WO2024100293A1 - Topical hair tonic formulation - Google Patents
Topical hair tonic formulation Download PDFInfo
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- WO2024100293A1 WO2024100293A1 PCT/EP2023/081531 EP2023081531W WO2024100293A1 WO 2024100293 A1 WO2024100293 A1 WO 2024100293A1 EP 2023081531 W EP2023081531 W EP 2023081531W WO 2024100293 A1 WO2024100293 A1 WO 2024100293A1
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Definitions
- the present invention relates to the field of topical hair tonic formulations.
- Hair is regarded as one of the characteristic features of mammals and serves a number of different functions which include protection against external factors, production of sebum, apocrine sweat and pheromones, impact on social and sexual interactions, thermoregulation and provision of a resource for stem cells.
- a hair follicle HF
- HF hair follicle
- Dermal papilla cells are the main components of the mesenchymal compartments in hair bulb, serving an instructional role by generating signals to regulate the behaviour of neighbouring epithelial cells during the hair cycle. These epithelial cell signalling pathways govern the dermal papilla and thereby hair growth and maintenance. Hair growth is a continuous cyclic process and all mature follicles go through a growth cycle consisting of four main phases; growth (anagen), regression (catagen), rest (telogen), and shedding (exogen). The duration of each phase varies based on the location of the hair, nutritional and hormonal status, and age.
- Hair loss is a common problem, experienced by men and women of all ages.
- the most common cause of hair loss is male-pattern hair loss (MPHL) and female pattern hair loss (FPHL), which is hair loss that primarily affects the top and front of the scalp.
- MPHL hair loss often presents as a receding and often begins above the temples and vertex of the scalp. As it progresses, a rim of hair at the sides and rear of the head remains. Pattern hair loss by the age of 50 affects about half of males and a quarter of females.
- DHT dihydrotestosterone
- topical minoxidil has been associated with adverse effects such as inferior sexual function
- topical minoxidil is a popular, well tolerated topic drug with a favourable risk profile.
- it has to be continuously applied twice daily to counter hair loss and until recently its mechanism of action has not been well understood.
- HIF-la Hypoxia Inducible Factor-lalpha
- HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing.
- Minoxidil has been shown to have a short-lasting positive effect on hair loss due to inhibiting the HIF degrading enzyme PHD.
- Minoxidil topically applied to the scalp activates the angiogenic HIF-l-VEGF axis, demonstrating a potential positive pharmacologic effect for hair growth by inhibiting the HIF degrading enzyme prolylhydroxylase (PHD). It was suggested that by inhibiting PHD, minoxidil prevents the hydroxylation of cellular HIF-la, which then leads to degradation and HIF inactivation. This explains why the drug has to be applied twice daily. PHD inhibition only works if there is a constant supply of minoxidil available to the cell. If a patient stops the treatment, hair loss will reoccur immediately.
- PHD prolylhydroxylase
- Deferiprone is known to be a hypoxia-inducible factor alpha (HIF-la) activity potentiating agent.
- Deferiprone acts as an ion chelator and is known to be a lipophilic compound (Jamuar, Ther Adv Hematol. 2012 Oct; 3(5): 299-307; Tanner, Circulation. 2007;115: 1876- 1884.).
- the solubility of deferiprone in water is 16-18 g/L at 24°. For this reason, stable aqueous formulations of deferiprone require the presence of at least one lipophilic substance.
- Deferiprone is used as an active pharmaceutical ingredient in medicines for the treatment of iron overload in patients with thalassaemia major.
- the therapeutic doses are usually given orally in application rates of 25 mg/kg body weight, three times a day for a total daily dose of 75 mg/kg body weight. Because of the indication and the mode of action - complexation and subsequent elimination of iron from the body - only the oral application is described as therapeutic.
- Deferiprone may be administered as a 500 mg film-coated tablet, or as an oral solution (100 mg/mL)
- the present invention provides an aqueous topical hair care formulation for topical administration, comprising
- the present invention provides a hair care product, comprising the formulation of the present invention.
- the present invention provides a method for the production of the formulation according to the invention, said method comprising the steps:
- step (II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
- step (III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
- step (IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
- step (VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
- the present invention provides an aqueous topical hair care formulation, obtainable by the method of the invention.
- the present invention provides a method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of the invention to the hair and/or the scalp.
- alopecia refers to different forms of hair loss with varying underlying causes.
- pattern hair loss as used within the context of the present specification includes male and female pattern hair loss and refers to a hair loss that affects primarily the top and front of the scalp.
- hair loss as used within the context of the present specification may refer to a decrease in the number of active hair follicles, a shortening of the anagen phase, a prolongation of the catagen and/or telogen phase, and/or shrinking of individual hair follicles.
- HIF-la activity potentiating agent refers to a compound that increases HIF-la activity.
- HIF-la activity potentiating agents that exert their function by stabilizing HIF-la are also called “HIF-la stabilizing compounds”. In most cases, stabilization of HIF-la is achieved via inhibition of the HIF-la degrading enzyme prolylhydroxylase (PHD).
- PBD prolylhydroxylase
- An example of a HIF-la activity potentiating agent is deferiprone.
- a “hair tonic” or “hair tonic formulation” is a liquid substance applied to the hair on one's head to improve its appearance in various ways and/or to deliver nutrients and nourishing substances.
- weight per weight means the weight concentration or mass concentration of a component in a formulation described herein.
- the weight or mass of a component is expressed as a percentage of a formulation.
- the weight or mass of a component can be expressed as a percentage of the total weight or mass of the formulation of the invention.
- a “solvent” is a substance that dissolves a solute, resulting in a solution.
- typical hydrophilic solvents are water, glycerol and mixtures thereof.
- a typical hydrophobic (lipophilic) solvent is octyldodecanol.
- humectant is a substance used to reduce the loss of moisture, for example in the skin, when the formulation of the invention is applied to the hair.
- Typical humectants are glycerol and ethylhexylglycerol.
- moisturizer is used to prevent dryness, for example in the skin, when the formulation of the invention is applied to the hair.
- Typical moisturizers used in the formulation of the invention are panthenol and/or octyldodecanol.
- an “emulsifier” is a substance that stabilizes an emulsion.
- a typical emulsifier used in the formulation of the invention is PEG-40 hydrogenated castor oil.
- a “preservative” is a substance used to preserve the formulation of the invention.
- a typical preservative used in the formulation of the invention is phenoxyethanol.
- an “active ingredient” includes an active cosmetic agent (herein also termed “cosmetic active agent”).
- an active agent is defined as the chemical, biological mineral or any other entity or component responsible for the effect in a product.
- an active cosmetic agent is defined as the chemical, biological mineral or any other entity or component responsible for the cosmetic effects in a product.
- Typical active agents used in the formulation of the invention are niacinamide (also termed herein “nicotinamide”), tocopherol and/or deferiprone.
- niacinamide and tocopherol can have an anti-oxidative effect on the skin and/or can improve the epidermal barrier.
- a “emollient” serves to soften and/or soothing the skin.
- Typical emollients used in the formulation of the invention are octyldodecanol, Ribes nigrum seed oil, Helianthus annuus seed oil unsaponifiables, tocopherol, Cardiospermum halicacabum flower/leaf/vine extract, Helianthus annuus seed oil, Camilla sinensis extract (green tea extract) and/or Rosmarinus officinalis leaf extract.
- a “chelator” is a compound containing a ligand (typically organic) capable of bonding a metal atom at two or more points.
- a typical chelator used in the formulation of the invention is deferiprone, capable of chelating an iron ion.
- Prolylhydroxylase uses Fe 2+ ions as a cofactor, and one way to inhibit PHD is by reducing the availability of Fe 2+ using iron chelators or by introducing metal ions like Ni 2+ , Mn 2+ or Co 2+ that will compete with Fe 2+ .
- iron chelator as used within the context of the present specification in particular refers to a compound that binds Fe 2+ and thus reduces the amount of free Fe 2+ available for PHD mediated HIF hydroxylation reaction.
- a “buffer” or a “buffer substance“ is a substance making a solution resistant against changes in pH when acid or alkali is added to it.
- Typical buffer substances used in the formulation of the invention are glycine and/or lactic acid.
- an “antistatic” or “antistatic compound” is a compound used for treatment of hairs or their surfaces in order to reduce or eliminate buildup of static electricity.
- a typical antistatic used in the formulation of the invention is glycine.
- a “conditioner” or “hair conditioner” is cosmetic compound used to improve the condition, the feel, texture, appearance, and manageability of hair.
- Typical conditioners or hair conditioners used in the formulation of the invention are Larix europaea wood extract, Helianthus annuus seed oil unsaponifialbles, tocopherol, Cardiospermum halicacabum flower/leaf/vine extract, Helianthus annuus seed oil, Camilla sinensis extract, and/or Rosmarinus officinalis leaf extract
- an “antioxidant” or “antioxidative compound” is a substance that inhibits oxidation of the ingredients of the formulation of the invention.
- a typical antioxidant used in the formulation of the invention is sodium metabisulfite.
- an “astringent” or “astringent compound” is a cosmetic compound used to make body tissue less oily and tightens the skin.
- a typical astringent used in the formulation of the invention is zinc chloride.
- deferiprone refers to 3-hydroxy-l,2-dimethylpyridin-4(U7)-one (also termed l,2-dimethyl-3-hydroxy-4-pyridone).
- the CAS number of deferiprone is 30652-11-0.
- the inventors herein provide an aqueous topical hair care formulation containing deferiprone.
- Deferiprone acts as an ion chelator and is known to be a lipophilic compound.
- a lipophilic substance used to prepare a formulation of deferiprone could be disadvantageous.
- the lipophilic substance can accumulate on the hair and affects the appearance of the hair, which may be unacceptable from an aesthetic point of view. This is particularly disadvantageous in the daily use of a hair tonic formulation of deferiprone, especially for long hair, freshly blow-dried hair, hair extensions or hairstyles like curls and permanent waves.
- the formulation is stable and has skin-friendly and hair-friendly properties.
- the lipophilic ingredients necessary to formulate deferiprone do not adversely affect its use as a hair care product.
- deferiprone can act as an ion chelator.
- the formulation of the invention caused no relevant skin reactions (reddening, flaking, dryness, others) in the test area, and the formulation was very well tolerated (Example 4). Neither intolerance reactions in the sense of irritation nor allergic reactions (contact dermatitis) were found. Accordingly, from a dermatological point of view, the formulation of the invention has a low potential for irritation and sensitization.
- the inventors showed in a follow-up survey (Example 5) that all participants were generally satisfied with the product and also reported perfect tolerability. The generally high rate of participant satisfaction corresponds well with the other survey results. All patients were happy with how the skin felt after application of the formulation, with subjectively reduced hair loss in all but two and the feeling of stronger and healthier hair in all but one study participant. The inventors showed in a blinded clinical trial over a period of 9 months (Example 6) that the formulation of the invention is safe and effective to counteract Androgenetica alopecia (AGA). This study shows that the formulations of the invention are water-soluble alternatives to the market leaders in hair loss treatments Minoxidil and Caffeine.
- the formulation of the invention demonstrates significantly reduced hair loss and increased hair growth in humans.
- Treatment with the formulation of the invention is associated with beneficial effects on hair quality such as thickness, hair density, shine and elasticity, and scalp health. These favorable characteristics are further supported by its satisfactory outcomes and the absence of negative skin reactions.
- the present invention provides an aqueous topical hair care formulation for topical administration, comprising
- the formulation is a liquid formulation.
- a “liquid” formulation is a watery, stable, dissolved, or suspended form of cosmetic ingredients.
- a “liquid”, as used herein can have significantly lower viscosity compared to gels and/or does not produce any foaming effects associated with foam formulations.
- panthenol is D-panthenol.
- the water is de-ionized water.
- the pH of the formulation may be adjusted to 5-6, in particular to 5.4-5.8, for example with lactic acid.
- the amount of lactic acid added to the formulation may be adjusted to achieve this pH.
- an amount of lactic acid may be present in the formulations of the invention, to achieve a pH of 5-6, preferably 5.4-5.8.
- the formulation as described herein is free of alcohol.
- the formulation as described herein is free of ethanol.
- the formulation as described herein is free of propanol.
- the present invention provides an aqueous topical hair care formulation, comprising
- the present invention provides an aqueous topical hair care formulation, comprising
- the present invention provides an aqueous topical hair care formulation, said formulation comprising
- niacinamide in an amount of 0.4-0.6 % w/w
- the present invention provides an aqueous topical hair care formulation, said formulation comprising
- niacinamide in an amount of 0.5% w/w
- panthenol is D-panthenol.
- the aqueous topical hair care formulation of the present invention is formulated as a hair tonic formulation.
- the aqueous topical hair care formulation of the present invention is a cosmetic formulation.
- the formulation of the present invention can be used in cosmetics, in particular for cosmetic restoration of hair, more particular to cosmetic treatment of hereditary hair loss and/or thinning hair. Treatment with the formulation can counteract the progression of hereditary hair loss, especially at an early stage, and/or can promote the growth of existing hair.
- New hair can often be thin and become thicker and darker over time.
- the formulation of the present invention can be used for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
- the formulation of the present invention comprising deferiprone, can be used to reactivate hair follicle development by stimulating HIF-la.
- HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing, thereby restores the nutrient supply of the hair follicle.
- the cosmetic treatment of the invention may include topical application to scalp and massage.
- Massage may be performed for 1-5 min, 1-4 min, 1-3 min or 1-2 min.
- Massage performed for 1-2 min is preferred.
- the formulation of the invention may be applied once daily, twice daily, three times daily or even more often.
- the application of the formulation once daily is preferred.
- the cosmetic treatment of the invention may be performed for at least 1-6 months, at least 2-6 months, at least 3-6 months or at least 4-6 months. Cosmetic treatment performed for at least 4-6 months is preferred.
- the aqueous topical hair care formulation of the present invention is not a pharmaceutical formulation.
- the present invention provides a hair care product, comprising the formulation of the present invention.
- the present invention provides a method for the production of the formulation of the present invention, said method comprising the steps:
- step (II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
- step (III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
- step (IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
- step (VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
- Step (I)-(IV) of the method of the invention describe the manufacture of an aqueous solution, comprising deferiprone, and niacinamide, ethylhexylglycerol, phenoxyethanol, tocopherol, zinc chloride, green tea (Camilla sinensis) extract, glycerol, glycine, Larix europaea wood extract, and sodium metabisulfite.
- This aqueous solution has predominantly hydrophilic properties.
- step (V) a solution based on the lipophilic substance with the emulator PEG-40 hydrogenated castor oil is prepared. This solution has predominantly hydrophobic properties.
- step (VI) by contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion, the aqueous topical hair care formulation containing deferiprone of the invention can be formed.
- This formulation is stable and has skin-friendly and hair-friendly properties.
- the lipophilic ingredients necessary to formulate deferiprone do not adversely affect its use as a hair care product.
- a “homogenous emulsion” is in particular clear, transparent and odorless.
- Controlling factors in the formation of an emulsion are, for example: mechanical energy, agitation time, temperature, volumetric ratio between the two phases, degree of dispersion of the internal phase and presence of impurities or surfactants.
- an elevated temperature is used to achieved complete dissolution.
- deferiprone in contacted with de-ionized water at least 50 °C, preferable at least 60 °C, more preferred at least 70, most preferably at about 75 °C.
- the conditions allowing to dissolve the deferiprone may include stirring at about 220 rpm, for example for 100 min.
- step (I) and cool down to about 25 °C may be performed by adding de-ionized water, and/or be additional cooling, for example for 30 min.
- the conditions allowing to dissolve the niacinamide may include stirring at about 220 rpm, for example for 100 min.
- the conditions allowing to dissolve the glycerol, panthenol, and the first mixture may include stirring at about 220 rpm, for example for 100 min.
- the conditions allowing to dissolve the second mixture may include stirring at about 220 rpm, for example for 100 min.
- the conditions allowing formation of a clear solution may include stirring at about 220 rpm, for example for 100 min.
- the conditions allowing formation of a homogeneous emulsion may include stirring at about 220 rpm, for example for 100 min.
- step (VII) may be repeated once or more times, to re-adjust the pH, for example after 1 h.
- the first mixture can comprise:
- the first mixture can be a commercially available composition, for example a composition sold under the trade name "Euxyl PE 9010 / Microcare PEHG”.
- the second mixture can comprise:
- the second mixture can be a commercially available composition, for example a composition sold under the trade name "Redensyl 34158".
- the third mixture can comprise:
- the third mixture can be a commercially available composition, for example a composition sold under the trade name "Defensil Plus”.
- the present invention provides an aqueous topical hair care formulation, obtainable by the method of the invention.
- the present invention provides a method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of the invention to the hair and/or the scalp.
- the advantageous effects of the inventive formulation are particularly evident when the composition is applied onto the hair and/or scalp of a subject.
- cosmetically treat refers to the contacting of a subject with a cosmetic agent, preferably by topical application to the hair and/or the scalp of a subject.
- a “cosmetic treatment” in contrast to a therapeutic treatment, has the effect of preventing, mitigating and/or correcting a cosmetically undesirable condition such as signs of hair loss and/or thinning hair.
- the term “subject” is understood to include a mammal such as an animal and, more preferably, a human that is receiving or intended to receive treatment, as it is herein defined. While the term “subject” is often used herein to refer to a human, the invention is not so limited. Accordingly, the term “subject” refers to any animal, mammal or human having or at risk for a medical condition that can benefit from the treatment.
- the method of cosmetic treatment of the present invention is cosmetic restoration of hair, in particular to cosmetic treatment of hereditary hair loss and/or thinning hair.
- Treatment with the formulation can counteract the progression of hereditary hair loss, in particular at an early stage, and/or can promote the growth of existing hair.
- New hair can often be thin and become thicker and darker over time.
- the formulation of the present invention in the method of cosmetic treatment of the invention, can be used for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
- the formulation of the present invention comprising deferiprone, can be used to reactivate hair follicle development by stimulating HIF-la.
- HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing, thereby restores the nutrient supply of the hair follicle.
- the method of cosmetic treatment of the invention may include topical application to scalp and massage.
- Massage may be performed for 1-5 min, 1-4 min, 1-3 min or 1-2 min.
- Massage performed for 1-2 min is preferred.
- the formulation of the invention may be applied once daily, twice daily, three times daily or even more often.
- the application of the formulation once daily is preferred.
- in the method of cosmetic treatment of the invention may be performed for at least 1-6 months, at least 2-6 months, at least 3-6 months or at least 4-6 months. Cosmetic treatment performed for at least 4-6 months is preferred.
- An aqueous topical hair care formulation for topical administration comprising
- aqueous topical hair care formulation of item 1 comprising (a) glycerol in an amount of about 6.7 % w/w,
- niacinamide in an amount of 0.4-0.6 % w/w
- niacinamide in an amount of 0.5% w/w
- aqueous topical hair care formulation of any one of the preceding items formulated as a hair tonic.
- aqueous topical hair care formulation of any one of the items 1-6 which is a cosmetic formulation.
- aqueous topical hair care formulation of item 7 or 8 for cosmetic treatment of hereditary hair loss and/or thinning hair.
- aqueous topical hair care formulation of any one of the items 7-9, for counteracting the progression of hereditary hair loss, in particular at an early stage,
- aqueous topical hair care formulation of any one of the items 7-10, for promoting the growth of existing hair.
- aqueous topical hair care formulation of any one of the items 7-11, for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
- a hair care product comprising the topical hair care formulation of any one of the items 1- 13.
- step (II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
- step (III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
- step (IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
- step (VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
- An aqueous topical hair care formulation obtainable by the method of item 15.
- a method of cosmetic treatment of the hair and/or the scalp comprising administration of the formulation of any one of the items 1-14 and 16 to the hair and/or the scalp.
- the cosmetic method of item 17 including cosmetic restoration of hair.
- the cosmetic method of any one of items 17-19 counteracting the progression of hereditary hair loss, in particular at an early stage,
- the cosmetic method of any one of items 17-20 promoting the growth of existing hair.
- Figure 1 Questionnaire analysis demonstrates user satisfaction. The results were evaluated by the individual study participants via a questionnaire. All participants were generally satisfied with the product and also reported perfect tolerability.
- Figure 2 Typical pattern of androgenic hair loss in males (Norwood scale, above) and females (Ludwig scale, below).
- Figure 3 Hair quality was improved significantly by treatment with the formulation described in Example 2. The results were evaluated by board-certified dermatologists according to a standardized protocol. The formulation as described in Example 2 resulted in improvements in the clinical parameters of hair quality such as improvements in thickness of 7.2% (p ⁇ 0.001), hair density of 14.3% (p ⁇ 0.001) and shine and elasticity of 20.3% (p ⁇ 0.001) during the 9- month test period.
- Figure 4 The formulation as described in Example 2 significantly reduces hair loss.
- A The results of hair loss assessment via combing show a significant decrease in hair loss in the study group. The mean delta of hair loss across all study participants was -30.36%, resulting in an average reduction of 38 hairs lost at t(6) vs. 69 hairs lost at T(0) (* p ⁇ 0.05).
- B For responsive participants, an average hair loss reduction of 65.72% was measured, corresponding to 37 hairs lost on average at t(6) (* p ⁇ 0.05).
- Figure 5 The formulation as described in Example 2 significantly increases hair growth.
- A Clinical examples of macroscopic hair growth improvement in the study period.
- B After 9 months of treatment, an increase in hair growth of 10.76% on average in responsive patients was measured (* p ⁇ 0.001).
- Figure 6 The formulation as described in Example 2 harmonizes the hair growth cycle.
- the hair growth cycle was harmonized, with results of an average anagen hair percentage increase of +8.0% and telogen hair percentage reduction of -14.0% shown in the test area after 9 months of treatment.
- Phase 1 Supply H2O 75°C de-ionized.
- Phase 2 • Mixing vessel 1 and 2: all settings for stirrer remain unchanged from now on up to and including phase 7.
- Pre-dissolve Cremophor REMO and Defensil Plus in a pre-dissolving container. Predissolution must be clear. Then add the pre-solution to the preparation obtained in phase 5 while stirring and allow to dissolve.
- test product was applied to the hair and scalp of 17 test persons once a day over a period of 9 months.
- Demographic data, scalp status, and medical history were collected during an initial screening. Tolerability was evaluated by a board-certified dermatologist. Treated areas were examined under constant light conditions. Skin reactions (reddening, scaling, dryness, and others) were graded according to a predefined scoring scale: Negative reaction (0 reaction points); Doubtful reaction (“(+)”, 0.5 reaction points); Weak positive reaction (“+”, 1 reaction points); Strong positive reaction (“++”, 2 reaction points); Extreme positive reaction (“+++”, 3 reaction points). The overall results were summarized in cumulative irritation scores, the total number of skin reactions and total reaction points.
- the tested product has a low potential for irritation and sensitization when used as intended.
- Table 1 Demographic data, scalp status, and medical history were collected during an initial screening. Tolerability was evaluated by a board-certified dermatologist. Skin reactions (reddening, scaling, dryness, and others) were graded according to a pre-defined scoring scale. The overall results were summarized in cumulative irritation scores, the total number of skin reactions and total reaction points. After an application phase of nine months, no negative skin reactions of dermatological relevance were documented for the test product.
- the formulation of the invention counteracts androgenic hair loss and improves hair growth in a blinded clinical trial
- This example relates to the
- the aim of this study was to examine the tolerability and effectiveness of the formulation described in Example 2 according to clinical-dermatological test criteria. Before the subjects were included, the health and integrity of the scalp integument was examined. If a condition requiring medical treatment existed, the subject was excluded. There was also an informative discussion in which the study design, the study conditions and the rights and obligations of the test persons within the framework of the study were explained to the test persons by the supervising study nurse or the supervising dermatologist. The test persons were only included in the study if they did not show any pathological skin changes in the application area, signed the declaration of consent either self-determined or signed by the legal guardian and met all other inclusion and exclusion criteria.
- the subjects could consult the supervising study nurse or the supervising dermatologist for objective and subjective skin changes. According to the schedule, dermatological examinations took place. In order to keep fluctuations due to external influences such as room temperature and relative humidity as low as possible, the measurements were always carried out under the same physical environmental conditions when the patient was rested (20 °C, humidity 40-60%).
- Example 2 The formulation described in Example 2 was applied by blinded users once daily in the damp hair after shower and massaged in at areas of hair loss. The first product application was done under the supervision of a study nurse.
- Demographic data, scalp status, and medical history were collected during an initial screening.
- the tolerability of the formulation described in Example 2 was evaluated by a board-certified dermatologist. Treated areas were examined under constant light conditions.
- various parameters were determined visually and by touching the skin/hair. This assessment is carried out by a trained assessor using a visual analog scale to evaluate the relevant parameters (Hayes, M, Patterson G (1921). Psychological Bulletin, 18, 98-99).
- the scale is defined from "no intensity/excellent condition" to "maximum intensity/poor condition”.
- the individual intensities are displayed numerically by measuring the analogue scale (values 0.0 to 100.0).
- the TrichoScan HD method (DermoScan GmbH) is used to evaluate hair growth objectively.
- One measurement area is determined on the scalp of each subject.
- Pre-treatment of the measuring area on the scalp is carried out as follows: A measuring area in the transition zone between alopecia and regular hairy scalp is selected for each subject. The subsequent measurement area is defined with the aid of a perforated mask.
- the hair is threaded through the perforated mask and roughly shortened with scissors.
- the shortened hair is shaved to an even length of 0.8 mm with the Moser shaver (TrichoScan Edition). To do this, the razor is guided at a 90° angle to the scalp without applying pressure.
- the hair is colored two days after shaving: the hair color (Gol dwell Topchic 2N) is applied to a wooden spatula. The same amount of developer (Creme oxyd) is added to the hair color (1 : 1 mixture). Hair color and developer are mixed well together until they reach a creamy consistency. The coloring mass is applied to the measurement area (scalp) of the test subject and acts there for 15 minutes. After the exposure time, the stain is roughly removed with a swab and the measuring area is cleaned very carefully with an alcoholic tincture (e.g. Kodan Spray) and/or a soft swab. The camera handpiece of the TrichoScan HD is used to record the image files. The recordings must be free of air bubbles and surrounding hair. For taking the pictures, the measuring area is well moistened (Kodan Spray). Then the parameters hair density [1/cm 2 ], number of hairs, anagen hairs [%], telogen hairs [%] are determined using TrichoScan HD software.
- the results of the formulation of the invention were evaluated by board certified dermatologists according to a standardized protocol.
- the use of the formulation of the invention resulted in an improvement in the clinical parameters of hair quality such as thickness of 7.2%, hair density of 14.3%, shine and elasticity of 20.3% during the test period (Figure 3).
- the formulation of the invention significantly reduces hair loss
- the results of hair loss assessment via combing already show a significant decrease in hair loss after twelve weeks of daily treatment in the study group.
- the mean delta of hair loss across all study participants after 6 month of study was with -30,36% even more significant (Figure 4A).
- a reduction of hair loss was already observed in 80% of study participants. This further increased to 85% after 6 months.
- a mean reduction of hair loss of 65.72% was achieved corresponding to 32 hair lost on average after 6 months (Figure 4B).
- the average hair loss in the study cohort after 6 months corresponds well with the mean hair loss rate in healthy patients which was found to be approximately 40 according to the literature (Hoffmann, R., J. Investig. Dermatol. Symp. Proc. 2003, 8, 109-115).
- the maximum reduction of hair loss achieved in the study population was 100%.
- the formulation of the invention significantly increases hair growth
- the TrichoScan evaluation was carried out on a test area on the scalp after 9 months. After 9 months, hair growth improvement was visible macroscopically in most of the study participants (Figure 5A), and the difference between the before and after measurements on the TrichoScan was significant (p ⁇ 0.01).
- the hair density [1/cm 2 ], the proportion of anagen hair [%] and the proportion of telogen hair [%] were determined to assess the influence of the formulation of the invention on hair growth.
- Figure 5B An increase in hair growth of up to 32.5% (10.76% on average in responsive patients) was measured (Figure 5B). In only 3 patients there was no improvement in hair density which equals an 85% responder rate in our study cohort.
- the hair growth cycle was harmonized with the result of an average anagen hair percentage increase of 8.0% and telogen hair percentage reduction of -14.0% shown in the test area ( Figure 6)
- This report aims to determine clinical safety and efficacy of the formulation of the invention in the context of androgenic hair loss. From a clinical and also psychological perspective, hair shedding counts are very important, whereas the growth rate and the anagen/telogen ratio are of secondary importance (Hoffmann, R., J. Investig. Dermatol. Symp. Proc. 2003, 8, 109-115). Healthy people have between 80,000 and 120,000 hairs. In healthy individuals approximately 10-20% of the hair follicles are in the resting stage (telogen) at any given time, which means that they are ready for the strand to fall out. In our cohort we were able to reduce hair in telogen phase from 31.8% at the beginning of our study to 26.9% at the end of the study period.
- the mean hair loss rate for this method in healthy patients was found to be approximately 40 (Kligman AM., Arch Dermatol 1961 ;83 (2) 175-198).
- our study cohort of AGA patients we were able to reduce mean hairs lost via treatment with the formulation of the invention from 69 at T(0) to 38 after 6 months which represents a restoration of normal hair homeostasis. This is a best in class result not achieved by any other product in the market to the best of our knowledge.
- Minoxidil is beneficial for hair growth but detrimental to scalp health.
- Minoxidil is associated with a specific loss of lysyl hydroxylase activity; this loss is reversed by removing minoxidil (Murad S, Pinnell SR., J Biol Chem. 1987;262(25): 11973-8).
- Minoxidil inhibits the synthesis of lysyl hydroxylase by acting at the transcriptional level (Hautala T, Heikkinen J, Kivirikko KI, Myllyla R., Biochem J. 1992;283 ( Pt l)(Pt 1):51-4).
- This enzyme is essential for collagen stabilization.
- Treatment of cells with minoxidil is also associated with inhibition of cell proliferation (Pinnell SR, Murad S., Dermatologica 1987; 175 Suppl 2: 12-8).
- This effect of minoxidil is accompanied by inhibition ofDNA synthesis in skin cells.
- collagen is the major product of fibroblast activity and lysyl hydroxylase catalyzes a crucial reaction in collagen biosynthesis
- Minoxidil can be harmful to fibroblast functionality and consequentially skin homeostasis (Shao S, Zhang X, Duan L, Fang H, Rao S, Liu W., et al. Med Sci Monit. 2018;24:8592-601).
- minoxidil treatment requires patients to apply the drug to the scalp every 12 hours to achieve the desired effect of hair growth, due to its pharmacokinetic properties (Yum S, Jeong S, Kim D, Lee S, Kim W, Yoo JW, Int J Mol Sci. 2017; 19(1), 53).
- minoxidil in this context is its insolubility in water; it is dissolved in alcohol and sold as such. Applying it twice daily can hence lead to irritation of the skin, since alcohol as a vehicle is deeply dehydrating (Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S., Recent Pat Inflamm Allergy Drug Discov. 2012;6(2): 130-6).
- Stemoxydine is a PHD competitive inhibitor (Loussouarn, G. et al., Int. J. Trichology 2012, 4, 131-152) and therefore hypoxia-like signaling via HIF pathway modulation is the mechanism of action.
- HIF pathway a common denominator of efficacy with minoxidil but its delivery is also based on a hydro-alcoholic lotion potentially harmful to the scalp (Loussouarn, G. et al., Int. J. Trichology 2012, 4, 131-152).
- the formulation of the invention is formulated without alcoholic penetration enhancers enabling powerful HIF modulation without skin toxicity.
- competitors such as Minoxidil cause considerable skin irritation in a considerable number of customers.
- the safety advantage of the formulation of the invention is also accompanied by increased usability. With the different pharmacological mechanism underlying HIF modulation via the formulation of the invention less frequent application yields efficacy. In our study collective we are able to demonstrate significantly reduced hair loss and increased hair growth upon application of the formulation of the invention once daily.
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Abstract
The present invention relates to the field of cosmetics and in particular to an aqueous topical hair care formulation for topical administration.
Description
TOPICAL HAIR TONIC FORMULATION
FIELD OF THE INVENTION
The present invention relates to the field of topical hair tonic formulations.
BACKGROUND OF THE INVENTION
Hair is regarded as one of the characteristic features of mammals and serves a number of different functions which include protection against external factors, production of sebum, apocrine sweat and pheromones, impact on social and sexual interactions, thermoregulation and provision of a resource for stem cells. Essentially a mini-organ, a hair follicle (HF) has a complex but well-organized structure, differentiating from hair follicle stem and progenitor cells. During embryonic development, the formation of HF is primarily regulated by mesenchymal-epithelial interactions within the dermal papilla niche. These interactions remain responsible for the postnatal hair growth and regeneration cycle. Dermal papilla cells are the main components of the mesenchymal compartments in hair bulb, serving an instructional role by generating signals to regulate the behaviour of neighbouring epithelial cells during the hair cycle. These epithelial cell signalling pathways govern the dermal papilla and thereby hair growth and maintenance. Hair growth is a continuous cyclic process and all mature follicles go through a growth cycle consisting of four main phases; growth (anagen), regression (catagen), rest (telogen), and shedding (exogen). The duration of each phase varies based on the location of the hair, nutritional and hormonal status, and age.
Hair loss is a common problem, experienced by men and women of all ages. The most common cause of hair loss is male-pattern hair loss (MPHL) and female pattern hair loss (FPHL), which is hair loss that primarily affects the top and front of the scalp. In males, MPHL hair loss often presents as a receding and often begins above the temples and vertex of the scalp. As it progresses, a rim of hair at the sides and rear of the head remains. Pattern hair loss by the age of 50 affects about half of males and a quarter of females.
The development of male pattern hair loss has been shown to be a result of a combination of genetics and the metabolite of the male hormone testosterone, dihydrotestosterone (DHT). DHT is produced systemically and if a genetic predisposition exists, 5 -alpha-reductase transforms testosterone to DHT in the affected hair follicles, which then results in a continuous shortening of hair growth (anagen) phases and prolongation of longer telogen phases, which leads to the shrinking of the hair follicle and ultimately causes
hair growth to cease.
Alternative substances for the treatment of hair loss exist, with caffeine being used regularly in shampoos and tonic formulations. Caffeine has been argued to increase cAMP levels and promote cellular proliferation, which might to some degree counteract DHT-induced miniaturization of the hair follicle. The results of anti-hair loss treatments using caffeine are however unsatisfactory and more potent pharmaceutical solutions are currently the best available solution. As of today, the FDA has approved only two drugs, namely oral finasteride and topical minoxidil, for the effective treatment of this most common form of hair loss.
While finasteride has been associated with adverse effects such as inferior sexual function, topical minoxidil is a popular, well tolerated topic drug with a favourable risk profile. However, it has to be continuously applied twice daily to counter hair loss and until recently its mechanism of action has not been well understood.
Recently however it has been shown that hair follicle development is dependent on perfectly coordinated principles of tissue regeneration, and the control of cell growth and migration, which closely relates it to wound healing. A main response to injury pathway, the Hypoxia Inducible Factor-lalpha (HIF-la) regulatory pathway, has been identified as pivotal both in tissue regeneration and hair growth. HIF-la signaling is significantly involved in tissue homeostasis and neovascularization resulting in the production of new collagen, elastin and nourishing blood vessel. It was shown that human HF stem/progenitor cells are reactive to hypoxia and modulating the functionality of the HIF pathway has been demonstrated to significantly enhance both tissue regeneration and hair growth.
Hair follicle development and cycling is dependent on perfectly coordinated principles of tissue regeneration, and the control of cell growth and migration which closely relates it to wound healing. HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing. Minoxidil has been shown to have a short-lasting positive effect on hair loss due to inhibiting the HIF degrading enzyme PHD.
Minoxidil topically applied to the scalp activates the angiogenic HIF-l-VEGF axis, demonstrating a potential positive pharmacologic effect for hair growth by inhibiting the HIF degrading enzyme prolylhydroxylase (PHD). It was suggested that by inhibiting PHD, minoxidil prevents the hydroxylation of cellular HIF-la, which then leads to degradation and HIF inactivation. This explains why the drug has to be applied twice daily. PHD inhibition only works if there is a constant supply of minoxidil available to the cell. If a patient stops the
treatment, hair loss will reoccur immediately.
Deferiprone is known to be a hypoxia-inducible factor alpha (HIF-la) activity potentiating agent. Deferiprone acts as an ion chelator and is known to be a lipophilic compound (Jamuar, Ther Adv Hematol. 2012 Oct; 3(5): 299-307; Tanner, Circulation. 2007;115: 1876- 1884.). The solubility of deferiprone in water is 16-18 g/L at 24°. For this reason, stable aqueous formulations of deferiprone require the presence of at least one lipophilic substance.
Deferiprone is used as an active pharmaceutical ingredient in medicines for the treatment of iron overload in patients with thalassaemia major. The therapeutic doses are usually given orally in application rates of 25 mg/kg body weight, three times a day for a total daily dose of 75 mg/kg body weight. Because of the indication and the mode of action - complexation and subsequent elimination of iron from the body - only the oral application is described as therapeutic. Deferiprone may be administered as a 500 mg film-coated tablet, or as an oral solution (100 mg/mL)
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides an aqueous topical hair care formulation for topical administration, comprising
(a) glycerol in an amount of 6-7 % w/w,
(b) phanthenol in an amount of 2-3 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(d) phenoxyethanol in an amount of 0.8-1 % w/w,
(e) niacinamide in an amount of 0.4-0.6 % w/w,
(f) octyldodecanol in an amount of 0.3-0.4 % w/w,
(g) deferiprone in an amount of 0.05-0.15 % w/w,
(h) ethylhexylglycerol in an amount of 0.05-0.15 % w/w,
(i) Ribes nigrum seed oil in an amount of 0.08-0.01 % w/w,
(j) glycine in an amount of 0.02-0.03 % w/w,
(k) Larix europaea wood extract in an amount of 0.02-0.03 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of 0.01-0.02 % w/w,
(m) sodium metabisulfite in an amount of 0.01-0.02 % w/w,
(n) tocopherol in an amount of 0.01-0.02 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.002-0.003 % w/w,
(p) Helianthus annuus seed oil in an amount of 0.002-0.003 % w/w,
(q) green tea (Camilla sinensis) extract in an amount of 0.002-0.003 % w/w,
(r) zinc chloride in an amount of 0.002-0.003 % w/w,
(s) lactic acid in an amount of 0.0007-0.0009 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of 0.0004-0.0006 % w/w, and
(u) water ad 100 % w/w.
In a second aspect, the present invention provides a hair care product, comprising the formulation of the present invention.
In a third aspect, the present invention provides a method for the production of the formulation according to the invention, said method comprising the steps:
(I) contacting deferiprone with de-ionized water at least at 50 °C, under condition allowing to dissolve the deferiprone, and cool down to about 25 °C,
(II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
(III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture, under condition allowing to dissolve the glycerol, panthenol, and the first mixture,
(IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture under condition allowing to dissolve the second mixture,
(V) contacting PEG-40 hydrogenated castor oil with a third mixture, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture, under conditions allowing formation of a clear solution,
(VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
(VII) adjust pH to 5.4-5.8 with lactic acid, in particular 80% lactic acid.
In a fourth aspect, the present invention provides an aqueous topical hair care formulation, obtainable by the method of the invention.
In a fifth aspect, the present invention provides a method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of the invention to the hair and/or the scalp.
DESCRIPTION OF THE INVENTION
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In the following, the elements of the present invention will be described. These elements
are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, are to be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents, unless the content clearly dictates otherwise. The term “alopecia” as used within the context of the present specification refers to different forms of hair loss with varying underlying causes.
The term “alopecia” as used within the context of the present specification refers to different forms of hair loss with varying underlying causes.
The term “pattern hair loss” as used within the context of the present specification includes male and female pattern hair loss and refers to a hair loss that affects primarily the top and front of the scalp.
The term “hair loss” as used within the context of the present specification may refer to a decrease in the number of active hair follicles, a shortening of the anagen phase, a prolongation of the catagen and/or telogen phase, and/or shrinking of individual hair follicles.
The term “HIF-la activity potentiating agent” as used within the context of the present specification refers to a compound that increases HIF-la activity. HIF-la activity potentiating agents that exert their function by stabilizing HIF-la are also called “HIF-la stabilizing compounds”. In most cases, stabilization of HIF-la is achieved via inhibition of the HIF-la degrading enzyme prolylhydroxylase (PHD). An example of a HIF-la activity potentiating agent is deferiprone.
As used herein, a “hair tonic” or “hair tonic formulation” is a liquid substance applied
to the hair on one's head to improve its appearance in various ways and/or to deliver nutrients and nourishing substances.
As used herein, “weight per weight”, “weight/weight” or “w/w” means the weight concentration or mass concentration of a component in a formulation described herein. The weight or mass of a component is expressed as a percentage of a formulation. For example, the weight or mass of a component can be expressed as a percentage of the total weight or mass of the formulation of the invention.
As used herein, a “solvent” is a substance that dissolves a solute, resulting in a solution. In the present invention, typical hydrophilic solvents are water, glycerol and mixtures thereof. A typical hydrophobic (lipophilic) solvent is octyldodecanol.
As used herein, a “humectant” is a substance used to reduce the loss of moisture, for example in the skin, when the formulation of the invention is applied to the hair. Typical humectants are glycerol and ethylhexylglycerol.
As used herein, a “moisturizer” is used to prevent dryness, for example in the skin, when the formulation of the invention is applied to the hair. Typical moisturizers used in the formulation of the invention are panthenol and/or octyldodecanol.
As used herein, an “emulsifier” is a substance that stabilizes an emulsion. A typical emulsifier used in the formulation of the invention is PEG-40 hydrogenated castor oil.
As used herein, a “preservative” is a substance used to preserve the formulation of the invention. A typical preservative used in the formulation of the invention is phenoxyethanol.
As used herein, an “active ingredient” includes an active cosmetic agent (herein also termed “cosmetic active agent”). As used herein, an active agent is defined as the chemical, biological mineral or any other entity or component responsible for the effect in a product. As used herein, an active cosmetic agent is defined as the chemical, biological mineral or any other entity or component responsible for the cosmetic effects in a product. Typical active agents used in the formulation of the invention are niacinamide (also termed herein “nicotinamide”), tocopherol and/or deferiprone. In the present invention, niacinamide and tocopherol can have an anti-oxidative effect on the skin and/or can improve the epidermal barrier.
As used herein, a “emollient” serves to soften and/or soothing the skin. Typical emollients used in the formulation of the invention are octyldodecanol, Ribes nigrum seed oil, Helianthus annuus seed oil unsaponifiables, tocopherol, Cardiospermum halicacabum
flower/leaf/vine extract, Helianthus annuus seed oil, Camilla sinensis extract (green tea extract) and/or Rosmarinus officinalis leaf extract.
As used herein, a “chelator” is a compound containing a ligand (typically organic) capable of bonding a metal atom at two or more points. A typical chelator used in the formulation of the invention is deferiprone, capable of chelating an iron ion.
Prolylhydroxylase (PHD) uses Fe2+ ions as a cofactor, and one way to inhibit PHD is by reducing the availability of Fe2+ using iron chelators or by introducing metal ions like Ni2+, Mn2+ or Co2+ that will compete with Fe2+. The term “iron chelator” as used within the context of the present specification in particular refers to a compound that binds Fe2+ and thus reduces the amount of free Fe2+ available for PHD mediated HIF hydroxylation reaction.
As used herein, a “buffer” or a “buffer substance“ is a substance making a solution resistant against changes in pH when acid or alkali is added to it. Typical buffer substances used in the formulation of the invention are glycine and/or lactic acid.
As used herein, a “antistatic” or “antistatic compound” is a compound used for treatment of hairs or their surfaces in order to reduce or eliminate buildup of static electricity. A typical antistatic used in the formulation of the invention is glycine.
As used herein, a “conditioner” or “hair conditioner” is cosmetic compound used to improve the condition, the feel, texture, appearance, and manageability of hair. Typical conditioners or hair conditioners used in the formulation of the invention are Larix europaea wood extract, Helianthus annuus seed oil unsaponifialbles, tocopherol, Cardiospermum halicacabum flower/leaf/vine extract, Helianthus annuus seed oil, Camilla sinensis extract, and/or Rosmarinus officinalis leaf extract
As used herein, an “antioxidant” or “antioxidative compound” is a substance that inhibits oxidation of the ingredients of the formulation of the invention. A typical antioxidant used in the formulation of the invention is sodium metabisulfite.
As used herein, an “astringent” or “astringent compound” is a cosmetic compound used to make body tissue less oily and tightens the skin. A typical astringent used in the formulation of the invention is zinc chloride.
The term “deferiprone” as used within the context of the present specification refers to 3-hydroxy-l,2-dimethylpyridin-4(U7)-one (also termed l,2-dimethyl-3-hydroxy-4-pyridone). The CAS number of deferiprone is 30652-11-0.
DETAILED DESCRIPTION OF THE INVENTION
In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
The inventors herein provide an aqueous topical hair care formulation containing deferiprone.
Deferiprone acts as an ion chelator and is known to be a lipophilic compound. In aqueous formulations for application on the hair, the presence of a lipophilic substance use to prepare a formulation of deferiprone could be disadvantageous. For example, the lipophilic substance can accumulate on the hair and affects the appearance of the hair, which may be unacceptable from an aesthetic point of view. This is particularly disadvantageous in the daily use of a hair tonic formulation of deferiprone, especially for long hair, freshly blow-dried hair, hair extensions or hairstyles like curls and permanent waves.
These objects are surprisingly met by the present invention. The formulation is stable and has skin-friendly and hair-friendly properties. In the formulation according to the invention, the lipophilic ingredients necessary to formulate deferiprone do not adversely affect its use as a hair care product. Without wishing to be bound by theory, in the formulation of the invention, deferiprone can act as an ion chelator.
The inventors found that from a clinical-dermatological point of view, the formulation of the invention caused no relevant skin reactions (reddening, flaking, dryness, others) in the test area, and the formulation was very well tolerated (Example 4). Neither intolerance reactions in the sense of irritation nor allergic reactions (contact dermatitis) were found. Accordingly, from a dermatological point of view, the formulation of the invention has a low potential for irritation and sensitization.
The inventors showed in a follow-up survey (Example 5) that all participants were generally satisfied with the product and also reported perfect tolerability. The generally high rate of participant satisfaction corresponds well with the other survey results. All patients were happy with how the skin felt after application of the formulation, with subjectively reduced hair loss in all but two and the feeling of stronger and healthier hair in all but one study participant.
The inventors showed in a blinded clinical trial over a period of 9 months (Example 6) that the formulation of the invention is safe and effective to counteract Androgenetica alopecia (AGA). This study shows that the formulations of the invention are water-soluble alternatives to the market leaders in hair loss treatments Minoxidil and Caffeine. With proven efficacy in a clinical assessment, the formulation of the invention demonstrates significantly reduced hair loss and increased hair growth in humans. Treatment with the formulation of the invention is associated with beneficial effects on hair quality such as thickness, hair density, shine and elasticity, and scalp health. These favorable characteristics are further supported by its satisfactory outcomes and the absence of negative skin reactions.
In a first aspect, the present invention provides an aqueous topical hair care formulation for topical administration, comprising
(a) glycerol in an amount of 6-7 % w/w,
(b) phanthenol in an amount of 2-3 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(d) phenoxyethanol in an amount of 0.8-1 % w/w,
(e) niacinamide in an amount of 0.4-0.6 % w/w,
(f) octyldodecanol in an amount of 0.3-0.4 % w/w,
(g) deferiprone in an amount of 0.05-0.15 % w/w,
(h) ethylhexylglycerol in an amount of 0.05-0.15 % w/w,
(i) Ribes nigrum seed oil in an amount of 0.08-0.01 % w/w,
(j) glycine in an amount of 0.02-0.03 % w/w,
(k) Larix europaea wood extract in an amount of 0.02-0.03 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of 0.01-0.02 % w/w,
(m) sodium metabisulfite in an amount of 0.01-0.02 % w/w,
(n) tocopherol in an amount of 0.01-0.02 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.002-0.003 % w/w,
(p) Helianthus annuus seed oil in an amount of 0.002-0.003 % w/w,
(q) green tea (Camilla sinensis) extract in an amount of 0.002-0.003 % w/w,
(r) zinc chloride in an amount of 0.002-0.003 % w/w,
(s) lactic acid in an amount of 0.0007-0.0009 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of 0.0004-0.0006 % w/w, and
(u) water ad 100 % w/w.
In an embodiment, the formulation is a liquid formulation. As used herein, a “liquid”
formulation is a watery, stable, dissolved, or suspended form of cosmetic ingredients. A “liquid”, as used herein can have significantly lower viscosity compared to gels and/or does not produce any foaming effects associated with foam formulations.
In an embodiment, in the formulation as described herein, panthenol is D-panthenol.
In an embodiment, in the formulation as described herein, the water is de-ionized water.
In an embodiment, the pH of the formulation may be adjusted to 5-6, in particular to 5.4-5.8, for example with lactic acid. The amount of lactic acid added to the formulation may be adjusted to achieve this pH. Instead of the specific amounts of lactic acids as described herein, an amount of lactic acid may be present in the formulations of the invention, to achieve a pH of 5-6, preferably 5.4-5.8.
In an embodiment, the formulation as described herein is free of alcohol. In particular, the formulation as described herein is free of ethanol. In particular, the formulation as described herein is free of propanol.
In an embodiment, the present invention provides an aqueous topical hair care formulation, comprising
(a) glycerol in an amount of about 6.7 % w/w,
(b) phanthenol in an amount of about 2.3 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of about 1 % w/w,
(d) phenoxyethanol in an amount of about 0.89 % w/w,
(e) niacinamide in an amount of about 0.5% w/w,
(f) octyldodecanol in an amount of 0.39 % w/w,
(g) deferiprone in an amount of about 0.1 %w/w,
(h) ethylhexylglycerol in an amount of about 0.1 % w/w,
(i) Ribes nigrum seed oil in an amount of about 0.088 % w/w,
(j) glycine in an amount of about 0.024 % w/w,
(k) Larix europaea wood extract in an amount of about 0.024 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of about 0.015 % w/w,
(m) sodium metabisulfite in an amount of about 0.015 % w/w,
(n) tocopherol in an amount of about 0.013 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of about 0.0028 % w/w,
(p) Helianthus annuus seed oil in an amount of about 0.0028 % w/w,
(q) green tea (Camilla sinensis) extract in an amount of about 0.0024 % w/w,
(r) zinc chloride in an amount of about 0.0024 % w/w,
(s) lactic acid in an amount of about 0.0008 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of about 0.00045 % w/w, and
(u) water ad 100 % w/w.
In another embodiment, the present invention provides an aqueous topical hair care formulation, comprising
(a) glycerol in an amount of 6.7222 % w/w,
(b) phanthenol in an amount of 2.25 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of 1 % w/w,
(d) phenoxyethanol in an amount of 0.89 % w/w,
(e) niacinamide in an amount of 0.5% w/w,
(f) octyldodecanol in an amount of 0.3888 % w/w,
(g) deferiprone in an amount of 0.1 %w/w,
(h) ethylhexylglycerol in an amount of 0.1 % w/w,
(i) Ribes nigrum seed oil in an amount of 0.0875 % w/w,
(j) glycine in an amount of 0.024 % w/w,
(k) Larix europaea wood extract in an amount of 0.024 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of 0.015 % w/w,
(m)sodium metabisulfite in an amount of 0.015 % w/w,
(n) tocopherol in an amount of 0.01275 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.00275 % w/w,
(p) Helianthus annuus seed oil in an amount of 0.00275 % w/w,
(q) greet tea (Camilla sinensis) extract in an amount of 0.0024 % w/w,
(r) zinc chloride in an amount of 0.0024 % w/w,
(s) lactic acid in an amount of 0.0008 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of 0.00045 % w/w, and
(u) water ad 100 % w/w.
In yet another embodiment, the present invention provides an aqueous topical hair care formulation, said formulation comprising
(1) 99.5 % glycerol in an amount of 4-6 % w/w,
(2) 75 % phanthenol in an amount of 2-4 % w/w,
(3) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(4) a first mixture in the amount of 0.5- 1.5 % w/w, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture,
(5) niacinamide in an amount of 0.4-0.6 % w/w,
(6) a second mixture in the amount 0.4-0.6 % w/w, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture,
(7) a third mixture in the amount 0.4-0.6 % w/w, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture,
(8) deferiprone in an amount of 0.08-0.12 %w/w,
(9) 80% lactic acid in an amount of 0.0004-0.0012 % w/w, and
(10) water ad 100 % w/w.
In yet another embodiment, the present invention provides an aqueous topical hair care formulation, said formulation comprising
(1) 99.5 % glycerol in an amount of 5 % w/w,
(2) 75 % phanthenol in an amount of 3 % w/w,
(3) PEG-40 hydrogenated castor oil in an amount of 1 % w/w,
(4) a first mixture in the amount of 1 % w/w, said first mixture comprising
(i) ethylhexylglycerol in an amount of 10 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 89 % w/w of the first mixture, and
(iii) tocopherol in an amount of 1 % w/w of the first mixture,
(5) niacinamide in an amount of 0.5% w/w,
(6) a second mixture in the amount 0.5 % w/w, said second mixture comprising
(i) zinc chloride in an amount of 0.08 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.08 % w/w of the second mixture,
(iii) glycerol in an amount of 58.24 % w/w of the second mixture,
(iv) glycine in an amount of 0.8 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.8 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.5 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture,
(7) a third mixture in the amount 0.5 % w/w, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.55 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 3 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 77.76 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 17.50 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.09 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.55 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.55 % w/w of the third mixture,
(8) deferiprone in an amount of 0.1 %w/w,
(9) 80% lactic acid in an amount of about 0.001 % w/w, and
(10) water ad 100 % w/w.
In particular, panthenol is D-panthenol.
In yet another embodiment, the aqueous topical hair care formulation of the present invention is formulated as a hair tonic formulation.
In yet another embodiment, the aqueous topical hair care formulation of the present invention is a cosmetic formulation.
In an embodiment, the formulation of the present invention can be used in cosmetics, in particular for cosmetic restoration of hair, more particular to cosmetic treatment of hereditary hair loss and/or thinning hair. Treatment with the formulation can counteract the progression of
hereditary hair loss, especially at an early stage, and/or can promote the growth of existing hair.
New hair can often be thin and become thicker and darker over time. In yet another embodiment, the formulation of the present invention can be used for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
In yet another embodiment, the formulation of the present invention, comprising deferiprone, can be used to reactivate hair follicle development by stimulating HIF-la. HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing, thereby restores the nutrient supply of the hair follicle.
In another embodiment, the cosmetic treatment of the invention may include topical application to scalp and massage. Massage may be performed for 1-5 min, 1-4 min, 1-3 min or 1-2 min. Massage performed for 1-2 min is preferred.
In yet another embodiment, the formulation of the invention may be applied once daily, twice daily, three times daily or even more often. The application of the formulation once daily is preferred.
Normal hair growth amount to approx. 1 cm a month. Visible results therefore require a few months of continuous treatment. In yet another embodiment, the cosmetic treatment of the invention may be performed for at least 1-6 months, at least 2-6 months, at least 3-6 months or at least 4-6 months. Cosmetic treatment performed for at least 4-6 months is preferred.
In yet another embodiment, the aqueous topical hair care formulation of the present invention is not a pharmaceutical formulation.
In a second aspect, the present invention provides a hair care product, comprising the formulation of the present invention.
In a third aspect, the present invention provides a method for the production of the formulation of the present invention, said method comprising the steps:
(I) contacting deferiprone with de-ionized water at least 50 °C, under condition allowing to dissolve the deferiprone, and cool down to about 25 °C,
(II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
(III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture, under condition allowing to dissolve the glycerol, panthenol, and the first mixture,
(IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture under condition allowing to dissolve the second mixture,
(V) contacting PEG-40 hydrogenated castor oil with a third mixture, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture, under conditions allowing formation of a clear solution,
(VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
(VII) adjust pH to 5.4-5.8 with lactic acid, in particular 80% lactic acid.
Step (I)-(IV) of the method of the invention describe the manufacture of an aqueous solution, comprising deferiprone, and niacinamide, ethylhexylglycerol, phenoxyethanol, tocopherol, zinc chloride, green tea (Camilla sinensis) extract, glycerol, glycine, Larix europaea
wood extract, and sodium metabisulfite. This aqueous solution has predominantly hydrophilic properties. In step (V), a solution based on the lipophilic substance with the emulator PEG-40 hydrogenated castor oil is prepared. This solution has predominantly hydrophobic properties. In step (VI), by contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion, the aqueous topical hair care formulation containing deferiprone of the invention can be formed. This formulation is stable and has skin-friendly and hair-friendly properties. In the formulation according to the invention, the lipophilic ingredients necessary to formulate deferiprone do not adversely affect its use as a hair care product.
As used herein, a “homogenous emulsion” is in particular clear, transparent and odorless.
Controlling factors in the formation of an emulsion are, for example: mechanical energy, agitation time, temperature, volumetric ratio between the two phases, degree of dispersion of the internal phase and presence of impurities or surfactants. In step (I), an elevated temperature is used to achieved complete dissolution. In an embodiment, in step (I), deferiprone in contacted with de-ionized water at least 50 °C, preferable at least 60 °C, more preferred at least 70, most preferably at about 75 °C.
In another embodiment, in step (I), the conditions allowing to dissolve the deferiprone may include stirring at about 220 rpm, for example for 100 min.
In another embodiment, in step (I), and cool down to about 25 °C may be performed by adding de-ionized water, and/or be additional cooling, for example for 30 min.
In an embodiment, in step (II), the conditions allowing to dissolve the niacinamide may include stirring at about 220 rpm, for example for 100 min.
In an embodiment, in step (III), the conditions allowing to dissolve the glycerol, panthenol, and the first mixture may include stirring at about 220 rpm, for example for 100 min.
In an embodiment, in step (IV), the conditions allowing to dissolve the second mixture may include stirring at about 220 rpm, for example for 100 min.
In an embodiment, in step (V), the conditions allowing formation of a clear solution may include stirring at about 220 rpm, for example for 100 min.
In an embodiment, in step (VI), the conditions allowing formation of a homogeneous emulsion may include stirring at about 220 rpm, for example for 100 min.
In an embodiment, step (VII), may be repeated once or more times, to re-adjust the pH,
for example after 1 h.
As used herein in the aspects and/or embodiments, the first mixture can comprise:
(i) ethylhexylglycerol in an amount of 10 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 89 % w/w of the first mixture, and
(iii) tocopherol in an amount of 1 % w/w of the first mixture.
The first mixture can be a commercially available composition, for example a composition sold under the trade name "Euxyl PE 9010 / Microcare PEHG".
As used herein in the aspects and/or embodiments, the second mixture can comprise:
(i) zinc chloride in an amount of 0.08 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.08 % w/w of the second mixture,
(iii) glycerol in an amount of 58.24 % w/w of the second mixture,
(iv) glycine in an amount of 0.8 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.8 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.5 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture.
The second mixture can be a commercially available composition, for example a composition sold under the trade name "Redensyl 34158".
As used herein in the aspects and/or embodiments, the third mixture can comprise:
(i) Helianthus annuus seed oil in an amount of 0.55 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 3 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 77.76 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 17.50 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.09 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.55 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.55 % w/w of the third mixture.
The third mixture can be a commercially available composition, for example a composition sold under the trade name "Defensil Plus".
In a fourth aspect, the present invention provides an aqueous topical hair care formulation, obtainable by the method of the invention.
In a fifth aspect, the present invention provides a method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of the invention to the hair
and/or the scalp. The advantageous effects of the inventive formulation are particularly evident when the composition is applied onto the hair and/or scalp of a subject.
The terms “cosmetically treat” or "cosmetic treatment" refer to the contacting of a subject with a cosmetic agent, preferably by topical application to the hair and/or the scalp of a subject. A "cosmetic treatment", in contrast to a therapeutic treatment, has the effect of preventing, mitigating and/or correcting a cosmetically undesirable condition such as signs of hair loss and/or thinning hair.
In the context of the present invention, the term “subject” is understood to include a mammal such as an animal and, more preferably, a human that is receiving or intended to receive treatment, as it is herein defined. While the term “subject” is often used herein to refer to a human, the invention is not so limited. Accordingly, the term “subject” refers to any animal, mammal or human having or at risk for a medical condition that can benefit from the treatment.
In an embodiment, the method of cosmetic treatment of the present invention is cosmetic restoration of hair, in particular to cosmetic treatment of hereditary hair loss and/or thinning hair. Treatment with the formulation can counteract the progression of hereditary hair loss, in particular at an early stage, and/or can promote the growth of existing hair.
New hair can often be thin and become thicker and darker over time. In yet another embodiment, in the method of cosmetic treatment of the invention, the formulation of the present invention can be used for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
In yet another embodiment, in the method of cosmetic treatment of the invention, the formulation of the present invention, comprising deferiprone, can be used to reactivate hair follicle development by stimulating HIF-la. HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing, thereby restores the nutrient supply of the hair follicle.
In another embodiment, the method of cosmetic treatment of the invention may include topical application to scalp and massage. Massage may be performed for 1-5 min, 1-4 min, 1-3 min or 1-2 min. Massage performed for 1-2 min is preferred.
In yet another embodiment, in the method of cosmetic treatment of the invention, the formulation of the invention may be applied once daily, twice daily, three times daily or even more often. The application of the formulation once daily is preferred.
Normal hair growth amount to approx. 1 cm a month. Visible results therefore require a few months of continuous treatment. In yet another embodiment, in the method of cosmetic treatment of the invention may be performed for at least 1-6 months, at least 2-6 months, at least 3-6 months or at least 4-6 months. Cosmetic treatment performed for at least 4-6 months is preferred.
The invention is described by way of the following examples and figure which is to be construed as merely illustrative and not limitative of the scope of the invention.
The invention also pertains to the following embodiments:
1. An aqueous topical hair care formulation for topical administration, comprising
(a) glycerol in an amount of 6-7 % w/w,
(b) phanthenol in an amount of 2-3 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(d) phenoxyethanol in an amount of 0.8-1 % w/w,
(e) niacinamide in an amount of 0.4-0.6 % w/w,
(f) octyldodecanol in an amount of 0.3-0.4 % w/w,
(g) deferiprone in an amount of 0.05-0.15 % w/w,
(h) ethylhexylglycerol in an amount of 0.05-0.15 % w/w,
(i) Ribes nigrum seed oil in an amount of 0.08-0.01 % w/w,
(j) glycine in an amount of 0.02-0.03 % w/w,
(k) Larix europaea wood extract in an amount of 0.02-0.03 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of 0.01-0.02 % w/w,
(m) sodium metabisulfite in an amount of 0.01-0.02 % w/w,
(n) tocopherol in an amount of 0.01-0.02 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.002-0.003 % l i,
(p) Helianthus annuus seed oil in an amount of 0.002-0.003 % w/w,
(q) green tea (Camilla sinensis) extract in an amount of 0.002-0.003 % w/w,
(r) zinc chloride in an amount of 0.002-0.003 % w/w,
(s) lactic acid in an amount of 0.0007-0.0009 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of 0.0004-0.0006 % w/w, and
(u) water ad 100 % w/w.
2. The aqueous topical hair care formulation of item 1, comprising
(a) glycerol in an amount of about 6.7 % w/w,
(b) phanthenol in an amount of about 2.3 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of about 1 % w/w,
(d) phenoxyethanol in an amount of about 0.89 % w/w,
(e) niacinamide in an amount of about 0.5% w/w,
(f) octyldodecanol in an amount of 0.39 % w/w,
(g) deferiprone in an amount of about 0.1 %w/w,
(h) ethylhexylglycerol in an amount of about 0.1 % w/w,
(i) Ribes nigrum seed oil in an amount of about 0.088 % w/w,
(j) glycine in an amount of about 0.024 % w/w,
(k) Larix europaea wood extract in an amount of about 0.024 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of about 0.015 % w/w,
(m) sodium metabisulfite in an amount of about 0.015 % w/w,
(n) tocopherol in an amount of about 0.013 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of about 0.0028 % l i,
(p) Helianthus annuus seed oil in an amount of about 0.0028 % w/w,
(q) green tea (Camilla sinensis) extract in an amount of about 0.0024 % w/w,
(r) zinc chloride in an amount of about 0.0024 % w/w,
(s) lactic acid in an amount of about 0.0008 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of about 0.00045 % w/w, and
(u) water ad 100 % w/w. The aqueous topical hair care formulation of item 1 or 2, comprising
(a) glycerol in an amount of 6.7222 % w/w,
(b) phanthenol in an amount of 2.25 % w/w,
(c) PEG-40 hydrogenated castor oil in an amount of 1 % w/w,
(d) phenoxyethanol in an amount of 0.89 % w/w,
(e) niacinamide in an amount of 0.5% w/w,
(f) octyldodecanol in an amount of 0.3888 % w/w,
(g) deferiprone in an amount of 0.1 %w/w,
(h) ethylhexylglycerol in an amount of 0.1 % w/w,
(i) Ribes nigrum seed oil in an amount of 0.0875 % w/w,
(j) glycine in an amount of 0.024 % w/w,
(k) Larix europaea wood extract in an amount of 0.024 % w/w,
(l) Helianthus annuus seed oil unsaponifiables in an amount of 0.015 % w/w,
(m)sodium metabisulfite in an amount of 0.015 % w/w,
(n) tocopherol in an amount of 0.01275 % w/w,
(o) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.00275 % w/w,
(p) Helianthus annuus seed oil in an amount of 0.00275 % w/w,
(q) greet tea (Camilla sinensis) extract in an amount of 0.0024 % w/w,
(r) zinc chloride in an amount of 0.0024 % w/w,
(s) lactic acid in an amount of 0.0008 % w/w,
(t) Rosmarinus officinalis leaf extract in an amount of 0.00045 % w/w, and
(u) water ad 100 % w/w. The aqueous topical hair care formulation of any one of the preceding items, comprising
(1) 99.5 % glycerol in an amount of 4-6 % w/w,
(2) 75 % phanthenol in an amount of 2-4 % w/w,
(3) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(4) a first mixture in the amount of 0.5-1.5 % w/w, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture,
(5) niacinamide in an amount of 0.4-0.6 % w/w,
(6) a second mixture in the amount 0.4-0.6 % w/w, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture,
(7) a third mixture in the amount 0.4-0.6 % w/w, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture,
(8) deferiprone in an amount of 0.08-0.12 %w/w,
(9) 80% lactic acid in an amount of 0.0004-0.0012 % w/w, and
(10) water ad 100 % w/w. The aqueous topical hair care formulation of any one of the preceding items, comprising
(1) 99.5 % glycerol in an amount of 5 % w/w,
(2) 75 % phanthenol in an amount of 3 % w/w,
(3) PEG-40 hydrogenated castor oil in an amount of 1 % w/w,
(4) a first mixture in the amount of 1 % w/w, said first mixture comprising
(i) ethylhexylglycerol in an amount of 10 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 89 % w/w of the first mixture, and
(iii) tocopherol in an amount of 1 % w/w of the first mixture,
(5) niacinamide in an amount of 0.5% w/w,
(6) a second mixture in the amount 0.5 % w/w, said second mixture comprising
(i) zinc chloride in an amount of 0.08 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.08 % w/w of the second mixture,
(iii) glycerol in an amount of 58.24 % w/w of the second mixture,
(iv) glycine in an amount of 0.8 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.8 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.5 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture,
(7) a third mixture in the amount 0.5 % w/w, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.55 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 3 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 77.76 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 17.50 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.09 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.55 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.55 % w/w of the third mixture,
(8) deferiprone in an amount of 0.1 %w/w,
(9) 80% lactic acid in an amount of about 0.001 % w/w, and
(10) water ad 100 % w/w.
6. The aqueous topical hair care formulation of any one of the preceding items, formulated as a hair tonic.
7. The aqueous topical hair care formulation of any one of the items 1-6, which is a cosmetic formulation.
8. The aqueous topical hair care formulation of item 7, for cosmetic restoration of hair.
9. The aqueous topical hair care formulation of item 7 or 8, for cosmetic treatment of hereditary hair loss and/or thinning hair.
10. The aqueous topical hair care formulation of any one of the items 7-9, for counteracting the progression of hereditary hair loss, in particular at an early stage,
11. The aqueous topical hair care formulation of any one of the items 7-10, for promoting the growth of existing hair.
12. The aqueous topical hair care formulation of any one of the items 7-11, for elongation of the hair, and for growth of thicker, stronger and/or fuller hair.
13. The aqueous topical hair care formulation of any one of the items 7-12, wherein treatment reactivates hair follicle development by stimulating HIF-la.
14. A hair care product, comprising the topical hair care formulation of any one of the items 1- 13.
15. A method for the production of the formulation according to any one of the items 1-14, said method comprising the steps:
(I) contacting deferiprone with de-ionized water at least 50 °C, under condition allowing to dissolve the deferiprone, and cool down to about 25 °C,
(II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
(III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture, under condition allowing to dissolve the glycerol, panthenol, and the first mixture,
(IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture under condition allowing to dissolve the second mixture,
(V) contacting PEG-40 hydrogenated castor oil with a third mixture, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the
third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture, under conditions allowing formation of a clear solution,
(VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
(VII) adjust pH to 5.4-5.8 with lactic acid, in particular 80% lactic acid. An aqueous topical hair care formulation, obtainable by the method of item 15. A method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of any one of the items 1-14 and 16 to the hair and/or the scalp. The cosmetic method of item 17, including cosmetic restoration of hair. The cosmetic method of item 17 or 18, including cosmetic treatment of hereditary hair loss and/or thinning hair. The cosmetic method of any one of items 17-19, counteracting the progression of hereditary hair loss, in particular at an early stage, The cosmetic method of any one of items 17-20, promoting the growth of existing hair. The cosmetic method of any one of items 17-21, for elongation of the hair, and for growth of thicker, stronger and/or fuller hair. The cosmetic method of any one of items 17-22, wherein treatment reactivates hair follicle development by stimulating HIF-la.
24. The cosmetic method of any one of items 17-23, wherein administration comprises massage of the formulation into the hair and/or onto the scalp.
25. The cosmetic method of item 24, wherein massage is performed for 1-5 min.
26. The cosmetic method of any one of items 17-25, wherein the formulation is applied once daily.
27. The cosmetic method of any one of items 17-26, performed for at least 1-6 months.
LEGEND TO THE FIGURES
Figure 1: Questionnaire analysis demonstrates user satisfaction. The results were evaluated by the individual study participants via a questionnaire. All participants were generally satisfied with the product and also reported perfect tolerability.
Figure 2: Typical pattern of androgenic hair loss in males (Norwood scale, above) and females (Ludwig scale, below).
Figure 3: Hair quality was improved significantly by treatment with the formulation described in Example 2. The results were evaluated by board-certified dermatologists according to a standardized protocol. The formulation as described in Example 2 resulted in improvements in the clinical parameters of hair quality such as improvements in thickness of 7.2% (p < 0.001), hair density of 14.3% (p < 0.001) and shine and elasticity of 20.3% (p < 0.001) during the 9- month test period.
Figure 4: The formulation as described in Example 2 significantly reduces hair loss. (A) The results of hair loss assessment via combing show a significant decrease in hair loss in the study group. The mean delta of hair loss across all study participants was -30.36%, resulting in an average reduction of 38 hairs lost at t(6) vs. 69 hairs lost at T(0) (* p < 0.05). (B) For responsive participants, an average hair loss reduction of 65.72% was measured, corresponding to 37 hairs lost on average at t(6) (* p < 0.05). (C) Interestingly, it was found that for the top 20% of the study participants suffering from the most active hair loss
reflected by hair count att(O), it was still possible to achieve a dramatic reduction in hair loss with an average improvement of more than 60% at t(6) (* p < 0.05). Average physiological hair loss depicted by dashed line.
Figure 5: The formulation as described in Example 2 significantly increases hair growth. (A) Clinical examples of macroscopic hair growth improvement in the study period. (B) After 9 months of treatment, an increase in hair growth of 10.76% on average in responsive patients was measured (* p < 0.001).
Figure 6: The formulation as described in Example 2 harmonizes the hair growth cycle. The hair growth cycle was harmonized, with results of an average anagen hair percentage increase of +8.0% and telogen hair percentage reduction of -14.0% shown in the test area after 9 months of treatment.
EXAMPLE 1
Manufacture of hair tonic comprising deferiprone
Cleanliness of the raw material containers:
All raw material containers, must be inspected for visual cleanliness before being transported on to the preparation area, and then disinfected with a 70% ethanol solution.
Line Clearance:
All raw materials that are NOT required for the preparation have been removed from the preparation area.
Manufacturing instructions: hair tonic comprising deferiprone
Depending on which mixing vessel is used, proceed according to the specifications for this vessel.
Phase 1: Supply H2O 75°C de-ionized.
• Mixing vessel 1 : Set stirrer to 220 rpm
• Mixing vessel 2: Set stirrer to 750 rpm.
• Add the following ingredient while stirring and stir until completely dissolved: l,2-dimethyl-3 -hydroxy- 4(lH)-pyridone (deferiprone)
Phase 2:
• Mixing vessel 1 and 2: all settings for stirrer remain unchanged from now on up to and including phase 7.
• Add de-ionized cold H2O to the batch to cool the batch down to approx. 25°C. If necessary, start additional cooling.
Phase 3:
• Add the following component to the preparation and allow to dissolve:
Nicotinamide DAB
Phase 4:
• Add the following ingredients to the mixture and allow to dissolve: Glycerol 99.5% PhE veg.
D-Panthenol 75 W
Euxyl PE 9010/Microcare PEHG
Phase 5:
• Add the following ingredient to the mixture and allow to dissolve: Redensyl 34158
Phase 6:
• Pre-dissolve Cremophor REMO and Defensil Plus in a pre-dissolving container. Predissolution must be clear. Then add the pre-solution to the preparation obtained in phase 5 while stirring and allow to dissolve.
Phase 7:
• Adjust pH to 5.4-5.8 with Pharm 80% lactic acid.
• If readjustment is necessary, stir again for approx. 10 min.
EXAMPLE 2
Aqueous hair tonic formulation
The following Tables describe the components of an exemplary aqueous hair tonic formulation of the present invention, manufactured according to Example 1 :
EXAMPLE 3
The following Table describes the components of an exemplary aqueous hair tonic formulation of the present invention, manufactured according to Example 1, broken down by the individual ingredients and mixtures added in phases 1-7.
% of ingredient with respect to formulation
* * : % with respect to ingredient/mixture added
#: % with respect to formulation
EXAMPLE 4
Skin Tolerance of the formulation described in Examples 2 and 3.
The test product was applied to the hair and scalp of 17 test persons once a day over a period of 9 months.
Demographic data, scalp status, and medical history were collected during an initial screening. Tolerability was evaluated by a board-certified dermatologist. Treated areas were examined under constant light conditions. Skin reactions (reddening, scaling, dryness, and others) were graded according to a predefined scoring scale: Negative reaction (0 reaction points); Doubtful reaction (“(+)”, 0.5 reaction points); Weak positive reaction (“+”, 1 reaction points); Strong positive reaction (“++”, 2 reaction points); Extreme positive reaction (“+++”, 3 reaction points). The overall results were summarized in cumulative irritation scores, the total number of skin reactions and total reaction points.
The results are summarized in Table 1. From a clinical-dermatological point of view, there were no relevant skin reactions (reddening, flaking, dryness, others) in the test area, and the product was very well tolerated. Neither intolerance reactions in the sense of irritation nor
allergic reactions (contact dermatitis) were found.
Accordingly, from a dermatological point of view, the tested product has a low potential for irritation and sensitization when used as intended.
Table 1. Demographic data, scalp status, and medical history were collected during an initial screening. Tolerability was evaluated by a board-certified dermatologist. Skin reactions (reddening, scaling, dryness, and others) were graded according to a pre-defined scoring scale. The overall results were summarized in cumulative irritation scores, the total number of skin reactions and total reaction points. After an application phase of nine months, no negative skin reactions of dermatological relevance were documented for the test product.
EXAMPLE 5
Query of the subjective impression via a questionnaire
In a follow-up study of the trial of Example 4, different subjective parameters (subjectively experienced effect, smell, taste, consistency, influence on the skin's appearance, etc.) were recorded with a questionnaire (Figure 1). To do this, each test person filled out the relevant questionnaire independently at the 3 -month follow-up appointment. In the event of uncertainty, the supervising study nurse or the supervising doctor could be consulted and
questioned at any time.
A Likert scale was employed to assess the hair restoration outcome. The questionnaire results were analyzed by means of descriptive statistics. The results are summarized in Figure 1.
All participants were generally satisfied with the product and also reported perfect tolerability. The generally high rate of participant satisfaction corresponds well with the other survey results. All patients were happy with how the skin felt after application of the formulation, with subjectively reduced hair loss in all but two and the feeling of stronger and healthier hair in all but one study participant. Only three of the participants disagree with the statement „ After use my hair has grown back stronger“. Only one participant does not agree to an improvement in hair density.
EXAMPLE 6
The formulation of the invention counteracts androgenic hair loss and improves hair growth in a blinded clinical trial
This example relates to the
1) objective assessment of the safety and tolerability of the aqueous hair tonic formulation of the invention as described in Example 2 in humans.
2) objective measures of hair look and feel after treatment with the formulation described in Example 2.
3) objective examination of the capacity of the formulation described in Example 2 to counteract AGA in vivo by reducing hair loss and promoting hair growth.
Methods
The product tested in this application study was used in the intended application area over a longer period of time (9 months). A risk analysis of the components of the test product was carried out before the commencement of the study. All available information was systematically evaluated in order to identify potential dangers and avert risks.
The aim of this study was to examine the tolerability and effectiveness of the formulation described in Example 2 according to clinical-dermatological test criteria. Before the subjects were included, the health and integrity of the scalp integument was examined. If a condition requiring medical treatment existed, the subject was excluded. There was also an informative discussion in which the study design, the study conditions and the rights and obligations of the
test persons within the framework of the study were explained to the test persons by the supervising study nurse or the supervising dermatologist. The test persons were only included in the study if they did not show any pathological skin changes in the application area, signed the declaration of consent either self-determined or signed by the legal guardian and met all other inclusion and exclusion criteria. During the study, the subjects could consult the supervising study nurse or the supervising dermatologist for objective and subjective skin changes. According to the schedule, dermatological examinations took place. In order to keep fluctuations due to external influences such as room temperature and relative humidity as low as possible, the measurements were always carried out under the same physical environmental conditions when the patient was rested (20 °C, humidity 40-60%).
Patient recruitment and study conduct
Study conduct and data analysis were based on principles of GCP and were in line with the Declaration of Helsinki. Patients in overall good health, between the ages of 30 and 60 years, with genetically caused hair loss (Androgenetica alopecia, AGA) in hair growth stage according to Norwood III-IV (male test persons) or Ludwig- Level 1 (female subjects) qualified for inclusion (Figure 2). Pregnant or lactating women and patients with allergies to hair care products or those who received treatment with platelet rich plasma, laser treatments, or other scalp altering treatments within 6 months of the study start date were excluded. After informed consent, 4 female subjects (mean age 46.5, range 37 - 52 years) and 16 male subjects (mean age 41.6, range 31 - 57 years) were included in this study.
The formulation described in Example 2 was applied by blinded users once daily in the damp hair after shower and massaged in at areas of hair loss. The first product application was done under the supervision of a study nurse.
Dermatological assessment of skin tolerability and hair quality
Demographic data, scalp status, and medical history were collected during an initial screening. The tolerability of the formulation described in Example 2 was evaluated by a board-certified dermatologist. Treated areas were examined under constant light conditions. In the dermatological assessment after the in-vivo touching evaluation, various parameters were determined visually and by touching the skin/hair. This assessment is carried out by a trained assessor using a visual analog scale to evaluate the relevant parameters (Hayes, M, Patterson G
(1921). Psychological Bulletin, 18, 98-99). The scale is defined from "no intensity/excellent condition" to "maximum intensity/poor condition". The individual intensities are displayed numerically by measuring the analogue scale (values 0.0 to 100.0).
Determining reduced hair loss
Hair loss after combing was determined according to an accepted method described in the literature (Wasko CA, Mackley CL, Sperling LC, Mauger D, Miller JJ., Arch Dermatol. 2008;144(6):759-762. doi: 10.1001 /archderm.144.6.759). After the hair had been washed, the still damp hair was thoroughly combed for 60 seconds with a standardized comb. The teeth of the comb, which was 15 cm long, were separated by 1 mm on one half of the comb and by 2 mm on the other half. The hair that had fallen out was counted by a qualified study nurse. Two- tailed Student's t test was used to perform a direct comparison between the timepoints and results were considered significant at p < 0.05.
Determining increased hair growth
For a visual assessment of the affected skin areas, digital images (macro images) were taken with the Nikon D200 and the AF-S Micro Nikkor lens (focal length 60 mm; speed 1 :2.8; type G ED glass; exposure time 1 :200; aperture F/ 22; ISO 200). For each subject, one picture was taken before the start of the application and one picture after the end of the application.
The TrichoScan HD method (DermoScan GmbH) is used to evaluate hair growth objectively. One measurement area is determined on the scalp of each subject. Pre-treatment of the measuring area on the scalp is carried out as follows: A measuring area in the transition zone between alopecia and regular hairy scalp is selected for each subject. The subsequent measurement area is defined with the aid of a perforated mask. The hair is threaded through the perforated mask and roughly shortened with scissors. The shortened hair is shaved to an even length of 0.8 mm with the Moser shaver (TrichoScan Edition). To do this, the razor is guided at a 90° angle to the scalp without applying pressure. The hair is colored two days after shaving: the hair color (Gol dwell Topchic 2N) is applied to a wooden spatula. The same amount of developer (Creme oxyd) is added to the hair color (1 : 1 mixture). Hair color and developer are mixed well together until they reach a creamy consistency. The coloring mass is applied to the measurement area (scalp) of the test subject and acts there for 15 minutes. After the exposure time, the stain is roughly removed with a swab and the measuring area is cleaned very carefully
with an alcoholic tincture (e.g. Kodan Spray) and/or a soft swab. The camera handpiece of the TrichoScan HD is used to record the image files. The recordings must be free of air bubbles and surrounding hair. For taking the pictures, the measuring area is well moistened (Kodan Spray). Then the parameters hair density [1/cm2], number of hairs, anagen hairs [%], telogen hairs [%] are determined using TrichoScan HD software.
Results
Dermatological assessment proves tolerability of the formulation of the invention
The examinations were carried out according to clinical-dermatological assessment criteria. All test subjects showed healthy skin in the test area before, during and after the application study. No pathological skin changes were found. Test interruptions or even dermatological treatments were not carried out in any case. The preparation mentioned was very well tolerated and did not lead to dermatologically relevant skin changes in any of the test persons. The results are presented in Table 2 and discussed below.
Table 2: Comparison before and after use of the formulation described in Example 2
Variable N Before After p Value
Thickness, mean (SD) 20 57.89 (16.43) 53.94 (16.55) <0.001
Hair density, mean (SD) 20 59.39 (18.76) 51.68 (20.22) <0.001
Shine and elasticity, mean (SD) 20 64.84 (19.46) 52.67 (19.24) <0.001
Hair loss, mean (SD) 20 68.55 (127.49) 38.25 (81.32) <0.05
Hair loss, responders, mean (SD) 16 77.29 (33.22) 36.76 (21.29) <0.05
Hair loss, top 20%, mean (SD) 4 275.25 (174.97) 137.25 (152.38) <0.05
Hair growth, mean (SD) 20 232.67 (42.21) 250.20 (40.60) <0.01
Hair growth, responders, mean (SD) 17 229.45 (44.77) 252.27 (42.84) <0.001
Dermatological assessment demonstrates improvement of hair quality via the formulation of the invention
The results of the formulation of the invention were evaluated by board certified dermatologists according to a standardized protocol. The use of the formulation of the invention resulted in an improvement in the clinical parameters of hair quality such as thickness of 7.2%, hair density of 14.3%, shine and elasticity of 20.3% during the test period (Figure 3).
The formulation of the invention significantly reduces hair loss
The results of hair loss assessment via combing already show a significant decrease in hair loss after twelve weeks of daily treatment in the study group. However the mean delta of hair loss across all study participants after 6 month of study was with -30,36% even more significant (Figure 4A). At the 3-month follow-up a reduction of hair loss was already observed in 80% of study participants. This further increased to 85% after 6 months. In these responding subjects even a mean reduction of hair loss of 65.72% was achieved corresponding to 32 hair lost on average after 6 months (Figure 4B). Interestingly we found that in the top 20% study participants suffering from the most active hair loss reflected by hair count at t(0) it was still possible to achieve a dramatic reduction of hair loss with an average improvement of more than 62% after 6 months effectively reducing their hair shedding from an average of 275 hair a day to 137 almost normalizing their hair turnover to a physiological range (up to 100 hairs lost per day) (Figure 4C).
The average hair loss in the study cohort after 6 months corresponds well with the mean hair loss rate in healthy patients which was found to be approximately 40 according to the literature (Hoffmann, R., J. Investig. Dermatol. Symp. Proc. 2003, 8, 109-115). The maximum reduction of hair loss achieved in the study population was 100%.
The formulation of the invention significantly increases hair growth
The TrichoScan evaluation was carried out on a test area on the scalp after 9 months. After 9 months, hair growth improvement was visible macroscopically in most of the study participants (Figure 5A), and the difference between the before and after measurements on the TrichoScan was significant (p < 0.01). The hair density [1/cm2], the proportion of anagen hair [%] and the proportion of telogen hair [%] were determined to assess the influence of the formulation of the invention on hair growth. After 9 months of treatment an increase in hair growth of up to 32.5% (10.76% on average in responsive patients) was measured (Figure 5B). In only 3 patients there was no improvement in hair density which equals an 85% responder rate in our study cohort. The hair growth cycle was harmonized with the result of an average anagen hair percentage increase of 8.0% and telogen hair percentage reduction of -14.0% shown in the test area (Figure 6)
Discussion and conclusion
Many products, especially cosmetics, consumer goods and medical devices, are in daily contact with the skin, often for long periods of time. Good tolerability is therefore a prerequisite for the use of these products. Since alternative test methods such as animal experiments are prohibited in Europe and cell culture experiments can only be transferred to humans to a limited extent, tests on humans carried out under medical supervision are currently necessary from an ethical and scientific point of view.
This report aims to determine clinical safety and efficacy of the formulation of the invention in the context of androgenic hair loss. From a clinical and also psychological perspective, hair shedding counts are very important, whereas the growth rate and the anagen/telogen ratio are of secondary importance (Hoffmann, R., J. Investig. Dermatol. Symp. Proc. 2003, 8, 109-115). Healthy people have between 80,000 and 120,000 hairs. In healthy individuals approximately 10-20% of the hair follicles are in the resting stage (telogen) at any given time, which means that they are ready for the strand to fall out. In our cohort we were able to reduce hair in telogen phase from 31.8% at the beginning of our study to 26.9% at the end of the study period.
Using a standardized combing test is a widely accepted standard method for assessing the number of hairs shed (Wasko CA, Mackley CL, Sperling LC, Mauger D, Miller JJ., Arch Dermatol. 2008;144(6):759-762. doi: 10.1001 /archderm.144.6.759). The 60-second hair count is a simple, practical, and objective tool for monitoring conditions associated with hair shedding. Low intrapatient variability demonstrates that dependable results over an extended period of time are obtainable (Wasko CA, Mackley CL, Sperling LC, Mauger D, Miller JJ., Arch Dermatol. 2008;144(6):759-762. doi: 10.1001 /archderm.144.6.759). The mean hair loss rate for this method in healthy patients was found to be approximately 40 (Kligman AM., Arch Dermatol 1961 ;83 (2) 175-198). In our study cohort of AGA patients we were able to reduce mean hairs lost via treatment with the formulation of the invention from 69 at T(0) to 38 after 6 months which represents a restoration of normal hair homeostasis. This is a best in class result not achieved by any other product in the market to the best of our knowledge. In our cohort we observed 85% responders where either reduction of hair loss or halting of progression of hair loss could be achieved. Interestingly we found that in the top 25% study participants suffering from the most active hair loss reflected by hair count at t(0) we were still able to achieve a dramatic reduction of hair loss with an average improvement of more than 60% after 6 months.
This is strong indicator that the formulation of the invention is also able to achieve best results when applied in the condition of aggressive hair loss.
Traditional goals of a quality hair growth product are to heal damaged hair follicles and prolong their growth phase. Any successful treatment should therefore stop or reverse the process of hair follicle miniaturization, increase the number of terminal hair follicles, while reducing vellus hair counts and/or increase the number of anagen hairs. However, anagen phase prolongation also is the main reason for the shedding phenomenon associated with Minoxidil. HIF modulators/PHD inhibitors have been shown to execute their beneficial effects on hair biology via a reduction of the kenogen phase, the latency period required for a new hair growth to engage (Rathman-Josserand M, Bernard BA, Misra N., Hair Int J Trichology. 2014 Jul-Sep; 6(3): 113-139, Loussouam, G. et al., Int. J. Trichology 2012, 4, 131-152). This enables a positive influence on hair cycle dynamics while preventing abrupt shedding when the treatment is began or discontinued.
An ideal hair growth product is not only beneficial for hair quality and count but also makes your existing hair healthier and nourishes the skin beneath it. A major problematic aspect of Minoxidil treatment is that Minoxidil is beneficial for hair growth but detrimental to scalp health. Minoxidil is associated with a specific loss of lysyl hydroxylase activity; this loss is reversed by removing minoxidil (Murad S, Pinnell SR., J Biol Chem. 1987;262(25): 11973-8). Minoxidil inhibits the synthesis of lysyl hydroxylase by acting at the transcriptional level (Hautala T, Heikkinen J, Kivirikko KI, Myllyla R., Biochem J. 1992;283 ( Pt l)(Pt 1):51-4). This enzyme is essential for collagen stabilization. Treatment of cells with minoxidil is also associated with inhibition of cell proliferation (Pinnell SR, Murad S., Dermatologica 1987; 175 Suppl 2: 12-8). This effect of minoxidil is accompanied by inhibition ofDNA synthesis in skin cells. Since collagen is the major product of fibroblast activity and lysyl hydroxylase catalyzes a crucial reaction in collagen biosynthesis Minoxidil can be harmful to fibroblast functionality and consequentially skin homeostasis (Shao S, Zhang X, Duan L, Fang H, Rao S, Liu W., et al. Med Sci Monit. 2018;24:8592-601).
This is further aggravated by the fact that minoxidil treatment requires patients to apply the drug to the scalp every 12 hours to achieve the desired effect of hair growth, due to its pharmacokinetic properties (Yum S, Jeong S, Kim D, Lee S, Kim W, Yoo JW, Int J Mol Sci.
2017; 19(1), 53). One important factor of minoxidil in this context is its insolubility in water; it is dissolved in alcohol and sold as such. Applying it twice daily can hence lead to irritation of the skin, since alcohol as a vehicle is deeply dehydrating (Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S., Recent Pat Inflamm Allergy Drug Discov. 2012;6(2): 130-6). This set of negative characteristics is likely to be shared by newer compound developments such as Stemoxydine (proprietary to L’Oreal, France). Stemoxydine is a PHD competitive inhibitor (Loussouarn, G. et al., Int. J. Trichology 2012, 4, 131-152) and therefore hypoxia-like signaling via HIF pathway modulation is the mechanism of action. However, Stemoxydine does not only share the HIF pathway as a common denominator of efficacy with minoxidil but its delivery is also based on a hydro-alcoholic lotion potentially harmful to the scalp (Loussouarn, G. et al., Int. J. Trichology 2012, 4, 131-152). In stark contrast, the formulation of the invention is formulated without alcoholic penetration enhancers enabling powerful HIF modulation without skin toxicity. This results in the complete absence of complications and adverse events in the clinical assessment while competitors such as Minoxidil cause considerable skin irritation in a considerable number of customers. For Stemoxydine no peer reviewed data on adverse reactions is available at this point. The safety advantage of the formulation of the invention is also accompanied by increased usability. With the different pharmacological mechanism underlying HIF modulation via the formulation of the invention less frequent application yields efficacy. In our study collective we are able to demonstrate significantly reduced hair loss and increased hair growth upon application of the formulation of the invention once daily.
Taken together our clinical data clearly demonstrate the formulation of the invention to be safe and effective to counteract AGA. Applicable in both sexes and free of complications and side effects this novel product provides objectively measurable results. This study shows that the formulations of the invention are water-soluble alternatives to the market leaders in hair loss treatments Minoxidil and Caffeine. With proven efficacy in a clinical assessment, the formulation of the invention demonstrates significantly reduced hair loss and increased hair growth in humans. Treatment with the formulation of the invention is associated with beneficial effects on hair quality and scalp health. These favorable characteristics are further supported by its satisfactory outcomes and the absence of negative skin reactions. Given the promising results, the formulation of the invention represents a true innovation in AGA treatment.
Claims
(1) 99.5 % glycerol in an amount of 4-6 % w/w,
(2) 75 % phanthenol in an amount of 2-4 % w/w,
(3) PEG-40 hydrogenated castor oil in an amount of 0.5-1.5 % w/w,
(4) a first mixture in the amount of 0.5-1.5 % w/w, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture,
(5) niacinamide in an amount of 0.4-0.6 % w/w,
(6) a second mixture in the amount 0.4-0.6 % w/w, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture,
(7) a third mixture in the amount 0.4-0.6 % w/w, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture,
(8) deferiprone in an amount of 0.08-0.12 %w/w,
(9) 80% lactic acid in an amount of 0.0004-0.0012 % w/w, and
(10) water ad 100 % w/w. The aqueous topical hair care formulation of any one of the preceding claims, formulated as a hair tonic. The aqueous topical hair care formulation of any one of the claims 1-4, which is a cosmetic formulation. The aqueous topical hair care formulation of claim 5,
(a) for cosmetic restoration of hair
(b) for cosmetic treatment of hereditary hair loss and/or thinning hair,
(c) for counteracting the progression of hereditary hair loss, in particular at an early stage,
(d) for promoting the growth of existing hair, and/or
(e) for elongation of the hair, and for growth of thicker, stronger and/or fuller hair. The aqueous topical hair care formulation of any one of the claims 5-6, wherein treatment reactivates hair follicle development by stimulating HIF-la. A hair care product, comprising the topical hair care formulation of any one of the claims 1-
7. A method for the production of the formulation according to any one of the claims 1-8, said method comprising the steps:
(I) contacting deferiprone with de-ionized water at least 50 °C, under condition allowing to dissolve the deferiprone, and cool down to about 25 °C,
(II) contacting the solution formed in step (I) with niacinamide, under condition allowing to dissolve the niacinamide,
(III) contacting the solution formed in step (II) with glycerol, panthenol, and a first mixture, said first mixture comprising
(i) ethylhexylglycerol in an amount of 8-12 % w/w of the first mixture,
(ii) phenoxyethanol in an amount of 87-91 % w/w of the first mixture, and
(iii) tocopherol in an amount of 0.5-1.5 % w/w of the first mixture, under condition allowing to dissolve the glycerol, panthenol, and the first mixture,
(IV) contacting the solution formed in step (III) with a second mixture, said second mixture comprising
(i) zinc chloride in an amount of 0.06-0.1 % w/w of the second mixture,
(ii) green tea (Camilla sinensis) extract in an amount of 0.06-0.1 % w/w of the second mixture,
(iii) glycerol in an amount of 56-60 % w/w of the second mixture,
(iv) glycine in an amount of 0.6-1 % w/w of the second mixture,
(v) Larix europaea wood extract in an amount of 0.6-1 % w/w of the second mixture,
(vi) sodium metabisulfite in an amount of 0.4-0.6 % w/w of the second mixture, and
(vii) water ad 100 % w/w of the second mixture under condition allowing to dissolve the second mixture,
(V) contacting PEG-40 hydrogenated castor oil with a third mixture, said third mixture comprising
(i) Helianthus annuus seed oil in an amount of 0.5-0.6 % w/w of the third mixture,
(ii) Helianthus annuus seed oil unsaponifiables in an amount of 2-4 % w/w of the third mixture,
(iii) octyldodecanol in an amount of 75-80 % w/w of the third mixture,
(iv) Ribes nigrum seed oil in an amount of 15-20 % w/w of the third mixture,
(v) Rosmarinus officinalis leaf extract in an amount of 0.07-0.11 % w/w of the third mixture,
(vi) tocopherol in an amount of 0.5 -0.6 % of the third mixture, and
(vii) Cardiospermum halicacabum flower/leaf/vine extract in an amount of 0.5-0.6 % w/w of the third mixture, under conditions allowing formation of a clear solution,
(VI) contacting the solutions formed in step (IV) and (V), under conditions allowing formation of a homogeneous emulsion.
(VII) adjust pH to 5.4-5.8 with lactic acid, in particular 80% lactic acid.
10. An aqueous topical hair care formulation, obtainable by the method of claim 9.
11. A method of cosmetic treatment of the hair and/or the scalp, comprising administration of the formulation of any one of the claims 1-8 and 10 to the hair and/or the scalp.
12. The cosmetic method of claim 11,
(a) including cosmetic restoration of hair,
(b) including cosmetic treatment of hereditary hair loss and/or thinning hair,
(c) counteracting the progression of hereditary hair loss, in particular at an early stage,
(d) promoting the growth of existing hair,
(e) for elongation of the hair, and for growth of thicker, stronger and/or fuller hair, and/or
(f) wherein treatment reactivates hair follicle development by stimulating HIF-la.
13. The cosmetic method of any one of claims 11-12, wherein administration comprises massage of the formulation into the hair and/or onto the scalp, wherein massage is preferably performed for 1-5 min.
14. The cosmetic method of any one of claims 11-13, wherein the formulation is applied once daily.
15. The cosmetic method of any one of claims 11-14, performed for at least 1-6 months.
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