Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K8/60—Sugars; Derivatives thereof
• • 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
  • A61K8/60—Sugars; Derivatives thereof
  • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • 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

Definitions

• the present invention relates to an agent for preventing or treating an abnormality in skin water permeation function.
• the present invention further relates to an agent for adjusting TEWL (transepidermal water loss) value, the amount of water evaporated from the skin, to normal levels.
• the present invention relates to a method for preventing or treating an abnormality in skin water permeation function, for adjusting TEWL value, for preventing or treating abnormal TEWL in skin, or for improving skin water permeation function/ and uses thereof.
• the skin plays several roles.
• the principal roles of the skin are providing protection from UV rays, foreign substances, microorganisms, etc., and providing water content adjustment function of the outermost skin layer, which contribute to skin homeostasis.
• the skin normally has an appropriate level of elasticity, flexibility, and strength, and can protect itself against physical force. However, for this ability to function, the skin must contain an appropriate amount of water, and be flexible.
• the outer skin layer contains natural moisturizing factors (NMF) and ceramides, whose combined effects enable the entire skin to maintain an appropriate water content and keep the skin flexible.
• NMF moisturizing factors
• moisture retention involves the suppression of the TEWL value and the inhibition of water permeation through the skin to thereby control water evaporation from the skin.
• the human skin has portions that are susceptible to dryness, eczema, or the like. Each skin site has different properties. However, it is difficult to selectively use, according to the skin site, a preparation that is effective for increasing or reducing the TEWL value. Therefore, the development of a single preparation that can both increase and decrease the TEWL value according to the skin site to adjust the TEWL value to an appropriate level has long been desired.
• purine nucleic acid has an effect of appropriately adjusting TEWL value according to the skin condition. More specifically, the inventors found that purine nucleic acid can increase TEWL value to normal levels when the skin has reduced TEWL, and can also decrease TEWL to normal levels when the skin has excessive TEWL; accordingly, purine nucleic acid can prevent or treat an abnormality in skin water permeation function.
• the present invention provides an agent for preventing or treating an abnormality in skin water permeation function having the following features.
• Item 1-1 An agent for preventing or treating an abnormality in skin water permeation function comprising, at least one purine nucleic acid as an active ingredient.
• Item 1-2 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 wherein the at least one purine nucleic acid is selected from the group consisting of adenosine monophosphates and salts thereof.
• Item 1-3 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 containing the purine nucleic acid in an amount of 0.1 to 20 wt.%.
• Item 1-4 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 which is used to adjust TEWL (transepidermal water loss) value.
• Item 1-5 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 which is used to prevent or treat a skin condition or a skin disease with abnormal TEWL value.
• Item 1-6 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1, wherein the abnormality in skin water permeation function is due to aging.
• Item 1-7 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 which is used to prevent or treat rough skin, itching, chapped skin, hyperkeratosis, or senile xerosis.
• Item 1-8 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 which is in the form of a cosmetic, or a pharmaceutical or quasi-drug for external application to the skin.
• Item 1-9 The agent for preventing or treating an abnormality in skin water permeation function according to Item 1-1 which is used for non-therapeutic purpose.
• Item 1-10 Use of at least one purine nucleic acid for manufacture of an external composition for preventing or treating an abnormality in skin water permeation function.
• Item 1-11 Use of at least one purine nucleic acid, in an external composition, for preventing or treating an abnormality in skin water permeation function.
• Item 1-12 A purine nucleic acid for preventing or treating an abnormality in skin water permeation function.
• the present invention provides an agent for adjusting TEWL (transepidermal water loss) value having the following features.
• Item 2-1 A agent for adjusting for TEWL (transepidermal water loss) value comprising t least one purine nucleic acid as an active ingredient.
• Item 2-2. The agent for adjusting TEWL value according to Item 2- 1 wherein the purine nucleic acid is selected from the group consisting of adenosine monophosphate and salts thereof.
• Item 2-3. The agent for adjusting TEWL value according to Item 2- 1 containing the purine nucleic acid in an amount of 0.1 to 20 wt. %.
• Item 2-4 The agent for adjusting TEWL value according to Item 2- 1 which is used to improve skin water permeation function.
• Item 2-7 The agent for adjusting TEWL value according to Item 2-
• Item 2-8 The agent for adjusting TEWL value according to Item 2-
• Item 2-9 Use of at least one purine nucleic acid for manufacture of an external composition for adjusting TEWL (transepidermal water loss) value.
• Item 2-11 Use of at least one purine nucleic acid, in an external composition, for adjusting TEWL (transepidermal water loss) value.
• Item 2-12 A purine nucleic acid for adjusting TEWL (transepidermal water loss) value.
• a method for adjusting TEWL (transepidermal water loss) value comprising administering at least one purine nucleic acid to a subject in need of adjusting TEWL (transepidermal water loss) value.
• the present invention also provides following agents, use of the compounds, and methods.
• Item 3-1 A agent for preventing or treating abnormal TEWL
• transepidermal water loss in skin comprising at least one purine nucleic acid as an active ingredient.
• Item 3-2 Use of at least one purine nucleic acid for manufacture of an external composition for preventing or treating abnormal
• TEWL transepidermal water loss
• Item 3-3 Use of at least one purine nucleic acid, in an external composition, for preventing or treating abnormal TEWL (transepidermal water loss) in skin.
• TEWL transepidermal water loss
• Item 3-4 A purine nucleic acid for preventing or treating abnormal TEWL (transepidermal water loss) in skin.
• Item 3-5 A method for preventing or treating abnormal TEWL (transepidermal water loss) in skin, comprising administering at least one purine nucleic acid to a subject in need of preventing or treating abnormal TEWL.
• TEWL transepidermal water loss
• Item 3-6 An agent for improving skin water permeation function comprising least one purine nucleic acid as an active ingredient.
• Item 3-7. Use of at least one purine nucleic acid for manufacture of an external composition for improving skin water permeation function.
• Item 3-8 Use of at least one purine nucleic acid, in an external composition, for improving skin water permeation function.
• Item 3-9. A purine nucleic acid for improving skin water permeation function.
• Item 3-10 A method of improving skin water permeation function, comprising administering at least one purine nucleic acid to a subject in need of restoring or maintaining skin water permeation function.
• TEWL value can be adjusted according to the skin condition to thereby normalize skin water permeation function, thus enhancing skin water content regulation effect.
• skin conditions and skin diseases with abnormal skin water permeability such as rough skin, itching, chapped skin, hyperkeratosis, and senile xerosis, can be prevented or treated.
• Fig. 1 shows the TEWL measurement results obtained in Test Example 3, indicating the changes in TEWL value at the skin site where a test sample containing AMP was applied and at the skin site where the test sample was not applied.
• Fig. 2 shows the stratum corneum water content measurement results obtained in Test Example 3, indicating the changes in over time at the AMP-containing test sample application skin site, and at the non-application skin site.
• Fig. 3a is a photograph of the skin surface condition of the non-application skin site, which was observed after 7 days from the start of the test in Test Example 3.
• Fig. 3b is a photograph of the skin surface condition of the test sample application skin site, which was observed after 7 days from the start of the test in Test Example 3.
• a mode for carrying out the invention will be described below.
• a feature of the agent for preventing or treating an abnormality in skin water permeation function of the present invention is containing at least one purine nucleic acid as an active ingredient.
• the agent for preventing or treating an abnormality in skin water permeation function of the present invention may be referred to as “the agent of the invention” .
• purine nucleic acid used as an active ingredient in the present invention, is a general term that includes purine per se, various purine derivatives having a purine nucleus as the skeleton, and salts thereof, purine nucleic acid as used herein are not particularly limited insofar as they are pharmaceutically or cosmetically acceptable.
• adenosine phosphates are preferable, and adenosine monophosphates, particularly adenosine 5' -monophosphate (AMP), are more preferable.
• AMP adenosine 5' -monophosphate
• These purine nucleic acids can be used singly, or in a combination of two or more. Salts used as the purine nucleic acid are not particularly limited insofar as they are pharmaceutically or cosmetically acceptable.
• salts examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts, calcium salts, and barium salts; basic amino acid salts such as arginine salts and lysine salts; ammonium salts such as ammonium salts and tricyclohexylammonium salts; various kinds of alkanolamine salts such as monoethanolamine salts, diethanolamine salts, triethanolamine salts, monoisopropanolamine salts, diisopropanolamine salts, and triisopropanolamine salts; etc.
• alkali metal salts such as sodium salts and potassium salts
• alkaline earth metal salts such as magnesium salts, calcium salts, and barium salts
• basic amino acid salts such as arginine salts and lysine salts
• ammonium salts such as ammonium salts and tricyclohexylammonium salts
• alkali metal salts are preferable, and sodium salts are particularly preferable.
• the agent of the invention is applied to the skin to improve the water permeation function of the stratum corneum, and enhance skin water content regulation effect. Accordingly, the agent of the invention is provided as an external composition (an external preparation) , such as a cosmetic, or a pharmaceutical or quasi-drug for external application to the skin, which is used to prevent or treat an abnormality in skin water permeation function, or adjust TEWL value.
• an external composition such as a cosmetic, or a pharmaceutical or quasi-drug for external application to the skin, which is used to prevent or treat an abnormality in skin water permeation function, or adjust TEWL value.
• the amount of the purine nucleic acid in the external composition can be suitably selected according to the form of the preparation, application site, desired effect, etc. More specifically, the amount of the purine nucleic acid in the external composition is 0.1 to 20 wt.%, preferably 0.5 to 10 wt.%, and more preferably 1 to 5 wt.%, based on the total amount of the external composition.
• the external composition which contains a purine nucleic acid in the above-mentioned proportion, can exhibit a TEWL adjustment effect etc.
• the purine nucleic acid may be formulated with various optional components that are typically used in preparations for external application to the skin, such as pharmaceutically or cosmetically acceptable carriers and additives. Such carriers and additives are known in the art, and amounts thereof can be suitably selected.
• pH and osmotic pressure of the external composition can be suitably selected from the range that does not adversely affect low irritation to the skin or mucosa, and good skin feel upon application.
• the form of the external composition is not particularly limited, insofar as it is in a form externally applicable to the skin, such as a cosmetic, or pharmaceutical or quasi-drug for external application to the skin.
• the agent of the invention can be provided as an external preparation in the form of a paste, mousse, gel, liquid, emulsion, suspension, cream, ointment, sheet, aerosol, spray, liniment, or like desired forms, by adding the above-mentioned optional components and further optionally adding other solvents, and bases or carriers that are typically used in external preparations.
• liquids, emulsions, suspensions, and creams are preferable, and liquids and emulsions are particularly preferable.
• These products can be prepared by methods commonly used in the art.
• the agent of the invention is used to apply to the skin of a mammal (including a human) having an abnormality in skin water permeation function.
• the abnormality in skin water permeation function include skin diseases and skin conditions with excess TEWL value or reduced TEWL value.
• Specific examples of the abnormality in skin water permeation function include rough skin, itching, chapped skin, hyperkeratosis, senile xerosis, etc.
• preferable examples of the abnormality in skin water permeation function include that caused by aging.
• TEWL values reference can be made to Hachiro Tagami, "Kousho-kaishi (Journal of Cosmetic Science)" 27 (2003): 158.
• the agent of the invention can be used to apply to the target skin of a mammal (including a human) in need of restoring or maintaining TEWL value at normal levels, preventing or treating abnormal TEWL in skin, restoring or maintaining skin water permeation function, or adjusting TEWL value ability.
• the agent of the invention can prevent or treat an abnormal skin water permeation function.
• the agent of the invention can normalize the skin water permeation function in mammals such as humans by adjusting TWEL value to normal levels. Therefore, the agent of the invention can be used for providing a skin moisturizing effect and a skin water penetration enhancement effect, or regulating or restoring skin water content. More specifically, when applied to the skin with reduced TEWL value, the agent of the invention increases TEWL to thereby restore TEWL value to normal levels. When applied to the skin with excess TEWL value, the agent of the invention reduces TEWL value to thereby restore TEWL value to normal levels. Therefore, the agent of the invention is effective to prevent or treat skin conditions and skin diseases with abnormal TEWL value.
• the agent of the invention is effective for preventing or treating skin diseases and skin conditions (such as dry skin, itching, chapped skin, hyperkeratosis, and senile xerosis) with reduced TEWL value.
• the agent of the invention is also effective for preventing or treating skin diseases and skin conditions (such as rough skin) with excess TEWL value.
• the agent of the invention can adjust the skin with an excessive water content to an appropriate level, and can also restore the skin with a low water content to an appropriate level. Therefore, the agent of the invention is also effective for restoring deteriorated water retention ability.
• the agent of the invention may be applied in an appropriate amount to the skin once to several times per day according to the kind and concentration of the active ingredient, the user's age, sex, severity of skin condition, application form, desired effect, etc.
• the dose of the agent of the invention is such that the amount of the purine nucleic acid applied per application is 0.0001 to 1 mg, and preferably about 0.001 to about 1 mg, per cm 2 of the skin.
• the agent of the invention can adjust TEWL value to normal levels to thereby maintain skin water content at appropriate levels and appropriately evaporate water from the epidermis, thus appropriately adjusting TEWL value ability. Therefore, the agent of the invention can be used as an agent for improving skin water permeation function or an agent for adjusting TEWL value ability.
• the agent of the invention can normalize TEWL value in the skin. Therefore, the agent of the invention can be used as an agent for preventing or treating abnormal TEWL (transepidermal water loss) in skin.
• Test Example 1 Examination 1 of skin water permeation-promoting effect of adenosine phosphate
• 12 healthy human adults (10 males and 2 females; average age: 41.2 years old) were used as subjects. More specifically, 9 cm x 8 cm areas of the upper front right and left arms were used as test sites.
• An appropriate amount of a 20% hydrous ethanol solution containing 3% adenosine 5' -sodium monophosphate (AMP) (test sample) was applied to a test site on one arm, whereas the same amount of a 20% hydrous ethanol solution not containing AMP (reference sample) was applied to a test site on the other arm.
• the application was performed twice per day (in the morning and in the evening) for 28 days.
• the TEWL and the water content of the stratum corneum were measured before application (i.e., before the test) and after application (i.e., after 28 days of application) .
• the TEWL value (g/m 2 /h) was measured by using a DermaLab tester (manufactured by Cortex Technology) according to the instructions included with the DermaLab tester (manufactured by Cortex Technology) .
• the average TEWL value of each subject was calculated.
• the electric conductivity ( ⁇ S) was measured by using a SKICON-200 tester (manufactured by I. B. S Co., Ltd.) according to the instructions included with the SKICON-200 tester (manufactured by I. B. S Co., Ltd.), and used as an index for the water content of the stratum corneum.
• Table 1 shows the TEWL measurement results. Table 1 shows that when the reference sample was applied, there was substantially no difference between the TEWL values before and after the test; in contrast, when the test sample was applied, a tendency toward TEWL value increase was observed after 28 days of application, thus confirming enhanced skin water permeation function. Table 1
• Table 2 shows the stratum corneum water content measurement results. Table 2 shows that when the test sample was applied, a remarkable increase in the water content of the stratum corneum was observed after 28 days of application. Increased TEWL is generally considered to reduce the water content of the stratum corneum. However, the above test results revealed that AMP can increase both TEWL and the water content of the stratum corneum. Table 2
• test Example 1 a test was performed in a manner similar to Test Example 1, using an emulsion, which is generally used as an external cosmetic, in place of the aqueous ethanol solution used in Test Example 1.
• the test conditions such as the subject and the test period, were the same as in Test Example 1, except for the medium of the test sample and the test sites in the upper front arms.
• the emulsion used in this test has a general composition.
• cornified envelope (CE) in the stratum corneum was observed to investigate whether application of AMP affects skin barrier function. More specifically, to confirm the effect of application of AMP on the number of immature keratinocytes, tape was applied to the test sites so as to obtain the stratum corneum after 28 days of application of the test sample or the reference sample. The stratum corneum thus obtained was stained with a fluorescent-labeled anti-involucrin antibody, and mature keratinocytes were then stained with a fluorescent-labeled anti- mature cell antibody. Subsequently, each stained sample was observed under a fluorescence microscope to calculate the ratio of the number of immature keratinocytes to the total number of keratinocytes .
• Table 3 shows the TEWL measurement results. Table 3 shows that when the reference sample was applied, there was substantially no difference between the TEWL values before and after the test; in contrast, when the test sample was applied, a significant increase in TEWL was observed after 28 days of application, thus confirming enhanced skin water permeation function. Table 3
• Table 4 shows the stratum corneum water content measurement results. Table 4 shows that when the reference sample was applied, an increase in the water content of the stratum corneum was observed; when the test sample was applied, a more remarkable increase was observed.
• the increased water content of the stratum corneum achieved by application of the reference sample is believed to be due to a so-called temporal stratum corneum water retention effect obtained by coating the skin with a film.
• the increased water content of the stratum corneum and enhanced water permeation function achieved by application of the test sample are believed to result from enhanced stratum corneum function and increased ability to supply water from the deep layers of the skin to the outermost layer. Since these effects are provided by iraproving the skin' s own function and ability, the effects are expected to persist even after application of the test sample is completed.
• Table 5 shows the ratio of the number of immature keratinocytes to the total number of keratinocytes. It is generally believed that the observation of many immature keratinocytes in the stratum corneum indicates rough skin or reduced stratum corneum barrier function. As shown in Table 5, the results show that when the test sample containing AMP was applied, the ratio of the number of immature keratinocytes did not increase. Thus, the results confirmed that application of the test sample containing AMP does not reduce the skin barrier function.
• Test Example 3 Examination of skin water permeation-inhibitory effect of adenosine phosphate
• a test was conducted to examine the effect of an adenosine phosphate on a skin with overly enhanced skin water permeation function.
• the test was conducted using 9 healthy human adults (9 males; average age: 43.1 years old) as subjects. More specifically, 7 cm x 4.5 cm areas on the outer right and left calves of each subject were used as test sites.
• a 0.25 w/v% aqueous solution of sodium dodecyl sulfate (aqueous SDS solution, manufactured by Wako Pure Chemical Industries) was applied to the test sites on both the right and left calves in such a manner as to cover the test sites with an occlusive barrier for 24 hours.
• the application sites were washed and used as rough skin models.
• An emulsion containing 3% sodium adenosine 5' -monophosphate was used as a test sample.
• An appropriate amount of the emulsion containing sodium adenosine 5' -monophosphate was applied to a test site on one calf, whereas nothing was applied to a test site on the other calf.
• the application of the emulsion was started after the treatment with the aqueous SDS solution (day 0) , and was performed twice per day for 7 days.
• TEWL value and the stratum corneum water content were measured in the same manner as in Test Example 1, before and after treatment with the aqueous SDS solution; and after 1 day, 3 days, and 7 days of application of the test sample. Further, the surface condition of the skin after 7 days of application of the test sample was observed. The condition of the skin surface was observed using a microscope (manufactured by Scalar) .
• Fig. 1 shows the TEWL measurement results. As shown in
• Fig. 1 the treatment with the aqueous SDS solution clearly increased TEWL value, and also caused unmistakably rough skin; afterward, TEWL value was more sharply reduced at the test sample application skin site than at the non-application skin site according to observations after 3 days and 7 days of application.
• Fig. 2 shows the water content of the stratum corneum. As shown in Fig. 2, the treatment with the aqueous SDS solution obviously reduced the water content of the stratum corneum; afterward, the water content of the stratum corneum did not increase at the non-application skin site even after 7 days, whereas the water content of the stratum corneum was remarkably increased at the skin site where the test sample was applied.
• Figs. 3a and 3b show the skin surface condition observation results.
• the skin surface pattern composed of sulcus cutis, cristae cutis, and area cutanea, disappeared, and flaking of the stratum corneum was observed.
• the AMP-containing test sample application site Fig. 3b
• a skin surface pattern was observed, and no flaking of the stratum corneum was observed. The above results confirmed that application of the AMP-containing test sample is effective for ameliorating rough skin caused by excessive TEVJL value.

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