WO1994021225A1 - Skin care composition - Google Patents

Skin care composition Download PDF

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Publication number
WO1994021225A1
WO1994021225A1 PCT/SE1994/000235 SE9400235W WO9421225A1 WO 1994021225 A1 WO1994021225 A1 WO 1994021225A1 SE 9400235 W SE9400235 W SE 9400235W WO 9421225 A1 WO9421225 A1 WO 9421225A1
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WO
WIPO (PCT)
Prior art keywords
skin
vitamin
preparation
cyclodextrin
skin care
Prior art date
Application number
PCT/SE1994/000235
Other languages
French (fr)
Inventor
Jan Wadstein
Mats Samuelsson
Original Assignee
Jan Wadstein
Mats Samuelsson
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
Application filed by Jan Wadstein, Mats Samuelsson filed Critical Jan Wadstein
Priority to AU63884/94A priority Critical patent/AU6388494A/en
Publication of WO1994021225A1 publication Critical patent/WO1994021225A1/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/738—Cyclodextrins
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A61K8/981—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of mammals or bird
    • A61K8/986—Milk; Derivatives thereof, e.g. butter
    • 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 a skin care com- position for therapeutic or prophylactic treatment of ageing symptoms in skin.
  • Vitamin A in various forms has been found to produce a very good effect when treating ageing symptoms in skin, especially for preventing or treating wrinkles (1, 2).
  • vitamin A acid has a good effect on ageing symptoms in skin (3-6).
  • Various types of creams containing vitamin A esters have been available for a long time, and they have satisfactory cosmetic properties but no anti-wrinkle properties (7). It has been found in studies on animals that an essen ⁇ tial condition for vitamin A preparations to have an effect is that they penetrate the skin in a satisfactory manner.
  • Vitamin A acid is relatively hydrophilic, whereas e.g. the esters thereof are relatively lipophilic.
  • the solu ⁇ bility of the vitamin A esters may be changed such that the skin penetrability is improved by combining the vitamin A ( derivatives with some sort of carrier.
  • the known type of carrier improves the solubility of some lipophilic sub ⁇ stances.
  • Examples of such carriers are various types of "Tween” (7, 8, 9). However, these carriers produce but a slight improvement of the skin penetrability of the vitamin A derivatives.
  • vitamin A derivatives The effect of the vitamin A derivatives depends on their being converted in the skin into vitamin A acid.
  • the conversion of vitamin A esters into vitamin A is effected by enzymatic splitting of the ester bond (10).
  • the skijn must be able to oxidise retinol (vitamin A 1 ) to retine acid (vitamin A acid).
  • vitamin A acid oxidise retinol
  • skin converts retinyl derivatives into retine acid (11). This conversion occurs in deeper skin layers and not on the surface of the skin. Therefore the vitamin A deriva ⁇ tive (retinyl derivative) must necessarily be able to pene- trate the skin to produce the intended effect.
  • ⁇ -cyclodextrin A substance which in other contexts has been found to produce improved skin penetrability is ⁇ -cyclodextrin. This substance has been used to increase the bioavailability of pharmacologically active substances both in oral and in topical administration (12). ⁇ -cyclodextrin acts by en ⁇ closing the fat-soluble end of a lipophilic substance and then utilises its own water solubility for penetrating a surface.
  • vitamin A acid on skin is an increase of the skin thickness and elasticity, which counteracts the formation of wrinkles and smoothes existing wrinkles.
  • Vitamin A acid is much more hydrophilic than other vitamin A derivatives and may therefore be used as such in skin preparations. It has, however, been reported that administration of vitamin A acid produces a relatively high frequency of dermatitis-type side-effects in the form of skin wounds and irritations. This may be avoided by ad ⁇ ministering a vitamin A derivative instead.
  • the present invention solves the problem of improving the penetrability of lipophilic vitamin A derivatives into the skin such that after conversion into vitamin A acid they may have a promoting effect on skin thickness and skin elasticity. Therefore, the invention provides a skin care com ⁇ position containing a conjugate of a vitamin A derivative and ⁇ --cyclodextrin as an active ingredient.
  • the invention relates to a method of treating or preventing ageing symptoms in skin by increasing the skin thickness and elasticity, said method comprising application to the skin of a composition com ⁇ prising a conjugate of a vitamin A derivative and ⁇ - cyclodextrin and, optionally, colostrum together with a pharmaceutically acceptable carrier and/or fillers.
  • the mechanism behind the improvement of penetration of the vitamin A derivative after conjugation with ⁇ -cyclo ⁇ dextrin is not known in detail.
  • the ⁇ -cyclodextrin mole ⁇ cules are per se too large to be able to penetrate the skin, but they have the effect that the vitamin A deriva ⁇ tive, which is a strongly lipid-soluble molecule, becomes "artificially" hydrophilic.
  • the vitamin A derivative and the ⁇ -cyclodextrin are included in the conjugate in stoichiometric proportions, i.e. with a 1:2 ratio.
  • the conjugate is mixed with ordinary pharmaceutically acceptable carriers and/or fillers.
  • the skin care composition according to the invention may also be given an antibacterial effect by adding co ⁇ lostrum (raw milk).
  • co ⁇ lostrum raw milk
  • the presence of colostrum keeps the skin clean.
  • Preferred vitamin A derivatives are retinyl esters, especially retinyl palmitate. Comparative clinical tests prove that administration of vitamin A palmitate conjugated with ⁇ -cyclodextrin produces both objective (skin thickness, skin elasticity) and subjective (skin quality) effects which are signifi ⁇ cantly better than for non-conjugated vitamin A palmitate.
  • the invention will be illustrated in more detail by means of the following, nonrestrictive examples together with the accompanying drawing. The Figure shows the result of an in vitro comparison of the skin penetrability for different preparations. EXAMPLE 1 Clinical test A study was carried out in order to test and compare the clinical effect of two different preparations of re ⁇ tinyl palmitate of the same concentration.
  • retinyl palmitate was conjugated with ⁇ -cyclodextrin (according to the invention), whereas in the other prepara- tion, retinyl palmitate was included without conjugation (comparative preparation).
  • the object of the test thus was to test and compare the effect of the two preparations measured with objective as well as subjective parameters.
  • the test was carried out as a comparative double blindfold test in a patient study, i.e. each patient was his own controller.
  • Preparation A contained retinyl palmitate conjugated with ⁇ -cyclodextrin
  • preparation B contained non-conjugated retinyl palmitate.
  • the conjugated retinyl palmitate was prepared by Pedersens Laboratorium, Vejle, Denmark.
  • the retinyl palmitate derived from Roche.
  • the preparations were administered on the inside of the forearm. Two administrations a day (morning and eve ⁇ ning) were effected during 3 months.
  • the arm to which preparation A and preparation B, respectively, should be applied was randomly determined.
  • All skin thickness and elasticity measurements were carried out in the middle of the forearm (measured from wrist to elbow). Measurements of the parameters (skin thickness, elas ⁇ ticity) were carried out by the same person on all subjects on every measuring occasion. The measurements were carried out according to the procedures recommended by the manufac- turer of the used test apparatus "DERMASCAN" .
  • Skin thickness skin thickness, elas ⁇ ticity
  • preparation A gives a signifi- cant increase of the skin thickness when the preparation is used on the inside of the forearm twice a day for three months.
  • preparation B gives no significant increase of the skin thickness as compared to the initial values. This indicates that preparation A is biologically active, whereas preparation B does not seem to have this effect.
  • Skin elasticity Another parameter which is affected and reduced in ageing skin is the elasticity.
  • preparation B does not seem to have any effect on skin elasticity, whereas preparation A seems to produce a significant increase of the elasticity. Evaluation of skin quality
  • Preparation A (according to the invention) thus results in a significantly higher value in the self-evaluation after three months' use as compared to preparation B (product for comparison).
  • Preparation B has no visible effect. No significant difference in tolerance between the two preparations was noticed. Both preparations were well toler ⁇ ated by all subjects of the test. Results The results of this test indicate that the galenical preparation of retinyl palmitate is of vital importance for the clinical effect.
  • A-vita H J Medical, Gothenburg
  • DMn Suduelsson & Wadstein Medicina AB, Lund
  • crystalline lipid carrier with water-soluble vitamin A palmitate according to the invention.
  • isopropyl alcohol both as receptor sub- stance and on the diaphragm
  • the figure is 3.8% an hour
  • the preparation DMn the figure is 1%.
  • the water-soluble preparation of A vitamin palmitate has a better penetrating activity on an artificial diaphragm used as skin model, which is apparent from the enclosed
  • Vitamin A densatum Ph. Eur. 0.20 g ( 2000 IU/ml) Methyl-p-hydroxybenzoate Ph. Eur. 0.10 g

Abstract

A skin care composition is disclosed, comprising as an active ingredient a conjugate of a vitamin A derivative and β-cyclodextrin, and pharmaceutically acceptable carriers and/or fillers. There is also disclosed the use of a conjugate of a vitamin A derivative and β-cyclodextrin and, optionally, colostrum for preparing a composition for therapeutic or prophylactic treatment of ageing symptoms in skin.

Description

SKIN CARE COMPOSITION
The present invention relates to a skin care com- position for therapeutic or prophylactic treatment of ageing symptoms in skin.
Vitamin A in various forms has been found to produce a very good effect when treating ageing symptoms in skin, especially for preventing or treating wrinkles (1, 2). In clinical studies, it has been found that vitamin A acid has a good effect on ageing symptoms in skin (3-6). Various types of creams containing vitamin A esters have been available for a long time, and they have satisfactory cosmetic properties but no anti-wrinkle properties (7). It has been found in studies on animals that an essen¬ tial condition for vitamin A preparations to have an effect is that they penetrate the skin in a satisfactory manner. To make the various vitamin A derivatives effective, it is further necessary to convert them into vitamin A acid in the skin, since the cells have receptors for vitamin A acid only.
Vitamin A acid is relatively hydrophilic, whereas e.g. the esters thereof are relatively lipophilic. The solu¬ bility of the vitamin A esters may be changed such that the skin penetrability is improved by combining the vitamin A ( derivatives with some sort of carrier. The known type of carrier improves the solubility of some lipophilic sub¬ stances. Examples of such carriers are various types of "Tween" (7, 8, 9). However, these carriers produce but a slight improvement of the skin penetrability of the vitamin A derivatives.
The effect of the vitamin A derivatives depends on their being converted in the skin into vitamin A acid. The conversion of vitamin A esters into vitamin A is effected by enzymatic splitting of the ester bond (10). Moreover, the skijn must be able to oxidise retinol (vitamin A1 ) to retine acid (vitamin A acid). It has also been demonstrated that skin converts retinyl derivatives into retine acid (11). This conversion occurs in deeper skin layers and not on the surface of the skin. Therefore the vitamin A deriva¬ tive (retinyl derivative) must necessarily be able to pene- trate the skin to produce the intended effect.
A substance which in other contexts has been found to produce improved skin penetrability is β-cyclodextrin. This substance has been used to increase the bioavailability of pharmacologically active substances both in oral and in topical administration (12). β-cyclodextrin acts by en¬ closing the fat-soluble end of a lipophilic substance and then utilises its own water solubility for penetrating a surface.
The effect of vitamin A acid on skin is an increase of the skin thickness and elasticity, which counteracts the formation of wrinkles and smoothes existing wrinkles.
Vitamin A acid is much more hydrophilic than other vitamin A derivatives and may therefore be used as such in skin preparations. It has, however, been reported that administration of vitamin A acid produces a relatively high frequency of dermatitis-type side-effects in the form of skin wounds and irritations. This may be avoided by ad¬ ministering a vitamin A derivative instead.
For a vitamin A derivative to have the expected clini- cal effect on ageing symptoms in skin, the following cri¬ teria must be satisfied:
1) Satisfactory skin penetrability.
2) Conversion of the vitamin A derivative into vitamin A acid in the skin. 3) The effect of vitamin A acid on the cellular plane.
The present invention solves the problem of improving the penetrability of lipophilic vitamin A derivatives into the skin such that after conversion into vitamin A acid they may have a promoting effect on skin thickness and skin elasticity. Therefore, the invention provides a skin care com¬ position containing a conjugate of a vitamin A derivative and ^--cyclodextrin as an active ingredient.
In a further aspect, the invention relates to a method of treating or preventing ageing symptoms in skin by increasing the skin thickness and elasticity, said method comprising application to the skin of a composition com¬ prising a conjugate of a vitamin A derivative and β- cyclodextrin and, optionally, colostrum together with a pharmaceutically acceptable carrier and/or fillers.
The mechanism behind the improvement of penetration of the vitamin A derivative after conjugation with ^-cyclo¬ dextrin is not known in detail. The ^-cyclodextrin mole¬ cules are per se too large to be able to penetrate the skin, but they have the effect that the vitamin A deriva¬ tive, which is a strongly lipid-soluble molecule, becomes "artificially" hydrophilic.
The vitamin A derivative and the β-cyclodextrin are included in the conjugate in stoichiometric proportions, i.e. with a 1:2 ratio.
To make the form of the conjugate acceptable for topical application, the conjugate is mixed with ordinary pharmaceutically acceptable carriers and/or fillers.
The skin care composition according to the invention may also be given an antibacterial effect by adding co¬ lostrum (raw milk). The presence of colostrum keeps the skin clean.
Preferred vitamin A derivatives are retinyl esters, especially retinyl palmitate. Comparative clinical tests prove that administration of vitamin A palmitate conjugated with β-cyclodextrin produces both objective (skin thickness, skin elasticity) and subjective (skin quality) effects which are signifi¬ cantly better than for non-conjugated vitamin A palmitate. The invention will be illustrated in more detail by means of the following, nonrestrictive examples together with the accompanying drawing. The Figure shows the result of an in vitro comparison of the skin penetrability for different preparations. EXAMPLE 1 Clinical test A study was carried out in order to test and compare the clinical effect of two different preparations of re¬ tinyl palmitate of the same concentration. In one prepara¬ tion, retinyl palmitate was conjugated with β-cyclodextrin (according to the invention), whereas in the other prepara- tion, retinyl palmitate was included without conjugation (comparative preparation). The object of the test thus was to test and compare the effect of the two preparations measured with objective as well as subjective parameters. The test was carried out as a comparative double blindfold test in a patient study, i.e. each patient was his own controller.
Two preparations A and B were prepared and packed in identical jars. Preparation A contained retinyl palmitate conjugated with β-cyclodextrin, and preparation B contained non-conjugated retinyl palmitate. The conjugated retinyl palmitate was prepared by Pedersens Laboratorium, Vejle, Denmark. The retinyl palmitate derived from Roche.
As subjects of the test, 20 women aged 40-60 (average age 50.3 years) were used. The subjects were treated with preparation A and preparation B, respectively, for 3 months.
The preparations were administered on the inside of the forearm. Two administrations a day (morning and eve¬ ning) were effected during 3 months. The arm to which preparation A and preparation B, respectively, should be applied was randomly determined. Half of the subjects used preparation A on the right forearm, while the other half used preparation B. All skin thickness and elasticity measurements were carried out in the middle of the forearm (measured from wrist to elbow). Measurements of the parameters (skin thickness, elas¬ ticity) were carried out by the same person on all subjects on every measuring occasion. The measurements were carried out according to the procedures recommended by the manufac- turer of the used test apparatus "DERMASCAN" . Skin thickness
"DERMASCAN" measurements were carried out on all patients initially (i.e. before starting the treatment), after one month's treatment and after 3 months' treatment. The results are shown in Table 1.
Table 1 Average values, limit values and standard deviations of skin thickness
Skin thickness Initially After After (N=20) 1 month 3 months
Prepara- Average tion A value
(SD) 90.5 (10.2) 97.5 (10.4) 118.7 (10.3)
Limit values 69.1-123.0 68.0-126.2 87.1-132.0
Prepara- Average tion B value
(SD) 91.2 (9.7) 93.1 (10.0) 92.7 (9.9)
Limit values 70.1-110.2 73.1-111.5 74.2-109.8
The results indicate that there is a significant in- crease of the skin thickness of the forearm treated with preparation A, but not of the forearm treated with prepara¬ tion B. The initial values of the skin thickness on the right and left forearm were initially comparable.
It may be concluded that preparation A gives a signifi- cant increase of the skin thickness when the preparation is used on the inside of the forearm twice a day for three months. However, preparation B gives no significant increase of the skin thickness as compared to the initial values. This indicates that preparation A is biologically active, whereas preparation B does not seem to have this effect. Skin elasticity Another parameter which is affected and reduced in ageing skin is the elasticity.
In a manner corresponding to the measurement of the skin thickness, the skin elasticity was measured initially, after one month and after three months. The results of these measurements are shown in Table 2.
Table 2 Average values, limit values and standard deviations of skin elasticity
Skin elasticity Initially After After (N=20) 1 month 3 months
Prepara- Average tion A value
(SD) 60.4 (7.4) 67.2 (7.8) 71.5 (7.9)
Limit values 45.1-80.1 49.1-80.4 50.9-84.20
Prepara- Average tion B value
(SD) 59.9 (7.1) 60.1 (6.9) 60.2 (6.5)
Limit values 44.3-70.1 45.2-71.4 44.7-70.4
The results indicate that the skin elasticity is af- fected by preparation A, but not by preparation B. There is a significant increase of the skin elasticity after three months' use of preparation A, whereas there is no sigificant change after using preparation B.
Just as regarding skin thickness, preparation B does not seem to have any effect on skin elasticity, whereas preparation A seems to produce a significant increase of the elasticity. Evaluation of skin quality
The subjects of the test were allowed to evaluate the change of their skin quality by means of a visual analogous scale of 10 cm having the defined terminal points "no change" and "very great change". The patients were specifi¬ cally asked to register any change in respect of softness and healthy flush of the skin. The results of this self- evaluation are shown in Table 3.
Table 3 Average values, limit values and standard deviations of skin quality
Skin quality After After (N=20) 1 month 3 months
Prepara¬ Average tion A value
(SD) 1.6 (1.0) 5.9 (0.9)
Limit values 0.0-3.1 0.8-8.4
Prepara¬ Average tion B value
(SD) 0.7 (1.2) 0.9 (1.3)
Limit values 0.0-1.2 0.0-1.6
The results indicate that there is a significantly higher value when using preparation A as compared to pre¬ paration B after 3 months (p < 0.001). The tendency is clearly to be seen as soon as after one month. For prepara¬ tion B there is no significant change.
Preparation A (according to the invention) thus results in a significantly higher value in the self-evaluation after three months' use as compared to preparation B (product for comparison). Preparation B has no visible effect. No significant difference in tolerance between the two preparations was noticed. Both preparations were well toler¬ ated by all subjects of the test. Results The results of this test indicate that the galenical preparation of retinyl palmitate is of vital importance for the clinical effect.
Even if retinyl palmitate is administered in the same concentration (0.2%), it has been found that a preparation in which retinyl palmitate is conjugated with a carrier and has thus been made "artificially" water-soluble, has a sig¬ nificantly better clinical effect, measured by both objec¬ tive and subjective measurements, as compared to a prepara¬ tion with non-conjugated retinyl palmitate. Non-conjugated retinyl palmitate does not seem to have any effect either on objective or on subjective parameters during three months' administration, as compared to the initial values (skin thickness, skin elasticity and assess¬ ment of skin quality). The results of this test conform with those noticed in experiments on animals. EXAMPLE 2
Penetration of various retenoid preparations in a model barrier system (Franz's diffusion cell) An artificial 50 μm thick diaphragm was used as skin model (13, 14). The diaphragm was treated either with iso¬ propyl alcohol or with water, and the receptor solutions were isopropyl alcohol or methanol.
The following preparations were used: 1. Sincera TM (Samuelsson & Wadstein Medicina AB, Lund) containing 2000 IU water-soluble vitamin A palmitate
(according to the invention)
2. A-vita (H J Medical, Gothenburg) as an example of a commercial cream containing vitamin A palmitate, and 3. DMn (Samuelsson & Wadstein Medicina AB, Lund), crystalline lipid carrier with water-soluble vitamin A palmitate (according to the invention). While using isopropyl alcohol both as receptor sub- stance and on the diaphragm, Sincera TM penetrates the diaphragm during a 24 h exposure by 5.5% of the total amount an hour. For A-vita, the figure is 3.8% an hour, and for the preparation DMn, the figure is 1%. By using water on the diaphragm, which is more similar to the in vivo system, Sincera TM penetrates the skin by 3.1%, and A-vita can barely be detected. DMn penetrates by up to 5.8% an hour. The difference between A-vita, Sincera TM and DMn depends on the water solubility of A vitamin palmitate in Sincera TM and
DMn.
Results
The water-soluble preparation of A vitamin palmitate has a better penetrating activity on an artificial diaphragm used as skin model, which is apparent from the enclosed
Figure.
EXAMPLE 3
Examples of preparations
Day cream
Contents per 100 ml
Soybean oil 19.05 ml
Arachis oil 15.00 ml Non-ionic emulsifier 6.00 g β-cyclodextrin 0.80 g
Vitamin A densatum Ph. Eur. 0.20 g (= 2000 IU/ml) Methyl-p-hydroxybenzoate Ph. Eur. 0.10 g
Ethyl-p-oxybenzoate DLS 0.10 g Colostrum protein 1.350 g
Sunscreen agent F-6 PABA 3%
Distilled water up to 100 ml Night cream Contents per 100 ml Arachis oil 19.05 ml Soybean oil 19.05 ml
Emulsifier E 471 and E 472 c 6.20 g Methyl-p-hydroxybenzoate Ph. Eur. 0.143 g Ethyl-p-oxybenzoate DLS 0.143 g β-cyclodextrin 0.800 g Vitamin A densatum Ph. Eur. 0.200 g (= 2000 IU/ml)Colostrum protein 1.350 g Distilled water up to 100 ml
Literature
1. Boyd A S, An overview of the retinoids. The American J of Medicine 1989; 86: 568-574
2. Thome E G, Topical tretinoin research: A historical perspective. The J of Int Medical Research 1990; 18: 18c-25c
3. Kligman A M, Grave G L, Hirose R, Leyden J J, Topical tretinoin for photoaged skin. J Am Aced Dermatol,
1986; 836-859
4. Weiss J S, Ellis C N, Headington J T, Hamilton T A, Voorhees J J. Topical tretinoin improves photoaged skin: a double-blind vehicle controlled study. JAMA, 1988; 259: 527-532
5. Bhawan J, Gonzales-Serva A, Nenal K, Labadie R, Lufrano L, Thorne G et al. Effect of tretinoin on photodamaged skin. Arch Dermatol 1991; 127: 666-672
6. Rafal E S, Griffiths C E M, Cherie M P C P, Ditra M, Finkel L J, Hamilton T A et al. Topical tretinoin
(retinoic acid) treatment for liver spots associated with photodamage. The New England J of Medicine 1992; 6: 368-374
7. Jarrett A, Jackson R J. The effects of vitamin A on the skin and its role as a cosmetic agent.
8. Spearman R I C, Jarrett A. Biological comparison of isomers and chemical forms of vitamin A (retinol). Br J of Dermatology 1974; 90: 553-560
9. Stuttgen G. Zur Lokalbehandlung von Keratosen mit Vitamin A-saure. Dermatologica. 1962; 124: 65-80
10. Shapiro S. Retinoids and epithelial differentiation in retinoids and cell differentiation. M Sherman Id. CRC Press Inc. Boca Raton 1986; 25-59
11. Connor M, Smit M H. The formation of all-trans retinyl in hairless mouse skin. Biochem Pharmacol 1987; 36:
919-924 12. Pagington J S. Beta-cyclodextrin: The success of molecular inclusion. Chemistry in Britain 1987; 23: 455-458
13. Thomas J Franz: Current problems in dermatology. Vol 7, s 56-58, 1978
14. Christian Surber et al: J Pharm Pharmacol 1991, 43:836-840

Claims

1. Skin care composition, c h a r a c t e r i s - e d by comprising, as an active ingredient, a conjugate of a vitamin A derivative and -cyclodextrin, and a phar¬ maceutically acceptable carrier and/or fillers.
2. Skin care composition as claimed in claim 1, c h a r a c t e r i s e d by further comprising colos- trum.
3. Skin care composition as claimed in claim 1 or 2, c h a r a c t e r i s e d in that the vitamin A deriva¬ tive is a retinyl ester.
4. Skin care composition as claimed in claim 3, c h a r a c t e r i s e d in that the retinyl ester is retinyl palmitate.
5. Use of a conjugate of a vitamin A derivative and ^-cyclodextrin and, optionally, colostrum for preparing a composition for therapeutic or profylactic treatment of ageing symptoms in skin.
PCT/SE1994/000235 1993-03-24 1994-03-17 Skin care composition WO1994021225A1 (en)

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SE19939300971A SE9300971D0 (en) 1993-03-24 1993-03-24 HUDVAARDSKOMPOSITION

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WO1997002117A1 (en) * 1995-06-30 1997-01-23 The Gillette Company Shaving aid composite with an inclusion complex of a skin-soothing agent and cyclodextrin
DE19619990A1 (en) * 1996-05-17 1997-11-20 Charlotte Adler Process for the production of colostral milk products and their use
WO1998022083A1 (en) * 1996-11-15 1998-05-28 Interhealth Ab Therapeutic and cosmetic compositions, their use and method for the preparation thereof
US5985296A (en) * 1997-03-27 1999-11-16 Wacker-Chemie Gmbh Complexes of gamma-cyclodextrin and retinol or retinol derivatives, processes for their preparation and their use
WO1999058104A1 (en) * 1998-05-12 1999-11-18 Interhealth Ab Therapeutic compositions
US6350459B1 (en) * 1996-11-14 2002-02-26 Shiseido Company, Ltd. Solubilized cosmetic composition with a pharmaceutical or cosmetic agent, a methacrylate copolymer and a cyclodextrin
WO2002038123A1 (en) * 2000-11-13 2002-05-16 Wadlund As A skin cream composition
KR100404868B1 (en) * 2000-03-28 2003-11-15 김삼 Stable retinol palmitate and cosmetic composition containing the same
DE10257246A1 (en) * 2002-12-07 2004-06-24 Beiersdorf Ag Aqueous or aqueous-alcoholic cosmetic or dermatological composition useful for matting shiny facial skin includes one or more powder raw materials selected from sugar derivatives
EP1738752A1 (en) * 2002-12-27 2007-01-03 Schering Aktiengesellschaft Pharmaceutical combinations comprising cis-retine acid
WO2008035982A1 (en) * 2006-09-20 2008-03-27 Pharma Medico Research Limited COMBINATION OF A GLUCOCORTICOID AND A β-CYCLODEXTRIN CONJUGATED VITAMIN A DERIVATE COMPLEX
WO2009020398A2 (en) * 2007-08-06 2009-02-12 Spero As Skin care product
WO2013036286A3 (en) * 2011-09-07 2014-05-01 Island Kinetics Inc. Retinal cyclodextrin acetals and hemiacetals for clarifying skin complexion
WO2014055532A3 (en) * 2012-10-02 2014-10-16 Allergan, Inc. Dermal filler hydrogels with vitamin a/cyclodextrin inclusion complexes
EP2956216A4 (en) * 2013-02-15 2016-10-19 Perricone Nv Llc Topical composition for stimulating epidermis and dermis layers of the skin

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Cited By (27)

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WO1997002117A1 (en) * 1995-06-30 1997-01-23 The Gillette Company Shaving aid composite with an inclusion complex of a skin-soothing agent and cyclodextrin
AU695164B2 (en) * 1995-06-30 1998-08-06 Gillette Company, The Shaving aid composite with an inclusion complex of a skin-soothing agent and cyclodextrin
DE19619990A1 (en) * 1996-05-17 1997-11-20 Charlotte Adler Process for the production of colostral milk products and their use
US6350459B1 (en) * 1996-11-14 2002-02-26 Shiseido Company, Ltd. Solubilized cosmetic composition with a pharmaceutical or cosmetic agent, a methacrylate copolymer and a cyclodextrin
AU727291B2 (en) * 1996-11-15 2000-12-07 Interhealth Ab Therapeutic and cosmetic compositions, their use and method for the preparation thereof
WO1998022083A1 (en) * 1996-11-15 1998-05-28 Interhealth Ab Therapeutic and cosmetic compositions, their use and method for the preparation thereof
US5985296A (en) * 1997-03-27 1999-11-16 Wacker-Chemie Gmbh Complexes of gamma-cyclodextrin and retinol or retinol derivatives, processes for their preparation and their use
WO1999058104A1 (en) * 1998-05-12 1999-11-18 Interhealth Ab Therapeutic compositions
US6406708B1 (en) 1998-05-12 2002-06-18 Interhealth Ab Therapeutic compositions
KR100404868B1 (en) * 2000-03-28 2003-11-15 김삼 Stable retinol palmitate and cosmetic composition containing the same
US7557094B2 (en) * 2000-11-13 2009-07-07 Ethics Cosmeceuticals Ab Skin cream composition
WO2002038123A1 (en) * 2000-11-13 2002-05-16 Wadlund As A skin cream composition
DE10257246A1 (en) * 2002-12-07 2004-06-24 Beiersdorf Ag Aqueous or aqueous-alcoholic cosmetic or dermatological composition useful for matting shiny facial skin includes one or more powder raw materials selected from sugar derivatives
EP1738752A1 (en) * 2002-12-27 2007-01-03 Schering Aktiengesellschaft Pharmaceutical combinations comprising cis-retine acid
WO2008035982A1 (en) * 2006-09-20 2008-03-27 Pharma Medico Research Limited COMBINATION OF A GLUCOCORTICOID AND A β-CYCLODEXTRIN CONJUGATED VITAMIN A DERIVATE COMPLEX
WO2009020398A3 (en) * 2007-08-06 2009-04-02 Spero As Skin care product
WO2009020398A2 (en) * 2007-08-06 2009-02-12 Spero As Skin care product
KR102008925B1 (en) 2011-09-07 2019-08-08 아일랜드 키네틱스 인코포레이티드 Retinal cyclodextrin acetals and hemiacetals for clarifying skin complexion
WO2013036286A3 (en) * 2011-09-07 2014-05-01 Island Kinetics Inc. Retinal cyclodextrin acetals and hemiacetals for clarifying skin complexion
KR20140064920A (en) * 2011-09-07 2014-05-28 아일랜드 키네틱스 인코포레이티드 Retinal cyclodextrin acetals and hemiacetals for clarifying skin complexion
CN103987391A (en) * 2011-09-07 2014-08-13 爱兰德动力学公司 Chirally Correct Retinal Cyclodextrin Acetals for Clarifying Skin Complexion
JP2014528008A (en) * 2011-09-07 2014-10-23 アイランド キネティックス インコーポレイテッド Retinal cyclodextrin acetals and hemiacetals for cleansing the skin appearance
AU2012304886B2 (en) * 2011-09-07 2016-09-29 Island Kinetics Inc. Retinal cyclodextrin acetals and hemiacetals for clarifying skin complexion
WO2014055532A3 (en) * 2012-10-02 2014-10-16 Allergan, Inc. Dermal filler hydrogels with vitamin a/cyclodextrin inclusion complexes
AU2013327489B2 (en) * 2012-10-02 2018-01-04 Allergan, Inc. Dermal filler hydrogels with vitamin A/cyclodextrin inclusion complexes
EP3656371A1 (en) * 2012-10-02 2020-05-27 Allergan, Inc. Dermal filler hydrogels with vitamin a/cyclodextrin inclusion complexes
EP2956216A4 (en) * 2013-02-15 2016-10-19 Perricone Nv Llc Topical composition for stimulating epidermis and dermis layers of the skin

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