Topical pharmaceutical composition

Abstract

A topical pharmaceutical composition, which comprises an active ingredient upadacitinib or a pharmaceutically acceptable salt thereof, an emulsifier, a permeation enhancer, an oil phase, and an aqueous phase, wherein the pH of the topical pharmaceutical composition is 5.0-8.5.

Description

A topical pharmaceutical composition TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a topical pharmaceutical composition which can be used for preventing or treating skin or mucosal surface lesions. BACKGROUND

[0002] Uipatitn is a selective Janus kinase (JAK) inhibitor, and its chemical structural formula is shown as formula I, which is developed by AbbVie, USA, and is used for treating moderate to severe atopic dermatitis in adults.

[0003] The marketed uipatitn preparation is an oral preparation, which is known from document 1 and contains a hydrophilic polymer and a pH adjuster.

[0004] The uipatitn cream is recorded in document 2, and the emulsifier in the preparation is SEPINEO TM P600, and the penetration enhancer is Transcutol HP.

[0005] Developing an oral preparation into a topical external preparation is beneficial to the rapid effect of the drug or the reduction of the side effects of the drug. When developing a topical pharmaceutical composition, not only the permeability of the drug needs to be investigated, but also the stability of the pharmaceutical composition. The present application provides a topical pharmaceutical composition containing uipatitn, which has good permeability and good stability.

[0006] Document 1 WO2017066775

[0007] Document 2 CN106794126A SUMMARY

[0008] The present application provides a topical pharmaceutical composition, characterized in that the composition contains an active ingredient uipatitn or a pharmaceutically acceptable salt thereof, an emulsifier, a penetration enhancer, an oil phase and an aqueous phase; and the pH of the topical pharmaceutical composition is 5.0-8.5.

[0009] Suitable oil phase of the present application

[0010] The oil phase of the present application includes but is not limited to vaseline, liquid paraffin, beeswax, stearyl alcohol, cetyl alcohol, cetylstearyl alcohol, stearic acid, lanolin and its derivatives, oleic acid, dimethicone, vegetable oil, medium-chain triglyceride (MCT) and the like. The percentage content of the oil phase in the topical pharmaceutical composition of the present application is 1-40% by weight; preferably, the percentage content of the oil phase in the topical pharmaceutical composition of the present application is 5-30%.

[0011] In a preferred embodiment of the present invention, the oil phase is petrolatum or liquid paraffin.

[0012] In a preferred embodiment of the present invention, the percentage content of petrolatum or liquid paraffin in the topical pharmaceutical composition of the present invention is 5-30%.

[0013] The aqueous phase of the topical pharmaceutical composition of the present invention is water.

[0014] Suitable emulsifiers for this invention

[0015] The emulsifiers described in this invention include, but are not limited to: SEPINEO PHD100, DERM, and SE68; or Gefion. Series (polyoxyethylene stearate blend), Gelot TM 64 Emulsifiers; or Tween-type, polyoxyethylene alkyl ether / ester, and glycerol ester nonionic emulsifiers.

[0016] In a preferred embodiment of the present invention, the emulsifier is selected from SEPINEO. TM P600 (a mixture of acrylamide / sodium acryloyl dimethyl taurate copolymer, isohexadecane, and polysorbate 80) CES (emulsifier blend of cetearyl alcohol, dicetyl phosphate and cetyl alcohol polyether-10 phosphate). CES emulsifier blend is a self-emulsifying wax, which is mainly a mixture of waxy substances cetearyl alcohol and stearyl alcohol, 10-20% dicetyl phosphate, and 10-20% cetyl alcohol polyether-10 phosphate.

[0017] In a preferred embodiment of the present invention, the emulsifier is an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate and cetyl alcohol polyether-10 phosphate.

[0018] In a preferred embodiment of the present invention, the emulsifier is CES.

[0019] In a preferred embodiment of the present invention, the emulsifier is SEPINEO. TM P600.

[0020] In a preferred embodiment of the present invention, the emulsifier comprises 1 to 30% of the topical pharmaceutical composition of the present invention.

[0021] Suitable penetration enhancer of the present invention

[0022] The penetration enhancers described in this invention include, but are not limited to: diethylene glycol monoethyl ether, polyglycerol oleate (e.g., ... Oleique CC 497), propylene glycol, butylene glycol, hexylene glycol, isopropyl alcohol, polyethylene glycol, dimethyl isosorbide (DMI), caprylic / capric triglycerides (Labrasol), PPG-5-ceteth-20 (e.g., Procetyl TM at least one of the following: natural essential oils, fatty acids, azone.

[0023] In a preferred embodiment of the present application, the penetration enhancer comprises diethylene glycol monoethyl ether. Diethylene glycol monoethyl ether is known by the trade name Transcutol, and various grades of Transcutol can be used in the pharmaceutical composition of the present application, including Transcutol P, Transcutol HP, Transcutol V, and Transcutol CG.

[0024] In a preferred embodiment of the present application, the topical pharmaceutical composition of the present application contains two penetration enhancers.

[0025] In a preferred embodiment of the present application, the topical pharmaceutical composition of the present application contains a first penetration enhancer, diethylene glycol monoethyl ether, and a second penetration enhancer.

[0026] In a preferred embodiment of the present application, the second penetration enhancer is selected from the group consisting of propylene glycol, polyglyceryl oleate, dimethyl isosorbide (DMI).

[0027] In a preferred embodiment of the present application, the second penetration enhancer is selected from propylene glycol.

[0028] In a preferred embodiment of the present application, the penetration enhancer of the present application consists of diethylene glycol monoethyl ether and propylene glycol.

[0029] In a preferred embodiment of the present application, the penetration enhancer of the present application contains diethylene glycol monoethyl ether in a percentage of 10.0-35.0% in the topical pharmaceutical composition; further preferred is a percentage of 15.0-30.0% of diethylene glycol monoethyl ether.

[0030] In a preferred embodiment of the present application, the penetration enhancer of the present application contains propylene glycol in a percentage of 1.0-15.0% in the topical pharmaceutical composition; further preferred is a percentage of 1.0-10.0% of propylene glycol.

[0031] In a preferred embodiment of the present application, the penetration enhancer of the present application contains diethylene glycol monoethyl ether in a percentage of 10.0-35.0% and propylene glycol in a percentage of 1.0-15.0%.

[0032] In a preferred embodiment of the present application, the penetration enhancer of the present application contains 10.0-30.0% of diethylene glycol monoethyl ether and 1.0-10.0% of propylene glycol.

[0033] Suitable pH value and pH adjuster of the present application

[0034] Suitable pH range is important in the formulation of the present application, too high pH, such as higher than 8.0, especially higher than 8.5, can lead to the precipitation of crystal of upatin in the cream (see Figure 1); while low pH can lead to the discoloration of the formulation of the present application, such as lower than 5.0, the cream appears gray (see Figure 2).

[0035] Therefore, in a preferred embodiment of the present application, the topical pharmaceutical composition of the present application has a pH range of 5.0-8.5.

[0036] In a preferred embodiment of the present application, the topical pharmaceutical composition has a pH range of 5.5-8.0; further preferably, the topical pharmaceutical composition has a pH range of 6.0-8.0.

[0037] The topical pharmaceutical composition of the present application can or can not contain a pH adjuster; when added, the pH adjuster can be any ingredient that can make the topical pharmaceutical composition of the present application obtain a suitable pH range.

[0038] Suitable pH adjusters include: organic bases, inorganic bases, or buffer systems composed of acids and bases. Inorganic bases include but are not limited to alkali hydroxides, carbonates, bicarbonates.

[0039] In a preferred embodiment of the present application, the topical pharmaceutical composition further contains a pH adjuster.

[0040] In a preferred embodiment of the present application, the pH adjuster is inorganic bases (including but not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, phosphate), organic bases (including but not limited to tromethamine), organic acid salts (including but not limited to sodium citrate, sodium acetate, sodium tartrate, etc.).

[0041] Other excipients of the present application

[0042] The topical pharmaceutical composition of the present application can also further add other types of pharmaceutically acceptable excipients according to the needs of the formulation, including preservatives, humectants, thickening agents, stabilizers, surfactants, etc.

[0043] Suitable preservatives include: propionates, phenoxyethanol, sorbic acid, etc., such as methylparaben, propylparaben or a combination thereof.

[0044] Suitable humectants include: Crodamol IPP, 1,2,6-hexanetriol, 2-ethyl-1,6- hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, and stearyl alcohol

[0045] Suitable surfactants include: sodium stearate, sodium laurate, sodium lauryl sulfate, octoxynol, dodecylpolyoxyethylene, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, mannitol laurate, and the like.

[0046] Suitable thickening agents include: cellulose, carbomer, polycarbophil, xanthan gum, carrageenan, polyvinyl alcohol, PVP, poloxamer, and the like.

[0047] The topical pharmaceutical composition described in the present application is a cream preparation or a gel preparation.

[0048] The percentage content of upatinib in the topical pharmaceutical composition is 0.1-3.5%; preferably, the percentage content of upatinib in the topical pharmaceutical composition is 0.1-3.0%. Upatinib includes pharmaceutically acceptable salts thereof. Upatinib can also be in the form of a hydrate, such as hemihydrate, etc.

[0049] In a preferred aspect of the present application, the upatinib is upatinib hemihydrate.

[0050] The composition can be administered once or multiple times per day, preferably the composition is administered 1-3 times per day.

[0051] In a specific embodiment of the present application, the topical pharmaceutical composition comprises: an active ingredient upatinib or a pharmaceutically acceptable salt thereof; an emulsifying agent; a penetration enhancer; an oil phase and an aqueous phase; the penetration enhancer consists of diethylene glycol monoethyl ether and propylene glycol.

[0052] The second aspect of the present application provides a use of the topical pharmaceutical composition in the preparation of a medicament for the treatment, preparation, prevention or treatment of skin or mucosal lesions; the lesions include psoriasis, arthritis, hidradenitis, alopecia areata, alopecia totalis, and hair loss.

[0053] The beneficial effects of the present application are that the discoloration of the external cream preparation is often unacceptable, such as the blackening or greying of the white cream during use or storage. The topical pharmaceutical composition of the present application can achieve good stability without color change. At the same time, the topical pharmaceutical composition of the present application has excellent IVPT parameters, such as excellent intradermal retention rate, which can significantly improve the therapeutic effect of the external upatin preparation. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 is a diagram of the crystallization phenomenon of upatin cream;

[0055] Figure 2 is a color diagram of upatin cream. DETAILED DESCRIPTION

[0056] The present application is used to illustrate the spirit of the present application without further limiting the scope of the present application. Unless otherwise specified, the experimental materials and experimental animals used in the embodiments of the present application can be obtained by conventional methods in the art.

[0057] In vitro skin permeation test (IVPT) determination method:

[0058] Select the back skin of Bama miniature pigs with a thickness of 1000 μm, and screen the skin with qualified transepidermal water loss (TEWL) for testing. Place the treated skin (horn layer upwards) between the donor chamber and the receptor chamber of the Franz diffusion cell, with a sample amount of 30 mg. The skin temperature is maintained at 32±1℃. After 24 h, determine the drug concentration in the receiving pool (skin permeation rate % = receiving pool drug amount / sample drug amount * 100 %). Remove the residual cream outside the skin, and determine the amount of drug retained in the skin (intradermal retention rate % = skin drug amount / sample drug amount * 100 %).

[0059] pH determination method:

[0060] Dilute 1 g of cream with 10 ml of purified water, and then use a pH meter to determine the pH.

[0061] Content determination method:

[0062] Determine by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Test 0512), with acetonitrile-water (50:50) as the solvent. Take an appropriate amount of the product, shake it with an appropriate amount of solvent to dissolve and dilute it to about 0.2 mg per 1 ml to prepare a solution as the test solution. Take about 20 mg of upatin reference substance, accurately weigh it, and place it in a 100 ml volumetric flask. Add an appropriate amount of solvent, shake to dissolve and dilute to the mark, and shake well to obtain the reference solution.

[0063] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (CAPCELL PAK-MG II-C18 4.6mm*150mm 5μm or a chromatographic column with equivalent performance); 0.025 mol / L ammonium acetate solution-methanol (55:45) as the mobile phase; the detection wavelength was 340 nm; the flow rate was 1.0 ml per minute; the column temperature was 40°C; the injection volume was 10 μl; the running time was 20 min.

[0064] Determination method: precisely measuring the test sample solution and the control sample solution, respectively injecting into the liquid chromatograph, recording the chromatogram, and calculating the content by the external standard method with the peak area.

[0065] The "percentage content" and "percentage" in the present application refer to the weight ratio of the pharmaceutical excipient in a unit pharmaceutical preparation.

[0066] Example 1

[0067] The upatinib cream was prepared according to the following prescription composition ratio:

[0068] Cream preparation method:

[0069] 4 g of sodium hydroxide was weighed, and 96 g of purified water was added to obtain 100 g of 1N NaOH solution.

[0070] 10 g of vaseline, 5 g of isopropyl palmitate, 10 g of phosphate ester self-emulsifying wax CES was added to a beaker, stirred with a stirring paddle, and heated to 75-80°C for preservation to obtain an oil phase; 0.05 g of EDTA-2Na was dissolved in 44 g of purified water, 3 g of NaOH solution was added and mixed, and heated to 75-80°C for preservation to obtain an aqueous phase; 0.2 g of hydroxybenzyl ester, 0.05 g of hydroxybenzyl propyl ester, and 2.05 g of upatinib raw material (upatinib hemihydrate) were added to 25 g of Transcutol P solvent, stirred to clarify to obtain an API phase. The oil phase at 75-80°C was slowly added to the aqueous phase at 75-80°C, and high shear was used to obtain a uniform blank cream, and then the temperature was lowered to 45-50°C, and the API phase was slowly added to the blank cream, and high shear was continued. The pH was adjusted to 7.0 to obtain an upatinib cream and was packaged (8 g / tube, containing 2% upatinib per tube).

[0071] Example 2

[0072] According to the same method and composition of Example 1 (adjusting pH=7.0), different proportions of penetration enhancers and combinations were added to evaluate the effects of different penetration enhancers and combinations on the pharmaceutical composition.

[0073] The results of the IVPT experiment are as follows:

[0074] When 25% Transcutol P is used as a penetration enhancer in the prescription, the retention rate in the skin in the in-vitro transdermal experiment is 22.03%, and the combination of Transcutol P and hexylene glycol does not significantly improve. When 20% Transcutol P and 2%, 4%, and 6% propylene glycol are used, the retention amount of the drug in the skin can be significantly improved, and the skin retention rate is between 33.28% and 49.58%; when Transcutol P and DMI, and propylene glycol and DMI are used as a composite penetration enhancer, the skin retention rate is also not significantly improved.

[0075] The proportion of the pharmaceutical preparation of the present application penetrating through the skin is less than 1%, indicating that a considerable proportion of the drug can be retained in the target site of the disease, the skin epidermis and dermis, and the drug is expected to have significant efficacy and small systemic side effects when administered topically.

[0076] Example 3

[0077] The cream is prepared according to the preparation method of Example 1 with the penetration enhancer content of Examples 2-3, and different pH-adjusted upatin creams are prepared by adding different contents of pH adjusters, and the residual amount of upatin in the skin is determined by IVPT experiment, and the results are as follows (2% specification, mean ± SD, n = 3):

[0078] The stability of the cream with different pH values is investigated, when the prescription pH is 5.0, the color of the cream changes from white to gray, and when the pH is 6.0 and above, the color does not change, and the color stability is good, and the content does not change significantly. The pH affects the skin distribution of the drug, and when the pH is 7.0, the skin retention amount is the largest, and when the pH is higher than 7.0, the skin retention rate decreases with the increase of the pH, and the present application preferably ranges from pH 6.0 to 8.0.

[0079] Example 4

[0080] 3g SEPINEO TM P600 is added to a container containing 15g of liquid paraffin and stirred uniformly; 2.05g of upatin raw material, 0.2g of hydroxybenzyl, and 0.05g of hydroxybenzyl propyl are added to 20g of a mixed solvent of Transcutol P and 5g of propylene glycol, stirred and dissolved, and transferred to the above-mentioned container, and stirred uniformly; 0.05g of EDTA-2Na is dissolved in 54.7g of water, and then transferred to the above-mentioned container, and stirred uniformly to obtain a cream.

[0081] Example 5

[0082] Add 3g of SEPINEO TM P600 was added to a container containing 15g of liquid paraffin and stirred evenly; 2.05g of Ulipristal raw drug, 0.2g of hydroxybenzyl, 0.05g of hydroxybenzyl propyl were added to a mixed solvent of 20g of Transcutol P and 5g of DMI, stirred and dissolved, and then transferred to the above container and stirred evenly; 0.05g of EDTA-2Na was dissolved in 54.7g of water, then transferred to the above container and stirred evenly to obtain a cream.

[0083] The in-vitro transdermal experiment showed that the intradermal retention rate of the drug was 34.68% with Transcutol P and propylene glycol as the composite penetration enhancer, which was significantly higher than that of DMI as the composite penetration enhancer.

[0084] In the ulipristal cream with different emulsifiers, the combination of penetration enhancer diethylene glycol monoethyl ether and propylene glycol can obtain good intradermal retention rate.

Claims

1. A topical pharmaceutical composition, characterized in that, The composition comprises: an active ingredient, upatinib or a pharmaceutically acceptable salt thereof; an emulsifier; a penetration enhancer; an oil phase and an aqueous phase; the pH of the topical pharmaceutical composition is 5.0-8.

5.

2. The composition according to claim 1, wherein the penetration enhancer contains diethylene glycol monoethyl ether, propylene glycol.

3. The composition according to claim 1, wherein the pH of the topical pharmaceutical composition is 5.5-8.0; preferably, the pH of the topical pharmaceutical composition is 6.0-8.

0.

4. The composition according to claim 1, wherein the percentage content of the penetration enhancer, diethylene glycol monoethyl ether, in the topical pharmaceutical composition is 10.0-35.0%.

5. The composition according to claim 1, wherein the percentage content of the penetration enhancer, propylene glycol, in the topical pharmaceutical composition is 1.0-15.0%.

6. The topical pharmaceutical composition of claim 1, wherein, The composition comprises: an active ingredient, upatinib or a pharmaceutically acceptable salt thereof; an emulsifier; a penetration enhancer; an oil phase and an aqueous phase; the pH of the topical pharmaceutical composition is 5.0-8.5; the topical pharmaceutical composition contains a penetration enhancer in a percentage content of 10.0-35.0% of diethylene glycol monoethyl ether and in a percentage content of 1.0-15.0% of propylene glycol.

7. A topical pharmaceutical composition, characterized in that, The composition comprises: an active ingredient, upatinib or a pharmaceutically acceptable salt thereof; an emulsifier; a penetration enhancer; an oil phase and an aqueous phase; the penetration enhancer consists of diethylene glycol monoethyl ether and propylene glycol.

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