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WO1997018804A1 - Rajeunissement de la peau a l'aide d'une combinaison de vitamine a et d'acides alphahydroxy - Google Patents

Rajeunissement de la peau a l'aide d'une combinaison de vitamine a et d'acides alphahydroxy Download PDF

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Publication number
WO1997018804A1
WO1997018804A1 PCT/US1996/018758 US9618758W WO9718804A1 WO 1997018804 A1 WO1997018804 A1 WO 1997018804A1 US 9618758 W US9618758 W US 9618758W WO 9718804 A1 WO9718804 A1 WO 9718804A1
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WO
WIPO (PCT)
Prior art keywords
composition
skin
vitamin
acid
present
Prior art date
Application number
PCT/US1996/018758
Other languages
English (en)
Inventor
James E. Fulton, Jr.
Original Assignee
Vivante Pharmaceuticals, Inc.
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 Vivante Pharmaceuticals, Inc. filed Critical Vivante Pharmaceuticals, Inc.
Priority to AU10813/97A priority Critical patent/AU1081397A/en
Publication of WO1997018804A1 publication Critical patent/WO1997018804A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/05—Phenols
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • vitamin A was responsible for the benefits of fruits and vegetables and that it acted by stimulating new cell growth in the epithelium, producing softer, smoother skin.
  • vitamin A was synthesized and became available as a therapeutic agent. From that time forward, it has been recognized that vitamin A is an essential vitamin for the nutrient health of the skin.
  • the vitamin was administered internally in large doses, usually in the form of an ester of vitamin A called vitamin A palmitate.
  • vitamin A palmitate an ester of vitamin A
  • internal administration of these esters proved toxic and produced hypervitaminosis A, a cluster of toxic symptoms such as hair loss, migraine headache, fatigue, bone pain and congenital defects.
  • U.S. Patent No. 3,729,568 disclosed that repeated topical applications of vitamin A acids to areas of the skin alleviated these symptoms. Although the treatments disclosed in this patent were targeted predominately at the treatment of acne vulgaris, vitamin A became a general topical therapeutic agent well-known to the art of dermatology.
  • U.S. Patent No. 4,603,146 disclosed the beneficial effect of this vitamin A acid on retarding the effects of aging on skin.
  • This patent disclosed that vitamin A acid results in a lightening of skin, diminished wrinkling and disappearance of early sun damaged spots such as actinic keratoses.
  • treatment with this vitamin A acid causes excessive visible irritation and inflammation of the skin.
  • the skin exhibited an abnormal redness or erythema followed by painful, unpleasant peeling of the skin which could be severe. Large chunks of skin are sloughed from the surface, giving the appearance of peeling, or in the case of the scalp, dandruff. This is seen clinically as surface roughness along with abnormal redness.
  • alphahydroxy acid treatments were not as effective as the vitamin A acid treatments. Using alphahydroxy acids, it was difficult to produce visible peeling and to slough out the acne impactions or to pool off the keratoses. In addition, the high concentrations of alphahydroxy acids required to produce such effects resulted in excessive burning, erosions, or even scarring when applied to the skin.
  • vitamin A acid or alphahydroxy acids induces skin proliferation and new cell growth. Because of the rapid stimulation of skin proliferation and new cell growth, these individual ingredients are effective in the treatment of acne and other hyperkeratotic skin conditions. Normally, the turnover of skin is 28 days for a new cell to form and then, finally, shed itself off at the surface. Both these compounds reduce this regenerative time to between 10 and 15 days.
  • the regenerative portion of the skin, the epidermis, is doubled in thickness to compensate for this stimulation.
  • the top layer of skin is reduced from 14 layers of impacted cells to 8 or 9 layers of loosely woven cells.
  • the present invention relates to improved methodologies and improved associated pharmaceutical compositions for therapeutically reducing the effects of skin damage and for the treatment of various dermatologic disorders such as acne without the abrasive and irritating characteristics of previous compounds such as vitamin A acid.
  • compositions of the present invention are applied topically in the form of lotions, including cream vehicles.
  • the combination of vitamin A and alphahydroxy acids is effective for rejuvenation of human skin, treatment of skin disorders, and the general improvement of the quality and appearance of skin. Additionally, the combination provides an effective method to retard and reduce the effects of photoaging and environmental damage on skin.
  • the combination is effective in treating hyperkeratotic skin diseases such as acne vulgaris, disorders of keratinization such as ichthyosis, Darier's disease, acne, psoriasis and other similar conditions, early skin degenerations and precancerous conditions such as actinic keratoses, lentigos, lentigo malignas and melasma.
  • hyperkeratotic skin diseases such as acne vulgaris, disorders of keratinization such as ichthyosis, Darier's disease, acne, psoriasis and other similar conditions
  • early skin degenerations and precancerous conditions such as actinic keratoses, lentigos, lentigo malignas and melasma.
  • the vitamin A is covalently linked to an aicd throuhg an ester bond.
  • A/alphahydroxy acid combination is vitamin A propionate/glycolic acid.
  • the viatmin A propionate may be present at a concentration of about 0.1 % to 10%.
  • the vitamin A propionate is present at a concentration of about 0.1 % to 4%.
  • the glycolic acid is present at a concentration of about 2% to 10%.
  • This formulation is distinct from previous compositions which employed long chain esters such as vitamin A palmitate alone. Vitamin A palmitate is ill suited for use in externally applied lotions because it is too large a molecule to effectively penetrate into the skin.
  • the present combination is distinct from prior formulations which employed vitamin A propionate alone.
  • This formulation is also distinct from previous compositions employing alphahydroxy acids such as glycolic acid, lactic acid and citric acid by themselves
  • alphahydroxy acids such as glycolic acid, lactic acid and citric acid by themselves
  • the combination of vitamin A with alphahydroxy acids is more effective than alphahydroxy acids alone.
  • compositions and methods of the present invention provide advantages over the currently used treatments of the above conditions For example, because the combination of vitamin A with alphahydroxy acids causes cells to fall off one at a time, the large chunks of peeling caused by treatment with vitamin A acid alone is avoided Thus, the present invention achieves the benefits of increased turnover of skin without the detrimental visible effects of prior treatments. Additionally, with the present invention the treatments are easier for patients to tolerate and to disguise by applying make-up
  • the present invention also provides advantages over current treatments of acne vulga ⁇ s Using the present invention, the unpleasant side effects associated with oxidizing the skin with benzoyl peroxide and the skin irritation caused by detergents are avoided.
  • the present invention is also uniquely effective in increasing the penetration of other active molecules.
  • active molecules include antifungals such as Ketoconazole or Tolnafate, anti cancer agents such as Methotrexate or 5-Fluorourac ⁇ l, and anti bacterial agents such as Chlorhexidine or Gentamicin.
  • antifungals such as Ketoconazole or Tolnafate
  • cancer agents such as Methotrexate or 5-Fluorourac ⁇ l
  • anti bacterial agents such as Chlorhexidine or Gentamicin.
  • additional agents can be combined with the compositions of the present invention by incorporating them in the carrier base of lotions containing a combination of vitamin A and alphahydroxy acids
  • Another objective of the present invention is to develop a method of maintaining the skin in its rejuvenated state over a long period of time, thereby avoiding the visible effects of skin damage or aging
  • the present compositions and skin care regimens provide a refreshing renewal of the skin on a long term basis. Further features and advantages of the present invention shall become apparent to those skilled in the art from the consideration of the following detailed description of the invention.
  • this invention is based upon the discovery that appropriately formulated and allied combinations of vitamin A and alphahydroxy acid compositions unexpectedly exhibit a high degree of skin regenerative activity without the associated peeling, erythema and irritant effects of the use of vitamin A acid alone.
  • the present invention is useful in reducing the visible effects of skin damage or aging
  • the present invention also finds application in treating numerous skin disorders and conditions, as well as benign epidermal tumors.
  • the present invention may also be used to enhance the penetration of other active substances into the skin.
  • the present invention produces these benefits without the excessive peeling associated with vitamin A acid treatment or the burning associated with glycolic acid treatment.
  • the therapeutic properties of the combination of the present invention are especially surprising in light of the absence of similar properties of other derivatives such as the alcohol and ester forms of vitamin A.
  • the following description includes combination systems for delivering vitamin A propionate and glycolic acid topically to the area of skin.
  • vitamin A and the use of alphahydroxy acids may be aware of a large variety of applications used for treating skin disorders and conditions responsive to induced proliferation and increased epidermal penetration.
  • the following examples are offered. It is understood that these examples do not limit the scope of the invention.
  • the compositions produced in accordance with the teachings of the present invention will be gels that are easily applied to the skin. Alcohol based or cream based carriers can be used to deliver therapeutic amounts of the present combinations of active agents to the skin.
  • the alcohol gels are preferred for applications on the face where a high-potency effect is required.
  • the handling characteristics of the alcohol-based carrier system in the present invention can be varied by addition of thickening agents which add body to the composition and are capable of increasing the viscosity of the alcohol base.
  • Hydroxy propyl celluloses are particularly effective as thickening agents.
  • the amount of the thickening agent depends upon the desired consistency and viscosity.
  • the carrier system contain the thickening agents with viscosity characteristics can be dependent upon the non-polarity or polarity of the solvent system, the pH, and that other thickeners may be added to meet these requirements.
  • the combination of vitamin A and alphahydroxy acids can also be applied to the skin in a cream vehicle.
  • the cream ointment vehicles are not as effective as the alcohol gels.
  • the more subtle effects of a cream base over a longer period of time may be beneficial, on the arms and legs for ichthyosis and actinic keratoses.
  • the cream vehicles should be a special formulation that allow the active ingredients to diffuse into the skin and are not irritating or comedogenic such that they may be used without causing dermatitis or the flaring up of acne conditions.
  • Other non-irritating additives may be useful to prolong the shelf life, such as preservatives or to beneficially aid the user, such as sunscreens.
  • There are appropriate components for the present invention that have additional benefits of protecting the skin and adding as natural moisturizers to prevent further skin dehydration and sun damage.
  • sunscreens such as para aminobenzoic acid and its derivatives
  • extract of aloe vera plants and often common lotion additives such as sodium, PCA, sodium lactate, urea, nicotinamide, fructose and other natural conditions and moisturizers of skin.
  • preservatives in the amounts that do not alter the safety and efficacy of the preparation, but preserve its usefulness.
  • Any compatible preservative which is pharmaceutically active is appropriate for this application.
  • Preferred preservatives are butylated hydroxy toluene and methyl and pr ⁇ pylparaben and phenoxyethenol.
  • other therapeutically active additives that are commonly in externally applied lotions. The combination of additional active ingredients are more effective when applied in these vehicles. Other active molecules may become more potent in the presence of these formulations that increase the metabolism of the skin.
  • Example 2 demonstrates that the compositions of the present invention produce a dramatic increase in the size of the epidermal cell population. Furthermore, synergistic effects were observed when a combination of vitamin A propionate and glycolic acid was administered.
  • EXAMPLE 2 Guinea Pig Epidermal Proliferation Study The vitamin A propionate-glycolic acid formulation described in Example 1 was applied to the back of six hairless guinea pigs. This controlled study included (1) the formulation without vitamin A and glycolic acid (2) the formulation with the glycolic acid at 5% and (3) the formulation with the vitamin A propionate at 2% and (4) a control of vitamin A acid .01 %. The applications were continued for 14 days, after which biopsies were taken from the treated sites. After fixation in formaldehyde and sectioning in paraffin, the sections were stained with hematoxlin eosin. The number of epidermal cells within a 100 micron area was counted at these five treated sites. Table 1 lists the results. The synergy of the vitamin A propio ⁇ ate/glycolic mixture was apparent. There was a dramatic increase in the size of the epidermal cell population.
  • Vitamin A Acid .01% 22.1%
  • Example 3 demonstrates that the present compositions were effective in reducing the depth of crow's feet.
  • EXAMPLE 3 Computer Imaging for Contour Analysis Twelve human subjects applied the vitamin A propionate glycolic lotion to the right lateral eyelid area in the area of crow's feet. The vehicle was used in a similar area in the left lateral eyelid area of crow's feet. The two formulations were applied daily for one month. A contour analysis which provides quantified values and three- dimensional graphic representations of the skin surface was performed on all subjects before and after one month of treatment. The skin smoothness and wrinkle depth was recorded and compared to their pre-treatment value. There was a 21.2% improvement in the depth of superficial fine Iines on the active formulation side and a 3.5% improvement in the depth of fine iines on the vehicle treated side.
  • Example 4 demonstrates that the present compositions were effective in reducing the thickness of the stratum corneum.
  • Transepidermal Water Loss The use of the rate of transepidermal water loss (TEWL) is a well recognized means for measuring the stratum corneus thickness.
  • the TEWL increases when the top layer of stratum corneums are reduced in thickness.
  • compositions of the present invention are effective in increasing the penetration of other active agents into the skin, as shown in the experiments of Example 5.
  • Dansyl Chloride is the fluorescent molecule that penetrates through the skin. The rate of penetration is dependent upon the number of layers of the intact stratum corneum The reduced stratum corneum would allow for more rapid penetration of Dansyl Chloride and other similar types of molecules.
  • the inner aspect of the right forearm was treated on ten subjects with the combination vitamin A propi ⁇ ate/glycoiic acid conditioning lotion The other forearm was treated with the vehicle alone. After two weeks of twice daily applications, the Dansyl Chloride penetration test was conducted The 10% Dansyl Chloride in petroleum was applied on a 1 cm patch to six separate areas.
  • Example 6 describes the results of experiments demonstrating the efficacy of the present compositions as a treatment for acne vulga ⁇ s With the present compositions, a 60% reduction in the effects of acne vulga ⁇ s was obtained.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des procédés d'accélération du rajeunissement de la peau et des procédés de traitement sous forme de soin de la peau utilisant une combinaison de vitanime A et d'acides alphahydroxy, telle que la combinaison de propionate de vitamine A et d'acide glycolique. On peut préparer la composition dans un support à base d'alcool présentant des concentrations allant d'approximativement 0,01 % à 10 % de proponiate de vitamine A, de préférence 0,1 à 4 %, et de 0,1 à 30 % d'acide glycolique, de préférence de 2 à 10 % d'acide glycolique. En plus de l'alcool, le support peut également comprendre du propylène glycol, des agents conservateurs, des agents épaississants et des tensio-actifs non ioniques. On applique la formulation localement sur la peau à une fréquence produisant une légère desquamation. On peut également utiliser la formulation afin d'accélérer la pénétration d'autres agents thérapeutiques dans la peau.
PCT/US1996/018758 1995-11-21 1996-11-21 Rajeunissement de la peau a l'aide d'une combinaison de vitamine a et d'acides alphahydroxy WO1997018804A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10813/97A AU1081397A (en) 1995-11-21 1996-11-21 Rejuvenating the skin using a combination of vitamin a and alphahydroxy acids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US741095P 1995-11-21 1995-11-21
US60/007,410 1995-11-21

Publications (1)

Publication Number Publication Date
WO1997018804A1 true WO1997018804A1 (fr) 1997-05-29

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ID=21725991

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/018758 WO1997018804A1 (fr) 1995-11-21 1996-11-21 Rajeunissement de la peau a l'aide d'une combinaison de vitamine a et d'acides alphahydroxy

Country Status (2)

Country Link
AU (1) AU1081397A (fr)
WO (1) WO1997018804A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2138571A1 (es) * 1998-06-26 2000-01-01 Gimenez Gella Tatiana Procedimiento cosmetico para el tratamiento de la piel.
FR2780888A1 (fr) * 1998-07-09 2000-01-14 Benac Lotion nettoyante et traitante destinee au traitement des comedons
US6183761B1 (en) 1998-03-16 2001-02-06 The Procter & Gamble Company Compositions for regulating skin appearance

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091171A (en) * 1986-12-23 1992-02-25 Yu Ruey J Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use
US5554652A (en) * 1986-12-23 1996-09-10 Tristrata Inc Method of treating wrinkles using alpha hydroxyacids, alpha ketoacids and a sunscreen agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091171A (en) * 1986-12-23 1992-02-25 Yu Ruey J Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use
US5091171B1 (en) * 1986-12-23 1995-09-26 Ruey J Yu Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use
US5554652A (en) * 1986-12-23 1996-09-10 Tristrata Inc Method of treating wrinkles using alpha hydroxyacids, alpha ketoacids and a sunscreen agent
US5091171B2 (en) * 1986-12-23 1997-07-15 Tristrata Inc Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6183761B1 (en) 1998-03-16 2001-02-06 The Procter & Gamble Company Compositions for regulating skin appearance
ES2138571A1 (es) * 1998-06-26 2000-01-01 Gimenez Gella Tatiana Procedimiento cosmetico para el tratamiento de la piel.
FR2780888A1 (fr) * 1998-07-09 2000-01-14 Benac Lotion nettoyante et traitante destinee au traitement des comedons
WO2000002593A3 (fr) * 1998-07-09 2000-08-24 Benac Sa Lotion nettoyante et traitante destinee au traitement des comedons

Also Published As

Publication number Publication date
AU1081397A (en) 1997-06-11

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