Local external medicine composition for treating acne as well as preparation method and application thereof

Abstract

The invention provides a local external medicine composition for treating acne as well as a preparation method and application of the local external medicine composition. The pharmaceutical composition disclosed by the invention is prepared from ozlafloxacin, adapalene, a solubilizer, a surfactant and a solvent, wherein the solubilizer is an alcohol compound and / or an ester compound, the hydrophilic-lipophilic balance value of the surfactant is 20-30, and the pH value of the pharmaceutical composition is 4s < 10 >. According to the pharmaceutical composition disclosed by the invention, the ozlafloxacin and adapalene can be effectively released, and in a stability experiment, the content of the ozlafloxacin and adapalene can be kept stable, obvious degradation does not occur, and the particle size distribution is not obviously changed.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine. Specifically, the present application relates to a topical pharmaceutical composition for treating acne and a preparation method and use thereof. BACKGROUND

[0002] Ozegar is the third non-fluoroquinolone antibacterial drug approved globally after nairoxacin and garenoxacin, which has effective antibacterial activity against gram-negative and gram-positive bacteria and is widely used for the treatment of inflammatory acne. Traditional fluoroquinolones may cause adverse reactions such as liver toxicity and phototoxicity due to the presence of fluorine atoms at the 6-position of the mother nucleus. In contrast, ozegar is a new non-fluoroquinolone drug with lower adverse reactions and a wider antibacterial spectrum. The substitution of the pyridine ring at C-7 of ozegar increases the antibacterial activity against gram-positive bacteria, and the inhibition of DNA gyrase and topoisomerase IV of methicillin-resistant Staphylococcus aureus, ox-floxacin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and ox-floxacin-resistant Staphylococcus epidermidis is significantly stronger than that of norfloxacin, ofloxacin, levofloxacin, clindamycin, erythromycin, and gentamicin, and has stronger antibacterial activity against drug-resistant bacteria. Ozegar is currently marketed in the form of emulsion and cream. The dosage form developed by Japan Toyama Chemical (a subsidiary of FUJIFILM Toyama Chemical) is a lotion with the trade name Zebiax and a specification of 2%, which is mainly used for the treatment of superficial skin infections and acne. Ozegar is marketed in the United States in the form of a cream with the trade name Xepi and a specification of 1%, which is used for the topical treatment of impetigo caused by Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients aged 2 months and above.

[0003] Adapalene is the third generation of retinoid drugs, which has stronger anti-inflammatory effect in addition to stronger regulation of epidermal cell differentiation, inhibition of keratinocyte proliferation and keratinization at the hair follicle orifice, inhibition of sebaceous gland cell proliferation, dissolution of keratotic plugs, and comedone-dissolving effect than other retinoid drugs such as tretinoin. Due to its unique stability, it has significantly improved efficacy and tolerability compared to other retinoid drugs, and is usually the first choice for the treatment of acne.

[0004] Acne vulgaris is one of the most common skin diseases in adolescents and young people. Statistics show that up to 80% of the population is affected by the disease at some stage of their life. Acne pathogenesis begins with abnormal keratinization at the base of the hair follicle, which leads to follicular occlusion and the formation of non-inflammatory comedones, which develop into papules and pustules, forming inflammatory acne. Topical antibiotics are prone to induce P. acnes resistance and are not recommended for use alone or for long-term use, and are usually used in combination with retinoids such as adapalene gel and antibacterial drugs such as benzoyl peroxide, erythromycin, lincomycin, clindamycin, chloramphenicol, fusidic acid, etc. Ozenoxacin is a topical antibiotic, which can be used in combination with adapalene to treat acne from different mechanisms and reduce the resistance of P. acnes.

[0005] Topical antimicrobial therapy has several potential advantages over systemic therapy. First, it can avoid unnecessary exposure of the intestinal flora that can produce resistance selection. Second, high local drug concentrations in topical application are desirable. Third, topical application results in a lower likelihood of side effects compared to systemic therapy. Certain single topical or compound topical formulations containing ozenoxacin and adapalene have been reported in the art.

[0006] JP2022356426A discloses an ointment and a gel for the skin, and the ointment specifically disclosed in Example 2 contains: ozenoxacin 1%, N-methyl-2-pyrrolidone 8%, propylene glycol 14.9%, oleic acid 0.9%, diisopropyl alcohol amine 2.3%, polyethylene glycol 400 20.2%, polyethylene glycol 4000 50.2%, and water 3.2%. EP1731138A1 discloses a fine particle dispersion containing ozenoxacin for the preparation of a pharmaceutical composition. WO20070154531A1 discloses a lotion containing ozenoxacin. US10022363B2 discloses the components and preparation process of a cream formulation containing ozenoxacin. The formulation has been marketed in the United States and Europe under the trade name Xepi.

[0007] WO2020044344 discloses a composition of ozenoxacin alone or in combination with retinoids and peroxides for the treatment of rosacea skin diseases and conditions. Among them, Example 2 discloses a compound formulation containing ozenoxacin and adapalene, specifically containing povidone K29 / 32 (gel base) 0.1%, glycerol 4.72%, hydroxyethyl cellulose (thickening agent, gel base) 1.18%, hydroxypropyl cellulose 0.24%, hydrochloric acid, purified water, ozenoxacin 2%, adapalene 0.3%. Although WO2020044344 discloses a compound gel formulation containing adapalene and ozenoxacin, adapalene and ozenoxacin are poorly soluble drugs, which are difficult to dissolve and release in the disclosed aqueous gel formulation containing only glycerol, and cannot meet the clinical requirements. Moreover, the patent application does not disclose the results of relevant pharmaceutical research and clinical trials.

[0008] Currently, there is an Adapalene and benzoyl peroxide compound preparation on the market, and it has been proven that the compound preparation has obvious clinical advantages. Related research results show that in the preparation containing retinoids (tretinoin or adapalene) and benzoyl peroxide, benzoyl peroxide gradually degrades and oxidizes retinoids over time, and the stability is limited, which weakens the efficacy of adapalene during use. On the other hand, dissolved benzoyl peroxide directly contacts the epidermal viable layer, which in some cases can cause serious side effects, including local irritation, excessive skin dryness, and allergic reactions. These side effects occur in the early stages of the administration process, making it difficult for patients to adhere to treatment. The high incidence of side effects combined with their early occurrence leads to premature termination of treatment in many cases, thereby limiting treatment. Therefore, it is necessary to develop a new compound preparation for treating inflammatory acne.

[0009] In the preparation of compositions containing retinoids, the problem to be overcome is that most retinoids are particularly sensitive to natural oxidation, visible light and ultraviolet light, which easily leads to degradation, thereby increasing adverse reactions such as skin allergies. However, for antibacterial drugs, in order to increase the local antibacterial effect and reduce the generation of drug resistance, it is necessary to increase the local concentration of antibacterial drugs as much as possible during use. For example, the higher pH value selected in the ozenoxacin lotion and ointment on the market in Japan to increase the solubility of the active ingredient (ozenoxacin is difficult to dissolve in solvents such as water and ethanol, but it is soluble in alkaline aqueous solution). However, the present inventors found that adapalene has stability problems under alkaline conditions, and the degradation of adapalene accelerates as the pH value increases.

[0010] Based on the above reasons, the problem to be solved in developing a physically and chemically stable composition containing ozenoxacin and adapalene is to ensure that adapalene does not significantly degrade during storage while increasing the release rate of ozenoxacin to achieve a sufficient bactericidal (such as Propionibacterium acnes) concentration on the skin surface. There is still no physically and chemically stable composition containing ozenoxacin and adapalene on the current market. How to obtain a stable compound gel composition containing ozenoxacin and adapalene is of great significance for achieving good therapeutic effect. SUMMARY

[0011] The present application aims to provide a topical pharmaceutical composition for treating acne, and a preparation method and use thereof. The present application greatly improves the release rate of ofloxacin, increases the drug concentration applied to the skin, and achieves good therapeutic effect without affecting the stability of adapalene by selecting specific solubilizers and surfactants and combining with a specific pH range. The pharmaceutical composition provided by the present application has physical and chemical stability, and the ofloxacin and adapalene can be effectively released on the surface of the skin, and the content of ofloxacin and adapalene remains stable in the chemical stability experiment without obvious degradation, and the particle size distribution does not change significantly.

[0012] The above-mentioned object of the present application is achieved by providing the following technical solutions:

[0013] In a first aspect, the present application provides a topical pharmaceutical composition for treating acne, comprising: ofloxacin, adapalene, a solubilizer, a surfactant and a solvent; wherein the solubilizer is an alcohol compound and / or an ester compound; the hydrophilic-lipophilic balance of the surfactant is 20-30, and the pH value of the pharmaceutical composition is 4-10.

[0014] Preferably, the alcohol compound is selected from one or more of propylene glycol, dipropylene glycol and diethylene glycol monoethyl ether (Transcutol P), preferably propylene glycol and / or diethylene glycol monoethyl ether.

[0015] Preferably, the ester compound is propylene glycol dinoctanoate.

[0016] Preferably, the surfactant is a non-ionic surfactant, preferably a polyoxyethylene copolymer and / or a polyoxypropylene copolymer, further preferably a poloxamer, more preferably selected from one or more of poloxamer 188, poloxamer 182 and poloxamer 124.

[0017] Preferably, the pH value of the pharmaceutical composition is 5-7.

[0018] Preferably, the particle size distribution of the ofloxacin and / or adapalene is that D90 is less than 25 μm.

[0019] In the present application, both ofloxacin and adapalene are poorly soluble drugs, and micronization treatment of ofloxacin and adapalene can improve the solubility of ofloxacin and adapalene. The favorable particle size of ofloxacin and adapalene is that the particle size distribution D90 measured by laser diffraction method is less than 25 μm.

[0020] According to some embodiments of the present application, the pharmaceutical composition further comprises a penetrant.

[0021] Preferably, the penetrant is 1,3-butanediol.

[0022] According to some embodiments of the application, the solvent is water.

[0023] According to some embodiments of the application, the pharmaceutical composition further comprises a gelling agent.

[0024] Preferably, the gelling agent is a hydrophilic compound. In the present application, the gelling agent is used to ensure that the gel matrix does not undergo physical, chemical changes such as flocculation, thinning, changes in rheological properties, etc. The gelling agent preferably exhibits high hydrophilicity, a water-dispersible polymer. This polymer preferably contains free carboxyl groups, which are fully or partially neutralized with a base to form a carboxylate form. The preferred gelling agent is a vinyl polymer having a water-dispersible carboxylate group, such as a polyacrylic acid gel, which is neutralized with a base, such as sodium hydroxide. The gelling agent also includes cross-linked polyacrylic acid, such as polyacrylic acid with a polyalkylene glycol network.

[0025] More preferably, the gelling agent is selected from one or more of the following: electrolyte-insensitive carbomers, preferably carbomer 980 and / or carbomer 974; polysaccharides, preferably selected from one or more of xanthan gum, guar gum, chitosan and carraghenanes; celluloses and derivatives thereof, preferably hydroxypropylmethylcellulose and / or hydroxyethylcellulose; silicates, preferably aluminum silicate and / or magnesium silicate; acrylate polymers coupled with hydrophobic chains; modified starches, preferably potato starch; polyacrylamides, preferably a mixture of acrylamide / sodium acryloyldimethyltaurate copolymer, isohexadecane and Tween 80, more preferably Simulgel 1600 and / or Sepineo P600 sold by the company Seppic.

[0026] More preferably, the gelling agent is selected from one or more of carbomer 980, carbomer 974, Simulgel 600 and Sepineo P600.

[0027] According to some embodiments of the application, the pharmaceutical composition further comprises a wetting agent; preferably, the wetting agent is glycerin and / or sorbitol, preferably glycerin.

[0028] According to some embodiments of the application, the pharmaceutical composition further comprises a pH adjuster; preferably, the pH adjuster is sodium hydroxide or hydrochloric acid.

[0029] According to some embodiments of the present application, the pharmaceutical composition further comprises other additives; preferably, the other additives are selected from one or more of chelating agents, antioxidants, light screening agents, preservatives, fillers, stabilizers, electrolytes, coloring agents, common minerals, organic acids, organic bases, fragrances, essential oils, cosmetic active agents, humectants, vitamins, and fatty acids; more preferably, the chelating agents are selected from one or more of ethylenediaminetetraacetic acid and salts or derivatives thereof, dihydroxyethylglycine, citric acid, and tartaric acid, preferably ethylenediaminetetraacetic acid and / or ethylenediaminetetraacetic acid disodium, more preferably disodium ethylenediaminetetraacetate (EDTA disodium); more preferably, the preservatives are selected from one or more of benzalkonium chloride, phenoxyethanol, benzyl alcohol, benzoic acid and salts thereof, p-hydroxybenzoic acid esters and salts thereof, and p-hydroxyphenylacetic acid esters and salts thereof.

[0030] According to some embodiments of the present application, the content of ozegemycin in the pharmaceutical composition is 0.1-10% by weight, preferably 0.2-6% by weight, more preferably 0.5-5% by weight, based on the total weight of the pharmaceutical composition.

[0031] According to some embodiments of the present application, the content of adapalene in the pharmaceutical composition is 0.0001-5% by weight, preferably 0.01-1% by weight, more preferably 0.05-0.5% by weight, based on the total weight of the pharmaceutical composition.

[0032] According to some embodiments of the present application, the content of the surfactant in the pharmaceutical composition is 0.01-10% by weight, preferably 0.1-2% by weight, more preferably 0.1-0.5% by weight, based on the total weight of the pharmaceutical composition.

[0033] According to some embodiments of the present application, the content of the solubilizing agent in the pharmaceutical composition is 0.01-15% by weight, preferably 1-10% by weight, more preferably 2-6% by weight, based on the total weight of the pharmaceutical composition.

[0034] In the present application, the amount of the solubilizing agent used helps the dissolution of the active ingredient, but does not cause the recrystallization of the active ingredient and the change in the particle size distribution of the active ingredient particles during storage; at the same time, the amount of the solubilizing agent used can assist the active ingredient to achieve satisfactory dispersion and have better penetration-promoting effect.

[0035] According to some embodiments of the present application, the content of the penetration agent in the pharmaceutical composition is 0.01-10% by weight, preferably 1-6% by weight, more preferably 2-4% by weight, based on the total weight of the pharmaceutical composition.

[0036] According to some embodiments of the present application, the content of the solvent in the pharmaceutical composition is 1-90% by weight, preferably 70-90% by weight, more preferably 80-90% by weight, based on the total weight of the pharmaceutical composition.

[0037] According to some embodiments of the present application, the content of the gelling agent in the pharmaceutical composition is 0.1-15% by weight, preferably 0.1-10% by weight, more preferably 0.5-6% by weight, in particular 0.9-1.1% by weight, based on the total weight of the pharmaceutical composition.

[0038] According to some embodiments of the present application, the content of the wetting agent in the pharmaceutical composition is 0-20% by weight, preferably 1-10% by weight, more preferably 2-6% by weight, based on the total weight of the pharmaceutical composition.

[0039] According to some embodiments of the present application, the content of the other additive in the pharmaceutical composition is 0-20% by weight, based on the total weight of the pharmaceutical composition.

[0040] According to some embodiments of the present application, the content of the chelating agent in the pharmaceutical composition is 0-2% by weight, preferably 0.01-1.5% by weight, further preferably 0.05-0.5% by weight, more preferably 0.02-0.2% by weight, based on the total weight of the pharmaceutical composition.

[0041] According to some embodiments of the present application, the content of the preservative in the pharmaceutical composition is 0.05-0.15% by weight, based on the total weight of the pharmaceutical composition.

[0042] According to some embodiments of the present application, the pharmaceutical composition comprises 0.5-5% by weight of ozegamycin, 0.05-0.5% by weight of adapalene, 0.1-0.5% by weight of poloxamer, 2-6% by weight of glycerin, 2-6% by weight of propylene glycol and / or diethylene glycol monoethyl ether, 0.5-2% by weight of carbomer, a pH adjusting agent, and the balance water, based on the total weight of the pharmaceutical composition, and the pH of the pharmaceutical composition is 5.0-7.0.

[0043] According to some embodiments of the present application, the pharmaceutical composition comprises 0.5-5% by weight of ozegamycin, 0.05-0.5% by weight of adapalene, 0.1-0.5% by weight of poloxamer, 2-6% by weight of glycerin, 2-6% by weight of propylene glycol and / or diethylene glycol monoethyl ether, 3-6% by weight of Simulgel 600 and / or Sepineo P600, a pH adjusting agent, and the balance water, based on the total weight of the pharmaceutical composition, and the pH of the pharmaceutical composition is 5.0-7.0.

[0044] According to some embodiments of the present application, the pharmaceutical composition further comprises 2-4 wt% 1,3-butanediol, based on the total weight of the pharmaceutical composition.

[0045] According to some embodiments of the present application, the pharmaceutical composition further comprises 0.02-0.2 wt% disodium ethylenediaminetetraacetate, based on the total weight of the pharmaceutical composition.

[0046] According to some embodiments of the present application, the pharmaceutical composition further comprises 0.05-0.15 wt% methyl paraben, based on the total weight of the pharmaceutical composition.

[0047] In a second aspect, the present application provides a topical gel for treating acne, comprising the topical pharmaceutical composition according to the first aspect of the present application.

[0048] In a third aspect, the present application provides a preparation method of the topical gel according to the second aspect of the present application, comprising the following steps:

[0049] (1) mixing and uniformly dispersing ofloxacin and adapalene with a solubilizer, and optionally a preservative and a penetrant, to obtain an intermediate mixture;

[0050] (2) adding a gelling agent and a surfactant, and optionally a humectant and a chelating agent, into a part of the solvent, stirring and dissolving and swelling to obtain a gel base;

[0051] (3) mixing the intermediate mixture with the gel base, adjusting the pH to 4-10, and then adding the remaining solvent and mixing uniformly to obtain the pharmaceutical composition.

[0052] Preferably, in step (2), the part of the solvent is 40-60 wt%, preferably 50 wt% of the total solvent.

[0053] Preferably, in step (3), the pH is adjusted to 5-7.

[0054] In a fourth aspect, the present application provides use of the topical pharmaceutical composition according to the first aspect of the present application or the topical gel according to the second aspect of the present application in the preparation of a topical drug for preventing and / or treating acne.

[0055] The present application has at least the following beneficial effects:

[0056] The inventors have found that the pH of the pharmaceutical composition has a great influence on the solubility of ofloxacin and adapalene, and the increase of pH helps the dissolution of ofloxacin, but too high pH will cause the degradation of adapalene, resulting in the instability of the pharmaceutical composition. The inventors have surprisingly found that, under the conditions of using the solubilizer and surfactant of the present application, when the pH range is controlled in the range of 4-10, especially 5-7, the solubility of ofloxacin and adapalene in the pharmaceutical composition is significantly improved, so that both of them have good release, so as to achieve effective therapeutic concentration; moreover, there is no obvious increase in related impurities in the pharmaceutical composition, and there is no obvious change in the particle size of the active ingredients.

[0057] The present application greatly improves the release rate of ofloxacin without affecting the stability of adapalene by selecting specific solubilizers and surfactants and combining with specific pH range, increases the drug concentration of ofloxacin applied to the skin, and thus achieves good therapeutic effect.

[0058] In addition, the inventors have also found that by simultaneously using the solubilizer, surfactant and penetrant of the present application, and combining with a specific pH range, the in vitro release rate of ofloxacin can be further increased, and there is no adverse effect on the release of adapalene, so that the pharmaceutical composition of the present application can further increase the concentration of antibacterial drug ofloxacin when treating acne, and has no adverse effect on the stability of adapalene. DETAILED DESCRIPTION

[0059] The present application will be further described in detail below in combination with specific embodiments, and the examples given are only for illustrating the present application, but not for limiting the scope of the present application. Unless otherwise specified, the % in the following examples is weight %.

[0060] Example 1

[0061] Table 1 Composition of compound gel with batch number R15-01

[0062]

[0063] The preparation method of R15-01 compound gel is as follows:

[0064] 1) Weigh the prescription amount of ofloxacin (D90=10.40), adapalene (D90=7.89) and methyl paraben into propylene glycol, and stir to disperse uniformly to obtain an intermediate mixture;

[0065] 2) Add carbomer 980, poloxamer 188, disodium EDTA and glycerol into part of purified water, stir to dissolve and swell to obtain a gel base;

[0066] 3) Add the above intermediate mixture to the gel base, adjust to pH 5.5 using a pH adjuster, make up to the prescription amount with water, and mix well to obtain the R15-01 compound gel.

[0067] Example 2

[0068] The following compound gels were prepared according to the method of Example 1, except that the pH of the compound gels was different, as shown in the following table.

[0069] Table 2 Composition of compound gels with batch numbers R15-02 to R15-07

[0070]

[0071] In this example, the R15-02 batch gel had some flowability, and the R15-07 batch gel was significantly thinner when the pH was adjusted to 12 during preparation.

[0072] Example 3

[0073] The following compound gels were prepared according to the method of Example 1, except that the content of the active ingredients (APIs) of oxazaitomycin and adapalene in the compound gels was different, as shown in the following table.

[0074] Table 3 Composition of compound gels with batch numbers R15-08 to R15-10

[0075]

[0076] Example 4

[0077] The following compound gels were prepared according to the method of Example 1, except that the type or amount of the solubilizing agent, surfactant, and gelling agent was different, as shown in the following table.

[0078] Table 4 Composition of compound gels with batch numbers R15-11 to R15-16

[0079]

[0080]

[0081] Example 5

[0082] The following compound gels were prepared according to the method of Example 1, the main difference from Example 1 being that Simulgel 600 or Sepineo P600 (purchased from Seppic Company) was used as the gelling agent, as shown in the following table. Simulgel 600 and Sepineo P600 are polyacrylamide mixtures that will swell into a gel after mixing with water at room temperature, and are a new type of gelling agent. They have the advantages of optimizing the preparation process of the composition and reducing the quality risk in the production process.

[0083] Table 5 Composition of compound gels with batch numbers R15-17 to R15-19

[0084]

[0085] Example 6

[0086] The solubility of ofloxacin and adapalene was determined according to the following method:

[0087] Ofloxacin: 1 mg of ofloxacin API was taken and 10 ml of medium was added, and constant temperature oscillation was carried out at room temperature for 24 h, and observation was carried out every 1 h. If complete dissolution was observed, 1 mg of ofloxacin API was added again, and this was continued until no dissolution was observed.

[0088] Adapalene: 1 mg of adapalene API was taken and 10 ml of medium was added, and constant temperature oscillation was carried out at room temperature for 24 h, and observation was carried out every 1 h. If complete dissolution was observed, 1 mg of adapalene API was added again, and this was continued until no dissolution was observed.

[0089] Table 6 Results of determination of solubility of active ingredients

[0090]

[0091]

[0092] From the above table, it can be seen that in the absence of a solubilizing agent, the solubility of ofloxacin in a strong acid medium (such as a hydrochloric acid solution with pH 1.2) is high, and as the acidity decreases, the solubility decreases significantly. Adapalene is not soluble under acidic conditions. In the presence of a solubilizing agent (Transcutol P, propylene glycol or ethanol), the solubility of the active ingredients increases, and within a certain range, as the pH value increases, the solubility of the active ingredients all shows a growth trend, and the growth trend of adapalene is more obvious. In the medium in which the osmotic agent 1,3-butanediol is added and the amount of the solubilizing agent propylene glycol is reduced, the solubility of ofloxacin increases significantly under the same pH conditions, while the solubility of adapalene does not change significantly.

[0093] Example 7

[0094] The following compound gels were prepared according to the method of Example 1, with the difference from Example 1 being the composition of the compound gels, as shown in the following table. In the preferred compound gels of the present application, it is required that ofloxacin achieve an effective bacteriostatic concentration when used, so the release rate of ofloxacin needs to be increased, while adapalene requires slow release at a certain release rate, and the quality needs to be relatively stable during storage. Based on the above requirements, the compound gels were prepared using the surfactants, solubilizers and penetrants shown in the following table at the same time.

[0095] Table 7 Composition of compound gels with batch number R15-20

[0096]

[0097] Comparative Example 1

[0098] The following compound gels were prepared according to the method of Example 1, with the difference from Example 1 being the composition of the compound gels, as shown in the following table.

[0099] Table 8 Composition of compound gels with batch numbers R15-21 to R15-23

[0100]

[0101]

[0102] Comparative Example 2

[0103] The compound gels were prepared according to the method of Example 2 of patent application WO2020044344A1, and the composition of the compound gels is shown in the following table.

[0104] Table 9 Composition of compound gels with batch number R15-24

[0105]

[0106] The specific preparation method is as follows:

[0107] PVP (Plasdone K-29 / 30) 20.0 g was mixed with 80 g of water to make a 20% PVP solution 100 g. 850.0 g of glycerin (99.5%) and 14000 g of water were mixed and stirred at 2800 rpm for 10 minutes. Then 212.5 g of hydroxyethyl cellulose (Natrosol 250 HHX) and 42.5 g of hydroxypropyl cellulose (Klucel HF Pharm) were added and homogenized at 8400 rpm for at least 70 minutes until no lumps were present. Under high shear conditions, the PVP 100 g (20%), ofloxacin 360.0 g, and adapalene micronized 54.0 g were added. The pH of the gel was adjusted to 5 with HC1 5N. Water was added to bring the total weight of the mixture to 18 kg and the mixture was finally mixed until homogeneous.

[0108] In the preparation process, because ofloxacin and adapalene are solid powders and both are water-insoluble substances, there is strong hydrophobic property, and both of them appear to be agglomerated, mixed unevenly in the gel, and there is a large amount of active ingredients adhering to the kettle wall.

[0109] In vitro release test

[0110] The above-mentioned ofloxacin and adapalene compound gel prepared in the examples of the present application was compared with the marketed ofloxacin cream and adapalene gel in terms of in vitro release rate to evaluate whether the release rate of the active ingredients in the compound preparation is consistent with or superior to that of the single preparation. The in vitro release was detected by the Franz diffusion cell method according to the general rule <1724> of USP, and if the 90% confidence interval of the release slope is in the range of 75%-133.33% (0.75-1.3333), it is considered that the release rates of the two preparations are consistent. The specific in vitro release results are shown in the following table.

[0111] Table 10 Release results of ofloxacin in the gel

[0112]

[0113]

[0114] Table 11 Release results of adapalene in the gel

[0115]

[0116]

[0117] The in vitro release results of the complex gels prepared from Example 2 show that the change in pH significantly affects the release rate of the active ingredients in the complex gels. As the pH increases, the release rate of the active ingredients gradually increases, and when the pH increases to a certain extent, the release of the active ingredients is better than that of the active substances in the single formulation, but the gel properties change when the pH exceeds 10.

[0118] Stability experiment

[0119] The gels in Examples 1 and 2 above, the gels of R15-11 and R15-15 lots in Example 4, the gels of R15-18 and R15-19 lots in Example 6, and the gel of R15-20 lot in Example 7 were subjected to accelerated stability studies, and the stability of the formulations was evaluated by appearance, related substances, content, API particle size distribution, and in vitro release.

[0120] Table 12 Accelerated stability results of R15-01 lot gel

[0121]

[0122]

[0123] Table 13 Accelerated stability results of R15-02 (control) lot gel

[0124]

[0125] Table 14 Accelerated stability results of R15-03 lot gel

[0126]

[0127]

[0128] Table 15 Accelerated stability results of R15-04 lot gel

[0129]

[0130] Table 16 Accelerated stability results of R15-05 lot gel

[0131]

[0132] Table 17 Accelerated stability results of R15-06 lot gel

[0133]

[0134]

[0135] Table 18 Accelerated stability results of R15-07 (control) lot gel

[0136]

[0137] Table 19 Accelerated stability results for R15-11 lot gels

[0138]

[0139]

[0140] Table 20 Accelerated stability results for R15-15 lot gels

[0141]

[0142] Table 21 Accelerated stability results for R15-18 lot gels

[0143]

[0144] Table 22 Accelerated stability results for R15-19 lot gels

[0145]

[0146]

[0147] Table 23 Accelerated stability results for R15-20 lot gels

[0148]

[0149] The in vitro release (IVRT) results show that the two active ingredients in the compound gels of the present application can be effectively released. The IVRT results of the compound gels of Example 2 show that the in vitro release rate of the two active ingredients increases with the increase of pH value, and the release rate of the active ingredients at pH 4-10 is equivalent to or better than that of the single preparation of ofloxacin or the single preparation of adapalene. The IVRT results of the compound gels of Example 3 show that the in vitro release rate of the active ingredients is accelerated to a certain extent with the increase of the concentration of the active ingredients. The IVRT results of the compound gels of Example 4 and Example 5 show that the compound gels meeting the requirements can be prepared by using the solubilizer and the surfactant of the present application. The IVRT results of the compound gels of Example 7 show that the in vitro release rate of ofloxacin can be further increased by simultaneously using the surfactant, the solubilizer and the penetrant of the present application, while the release of adapalene is not adversely affected, so that the concentration of the antibacterial drug is further increased in the treatment of acne, and the stability of adapalene is not adversely affected. The IVRT results of the preparation of Comparative Example 1 show that the release rate of the active ingredients is reduced when only propylene glycol or diethylene glycol monoethyl ether is added to the compound gels without the addition of the surfactant such as poloxamer, and the combination of propylene glycol or diethylene glycol monoethyl ether with poloxamer is beneficial to the dispersion of the active ingredients in the compound gels and the increase of the in vitro release rate. The IVRT results of the preparation of Comparative Example 2 show that the agglomeration of the active ingredients occurs when hydroxyethyl cellulose is used to prepare the gels, and the active ingredients are not uniformly distributed in the gels. In addition, when other solubilizers such as povidone (PVP K29 / 32) are used, the release rate of the active ingredients is low under neutral conditions.

[0150] The stability experiment results show that the contents of ofloxacin and adapalene in the compound gels of Example 1 remain stable with time, and no obvious degradation occurs, and the particle size distribution of the active ingredients in the compound gels is not obviously changed, and the quality of the compound gels is stable. The stability results of the compound gels of Example 2 show that the quality of the compound gels is stable when the pH value of the compound gels is 4.0-7.0, the appearance of the gels is obviously changed when the pH value is 12, the impurity content is significantly increased, the active ingredients are degraded under alkaline conditions, and the particle size is obviously reduced; although the contents of the active ingredients and the related substances in the compound gels are relatively stable when the pH value is 3, the recrystallization of the active ingredients occurs, the particle size of the active ingredients is increased, and the quality is unstable. In the compound gels of Example 4 and Example 5, the release rate of ofloxacin in the compound gels is reduced under the same conditions when the surfactant is replaced by sodium docusate, and the quality of the compound gels is not obviously changed when the gelling agent is replaced by a mixture of polyacrylamide.

[0151] The results prove that the compound gel of the present application has better release of ozegamipant and adapalene under neutral conditions (pH 4.0-10.0, preferably 5.0-7.0), which is similar to or better than the ozegamipant cream and adapalene gel that have been marketed, and the quality of the compound gel is stable.

[0152] The above merely illustrates some exemplary embodiments of the present application, and does not limit the present application in any form. Although the present application is disclosed with the preferred embodiments as above, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the above disclosed technical contents without departing from the scope of the technical solutions of the present application, and the equivalent or equivalent embodiments obtained by the changes or modifications are within the scope of the present application.

Claims

1. A topical pharmaceutical composition for treating acne comprising: ofloxacin, adapalene, a solubilizer, a surfactant, and a solvent; wherein, The solubilizing agent is an alcohol compound and / or an ester compound, the hydrophilic-lipophilic balance of the surfactant is 20-30, and the pH value of the pharmaceutical composition is 4-10.

2. The topical pharmaceutical composition according to claim 1, wherein, The alcohol compound is selected from one or more of propylene glycol, dipropylene glycol, and diethylene glycol monoethyl ether, preferably propylene glycol and / or diethylene glycol monoethyl ether; Preferably, the ester compound is propylene glycol dinoctanoate; Preferably, the surfactant is a non-ionic surfactant, preferably a polyoxyethylene copolymer and / or a polyoxypropylene copolymer, further preferably a poloxamer, more preferably selected from one or more of poloxamer 188, poloxamer 182, and poloxamer 124; Preferably, the pH value of the pharmaceutical composition is 5-7; Preferably, the particle size distribution of the ofloxacin and / or adapalene is D90 less than 25 μm.

3. The topical pharmaceutical composition according to claim 1 or 2, wherein The pharmaceutical composition further comprises a penetrant; Preferably, the penetrant is 1,3-butanediol.

4. The topical pharmaceutical composition according to any one of claims 1 to 3, wherein, The solvent is water; Preferably, the pharmaceutical composition further comprises a gelling agent; further preferably, the gelling agent is a hydrophilic compound; more preferably, the gelling agent is selected from one or more of: carbomers, preferably carbomer 980 and / or carbomer 974; polysaccharides, preferably selected from one or more of xanthan gum, guar gum, chitosan, and carrageenan; celluloses and derivatives thereof, preferably hypromellose and / or hydroxyethyl cellulose; silicates, preferably aluminum silicate and / or magnesium silicate; acrylic polymers coupled with hydrophobic chains; modified starches, preferably potato starch; polyacrylamides, preferably a mixture of acrylamide / sodium acryloyl dimethyl taurate copolymer, isohexadecane, and Tween 80, more preferably Simulgel 600 and / or Sepineo P600; more preferably, the gelling agent is selected from one or more of carbomer 980, carbomer 974, Simulgel 600, and Sepineo P600; Preferably, the pharmaceutical composition further comprises a wetting agent; further preferably, the wetting agent is glycerin and / or sorbitol, preferably glycerin; Preferably, the pharmaceutical composition further comprises a pH adjuster; further preferably, the pH adjuster is sodium hydroxide or hydrochloric acid; Preferably, the pharmaceutical composition further comprises other additives; further preferably, the other additives are selected from one or more of chelating agents, antioxidants, sunscreens, preservatives, fillers, stabilizers, electrolytes, coloring agents, common minerals, organic acids, organic bases, fragrances, essential oils, cosmetically active agents, humectants, vitamins, and fatty acids; more preferably, the chelating agent is selected from one or more of ethylenediaminetetraacetic acid and salts or derivatives thereof, dihydroxyethylglycine, citric acid, and tartaric acid, preferably ethylenediaminetetraacetic acid and / or disodium ethylenediaminetetraacetate, more preferably disodium ethylenediaminetetraacetate; more preferably, the preservative is selected from one or more of benzalkonium chloride, phenoxyethanol, benzyl alcohol, benzoic acid and salts thereof, parabens and salts thereof, and p-hydroxybenzoic acid esters and salts thereof.

5. The topical pharmaceutical composition according to any one of claims 1 to 4, wherein, The content of ozegamycin in the pharmaceutical composition is 0.1-10% by weight, preferably 0.2-6% by weight, more preferably 0.5-5% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of adapalene in the pharmaceutical composition is 0.0001-5% by weight, preferably 0.01-1% by weight, more preferably 0.05-0.5% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of surfactant in the pharmaceutical composition is 0.01-10% by weight, preferably 0.1-2% by weight, more preferably 0.1-0.5% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of solubilizer in the pharmaceutical composition is 0.01-15% by weight, preferably 1-10% by weight, more preferably 2-6% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of penetrant in the pharmaceutical composition is 0.01-10% by weight, preferably 1-6% by weight, more preferably 2-4% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of solvent in the pharmaceutical composition is 1-90% by weight, preferably 70-90% by weight, more preferably 80-90% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of gelling agent in the pharmaceutical composition is 0.1-15% by weight, preferably 0.1-10% by weight, more preferably 0.5-6% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of wetting agent in the pharmaceutical composition is 0-20% by weight, preferably 1-10% by weight, more preferably 2-6% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of other additives in the pharmaceutical composition is 0-20% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of chelating agent in the pharmaceutical composition is 0-2% by weight, preferably 0.01-1.5% by weight, further preferably 0.05-0.5% by weight, more preferably 0.02-0.2% by weight, based on the total weight of the pharmaceutical composition; Preferably, the content of preservative in the pharmaceutical composition is 0.05-0.15% by weight, based on the total weight of the pharmaceutical composition.

6. The topical pharmaceutical composition according to any one of claims 1 to 5, wherein, The pharmaceutical composition comprises 0.5-5% by weight of ozegamycin, 0.05-0.5% by weight of adapalene, 0.1-0.5% by weight of poloxamer, 2-6% by weight of glycerol, 2-6% by weight of propylene glycol and / or diethylene glycol monoethyl ether, 0.5-2% by weight of carbomer, a pH adjuster, and the balance water, based on the total weight of the pharmaceutical composition, and the pH of the pharmaceutical composition is 5.0-7.0; Preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises: 0.5-5 wt% ofloxacin, 0.05-0.5 wt% adapalene, 0.1-0.5 wt% poloxamer, 2-6 wt% glycerin, 2-6 wt% propylene glycol and / or diethylene glycol monoethyl ether, 3-6 wt% Simulgel 600 and / or Sepineo P600, a pH adjuster, and the balance water, the pH of the pharmaceutical composition being 5.0-7.0; Preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 2-4 wt% 1,3-butanediol; Preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.02-0.2 wt% disodium ethylenediaminetetraacetate; Preferably, based on the total weight of the pharmaceutical composition, the pharmaceutical composition further comprises 0.05-0.15 wt% methyl paraben.

7. A topical gel for treating acne, comprising the topical pharmaceutical composition according to any one of claims 1-6.

8. A method for preparing the topical gel of claim 7, comprising the following steps: (1) mixing ofloxacin and adapalene with a solubilizing agent, and optionally a preservative and a penetrant, and uniformly dispersing to obtain an intermediate mixture; (2) adding a gelling agent and a surfactant, and optionally a humectant and a chelating agent, to a portion of the solvent, stirring to dissolve and swell to obtain a gel base; (3) mixing the intermediate mixture with the gel base, adjusting the pH to 4-10, and then adding the balance of the solvent and mixing uniformly to obtain the pharmaceutical composition.

9. The method of preparing a topical gel according to claim 8, wherein, In step (2), the portion of the solvent is 40-60 wt%, preferably 50 wt%, of the total solvent; Preferably, in step (3), the pH is adjusted to 5-7.

10. Use of the topical pharmaceutical composition according to any one of claims 1-6 or the topical gel of claim 7 in the preparation of a topical medicine for preventing and / or treating acne.

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