WO2016060626A1 - Methods and compositions for prevention and treatment of hyperhidrosis - Google Patents
Methods and compositions for prevention and treatment of hyperhidrosis Download PDFInfo
- Publication number
- WO2016060626A1 WO2016060626A1 PCT/TR2014/000380 TR2014000380W WO2016060626A1 WO 2016060626 A1 WO2016060626 A1 WO 2016060626A1 TR 2014000380 W TR2014000380 W TR 2014000380W WO 2016060626 A1 WO2016060626 A1 WO 2016060626A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- strontium salts
- strontium
- hyperhidrosis
- calcium
- chloride
- Prior art date
Links
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- 210000000278 spinal cord Anatomy 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003438 strontium compounds Chemical class 0.000 description 1
- 229940026236 strontium nitrate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000021966 synaptic vesicle transport Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 208000005057 thyrotoxicosis Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007556 vascular defect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q15/00—Anti-perspirants or body deodorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the methods of the present invention relate to the topical application of a composition comprising a therapeutically effective amount of strontium salts (strontium chloride, strontium chloride hexahydrate, strontium nitrate, strontium gluconat) and a therapeuticallly effective combination of strontium salts (like those above) with aluminum chloride hexahydrate in the prevention and treatment of hyperhydrosis.
- strontium salts sodium chloride, strontium chloride hexahydrate, strontium nitrate, strontium gluconat
- a therapeuticallly effective combination of strontium salts like those above
- Eccrine sweat glands are the most numerous of all glands and can be found throughout the body surface except for the lips and the glans penis. Eccrine sweat glands consist of a ductal portion and a secretory portion. The major function of the ductal portion is to reabsorb ions from the primary sweat to create an isotonic sodium chloride solution. The major function of the secretory portion is as its name suggests: secretion. Eccrine sweat is composed primarily of water in addition to other ions such as sodium, chloride, potassium, and calcium.
- Eccrine sweat glands are innervated by postganglionic sympathetic fibers and the major neurotransmitter is acetylcholine.
- Many different types of muscarinic acetylcholine receptors can be found on eccrine sweat glands and thus these receptors can be blocked by antimuscarinic agents.
- Apocrine glands can be found on the hairy areas of the body like the axilla, mammary, perineal, and genital regions.
- Apocrine sweat is oily, lacks an odor, and is rich in proteins, lipids, and steroids.
- Apocrine glands receive sympathetic innervation and the major neurotransmitters are epinephrine and norepinephrine.
- Apoeccrine glands are mixed glands found in the hairy regions other body that develop during puberty from eccrine glands as the number of eccrine glands decrease with age. Apoeccrine glands secrete a watery solution similar to that of eccrine sweat. These glands receive cholinergic, alpha adrenergic, and beta adrenergic innervations. It is vital that an individual's core body temperature remain within physiological range in order for the body to function normally. The major function of sweating is to decrease the core body temperature when environmental temperatures exceed the normal physiological "set point" established by the hypothalamus. This is carried out by the evaporation of water from the skin and the release of heat energy.
- the body's ability to sweat up to 1.8 liters per hour allows survival in a wide range of temperatures. When temperatures consistently remain above forty degrees Celsius, protein denaturation and cell death result.
- the sweating pathway starts in the preoptic area in the anterior hypothalamus and descends to the lateral funiculus of the brainstem and synapses in the intermediolateral region of the spinal cord.
- Hyperhidrosis is the excessive production of sweat by the eccrine sweat glands due to overactive cholinergic innervation of these glands. Hyperhidrosis affects about 1% of the population and includes people of both sexes and all races. Histologically, though, the eccrine sweat glands are morphologically and functionally normal. It can affect any region of the body. Currently, one percent of the population suffers from this condition. It can be primary (idiopathic/essential) or secondary to another condition. Secondary hyperhidrosis can be further classified as generalized, local, or emotionally induced. Emotionally- induced hyperhidrosis, like from fear or anxiety, targets the palms, soles, and axillae.
- Generalized hyperhidrosis can be due to autonomic dysregulation or it can arise secondary to an underlying condition like a malignancy, diabetes mellitius, thyrotoxicosis, diabetes insipidus, anxiety, menopause, and carcinoid syndrome among many other conditions.
- Localized hyperhidrosis results from the abnormal regeneration of sympathetic nerves following injury, from a defect in the number of or distribution of eccrine sweat glands, or from a vascular defect.
- Primary (idiopathic/essential) hyperhidrosis affects the eccrine sweat glands and is due to excessive sympathetic activity. It does not affect the vascular endothelium.
- the primary sites of the body affected with hyperhidrosis include: The palms of the hand, known as palmer hyperhidrosis; the soles of the feet, known as plantar hyperhidrosis; the armpits, known as axillary hyperhidrosis; the head, known as scalp and facial hyperhidrosis; the trunk or thighs, known as truncal or thigh hyperhidrosis; the lips, nose, and forehead, known as gustatory hyperhidrosis. Many individuals suffer from a combination of the above categories.
- Hyperhidrosis treatment varies, depending on the severity of the problem. In most cases, most doctors will want to try conservative treatments before suggesting more-invasive options such as surgery. Many treatments exist to treat hyperhidrosis.
- Aluminum compounds are antiperspirants used to treat hyperhidrosis.
- Aldehydes are another treatment option that denature the keratin in the skin and occlude the pores of the sweat glands to reduce sweating. They are particularly effective in the palms and soles but not the axillae.
- Acetycholine is the major neurotransmitter that mediates sweat secretion. Therefore, drugs that inhibit the binding of acetylcholine, called anticholinergic agents, can be used to treat hyperhidrosis.
- Glycopyrrolate is an anticholinergic agent that blocks the muscarinic acetylcholine receptors in the smooth muscle, central nervous system, and secretory glands.
- Benztropine is another anticholinergic agent that may be useful in the treatment of hyperhidrosis.
- Oxybutynin inhibits smooth muscle spasms primarily by blocking the action of acetylcholine and can also be used to treat hyperhidrosis.
- Neuromuscular blocking drugs such as botulinum toxin-A can treat hyperhidrosis by inhibiting synaptic vesicle fusion and release of acetylcholine into the synaptic cleft which prevents acetylcholine action at the post-synaptic receptors and prevents sweating.
- Antiperspirants decrease the amount of sweat that is secreted by the eccrine sweat glands.
- Metal salt antiperspirants function by blocking the eccrine ducts with plugs composed of metal salts and keratin fibrils.
- Surgical removal of the sympathetic chain which is called sympathectomy, is another approach to treat hyperhidrosis. It is effective in treating palmar, axillary, and facial hyperhidrosis. Complications of sympathectomy include compensatory and gustatory hyperhidrosis, Homers syndrome, and neuralgia.
- Iontophoresis is another treatment that involves soaking the skin in a solution and applying low intensity electrical current which introduces charged ions into the skin and inhibits the function of the sweat glands in that area. Sweat gland suction is a new surgical technique in which local anesthesia is applied and the sweat glands are carefully removed (1).
- Aluminum was thought to physically occlude the sweat gland orifice.
- Aluminum has anticholinergic effects by acting on choline transport in the presynaptic nerve terminals. It regulates the activity of the Na+/K+ ATPase enzyme located in the plasma membrane which is necessary for maintaining an appropriate cell potential and cell volume. It also affects cell membrane structures, intracellular calcium homeostasis, and transport of ions within the secretory cells of the gland.
- Aluminum chloride causes degeneration of eccrine sweat glands after long term application.
- this new theory presents the idea that aluminum affects the secretion of sweat by constricting the lumen of the dermal duct. This is accomplished by its direct actions on the structure and function of the ductal membranes or by its anticholinergic effects (2).
- Strontium salts as alkalin-earth metal salts are important in cosmetic, pharmaceutical, 100 veterinary and/or dermatological compositions, these salts make it possible to treat, via the topical route, pathological and/or physiological disorders associated with the release of substance P and/or of TNF-alpha (Tumour Necrosis Factor-alpha) and especially to treat sensitive skins, skin disorders and skin diseases involving a pruritus, sensitive skin, and rosacea.
- TNF-alpha Tuour Necrosis Factor-alpha
- topically-applied strontium salts are effective for reducing histamine- 115 induced and IgE-mediated itch in humans, and has a suppressing effect for sensorial irritation (4).
- Cultured sweat gland cells retain the ability to respond to a variety of secreagogues by receptor mediated process, including the adrenergic agonists isoproterenol, prostaglandin E2, 120 phenylephrine, and cholinergic agonists methacoline and pilocarpin.
- Cultured human sweat cells also respond to acethylcolin and adrenalin. Acethylcolin and adrenaline stimulate sweat secretion in isolated human sweat glands, but adrenaline appears to activate calcium influx without mobilizing intracellular calcium, in contrast to acetylcolin.
- Adrenaline reportedly acts via alpha adrenergic receptors.
- IPP's Inositol polyphosphates
- the signal transduction pathway for calcium's rapid agonist responses in many tissues involves the activation of the enzyme phospholipase C, which acts on the substrate phosphatidylinositol 4,5 biphosphate, and which results in the formation of inositol 1,4,5 triphosphate ( ⁇ 3) and diacylglycerol.
- phospholipase C acts on the substrate phosphatidylinositol 4,5 biphosphate, and which results in the formation of inositol 1,4,5 triphosphate ( ⁇ 3) and diacylglycerol.
- the second messenger of this reaction-IP3 generated at the cell membrane, causes the rapid relase of
- IPP's could also mediate calcium entry from ECF, and not just from intracellular stores. It has recently been reported that depletion of internal stores of calcium triggers a capacitative influx of extracellular calcium across the plasma membrane. Because internal calcium stores are finite, prolonged bouts of signaling depend on the influx of external calcium through store operated channels in the plasma membrane. The increased
- cytoplasmic calcium due to the transient and sustained acethylcoline phases, through the activation of IPP's, simulates chloride channels in the apical (luminal) membrane, and potassium channels in the BLM of the secretory clear cell, resulting in the efflux of both ions.
- the rise in cytoplasmic calcium is reportedly the key factor in the activation of potassium channels.
- Calcium-activated potassium channels which are gated by intarcellular calcium
- Chloride enters the secretory cell via either a Na-2C1-K or Na-Cl cotransport system, and leaves the cells by diffusion into the lumen of the sweat duct.
- the cholinergic stimulation of eccrine sweat secretory cells, and the associated rise in intracellular calcium concentration, is also associated with an influx into the cells of sodium, along with the efflux of potassium and
- Strontium is very similar to calcium in its physiological behaviour and can act as an imperfect surrogate for calcium. As with calcium, approximately 99% of the total body burden of strontium is found in the skeleton. The skeletal burden of stable strontium in Japanese adult males was estimated to be approximately 440 mg, compared with 850 g calcium. Co- 160 ingestion of strontium and calcium reduced strontium uptake and skeletal strontium retention.
- strontium salts could be a candidate molecules in the prevention and treatment of hyperhydrosis. Additionally, it is well known that metal salt antiperspirants 165 function by blocking the eccrine ducts with plugs composed of metal salts and keratin fibrils.
- topical strontium salts especially strontium chloride hexahydrate
- sweating in the cases with palmoplantary and axillary hyperhydrosis
- This clinically positive effect was shown by iodine starch test (Tap water and 5% NaCl were used as vehicle and control), and gravimetric analysis.
- Aluminium salts can be used in the prevention and treatment of the hyperhydrosis and new theory of its action mechanism is that aluminum affects the secretion of sweat by constricting the lumen of the dermal duct. This is accomplished by its direct actions on the structure and function of the ductal membranes or by its anticholinergic effects. Taking this into consideration, we tried to make also a combination with strontium salts and aluminium
- Strontium salts alone can provide the opportunity to treat hyperhidrosis.
- strontium salts with its different action mechanism increase the effectiveness of aluminium chlorohydrate in the prevention and treatment of hyperhydrosis. They both work by different mechanisms. In this way, a stronger effect can be achieved.
- Strontium competes with calcium to pass through the calcium channels, and there will not be an increased intracytoplasmic 190 calcium, and so activation of potassium channels do not occur. Thereupon, sweating decrases.
- compositions may be provided especially in the form of aqueous, aqueous-alcoholic or oily solutions, of dispersions of the solution type or dispersions of the lotion or serum type, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or conversely (W/O), or of 195 suspensions or emulsions of soft, semi-solid or solid consistency of the cream type, of an aqueous or anhydrous gel, or alternatively of microemulsions, microcapsules, microparticles, or vesicular dispersions of the ionic and/or nonionic type.
- dispersions of the solution type or dispersions of the lotion or serum type emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or conversely (W/O), or of 195 suspensions or emulsions
- compositions constitute especially creams for the prevention and treatment of hyperhydrosis for the hands, for the feet, for the axillary region and other anatomical skin- 200 folds or for whole the body (for example creams, body milks, lotions, gels or foams, bath compositions, deodorant compositions) (See examples 1-4).
- Effective concentration ranges for strontium salts and Aluminum chlorohydrate in our formulations are 1-20% and 15-40% respectively.
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Abstract
This method, including strontium salts and combinations of strontium salts and aluminium chlorohydrate, is for treating hyperhidrosis, perspiration and apocrine sweating. The method includes topical preparations in the form of aqueous solutions, non-aqueous solutions, lotions, creams, gels, oils, ointments, foams, mousses, sprays, emulsions, shampoos, soaps and microemulsions comprising a therapeutically effective amount of strontium salts or combinations with strontium salts and aluminium chlorohydrate in a dermatologically acceptable excipient or carrier.
Description
METHODS AND COMPOSITIONS FOR PREVENTION AND TREATMENT OF
HYPERHIDROSIS
FIELD OF THE INVENTION The methods of the present invention relate to the topical application of a composition comprising a therapeutically effective amount of strontium salts (strontium chloride, strontium chloride hexahydrate, strontium nitrate, strontium gluconat) and a therapeuticallly effective combination of strontium salts (like those above) with aluminum chloride hexahydrate in the prevention and treatment of hyperhydrosis. BACKGROUND
There are three major types of sweat glands: eccrine, apocrine, and apoeccrine. Eccrine sweat glands are the most numerous of all glands and can be found throughout the body surface except for the lips and the glans penis. Eccrine sweat glands consist of a ductal portion and a secretory portion. The major function of the ductal portion is to reabsorb ions from the primary sweat to create an isotonic sodium chloride solution. The major function of the secretory portion is as its name suggests: secretion. Eccrine sweat is composed primarily of water in addition to other ions such as sodium, chloride, potassium, and calcium. Eccrine sweat glands are innervated by postganglionic sympathetic fibers and the major neurotransmitter is acetylcholine. Many different types of muscarinic acetylcholine receptors can be found on eccrine sweat glands and thus these receptors can be blocked by antimuscarinic agents. Apocrine glands can be found on the hairy areas of the body like the axilla, mammary, perineal, and genital regions. Apocrine sweat is oily, lacks an odor, and is rich in proteins, lipids, and steroids. Apocrine glands receive sympathetic innervation and the major neurotransmitters are epinephrine and norepinephrine. Apoeccrine glands are mixed glands found in the hairy regions other body that develop during puberty from eccrine glands as the number of eccrine glands decrease with age. Apoeccrine glands secrete a watery solution similar to that of eccrine sweat. These glands receive cholinergic, alpha adrenergic, and beta adrenergic innervations. It is vital that an individual's core body temperature remain within physiological range in order for the body to function normally. The major function of sweating is to decrease the core body temperature when environmental temperatures exceed
the normal physiological "set point" established by the hypothalamus. This is carried out by the evaporation of water from the skin and the release of heat energy. The body's ability to sweat up to 1.8 liters per hour allows survival in a wide range of temperatures. When temperatures consistently remain above forty degrees Celsius, protein denaturation and cell death result. The sweating pathway starts in the preoptic area in the anterior hypothalamus and descends to the lateral funiculus of the brainstem and synapses in the intermediolateral region of the spinal cord.
Hyperhidrosis is the excessive production of sweat by the eccrine sweat glands due to overactive cholinergic innervation of these glands. Hyperhidrosis affects about 1% of the population and includes people of both sexes and all races. Histologically, though, the eccrine sweat glands are morphologically and functionally normal. It can affect any region of the body. Currently, one percent of the population suffers from this condition. It can be primary (idiopathic/essential) or secondary to another condition. Secondary hyperhidrosis can be further classified as generalized, local, or emotionally induced. Emotionally- induced hyperhidrosis, like from fear or anxiety, targets the palms, soles, and axillae. Generalized hyperhidrosis can be due to autonomic dysregulation or it can arise secondary to an underlying condition like a malignancy, diabetes mellitius, thyrotoxicosis, diabetes insipidus, anxiety, menopause, and carcinoid syndrome among many other conditions. Localized hyperhidrosis results from the abnormal regeneration of sympathetic nerves following injury, from a defect in the number of or distribution of eccrine sweat glands, or from a vascular defect. Primary (idiopathic/essential) hyperhidrosis affects the eccrine sweat glands and is due to excessive sympathetic activity. It does not affect the vascular endothelium. Patients with essential hyperhidrosis constantly sweat from the skin surfaces which can be so severe as to make these individuals embarrassed and ashamed to shake their hands with others. The primary sites of the body affected with hyperhidrosis, and the associated nomenclature, include: The palms of the hand, known as palmer hyperhidrosis; the soles of the feet, known as plantar hyperhidrosis; the armpits, known as axillary hyperhidrosis; the head, known as scalp and facial hyperhidrosis; the trunk or thighs, known as truncal or thigh hyperhidrosis; the lips, nose, and forehead, known as gustatory hyperhidrosis. Many individuals suffer from a combination of the above categories.
Hyperhidrosis treatment varies, depending on the severity of the problem. In most cases, most doctors will want to try conservative treatments before suggesting more-invasive options such
as surgery. Many treatments exist to treat hyperhidrosis. Aluminum compounds are antiperspirants used to treat hyperhidrosis. Aldehydes are another treatment option that denature the keratin in the skin and occlude the pores of the sweat glands to reduce sweating. They are particularly effective in the palms and soles but not the axillae. Acetycholine is the major neurotransmitter that mediates sweat secretion. Therefore, drugs that inhibit the binding of acetylcholine, called anticholinergic agents, can be used to treat hyperhidrosis. Glycopyrrolate is an anticholinergic agent that blocks the muscarinic acetylcholine receptors in the smooth muscle, central nervous system, and secretory glands. Benztropine is another anticholinergic agent that may be useful in the treatment of hyperhidrosis. Oxybutynin inhibits smooth muscle spasms primarily by blocking the action of acetylcholine and can also be used to treat hyperhidrosis. Neuromuscular blocking drugs such as botulinum toxin-A can treat hyperhidrosis by inhibiting synaptic vesicle fusion and release of acetylcholine into the synaptic cleft which prevents acetylcholine action at the post-synaptic receptors and prevents sweating. Antiperspirants decrease the amount of sweat that is secreted by the eccrine sweat glands. Metal salt antiperspirants function by blocking the eccrine ducts with plugs composed of metal salts and keratin fibrils. Surgical removal of the sympathetic chain, which is called sympathectomy, is another approach to treat hyperhidrosis. It is effective in treating palmar, axillary, and facial hyperhidrosis. Complications of sympathectomy include compensatory and gustatory hyperhidrosis, Homers syndrome, and neuralgia. Iontophoresis is another treatment that involves soaking the skin in a solution and applying low intensity electrical current which introduces charged ions into the skin and inhibits the function of the sweat glands in that area. Sweat gland suction is a new surgical technique in which local anesthesia is applied and the sweat glands are carefully removed (1).
Aluminum chloride hexahydrate
According to a prior theory, aluminum was thought to physically occlude the sweat gland orifice. Evidence gathered recently explores a different mechanism by which aluminum possibly alters the flow from eccrine sweat glands. Aluminum has anticholinergic effects by acting on choline transport in the presynaptic nerve terminals. It regulates the activity of the Na+/K+ ATPase enzyme located in the plasma membrane which is necessary for maintaining an appropriate cell potential and cell volume. It also affects cell membrane structures, intracellular calcium homeostasis, and transport of ions within the secretory cells of the gland. Aluminum chloride causes degeneration of eccrine sweat glands after long term application.
95 More specifically, this new theory presents the idea that aluminum affects the secretion of sweat by constricting the lumen of the dermal duct. This is accomplished by its direct actions on the structure and function of the ductal membranes or by its anticholinergic effects (2).
Strontium salts
Strontium salts as alkalin-earth metal salts are important in cosmetic, pharmaceutical, 100 veterinary and/or dermatological compositions, these salts make it possible to treat, via the topical route, pathological and/or physiological disorders associated with the release of substance P and/or of TNF-alpha (Tumour Necrosis Factor-alpha) and especially to treat sensitive skins, skin disorders and skin diseases involving a pruritus, sensitive skin, and rosacea.
105 One human study has indicated that undamaged skin is a relatively effective barrier to penetration by strontium. Following application of 85 Sr-labelled strontium chloride solution to the intact forearm skin (average area 8 cm 2 ) of three volunteers for 6 h, absorption over the next 40 days was estimated to be 0.26% (range 0.14- 0.37%) of the applied dose. When 0.01-1.0% strontium chloride solutions containing 90 Sr were applied to the epidermal
110 surface of abdominal skin removed from 5- or 9-day-old rats, penetration of radiostrontium was inversely related to concentration. In the case of a 0.1% solution, penetration was 0.5% for the (hairless) skin of 5-day-old rats compared with 2% for (hairy) skin of 9-day-old rats, suggesting that the hair follicles in skin of the older rats allowed increased permeation (3).
It is well known that topically-applied strontium salts are effective for reducing histamine- 115 induced and IgE-mediated itch in humans, and has a suppressing effect for sensorial irritation (4).
DETAILED DESCRIPTION OF THE INVENTION
Cultured sweat gland cells retain the ability to respond to a variety of secreagogues by receptor mediated process, including the adrenergic agonists isoproterenol, prostaglandin E2, 120 phenylephrine, and cholinergic agonists methacoline and pilocarpin. Cultured human sweat cells also respond to acethylcolin and adrenalin. Acethylcolin and adrenaline stimulate sweat secretion in isolated human sweat glands, but adrenaline appears to activate calcium influx without mobilizing intracellular calcium, in contrast to acetylcolin. Adrenaline reportedly acts via alpha adrenergic receptors.
125 Calcium ions are ubiquitos regulators of many cellular processes, and eukaryotic cells have evolved a complex system of channels, pumps and exchangers, and transmembrane molecules, which maintain intracellular calcium concentrations at very low levels 10-100 nM. This allows for rapid metabolic responses to calcium fluxes. Inositol polyphosphates (IPP's) are important mediators of intracellular calcium mobilization and calcium influx, and are
130 rapidly generated following cholinergic stimulation. The signal transduction pathway for calcium's rapid agonist responses in many tissues involves the activation of the enzyme phospholipase C, which acts on the substrate phosphatidylinositol 4,5 biphosphate, and which results in the formation of inositol 1,4,5 triphosphate (ΓΡ3) and diacylglycerol. The second messenger of this reaction-IP3, generated at the cell membrane, causes the rapid relase of
135 calcium from intracellular stores by activating specific receptors and directly opening calcium channels, on the membranes of these stores in specific organelles, such as the endoplasmic reticulum. Cytoplasmic calcium is significantly reduced when extracellular calcium is removed, and thus the formation of IP3 may be of limited importance in the sustained elevation of cytoplasmic calcium during sweat gland stimulation. However, it has been
140 speculated that IPP's could also mediate calcium entry from ECF, and not just from intracellular stores. It has recently been reported that depletion of internal stores of calcium triggers a capacitative influx of extracellular calcium across the plasma membrane. Because internal calcium stores are finite, prolonged bouts of signaling depend on the influx of external calcium through store operated channels in the plasma membrane. The increased
145 cytoplasmic calcium, due to the transient and sustained acethylcoline phases, through the activation of IPP's, simulates chloride channels in the apical (luminal) membrane, and potassium channels in the BLM of the secretory clear cell, resulting in the efflux of both ions. The rise in cytoplasmic calcium is reportedly the key factor in the activation of potassium channels. Calcium-activated potassium channels, which are gated by intarcellular calcium,
150 result in the coupling of intracellular calcium levels and membrane potential. Chloride enters the secretory cell via either a Na-2C1-K or Na-Cl cotransport system, and leaves the cells by diffusion into the lumen of the sweat duct. The cholinergic stimulation of eccrine sweat secretory cells, and the associated rise in intracellular calcium concentration, is also associated with an influx into the cells of sodium, along with the efflux of potassium and
155 chloride (5, 6).
Strontium is very similar to calcium in its physiological behaviour and can act as an imperfect surrogate for calcium. As with calcium, approximately 99% of the total body burden of
strontium is found in the skeleton. The skeletal burden of stable strontium in Japanese adult males was estimated to be approximately 440 mg, compared with 850 g calcium. Co- 160 ingestion of strontium and calcium reduced strontium uptake and skeletal strontium retention.
Because Strontium is very similar to calcium in its physiological behaviour and can act as an imperfect surrogate for calcium, and calcium influx has an important key role in the mechanism of sweating, strontium salts could be a candidate molecules in the prevention and treatment of hyperhydrosis. Additionally, it is well known that metal salt antiperspirants 165 function by blocking the eccrine ducts with plugs composed of metal salts and keratin fibrils.
Indeed, we established that topical strontium salts (especially strontium chloride hexahydrate) decreased sweating in the cases with palmoplantary and axillary hyperhydrosis (unpublished data). This clinically positive effect was shown by iodine starch test (Tap water and 5% NaCl were used as vehicle and control), and gravimetric analysis.
170 Aluminium salts (chloride) can be used in the prevention and treatment of the hyperhydrosis and new theory of its action mechanism is that aluminum affects the secretion of sweat by constricting the lumen of the dermal duct. This is accomplished by its direct actions on the structure and function of the ductal membranes or by its anticholinergic effects. Taking this into consideration, we tried to make also a combination with strontium salts and aluminium
175 chloride.
A topical cream composed of Strontium (-chloride hexahydrate) (5%) and aluminium salts (- chlorohydrate) (19%) (See examples) was developed and applied to the cases with palmoplantary and axillary hyperhydrosis. Cases were divided into four groups: First group (only strontium chloride), second group (only aluminium chloride), and third group (a 180 combination with strontium chloride and aluminium chloride), and fourth group (placebo).
Although Group 1 , 2 and 3 have shown a decrease in sweating according to gravimetric test, fourth group has no significant change. When the first three groups were compared, third group had a pronounced and significant decrease in sweating than the other groups (group 2 and 3).
185 Strontium salts alone can provide the opportunity to treat hyperhidrosis. Additionally, strontium salts with its different action mechanism increase the effectiveness of aluminium chlorohydrate in the prevention and treatment of hyperhydrosis. They both work by different mechanisms. In this way, a stronger effect can be achieved. Strontium competes with calcium
to pass through the calcium channels, and there will not be an increased intracytoplasmic 190 calcium, and so activation of potassium channels do not occur. Thereupon, sweating decrases.
For a topical application, the compositions may be provided especially in the form of aqueous, aqueous-alcoholic or oily solutions, of dispersions of the solution type or dispersions of the lotion or serum type, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or conversely (W/O), or of 195 suspensions or emulsions of soft, semi-solid or solid consistency of the cream type, of an aqueous or anhydrous gel, or alternatively of microemulsions, microcapsules, microparticles, or vesicular dispersions of the ionic and/or nonionic type.
These compositions constitute especially creams for the prevention and treatment of hyperhydrosis for the hands, for the feet, for the axillary region and other anatomical skin- 200 folds or for whole the body (for example creams, body milks, lotions, gels or foams, bath compositions, deodorant compositions) (See examples 1-4).
Effective concentration ranges for strontium salts and Aluminum chlorohydrate in our formulations are 1-20% and 15-40% respectively.
Example 1. Antiperspirant cream for axillary hyperhydrosis (without aluminium 205 chlorohydrate)
1. Mauro TM, Goldsmith LA. Disorders of the ecrine and apocrine glands.In: Fitzpatrick's Dermatology in General Medicine, seventh edition, McGrawHill, New York, 2008, p: 713-738.
2. Bellet JS. Diagnosis and Treatment of Primary Focal Hyperhidrosis in Children and 220 Adolescents. Semin Cutan Med Surg 2010; 29: 121-126.
3. Concise International Chemical Assessment Document 77. Strontium and strontium compounds. WHO, 2010.
4. Hahn G. Strontium is a potent and a selective inhibitor of sensory irritation. Dermatol Surg 1999; 25: 689-694.
225 5. Olah A, et al. The channel physiology of the skin. Rev Physiol Biochem Pharmacol, doi:
10.1007/112_2012_7.
6. Elwary SMA, et al. Calcium homeostasis influences epidermal sweating in patients with •vitiligo. Br J Dermatol 1997; 137: 81-85.
230
235
240
Claims
1- A method for treating hyperhidrosis, perspiration and apocrine sweating, wherein the 245 method comprises topically administering to a subject in need thereof dermatological compositions comprising a therapeutically effective amount of strontium salts (especially chloride, chloride hexhydrate, nitrate, gluconate) or therapeutically effective combinations with strontium salts and aluminium chlorohydrate in a dermatologically acceptable excipient or carrier.
250 2. The method according to claim 1, wherein the active agents are strontium salts and combinations with strontium salts and aluminium chlorohydrate (Aluminium chloride or aluminium chloride hexhydrate).
3. The method according to claim 1 and 2, wherein strontium salts are provided in a concentration of about 1-20% (w/v) alone.
255 4. The method according to claim 2, wherein aluminium chlorohydrate is provided in a concentration of about 15-40% (w/v) in combination with strontium salts.
5. The method according to claim 1, wherein the composition is provided in the form selected from the group consisting of an aqueous solution, a non-aqueous solution, lotion, cream, gel, oil, ointment, foam, mousse, spray, an emulsion, a shampoo, soap and microemulsion.
260 6. The method according to claim 5, wherein all compositions in claim 5 comprises from about 1% to about 20% w/v strontium salts, and from about 15% to about 40% w/v aluminium chlorohydrate in a combination with strontium salts (%l-20 w/v).
7. The method according to claim 1, wherein the composition is formulated for topical application to the hands, feet including soles, face, scalp, neck, trunk, back, limbs, axillae 265 · and/or groin, and other anatomical regions of the subject.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2014/000380 WO2016060626A1 (en) | 2014-10-16 | 2014-10-16 | Methods and compositions for prevention and treatment of hyperhidrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2014/000380 WO2016060626A1 (en) | 2014-10-16 | 2014-10-16 | Methods and compositions for prevention and treatment of hyperhidrosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016060626A1 true WO2016060626A1 (en) | 2016-04-21 |
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ID=52293150
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2014/000380 WO2016060626A1 (en) | 2014-10-16 | 2014-10-16 | Methods and compositions for prevention and treatment of hyperhidrosis |
Country Status (1)
| Country | Link |
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| WO (1) | WO2016060626A1 (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0737471A2 (en) * | 1995-04-10 | 1996-10-16 | L'oreal | Use of alkaline earth metal salts as TNF-alpha inhibitor in a topical composition and composition obtained therefrom |
| US5788956A (en) * | 1995-10-26 | 1998-08-04 | Societe L'oreal S.A. | Antiperspirant compositions comprising substance P antagonists |
| US20030031727A1 (en) * | 1994-12-21 | 2003-02-13 | Cosmederm Technologies, Llc | Topical product formulations containing strontium for reducing skin irritation |
| US20050036967A1 (en) * | 2003-08-14 | 2005-02-17 | The Gillette Company | Enhanced efficacy antiperspirant compositions containing strontium or calcium |
| US20050036968A1 (en) * | 2003-08-14 | 2005-02-17 | The Gillette Company | Enhanced efficacy antiperspirant compositions containing strontium |
| WO2009114812A1 (en) * | 2008-03-14 | 2009-09-17 | Ernest Bloom | Antiperspirant compositions containing a copper salt and methods of using |
-
2014
- 2014-10-16 WO PCT/TR2014/000380 patent/WO2016060626A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030031727A1 (en) * | 1994-12-21 | 2003-02-13 | Cosmederm Technologies, Llc | Topical product formulations containing strontium for reducing skin irritation |
| EP0737471A2 (en) * | 1995-04-10 | 1996-10-16 | L'oreal | Use of alkaline earth metal salts as TNF-alpha inhibitor in a topical composition and composition obtained therefrom |
| US5788956A (en) * | 1995-10-26 | 1998-08-04 | Societe L'oreal S.A. | Antiperspirant compositions comprising substance P antagonists |
| US20050036967A1 (en) * | 2003-08-14 | 2005-02-17 | The Gillette Company | Enhanced efficacy antiperspirant compositions containing strontium or calcium |
| US20050036968A1 (en) * | 2003-08-14 | 2005-02-17 | The Gillette Company | Enhanced efficacy antiperspirant compositions containing strontium |
| WO2009114812A1 (en) * | 2008-03-14 | 2009-09-17 | Ernest Bloom | Antiperspirant compositions containing a copper salt and methods of using |
Non-Patent Citations (6)
| Title |
|---|
| "Strontium and strontium compounds", 2010, WHO, article "Concise International Chemical Assessment Document 77" |
| BELLET JS: "Diagnosis and Treatment of Primary Focal Hyperhidrosis in Children and Adolescents", SEMIN CUTAN MED SURG, vol. 29, 2010, pages 121 - 126, XP027085280 |
| ELWARY SMA ET AL.: "Calcium homeostasis influences epidermal sweating in patients with vitiligo", BR J DERMATOL, vol. 137, 1997, pages 81 - 85 |
| HAHN G.: "Strontium is a potent and a selective inhibitor of sensory irritation", DERMATOL SURG, vol. 25, 1999, pages 689 - 694, XP002225553, DOI: doi:10.1046/j.1524-4725.1999.99099.x |
| MAURO TM; GOLDSMITH LA: "Fitzpatrick's Dermatology in General Medicine", 2008, MCGRAWHILL, article "Disorders of the ecrine and apocrine glands", pages: 713 - 738 |
| OLAH A ET AL.: "The channel physiology of the skin", REV PHYSIOL BIOCHEM PHARMACOL |
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