel phase; or weighing a certain amount of poloxamer 407, adding purified water, completely dissolving, and preparing into 25% poloxamer 407 water solution to obtain poloxamer 407 water phase;

3) Mixing the medicine phase obtained in the step 1) with the carbomer gel phase or the poloxamer 407 water phase obtained in the step 2) according to different prescriptions, supplementing corresponding water to the prescription amount of 100%, and fully stirring and uniformly mixing to obtain the luccotinib gel.

Table 5: luketinib gel (prescription 1-prescription 6)

Table 6: luketinib gel (prescription 7-prescription 12)

Table 7: luketinib gel (prescription 13-18)

As can be seen from tables 5 to 7, when Transcutol is used alone, the concentration of Transcutol needs to be more than 30%, and a gel having no crystallization and a clear appearance can be formed; when only propylene glycol or ethanol is used, the gel with transparent appearance and no crystallization can not be prepared when the concentration reaches 30 percent; when Transcutol plus propylene glycol and/or ethanol is used as a penetration enhancer, a gel which is free of crystallization and has a transparent appearance can be formed when the concentration of Transcutol is 20-35% and the concentration of propylene glycol and/or ethanol is 10-30%.

Example 4: in vitro gel release assay

The in vitro release effect of the gel was examined by taking prescription 6, prescription 8 and prescription 10 in example 3. The comparative example is prepared by referring to a formula (1.0% of free base of the rucotinib) shown in table 4 in the specification of example 3 of Chinese patent CN103002875B of Netsche GmbH.

The experimental method comprises the following steps: an artificial transdermal membrane (Strat-

Membrane) was fixed between a diffusion cell having a diameter of 1.5cm and a receiving cell having a volume of 15mL, the diffusion cell was filled with 300mg of a sample of the lucentianib gel preparation, and the receiving cell was filled with a receiving solution (15% ethanol solution). The water bath temperature is 32 +/-1 ℃, and the constant temperature magnetic stirring rotating speed is 300rpm/min. Taking out 1.5mL from the receiving pool in 1h, 2h, 4h, 6h and 8h respectively, simultaneously adding the same amount of receiving liquid with the same temperature to the receiving pool in time, centrifuging the taken out receiving liquid sample at high speed (18000 rpm/min, centrifuging for 10 min), taking supernatant liquid and measuring the concentration of the solution at different time points by HPLC (C) _n )。

The cumulative amount of drug permeation per unit area is calculated as follows:

wherein,

qn: is the cumulative drug permeation amount per unit area at the nth time point (unit: mu g/cm) ² )；

Cn: the drug concentration at the nth time point (unit: μ g/mL);

C _i-1 : is the drug concentration at the i-1 st time point (unit: μ g/mL);

v: is the receiving well volume (unit: mL);

s: for effective penetration area, 1.76625cm is used in this test ² ；

Table 8: in vitro cumulative release amount (unit: mu g/cm) ² )

Time of sampling	Prescription	6	Prescription 8	Prescription 10	Comparative example
						1h	10.8	8.4	17.1	3.0
2h	31	25	51.2	6.8
					4h	84.7	66.7	145.6	29.4
6h	133.3	114.2	278.1	50.8
					8h	208	182.5	372.2	69.4

As can be seen from table 8, the in vitro release effect of the luccotinib gel provided by the present invention is significantly better than that of the comparative example under the condition of the same content of the active ingredient.

Example 5: drug effect investigation of psoriasis

The medicine can effectively improve the psoriasis symptoms, and the treatment effect of the medicine on the psoriasis can be further proved by the following experimental research.

Animal experiments: establishment and drug treatment of psoriasis vulgaris (PSO) mouse model

1 drugs and agents

Experimental materials: healthy SPF grade C57BL/6J mice (female and male halves, 8-9 weeks old, weight 20-25 g) 42, model building drugs (5% imiquimod cream, sichuan mingxin pharmacy); positive control drugs (commercially available calcipotriol ointment, commercially available yivinmod cream); a blank gel formulation; prescription 14 (gel for short) of embodiment 4 of the invention; the phosphate emulsifiable paste of available reed cotinib (the original emulsifiable paste is abbreviated as former emulsifiable paste, and the free alkali of reed cotinib is 1.5%);

2 method of experiment

2.1 Experimental groups

Experimental grouping: the experiments are divided into 7 groups, each group comprises 6 experiments, and the total number of the experiments is 42.

1) Blank control group (no treatment except shaving) (N = 6)

2) PSO model group (no treatment except imiquimod coating) (N = 6)

3) PSO model + blank gel formulation group (external application, frequency 2 times/day, 15 mg/cm) ² Continuous treatment for 7 days) (N = 6)

4) PSO model + group A of Positive drugs (treated with 0.005% calcipotriol ointment and applied topically)Wiping, frequency 2 times/day, 15mg/cm ² Continuous treatment for 7 days) (N = 6)

5) PSO model + group B of positive drugs (1% treatment with Benvimod cream, external application, frequency 2 times/day, 15 mg/cm) ² Tentative continuous treatment for 7 days) (N = 6)

6) PSO model + gel sample (external application spread, frequency 2 times/day, 15 mg/cm) ² Continuous treatment for 7 days) (N = 6)

7) PSO model + commercially available Lucotinib cream (topical application, frequency 2/day, 15 mg/cm) ² Continuous treatment for 7 days) (N = 6)

The experimental steps are as follows:

molding: mice were bred adaptively for 7 days, and a psoriasis vulgaris (PSO) mouse model was made. The molding method is as follows: the skin area of the back of the mouse is cleaned to be about 2cm x 3cm, and the exposed skin is externally applied with 5% imiquimod cream 50mg every morning for 3 days continuously for preparing a model, and the model making medicine is continuously given in the later period.

And (3) model verification: the model already has a mature SOP standard, and no additional mouse is required for model verification.

Treatment: (after 3 days of molding), the corresponding drug treatment was carried out on day 4, and the administration of IMQ was continued by 5% during the administration treatment period, and the administration of the molding drug was maintained in accordance with the number of days of administration.

Group 1) of: the blank control group (no treatment) was not treated;

group 2) of: the model group is smeared with 62.5mg of 5 percent imiquimod ointment/model group, and no treatment is carried out;

group 3) of: the model group is smeared with 62.5mg of 5% imiquimod ointment/patient for maintaining the model building, and is smeared with blank gel every day, the frequency is 2 times/day, and the treatment is continuously carried out for 7 days;

group 4) of: the model group is coated with 5% imiquimod ointment 62.5 mg/model, and is continuously treated for 7 days by coating positive drug A (calcipotriol ointment) every day at a frequency of 2 times/day;

group 5) of: the model group is smeared with 5% imiquimod ointment 62.5 mg/model, and is smeared with positive drug B (the yivinmod cream) every day at a frequency of 2 times/day for 7 days;

group 6) of: the model group is coated with 62.5mg of 5% imiquimod ointment/patient, and is maintained for molding, and is coated with the test drug (14 samples of the prescription in the invention, example 4) every day at a frequency of 2 times/day for 7 days;

group 7) of: model groups were applied with 62.5mg of 5% imiquimod ointment per maintenance model, and additionally with test drug (commercially available Lucotinib phosphate cream) daily, at a frequency of 2 times per day, for a 7 day continuous treatment in the order of administration: 1 treatment dose was given in the morning, 1 molding dose was given in the noon, and 1 treatment dose was given in the evening.

Note: to prevent animals from licking drugs. After the back of the animal is coated with the gel, the animal is independently placed in an independent cage without padding for moving for a period of time, the gel is naturally dried (within 1 hour expected), and then the animal is placed in a rearing cage for normal rearing. The food is prohibited from being fed alone, so that depression is easy to appear; the gauze is forbidden to wrap the smearing part, and the medicine can be absorbed away.

2.2 Experimental results: pathological detection after PSO animal model drug treatment

The experimental steps are as follows:

(1) Psoriasis-like lesion area and disease severity (PASI) score for each group of mice: the weight and skin damage change conditions of each group of mice are observed every day (weight measurement: 1 time per day from adaptive feeding to dosing end, 17 times in total; skin damage scoring: scoring from molding period to dosing period, 1 time per day, 10 times in total), the digital photography method is adopted for daily recording, the integral of erythema, scales and infiltration thickening degree of 0-4 at the skin damage of the mice is given according to the PASI scoring standard, the total skin damage severity scoring is obtained by adding the scores of the three, the skin damage score trend line is drawn after the integral of each group of mice is averaged, and the change conditions of the skin damage of each group of mice are observed.

(2) Histopathological Baker score: after treatment is finished, after an experiment is finished, a mouse skin lesion tissue is taken and fixed by 4% paraformaldehyde, skin tissue staining is carried out by hematoxylin-eosin (HE) after conventional paraffin embedding, the tissue pathological change of a tested area on the back of the mouse is observed under an optical microscope, skin lesions of a stratum corneum, an epidermis layer and a dermis layer are scored according to Baker scoring, total pathological skin lesion scoring is obtained by adding scores of the three, and the thickness of the epidermis is measured.

2.3 statistical methods:

results are expressed as means ± standard error (Mean ± s.e.m.) and analyzed using SPSS 17.0 statistical software, and comparisons of differences between groups were analyzed by One-way ANOVA (One-way ANOVA) (Dunnett's T3, homogeneity of variance is not assumed). P <0.05 indicates that the difference is statistically significant.

3, results:

3.1 Effect of the gels and Positive drugs of the invention and of the marketed Lucotinib phosphate cream on the appearance of PaSI as an Imquimod-induced psoriasis model

And (3) performing PASI scoring according to erythema, scales and infiltration thickening degree of the skin lesion of the mouse, and observing from a scoring trend graph of 7 days after administration of the medicament, wherein the PASI scoring has an obvious reduction trend compared with a model group after the medicament is administered for 4 days. On day 4, there was a significant decrease in both the geymode and the gel of the invention compared to the model group, and also a significant decrease compared to the blank gel group (p <0.05 or p < 0.01). On day 5 of dosing, the PASI score was significantly reduced in the gel group of the invention compared to the model group and significantly reduced in the gel group compared to the blank gel. On day 6 and day 7 of dosing, the gel group of the invention scored significantly lower (p < 0.01) compared to the model group and blank gel group, as shown in detail in fig. 1 and 2.

3.2 Effect of the inventive gel and Positive drugs and the commercially available Lucotinib phosphate cream on Imquimod-induced mouse skin lesion histopathology (Baker)

Pathological analysis: the skin structure of a normal control group is clear and complete, the horny layer is obviously not angular, the spinous layer and the granular layer of the epidermal layer are obvious, and obvious inflammatory cells and capillary vessel hyperplasia are not seen in the dermis layer; hyperkeratosis of the stratum corneum of the model group, accompanied by parakeratosis, uneven epidermal structure, thickened spinous layer, infiltration of a large number of inflammatory cells in the dermis layer, capillary hyperplasia and dilatation congestion; the blank gel group has no obvious difference with the model group, and the pathological degree is equivalent; all treatment groups have different degrees of effects, the phenomena of keratinocyte hyperplasia and parakeratosis are improved in the calcipotriol and the vacumm group, but the epidermis layer still has acanthosis thickening, and the inflammatory cell infiltration condition of the dermis layer is reduced; in the gel group, a small amount of samples are seen to have parakeratosis, the hyperkeratosis phenomenon of different degrees exists, the phenomena of acanthosis pachyderma and telangiectasis are improved, and the inflammatory cell infiltration is relieved to a certain extent; according to Baker score judgment and overall observation, the treatment effect of the iguratimod group in the positive medicament group is optimal, and the gel effect of the invention in all the treatment medicaments is optimal. See figure 3 for details.

4 conclusion

The research adopts an imiquimod to induce a psoriasis mouse model to evaluate the protective effect of a patent formula, a positive medicament and a marketed troxerutinib cream on the troxerutinib cream, and the results show that the gel, the positive medicament and the marketed troxerutinib cream can obviously reduce the PASI score of the mouse and improve the skin lesion histomorphology (Baker evaluation) condition, but compared with the positive medicament and the marketed troxerutinib cream, the gel has a better gel effect, so that the gel, the positive medicament and the marketed troxerutinib cream have the effect of treating psoriasis, and the effect of externally treating psoriasis by using the gel is better than that of the positive medicament and the marketed troxerutinib cream.

In the description herein, references to the terms "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In the description of the invention, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the features of the different embodiments or examples described in this specification may be combined or combined by those skilled in the art without being mutually inconsistent.

Although embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and not to be construed as limiting the present invention and that various changes, modifications, substitutions and alterations can be made therein by those of ordinary skill in the art within the scope of the present invention.

Claims

1. An luccotinib composition, characterized in that, the composition comprises the active ingredient luccotinib or its pharmaceutically acceptable salt, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol.

2. The reed cotinib composition of claim 1, wherein said reed cotinib composition comprises, based on total weight of the composition:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 20 percent

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

And to 100wt% water;

preferably, the luccotinib composition comprises, based on the total weight of the composition:

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

And to 100wt% water;

more preferably, the luccotinib composition comprises, based on the total weight of the composition:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

And to 100wt% water.

3. An ruthenamide composition according to claim 1 or 2, characterised in that said diethylene glycol monoalkyl ether is selected from one or both of diethylene glycol monoethyl ether and diethylene glycol monomethyl ether, preferably diethylene glycol monoethyl ether.

4. A topical formulation based on the composition of reed cotinib as claimed in claim 1 or 2, wherein said topical formulation is one of a cream, an ointment, a gel, a lotion, a spray, an aerosol, a foam or a suspension.

5. An reed cotinib gel, characterized in that said reed cotinib gel comprises, based on a total weight of said gel: the composition of luccotinib and gel matrix of any one of claims 1 to 3, wherein said gel matrix is one or more of carbomer, cellulose derivative, xanthan gum, acacia, tragacanth, carrageenan, gelatin, sodium alginate, poloxamer, preferably carbomer, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate and poloxamer.

6. The reed cotinib gel of claim 5, wherein said reed cotinib gel comprises, based on a total weight of said gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 20 percent

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

Carbomer: 0.1 to 20 percent

And to 100wt% water;

preferably, the reed canatinib gel comprises, based on the total weight of the gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 10 percent

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

Carbomer: 0.1 to 10 percent

And to 100wt% water;

more preferably, the luccotinib gel comprises, based on the total weight of the gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

Carbomer: 0.1 to 10 percent

And to 100wt% water.

7. The reed canatinib gel of claim 5, wherein said reed canatinib gel comprises, based on the total weight of the gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 20 percent

Diethylene glycol monoalkyl ether: 10 to 50 percent

Ethanol and/or propylene glycol: 1 to 50 percent

Poloxamer: 1 to 50 percent

And to 100wt% water;

preferably, characterized in that the luccotinib gel comprises, based on the total weight of the gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.1 to 10 percent

Diethylene glycol monoalkyl ether: 20 to 50 percent

Ethanol and/or propylene glycol: 5 to 50 percent

Poloxamer: 5 to 40 percent

And to 100wt% water;

more preferably, characterized in that the reed canatinib gel comprises, based on the total weight of the gel:

ricochantinib, or a pharmaceutically acceptable salt thereof: 0.5 to 2 percent

Diethylene glycol monoalkyl ether: 20 to 45 percent

Ethanol and/or propylene glycol: 5 to 40 percent

Poloxamer: 10 to 30 percent

And to 100wt% water.

8. Use of the luccotinib composition of claim 2 for treating one or more of dermatitis, psoriasis, vitiligo, hidradenitis, urticaria, alopecia areata.

9. Use of the luccotinib gel of any one of claims 5-7 for the treatment of one or more of dermatitis, psoriasis, vitiligo, hidradenitis, urticaria, alopecia areata.