CN117618577A - Semisolid preparation for improving skin disease symptoms - Google Patents

Abstract

The present invention is a semi-solid formulation of a composition for improving the symptoms of skin disorders, the components of which include a skin immune response modulator and an antiproliferative agent, in particular, budesonide and Qu Faluo, the semi-solid being in particular a cream, ointment or gel. Can be used for improving skin symptoms, inflammation and pruritus of patients with psoriasis, atopic dermatitis, acne, rosacea, etc. The invention has the advantages that: the composition has reasonable formula design, can effectively improve the skin symptoms of psoriasis, has excellent stability, skin moisturizing property, safety and effectiveness, and can be used for local treatment of the psoriasis for a long time.

Description

Semisolid preparation for improving skin disease symptoms

Technical Field

The invention relates to a composition semisolid preparation for improving skin disease symptoms, in particular to a composition semisolid preparation for improving skin disease symptoms such as psoriasis, atopic dermatitis, acne, rosacea, inflammation, pruritus and the like, and in particular relates to a composition semisolid preparation for improving skin disease symptoms of psoriasis.

Background

Psoriasis is a common skin disorder characterized by inflamed and reddish skin covered with thick silver scales. The prevalence of psoriasis varies widely throughout the world and is related to race, territory and environment. According to the current study, 1.25 million people worldwide have psoriasis, accounting for 2-3% of the general population, while 0.56% of people in china have psoriasis. It is estimated that 30% of psoriatic patients will simultaneously develop psoriatic arthritis. Plaque psoriasis is the most common phenotype (84.5%), followed by recessed psoriasis (12.3%), pustular psoriasis (3.0%) and erythrodermic psoriasis (3.6%). The major skin sites affected by psoriasis are scalp, elbows, knees, skin folds, nails, feet, trunk, buttocks and other sites. In addition, psoriasis increases the risk of developing other common diseases, such as cardiovascular disease and lymphomas. Psoriasis increases the physiological, emotional and social stress of the patient, resulting in an increase in depression rate and affecting quality of life.

In the prior art, treatment regimens for psoriasis generally include non-systemic and systemic treatments. Non-systemic treatment includes: topical therapies such as the active drugs calcipotriol, betamethasone, clobetasol propionate, tazarotene and betamethasone used in combination or alone; ultraviolet (UV) phototherapy having wavelengths of 320-400 nanometers (UVA), 290-320 nanometers (UVB), and 180-290 nanometers (UVC); external treatment methods of traditional Chinese medicine include external medicine, herbal medicine bag, medicated bath, fumigation, soaking (dyeing) and acupuncture therapy, and non-drug therapy including cupping, acupuncture, catgut embedding, fire needle, triangular needle and ear needle. The system treatment includes: drug therapies such as methotrexate, cyclosporin a and tretinoin (e.g. acitretin); biological agents such as etanercept, infliximab, adalimumab, ulinastab, celecoxib, and icoizumab; an oral administration therapeutic method of traditional Chinese medicine.

In china, 59.3% of patients receive topical treatment, the most common topical drugs are glucocorticoids (35.0%) and vitamin D3 analogues (21.8%). A total of 37.7% of patients received non-biological systemic treatment, including phototherapy (11.4%) and oral systemic medications, most of which were oral traditional Chinese medicine (13.4%) and acitretin (6.8%). In addition, 28.7% of patients used biological agents at baseline, with 80.8% using secukinumab and 10.1% using adalimumab.

Topical therapies include anti-inflammatory corticosteroids, particularly super-potent halobetasol propionate, vitamin D derivatives (such as calcipotriol), tretinoin (such as tazarotene) and coal tar. Halobetasol propionate is quite effective in ameliorating the symptoms and signs of psoriasis, but local and systemic adverse effects limit its long-term use. All treatment regimens have a certain efficacy, but have limitations in improving symptoms. The local treatment and the ultraviolet ray or systemic administration are used together most conveniently and effectively. Topical treatment not only reduces inflammation by restoring excessively proliferating cells to normal, but also relieves the associated symptoms by moisturizing the skin.

Deaned is a moderately inefficient synthetic non-fluorocorticosteroid that is used to alleviate the inflammatory and pruritic symptoms of corticosteroid-responsive dermatoses, in a variety of topical dosage forms, such as creams, ointments, gels, and lotions. The biosynthesis of potent inflammatory mediators such as prostaglandins and leukotrienes is controlled by inhibiting the release of arachidonic acid, a common precursor of prostaglandins and leukotrienes. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Halobetasol propionate is widely used for the topical treatment of adult plaque psoriasis. The mechanism of action of budesonide and halobetasol propionate is similar. The obtained tranilast can also be used for treating plaque psoriasis, and has the advantages of similar action mechanism, low drug effect and safe use.

Qu Faluo the medicine is a terphenyl acid derivative, is a vitamin A acid medicine, and is suitable for the local treatment of common acne of patients aged 9 years and older. Qu Faluo is a Retinoic Acid Receptor (RAR) agonist with specific activity against gamma subtypes of RAR. Stimulation of RAR can regulate target genes involved in various processes such as cell differentiation and inflammatory regulation. Tazarotene is suitable for topical treatment of patients with plaque psoriasis. However, its use in psoriasis is severely limited due to irritation of the local skin. The tazarotene and the trefoil are similar in action mechanism and are all tretinoin medicines, but Qu Faluo is less in skin irritation and can be used for treating psoriasis.

In the prior art, patients are generally treated with corticosteroids on daytime and tazarotene on night when receiving alternating topical treatments for psoriasis. The commercial compound preparation of the halobetasol propionate and the tazarotene has the problem of insufficient safety and can cause local adverse reactions such as atrophy, stripes, telangiectasia, folliculitis, contact dermatitis and the like. Some local adverse reactions may be irreversible and if these adverse reactions occur, the treatment needs to be stopped. Topical formulations of clobetasol propionate and halobetasol propionate and related super-strong corticosteroid hormones have been prohibited for long-term use, allowed for short-term use only, and not longer than 14 days. Furthermore, skin-treated tretinoin shows increased collagen type I formation, whereas tazarotene may lead to post inflammatory pigmentation. In addition, the commercially available dosage forms are typically emulsions which, although they are easily applied, are also easily rubbed off. The skin of psoriasis patients is itchy and dry, and therefore there is a need to improve the moisturizing properties of the formulations to achieve better therapeutic results.

In view of the above, it is contemplated to develop a combination of therapeutically active ingredients and to formulate them into a suitable semi-solid dosage form with improved stability, moisturization, safety and efficacy for long-term topical use in psoriasis.

Disclosure of Invention

The invention provides a composition semisolid preparation for improving skin disease symptoms, which aims to overcome the defects in the prior art and improve the stability, skin moisturizing property, safety and effectiveness of the composition semisolid preparation for long-term local treatment of psoriasis.

The technical solution of the invention is as follows: a semi-solid formulation of a composition for improving symptoms of skin disorders, the components of which include a skin immune response modulator and an antiproliferative agent. Can be used for improving skin symptoms, inflammation and pruritus of patients with psoriasis, atopic dermatitis, acne, rosacea, etc.

Preferably, the skin immune response modifier is a moderate-low potency corticosteroid or a pharmaceutically acceptable salt or ester thereof, and the antiproliferative agent is tretinoin or a pharmaceutically acceptable salt or ester thereof. In particular for improving the skin symptoms of psoriasis patients.

Preferably, the medium-low-efficiency corticosteroid is a medium-low-efficiency synthetic non-fluorine corticosteroid, and the tretinoin is a triphenylacid derivative tretinoin.

Preferably, the semi-solid refers to a cream, ointment, gel, hydrogel, milk gel or organogel.

Preferably, the medium-low efficiency synthetic non-fluorine corticosteroid is budesonide, and the triphenylacid derivative tretinoin is trefoil.

Preferably, the mass concentration of the budesonide or the pharmaceutically acceptable salt or ester thereof is 0.01% -0.1%, and the mass concentration of the Qu Faluo statin or the pharmaceutically acceptable salt or ester thereof is 0.001% -0.01%. The psoriasis is plaque psoriasis.

Preferably, the mass concentration of the budesonide or the pharmaceutically acceptable salt or ester thereof is 0.05%, and the mass concentration of the Qu Faluo statin or the pharmaceutically acceptable salt or ester thereof is 0.005%.

Preferably, the semi-solid is a cream. The composition further comprises one or more of an aqueous solvent, an oil phase, a surfactant, a humectant, a preservative, a chelating agent, a viscosity modifying agent, and a pH modifying agent.

Preferably, the components include glycerol stearate and PEG-100 stearate, PEG-6 caprylic/capric triglyceride, propylene glycol monocaprylate, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate.

Preferably, the components further comprise purified water, propylene glycol, medium chain triglycerides, isododecane, glycerol, phenoxyethanol, disodium edetate, carbomer homopolymers and potassium hydroxide or phosphoric acid.

Preferably, the method specifically comprises the following steps of: 40-70% purified water, 5-10% propylene glycol, 1-10% medium chain triglycerides, 1-10% isododecane, 1-10% glycerol stearate and PEG-100 stearate, 1-5% PEG-6 caprylic/capric triglyceride, 1-3% propylene glycol monocaprylate, 1-3% hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, 1-3% propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate, glycerol, 0.25-2% phenoxyethanol, 0.05-0.1% disodium ethylenediamine tetraacetate, 0.005-0.05% potassium hydroxide or phosphoric acid.

Alternatively, preferably, the semi-solid is a gel. The composition further comprises one or more of an aqueous solvent, a humectant, an excipient or solvent, a preservative, a chelating agent, a polymer, and a pH adjusting agent.

Preferably, the components include polyglycerol-3 oleate and acryloylpropionyl polyoxyethylene-8 glyceride.

Preferably, the components further comprise purified water, propylene glycol, glycerin, disodium edetate, phenoxyethanol, and potassium hydroxide or phosphoric acid.

Preferably, the method specifically comprises the following steps of: 40-90% of purified water, 5-15% of propylene glycol, 1-10% of glycerol, disodium ethylenediamine tetraacetate with the concentration of about 0.01-0.1%, 1-3% of polyglycerol-3 oleate, 1-6% of caprylyl polyoxyethylene ether-8 glyceride, 0.1-3% of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, 0.005-0.05% of phenoxyethanol, and 0.005-0.5% of potassium hydroxide or phosphoric acid.

Alternatively, preferably, the semi-solid is a vaseline-based ointment, and the components include medium chain triglycerides, isopropyl myristate, mineral oil, white vaseline oil, and synthetic beeswax.

Preferably, the method specifically comprises the following steps of: 1-10% of medium chain triglyceride, 1-10% of isopropyl myristate, 10-30% of mineral oil, 40-90% of white vaseline and 1-10% of synthetic beeswax.

Or, preferably, the semisolid is a polyethylene glycol ointment, and specifically comprises 30-50% of polyethylene glycol 300 and 50-70% of polyethylene glycol 3350 by mass fraction.

The invention has the advantages that: the composition has reasonable formula design, can effectively improve the skin symptoms of psoriasis, has excellent stability, skin moisturizing property, safety and effectiveness, and can be used for local treatment of the psoriasis for a long time.

Drawings

FIG. 1 is a graph of the in vitro permeability control of budesonide of example 17.

FIG. 2 is a graph of the in vitro permeability control of the trefoil of example 17.

Description of the embodiments

The present invention will be described in further detail with reference to examples and embodiments.

A semisolid formulation for improving skin disease symptoms, and the use of the composition for improving skin disease patients symptoms such as psoriasis, atopic dermatitis, acne, rosacea, inflammation and pruritus. Comprising a skin immune response modulator and an antiproliferative agent. In particular for treating or ameliorating psoriatic skin symptoms in patients suffering from moderate to severe plaque psoriasis. More specifically, psoriasis is 15% of the Body Surface Area (BSA).

The skin immune response modifier and the antiproliferative agent have synergistic effect, and the curative effect is better than that of two independent preparation compositions, and the skin immune response modifier is a medium-low-efficiency synthetic non-fluorine corticosteroid or pharmaceutically acceptable salt or ester thereof, and the antiproliferative agent is a triphenylacid derivative tretinoin or pharmaceutically acceptable salt or ester thereof.

More specifically, the intermediate and low-efficiency synthetic non-fluorine corticosteroid is budesonide, and the triphenylacid derivative tretinoin is trefoil.

Thickeners may also be suitably included to increase the volume of the composition and provide viscosity to the formulation. The thickener is preferably, but not necessarily, miscible with, or soluble in, aqueous or non-aqueous fluids. Including but not limited to acacia, alginic acid and its salts, hyaluronic acid and its salts, carbomers, carboxymethyl cellulose, ethyl cellulose, gelatin, carboxyvinyl polymers, ethyl cellulose of tretinoin, gelatin, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyhydroxy amines, polyvinylpyrrolidone, polyvinyl alcohol, xanthan gum, magnesium aluminum silicate, and bentonite. Thickeners may also be present in the oil or lipophilic portion of the formulation. Suitable lipophilic thickeners include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymers, and emulsifying waxes.

The thickener is preferably a pH dependent polymer carbomer, optionally: carbomer homopolymers, which are polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol; carbomer copolymers, which are polymers of acrylic acid and alkyl esters of C10-C30 acrylic acid crosslinked with pentaerythritol allyl ether; carbomer interpolymers, which are carbomer homopolymers or copolymers, block copolymers containing polyethylene glycol and long chain alkyl acid esters; polycarbophil is an acrylic polymer crosslinked with divinyl glycol.

Specifically including one or more combinations of carbomer homopolymers.

Alternatively, the thickener is preferably a pH independent polyacrylamide series thickener such as SIMULGEL 600 acrylamide/sodium acryloyldimethyl tertiary acid copolymer from SEPPIC company and a mixture of isohexadecane and polysorbate 80, a mixture of polyacrylamide with isoparaffin C13-12 and laureth-7 such as SEPIGEL 305 from SEPPIC company, a combination of acrylic polymer series with hydrophobic chains such as ACULYN 44 PEG-150/decyl/SMDI copolymer, a modified starch series such as Structure Solanace modified potato starch, or a mixture thereof.

Particularly, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and novel polymers are selected.

Penetration enhancers may also be suitably included, meaning compounds that increase the permeability of the active drug molecule through the skin or mucosa, for example, temporarily reducing the impermeability of the skin or mucosa. Is generally an ingredient for increasing the permeability of a steroid through the skin or mucosa, such as temporarily reducing the impermeability of the skin or mucosa. Including, but not limited to, polyols, ethylene glycol (propylene glycol removal), ethers, glycol ethers, esters, thioethers, fatty acids, fatty acid esters, fatty alcohols, essential oils, terpenes, terpenoids, polyglycolized fatty acids, polyglycolized fatty acid esters, polyglycolized fatty alcohols, and mixtures thereof, including polyethylene glycol, polyethylene glycol monolaurate, and butylene glycol; tretinoin thioethers, including diethylene glycol monoethyl ether and diethylene glycol monomethyl ether; tretinoin fatty acids including lauric acid, oleic acid, and valeric acid; fatty acid esters including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; tretinoin nitrogen-containing compounds including urea, dimethylacetamide, dimethylformamide-2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine; a terpene; terpenoids; an alkanone; organic acids including salicylic acid, citric acid, and succinic acid; and combinations comprising one or more of the foregoing materials. In certain embodiments, the permeation enhancer is diethylene glycol monoethyl ether. In certain embodiments, the permeation enhancer is not polypropylene glycol. The permeation enhancer may be used alternately as a solvent.

Also included are co-emulsifiers or secondary emulsifiers including, but not limited to, polyoxyethylene glycerides such as oleoyl macroglyceride (LABRAFIL cube M1944 CS), linoleoyl macroglyceride (LABRAFIL cube M2125 CS), octanoyl macroglyceride (LABRASOL), cetyl (and) ether of valinate-20 (and) stearyl ether-20 (emulicre ™ 61 WL 2659), glycerol stearate (and) PEG-75 vitamin a acid stearate (gel 64), d-alpha-tocopheryl polyethylene glycol vitamin a acid 1000 vitamin a acid succinate (TPGS), and mixtures thereof.

The emulsifier may be selected from nonionic or ionic surfactants depending on the desired HLB value of the oil phase. The combination of hydrophilic surfactant and lipophilic surfactant can better meet the requirements of low HLB value and high HLB value. More specifically, the emulsifier combination is selected from the group consisting of sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters. Polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate.

Also included are viscosity modifiers, optionally but not limited to Sepineo harm (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer), emulfree @ Duo (propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate), sepineo ™ P600 (acrylamide/sodium acryloyldimethyl taurate copolymer/isohexadecane and polysorbate 80).

The oil phase may be selected from fatty oils or alcohols with a high carbon content, not limited to medium chain triglycerides, isopropyl myristate, mineral oil, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol.

Preferably medium chain triglycerides, selected from the group consisting of medium chain triglycerides of olive oil, coconut oil or palm kernel oil, more preferably medium chain triglycerides of coconut oil.

The penetration enhancer is preferably a polyhydric alcohol, more preferably polyethylene glycol, propylene glycol, hexylene glycol, butylene glycol, glycerin, erythritol or sorbitol, and still more preferably propylene glycol or hexylene glycol.

Alternatively, the penetration enhancer is preferably a fatty acid ester, more preferably a higher fatty acid such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid and undecylenic acid, still more preferably isopropyl myristate or isopropyl palmitate of the fatty acid ester.

Alternatively, the oil phase may be selected from the group consisting of hard paraffin, white soft paraffin, and low viscosity or high viscosity liquid paraffin.

Also included are preservatives selected from phenoxyethanol, parabens (e.g., methylparaben and propylparaben), sodium benzoate, benzalkonium chloride, propylene glycol, sorbate, benzyl alcohol, butylhydroxytoluene, urea derivatives (e.g., diazolidinyl urea), and the like, or any combinations thereof.

One or more humectants selected from glycerol, propylene glycol, sorbitol, mannitol, xylitol and maltitol, polymeric polyols (such as polydextrose) or natural extracts (such as stachyose, lactic acid or urea), or diluted solutions thereof in any proportion, may also be suitably included.

The semisolid is an oil-based emulsion ointment, which can be composed of paraffin-based ointment or polyethylene glycol-based ointment, wherein the paraffin used in the ointment can be selected from light liquid paraffin, hard paraffin or white soft paraffin, and the polyethylene glycol-based ointment can be selected from any combination of polyethylene glycols or any polyethylene glycol.

One or more humectants may also be suitably included including, but not limited to, collagen, elastin, keratin, sodium hyaluronate, cholesterol, squalene, fatty acids and fatty alcohols, preferably sodium hyaluronate.

One or more antioxidants may also be suitably included, including but not limited to: alpha-tocopherol, TPGS, glutathione, ascorbic acid, lipoic acid, uric acid, sorbic acid, carotene, butyl Hydroxy Anisole (BHA), butylated water-oxidized toluene (BHT), monothioglycerol, potassium metabisulfite, sodium ascorbate, sodium bisulphite, sodium thiosulfate, sodium metabisulfite, sodium sulfite, panthenol, sodium benzoate, propyl gallate and tert-butyl hydroquinone, preferably BHT, alpha-tocopherol and sodium thiosulfate, more preferably at a mass concentration of 0.05% -1%.

One or more preservatives may also be suitably included including, but not limited to, methylparaben, propylparaben, benzyl alcohol, chlorocresol, benzalkonium chloride, cetrimonium chloride, sodium ethylenediamine tetraacetate, boric acid, sorbic acid, or mixtures thereof.

One or more wetting agents may also be suitably included including, but not limited to, sodium docusate, xin Xinchun-9, nonylol-9, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate and sorbitan trioleate, preferably sodium docusate.

Neutralizing agents may also be suitably included including, but not limited to, triethanolamine, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide.

Some of the above adjuvants may have more than one function in the composition. For example, the adjuvant may be both a solvent and a permeation enhancer, or both a solvent and a carrier. The above classification of excipients should not be construed as limiting or restricting in any way.

The specific mass concentration of the budesonide or the pharmaceutically acceptable salt or ester thereof in the composition is 0.01% -0.1%, preferably 0.05% -0.08%, more preferably 0.05% -0.07%, and even more preferably 0.05%.

The specific mass concentration of Qu Faluo or a pharmaceutically acceptable salt or ester thereof in the composition is 0.001% -0.01%, preferably 0.0025% -0.008%, more preferably 0.003% -0.008%, even more preferably 0.004% -0.006%, even more preferably 0.005%.

The method specifically comprises the following steps:

(1) 0.05% by mass of budesonide;

(2) 0.005% by mass of trefoil;

(3) An oil phase comprising one or more of medium chain triglycerides, isopropyl myristate, isopropyl palmitate, cetostearyl alcohol, mineral oil of low or high viscosity and specific gravity, white petrolatum of various consistencies and viscosities;

(4) The water phase comprises one or more of purified water, propylene glycol, butanediol, glycerol, sorbitol solution and polyethylene glycol;

(5) Preservative comprising one or more of methyl parahydroxybenzoate, propyl parahydroxybenzoate, phenoxyethanol, sodium benzoate, benzyl alcohol;

(6) A surfactant or emulsifier comprising a sorbitol fatty acid ester and a nonionic polyoxyethylene sorbitol fatty acid ester;

(7) A polymer consisting of a pH-dependent polymer and a separate polymer;

(8) A pH regulator for regulating pH value to 4-7;

(9) Chelating agents such as disodium edetate;

(10) A humectant.

Specifically comprises 1% -20% of caprylic/capric triglyceride, 1% -25% of propylene glycol, 1% -10% of isopropyl myristate, 1% -5% of polysorbate 60, 1% -5% of sorbitol oleate, 5% -20% of humectant, 0.1% -5% of polymer, 1% -2% of pH regulator, 0.05% -2% of preservative and 0.01% -1% of chelating agent.

Examples 1 to 3

The cream compositions of examples 1-3 are shown in the following table:

wherein, arlacel 165: glycerol stearate and PEG-100 stearate; glycerox ™ 767: PEG-6 caprylic/capric triglyceride; capryol 90: propylene glycol monocaprylate; sepineo harm: hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer; emulfree Duo: propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate.

The preparation method comprises the following steps:

mixing medium chain triglyceride, isododecane, capryol 90 and Emulfree Duo to prepare oil phase;

butyl hydroxytoluene and Qu Faluo statin were added to Arlacel 165 and this phase was added to the oil phase;

dissolving disodium edetate in a mixture of part of propylene glycol, purified water and glycox ™ 767 to prepare an aqueous phase;

adding the oil phase into the water phase, and homogenizing for 30min;

adding the budesonide dispersed in the glycerol with stirring, and adding the solution to the emulsion powder;

adding phenoxyethanol and Sepineo DERM, and uniformly dispersing under stirring and homogenizing;

the pH of the solution was adjusted to 5.0 with potassium hydroxide or phosphoric acid.

Examples 4 to 6

The cream compositions of examples 4-6 are shown in the following table:

wherein, gelot ™ 64: mono-, di-and polyoxyethylene stearates; labrasol cube: caproylacryl polyoxyethylene-8 glyceride.

The preparation method comprises the following steps:

mixing octyl dodecanol, arlacel 165, gelot ™ 64, methyl glucose-10, white soft paraffin and microcrystalline wax to prepare an oil phase;

adding and dissolving butyl hydroxy toluene in Labrasol, and then adding the trefoil under stirring;

sequentially dissolving aluminum sulfate or calcium acetate and disodium ethylenediamine tetraacetate in a mixture of partial amount of glycerin and purified water to prepare an aqueous phase;

adding the oil phase into the water phase, and homogenizing for 30min;

denodard dispersed in glycerin was added with stirring, and this solution was added to the emulsified mass, and phenoxyethanol was added with stirring and mixed uniformly.

Examples 7 to 9

Examples 7-9 gel (including pH independent polymers) components are shown in the following table:

wherein Plurol is Oleique CC 497: polyglycerol-3 oleate; labrasol cube: acryl propionyl polyoxyethylene-8 glyceride; emulfree Duo: propylene glycol monolaurate NF ethyl cellulose NF propylene glycol isostearate.

The preparation method comprises the following steps:

dissolving disodium edetate in a certain amount of propylene glycol and purified water to prepare a water phase;

under stirring, adding the trafarotene into a mixture of Plurol Oleique CC 497, labrasol cube and Emulfree cube Duo, and then adding the obtained dispersion into gel;

adding the budesonide in the glycerol dispersion with stirring, and adding the solution to the gel for mixing;

adding phenoxyethanol, stirring and mixing, adding Sepineo DERM, stirring and hydrating for 40min;

the pH of the solution was adjusted to 5.0 with sodium hydroxide or phosphoric acid and the powder was mixed.

Example 10

Example 10 gel (including pH independent polymers) components are shown in the following table:

the preparation method comprises the following steps:

dissolving disodium edetate in a certain amount of propylene glycol to prepare a water phase;

adding hydroxypropyl methyl cellulose to uniformly disperse the hydroxypropyl methyl cellulose;

adding purified water and ethanol to hydrate the polymer for 60min;

adding the trefoil in propylene glycol with stirring, and adding the resulting dispersion to the gel;

adding the budesonide in the glycerol dispersion with stirring, and adding the solution to the gel for mixing;

the pH of the solution was adjusted to 5.0 with sodium hydroxide or citric acid, and the powder was mixed.

Example 11

Example 11 ointment (polyethylene glycol base) composition is shown in the following table:

the preparation method comprises the following steps:

dissolving methyl parahydroxybenzoate, propyl parahydroxybenzoate and disodium edentate in a mixture of propylene glycol, glycerol and purified water one by one to prepare a water phase;

adding the trefoil in propylene glycol under stirring, and then adding the obtained dispersion liquid into gel;

adding the budesonide in the glycerol dispersion with stirring, and adding the solution to the gel for mixing;

adding Sepieno DERM polymer, and hydrating the polymer for 1h under stirring;

the pH of the solution was adjusted to 5.0 with sodium hydroxide or citric acid and then mixed.

Example 12

Example 12 ointment (polyethylene glycol base) composition the following table shows:

the preparation method comprises the following steps:

mixing medium chain triglyceride and isopropyl myristate, and dissolving butyl hydroxy toluene to obtain oil phase;

adding and dispersing the trefoil and the budesonide into the oil phase one by one under stirring to obtain a medicine phase;

melting white vaseline to prepare ointment matrix;

the drug phases are added to an ointment base and mixed into an ointment.

Example 13

Example 13 ointment (polyethylene glycol base) composition is shown in the following table:

the preparation method comprises the following steps:

mixing mineral oil, medium chain triglyceride and isopropyl myristate, and dissolving butyl hydroxy toluene to obtain oil phase;

adding and dispersing the budesonide and the Qu Faluo statin into the oil phase one by one under stirring to obtain a medicine phase;

melting synthetic beeswax and white vaseline to prepare ointment matrix;

the drug phases are added to the ointment base and mixed into an ointment.

Example 14

Example 14 ointment (PEG base) composition the following table shows:

example 15

Initial and stability test:

stability studies were performed on examples 1-14 and physical parameters at the initial time points and physical and chemical parameters of the stability study were monitored, and the results are shown in the following table:

examples 2, 5, 8, 10, 11 were more stable and were selected for in vitro release studies and permeation studies.

Example 16

In vitro release study:

a synthetic nylon membrane having a pore size of 0.45 μm was used, a combination of methanol and water was used as a release medium, release was performed at time points of 1, 2, 4, 6, 8 and 12 hours, and the cumulative release amounts were compared as a reaction.

The formulations of examples 10 and 11 released less of the budesonide and Qu Faluo statin than the other formulations. Example 5 has a better release effect on budesonide and a poorer release effect on Qu Faluo statin. Examples 2 and 8 showed good release effects for both drugs.

Examples

In vitro permeation study:

in vitro permeation studies were performed on vertical franz diffusion cells using isolated porcine abdominal skin and a suitable drug delivery medium.

As shown in fig. 1 and 2, examples 2 and 8 were better permeable to both the drugs, budesonide and Qu Faluo statin. The novel adjuvant plays an important role in skin penetration of the drug, and the formulation of example 2 is a combination of surfactant and polymer, helping the drug to penetrate faster than the gel formulation. The combination of glycerol stearate and PEG-100 stearate, PEG-6 caprylic/capric triglyceride, propylene glycol monocaprylate, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate in a cream formulation plays an important role in the penetration of the drug substance.

The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.

Claims (10)

1. A semi-solid formulation of a composition for improving symptoms of skin disorders, comprising a skin immune response modifier and an antiproliferative agent, wherein the skin immune response modifier is a medium-low-potency corticosteroid or a pharmaceutically acceptable salt or ester thereof, and the antiproliferative agent is tretinoin or a pharmaceutically acceptable salt or ester thereof, for improving the skin symptoms of a psoriatic patient.

2. A semi-solid formulation of a composition for ameliorating the symptoms of skin disorders according to claim 1, wherein said skin immune response modifier is a moderately low potency synthetic non-fluorocorticosteroid and said antiproliferative agent is the triphenylic derivative retinoid acid.

3. A semi-solid formulation of a composition for improving symptoms of skin disorders according to claim 2, wherein said intermediate and low-potency synthetic non-fluorocorticosteroid is budesonide, said triphenylacid derivative tretinoin is trefoil, said budesonide is present in a mass concentration of 0.01% to 0.1% and said Qu Faluo statin is present in a mass concentration of 0.001% to 0.01%.

4. A semisolid formulation of a composition for improving skin conditions according to claim 3, wherein the mass concentration of budesonide is 0.05% and the mass concentration of Qu Faluo statin is 0.005%.

5. A semi-solid formulation of a composition for improving symptoms of skin disorders according to claim 3 or 4, wherein said semi-solid is a cream and the components further comprise one or more of an aqueous solvent, an oil phase, a surfactant, a humectant, a preservative, a chelating agent, a viscosity modifying agent and a pH modifying agent.

6. A semi-solid formulation of a composition for the amelioration of symptoms of skin disorders according to claim 5, wherein said components include glycerol stearate and PEG-100 stearate, PEG-6 caprylic/capric triglyceride, propylene glycol monocaprylate, hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer, propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate, purified water, propylene glycol, medium chain triglycerides, isododecane, glycerol, phenoxyethanol, disodium ethylenediamine tetraacetate, carbomer homopolymer and potassium hydroxide or phosphoric acid.

7. A semisolid formulation of a composition for improving skin conditions according to claim 6, characterized in that it comprises in particular, by mass: 40-70% purified water, 5-10% propylene glycol, 1-10% medium chain triglycerides, 1-10% isododecane, 1-10% glycerol stearate and PEG-100 stearate, 1-5% PEG-6 caprylic/capric triglyceride, 1-3% propylene glycol monocaprylate, 1-3% hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, 1-3% propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate, glycerol, 0.25-2% phenoxyethanol, 0.05-0.1% disodium ethylenediamine tetraacetate, 0.005-0.05% potassium hydroxide or phosphoric acid.

8. A semisolid formulation of a composition for improving skin conditions according to claim 3 or 4, wherein the semisolid is a gel, and the components specifically comprise, by mass: 40-90% of purified water, 5-15% of propylene glycol, 1-10% of glycerol, disodium ethylenediamine tetraacetate with the concentration of about 0.01-0.1%, 1-3% of polyglycerol-3 oleate, 1-6% of caprylyl polyoxyethylene ether-8 glyceride, 0.1-3% of hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, 0.005-0.05% of phenoxyethanol, and 0.005-0.5% of potassium hydroxide or phosphoric acid.

9. A semisolid formulation of a composition for improving skin conditions according to claim 3 or 4, wherein the semisolid is a vaseline-based ointment, comprising in particular the following mass fractions: 1-10% of medium chain triglyceride, 1-10% of isopropyl myristate, 10-30% of mineral oil, 40-90% of white vaseline and 1-10% of synthetic beeswax.

10. A semisolid formulation of a composition for improving skin disease symptoms according to claim 3 or 4, wherein the semisolid is a polyethylene glycol-based ointment, specifically comprising 30-50% by mass of polyethylene glycol 300 and 50-70% by mass of polyethylene glycol 3350.