WO2006049404A1 - Activateur de la sphingosine kinase et agent de traitement de maladies cutanees comprenant celui-ci - Google Patents

Activateur de la sphingosine kinase et agent de traitement de maladies cutanees comprenant celui-ci Download PDF

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Publication number
WO2006049404A1
WO2006049404A1 PCT/KR2005/003586 KR2005003586W WO2006049404A1 WO 2006049404 A1 WO2006049404 A1 WO 2006049404A1 KR 2005003586 W KR2005003586 W KR 2005003586W WO 2006049404 A1 WO2006049404 A1 WO 2006049404A1
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WO
WIPO (PCT)
Prior art keywords
skin
wrinkles
sphingosine kinase
sphingosine
k6pc
Prior art date
Application number
PCT/KR2005/003586
Other languages
English (en)
Inventor
Byeong-Deog Park
Jong-Kyung Youm
Hyung-Sub Gwak
Mi-Jong Kwon
Yong-Moon Lee
Yoo-Hun Kim
Hwan-Mook Kim
Song-Kyu Park
Ki-Ho Lee
Chang-Woo Lee
Myong-Lyoll Lee
Original Assignee
Neopharm Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020050096591A external-priority patent/KR100607438B1/ko
Application filed by Neopharm Co., Ltd. filed Critical Neopharm Co., Ltd.
Priority to EP05817632A priority Critical patent/EP1807067A4/fr
Priority to JP2007538828A priority patent/JP4748164B2/ja
Publication of WO2006049404A1 publication Critical patent/WO2006049404A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton

Definitions

  • the present invention relates to a non-natural ceramide compound effective as a skin disease-treating agent. More particularly, the present invention relates to a specific sphingosine kinase activator, which enhances biosynthesis of sphingosine-1 -phosphate by the sphingosine kinase to show various physiological activities provided by sphingosine-1 -phosphate, wherein the physiological activities include: effects of inducing intracellular calcium movement and thus controlling multiplication and dif ⁇ ferentiation of keratinocytes in skin cells; multiplication of fibroblasts and collagen synthesis, resulting in treatment of wounds; recovery of damaged skin functions in atopic dermatitis and psoriasis; inhibition of wrinkles and skin irritation caused by ul ⁇ traviolet rays, followed by improvement of wrinkles and inhibition of skin aging; and reduction of skin atrophy, which is a typical side effect of local application steroids.
  • the sphingosine kinase activator is useful for an agent for treating skin diseases including skin wounds, wrinkles, atopic dermatitis, eczema, psoriasis, and skin atrophy caused by side effects of local application steroids.
  • sphingosine-1 -phosphate (SlP) is known merely as one of the metabolic by-products of sphingolipids.
  • SlP sphingosine-1 -phosphate
  • the above compound has physiological activities to control various biological processes. More particularly, it is known that the above compound functions as a secondary signal transferring agent that controls multiplication and survival of cells, from the intracellular point of view, while functioning as a ligand for EDG (endothelial differentiation gene) receptors (EDG-I, 3, 5, 6, 8) that belong to G-protein coupled receptors, from the extracellular point of view (see Spiegel S. et al., Biochem. Biophys. Acta, 1484, 107-116, 2000).
  • EDG endothelial differentiation gene
  • 1 -phosphate causes calcium to move from internal depots into cytoplasm, inde ⁇ pendently from the calcium signal transfer system caused by 1,4,5-triphosphate, thereby forming various signal transfer paths resulting in multiplication of cells and inhibition of cell destruction. It is also reported that a competitive inhibitor against the sphingosine kinase prevents production of sphingosine-1 -phosphate, inhibits calcium movement selectively, and affects multiplication, differentiation and survival of cells by various stimuli depending on the type of cell (see Spiegel S. et al., J. Leukoc. Biol., 65, 341-344, 1999).
  • sphingosine-1 -phosphate which is normally stored in platelets of the human body, is delivered to the site of a skin wound, so as to play an important role in treating wounds (see Lee et al., Am J Physiol Cell Physiol, 278, C612-C618, 2000). Further, it is reported that 1 ⁇ ,25-dihydroxy vitamin D known as a sphingosine kinase activator, inhibits cell destruction of keratinocytes (see Manggau et al., J Invest Dermatol, 117, 1241-1249, 2001).
  • sphingosine-1 -phosphate plays a very important role in treating skin wounds, because the compound inhibits cell destruction for keratinocytes, enhances movement of cells, enhances multiplication of fibroblasts, and stimulates extracellular formation of matrix proteins (see Vogler et al., J Invest Dermatol, 120, 693-700, 2003).
  • ,25-dihydroxyvitamin D is commercially available as a psoriasis treating agent, and the other materials have problems in that they are strongly toxic materials which cause cancer, or have difficulty in their synthesis.
  • sphingosine 1 -phosphate may be obtained by chemical synthesis, it is difficult to synthesize sphingosine- 1 -phosphate and such synthetic processes are not cost-efficient. Disclosure of Invention
  • the present invention has been made in view of the above-mentioned problems. It is an object of the present invention to provide a sphingosine kinase activator, which enhances production of sphingosine-1 -phosphate to provide phys ⁇ iological activities of sphingosine-1 -phosphate efficiently, and thus is useful for treating skin diseases including skin wounds, atopic dermatitis, eczema, psoriasis and skin atrophy caused by side effects of local application steroids, for improving wrinkles, and for preventing skin aging.
  • skin diseases including skin wounds, atopic dermatitis, eczema, psoriasis and skin atrophy caused by side effects of local application steroids, for improving wrinkles, and for preventing skin aging.
  • Another object of the present invention is to provide a composition for treating skin diseases, which comprises the above sphingosine kinase activator.
  • Still another object of the present invention is to provide a skin disease treating agent comprising the above sphingosine kinase activator as active component.
  • Yet another object of the present invention is to provide use of the sphingosine kinase activator for preparing the above skin disease treating agent.
  • a sphingosine kinase activator useful for treating skin diseases including skin wounds, atopic dermatitis, eczema, psoriasis and skin atrophy caused by side effects of local ap ⁇ plication steroids, for treating wrinkles, and for preventing skin aging which is at least one selected from the group consisting of compounds represented by the following formulae 1 to 8:
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • each of R and R is a linear or branched C4-C22 alkyl group.
  • composition for treating skin diseases which comprises at least one sphingosine kinase activator, selected from the group consisting of compounds represented by the above formulae 1 to 8, in an amount of 0.001 to 50.0 wt% based on the total weight of composition.
  • a skin disease treating agent for treating skin diseases including skin wounds, atopic dermatitis, eczema, psoriasis and skin atrophy caused by side effects of local ap ⁇ plication steroids, for improving wrinkles, and for preventing skin aging, which comprises at least one sphingosine kinase activator selected from the group consisting of compounds represented by the above formulae 1 to 8 as active component .
  • sphingosine kinase activator selected from the group consisting of compounds represented by the above formulae 1 to 8 for preparing the above skin disease treating agent for treating skin diseases including skin wounds, atopic dermatitis, eczema, psoriasis and skin atrophy caused by side effects of local ap ⁇ plication steroids, for improving wrinkles, and for preventing skin aging.
  • the skin disease treating agent comprising the sphingosine kinase activator as active component is efficient for treating skin wounds, for alleviating, mitigating and treating atopic dermatitis, eczema and psoriasis conditions, for improving wrinkles, for preventing skin aging, and for inhibiting side effects caused by local application steroids.
  • the treating agent comprising the sphingosine kinase activator according to the present invention activates sphingosine kinase, so as to enhance biosynthesis of sphingosine- 1 -phosphate and to provide various physiological activities of sphingosine- 1 -phosphate.
  • the present inventors have found that the above sphingosine kinase activator inhibits multiplication of keratinocytes, enhances differentiation of keratinocytes, enhances multiplication of fibroblasts and stimulates collagen synthesis, and thus is highly efficient for treating wounds, inhibiting multiplication of keratinocytes and enhancing differentiation of keratinocytes in the real skin.
  • the above sphingosine kinase activator provides the effects of recovering damaged skin functions in atopic dermatitis, eczema and psoriasis, inhibiting wrinkles and skin irritation caused by ultraviolet rays, so as to improve wrinkles and inhibiting skin aging, and inhibiting skin atrophy caused by local ap ⁇ plication steroids, so as to reduce side effects of steroids.
  • the sphingosine kinase activator is present preferably in an amount of 0.001 to 50 wt%, more preferably in an amount of 0.01 to 30 wt%, based on the total weight of the treating agent.
  • the treating agent cannot provide the desired effects to a sufficient degree or is not cost-efficient.
  • the treating agent comprising the sphingosine kinase activator as active component can be applied to any formulations for skins. More particularly, the treating agent may be formulated into the form of a toner, lotion, cream, essence, pack, powder, ointment, suspension, emulsion, spray, cosmetic solution, soap, shampoo, skin patch, gel, and so on. Additionally, the sphingosine kinase activator may be formulated in the form of a skin-contacting material such as a cosmetic product, detergent and fiber.
  • FlGs. 1 to 4 are graphs each showing intracellular calcium movement induced by the sphingosine kinase activator according to the present invention, in a signal transfer system for providing physiological activities of the cells;
  • FlG. 5 is a photograph showing the results of polyacrylamide gel electrophoresis, which demonstrates the effects of the sphingosine kinase activator upon differentiation of keratinocytes; [47] FlGs.
  • FIG. 6 to 8 are photographs each showing the effects of the sphingosine kinase activator upon calcium gradient in a skin horny layer, when evaluated in an acute disruption model using tape striping against the back of a hairless mouse;
  • FlGs. 9 and 10 are graphs showing the effect of the sphingosine kinase activator upon inhibition of wrinkles caused by ultraviolet rays, and a photograph of the real skin of a rat, respectively;
  • FlG. 11 is a photograph of mouse skin tissues, which shows the effect of the sphingosine kinase activator upon inhibition of skin atrophy caused by side effects of steroids;
  • FlGs. 12 and 13 are a graph and photograph of a silicone replica, each showing the effect of the sphingosine kinase activator upon improvement of wrinkles around the eye in a clinical test to humans.
  • each compound has the effects of treating wounds, aiding recovery of skin barrier functions in treating atopic dermatitis, eczema and psoriasis, improving wrinkles, inhibiting skin aging, and treating skin atrophy caused by side effects of local application steroids.
  • the sphingosine kinase activator compounds were determined for capability of inducing intracellular calcium movement by using a RBL-2H3 cell line, which is one of the typical cell lines showing intracellular calcium movement.
  • the cells are cultured by using an RPMI 1640 culture medium and the cells were washed simultaneously with removal of the medium. Then, 10 ⁇ M of fura-2/Am and 250 ⁇ M of sulfinpyrazone were added thereto, followed by incubation for 30 minutes. Cell pellets were obtained by centrifugal separation and the cell pellets were dispersed in Ca -free Locke's solution. The dispersion was divided into a unit of IXlO 6 cells for use in treating samples.
  • each sphingosine kinase activator compound was added thereto, and in ⁇ tracellular calcium movement was observed by the fluorescence microscope (RF-5310PC, Spectrofluoro photometer, SHIMADZU).
  • RF-5310PC Spectrofluoro photometer
  • SHIMADZU Spectrofluoro photometer
  • F9-12 cells were treated with 300 nM of PMA (phorbol microstate acetate) as positive control, and 50 ⁇ M of each of K6PC-4 and K6PC-5 for 24 hours and collected. Then, activity of sphingosine kinase was measured as production of C - sphingosine-1 -phosphate based on 50 ⁇ g of protein. Sphingosine-1-phospate was extracted from the collected cells by the steps of: (1) treating with trypsin-EDTA, (2) centrifugal separation at 1,500 rpm for 10 minutes, and (3) washing with PBS, followed by freeze-drying. Then, PBS was added to the freeze-dried product and the resultant product was treated with ultrasonic waves to destroy cells.
  • PMA phorbol microstate acetate
  • Sphingosine- 1 -phosphate was determined by HPLC, and OPA (o-phthalaldehyde) reagent and boric acid buffer were added to the extracted sample and the mixture was reacted at room temperature for 20 minutes.
  • OPA o-phthalaldehyde
  • fluorescence intensity was measured at each wavelength of 340 nm and 455 nm with a solution in 90% ace- tonitrile, and a ratio to the internal standard was calculated.
  • K6PC-4 and K6PC-9 showed an increase in production of sphingosine-1 -phosphate by about 30%
  • K6PC-5 and K6PC-7 showed an increases in production of sphigosine-1 -phosphate by about 46%, as shown in the following Table 1.
  • PMA used as positive control showed an increase of about 48%. Therefore, it can be seen that the above compounds according to the present invention serve as sphingosine kinase activators.
  • Enhancement of collagen synthesis upon application to the human body contributes to treatment of wounds, treats wrinkles caused by skin aging and inhibits skin atrophy occurring as a atypical side effect of steroids.
  • Each of K6PC-4, K6PC-5, K6PC-7 and K6PC-9 was dissolved in DMSO at a con- centration of 0.3 and 1.0 ⁇ g/ml.
  • the solutions were used as samples and analyzed for collagen synthesis after incubation for 72 hours.
  • 72 hours after the treatment of the sample culture solution was discarded, cells were washed with serum-free DMEM three times, and cells were cultured again by using fresh serum-free DMEM.
  • supernatant in each well was combined and analyzed for the amount of PICP (procollagen type I C-peptide) by using a collagen measuring kit.
  • the standard solution contained in the collagen measuring kit was diluted with a sample and absorption at 450 nm was measured to construct a standard concentration curve (see the following Table 2).
  • Example 4 Effect for Inducing Differentiation of Keratinocy tes
  • Effects of the sphingosine kinase activator according to the present invention upon inhibition of cell multiplication and differentiation were evaluated by using ker- atinocytes.
  • Keratinocytes form the outermost layer of the skin and play a very important role in skin moisturizing and protecting functions. It is preferable to inhibit excessive growth of keratinocytes and cell destruction and to enhance differentiation of ker ⁇ atinocytes. Excessive multiplication of keratinocytes results in abnormal extension of the stratum corneum, followed by roughening and thickening of the skin. Additionally, abnormal differentiation of keratinocytes inhibits normal skin barrier functions, and thus may cause various troubles, including skin dryness, atopic dermatitis and psoriasis.
  • each of K6PC-4, K6PC-5, K6PC-7 and K6PC-9 was dissolved in DMSO at a concentration of 10 ⁇ M and used as sample. Evaluation was performed by using the western blotting method. As differentiation markers, involucrin and keratine-1, which were differentiation markers of ker ⁇ atinocytes, were measured. Next, 48 hours after the treatment of samples, the culture solution was discarded and the cells were washed with PBS and collected by filtering. The collected cells were washed again and subjected to centrifugal separation to remove supernatant.
  • the cells were dissolved in a solvent and subjected to centrifugal separation at 12,000 rpm for 10 minutes, thereby removing cell membranes, etc. Protein concentration was determined by the Bradford method. Proteins were separated by mini gel type SDS-PAGE (polyacrylamide gel electrohoresis) and transferred to a PVDF (polyvinylidene fluoride) membrane at 100V for 1 hour, so that gel-like proteins were subjected to blotting with a transfer membrane. Then, the membrane was colored with Ponceau S solution to determine whether transfer was accomplished or not. The membrane was blocked by using TTBS (TBS+0.1% Tween 20) solution containing 5% non-fat dried milk.
  • TTBS TBS+0.1% Tween 20
  • involucrin As differentiation marker of keratinocytes, primary antibody involucrin (Neomarkers Co.) was diluted at a ratio of about 1/200 to 1.400, and keratin- 1 (Covance Co.) was diluted at a ratio of about 1/1000. Reactions were performed overnight at 4 °C .
  • secondary antibody anti- mouse IgG and anti-rabbit IgG combined with horseradish peroxidase (HRP) was diluted at a ratio of 1:2000. Then, the secondary antibody was bonded to the primary antibody by making them react at room temperature for 1 hour. The membrane was washed with TTBS three times, reacted with an ECL substrate (Amersham Co.) for 1-3 minutes, and exposed to X-ray films.
  • K6PC-5, K6PC-7 and K6PC-9 expressed the differentiation markers, as shown in FIG. 5. Particularly, better results were obtained in the case of involucrine. Therefore, it can be seen that the above compounds enhance differentiation of keratinocytes. As demonstrated by such increased expression of differentiation markers compared to the control, the compounds according to the present invention can enhance differentiation of keratinocytes, resulting in rapid recovery of the skin barrier functions.
  • K6PC-5 which represents for the compounds according to the present invention (i.e. K6PC-4, K6PC-5, K6PC-7 and K6PC-9), was performed through the following Examples 5 to 7.
  • K6PC-5 showed excellent effects of recovering a calcium gradient in the epidermis, differ ⁇ entiating keratinocytes on the epidermis, inhibiting wrinkles cause by ultraviolet rays and reducing side effects of steroids.
  • the calcium gradient in the epidermis plays very important role in maintaining ho- moeostasis of the skin barrier function. For example, when a hairless mouse is subjected to acute disruption on its back by tape stripping, the calcium ion gradient in the epidermis is lost. Therefore, it is possible to evaluate the effect of a test sample upon recovery of a damaged skin barrier by observing recovery of the calcium gradient loss in an acute disruption model.
  • K6PC-5 according to the present invention was evaluated for the effect upon variations in calcium gradient in an acute disruption model.
  • FIG. 6 is a photograph illustrating the calcium loss in the epidermis right after the tape stripping.
  • FIG. 7 is a photograph taken after the lapse of 6 hours as control.
  • FIG. 8 is a photograph showing the result obtained 6 hours after the treatment with K6PC-5.
  • the sphingosine kinase activator according to the present invention enhances rapid recovery of the skin barrier functions, because calcium functions as important signal transfer material in a damaged skin barrier. Therefore, it can be seen from the above in vivo test that the sphingosine kinase activator according to the present invention has the effects of treating wounds, treating atopic dermatitis, eczema and psoriasis, and preventing skin from aging.
  • a rat model in which wrinkles are induced by ultraviolet rays, is used to determine the effects of inhibiting wrinkles and preventing side effects caused by ultraviolet rays.
  • continuous exposure to UV causes wrinkles and side effects such as sun burn and skin irritation, resulting in stimulation of skin aging.
  • an SD rat with three wrinkles is irradiated with UVB under an intensity of 130 mJ/cm at its rear leg three times for 6 weeks. Then, 10 ⁇ 1 (1% in 80% EtOH) of K6PC-5 was applied to the skin of rear leg right after each time of UV irradiation, UV irradiation being performed 5 times per week during 6 weeks from the start day of the UV irradiation.
  • the rat was anesthetized with albutin and the wrinkles were photographed.
  • wrinkle- forming portions were replicated by using an exafine hydrophilic vinyl polysiloxane impression material. The replicated images were analyzed quantitively for shadow images by using an image analyzer.
  • the vehicle control (VC) irradiated with UV caused a significant amount of wrinkles, compared to the control non-irradiated with UV, as shown in FIG. 9 illustrating the results of the evaluation for inhibition of wrinkles.
  • K6PC-5 inhibited wrinkles by about 63%.
  • the sample treated with K6PC-5 showed a decrease in erythema (a typical side effect caused by UV) compared to the VC.
  • the sphingosine kinase activator according to the present invention is effective for improving wrinkles and preventing skin aging, as demonstrated the above results indicating inhibition of wrinkles and erythema that are typical side effects caused by UV.
  • the treating agents were applied to the back of a hairless mouse 9 times per day and the tissue was collected.
  • the epidermis and dermis were observed by carrying out the H & E staining method (hematoxylin and eosin staining) known to one skilled in the art.
  • the control free from steroids showed little change in the epidermis and dermis.
  • the group treated with chlorbetason-17-propionate combined with K6PC-5 showed significant inhibition of side effects caused by steroids in a similar manner to the control. Therefore, it can be seen that the compound according to the present invention inhibits skin atrophy, which is a typical side effect caused by steroids.
  • Example 9 aims to demonstrate clinical availability of the results obtained from the above in vivo and in vitro tests in human subjects.
  • FIG. 12 shows the effect of K6PC-5 upon a statistically significant improvement in the condition of wrinkles, as demonstrated by comparing the results obtained after the treatment with K6PC-5-containing cream for 8 weeks to the control (P ⁇ 0.05, t-test).
  • FIG. 13 is a photograph showing a real silicone replica, wherein improvement in the condition of wrinkles can be observed by the naked eyes. Additionally, according to catechetical and ocular inspection of dermatologists after the treatment with K6PC-5-containing cream for 4 weeks and 8 weeks, there is no skin irritation or hyper ⁇ sensitive reaction.
  • the sphingosine kinase activator according to the present invention shows consistent results in the above in vitro test, in vivo test and clinical test.
  • a moisturizing agent was added to purified water and heated to 70 °C .
  • K6PC-5 and oil phase components were dissolved by heating, and an emulsifier, preservative, or the like were added thereto, followed by heating to 70 °C .
  • the oil phase was added to the above aqueous phase. Then, emulsified particles were homogenized by using a homomixer, followed by deaerating, filtering and cooling.
  • Formulation 2 Ointment for External Use
  • K6PC-5 and oil phase components were dissolved by heating, and an emulsifier, preservative, or the like was added thereto, followed by adjustment of the temperature to 70 °C .
  • the resultant mixture was mixed homogeneously by using a homomixer, followed by deaerating, filtering and cooling.
  • a moisturizing agent was added to purified water and heated to 70 °C .
  • K6PC-5 and oil phase components were dissolved by heating, and an emulsifier, preservative, or the like were added thereto, followed by heating to 70 °C .
  • the oil phase was added to the above aqueous phase, and the resultant mixture was mixed homogeneously by using a homomixer, followed by deaerating, filtering and cooling.
  • the sphingosine kinase activator according to the present invention enhances production of sphingosine- 1 -phosphate, and thus permits various physiological effects of sphingosine- 1 -phosphate to be utilized ef ⁇ ficiently.
  • the skin disease treating agent comprising the sphingosine kinase activator according to the present invention as active component enhances collagen synthesis in fibroblasts, enhances differentiation of keratinocytes, and allows an abnormal calcium gradient in the epidermis to be recovered into a normal calcium gradient promptly, resulting in recovery of the skin barrier functions.
  • the skin treating agent provides the effects of treating wounds, recovering damaged skin functions in atopic dermatitis, eczema and psoriasis, inhibiting wrinkle formation caused by ultraviolet rays, improving the condition of wrinkles in the eye rims, and preventing skin aging. Further, the skin-treating agent inhibits skin atrophy caused by side effects of steroids, and thus is useful for an agent for alleviating side effects caused by steroids. While this invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiment and the drawings. On the contrary, it is intended to cover various modifications and variations within the spirit and scope of the appended claims.

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Abstract

Composé céramide non naturel utilisé efficacement dans un activateur de la sphingosine kinase et de ce fait, pour un agent de traitement de maladies cutanées. L'activateur de la sphingosine kinase améliore la production de sphingosine-1-phosphate arborant plusieurs activités physiologiques. Les activités physiologiques, à savoir la surveillance de la multiplication de la différenciation de kératinocytes, la multiplication de fibroblastes et de la synthèse de collagène, ce qui se traduit par le traitement de blessures, la récupération de fonctions de la peau suite à une lésion dans la dermatite atopique et le psoriasis; inhibition des rides et de l'irritation de la peau causées par les rayons ultraviolets, amélioration des rides et inhibition du vieillissement de la peau; et réduction de l'atrophie de la peau, qui est un effet secondaire typique des stéroïdes à application locale. Par conséquent, l'activateur de sphingosine kinase est utilisé avec un agent de traitement de maladies cutanées en vue du traitement des blessures, des rides, de la dermatite atopique, de l'eczéma, du psoriasis ou de l'atrophie de la peau qui sont causées par les effets secondaires de stéroïdes à application locale.
PCT/KR2005/003586 2004-11-03 2005-10-27 Activateur de la sphingosine kinase et agent de traitement de maladies cutanees comprenant celui-ci WO2006049404A1 (fr)

Priority Applications (2)

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EP05817632A EP1807067A4 (fr) 2004-11-03 2005-10-27 Activateur de la sphingosine kinase et agent de traitement de maladies cutanees comprenant celui-ci
JP2007538828A JP4748164B2 (ja) 2004-11-03 2005-10-27 スフィンゴシンキナーゼ活性剤及びこれを含む皮膚疾患治療薬組成物、皮膚疾患治療薬、並びにその製造方法。

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KR20040088553 2004-11-03
KR10-2004-0088553 2004-11-03
KR1020050096591A KR100607438B1 (ko) 2004-11-03 2005-10-13 스핑고신키나제 활성화제를 포함하는 피부질환치료제
KR10-2005-0096591 2005-10-13

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WO2008023998A1 (fr) * 2006-08-22 2008-02-28 Industrial Research Limited N-acyléthanolamines utilisées comme agents de cicatrisation des plaies
CN109069454A (zh) * 2016-04-27 2018-12-21 株式会社新药 抗衰老组合物
CN109843278A (zh) * 2016-10-17 2019-06-04 株式会社新药 抗炎用组合物
CN109843277A (zh) * 2016-10-17 2019-06-04 株式会社新药 抗炎用组合物
CN113861060A (zh) * 2021-11-05 2021-12-31 江苏弘和药物研发有限公司 一种鞘氨醇激酶激动剂的合成方法

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Cited By (9)

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WO2008023998A1 (fr) * 2006-08-22 2008-02-28 Industrial Research Limited N-acyléthanolamines utilisées comme agents de cicatrisation des plaies
CN109069454A (zh) * 2016-04-27 2018-12-21 株式会社新药 抗衰老组合物
CN109069454B (zh) * 2016-04-27 2021-09-07 株式会社新药 抗衰老组合物
US11446223B2 (en) 2016-04-27 2022-09-20 Neopharm Co., Ltd. Anti-aging composition
CN109843278A (zh) * 2016-10-17 2019-06-04 株式会社新药 抗炎用组合物
CN109843277A (zh) * 2016-10-17 2019-06-04 株式会社新药 抗炎用组合物
CN109843277B (zh) * 2016-10-17 2022-08-02 株式会社新药 抗炎用组合物
CN113861060A (zh) * 2021-11-05 2021-12-31 江苏弘和药物研发有限公司 一种鞘氨醇激酶激动剂的合成方法
CN113861060B (zh) * 2021-11-05 2023-12-08 江苏弘和药物研发有限公司 一种鞘氨醇激酶激动剂的合成方法

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