WO2016182258A2 - 안정성과 피부투과율이 향상된 약학 조성물 - Google Patents

안정성과 피부투과율이 향상된 약학 조성물 Download PDF

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WO2016182258A2
WO2016182258A2 PCT/KR2016/004688 KR2016004688W WO2016182258A2 WO 2016182258 A2 WO2016182258 A2 WO 2016182258A2 KR 2016004688 W KR2016004688 W KR 2016004688W WO 2016182258 A2 WO2016182258 A2 WO 2016182258A2
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vitamin
pharmaceutical composition
calcipotriol
dihydroxy
pregna
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PCT/KR2016/004688
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English (en)
French (fr)
Korean (ko)
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WO2016182258A3 (ko
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김윤식
추의진
황규현
임유진
이환혁
최성훈
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(주)동구바이오제약
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Priority to JP2018510690A priority Critical patent/JP2018516276A/ja
Publication of WO2016182258A2 publication Critical patent/WO2016182258A2/ko
Publication of WO2016182258A3 publication Critical patent/WO2016182258A3/ko
Priority to PH12017501708A priority patent/PH12017501708A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems

Definitions

  • the present invention in the pharmaceutical composition containing one or more vitamin D or vitamin D analogues and one or more corticosteroids as an effective drug for treating skin diseases such as psoriasis, shows a marked difference in solubility for the two types of effective drugs
  • the present invention relates to a pharmaceutical composition for treating skin diseases, by using a non-aqueous solvent to block the reaction between the effective drugs, thereby improving the stability and skin permeability of the pharmacologically active ingredient.
  • Psoriasis is a chronic inflammatory dermatitis that is covered with silver-white scales, reddish papules or platy-shaped rashes with clear and varying size, which are repeated on the skin of the whole body. It is characterized by a frequency of 1 to 2% of the population.
  • Psoriasis is a chronic skin disease in which a small millet-like rash develops on the skin, with layers of dead skin, such as white dandruff, on top of the rash. These milly rashes spread around as they clump together or grow with new rashes that occur around them.
  • psoriasis if the symptoms of psoriasis spread a lot, almost all the skin of the whole body may be covered with a rash. Through this process, psoriasis is chronically progressed, and sometimes it may get better by itself, or it may spread to the whole body. Itching from psoriasis is often not as severe as other skin diseases, such as eczema.
  • psoriasis is most common in the knees and elbows, followed by hips and head skin. These areas of skin are also the first sites of psoriasis. It then develops on the arms, legs, and other parts of the body, followed by hands, feet, and so on.
  • Psoriasis is a representative disease of chronic skin disease, and most of the psoriasis can repeat its deterioration and improvement over a long period of time. Psoriasis occurs mainly at the age of about 20 years old. The development of psoriasis usually occurs first in late autumn or winter, with mild psoriasis symptoms worsening significantly. Symptoms of psoriasis can improve with sun exposure, and are often exacerbated by stress.
  • the choice of treatment depends on the severity, activity of the psoriasis, the type and condition of the lesion, and the site of occurrence. The age, accessibility and mental state of the patient are also important. If the symptoms of psoriasis are mild, the treatment is usually started with a topical medication. If the condition is moderate or severe, phototherapy or medicine is used.
  • combination therapies are used that combine two or more different pharmacologically active compounds.
  • vitamin D analogs alleviate the symptoms of psoriasis by inhibiting proliferation and promoting differentiation of keratinocytes.
  • steroids have the effect of temporarily improving psoriasis by calming inflammation and itching of the skin.
  • topical treatment of psoriasis includes a single dosage form containing a steroid compound such as a corticosteroid compound and a vitamin D analogue such as calcipotriol, or a therapeutic method in which each active ingredient is formulated as a separate independent agent. Commonly used.
  • Daibobet® ointment and Xamiol® gel are heterogeneous pharmaceutical formulations of ointments or gel formulations containing both vitamin D or vitamin D analogues and topical steroids. It is known to be an immiscible mixture.
  • the vitamin D or vitamin D analogue is only 0.005% by weight, if it is not completely dissolved in the solvent, a nonuniformity of content may occur.
  • the stability of the pharmaceutical composition may be lowered. Differences in skin transmittance may occur depending on the type of solvent and the blending ratio.
  • the present inventors have overcome many of the problems of the prior art to improve the long-term storage stability of the pharmaceutical composition and, at the same time, to prepare a new pharmaceutical composition, which greatly improves skin permeability, as a solvent for vitamin D analogs.
  • a combination composition containing vitamin D analogs and topical steroids using one or more solvents selected from linear C 12-16 alkanols and squalanes not only the skin permeability is markedly improved,
  • the present invention has been completed by discovering that the storage stability of the pharmaceutical composition can be greatly improved by inhibiting the reaction between the D analog and the steroid compound as much as possible.
  • An object of the present invention is to improve the skin permeability of a two- or multi-component topical skin pharmaceutical composition for the treatment of other inflammatory skin diseases, including psoriasis and nail disease, to increase the rate of treatment, and to exhibit uniform applicability of the drug. In order to ensure the storage stability of the pharmaceutical composition.
  • Another object of the present invention to solve the problem that occurs when mixing one or more vitamin D or vitamin D analogues and one or more corticosteroids, the difference in the solubility of the vitamin D or vitamin D analogues and corticosteroids
  • one or more solvents selected from linear C 12-16 alkanols and squalanes which represent relatively large amounts, at least one vitamin D or vitamin D analogue and one or more corticosteroids are prevented from contacting each other. It is to provide a pharmaceutical composition for treating psoriasis, which can secure the storage stability of the pharmaceutical composition while increasing the skin transmittance.
  • Still another object of the present invention is to prepare a pharmaceutical composition for treating psoriasis comprising the steps of 1) dispersing one or more components selected from corticosteroids or salts or esters thereof in soft paraffin; 2) dissolving by adding one or more components selected from vitamin D or vitamin D analogs to any one or more solvents selected from linear C 12-16 alkanols and squalanes; 3) adding the dispersion obtained in step 1) to the solution of step 2); It is to provide a method for preparing a pharmaceutical composition for treating psoriasis.
  • the present invention relates to a pharmaceutical composition for treating psoriasis comprising at least one vitamin D or vitamin D analogue and at least one corticosteroid, wherein the linear C 12-16 alkanol exhibiting different solubility for two types of effective drugs or By using squalane as a solvent, it is characterized by blocking the possibility of chemical reaction of two types of effective drugs to improve the storage stability of the pharmaceutical composition while greatly increasing the skin permeability of the effective drugs.
  • an object of the present invention in order to solve the problem that degeneration occurs due to the reaction between the effective drugs, when mixing one or more vitamin D or vitamin D analogues and one or more corticosteroids,
  • the two components of vitamin D or vitamin D analogues and corticosteroids are prevented from dissolving in the same phase, It is achieved by providing a pharmaceutical composition for treating psoriasis that can prevent the reaction by contact as much as possible, while increasing the skin permeability of the effective drug, while ensuring the storage stability of the pharmaceutical composition.
  • Solubility parameter is a numerical value representing the dissolution characteristics of a substance which is a measure of the dissolution between two compounds.
  • the molecular cohesion energy of the liquid is E and the molecular volume is V.
  • the heat of mixing ⁇ H M of two liquids is approximately given by ⁇ H M ( ⁇ 1 V 1 + ⁇ 2 V 2 ) ( ⁇ 1 - ⁇ 2 ) 2 ⁇ 1 ⁇ 2 .
  • thermodynamic properties of the solution depend on the difference in ⁇ values.
  • the mixed entropy is a function of molecular weight and concentration only and does not change very much depending on the material, so the value of ⁇ dominates the thermodynamic properties of the solution.
  • solubility coefficient shows a similarity to the solubility of the solvent.
  • the stronger the polarity of the solvent the larger the solubility coefficient value.
  • Still another object of the present invention is to provide a method comprising the steps of: 1) dispersing one or more components selected from corticosteroids or salts or esters thereof in soft paraffin; 2) dissolving by adding a solution of one or more components selected from vitamin D or vitamin D analogs to one or more solvents selected from linear C 12-16 alkanols and squalane; 3) adding the dispersion obtained in step 1) to the solution obtained in step 2) is achieved by providing a method for producing a pharmaceutical composition for treating psoriasis.
  • An object of the present invention is to improve the skin permeability of two or multi-component drugs for the treatment of other inflammatory skin diseases, including psoriasis and nail disease, to speed up the treatment, to have a uniform applicability of the drug, long-term storage of the pharmaceutical composition It is providing the pharmaceutical composition for psoriasis treatment which ensures stability.
  • the pharmaceutical composition of the present invention substantially improves the quality of life of non-compliant psoriasis patients with more severe, younger, younger and younger manifested severity of psoriasis than many psoriasis patients, particularly compliant psoriasis patients.
  • the present invention prevents a weakening of the composition due to the interaction between two or more effective drugs that are effective in the treatment of psoriasis, and makes it possible to provide a stable formulation with greatly improved long-term storage stability. As to enable safe distribution, it can be usefully applied to the industry.
  • Figure 2 is a result of observing the presence or absence of phase separation of the formulation of Comparative Examples and Examples in a container, stored for 1 week at 40 °C, 75% relative humidity (RH) conditions.
  • Figure 3 is a calcipotriol skin permeation HPLC HPLC data of Comparative Examples and Examples.
  • One or more active ingredients selected from vitamin D or vitamin D analogues, one or more active ingredients selected from corticosteroids or salts or esters thereof, selected from linear C 12-16 alkanols and squalanes It provides a pharmaceutical composition for treating psoriasis comprising one or more solvents.
  • a formulation containing at least one vitamin D or vitamin D analog and at least one corticosteroid In order to improve the stability of a formulation containing at least one vitamin D or vitamin D analog and at least one corticosteroid.
  • the linear C 12-16 alkanol, which selectively dissolves only vitamin D or vitamin D analogs, is used as a solvent, and the corticosteroid is dispersed in soft paraffin to prepare a dispersion, and then the solution and the dispersion are mixed with each other.
  • a pharmaceutical composition for treating psoriasis wherein a solution of D or a vitamin D analog can be applied simultaneously to two affected areas at a time without reducing the efficacy of the active ingredients without reacting to corticosteroids.
  • the corticosteroid component is vitamin D due to its low solubility in the linear C 12-16 alkanol solvent. It cannot react with the analog component and is dispersed only in the paraffin component system, thereby enabling the effect of the active drug to be exerted. Since the vitamin D or vitamin D analog is dissolved in a non-aqueous solvent, straight-chain C 12-16 alkanol solvent, and does not directly contact betamethasone dispersed in liquid paraffin, the two active ingredients react or influence differently. The likelihood of adverse effects is minimized or eliminated.
  • One or more components selected from the vitamin D or vitamin D analogues of the present invention may be selected from the following: cecalitol, calcipotriol, calcitriol, tacalcitol, maxacalcitol, paricalcitol, palecalcitol, 1,24S -Dihydroxy-vitamin D2, 1 (S), 3 (R) -dihydroxy-20 (R)-[((3- (2-hydroxy-2-propyl) -phenyl) -methoxy)- Methyl] -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene or mixtures thereof.
  • the vitamin D or the vitamin D analogue of the present invention is calcipotriol, calcitriol, tacalcitol, moxacalcitol, 1 (S), 3 (R) -dihydroxy-20 (R)- [((3- (2-hydroxy-2-propyl) -phenyl) -methoxy) -methyl] -9,10-seco-pregna-5 (Z), 7 (E), 10 (19)- Trienes and mixtures thereof.
  • Vitamin D or vitamin D analogs which may be preferably used in the present invention, are as follows well known in the art:
  • One or more components selected from corticosteroids or salts or esters thereof in the present invention are, as is well known in the art, betamethasone (9-fluoro-11,17,21-trihydroxy-16-methyl Legna-1,4-diene-3,20-dione) and esters thereof, alclomethasone and esters thereof, clobetasol and esters thereof, clobetasone and esters thereof, diflucortolone and esters thereof, diflora Hands and esters thereof, fluorinide, flumetasone and esters thereof, fluorcinolone and ethers and esters thereof, fluticasone and esters thereof, fluprednide and esters thereof, halogeninide, hydrocortisone and esters thereof, parent Metason and esters thereof, triamcinolone and ethers and esters thereof and mixtures thereof.
  • betamethasone (9-fluoro-11,17,21-trihydroxy-16-methyl Legna-1,4-diene-3,20-d
  • the one or more components selected from corticosteroids or salts or esters thereof are 17-valerate, 17-propionate, dipropionate, acetonide, acetonide-21-N-benzoyl -2-methyl-alanineate, acetonide-21- (3,3-dimethylbutyrate), and 17-butyrate, and any one or a mixture thereof.
  • linear C 12-16 alkanols and squalane (2,6,10,15,19,23-Hexamethyltetracosane) solvents of the present invention the most preferred solvent is linear cetanol.
  • Cetanol (CH 3 (CH 2 ) 15 OH) a characteristic solvent of the present invention, is a compound having a density of 811.00 kg / m 3, a melting point of 49 ° C., a boiling point of 344 ° C., and a molar mass of 242.44 g / mol. Unlike solvents, it is a linear higher alcohol.
  • Squalane (2,6,10,15,19,23-Hexamethyltetracosane), which is a characteristic solvent of the present invention, is obtained by hydrogenation of squalene.
  • non-aqueous pharmaceutical composition of the present invention can be incorporated into soft paraffin (also known as petrolatum) or liquid paraffin oil or microcrystalline wax, as the components are ointments or lotion based excipients well known in the art. It can manufacture.
  • soft paraffin also known as petrolatum
  • liquid paraffin oil or microcrystalline wax as the components are ointments or lotion based excipients well known in the art. It can manufacture.
  • a solution of a vitamin D analog (typically 0.0005 to 2.5% by weight) is added to a linear C 12-16 alkanol solvent or squalane, followed by a paraffin oil typically having a particle size of 0.1 to 20 ⁇ m.
  • the pharmaceutical composition of the present invention is prepared by adding a corticosteroid component dispersion dispersed in the air and then cooling the mixture.
  • Typical contents of the various components in the composition completed according to the present invention are 0.005 to 2.0% by weight of the active component of corticosteroids, 0.0001 to 0.2% by weight of the active ingredient of the vitamin D analog, and 0.1 to 40% by weight of the solvent component. And the remainder are typically primarily excipients such as the soft paraffin and / or paraffin oil mentioned above.
  • composition of the present invention may further comprise another additive commonly used, such as antioxidants (eg tocopherol).
  • antioxidants eg tocopherol
  • the present invention may be provided as an ointment, cream, lotion, gel, preferably scalp gel, scalp lotion, liniment. More preferably, topical pharmaceutical compositions in the form of other applicable liquid or semi-liquid formulations, or oil-in-water or water-in-oil emulsions, which are non-aqueous may be provided. Most preferably, the compositions of the present invention are two phase compositions, such as ointments and gels.
  • a method of treating such a disease including topically administering a composition of the present invention to a patient in need thereof.
  • Such method preferably comprises topically administering a medically sufficient dose of the composition once or twice a day.
  • composition according to the invention preferably comprises 0.001 to 0.5 mg / g or ml of vitamin D or vitamin D analogue component, more preferably 0.001 to 0.25 mg / g or ml and 0.05 to 2 mg / of corticosteroid component. g or ml.
  • Comparative Example 2 Simple Mixed Ointment Using Soft Paraffin as Solvent or Dispersion Medium
  • Tocopherol, calcipotriol hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of its dipropionate) were stirred in 999.3048g of liquid paraffin.
  • Comparative Example 4 Ointment comprising calcipotriol, betamethasone, liquid paraffin and butylene glycol
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol and butylene glycol were heated to 70 ° C., and then calcipotriol hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) were stirred for 10 minutes. After dissolution, the solution was slowly added to Solution 1, followed by stirring to cool to 30 ° C or lower.
  • Comparative Example 5 Gel comprising calcipotriol, betamethasone, liquid paraffin, and butylene glycol
  • Example 1 Ointment of the Invention Comprising Calcipotriol, Betamethasone, Liquid Paraffin and Cetanol
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol and cetanol were warmed to 70 ° C., and then calcipotriol hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) were stirred for 10 minutes. After dissolution, the solution was slowly added to Solution 1, stirred, and cooled to 30 ° C or lower to fill the tube.
  • Example 2 Gel of the Invention Comprising Calcipotriol, Betamethasone, Liquid Paraffin, and Cetanol
  • Example 3 Ointment of the Invention Comprising Calcipotriol, Betamethasone and Cetanol
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 Separately, after heating cetanol and tocopherol at 70 ° C., 0.0522 g of calcipotriol hydrate (0.05 g of calcipotriol) and betamethasone (0.5 g, 0.643 g in the form of dipropionate thereof) were stirred for 10 minutes and dissolved. The solution was slowly added to Solution 1, stirred and cooled to 30 ° C. or lower to fill the tube.
  • Example 4 Ointment Comprising Calcipotriol, Betamethasone, Liquid Paraffin, Cetanol and PEG400
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, cetanol and PEG400 were heated to 70 ° C., and then calcipotrihydrate hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) for 10 minutes. After stirring to dissolve, the solution was slowly added to Solution 1, stirred, cooled to 30 ° C. or lower, and charged into a tube.
  • Example 4 Calcipotriol Hydrate 0.0522 0.0522 Betamethasonedipropionate 0.643 0.643 Liquid paraffin 10 969.2848 Tocopherol 0.02 0.02 Cetanol 20 20 PEG400 10 10 Soft paraffin 959.2848 0
  • Example 6 Ointment Including Calcipotriol, Betamethasone, Liquid Paraffin, and Squalane
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, and squalane were heated to 70 ° C, and then dissolved by dissolving calcipotrihydrate hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) for 10 minutes. Then, the solution was slowly added to Solution 1, stirred, cooled to 30 ° C or less, and filled into a tube.
  • Example 8 Ointments Including Calcipotriol, Betamethasone, and Squalane
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 The soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • 0.0522 g of calcipotriol hydrate (0.05 g of calcipotriol) and betamethasone (0.5 g, 0.643 g in the form of dipropionate thereof) were stirred for 10 minutes to dissolve the solution. was slowly added to Solution 1, stirred and cooled to 30 ° C. or lower to fill the tube.
  • Example 9 Ointments Including Calcipotriol, Betamethasone, Liquid Paraffin, Squalane, and PEG400
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, squalane, and PEG400 were warmed to 70 ° C., followed by stirring calcipotriol hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) for 10 minutes. After dissolving, the solution was slowly added to Solution 1, stirred, cooled to 30 ° C or less, and filled into a tube.
  • Example 9 Example 10 Calcipotriol Hydrate 0.0522 0.0522 Betamethasonedipropionate 0.643 0.643 Liquid paraffin 10 969.2848 Tocopherol 0.02 0.02 Squalane 20 20 PEG400 10 10 Soft paraffin 959.2848 0
  • Example 11 Ointment Comprising Calcipotriol, Betamethasone, Liquid Paraffin, Cetanol and Squalane
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, cetanol and squalane were warmed to 70 ° C., and then calcipotrihydrate hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) for 10 minutes. After stirring to dissolve, the solution was slowly added to Solution 1, stirred, cooled to 30 ° C. or lower, and charged into a tube.
  • Example 13 Ointment Including Calcipotriol, Betamethasone, Cetanol and Squalane
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • cetanol, tocopherol and squalane are warmed to 70 ° C, and then dissolved by dissolving calcipotrihydrate hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof) for 10 minutes. Subsequently, this solution was slowly added to Solution 1, stirred, cooled to 30 ° C or less, and filled into a tube.
  • Example 14 Ointments Including Calcipotriol, Betamethasone, Liquid Paraffin, Cetanol, Squalane and PEG400
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, cetanol, squalane and PEG400 were warmed to 70 ° C., followed by calcipotriol hydrate 0.0522g (calcipotriol 0.05g) and betamethasone (0.5g, 0.643g in the form of dipropionate thereof). After stirring for a minute to dissolve, the solution was slowly added to Solution 1, stirred, cooled to 30 ° C. or lower, and filled into a tube.
  • the soft paraffin is melted at 80 ° C., then cooled to 70 ° C. and maintained at this temperature (solution 1).
  • solution 1 the liquid paraffin, tocopherol, and cetanol were heated to 70 using the composition ratios of Table 12, followed by 0.0522 g of calcipotriol hydrate (0.05 g of calcipotriol) and betamethasone (0.5 g, 0.643 g in the form of dipropionate thereof). After stirring for 10 minutes to dissolve, this solution was slowly added to Solution 1, stirred, cooled to 30 ° C. or less, and filled into a tube.
  • the formulation of the comparative example showed a change in color due to the interaction of calcipotriol and betamethasone, it was confirmed that the formulation of the example does not show such a change in color at all.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 Example 8
  • Example 9 Example 10 Color change - - - - - - - - - - Sample name
  • Example 11 Example 12
  • Example 13 Example 14
  • Example 15 Example 16
  • Example 17 Example 18 Color change - - - - - - - - - Sample name Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Color change - + + + + - + -: No phase separation +: With phase separation
  • Calcipotriol was dispersed in n-heptane from the preparation and extracted with methanol and 0.01 mol / L ammonium dihydrogen phosphate (70:30) mixed solution and quantified by HPLC.
  • Betamethasonedipropionate was dispersed from the formulation into n-heptane, extracted with acetonitrile 0.05 mol / L phosphoric acid (60:25) mixed solution and quantified by HPLC.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 Example 8
  • Example 9 Example 10
  • Example 10 Early 100.5 99.7 99.9 99.4 98.7 99.1 98.6 100.7 99.0 99.2 2 months later 100.3 99.9 99.1 98.9 99.2 99.7 98.4 100.2 98.2 99.7 content(%)
  • Example 11 Example 12
  • Example 13 Example 14
  • Example 15 Example 16
  • Example 18 Early 100.5 98.7 99.8 100.2 100.0 99.5 99.1 99.9 2 months later 99.9 99.3 98.6 99.7 99.8 99.3 98.9 99.4 content(%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Early 99.7 99.8 100.1 98.9 101.3 99.8 100.3 2 months later 93.5 94.2 93.8 90.9 90.5 97.2 96.8
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 Example 8
  • Example 10 Early 99.3 100.1 98.6 98.9 99.0 99.8 98.5 99.0 99.9 99.4 2 months later 99.5 99.7 98.2 99.5 99.7 100.0 98.3 98.7 99.6 99.8 content(%)
  • Example 11 Example 12
  • Example 13 Example 14
  • Example 15 Example 16
  • Example 18 Early 99.8 99.1 99.6 99.7 99.8 99.0 99.6 100.0 2 months later 100.2 98.7 99.2 99.0 99.5 99.2 99.1 99.7 content(%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Early 98.1 99.1 99.0 99.4 99.5 101.0 99.9 2 months later 96.8 94.1 93.4 94.3 92.7 96.9 96.3
  • the formulation of the present invention prevents a decrease in content due to the mutual reaction of calcipotriol and betamethasone, can be expected to have sufficient efficacy of the active ingredient.
  • Calcipotriol was dispersed from the formulation into n-heptane, extracted with mobile phase and quantified by HPLC.
  • Betamethasonedipropionate was dispersed from the formulation into n-heptane, extracted with mobile phase and quantified by HPLC.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6
  • Example 7 Example 8
  • Example 9 Example 10
  • Example 10 Early 0.6 0.6 0.7 0.6 0.7 0.6 0.6 0.6 0.7 2 months later 0.6 0.6 0.7 0.6 0.7 0.6 0.7 Total amount of lead substance (%)
  • Example 11 Example 12
  • Example 13 Example 14
  • Example 15 Example 16
  • Example 18 Early 0.6 0.7 0.7 0.6 0.7 0.6 0.7 2 months later 0.7 0.7 0.8 0.8 0.7 0.7 0.7 0.8 Total amount of lead substance (%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Early 1.2 1.1 1.0 1.6 1.5 0.6 0.6 2 months later 3.5 3.6 3.7 3.6 3.9 1.6 1.9
  • the formulation of the present invention prevents the content decrease by the mutual reaction of calcipotriol and betamethasone, can be expected sufficient drug efficacy of the active ingredient.
  • the betamethasone content test method of Experimental Example 3 whether the betamethasone was uniformly dispersed in the formulation, the betamethasone content was analyzed by five formulations of Examples and Comparative Examples to determine the content uniformity. The results are shown in Table 19 below.
  • Example 10 One 99.0 100.4 96.2 98.8 98.6 98.4 98.2 98.0 99.6 99.2 2 98.0 102.0 97.8 100.1 99.4 97.9 99.8 99.5 100.4 99.4 3 101.0 99.1 101.2 98.0 98.9 101.5 98.6 97.9 100.2 98.9 4 100.0 100.2 98.3 99.0 99.5 100.8 97.9 100.0 99.6 99.5 5 98.5 98.9 99.7 98.7 98.4 100.6 98.2 99.7 99.5 100.0 Deviation(%) 1.2 1.2 1.9 0.8 0.5 1.6 0.7 1.0 0.4 0.4 Sample name Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 One 100.6 99.8 99.7 99.3 99.5 99.7 98.9 101.0 2 100.1 99.6 97.6 98.9 100.3 99.3

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PCT/KR2016/004688 2015-05-08 2016-05-04 안정성과 피부투과율이 향상된 약학 조성물 WO2016182258A2 (ko)

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