Calcipotriol composition without ethanol or isopropanol

Abstract

The present invention is a calcipotriol composition free of ethanol or isopropanol, which is an aqueous solution, the formulation of which includes calcipotriol, a carrier, one or more excipients, and a pH buffer, and which is free of ethanol or isopropanol. The calcipotriol accounts for 0.005% of the total volume weight of the composition. The excipient comprises an antioxidant, a preservative, a solubilizer and a gelling agent. And the solubilizer is diethylene glycol monoethyl ether, dimethyl sulfoxide or dimethyl formamide, and the weight percentage is less than 50%. And the pH value is 8.0 + / -0.5. And the gelling agent is hydroxypropyl chitosan, hydroxy propyl cellulose or carbomer. The calcipotriol composition has the advantages that the formula and the preparation method are reasonable in design, and the use safety can be improved on the premise of ensuring that the calcipotriol composition has good stability and effectiveness.

Description

Technical Field

[0001] The present invention relates to a calcipotriol composition, in particular to a calcipotriol composition free of ethanol or isopropanol. Background Art

[0002] Calcipotriol is a white or off-white crystalline substance, a hypocalcemic vitamin D receptor (VDR) agonist, which has a 200-fold lower effect on calcium metabolism than vitamin D. It can induce the expression of thymic stromal lymphopoietin, thereby inducing the differentiation of keratinocytes. It is widely used in the form of creams, ointments, solutions and foams to treat psoriasis.

[0003] The 0.005% calcipotriol scalp composition contains 51% v / v isopropyl alcohol and propylene glycol, hydroxypropylcellulose, sodium citrate, menthol and water.

[0004] The calcipotriol non-aqueous gel disclosed in CN104138352B contains ethanol and an antioxidant as a stabilizer, which is selected from propyl gallate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene or tocopherol, or any combination thereof.

[0005] CN1968701A discloses a composition for treating psoriasis containing a silicone agent, a corticosteroid and vitamin D or a derivative thereof, wherein the solvent is selected from aliphatic alcohols having 1 to 6 carbon atoms, such as ethanol, isopropanol, butanol and mixtures thereof; and the composition contains an antioxidant selected from the following: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), DL-α-tocopherol, superoxide dismutase, panthenol or certain chelating agents.

[0006] The above calcipotriol topical compositions in the prior art all contain ethanol or isopropanol. However, ethanol or isopropanol can cause tissue damage, inflammatory disorder and reduced collagen production. In any case, their carcinogenic properties must be taken into account when conducting risk assessments on such products. After penetrating the skin, they may spread through the blood to more susceptible organs. They will extract lipids from the skin barrier function and damage the skin membrane. Therefore, products containing ethanol or isopropanol should be avoided in skin applications.

[0007] On the other hand, the above calcipotriol formulation ingredients in the prior art have higher impurity limits specified in the United States Pharmacopoeia, where the total amount of impurities in the cream is 4.2% and in the ointment is 3.5%. The content of impurity C in the cream is 2.0% and in the ointment is 1%; the content of impurity D in the cream is 3.6% and in the ointment is 1%. Therefore, the topical composition containing calcipotriol still has room for improvement.

[0008] Solutions have enhanced permeability compared to creams, ointments, and gels. Development of a calcipotriol composition solution that does not contain ethanol or isopropanol and buffers calcipotriol to a specified pH with an appropriate buffer is expected to improve stability, safety, and efficacy. Summary of the invention

[0009] The present invention provides a calcipotriol composition that does not contain ethanol or isopropanol, the purpose of which is to overcome the above-mentioned shortcomings of the prior art and improve safety while ensuring stability and effectiveness.

[0010] The technical solution of the present invention is: a calcipotriol composition that does not contain ethanol or isopropanol, which is an aqueous solution, and its formula includes calcipotriol, a carrier, one or more excipients, and a pH buffer, and does not contain ethanol or isopropanol.

[0011] Preferably, calcipotriol accounts for 0.001%-0.5% by volume of the total composition, more preferably 0.002%-0.4%, more preferably 0.003%-0.3%, more preferably 0.004%-0.2%, more preferably 0.005%-0.1%, and most preferably 0.005%.

[0012] Preferably, the excipients include antioxidants, preservatives, solubilizers and gelling agents.

[0013] Further preferably, the antioxidant comprises a mixture of one or more of glutathione, thioredoxin, superoxide dismutase, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquinone, ascorbyl palmitate, citric acid, thiols, sulfoxides, metal chelators, fatty acids, vitamins, phenols, stilbenes, uric acid, mannose, isoflavones, selenium and propyl gallate.

[0014] Further preferably, the preservative comprises a mixture of one or more of benzalkonium chloride, benzalkonium chloride, cetrimide, dequinolium chloride, cetylpyridinium chloride, phenylmercuric nitrate, phenylmercuric acetate and thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, parabens, chlorhexidine, chlorocresol, benzoic acid and polymyxin.

[0015] Further preferably, the solubilizer includes a mixture of one or more of diethylene glycol monoethyl ether, dimethyl sulfoxide, propylene glycol dimethylformamide, olein, isopropyl myristate, methyl laurate, N-lauroyl sarcosine, oleic acid (octadecenoic acid), sodium lauryl sulfoacetate, sodium octyl sulfate, trimethylamine (PG), propylene glycol dipelargonate (PGDP), oleyl alcohol, caprylic alcohol, decanol, propylene glycol dipelargonate (PGDP), lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, linoleyl alcohol and linolenic alcohol.

[0016] Most preferably, the solubilizing agent is diethylene glycol monoethyl ether, dimethyl sulfoxide or dimethylformamide.

[0017] Preferably, the solubilizer accounts for less than 50% by weight of the total composition.

[0018] Further preferably, the pH buffer comprises a mixture of one or more of sodium citrate dihydrate, citric acid, monobasic sodium phosphate, diethanolamine, triethanolamine, sodium hydroxide and hydrochloric acid.

[0019] More preferably, the buffer is sodium citrate or monobasic sodium phosphate, and the pH value is adjusted to 6.0±3, more preferably, the pH value is adjusted to 7.0±2.0, and more preferably, the pH value is adjusted to 8.0±0.5.

[0020] Further preferably, the gelling agent comprises a mixture of one or more of hydroxypropyl chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carrageenan, microcrystalline cellulose, alginate, gellan gum, xanthan gum, vitex, hydroxyethyl cellulose, ethyl cellulose, guar gum and carbomer.

[0021] Most preferably, the gelling agent is hydroxypropyl chitosan, hydroxypropyl cellulose or carbomer.

[0022] The invention has the advantages that the formula and the preparation method are reasonably designed, and the safety of use can be improved under the premise of ensuring that the calcipotriol composition has good stability and effectiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a graph showing the skin penetration study results of Example 10 of the present invention. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0025] A calcipotriol composition free of ethanol or isopropanol, the formulation of which comprises a therapeutically effective amount of calcipotriol or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, one or more pharmaceutically acceptable excipients, and a buffer buffered to a specific pH value, and substantially free of or completely free of ethanol or isopropanol.

[0026] Substantially free means that the content in the composition is less than about 10% (volume fraction), preferably less than about 5% (volume fraction), further preferably less than about 2.5% (volume fraction), further preferably less than about 1% (volume fraction), further preferably less than about 0.5% (volume fraction).

[0027] As a preferred embodiment, the concentration of calcipotriol is about 0.001% to about 0.5% by volume of the total composition, more preferably about 0.002% to about 0.4%, more preferably about 0.003% to about 0.3%, more preferably about 0.004% to about 0.2%, more preferably about 0.005% to about 0.1%, and most preferably about 0.005%.

[0028] As a preferred embodiment, the excipients include solubilizers, gelling agents, antioxidants, chelating agents, preservatives, colorants, spices, odor modifiers, propellants, penetration enhancers, stabilizers, etc., any of which are well known in the art. In addition, the composition may also include emollients, humectants, astringents, keratolytic agents, humectants, cleansers, sunscreens, and mixtures thereof. The composition may also include any pharmaceutically acceptable excipient that is compatible or miscible with the lipophilic carrier of the present invention to enhance the physical and / or chemical and / or microbial stability of the retinoic acid composition.

[0029] As a further preferred embodiment, the antioxidant includes glutathione, thioredoxin, superoxide dismutase, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquinone, ascorbyl palmitate, citric acid, thiols, sulfoxides, metal chelators, fatty acids, vitamins, phenols, stilbenes, uric acid, mannose, isoflavones, selenium and propyl gallate.

[0030] As a further preferred embodiment, the preservative includes quaternary ammonium compounds such as benzalkonium chloride, benzalkonium chloride, cetrimide, dequinolium chloride and cetylpyridinium chloride; mercury agents such as phenylmercuric nitrate, phenylmercuric acetate and thimerosal; alcohol agents such as chlorobutanol, phenylethyl alcohol and benzyl alcohol; antibacterial esters such as parabens; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.

[0031] As a preferred embodiment, additional active ingredients may be included, including retinoic acid or its derivatives, antibiotics, bactericides, bacteriostatics, anti-infectives and anti-inflammatory drugs.

[0032] As a further preferred embodiment, the antibiotics include macrolides, such as azithromycin, clarithromycin, lincomycin, clindamycin, erythromycin, pharmaceutically acceptable salts and esters thereof, and similar drugs and mixtures thereof.

[0033] As a further preferred embodiment, the bactericidal drugs include penicillins, cephalosporins, vancomycins, aminoglycosides, quinolones and polymyxins.

[0034] As a further preferred embodiment, the antibacterial drugs include erythromycin, tetracycline, chloramphenicol, lincomycin, clarithromycin, azithromycin and sulfonamides.

[0035] As a further preferred embodiment, the anti-infective drugs include topically applicable antibacterial, antifungal and antimycotic drugs.

[0036] As a further preferred embodiment, the solubilizing agent is selected from: diethylene glycol monoethyl ether, dimethyl sulfoxide, propylene glycol dimethylformamide, oleyl glyceride, isopropyl myristate, methyl laurate, N-lauroyl sarcosine, oleic acid (octadecenoic acid), sodium lauryl sulfoacetate, sodium octyl sulfate, trimethylamine (PG), propylene glycol dipelargonate (PGDP), fatty alcohols such as oleyl alcohol, octanol, decanol, propylene glycol dipelargonate (PGDP), fatty alcohols such as oleyl alcohol, octanol, decanol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol and linoleyl alcohol. The solubilizing agent used in the preferred composition is preferably selected from diethylene glycol monoethyl ether, dimethyl sulfoxide and dimethylformamide.

[0037] As a further preferred embodiment, based on the total weight of the composition, the weight percentage of the solubilizer is less than 50%.

[0038] As a further preferred embodiment, the buffer is selected from the group consisting of sodium citrate dihydrate, citric acid, monobasic sodium phosphate, diethanolamine, triethanolamine, sodium hydroxide and hydrochloric acid.

[0039] As the most preferred embodiment, the buffer is a combination of sodium citrate and monobasic sodium phosphate to adjust the appropriate pH value to 6.0±3.

[0040] As a further preferred embodiment, based on the total weight of the composition, the weight percentage of the buffer is about 0.01% w / w to about 2% w / w, so as to adjust the appropriate pH value to 7.0±2.0, further preferably about 0.1% by weight to about 1% by weight, and most preferably about 0.2% by weight, so as to adjust the appropriate pH value to 8.0±0.5.

[0041] As a further preferred embodiment, the gelling agent is selected from the group consisting of hydroxypropyl chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carrageenan, microcrystalline cellulose, alginate, gellan gum, xanthan gum, vitex, hydroxyethyl cellulose, ethyl cellulose, guar gum and carbomer.

[0042] As the most preferred embodiment, the gelling agent is selected from: hydroxypropyl chitosan, hydroxypropyl cellulose or carbomer.

[0043] As an application, in addition to treating psoriasis, the composition can also be used to treat various skin diseases, including acne, vitiligo, impetigo, rosacea, atopic dermatitis, secondary skin infections, reactive skin diseases and combinations thereof. Other specific skin diseases that can be treated by the topical composition include seborrhea and skin damage.

[0044] When used, it can be applied to the skin by directly applying or smearing or spraying on the epidermal tissue, especially the outer layer of the skin. It can be filled into a suitable packaging component to provide a uniform, reproducible and small amount of composition through a local route.

[0045] Example 1

[0046] Recipe composition:

[0047]

[0048] Preparation steps:

[0049] (a) adding and dispersing hydroxypropyl chitosan in purified water, stirring and hydrating for 60 minutes to obtain a hydrated polymer;

[0050] (b) adding disodium ethylenediaminetetraacetate, menthol and disodium hydrogen phosphate to a mixture of propylene glycol and dimethyl sulfoxide and dissolving them under stirring until a clear buffer solution is formed;

[0051] (c) adding calcipotriol to the buffer solution and dissolving it under stirring until a transparent drug phase solution is formed;

[0052] (d) Add the hydrated polymer to the drug phase and mix under stirring for 30 minutes.

[0053] Example 2

[0054] The formula composition differs from that of Example 1 in that it further includes additional disodium hydrogen phosphate as a pH adjuster sufficient to adjust the pH value to 8.5±0.5.

[0055] The preparation steps are different from those in Example 1 in that additional disodium hydrogen phosphate is added in step (b) to adjust the pH value to 8.5±0.5.

[0056] Example 3

[0057] The formula composition and preparation steps are different from those of Example 2 in that dimethyl sulfoxide is replaced by dimethylformamide.

[0058] Example 4

[0059] The formula composition and preparation steps are different from those of Example 2 in that dimethyl sulfoxide is replaced by diethylene glycol monoethyl ether.

[0060] Example 5

[0061] The formula composition and preparation steps are different from those of Example 2 in that dimethyl sulfoxide is replaced by n-methyl-2-pyrrolidone (NMP).

[0062] Example 6

[0063] The formula composition and preparation steps are different from those of Example 2 in that hydroxypropyl chitosan is replaced by carbomer.

[0064] Example 7

[0065] The formula composition and preparation steps are different from those of Example 2 in that hydroxypropyl chitosan is replaced by AA-1 Polycarbophil (USP).

[0066] Example 8

[0067] The formula composition and preparation steps are different from those of Example 2 in that hydroxypropyl chitosan is replaced by Ultrez 10NF polymer.

[0068] Example 9: Stability Study

[0069] Under accelerated storage conditions, the stability of the formulations of Examples 2 and 4 was studied using the validation method. The commercially available reagents have better stability, and the results are shown in the following table.

[0070]

[0071]

[0072] Note: BLOQ means below limit of quantitation.

[0073] Example 10: Skin penetration study

[0074] A Franz diffusion cell was used with porcine anterior abdominal skin as a thin membrane. The method was developed and validated according to the guidance document to compare the permeation of calcipotriol in various formulations. The experiments were conducted using the process parameters shown in the table below. After the study was completed, the samples were stripped with tape and the skin layers were separated for analysis. The skin layers were further processed to homogenize and extract the drug in a solvent. Analysis was performed using LC-MS.

[0075]

[0076]

[0077] The results are as follows Figure 1 As shown, compared with commercially available reagents, the permeation amount of the buffer formulations of Examples 2 and 4 using novel polymers such as hydroxypropyl chitosan is higher.

[0078] Example 11: Skin irritation study

[0079] Guinea pigs (400-500 g) of either sex were used to test skin irritation. They were fed with standard animal feed and had free access to water. The animals were housed under standard conditions and divided into four groups, two in each group, namely Group 1: control group, Group 2: Example 2, Group 3: Example 4, and Group 4: commercially available reagents.

[0080] Hair was taken from the back of the guinea pig, and a 4 cm2 area was marked. The sample (500 mg / guinea pig) was applied twice a day for 7 days to observe whether there was any sensitivity and reaction in the area. The sensitivity was divided into 0, 1, 2 and 3 levels, representing no reaction, mild plaque erythema, plaque erythema and severe erythema with or without edema, respectively. The specific results are shown in the following table.

[0081]

[0082]

[0083] Example 12: Psoriasis Animal Experiment

[0084] Methods: Psoriasis similar to psoriasis lesions was induced by applying 5% imiquimod topical cream to the dorsal skin of 40 mice at a dose of 62.5 mg per day for 7 consecutive days. Thirty mice were selected for the study and randomly divided into 3 groups. The evaluation was completed independently by two researchers (n=30 for each parameter), and the mean values ​​were calculated. The PASI clinical scoring system was used to evaluate the inflammatory status of the dorsal skin of mice for all 8 days. This system includes visual observation of the following three parameters of the dorsal skin of each mouse: erythema (redness), indentation (thickness), and desquamation (scalyness). Each parameter was scored between 0 and 4 (0-none, 1-mild, 2-moderate, 3-marked, 4-very marked), and the cumulative score was 0 to 12 points. The samples were applied for 8 weeks, and the observations were recorded independently by two researchers before the start of treatment, 2 weeks, 4 weeks, and 8 weeks.

[0085] The results of the animal experiment are shown in the table below. Compared with the commercially available reagents, the PASI table evaluation results of the formulations of Examples 2 and 4 showed that the symptoms of redness, thickening and scaling recovered faster. It is speculated that the polymer hydroxypropyl chitosan helps adhesion and stays on the skin for a longer time, keeping the skin moisturized, thereby increasing permeability and efficacy.

[0086]

[0087]

[0088] *Day 8 of imiquimod use.

[0089] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A calcipotriol composition free of ethanol or isopropanol, characterized in that: The invention is an aqueous solution, the formulation of which includes calcipotriol, a carrier, one or more excipients, and a pH buffer, and does not contain ethanol or isopropanol.

2. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 1, characterized in that: The calcipotriol accounts for 0.005% of the total composition by volume.

3. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 1 or 2, characterized in that: The excipients include antioxidants, preservatives, solubilizers and gelling agents.

4. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 3, characterized in that: The antioxidant comprises a mixture of one or more of glutathione, thioredoxin, superoxide dismutase, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquinone, ascorbyl palmitate, citric acid, thiol, sulfoxide, metal chelator, fatty acid, vitamin, phenol, stilbene, uric acid, mannose, isoflavone, selenium and propyl gallate.

5. The calcipotriol composition free of ethanol or isopropanol according to claim 3, characterized in that: The preservative comprises a mixture of one or more of benzalkonium chloride, benzalkonium chloride, cetrimide, dequinolium chloride, cetylpyridinium chloride, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, parahydroxybenzoate, chlorhexidine, chlorocresol, benzoic acid and polymyxin.

6. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 3, characterized in that: The solubilizer includes a mixture of one or more of diethylene glycol monoethyl ether, dimethyl sulfoxide, propylene glycol dimethylformamide, oleyl glyceride, isopropyl myristate, methyl laurate, N-lauroyl sarcosine, oleic acid, sodium lauryl sulfoacetate, sodium octyl sulfate, trimethylamine, propylene glycol dipelargonate, oleyl alcohol, octanol, decanol, propylene glycol dipelargonate, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, linoleyl alcohol and linoleyl alcohol.

7. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 6, characterized in that: The solubilizer is diethylene glycol monoethyl ether, dimethyl sulfoxide or dimethylformamide, and the solubilizer accounts for less than 50% of the total composition by weight.

8. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 7, characterized in that: The pH buffer is sodium citrate or monobasic sodium phosphate, which adjusts the pH value of the composition to 8.0±0.

5.

9. The calcipotriol composition free of ethanol or isopropanol according to claim 4, characterized in that: The gelling agent comprises a mixture of one or more of hydroxypropyl chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carrageenan, microcrystalline cellulose, alginate, gellan gum, xanthan gum, vitex, hydroxyethyl cellulose, ethyl cellulose, guar gum and carbomer.

10. A calcipotriol composition free of ethanol or isopropanol as claimed in claim 9, characterized in that: The gelling agent is hydroxypropyl chitosan, hydroxypropyl cellulose or carbomer.

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