Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
• • 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

Definitions

• the present invention relates to a composition that contains gibberellins, and the use of such compositions for the treatment of impaired hair growth (alopecia) , such as androgenic alopecia in mammals (including humans) and preferably for the treatment of male pattern baldness.
• alopecia impaired hair growth
• the inventive concept is adapted for the treatment method of progressive (on-going) alopecia that is reversible and therefore can be cured. This method enables that the final state of alopecia may be delayed.
• the hair can be divided into different types - hair of the scalp and hair of the remaining parts of the body, e.g. eye-brow, beard and fine vellus hair.
• the invention is primarily directed towards the treatment of alopecia of the scalp.
• Alopecia means decreased hair growth on the scalp and results in more or less apparent baldness. It may be divided into two main groups - diffuse and patchy. The most common type of alopecia in men is male pattern baldness or androgenic alopecia (diffuse) . This type of loss of scalp hair is androgen-dependent and increases with age. The triggering factor has been considered to be purely genetical. Other factors giving rise to alopecia are: fever and stress; syphilis; endocrine causes; nutritional; certain drugs; hair shaft defects etc.
• the gibberellins are a group of compounds which are found in higher plants and in certain fungi. Their basic carbon skeleton is (Formula I) :
• the glycosidic bond to a gibberellin is normally of the O- ⁇ -type with the sugar moiety selected from D-glucose, D-galactose, D-arabinose and D-xylose.
• the gibberellins with the highest activity are derived from basic compounds exhibiting the gibberellin skeleton (formula I) .
• the biological (hormonal) activity is increased by the oxidation of a methyl group (CH3-) at position 10 to a hydroxy methyl group (HOCH 2 -) or to an aldehyde group (OCH-) , or simply by direct hydroxylation at the 10-carbon (gives 10-OH gibberellins) .
• lactonization can occur subsequently with a carboxy at position 4 resulting in a 4-10 lactone bridge (essential for high activity in non-animal species (plants, fungi etc) .
• Other transformations that increase the activity in non-animal species are 3- and 12-hydroxylations (resulting in 3-OH and 12-OH gibberellins) , possibly combined with the oxidations and lactonizations previously mentioned.
• the active GAs regulate growth and differentiation of non-animal species, such as plants and fungi. They are active in very small amounts. Their mode of action is through receptor binding and transcriptor initiation, i.e. analogous to the steroid hormones in mammals.
• the normal amounts of GAs in plant material are in the range of 10-100 ng per g fresh weight.
• the concentration in pollen is about one order of magnitude higher than in vegetative tissue, i.e. up to ⁇ gs per gram.
• gibberellins (EP 79,074) in a hair composition with a proposed activity against alopecia.
• Five particular gibberellins were then mentioned - (i) four with a lactone bridge between positions 2 and 5 (designated GA ⁇ L, GA 2 , GA 3 , and GA 4 ) , and (ii) one (designated GA 3 1) with a lactone bridge between positions 10 and 4 together with a methylene group (CH2-) at position 4 binding to an unspecified group.
• the doses suggested were relatively high and no connection was made to the cause of the alopecia to be treated.
• activity against alopecia is not suggested, instead the composition is focused on various hair tonic effects, such as promotion of hair care and the prevention of dandruff and itch.
• various hair tonic effects such as promotion of hair care and the prevention of dandruff and itch.
• compositions containing pollen or pollen components have repeatedly been suggested in connection with improving hair appearance.
• Other compositions with an alleged effect on i.a. alopecia have previously been presented in: FR 2,641,164 that describes a dietetic composition containing 1-30% pollen; and Derwent Abstracts Nos 89-194760-3/27 and No 89- 214776/30 that give various compositions containing water extracts of pollen.
• a recent composition based on hop, particularly phytohormones present in hop pollen, has been suggested for androgen-dependent alopecia (DE 4,121,544, Derwent Abstract No 93-009623/02) .
• FR 2,587,208 suggests a composition for the treatment of diffuse alopecia that is androgen dependent.
• the constituents of the composition are alleged to act synergistically.
• One of the constituents may by zinc-ions.
• the ' above-mentioned publications are illustrative that during the centuries and depending on geographical area there have been great demands for agents that act against alopecia in both male and females.
• the common idea among doctors has been that "Patent remedies and hair tonics are of no proven value, and patients should be told of this" (MacKee, R.M. , Clinical Dermatology, Oxford Medical Publications (1986) p. 192) .
• the action of the active gibberellins are, based on today's knowledge, that they bind to the androgen receptor thereby blocking binding of androgens and inhibiting the negative effect the androgen-receptor complex has on hair development.
• the composition of the invention is characterized by containing an effective concentration or amount of one or more gibberellins with activity against androgenic alopecia.
• effective concentration/amount is meant a concentration/amount that delays or prevents this type of alopecia, i.e. with respect to androgenic alopecia the concentration/amount is anti-androgenic.
• concentration/amount depends on the specific gibberellin(s) selected and other ingredients of the composition, but as a rule of thumb the total level of GAs are often lower than in the gibberellin compositions presented in the prior art (EP-A-79,074) .
• the preferred concentration is in the range 10 ⁇ 9 -10 ⁇ 6 g per gram of the final composition that is to be applied directly onto the scalp.
• gibberellins with low biological activity for instance those having no hydroxyl group at any of positions 3, 12 and 13 or no lactone bridge, the upper and lower limits of the interval may have to be multiplied with a factor 10 3 or 10 4 .
• the four gibberellins described in EP-A-79,074 (having a 2-5 lactone bridge) are likely to be such low-activity gibberellins.
• Preferred gibberellins are illustrated by those having
• a lactone bridge between positions 4 and 10 (as defined above) together with a hydrogen, methyl, hydroxymethyl or carboxy at position 4, optionally in combination with a hydroxy at position 13, and/or (ii) a hydrogen or preferably a hydroxy group at at least one position selected from positions 3, 12 and 13.
• Preferred GA-variants also encompass gibberellins in which the previously mentioned carboxy and/or hydroxy groups forms glycoside esters and ethers, respectively.
• GAs having a carboxy group are particularly preferred because this group imposes a ionophoric property onto the molecule enabling the formation of hydrophobic ion complexes, the absorption of which may be enhanced according to general principles known in the field.
• Other advantageous forms of GAs carry a labilely esterified carboxy group that may become hydrolysed during use.
• a certain GA may be useful in the invention can be obtained by testing for hormonal/ biological activity in non-animal species.
• a suitable model is the Tan-ginbozu dwarf rice drop bioassay (Murakami, Botan. Magazine (Tokyo) 81 (1968) p. 33-) .
• final judgement of specific anti-androgenic effects against alopecia requires verification by case studies, for instance as described in the experimental section below.
• GAs are of fungal origin and are commercially available in bulk quantities. Other GAs can be synthesized from fungal GAs or obtained from other sources, such as higher plants, in particular from pollen.
• the inventive compositions do not require highly purified forms of GAs. It suffices to use partly purified fungal or more preferably partly purified plant and pollen preparations that are enriched in GAs (preferably in the form of extracts) . Pollen grains as such have been suggested to be incorporated into various cosmetic preparation. However, with respect to the availability of GAs, pollen grains are not recommendable to use in this invention because the pollen envelope will effectively prevent the release of their content of GAs.
• the pollen envelope must have been disintegrated or the gibberellins otherwise released from the pollen interior.
• a solvent that dissolves the GAs of interest.
• Suitable solvents are pure organic solvents or solvent mixtures containing water and one or more water-miscible organic solvent, such as methanol, ethanol, acetone etc, optionally together with a water-immiscible solvent that is miscible with the above-mentioned mixture of water and a water- miscible solvent.
• the water content of the extracting solvent may in most cases vary between 0-25% (v/v) , in particular between 2-25% (v/v) .
• the extract as such can be incorporated into the inventive compositions, otherwise the solvent has to be removed, for instance, by lyophilization, spray drying or evaporation under reduced pressure. Suitable extracting procedures gives extracts that are poor in protein components. Since pollen allergenicity is derived from proteins, it may be advantageous to secure complete removal of protein components (e.g. with Mw above 2xl0 3 dalton) by subjecting the extract to gel filtration or ultrafiltration.
• the extraction of GAs from plant material has been presented in WO 9108751 (Oden P) .
• the inventive composition may also contain minerals (compounds containing metal ions) , vitamins and hair/skin nutrients.
• Vascular dilation agents have previously been recognized to have a positive influence on hair condition probably because they increase the blood flow to the richly vascular papilla. This latter type of agents may be included as well.
• Minerals have a dual action in the inventive composition. Firstly, metal ions may form hydrophobic complexes with the carboxy forms of GAs thereby facilitating GA transport across the cell membranes. Secondly, they often act as essential micro nutrients (trace elements) and constituents in biological systems. In particular zinc has important functions in the growth of cells in the skin (cf. that deficiency in zinc in some cases may cause alopecia (hypozincaemia) .
• Zn 2+ -salts are particularly preferred to incorporate into the inventive compositions, e.g. zinc oxide (ZnO) , zinc chloride (ZnCl 2 ) or zinc sulphate (ZnS ⁇ 4 ) .
• the zinc mineral is insoluble in aqueous media or in the composition.
• physiologically acceptable organic zinc compounds can potentially be used.
• the Zn + -concentration in the composition is often in the range 0-200 mM, most preferably 2-100 mM. The same ranges also apply for the metal ion in other micro nutrients (trace elements) , although with variations in optimal subranges.
• Vitamin E (+)- ⁇ -tocopherol
• vitamin H d-biotin
• concentration range for vitamin E is in the normal case 0- 100 mM, particularly 0.5-20 mM, and for vitamin H 0.01-50 mM, particularly 0.05-10 mM.
• a synergistic effect between vitamin E and GAs can not be excluded.
• Vascular dilation agent that are useful in the invention shall be administratable topically onto the scalp to cause a local effect in the blood vessels of the scalp.
• the agent may be purely synthetic but in the field of hair conditioning it has been popular to use volatiles (particularly terpenes) that may be obtained from different plants, for instance oils from Melaleuca alterniflora Cheel that contains the volatile vascular dilation agents terpinen-4-ol (20-50%) and cineole (1-8%) .
• the content of the vascular dilation agent in the final composition may be 0-10%, for instance 0.01-10%, with the particular choice of plant volatiles, e.g. Melaleuca-derived volatiles in the range of 0.05-1%.
• the composition may also contain common liquid vehicles, for instance physiologically acceptable solvents, such as water, ethanol, glycerol etc; common ointment bases such as lipids; gel forming agents, such as polyalkylene glycols including polyethylene and polypropylene glycols, cellulose derivatives, etc.
• common liquid vehicles for instance physiologically acceptable solvents, such as water, ethanol, glycerol etc; common ointment bases such as lipids; gel forming agents, such as polyalkylene glycols including polyethylene and polypropylene glycols, cellulose derivatives, etc.
• additives such as antioxidants; preservatives such as germicides; and detergents.
• Detergents may have a dual action by stabilizing the composition (in case it is an emulsion) and solubilizing lipid material around the hair root.
• the inventive composition may be manufactured according to the commonly accepted principles for this type of hair compositions except that an active amount/concentration of the above-mentioned gibberellins is incorporated therein.
• the present composition may be in the form of an ointment, solution, gel etc.
• the treatment protocol encompasses applying topically 1-5 times, preferably once or twice, each day, in an evenly spread layer, to a skin area suffering from alopecia, preferably human scalp, an effective amount of the above- defined gibberellins.
• the preferred dose of GAs is 10" 11 - 10 ⁇ 6 g/cm 2 treated area.
• 0.5-10 ml of the inventive composition is given at each administration occasion, i.e. 0.5xl0 ⁇ 9 - 10 ⁇ 5 g active gibberellins.
• the scalp should be massaged when the composition has been applied.
• a previously applied composition should be removed at least prior to the first application of a day. For individuals in which the alopecia returns when the treatment is interrupted, years of treatment may be advisable.
• the treatment should be interrupted for a one-week pause. It should be borne in mind that the treatment, like any previously known non-surgery protocol for treating alopecia, is only applicable to scalps where the hair follicles still are alive. Hair follicles may die, and since new follicles can not be formed in adults this will result in hair loss that is always irreversible.
• Standardized rye pollen extract containing 3 ⁇ g/ml GA ⁇ g, 1 ⁇ g/ml GA 20 , 2 ⁇ g/ml GA 53 and 0.1 ⁇ g/ml 3- ⁇ -OH GA 2 Q. These GAs were present in the extract in both glycosidic ester forms and as free carboxy forms.
• the extract had been obtained by extracting rye pollen with a solvent for the gibberellins as described in WO-9108751 (Oden P) which hereby is incorporated by reference.
• Suitable solvents are methanol or ethanol, in both cases mixed with water
• (+) - ⁇ -Tocopherol (purity 67%, 500 g) was mixed in a first container with zinc oxide (ZnO) derm. p.a. to a homogeneous viscous mass under nitrogen atmosphere (other inert gaseous media could also be used) . The mixture was then "dissolved” in a total volume of 80 1 ethanol (95%) . The zinc oxide will appear as precipitate.
• Zinc chloride (ZnCl 2 , 250 g) was added to 20 1 distilled water (pH adjusted to 4.0 with HC1) in a second container. The pH- value can be adjusted afterwards with NaOH in order to achieve a value suitable for preparation of a gel from the solution.
• Solution B was then mixed into solution C whereafter the mixture was added to suspension A.
• Klucel HF (9.37 g, Hercules Inc) was added slowly under vigorous agitation that was continued for several hours (optimally 2 hours) . All operations, including premixing steps, were carried out under nitrogen atmosphere.
• the study was carried out with the basic composition described above during a period of four months, because follicles of the terminal hair have cyclic growth pattern that can be divided into three parts, anagen or growing phase, catagen or resting phase, and telogen or shedding phase. Photos were taken before and after the test period.
• the treatment was carried out by applying 1-2 ml of the composition twice a day in periods of three weeks followed by a pause of one week before restarting the treatment cycle. The exact dosage was dependent on the area to be treated.
• the composition was applied in the morning after washing the hair and scalp with a mild shampoo. The solution was massaged on bald parts to enhance penetration. A second application was done before bedtime without removing the previous application. This means that in principle the application time was around 24 hours.
• results The first results could be noted after two months. Fine hair, like vellus hair, began to grow on test persons No. 1 and 2. Test person No.3 with the bald in the middle of his scalp also got some thick hairs among the fine ones. After four months a difference in the hair growth could be observed. Test persons No.1 and 2, the men with the temporal balds, had signs of growth of hair on the outer parts of the bald which continued forward to the point that was the natural edge of the scalp before hair loss. On test person No.3, the new hair growth started in the middle of the bald.

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• 1993
  • 1993-05-07 SE SE19939301606A patent/SE9301606D0/sv unknown
• 1994
  • 1994-05-06 EP EP94915328A patent/EP0697851A1/en not_active Withdrawn
  • 1994-05-06 JP JP6525319A patent/JPH08509975A/ja active Pending
  • 1994-05-06 AU AU66627/94A patent/AU6662794A/en not_active Abandoned
  • 1994-05-06 WO PCT/SE1994/000423 patent/WO1994026240A1/en not_active Application Discontinuation

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