Topical Compositions

Abstract

To provide a stable topical composition comprising calcipotriol and betamethasone dipropionate.SOLUTION: The present invention relates to a composition for topical application comprising a polyaphron dispersion, the polyaphron dispersion comprising a continuous aqueous phase and at least one discontinuous oil phase(s), wherein the polyaphron dispersion comprises calcipotriol and betamethasone dipropionate; at least one of the discontinuous oil phase(s) comprises medium chain triglycerides and isopropyl myristate; the isopropyl myristate and the medium chain triglycerides are present in a weight ratio of from 3:1 to 12:1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to topical compositions. In particular, the present invention relates to topical compositions containing calcipotriol and diprostaglandin. The present invention relates to a topical composition comprising betamethasone pionate, which is a topical composition containing calcipotriol. and improved chemical stability compared to existing compositions containing betamethasone dipropionate. The formulation has the following characteristics: saturation, skin permeability, aesthetics, and / or patient compliance. [Background technology]

[0002] Contains calcipotriol and betamethasone dipropionate used to treat psoriasis Topical formulations are known. Traditionally, topical formulations in which both components are stable have been difficult to produce. This has been shown to be the case because the two compounds are stable at different pH values. In particular, calcipotriol requires a pH value above 8 for maximum stability, Betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpreg Na-1,4-diene-3,20-dione and its esters for maximum stability. A pH value in the range of 4 to 6 is therefore required. Combining two active ingredients in a single formulation while maintaining good stability is challenging. do.

[0003] One approach to achieving stability of the two active substances is to use a water-free composition. Following this approach, three commercial products have been developed: It is being marketed as: Daivobet® Ointment, Daivobet® Gel and Enstilar® foam. The absence of water prevents hydrolysis or The limited chemical degradation due to pH incompatibility and the occlusive nature of most of the excipients ensures active However, most ointments and oil-based In the case of the formulation of cereals, the lack of water and the presence of paraffin and wax components can cause the formulation to (SE Wolverton, Comprehensive Dermatological Dru g Therapy 3 rd Edition (2012), p. 13). A poor aesthetic profile can lead to poor patient compliance. The answer may be limited.

[0004] WO 2008 / 110815 describes calcipotriol and dimethicone. The pH incompatibility issue of betamethasone dipropionate was addressed by using them in polyaphrons. This is overcome by incorporating the dispersion into a composition containing water. They can be formulated into creams and used in non-steroidal anti-inflammatory drugs such as the Daivobet® products discussed above. They have a more satisfactory aesthetic profile than aqueous ointments and gels. This, in turn, allows for improved Patient compliance can be elicited. Summary of the Invention

[0005] Nevertheless, the examples in WO 2008 / 110815 are good. While demonstrating good chemical stability, the inventors have demonstrated that the chemical It was found that the mechanical stability could be improved.

[0006] Improvements suitable for topical application that address at least some of the problems with prior art compositions There is a need to formulate such compositions.

[0007] Therefore, Daivobet® ointment, Daivobet® gel, and and Enstilar® foam, providing better aesthetics than prior art non-aqueous formulations. To provide a formulation containing calcipotriol and betamethasone dipropionate This is one object of the present invention.

[0008] Daivobet® Ointment, Daivobet® Gel, and En Better patient compliance than prior art non-aqueous formulations such as stilar® foam Calcipotriol and betamethasone dipropionate can elicit irritation It is an alternative and / or additional aspect of the invention to provide a formulation comprising:

[0009] Existing cli- ents such as those disclosed in WO 2008 / 110815 are Calcipotriol and diproline with improved chemical stability compared to the steroid formulation An alternative and / or additional aspect of the present invention is to provide a formulation comprising betamethasone proionate. This is an additional aspect.

[0010] Daivobet® Ointment, Daivobet® Gel, and En Conventional techniques such as stilar® foam and / or existing cream formulations Non-aqueous formulations of the present invention, such as those disclosed in WO 2008 / 110815, Calcipotriol and dipropionic acid have better skin permeability than those It is an alternative and / or additional aspect of the present invention to provide a formulation comprising betamethasone. It seems that DETAILED DESCRIPTION OF THE INVENTION

[0011] According to a first aspect, the present invention provides a composition for topical application comprising a polyaphron dispersion. wherein the polyaphron dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, and ferol, and butylhydroxyanisole, The composition is provided wherein the composition has a pH of 7.75±0.5.

[0012] The inventors have surprisingly found that the antioxidants, α-tocopherol, and butyl hydrochloride The special combination of hydroxyanisole ensures that the pH of the composition is within the range of 7.75±0.5. interact in a way that results in significantly increased chemical stability of calcipotriol. This phenomenon was not observed when other combinations of antioxidants were tested. It was.

[0013] The present invention will now be further described. In the following sections, various aspects / embodiments of the present invention will be better understood. Each aspect / embodiment so defined shall be expressly Unless otherwise specified, it may be combined with any other aspect / embodiment. Any feature indicated as being preferred or advantageous is not to be construed as being preferred or advantageous. This feature may be combined with any other feature that may be used.

[0014] The present invention provides a composition for topical application. A composition is defined herein as a composition suitable for direct application to a part of an animal's body. Alternatively, the composition is suitable for direct application to the skin, for example, the face, scalp, feet, limbs, or torso. It is sharp.

[0015] The compositions of the present invention comprise polyaphron dispersions. The term "aphron dispersion" refers to (a) a hydrophilic liquid miscible phase, (b) a hydrophilic liquid phase immiscible or a second hydrophobic phase that is substantially immiscible with the first hydrophobic phase, and (c) one or more surfactants. Certain types of dispersions of hydrophilic liquids in hydrophobic liquids or hydrophobic liquids in hydrophilic liquids, including where the dispersed or discontinuous phase is small (e.g., micron to submicron diameter) but more usually in the form of droplets (at least 1 micron in diameter) and, overall, have the following characteristics: whereby the polyaphron dispersion is a conventional or common emulsion, and Distinguished from other distribution types: 1. They can exist in a stable form and the volume fraction of the dispersed phase (Φ ip ) is higher than 0.7 High, and may be as high as 0.97 (Φ ip is the ratio of the continuous phase to the discontinuous phase, expressed as a fraction (The volume ratio is the ratio of 2. Φ ip The microscopic appearance of polyaphron dispersions with a β-value greater than 0.7 is polyhedral. The appearance is of separate droplets tightly pressed together, resembling the appearance of gas foam. In this form, the dispersion has gel-like properties and is called a gel polyaphron dispersion (GPD). It is called. 3. Stable polyaphron dispersions are less than 3% by weight of the total composition, more typically double The surfactant may be used at a concentration of less than 100% by volume. 4. Gel polyaphron dispersions (as described in 2 above) lose their gel-like properties In this case, any degree of solubility can be achieved by adding more continuous phase without adding more surfactant. Can be diluted as needed. ip When the σ decreases to less than 0.7, the discrete droplets of the internal phase are divided into spherical droplets. separated to take the form of a stable and complete, but nevertheless loose association. They bind together through bonding and may float on top of the diluted dispersion or sink to the bottom (depending on the specific gravity of the two phases). In this diluted form, each droplet is called a colloidal liquid aphron (CLA). Simple shaking of the diluted dispersion immediately results in a homogeneous and stable dispersion of colloidal liquid aphrons. The dispersion is reformed.

[0016] Each of the above properties and their combinations make the polyaphron dispersion of the present invention and conventional emulsions and other dispersion types that do not have all of those properties. Polyaphron dispersions are disclosed by the following references: Sebb a:"Biliquid Foams", J. Colloid and Interface Science, 40 (1972) 468-474 and "Th e Behavior of Minute Oil Droplets Encapsulated in a Water Film", Colloid Polyme r Sciences, 257 (1979) 392-396, Hicks "Investigating the Generation, Characteris ation, and Structure of Biliquid Foams", PhD Thesis, University of Bristol, 2005 , Crutchley "The Encapsulation of Oils and Oil Soluble Substances Within Polymer Films", PhD Thesis, The University of Leeds, 2006, and Lye and Stuckey, Col Lloyd and Surfaces, 131 (1998) 119-136. Afron is a U.S. Patent holder. and WO 97 / 32559.

[0017] Polyaphron dispersions are available in various forms, including "Biliquid Foams" and "High Internal Phase Emulsifiers." "High Internal Phase Emulsion (HIPE)", "High Internal Phase Ratio Emulsion (HIPE)", and "Gel Emulsion" In U.S. Patent No. 5,573,757, Compositions containing fluorocarbon dispersions are described as "viscoelastic gels." All references to dispersions are to polyaphron dispersions as used in the present invention. .

[0018] The polyaphron dispersion comprises a continuous aqueous phase and at least one discontinuous oil phase. For example, a polyaphron dispersion comprises a dispersion of at least one discontinuous oil phase in a continuous aqueous phase. As mentioned above, in polyaphron dispersions, the discontinuous phase is in the form of droplets. The term "discontinuous phase" as used herein refers to a plurality of oil droplets that form that distinct oil phase. It is not used to refer to single oil droplets. The continuous phase is physically distinct from the discontinuous oil phase. become.

[0019] The inclusion of a continuous aqueous phase in the present composition allows the composition to be applied in the form of a lotion, as opposed to an ointment. The present composition can therefore be provided in the form of a softener or cream. It has an improved aesthetic profile compared to plasters, which may improve patient compliance Preferably, the composition is a lotion, cream, or spray, most preferably or in the form of a cream.

[0020] It is understood that each of the at least one discontinuous phases comprises a pharmaceutically acceptable oil. An example of a pharmaceutically acceptable oil that may be used in the present invention is coconut oil. , squalane, isopropyl myristate, isopropyl isostearate, palmitic Isopropyl Acetate, Modified Triglycerides, Caprylic / Capric Glycerides, Fractionated Triglycerides Lid, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate Glyceryl Tricaprylate / Caprate, Glyceryl Tricaprylate / Caprate, Tri Caprylic / Capric / Glyceryl Laurate, Caprylic / Capric / Glyceryl Linoleate Ceryl, Tricaprylic / Capric / Glyceryl Stearate, Glyceryl Trilaurate , Glyceryl trilinoleate, Glyceryl trilinolenate, Glyceryl trioleate, Glyceryl triundecanoate, linoleic acid glyceride, saturated polyglycolized glycerides , mainly C8-C 12 Synthetic medium-chain triglycerides containing fatty acid chains, medium-chain triglycerides Long-chain triglycerides, modified triglycerides, fractionated triglycerides, isostearic acid Isostearyl, diisopropyl adipate, mineral oil, dimethicone, cyclomethicone, hydrogenated Polyisobutene, heptamethylnonane, and mixtures thereof. The product does not contain any wax components that are solid at 25°C.

[0021] Preferably, at least one of the discontinuous oil phases comprises caprylic / capric triglyceride. ceride (CCT) and isopropyl myristate (IPM). The glyceryl caprylate triglyceride is present in an amount of 2 to 12 wt % based on the weight of the composition, more preferably are present in a total amount of 4 to 10 wt%, most preferably 5 to 8 wt%. Isopropyl acrylate is 30 to 50 wt%, more preferably 35 to 45 wt%, most preferably Preferably, it is present in a total amount of 37 to 43 wt%. Preferably, it is isopropyl myristate. and caprylic / capric triglyceride, 3:1 to 12:1, more preferably 4:1 The inventors have found that at least one of the discontinuous phases contains trace amounts of CCT. When blended with IPM, the effectiveness of betamethasone dipropionate was significantly improved compared to when IPM was used alone. It has been found that this results in improved transdermal diffusion of benzodiazepine and calcipotriol. This is because IPM is a known permeation enhancer, and IPM alone and the combination of CCT and IPM This is surprising because it would be expected to give better diffusion of the active substance than the combined CCT. and improved active diffusion is obtained only when IPM is present in the above (relative) amounts. It has been shown that excessive CCT content can have a detrimental effect on the percutaneous diffusion of the active substance. We know there is something.

[0022] Preferably, the at least one discontinuous oil phase comprises from 10 to 90 wt. % based on the weight of the composition. %, more preferably 40 to 90 wt %. Preferably, at least one The discontinuous oil phase is present in an amount of 65 to 80 wt %, more preferably 70 to 75 wt %, based on the weight of the composition. % by weight. Alternatively, the composition may include a smaller amount of a discontinuous oil phase. For example, the at least one discontinuous oil phase may comprise less than 70 wt. % of the composition by weight. More preferably, they are present in a total amount of 50 to 70 wt %. The oil phase is typical of scalp products.

[0023] The polyaphron dispersion contains calcipotriol. Calcipotriol is used in the treatment of psoriasis. Its chemical formula is shown in Figure 1. The source of calcipotriol used herein is preferably anhydrous calcipotriol or or calcipotriol hydrate, but other sources of calcipotriol, e.g. It will be understood that salts and solvates may be used. The amount of calcipotriol incorporated into the composition is determined by the anhydrous Based on morphology (i.e., based on the molecular weight of the chemical formula shown in Figure 1).

[0024] The polyaphron dispersion contains betamethasone dipropionate. Benzene is known for use in combination with calcipotriol in the treatment of psoriasis. It is an ester of betamethasone. The chemical formula of betamethasone dipropionate is shown in Figure 2. The source of betamethasone dipropionate used in the present invention is preferably free Water betamethasone dipropionate, but other sources of betamethasone dipropionate, e.g. It will be understood that, for example, salts, hydrates, and solvates thereof may be used. However, the amount of betamethasone dipropionate incorporated into the compositions described herein is , based on the anhydrous form of betamethasone dipropionate (i.e., the chemical formula shown in Figure 2 based on molecular weight).

[0025] Depending on the source of each used, it will provide the desired amount of each in the final composition. The source of calcipotriol and betaine dipropionate used in the preparation of the composition Adjusting the amount of the source of tazone will be within the ability of one skilled in the art.

[0026] The compositions of the present invention have a pH of 7.75±0.5. pH of 5±0.25. To adjust the pH to the correct value or pH range, It will be appreciated that any suitable acid or base may be used. Advantageously and preferably: The pH of the composition may be stabilized by incorporating a suitable buffer into the continuous aqueous phase. Suitable buffer systems having a pH within the specified range will be well known to those skilled in the art.

[0027] Surprisingly and unexpectedly, the inventors discovered that two special antioxidants, butyl hydride, hydroxyanisole and α-tocopherol interact within the pH range of 7.75±0.5. It has been discovered that the action of the compound results in significantly increased chemical stability of calcipotriol. In particular, butylhydroxyanisole alone and α-tocopherol alone showed no significant differences compared to the control. had no significant effect on calcipotriol stability (where antioxidants were used). Although the combination of the two antioxidants did not improve calcipotriol stability, The results showed a dramatic improvement in the overall chemical stability of the composition. This was not observed for other combinations of agents.

[0028] Therefore, the polyaphron dispersion was prepared by dissolving α-tocopherol and butylhydroxyanisole. The inclusion of these antioxidants provides a chemical The term "α-tocopherol" refers to all α-tocopherols. Therefore, α-tocopherol is RRR-α-tocopherol. Alternatively, the α-tocopherol may be an all-rac-α-tocopherol. It may be a mixture of any stereoisomers. The source is anhydrous α-tocopherol or its salts, such as α-tocopherol acetate, hydrates, etc. , solvates, or esters. The source is anhydrous α-tocopherol. Butylhydroxyanisole is typically 4 It is prepared from 2-tert-butyl phenol and isobutylene, typically 3-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole Alternatively, one of the isomers can be isolated and used. The source of butylated hydroxyanisole used in is anhydrous butylated hydroxyanisole. or a salt, hydrate, solvate, or ester thereof. The source of butylated hydroxyanisole is anhydrous butylated hydroxyanisole.

[0029] The polyaphron dispersion further contains a tocopherol isomer other than α-tocopherol. In particular, the polyaphron dispersion may contain β-tocopherol, γ-tocopherol, and / or δ-tocopherol. α-tocopherol, γ-tocopherol, and / or δ-tocopherol are preferably - maximum 100 wt. %, more preferably maximum 50 wt. %, based on the weight of tocopherols %, even more preferably at most 30 wt%, even more preferably at most 20 wt%, Most preferably it is present in a total amount of up to 10 wt%.

[0030] Preferably, the composition is stable at 25°C ± 5% measured at 60% RH for at least 6 months. The composition is chemically stable at 2°C. Preferably, the composition has a minimum humidity of 100% when measured at 60% RH ± 5%. Chemical stability is preferably at least 12 months at 5°C ± 3°C. A closed, airtight amber glass container with a clearance not exceeding 5% by volume of the container's total usable volume. The measurements were taken after storing the composition in a container. The container was preferably sparged with nitrogen. "Chemically stable" means that 24-epi-calcipotriol and The individual amounts of calcipotriol and 5,6-trans-calcipotriol increased compared to t=0. The increase in the amount of 17-propanol is less than 1 wt. % based on the weight of the triol and / or Betamethasone propionate, betamethasone 21-propionate, and 21-acetate-17- The individual amounts of betamethasone dipropionate are compared to t=0. This means that the impurities listed above will increase by less than 1 wt% based on the weight of the product. , a known major component of calcipotriol and betamethasone dipropionate in aqueous media. Preferably, the amount of each impurity is determined by the amount of the associated AP in the chromatogram. The area of ​​the peaks in the HPLC chromatogram is It is calculated by measuring the area of ​​the pure peak and is expressed as a percentage.

[0031] Preferably, the composition is stable at 25°C ± 5% measured at 60% RH for at least 6 months. 2°C. Preferably, the composition has a minimum humidity of 100% when measured at 60% RH ± 5%. Physical stability is preferably at least 12 months at 5°C ± 3°C. A closed, airtight amber glass container with a clearance not exceeding 5% by volume of the container's total usable volume. The measurements are taken after the composition has been stored in a container, which is preferably sparged with nitrogen. "Physically stable" means that the composition is significantly and clearly stable compared to t=0. This means that the cream appears as a homogeneous cream with no noticeable change in rheology or appearance.

[0032] Preferably, the continuous aqueous phase comprises at least 10 wt. % of the weight of the composition, more preferably at least 10 wt. % of the weight of the composition. Preferably 10 to 30 wt%, even more preferably 15 to 25 wt%, most preferably 18 to 30 wt%. 22 wt% water. Alternatively, the composition may contain a higher amount of water. For example: The continuous aqueous phase comprises at least 30 wt. % of the composition, more preferably 30-50 wt. %. % water by weight. These higher amounts of water are typical for scalp products.

[0033] Preferably, the continuous aqueous phase comprises at least 0.5 wt. % of the weight of the composition, more preferably at least 0.5 wt. % of the weight of the composition. or at least 4 wt%, even more preferably 4 to 10 wt%, most preferably 5 to Contains 7% by weight of isopropanol. Alcohol has a drying effect on the skin. While it is generally desirable to limit the alcohol content of topical compositions, the inventors have The presence of isopropanol in the continuous aqueous phase helped to improve the skin permeation of both active substances. Isopropanol also contributes to the preservation of the formulation.

[0034] Preferably, the continuous aqueous phase comprises 10 to 90 wt % of the weight of the composition, more preferably 1 Preferably, the continuous aqueous phase is present in a total amount of 2 to 60 wt % by weight of the composition. Preferably, the composition is present in an amount of 0 to 35 wt%, most preferably 25 to 30 wt%. For example, the continuous aqueous phase may comprise a small amount by weight of the composition. They may be present in an amount of at least 30 wt%, more preferably 30 to 50 wt%. Higher amounts of continuous aqueous phase are typical for scalp products.

[0035] Preferably, the composition contains 0.001 to 0.01 wt % of the composition by weight, more preferably Preferably 0.002 to 0.008 wt%, most preferably 0.004 to 0.006 wt% Preferably, the calcipotriol is present in the discontinuous oil phase. Predominantly present in at least one of the discontinuous oil phases means that the discontinuous oil phase is predominantly present in at least one of the discontinuous oil phases. , at least 60 wt%, preferably at least 70 wt%, most preferably at least 80 wt% of calcipotriol is present in at least one of the discontinuous oil phases Preferably, up to 99 wt % of the calcipotriol is in the discontinuous oil phase. present in at least one

[0036] Preferably, the composition contains 0.02 to 0.1 wt % of the composition by weight, more preferably Preferably 0.04 to 0.08 wt%, most preferably 0.05 to 0.07 wt% dipropionate. Preferably, the betamethasone dipropionate is present in the discontinuous oil phase. Predominantly present in at least one of the discontinuous oil phases. Predominantly present in at least one of the discontinuous oil phases. By this we mean at least 60 wt%, preferably at least 70 wt%, most preferably at least In both cases, 80 wt % of betamethasone dipropionate is present in at least one of the discontinuous oil phases. Preferably, up to 99 wt% of betamethasone dipropionate is present. is present in at least one of the discontinuous oil phases.

[0037] Preferably, the composition contains 0.001 to 0.005 wt %, more preferably 0.001 to 0.005 wt %, based on the weight of the composition. Preferably 0.0015 to 0.003 wt%, most preferably about 0.002 wt% α- Preferably, α-tocopherol is present in at least one of the discontinuous oil phases. Predominantly present in at least one of the discontinuous oil phases means that the At least 60 wt%, preferably at least 70 wt%, most preferably at least 80 wt% t% of α-tocopherol is present in at least one of the discontinuous oil phases. Preferably, up to 99 wt% of the α-tocopherol is present in at least one of the discontinuous oil phases. Both exist together.

[0038] Preferably, the composition contains 0.05 to 0.5 wt % of the composition by weight, more preferably Preferably 0.06-0.4 wt%, even more preferably 0.08-0.2 wt%, most preferably or about 0.1 wt% butylhydroxyanisole. The hydroxyanisole is present predominantly in at least one of the discontinuous oil phases. Present mainly in at least one of them means at least 60 wt%, preferably at least 70 wt. %, most preferably at least 80 wt. % butylhydroxyanisole is It means that it is present in at least one of the continuous oil phases. Preferably, it is present in a maximum of 99 wt. t% of butylhydroxyanisole is present in at least one of the discontinuous oil phases.

[0039] Preferably, the polyaphron dispersion further comprises a discontinuous phase comprising a non-solvent oil. "Oil" refers to an oil in which calcipotriol and / or betamethasone are present at a low temperature of 20°C. Solubility (calcipotriol less than 0.0011 wt% and betamethasone less than 0.01 % (less than 42 wt%) of an oil. May contain a further discontinuous phase containing a non-solvent oil. It has been found that this improves occlusion, thereby facilitating permeation of the active substance. Moreover, the additional discontinuous phase limits the amount of continuous aqueous phase present in the formulation, thereby This limits the partitioning of the active substance into the continuous aqueous phase.

[0040] Preferably, the non-solvent oil comprises at least 5 wt % by weight of the composition. More preferably, it is 10 to 40 wt%, even more preferably, it is 20 to 35 wt%, and most preferably, it is 10 to 40 wt%. Preferably present in an amount of 25-30 wt %. The non-solvent oil is preferably mineral oil and / or is a silicone oil, more preferably a mineral oil.

[0041] Preferably, the discontinuous oil phase comprises a first discontinuous phase, a second discontinuous phase, and optionally a third discontinuous phase comprising mineral oil; Calcipotriol is present primarily in the first discontinuous phase; Betamethasone dipropionate is present primarily in the second discontinuous phase; α-Tocopherol and butylhydroxyanisole are primarily present in the first discontinuous phase. The first and second discontinuous phases may be present in the first and second discontinuous phases or may be present primarily in the first and second discontinuous phases together.

[0042] The term "predominantly" has the same meaning as defined above. The first discontinuous phase is It will be understood that the non-aqueous phase is not dispersed in the discontinuous phase of the non-aqueous phase, or vice versa. In other words, the composition may be any of the compositions disclosed, for example, in WO 2005 / 082515. It does not contain a complex internal phase as shown.

[0043] Preferably, each of the first discontinuous phase and the second discontinuous phase is a pharmaceutically acceptable The first discontinuous phase and the second discontinuous phase each contain the same pharmaceutically acceptable oil. Alternatively, the first discontinuous phase and the second discontinuous phase may each comprise a different oil. The composition may contain any pharmaceutically acceptable oil.

[0044] Preferably, the pharmaceutically acceptable oil is medium chain triglyceride (MCT) and myristyl alcohol. Preferably, the medium chain triglycerides are a blend of isopropyl phosphate (IPM). 2 to 12 wt % of the weight of the composition, more preferably 4 to 10 wt %, most preferably 5 Preferably, isopropyl myristate is present in a total amount of 30 to 50 wt%. wt%, more preferably 35 to 45 wt%, most preferably 37 to 43 wt% Preferably, the isopropyl myristate and medium chain triglyceride are present in a ratio of 3:1 The present inventors have found that the API is present in a weight ratio of about 12:1, more preferably about 4:1 to about 8:1. When a trace amount of MCT was blended into the oil phase, the effects were greater than when IPM was used alone. It has been found that this results in improved transdermal diffusion of the active substance. IPM alone is a better active ingredient than the combination of MCT and IPM. This is surprising because MCT and IPM are expected to give a qualitative diffusion. It has been found that improved active diffusion is obtained only when present in (relative) amounts; Excessive MCT content has been shown to have a negative effect on the percutaneous diffusion of active substances. "Medium-chain triglycerides" are fatty acids whose constituent fatty acids have terminal aliphatic chains of 6 to 12 carbon atoms ( It means a triglyceride having a liphatic tail. Preferably, it is a medium chain triglyceride. is caprylic capric triglyceride.

[0045] The α-tocopherol and butylhydroxyanisole are preferably in the first discontinuous Preferably, α-tocopherol is present primarily in the first discontinuous phase and the second discontinuous phase. in the discontinuous phase and the second discontinuous phase, 1:3 to 3:1, more preferably 1:2 to 2:1; Most preferably, it is present in a weight ratio of about 1:1. Preferably, it is butylated hydroxyanisole. is in the first discontinuous phase and the second discontinuous phase in a ratio of 1:3 to 3:1, more preferably 1:2 They are present in a weight ratio of ∼2:1, most preferably about 1:1.

[0046] Preferably, the first discontinuous phase comprises 15 to 30 wt % of the weight of the composition, more preferably It is present in an amount of 20-25 wt%.

[0047] Preferably, the second discontinuous phase comprises 15 to 30 wt % of the weight of the composition, more preferably It is present in an amount of 20-25 wt%.

[0048] Preferably, the third discontinuous phase, if present, comprises 5 to 40 wt. % of the composition by weight. %, more preferably 20-35 wt %, and most preferably 25-30 wt %.

[0049] Preferably, the ratio of the first discontinuous phase to the second discontinuous phase is 1:3 to 3:1, more preferably are present in a weight ratio of 1:2 to 2:1, most preferably about 1:1.

[0050] Preferably, the composition of the present invention comprises a surfactant. The surfactant is a surfactant in the discontinuous oil phase. and / or the continuous aqueous phase. The agent is alkyl polyglycol ether, alkyl polyglycol ester, ethoxylated hydroxylated alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fat Acid ester, ionic or nonionic surfactants, containing 25 to 60 ethoxy groups Hydrogenated castor oil / polyoxyethylene glycol adduct, containing 25-45 ethoxy groups Castor oil / polyoxyethylene glycol adduct, sorbitan fatty acid ester (e.g., Span 20 or Span 80), ethylene oxide and propylene oxide blocks copolymers (e.g., poloxamer 407 or poloxamer 188), or It includes mixtures of these.

[0051] Preferably, the composition contains two or more surfactants, e.g., one or more A first surfactant incorporated into the discontinuous oil phase and a second surfactant incorporated into the continuous aqueous phase. The first and second surfactants preferably comprise different surfactants selected from the list above. The first surfactant is selected to be readily soluble or dispersible in the oil of the discontinuous phase and is laureth- 4 (Polyoxyethylene (4) monododecyl ether), Polysorbate 80, Span 8 0, and mixtures of two or more thereof. The second surfactant is readily soluble or dispersible in the continuous aqueous phase and may be polysorbate 20, poloxamer, or the like. Poloxamer 407, Poloxamer 188, PEG-40 Hydrogenated Castor Oil, and any combination thereof Preferably, the first boundary is selected from the group consisting of a mixture of two or more of the above. Most preferably, the first boundary is selected from the group consisting of a mixture of two or more of the above. The surfactant is laureth-4 (polyoxyethylene (4) monododecyl ether), The second surfactant is Poloxamer 407.

[0052] Preferably, the compositions disclosed herein contain less than 5 wt. % of the total weight of the composition, preferably less than 5 wt. % of the total weight of the composition. More preferably less than 3 wt. %, and even more preferably less than 2 wt. % total surfactant content. Preferably, the total surfactant content is at least 0.5 wt%.

[0053] Preferably, the composition of the present invention is dispersible in water. It can be diluted with water. This allows you to, for example, dry your hair or use it in case of emergency. or from rinsing the preparation from any topical surface or clothing if the need arises. The product is easily removed by rinsing from accidental stains on the head through the hair. The applicability of the present invention to improve application of the composition to the skin is enhanced. Improve the user experience and improve patient compliance.

[0054] Preferably, the composition of the present invention further comprises a rheological agent such as a gelling agent and / or a viscosity modifier. Gelling agents include, for example, gum alginate or salts thereof, guar gum, Gum, locust bean gum, xanthan gum, acacia gum, gelatin, hydroxymethyl ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carbo Hydroxymethylcellulose or its salt, bentonite, magnesium aluminum silicate , "carbomer" (a salt of a cross-linked polymer of acrylic acid), or polymethacrylate glycerol Other suitable gelling agents may be selected from the group consisting of propylene glycol, propylene glycol, propylene glycol, propylene glycol terpolymer, propylene glycol glycerol, propylene glycol terpolymer ... It will be appreciated that some of the gelling agents (e.g. For example, carbomer) may also function as a chemical buffer, thus aiding in storage and It has been found that viscosity modifiers prevent unwanted pH fluctuations in the composition during use. If used, this is preferably a polymeric cellulose-based thickener. The inclusion of rheology modifiers and / or rheology modifiers provides additional stability against creaming. This ensures that the active concentration is uniform throughout the composition. The use of these ingredients is described in WO 97 / 32559. The choice of thickener / thickener also controls the viscosity of the formulation, from a thin, easily pourable lotion to a thick, easily applied lotion. Control is possible up to thick creams with significant flow resistance.

[0055] Preferably, the composition of the present invention contains 0.05 to 5.0% by weight of the composition, preferably 0.1 The gelling agent is contained in an amount of from 0.2 to 1.0% by weight, more preferably from 0.2 to 1.0% by weight. In embodiments, the composition has the consistency of a gel.

[0056] The compositions of the present invention may also contain preservatives (e.g., to prevent microbiological spoilage), buffers (pH to control the acidity of the skin and to avoid destabilizing and damaging the skin's acid mantle), It may also contain other additives such as antioxidants. If a preservative is used, it may be Preferably, the amount is 0.5 to 1 wt %, more preferably 0.6 to 0.8 wt %, based on the weight of the composition. Preservatives are benzyl alcohol, phenoxyethanol, methyl From the group consisting of paraben, propylparaben, and mixtures of two or more thereof Preferably, the preservative is selected from the group consisting of phenoxyethanol, ... These additives may be contained in the continuous or discontinuous phase of the polyaphron dispersion. The inclusion of these additives is at levels and materials known to be effective and beneficial. It will be understood that the types of additives used will vary. Care should be taken in the selection and amounts of these additives. Therefore, it is necessary to prevent the other performance advantages of the present invention from being impaired.

[0057] Next, a particularly preferred embodiment of the first aspect of the present invention will be described.

[0058] In a particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The lon dispersion comprises a continuous aqueous phase and at least one discontinuous oil phase, The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The composition contains, by weight of the composition: 0.002-0.008 wt% calcipotriol; 0.04-0.08 wt% betamethasone; 0.0015 to 0.003 wt% α-tocopherol; and 0.08 to 0.2 wt% butylhydroxyanisole; At least 60 wt% of the calcipotriol is in at least one of the discontinuous oil phases. There are two At least 60 wt% of the betamethasone dipropionate is present in at least one of the discontinuous oil phases. At least one exists, At least 60 wt % of the α-tocopherol is present in at least one of the discontinuous oil phases. There are two At least 60 wt. % of the butylhydroxyanisole is present in at least one of the discontinuous oil phases. At least one exists, The polyaphron dispersion further comprises a discontinuous phase comprising mineral oil; The composition is in the form of a lotion or cream.

[0059] In a particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The lon dispersion comprises a continuous aqueous phase and at least one discontinuous oil phase, The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The composition contains, by weight of the composition: 0.002-0.008 wt% calcipotriol; 0.04-0.08 wt% betamethasone; 0.0015 to 0.003 wt% α-tocopherol; and 0.08 to 0.2 wt% butylhydroxyanisole; At least 60 wt% of the calcipotriol is in at least one of the discontinuous oil phases. There are two At least 60 wt% of the betamethasone dipropionate is present in at least one of the discontinuous oil phases. At least one exists, At least 60 wt % of the α-tocopherol is present in at least one of the discontinuous oil phases. There are two At least 60 wt. % of the butylhydroxyanisole is present in at least one of the discontinuous oil phases. At least one exists, The at least one discontinuous oil phase may be present in a total amount of 10 to 90 wt. % based on the weight of the composition. exists, and The continuous aqueous phase is present in an amount of 10 to 90 wt % based on the weight of the composition.

[0060] In a further particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The LIAFRON dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The composition contains, by weight of the composition: 0.002-0.008 wt% calcipotriol; 0.04-0.08 wt% betamethasone; 0.0015 to 0.003 wt% α-tocopherol; and 0.08 to 0.2 wt% butylhydroxyanisole; At least 60 wt% of the calcipotriol is in at least one of the discontinuous oil phases. There are two At least 60 wt% of the betamethasone dipropionate is present in at least one of the discontinuous oil phases. At least one exists, At least 60 wt % of the α-tocopherol is present in at least one of the discontinuous oil phases. There are two At least 60 wt. % of the butylhydroxyanisole is present in at least one of the discontinuous oil phases. At least one exists, At least one of the discontinuous phases comprises caprylic / capric triglyceride and aminoglycoside. Contains isopropyl lysate and caprylic / capric triglyceride, by weight of the composition isopropyl myristate is present in a total amount of 4 to 10 wt % of the composition by weight It is present in a total amount of 35-45 wt% of the total amount of isopropyl myristate and caprylic acid. capric acid triglyceride is present in a weight ratio of 4:1 to 8:1, The polyaphron dispersion further comprises a discontinuous phase comprising mineral oil; The composition is in the form of a lotion or cream.

[0061] In a further particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The LIAFRON dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The discontinuous oil phase comprises, by weight of the composition: Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a first discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a first discontinuous phase, wherein capric triglyceride is present in a weight ratio of 4:1 to 8:1; Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a second discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a second discontinuous phase, wherein capric triglyceride is present in a weight ratio of 4:1 to 8:1; 20-30 wt% of a third discontinuous phase comprising mineral oil; At least 60 wt. % of the calcipotriol is present in the first discontinuous phase; at least 60 wt. % of the betamethasone dipropionate is present in the second discontinuous phase; At least 60 wt% of α-tocopherol and butylhydroxyanisole are present in one discontinuous phase and a second discontinuous phase, the continuous aqueous phase comprises 4 to 10 wt % isopropanol based on the weight of the composition; α-Tocopherol is present in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. exists in the successive phase, Butylhydroxyanisole is used in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. 2 discontinuous phase, The composition is in the form of a lotion or cream.

[0062] In a further particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The LIAFRON dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The discontinuous oil phase comprises, by weight of the composition: Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a first discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a first discontinuous phase in which capric triglyceride is present in a weight ratio of 4:1 to 8:1; Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a second discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a second discontinuous phase in which capric triglyceride is present in a weight ratio of 4:1 to 8:1; 25-35 wt% of a third discontinuous phase comprising mineral oil; The composition contains, by weight of the composition: 0.002-0.008 wt% calcipotriol; 0.04-0.08 wt% betamethasone; 0.0015 to 0.003 wt% α-tocopherol; and 0.08 to 0.2 wt% butylhydroxyanisole; At least 60 wt. % of the calcipotriol is present in the first discontinuous phase; at least 60 wt. % of the betamethasone dipropionate is present in the second discontinuous phase; At least 60 wt% of α-tocopherol and butylhydroxyanisole are present in one discontinuous phase and a second discontinuous phase, the continuous aqueous phase comprises 4 to 10 wt % isopropanol based on the weight of the composition; α-Tocopherol is present in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. exists in the successive phase, Butylhydroxyanisole is used in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. 2 discontinuous phase, The composition is in the form of a lotion or cream.

[0063] In a further particularly preferred embodiment, the composition of the present invention comprises a polyaphron dispersion, The LIAFRON dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, ferol, and butylhydroxyanisole, the composition has a pH of 7.75±0.5; The discontinuous oil phase comprises, by weight of the composition: Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a first discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a first discontinuous phase, wherein capric triglyceride is present in a weight ratio of 4:1 to 8:1; Contains a blend of caprylic capric triglyceride and isopropyl myristate 15-30 wt% of a second discontinuous phase comprising isopropyl myristate and caprylic / capric triglyceride a second discontinuous phase, wherein capric triglyceride is present in a weight ratio of 4:1 to 8:1; 20-35 wt% of a third discontinuous phase comprising mineral oil; The composition contains, by weight of the composition: 0.002-0.008 wt% calcipotriol; 0.04-0.08 wt% betamethasone; 0.0015 to 0.003 wt% α-tocopherol; and 0.08 to 0.2 wt% butylhydroxyanisole; at least 95 wt% of the calcipotriol is present in the first discontinuous phase; at least 95 wt% of the betamethasone dipropionate is present in the second discontinuous phase; At least 95 wt% of α-tocopherol and butylhydroxyanisole are present in one discontinuous phase and a second discontinuous phase, The continuous aqueous phase is 15 to 25 wt% water and 4 to 10 wt% ibuprofen, based on the weight of the composition. Contains isopropanol, α-Tocopherol is present in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. exists in the successive phase, Butylhydroxyanisole is used in the first discontinuous phase and the second discontinuous phase in a weight ratio of 1:2 to 2:1. 2 discontinuous phase, the composition is in the form of a lotion or cream, The composition is chemically stable at 25°C ± 2°C for at least 6 months, measured at 60% RH ± 5%. It is chemically and physically stable.

[0064] The particularly preferred embodiments described above may be used interchangeably with the preferred embodiments described elsewhere in the specification. can be freely combined.

[0065] According to a second embodiment, there is provided a composition for topical application comprising a polyaphron dispersion, the LIAFRON dispersion comprises a continuous water phase and at least one discontinuous oil phase; The polyaphron dispersion contains calcipotriol, betamethasone dipropionate, α-tocopherol, and ferol, and butylhydroxyanisole, At least one of the discontinuous oil phases comprises a medium chain triglyceride and an isopropyl myristate. Contains isopropyl, Isopropyl myristate and medium-chain triglycerides in a weight ratio of 3:1 to 12:1 A composition is provided.

[0066] The composition of the second aspect may be freely combined with the preferred features of the composition of the first aspect. can be done.

[0067] According to a third aspect, there is provided a composition for topical application comprising a polyaphron dispersion, The rear flon dispersion is (i) Calcipotriol; (ii) betamethasone or its esters; (iii) α-tocopherol; and (iv) A composition is provided, comprising butylhydroxyanisole.

[0068] The composition of the third aspect can be freely combined with the preferred features of the compositions of the first and second aspects. It can be combined.

[0069] According to a further aspect, for use in the treatment of the human or animal body by therapy, Compositions as described herein are provided.

[0070] According to a further aspect, there is provided a method of treating the human or animal body with therapy, comprising: administering to a subject in need thereof an effective amount of a composition described herein. A method is provided.

[0071] According to a further aspect, a method for producing a medicament for treating a human or animal subject with a therapy is provided. The present invention also provides a use of the compositions described herein for treating atopic dermatitis.

[0072] According to a further aspect, a composition as described herein for use in the treatment of psoriasis. Things are provided.

[0073] According to a further aspect, there is provided a method of treating psoriasis in a human or animal subject, comprising administering to said subject a therapeutically effective amount of psoriasis to said subject. A method comprising administering to a subject in need thereof an effective amount of a composition described herein. The law is provided.

[0074] According to a further aspect, a method for producing a medicament for treating psoriasis in a human or animal subject is provided. The present invention provides a use of the compositions described herein for the treatment of

[0075] The compositions described herein may be applied to the scalp or other skin surfaces via the hair. Preferably, in this embodiment, the hair is damp (e.g., with or without shampoo). (Use water and then towel dry.) Then apply an appropriate amount of product to your scalp. You can then rub it through your hair and into your scalp. Then, leave your hair to dry naturally or Advantageously, the water in the formulation may be dispersed in a dispersible solvent. The morphology allows for this process to be used to distribute the active substance evenly on the skin. Alternatively, or in addition, the composition may be rubbed through dry hair into the scalp and After this time, any excess or residue is removed from the system. May be rinsed with water with or without shampoo.

[0076] According to a further aspect, there is provided a package containing the compositions described herein. Preferably, the package is a tube or an airless pump. The composition can be applied topically by squeezing.

[0077] According to a further aspect, there is provided a method of preparing a composition for topical application, comprising the steps of: (a) Calcipotriol, α-tocopherol, and butylhydroxyanisole preparing a first polyaphron dispersion comprising: (b) betamethasone dipropionate, preferably α-tocopherol and bromide preparing a second polyaphron dispersion further comprising ethyl hydroxyanisole; and; mixing the first and second polyaphron dispersions together to form a composition; A method is provided, comprising:

[0078] Preferably, the composition produced by the method is a composition as defined above.

[0079] Calcipotriol and betamethasone dipropionate are separated during the manufacturing process. While provided in a polyaphron dispersion, upon mixing, these form two discontinuous phases. It will be appreciated that a single polyaphron dispersion containing calcipotriol is formed. One discontinuous phase containing betamethasone dipropionate, and another discontinuous phase containing betamethasone dipropionate. When the first and second polyaphron dispersions are mixed, the oil phase remains separate but continuous. Phase intermixing, i.e., the first and second polyaphron dispersions therein. It will be appreciated that there will be one continuous phase in which the discrete oil droplets will be dispersed.

[0080] Preferably, the method includes the steps of preparing a third polyaphron dispersion comprising mineral oil; and and the third polyaphron dispersion is mixed with the first and second polyaphron dispersions to form a composition. Again, this embodiment further includes forming a third polyaphron dispersion. However, when mixing the first and second polyaphron dispersions, three non-contiguous A single polyaphron dispersion containing successive phases is formed: one dispersion containing calcipotriol. A continuous phase, a second discontinuous phase containing betamethasone dipropionate, and a third discontinuous phase containing mineral oil. Therefore, when the first, second, and third polyaphron dispersions are mixed, the oil phase The continuous phases remain separate but intermix, i.e., the first, second, and There is one continuous phase in which the separate oil droplets from the third polyaphron dispersion will be dispersed. It will be understood that this will be

[0081] Preferably, the method further comprises the step of packaging the composition.

[0082] According to a further aspect, there is provided a composition obtainable by a method as defined herein. will be done.

[0083] According to a further aspect, (i) calcipotriol; and / or (ii) Betamethasone dipropionate α-Tocopherol and butyl acrylate in compositions for topical application to stabilize The use of a combination of hydroxyanisole is provided.

[0084] The invention will now be described in relation to the following non-limiting drawings. [Brief explanation of the drawings]

[0085] [Figure 1] 1 illustrates the chemical structure of calcipotriol. [Figure 2] 1 illustrates the chemical structure of betamethasone dipropionate. [Figure 3] Figure 1 shows the variation of the amounts of the main degradation product of calcipotriol (24-epi-calcipotriol, lightly filled circles) and betamethasone dipropionate (betamethasone 21-propionate, darkly filled circles) with pH in a polyaphron composition containing two active substances, measured after 9 months of storage at 5°C. The y-axis shows the level of the degradation product, including the relevant peak, as a percentage of the total amount of active pharmaceutical ingredient from which it is derived, as determined in the HPLC chromatogram. [Figure 4] 1 shows the chemical stability of calcipotriol in polyaphron compositions as determined by the purity method described herein for different combinations of antioxidants. Error bars indicate standard deviation. [Figure 5] Figure 1 shows the cumulative amount of calcipotriol diffused through human skin over a 72-hour period from the three formulations tested in Example 9. The x-axis shows time in hours, and the y-axis shows the average cumulative amount of calcipotriol diffused through the skin in ng / cm2. The darkest circle represents MC01-53, the medium circle represents MC01-42, and the lightest circle represents MC01-54. Error bars indicate the standard error of the mean. [Figure 6] Figure 1 shows the cumulative amount of betamethasone dipropionate diffused through human skin over a 72-hour period from the three formulations tested in Example 9. The x-axis shows time in hours, and the y-axis shows the average cumulative amount of betamethasone dipropionate diffused through the skin in ng / cm2. The darkest circle represents MC01-53, the medium circle represents MC01-42, and the lightest circle represents MC01-54. Error bars indicate standard deviation. [Figure 7]Figure 1 shows the cumulative amount of calcipotriol diffused through human skin over 72 hours from the polyaphron dispersion-containing formulation tested in Example 10. The x-axis shows time in hours, and the y-axis shows the average cumulative amount of calcipotriol diffused through the skin in ng / cm². Small dark triangles represent 7% CCT, large lighter triangles represent IPM only, and squares represent 13% CCT. Error bars indicate standard deviation. [Figure 8] Figure 1 shows the cumulative amount of betamethasone dipropionate diffused through human skin over 72 hours from the polyaphron dispersion-containing formulation tested in Example 10. The x-axis shows time in hours, and the y-axis shows the average cumulative amount of betamethasone dipropionate diffused through the skin in ng / cm². Small dark triangles represent 7% CCT, large lighter triangles represent IPM only, and squares represent 13% CCT. Error bars indicate standard deviation. [Figure 9] 1 shows the cumulative amount of calcipotriol diffused through human skin over 72 hours from a formulation according to the invention (MC01-17, triangles) compared to commercially available Dovobet® ointment (diamonds). The x-axis shows time in hours, and the y-axis shows the average cumulative amount of calcipotriol diffused through the skin in ng / cm. Error bars indicate standard deviation. [Figure 10] Figure 1 shows the cumulative amount of betamethasone dipropionate diffused through human skin over 72 hours from a formulation according to the invention (MC01-17, triangles) compared to commercially available Dovobet® ointment (diamonds). The x-axis shows time in hours, and the y-axis shows the average cumulative amount of betamethasone dipropionate diffused through the skin in ng / cm². Error bars indicate standard deviation. [Example]

[0086] The invention will now be described with reference to the following non-limiting examples.

[0087] [Example 1] A composition according to the present invention was prepared by combining the following ingredients:

[0088] [Table 1-1]

[0089] [Table 1-2]

[0090] Polyaphron subcomponent A was first mixed with the oil phase components at 40°C until completely dissolved. The aqueous phase ingredients were also mixed appropriately until completely dissolved. The oil phase was then slowly added to the water phase with continuous moderate stirring. After the oil was completely added, the dispersion was mixed for an additional 30 minutes. Polyaphron subcomponents B and C were prepared by mixing the buffer phase D in a separate vessel. In another suitable vessel, the gel phase (E) was mixed vigorously until it was completely dispersed and hydrated. The solution was made by adding carbomer to water until the solution became thick.

[0091] Then, the polyaphron subcomponents (A, B, and C) were mixed together in a vessel with moderate mixing. The final formulation was prepared by mixing the above ingredients together. Then, the gel phase (E) was added to the mixture. After stirring and mixing, the buffer phase (D) and additional isopropanol (F) were added. Then, adjust the pH to 7.75 using the required amount of 50% by weight aqueous triethanolamine solution. After that, water was added to adjust the formulation to 100% by weight. It was made with

[0092] [Example 2] A further composition according to the present invention was prepared by combining the following ingredients:

[0093] [Table 2-1]

[0094] [Table 2-2]

[0095] The ingredients were combined as in Example 1.

[0096] [Example 3] A composition according to the present invention was prepared by combining the following ingredients:

[0097] [Table 3-1]

[0098] [Table 3-2]

[0099] The ingredients were combined as in Example 1.

[0100] [Example 4] A composition according to the present invention was prepared by combining the following ingredients:

[0101] [Table 4-1]

[0102] [Table 4-2]

[0103] The ingredients were combined as in Example 1.

[0104] [Example 5] A composition according to the present invention (MC01-42) was prepared by combining the following ingredients: did:

[0105] [Table 5-1]

[0106] [Table 5-2]

[0107] The ingredients were combined as in Example 1.

[0108] [Example 6] A further composition according to the invention (MC01-17) was prepared by combining the following ingredients: Prepared by:

[0109] [Table 6-1]

[0110] [Table 6-2]

[0111] Polyaphron subcomponent A was first mixed with the oil phase components at 40°C until completely dissolved. The aqueous phase ingredients were also mixed in the appropriate amount until completely dissolved and then allowed to cool. The oil phase was then slowly added to the water phase with continuous moderate stirring. After the oil was completely added, the dispersion was mixed for an additional 30 minutes. Polyaphron subcomponents B and C were prepared by mixing the buffer phase D in a separate vessel. In a separate suitable vessel, add Gel Phase E with vigorous mixing until completely dispersed and hydrated. It was made by adding carbomer to bulk water, followed by isopropanol. Then, sufficient triethanolamine (50% by weight in water) was added to adjust the pH to 7.0. Water was then added to bring the sub-ingredients to the desired weight.

[0112] Then, the polyaphron subcomponents (A, B, and C) were mixed together to form a gel phase ( The final formulation was made by mixing the soluble fiber with the soluble fiber (E). After this, the buffer phase (D) was added. Then, the required amount of 50% by weight aqueous triethanolamine solution was used to adjust the pH to 7.75. After adjusting the weight of the mixture to 100% by weight, water was added to the mixture. It was made on a g scale.

[0113] [Example 7] A variation of MC01-17 was prepared in a manner similar to that of Example 6. The formulation was: Except that different amounts of TEA were included in component F to achieve different formulation pH values. In particular, the pH values ​​of 7, 7.25, 7.5, 7.75, and 8.0 were identical. The formulations were prepared.

[0114] Samples were stored at 5°C for 9 months in sealed amber glass bottles with less than 5% headspace. The bottle was sealed in air. Purity (area %) values ​​were calculated based on the API peaks present in the analysis. The results were calculated from the HPLC trace as a ratio of the other API-related peaks present. Shown in Figure 3.

[0115] As shown in Figure 3, the main calcipotriol degradation product (24-epicalcipotriol) The levels of the major BDP degradation product (betamethasone) decreased with increasing pH. It can be seen that the amount of calcium phosphate (calciferol 21-propionate) increases with increasing pH. It was found that the decomposition of triols increased significantly at pH values ​​below 7.25. A pH range of 7.75±0.5, preferably 7.75±0.25 is preferred.

[0116] [Example 8] A selection of six formulations, including a control, were tested using different single antioxidants and their combinations. The samples were stored in sealed amber glass bottles with a head gap of less than 5% for 6 months. Stored at 0° C. The bottle was sealed but not sparged with nitrogen before sealing.

[0117] The antioxidants were evenly separated between the two API oil phases. Copherol, butylhydroxyanisole (BHA), butylhydroxytoluene (B HT), edetate disodium (EDTA), and citric acid. The level used for HT was 0.1%. EDTA was used at 0.05% and citric acid was used at 0.05%. The acid was used at 0.1%.

[0118] [Table 7]

[0119] MC01-42 is described in Example 5. The remaining formulations in the table were identical except for the antioxidant selection. It is identical to MC01-42 and is shown above.

[0120] Samples were monitored and tested at intervals for pH and API purity. The purity of lucipotriol was determined using the following method:

[0121] Chromatography conditions

[0122] [Table 8]

[0123] Sample preparation Acetonitrile is used as the sample diluent.

[0124] procedure: 1. Add 0.5g (±0.025g) of sample to a 10ml volumetric flask. Accurately weigh while minimizing sample from the neck. 2. Add approximately 5 mL of sample diluent to the volumetric flask and vortex mix for 2 minutes. do. 3. Equilibrate to room temperature. 4. Add the sample diluent to the volumetric flask, add a magnetic stir bar, and stir for 2 hours. Stir. 5. Transfer the solution to a 20 mL volumetric flask, rinse with heptane, and dilute to the required volume. To do so. 6. Shake for 1 minute and stir for 5 minutes. 7. Transfer an aliquot of the lower layer to a 2 ml centrifuge tube and centrifuge for 10 minutes at 13,000 rpm (16 Centrifuge at 1000 x g force (0.60 g force).

[0125] Standard Preparation Prepare a solution of calcipotriol in acetonitrile at a concentration of 2.5 μg / mL . 1. Accurately weigh 25 mg of calcipotriole into a 250 mL volumetric flask. Prepare a calcipotriol stock solution of calcipotriol standard and make up to volume with diluent. 2. Pipette 5.0 mL of the stock solution into a 20 mL volumetric flask. An intermediate solution is prepared and made up to volume with diluent. 3. Pipet 1.0 mL of the intermediate calcipotriol solution into a 10 mL volumetric flask. Prepare the final standard solution by mixing and bringing to volume with diluent.

[0126] Suitable equivalent preparations may also be used.

[0127] analysis Approximate retention time: Pre-calcipotriol 15.9 minutes trans-calcipotriol (Imp C) 16.1 min Calcipotriol 16.7 minutes 24-epi calcipotriol (Imp D) 17.2 minutes

[0128] The percentage peak purity of calcipotriol is calculated using the following formula:

[0129]

number

[0130] NOTE: For analytical calculations, a response factor of 1.9 was used for the pre-calcipotriol peak Applies to area.

[0131] BDP purity was determined using the following method:

[0132] Chromatography conditions

[0133] [Table 9]

[0134] mobile phase Mobile phase A: Rinse the bottle with acetonitrile, then add water. Use an amber bottle. It is recommended that the water be changed every 5 days to reduce bacterial growth.

[0135] Mobile phase B: Methanol and acetonitrile mixed in a 40 / 60% ratio for 10 min Sonicate. Stable for 30 days when stored at ambient temperature.

[0136] Sample preparation Acetonitrile is used as the sample diluent. Prepare in an amber glass container and rinse immediately before use. Rinse with acetonitrile. Samples are stable at ambient conditions for 4 days.

[0137] procedure: 1. Add 1.25g of sample to a 25ml volumetric flask. Accurately weigh while minimizing 2. Add approximately 10 mL of sample diluent and vortex mix for 1 minute. 3. Sonicate for 5 minutes. 4. Allow to cool to ambient temperature and make up to volume with diluent. 5. Add a magnetic stir bar and stir for 2 hours. 6. Leave to stand for 15 minutes. 7. Centrifuge at 13,000 rpm for 10 minutes. Prepare the roux. 8. Transfer the solution to a syringe, discard the first 1 mL, and fill with a 0.2 μm PTFE syringe. Filter through a difilter.

[0138] Standard Preparation Acetonitrile is used as the sample diluent. Prepare in an amber glass container and rinse immediately before use. Rinse with acetonitrile. Samples are stable for 15 days when stored at ambient temperature.

[0139] Prepare a solution of BDP in acetonitrile in duplicate at a concentration of 32 μg / mL.

[0140] Example steps: 1. Add exactly 25.0 mg (± 2 mg) of BDP reference material to a 25 mL flask. Weigh out, dissolve and dilute to the required volume with acetonitrile (100 μg / mL stock solution). To do so. 2. Pipette 0.8 ml of stock solution into a 25 ml volumetric flask and add diluent (32 Dilute to the desired volume with a standard diluted solution of 1 μg / mL. 3. Pipette 1.0 mL of stock solution into a 100 mL volumetric flask and add diluent (0 Bring to volume with 0.32 μg / mL stock sensitivity solution Dilute to give a final concentration. 4. Pipet 1.0 mL of stock sensitivity solution into a 10 mL volumetric flask and dilute Dilute to the required volume with diluent (0.032 μg / mL working solution, LOQ). do. 5. Pipette 1.0 mL of the stock sensitivity solution into a 20 mL volumetric flask and dilute Dilute to the required volume with diluent (0.016 μg / mL working solution, LOD). do.

[0141] analysis Relative Retention Time (RRT) and Relative Response Factor (RRF): RRT RRF Betamethasone 17-propionate (Impurity B) 0.65 1.03 E isomer of 21-aldehyde enol (impurity E) 0.76 1.05 Betamethasone 21-propionate (Impurity C) 0.79 1.14 Betamethasone 21-acetate 17-propionate (Impurity D): 0.95 0.98 BHA1 (unreported) 0.63 BHA2 (unreported) 0.65 trans-calcipotriol (unreported) 1.03 Calcipotriol (unreported) 1.05

[0142] The BDP retention time is approximately 18 minutes.

[0143] Calculation: Avoid integration of 0-5 minutes and 25-35 minutes. The peak due to lucipotriol was ignored.

[0144] Calculate the % w / w of BDP and impurities using the following formula:

[0145]

number

[0146] The RRF of any unknown peak is assumed to be 1.0.

[0147] The results for betamethasone dipropionate are shown in the table on the next page.

[0148] [Table 10]

[0149] Significant trends or changes in BDP purity that could not be explained by small changes in pH There is no difference.

[0150] The results for calcipotriol are shown in the table below and in FIG.

[0151] [Table 11]

[0152] The combination of BHA and α-tocopherol significantly improved calcipotriol stability In contrast, BHA alone, BHT alone, and α-tocopherol BHT alone and in combination with α-tocopherol were associated with a decrease in calcipotriol It was found to have a similar effect on qualitative.

[0153] [Example 9] Diffusion experiments were performed to assess the amount of calcipotriol and BDP diffused through human skin. This study investigated the effect of isopropanol (IPA) levels on the solubility of ethanol.

[0154] Three formulations were investigated as summarized in the table on the next page.

[0155] [Table 12]

[0156] MC01-42 is described in Example 5. The remaining formulations in the table were IP administered as indicated above. It is identical to MC01-42 except for the A level.

[0157] Skin diffusion studies were conducted over a 72-hour period. Nine samples were used for each of the three formulations. Fill the cell with receptor phase (70% phosphate buffer, 30% isopropyl alcohol). The receptor phase was performed for 16 hours, 24 hours, 40 hours, 48 ​​hours, and All samples were collected at 64 and 72 hours. The standard was a PTFE filter (13 mm diameter, 0.45 μm pore size, hydrophilic PTFE Filtration through a filter (Millipore, UK) to remove paper fibers and other particles from the sample. did.

[0158] A Waters H-class UPLC system was used for HPLC analysis. The system was equipped with a VanGuard pre-column filter (Waters, UK). H C18 50 x 2.1 mm (1.7 μm particle size (Waters, UK)). The column was maintained at 40°C throughout. Samples were kept at ambient temperature between analytical runs. It is not recommended to chill the samples between runs because buffer salts will precipitate from the receptor phase matrix. It wasn't recommended.

[0159] An isocratic HPLC method was used. 35 / 45 / 20 v / v / v water / acetonitrile / methanone The ethanol mobile phase was pumped at 0.5 ml / min. An injection volume of 10 μl was used for the total The assay was performed over a 30-minute period. Detection was performed using a UV-vis photodiode array detector. Chromatograms were extracted at 240 nm (BDP) and 263 nm (calcipotriol). A run time of 3 minutes was used. 0.9 minutes (BDP) and 1.3 minutes (Calcipotri) The retention time of the (all) was observed.

[0160] The cumulative amounts of the two active substances determined at each time point are summarized in the table below.

[0161] Cumulative amount of diffused calcipotriol through human skin.

[0162] [Table 13]

[0163] Cumulative amount diffused, BDP through human skin.

[0164] [Table 14]

[0165] The results are illustrated in FIGS.

[0166] For both betamethasone dipropionate and calcipotriol, the incidence was 5.7%. When isopropanol was included, the cumulative 72-hour The spread was significantly higher.

[0167] [Example 10] Two variations of MC01-17 (see Example 6) were prepared: Component A and A portion of the IPM from each of A and B was replaced with CCT (total CCT content was 13%), and CCT completely replaced by IPM. MC01-17 itself However, they contained a total of 7% CCT.

[0168] Human skin diffusion of each of the three formulations was measured using the same method as in Example 9. / cm 2 The average cumulative fluxes of calcipotriol and BDP are shown in Figures 7 and 8, respectively. and Figure 8 at various time points.

[0169] As can be seen from Figures 7 and 8, 7% CCT level was significantly associated with calcipotriol (p= 0.0015) and BDP (p=0.0162) for both solvent-free IPM (0% CCT) or 13% CCT (ANOVA) The addition of IPM, a known permeation enhancer, seemed to be more beneficial, but The surprising result is that more does not necessarily seem to be better in this case. It is something that should be done.

[0170] Further experiments were carried out, in which MC01-17 was used in the same skin diffusion test described above. and compared with commercially available Dovobet® ointment. 2 , Calcipot The average cumulative fluxes of riol and BDP at various time points are shown in Figs. 9 and 10, respectively. As can be seen from Figures 9 and 10, both calcipotriol and BDP Skin penetration was surprisingly higher for MC01-17 than for Dovobet®. good.

[0171] The foregoing detailed description has been provided by way of illustration and example, and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to those skilled in the art and are within the scope of the appended claims and their equivalents. The present invention may include the following aspects. [1] 1. A composition for topical application comprising a polyaphron dispersion, said polyaphron dispersion comprising a continuous aqueous phase and at least one discontinuous oil phase; the polyaphron dispersion comprises calcipotriol, betamethasone dipropionate, α-tocopherol, and butylhydroxyanisole; The composition has a pH of 7.75±0.5. [2] 10. The composition of claim 1 having a pH of 7.75±0.25. [3] by weight of the composition, 0.001-0.01 wt% calcipotriol, and / or 0.02-0.1 wt% betamethasone, and / or 0.001-0.005 wt% α-tocopherol, and / or 0.05-0.5 wt% butylhydroxyanisole 10. The composition of claim 1, comprising: [4] the calcipotriol is predominantly present in at least one of the discontinuous oil phases; and / or the betamethasone dipropionate is predominantly present in at least one of the discontinuous oil phases; and / or the α-tocopherol is predominantly present in at least one of the discontinuous oil phases; and / or 4. The composition of claim 1, wherein the butylhydroxyanisole is predominantly present in at least one of the discontinuous oil phases. [5] 5. The composition of claim 1, wherein at least one of the discontinuous oil phases comprises a medium chain triglyceride and isopropyl myristate, and wherein the isopropyl myristate and medium chain triglyceride are present in a weight ratio of from 3:1 to 12:1. [6] 6. The composition of any one of claims 1 to 5, wherein the polyaphron dispersion further comprises a discontinuous phase comprising a non-solvent oil, preferably wherein the non-solvent oil is a mineral oil. [7] the discontinuous oil phase comprises a first discontinuous phase, a second discontinuous phase, and optionally a third discontinuous phase comprising mineral oil; the calcipotriol is predominantly present in the first discontinuous phase; the betamethasone dipropionate is predominantly present in the second discontinuous phase; 7. The composition of claim 1, wherein the α-tocopherol and the butylhydroxyanisole are present predominantly in the first discontinuous phase or are present predominantly in the first and second discontinuous phases together. [8] each of the first discontinuous phases comprises a pharmaceutically acceptable oil; the pharmaceutically acceptable oil is a blend of caprylic capric triglyceride (CCT) and isopropyl myristate; 8. The composition of claim 7, wherein the isopropyl myristate and caprylic capric triglyceride are present in a weight ratio of 3:1 to 12:1. [9] 9. The composition of claim 1, wherein the continuous aqueous phase comprises at least 4 wt. % isopropanol, based on the weight of the composition.

[10] Chemically stable at 25°C ± 2°C for at least six months, measured at 60% RH ± 5%, and / or 10. The composition of any one of claims 1 to 9, which is chemically stable at 5°C ± 3°C for at least 12 months, measured at 60% RH ± 5%.

[11] 1. A composition for topical application comprising a polyaphron dispersion, said polyaphron dispersion comprising a continuous aqueous phase and at least one discontinuous oil phase; the polyaphron dispersion comprises calcipotriol, betamethasone dipropionate, α-tocopherol, and butylhydroxyanisole; at least one of the discontinuous oil phases comprises a medium chain triglyceride and isopropyl myristate; The composition, wherein the isopropyl myristate and medium chain triglyceride are present in a weight ratio of 3:1 to 12:1.

[12] 1. A composition for topical application comprising a polyaphron dispersion, said polyaphron dispersion comprising: (i) calcipotriol, (ii) betamethasone or its esters; (iii) α-tocopherol, and (iv) Butylhydroxyanisole A composition comprising:

[13] 13. A composition according to any one of claims 1 to 12 for use in a method of treating the human or animal body by therapy.

[14] A composition according to any one of claims 1 to 12 for use in the treatment of psoriasis. 1. A method of preparing a composition for topical application, comprising: (a) preparing a first polyaphron dispersion comprising calcipotriol, α-tocopherol, and butylhydroxyanisole; (b) preparing a second polyaphron dispersion comprising betamethasone dipropionate, and preferably further comprising α-tocopherol and butylhydroxyanisole; mixing said first polyaphron dispersion and said second polyaphron dispersion together to form said composition; A method comprising:

[16] preparing a third polyaphron dispersion comprising a non-solvent oil, preferably wherein the non-solvent oil is a mineral oil; mixing said third polyaphron dispersion with said first polyaphron dispersion and said second polyaphron dispersion to form said composition; 16. The method of claim 15, further comprising:

[17] A composition obtainable by the method of claim 15 or claim 16.

[18] (iii) calcipotriol, and / or (iv) Betamethasone dipropionate 2. Use of a combination of alpha-tocopherol and butylhydroxyanisole in a composition for topical application to stabilize

Claims

1. 1. A composition for topical application comprising a polyaphron dispersion, said polyaphron dispersion comprising a continuous aqueous phase and at least one discontinuous oil phase; the polyaphron dispersion comprises calcipotriol and betamethasone dipropionate; at least one of the discontinuous oil phases comprises caprylic capric triglyceride and isopropyl myristate; The composition, wherein said isopropyl myristate and caprylic capric triglyceride are present in a weight ratio of from 4:1 to 8:

1.

2. The composition of claim 1 further comprising α-tocopherol.

3. 10. The composition of claim 1 further comprising butylated hydroxyanisole.

4. The composition of any one of claims 1 to 3, wherein the composition has a pH of 7.75±0.

5.

5. 5. The composition of claim 4, wherein the composition has a pH of 7.75±0.

25.

6. by weight of the composition, 0.001 to 0.01 wt % calcipotriol, and / or 0.02 to 0.1 wt% betamethasone The composition of any one of claims 1 to 5, comprising:

7. by weight of the composition, 0.001 to 0.005 wt % α-tocopherol, or 0.05 to 0.5 wt% butylhydroxyanisole The composition according to any one of claims 2 to 6, comprising:

8. the calcipotriol is predominantly present in at least one of the discontinuous oil phases; and / or 8. The composition of any one of claims 1 to 7, wherein the betamethasone dipropionate is predominantly present in at least one of the discontinuous oil phases.

9. the α-tocopherol is predominantly present in at least one of the discontinuous oil phases; or 9. The composition of any one of claims 2 to 8, wherein the butylated hydroxyanisole is predominantly present in at least one of the discontinuous oil phases.

10. A composition according to any one of claims 1 to 9, wherein the polyaphron dispersion further comprises a discontinuous phase comprising a non-solvent oil, preferably wherein the non-solvent oil is a mineral oil.

11. the discontinuous oil phase comprises a first discontinuous phase, a second discontinuous phase, and optionally a third discontinuous phase comprising mineral oil; the calcipotriol is predominantly present in the first discontinuous phase; the betamethasone dipropionate is predominantly present in the second discontinuous phase; 11. The composition of any one of claims 2 to 10, wherein the α-tocopherol or the butylhydroxyanisole is predominantly present in the first discontinuous phase or predominantly present in the first discontinuous phase and the second discontinuous phase together.

12. the first discontinuous phase and the second discontinuous phase each comprise a blend of caprylic capric triglyceride (CCT) and isopropyl myristate; 12. The composition of claim 11, wherein the isopropyl myristate and caprylic capric triglyceride are present in a weight ratio of from 4:1 to 8:

1.

13. The composition of any one of claims 1 to 12, wherein the continuous aqueous phase comprises at least 4 wt% isopropanol, based on the weight of the composition.

14. chemically stable at 25°C ± 2°C for at least 6 months, measured at 60% RH ± 5%, and / or 14. The composition of any one of claims 1 to 13, which is chemically stable at 5°C ± 3°C for at least 12 months, measured at 60% RH ± 5%.

15. A composition according to any one of claims 1 to 14 for use in a method of treating the human or animal body by therapy.

16. A composition according to any one of claims 1 to 14 for use in the treatment of psoriasis.

17. A method for producing a composition according to any one of claims 1 to 14, said method comprising: (a) preparing a first polyaphron dispersion containing calcipotriol; (b) preparing a second polyaphron dispersion comprising betamethasone dipropionate; mixing said first polyaphron dispersion and said second polyaphron dispersion together to form said composition; A method comprising:

18. the first polyaphron dispersion further comprises α-tocopherol, or butylhydroxyanisole; and / or 18. The method of claim 17, wherein the second polyaphron dispersion further comprises α-tocopherol or butylhydroxyanisole.

19. preparing a third polyaphron dispersion comprising a non-solvent oil, preferably wherein the non-solvent oil is a mineral oil; mixing said third polyaphron dispersion with said first polyaphron dispersion and said second polyaphron dispersion to form said composition; 19. The method of claim 17 or 18, further comprising:

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