WO2008059190A1 - Treatment of excess sebum production - Google Patents
Treatment of excess sebum production Download PDFInfo
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- WO2008059190A1 WO2008059190A1 PCT/GB2007/002101 GB2007002101W WO2008059190A1 WO 2008059190 A1 WO2008059190 A1 WO 2008059190A1 GB 2007002101 W GB2007002101 W GB 2007002101W WO 2008059190 A1 WO2008059190 A1 WO 2008059190A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
Definitions
- This invention relates to the treatment of excess sebum production and/or excretion from sebaceous glands.
- Sebum is an oily secretion from sebaceous glands in the skin and serves many functions. Sebum is involved in the development epidermal structure and maintains an epidermal permeability barrier, as well as transporting anti-oxidants to the surface of the skin and providing protection from microbial colonisation. An increased rate of sebum excretion is termed seborrhoea. Seborrhoea is a feature of many conditions including Parkinson's disease.
- Seborrhoeic dermatitis is characterised by the appearance of red, flaking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. Seborrhoeic dermatitis of the scalp is often referred to as dandruff and may range from mild scalp flaking to pronounced dense, diffuse, adherent scale on the scalp. In the clinical literature seborrhoeic dermatitis may be also referred to as "sebopsoriasis”, “seborrhoeic eczema”, “dandruff” and "pityriasis captis”.
- yeast infections are a causative factor in seborrhoeic dermatitis.
- the yeast consumes the specific saturated fatty acids necessary for their proliferation leaving high concentrations of unsaturated fatty acids on the skin. It has been suggested that penetration of the modified sebaceous secretions result in inflammation, irritation and flaking of the skin.
- Treatments for seborrhoeic dermatitis include antifungal agents such as zinc pyrithione, cinnamic acid, azoles, cyclopirox, terbinafine, as well as non-specific topical agents such as selenium sulphide/sulphur, tar, lithium succinate, benzoyl peroxide, propylene glycol, and corticosteroids.
- Corticosteroids are effective topical anti-inflammatory treatments but have severe systemic side-effects. Most compounds are given topically although if topical antifungals prove ineffective then agents such as ketoconazole, itraconazole or terbinafine can be given orally.
- Acne is divided into three categories: comedonal, inflammatory and nodulocystic acne. Diagnosis of the condition into these categories determines the treatment schedule. Mild to moderate forms of comedonal and inflammatory acne are treated topically. Mild but significant comedonal acne responds well to topical retinoids (adapalene, tretinoin and isotretinoin) or benzoyl peroxide. Comedonal acne with inflammatory and nodulocystic acne are generally treated with oral antibiotics and retinoids.
- Clonidine is an ⁇ 2-adrenoceptor agonist and is primarily used clinically as an antihypertensive agent. It acts within the central nervous system to reduce sympathetic nervous tone to the periphery. Besides lowering blood pressure and heart rate, clonidine also causes pronounced sedation and dry mouth.
- Clonidine is one of many imidazole-type compounds that are used clinically to treat conditions such as hypertension, sedation as an adjunct to anaesthesia (premedication), muscle spasm (spasticity), and withdrawal symptoms of opiate and alcohol abuse, although side effects such as sedation and dry mouth are common Examples of other such compounds are rilmenidine, dexmedetomidine, tizanidine, moxonidine and lofexidine. Summary of the Invention The present invention is the use of an ⁇ 2-adrenoceptor agonist for the manufacture of a medicament for the treatment or prevention of a condition associated with excess sebum production or excretion. Brief Description of the Drawings
- Figure 1 is a bar chart of sebum excretion following clonidine administration compared to placebo, showing the results of experiments reported below.
- Preferred ⁇ 2-adrenoceptor agonists for use in the invention are clonidine, rilmenidine, dexmedetomidine, tizanidine, moxonidine, lofexidine, brimonidine and apraclonidine (para-aminoclonidine).
- the ⁇ 2-adrenoceptor agonists are preferably administered topically. When they are administered topically, systemic exposure is reduced, and therefore the unwanted centrally-mediated side-effects, such as sedation, dry mouth and hypotension, are reduced.
- the ⁇ 2-adrenoceptor agonists may be administered together with an anti- muscarinic agent.
- Preferred anti-muscarinic agents for use in the invention are darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro-3202904 (PSD-506), propantheline, methscopolamine, homatropine methylbromide, poldine, trospium or glycopyrrolate.
- PSD-506 darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro-3202904 (PSD-506), propantheline, methscopolamine, homatropine methylbromide, poldine, trospium or glycopyrrolate.
- Ipratropium and tiotropium are anti
- Examples of conditions associated with excess sebum production are seborrhoea, seborrhoeic dermatitis and acne vulgaris.
- each active agent either alone or in combination may be administered together with an antitingual, antiproliferative zinc pyrithione, cinnamic acid, an azole (such as clotrimazole, econazole, ketoconazole, miconazole and sulconazole), cyclopirox, terbinafine, selenium sulphide, coal tar, lithium succinate, benzoyl peroxide or a corticosteroid, given topically to affected areas.
- an antitingual, antiproliferative zinc pyrithione such as clotrimazole, econazole, ketoconazole, miconazole and sulconazole
- cyclopirox such as clotrimazole, econazole, ketoconazole, miconazole and sulconazole
- cyclopirox such as clotrimazole, econazole, ketoconazole, miconazole and sulconazole
- cyclopirox
- each active agent either alone or in combination may be administered together with benzoyl peroxide, azelaic acid, adapalene, a retinoid such as tretinoin or istretinoin, salicyclic acid, nicotinamide, a histone deacetylase inhibitor (such as valproic acid) or an antibacterial agent (such as tetracycline, erythromycin or clindamycin) given topically to affected areas.
- benzoyl peroxide azelaic acid, adapalene
- a retinoid such as tretinoin or istretinoin
- salicyclic acid nicotinamide
- an antibacterial agent such as tetracycline, erythromycin or clindamycin
- Each active agent either alone or in combination may also be administered with retinoid (such as isotretinoin), an anti-androgen (such as cyproterone or ethinylestradiol), a histone deacetylase inhibitor (such as valproic acid) or an antibiotic agent (such as tetracycline, oxytetracycline, doxycycline, minoxycycline, erythromycin or trimethoprim) given orally.
- retinoid such as isotretinoin
- an anti-androgen such as cyproterone or ethinylestradiol
- a histone deacetylase inhibitor such as valproic acid
- an antibiotic agent such as tetracycline, oxytetracycline, doxycycline, minoxycycline, erythromycin or trimethoprim
- Each active agent may be used, according to the invention, in any appropriate form, e.g. as a salt, hydrate or prodrug. If a chiral molecule, it may be used as a racemate, as a non-racemic mixture or as a substantially single enantiomer.
- each active agent either alone or in combination may be administered by known means, in any suitable formulation, by any suitable route.
- Each active agent either alone or in combination, is preferably administered topically or orally.
- topical administration it is preferably formulated as a solution, gel, lotion, cream, shampoo or a spray.
- oral administration it is preferably formulated as a tablet, troche, lozenge, capsule, emulsion, syrup or elixir.
- the respective active agents may be formulated together in a single dosage form. Alternatively, they may be formulated separately and packaged together, or they may be administered independently.
- compositions for use in the invention may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
- Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
- the compositions of the invention may contain 0.1-99% by weight of active compound.
- the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 0.01 to 100 mg.
- the excipients used in the preparation of these compositions are the excipients known in the art. Appropriate dosage levels may be determined by any suitable method known to one skilled in the art.
- the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination.
- the active compound is administered at a frequency of 1 to 4 times per day.
- compositions for topical administration are also suitable for use in the invention.
- the pharmaceutically active compound or combination of compounds may be dispersed in a pharmaceutically acceptable cream, lotion, shampoo, ointment or gel.
- a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in an aqueous medium using surfactants.
- An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax.
- a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent.
- Topically administrable compositions may also comprise a matrix in which the active compound is dispersed, so that the compound is held in contact with the skin, in order to administer the compound or combinations of compounds to the skin.
- compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible tablets, powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
- suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
- the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
- Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid, find use in the preparation of injectables. The following study provides evidence of utility of the present invention.
- Sebum output levels were plotted over time for each subject for each dose level (and placebo) and the areas under the resulting curves (AUCT 0 . 6h ) calculated and statistically evaluated compared to placebo. Results Comparison of the AUCT 0 -6 h 's shows a statistically significant reduction in sebum production when placebo was compared to 50 meg and 100 meg clonidine (see figure 1).
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Abstract
An α2-adrenoceptor agonist is useful for the treatment or prevention of a condition associated with excess sebum production and/or excretion.
Description
TREATMENT OF EXCESS SEBUM PRODUCTION Field of the Invention
This invention relates to the treatment of excess sebum production and/or excretion from sebaceous glands. Background of the Invention
Sebum is an oily secretion from sebaceous glands in the skin and serves many functions. Sebum is involved in the development epidermal structure and maintains an epidermal permeability barrier, as well as transporting anti-oxidants to the surface of the skin and providing protection from microbial colonisation. An increased rate of sebum excretion is termed seborrhoea. Seborrhoea is a feature of many conditions including Parkinson's disease.
Seborrhoeic dermatitis is characterised by the appearance of red, flaking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. Seborrhoeic dermatitis of the scalp is often referred to as dandruff and may range from mild scalp flaking to pronounced dense, diffuse, adherent scale on the scalp. In the clinical literature seborrhoeic dermatitis may be also referred to as "sebopsoriasis", "seborrhoeic eczema", "dandruff" and "pityriasis captis".
There now appears general agreement that yeast infections are a causative factor in seborrhoeic dermatitis. The yeast consumes the specific saturated fatty acids necessary for their proliferation leaving high concentrations of unsaturated fatty acids on the skin. It has been suggested that penetration of the modified sebaceous secretions result in inflammation, irritation and flaking of the skin.
Therefore, whilst the primary treatment may focus around controlling fungal levels, this does not address the entire problem. It would be highly desirable to control and decrease sebum production.
Treatments for seborrhoeic dermatitis include antifungal agents such as zinc pyrithione, cinnamic acid, azoles, cyclopirox, terbinafine, as well as non-specific topical agents such as selenium sulphide/sulphur, tar, lithium succinate, benzoyl peroxide, propylene glycol, and corticosteroids. Corticosteroids are effective topical anti-inflammatory treatments but have severe systemic side-effects. Most compounds are given topically although if topical antifungals prove ineffective then agents such as ketoconazole, itraconazole or terbinafine can be given orally. The efficacy of itraconazole and terbinafine may be attributed to the excretion of these agents in sebum.
It is accepted in the clinical community that acne vulgaris is accompanied with clinical seborrhoea and there is a direct relationship between the sebum excretion rate and the severity of acne vulgaris. Although sebum production increases during adolescence (particularly in boys, because of androgen stimulation), increased sebum alone does not cause acne. Bacteria, most importantly P. acnes, are present in increased numbers in persons who have acne. Much of the inflammation that eventually occurs arises from the action of enzymes produced by the bacteria.
Acne is divided into three categories: comedonal, inflammatory and nodulocystic acne. Diagnosis of the condition into these categories determines the treatment schedule. Mild to moderate forms of comedonal and inflammatory acne are treated topically. Mild but significant comedonal acne responds well to topical retinoids (adapalene, tretinoin and isotretinoin) or benzoyl peroxide. Comedonal acne with inflammatory and nodulocystic acne are generally treated with oral antibiotics and retinoids.
There is a need for new therapies that reduce sebum excretion rates which are well tolerated for the treatment of seborrhoea as well as producing effective combination treatments for seborrhoeic dermatitis and acne vulgaris.
Clonidine is an α2-adrenoceptor agonist and is primarily used clinically as an antihypertensive agent. It acts within the central nervous system to reduce sympathetic nervous tone to the periphery. Besides lowering blood pressure and heart rate, clonidine also causes pronounced sedation and dry mouth.
Clonidine is one of many imidazole-type compounds that are used clinically to treat conditions such as hypertension, sedation as an adjunct to anaesthesia (premedication), muscle spasm (spasticity), and withdrawal symptoms of opiate and alcohol abuse, although side effects such as sedation and dry mouth are common Examples of other such compounds are rilmenidine, dexmedetomidine, tizanidine, moxonidine and lofexidine. Summary of the Invention The present invention is the use of an α2-adrenoceptor agonist for the manufacture of a medicament for the treatment or prevention of a condition associated with excess sebum production or excretion.
Brief Description of the Drawings
Figure 1 is a bar chart of sebum excretion following clonidine administration compared to placebo, showing the results of experiments reported below. Description of the Preferred Embodiments Preferred α2-adrenoceptor agonists for use in the invention are clonidine, rilmenidine, dexmedetomidine, tizanidine, moxonidine, lofexidine, brimonidine and apraclonidine (para-aminoclonidine). The α2-adrenoceptor agonists are preferably administered topically. When they are administered topically, systemic exposure is reduced, and therefore the unwanted centrally-mediated side-effects, such as sedation, dry mouth and hypotension, are reduced.
The α2-adrenoceptor agonists may be administered together with an anti- muscarinic agent. Preferred anti-muscarinic agents for use in the invention are darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro-3202904 (PSD-506), propantheline, methscopolamine, homatropine methylbromide, poldine, trospium or glycopyrrolate. These may be administered together with the α2-adrenoceptor agonists either topically or orally. Preferably they are administered topically to affected areas. Ipratropium and tiotropium are antimuscarinic agents that can be given topically with the α2-adrenoceptor agonist.
Examples of conditions associated with excess sebum production are seborrhoea, seborrhoeic dermatitis and acne vulgaris.
For the treatment of seborrhoea or seborrhoeic dermatitis, each active agent either alone or in combination may be administered together with an antitingual, antiproliferative zinc pyrithione, cinnamic acid, an azole (such as clotrimazole, econazole, ketoconazole, miconazole and sulconazole), cyclopirox, terbinafine, selenium sulphide, coal tar, lithium succinate, benzoyl peroxide or a corticosteroid, given topically to affected areas.
For the treatment of acne vulgaris, each active agent either alone or in combination may be administered together with benzoyl peroxide, azelaic acid, adapalene, a retinoid such as tretinoin or istretinoin, salicyclic acid, nicotinamide, a histone deacetylase inhibitor (such as valproic acid) or an antibacterial agent (such as tetracycline, erythromycin or clindamycin) given topically to affected areas. Each active agent either alone or in combination may also be administered with retinoid (such as isotretinoin), an anti-androgen (such as cyproterone or ethinylestradiol), a histone deacetylase inhibitor (such as valproic acid) or an antibiotic agent (such as
tetracycline, oxytetracycline, doxycycline, minoxycycline, erythromycin or trimethoprim) given orally.
Each active agent may be used, according to the invention, in any appropriate form, e.g. as a salt, hydrate or prodrug. If a chiral molecule, it may be used as a racemate, as a non-racemic mixture or as a substantially single enantiomer.
In general, each active agent either alone or in combination may be administered by known means, in any suitable formulation, by any suitable route. Each active agent, either alone or in combination, is preferably administered topically or orally. For topical administration, it is preferably formulated as a solution, gel, lotion, cream, shampoo or a spray. For oral administration, it is preferably formulated as a tablet, troche, lozenge, capsule, emulsion, syrup or elixir.
The respective active agents may be formulated together in a single dosage form. Alternatively, they may be formulated separately and packaged together, or they may be administered independently.
Compositions for use in the invention may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 0.01 to 100 mg. The excipients used in the preparation of these compositions are the excipients known in the art. Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination. Preferably, the active compound is administered at a frequency of 1 to 4 times per day.
Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound or combination of compounds may be dispersed in a pharmaceutically acceptable cream, lotion, shampoo, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in an aqueous
medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the active compound is dispersed, so that the compound is held in contact with the skin, in order to administer the compound or combinations of compounds to the skin.
Compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible tablets, powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution
and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables. The following study provides evidence of utility of the present invention.
Study
The study examined the effects of clonidine on sebum production in 9 healthy male volunteers. This was a double-blind, randomised, placebo-controlled dose study. The subjects were assessed on each dosing occasion for sebum production pre-dose and 1 h, 2.5h, 4h and 6h post-dose. Skin sebum excretion rates were determined using a Sebumeter® (Optical measurement of sebum excretion using opalescent film imprint, 2006, Handbook of non-invasive methods and the skin, Second Edition). Vital signs were recorded at specified times during each study period and adverse events were reported throughout.
Sebum output levels were plotted over time for each subject for each dose level (and placebo) and the areas under the resulting curves (AUCT0.6h) calculated and statistically evaluated compared to placebo. Results Comparison of the AUCT0-6h's shows a statistically significant reduction in sebum production when placebo was compared to 50 meg and 100 meg clonidine (see figure 1).
Claims
I . Use of an α2-adrenoceptor agonist for the manufacture of a medicament for the treatment or prevention of a condition associated with excess sebum production or excretion. 2. Use according to claim 1 , wherein the α2-adrenoceptor agonist is clonidine, rilmenidine, dexmedetomidine, tizanidine, moxonidine, lofexidine, brimonidine or apraclonidine.
3. Use according to claim 1 or claim 2, wherein the patient to be treated is undergoing treatment with an anti-muscarinic agent. 4. Use according to claim 3, wherein the anti-muscarinic agent is darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro- 3202904 (PSD-506), propantheline, methscopolamine, homatropine methylbromide, poldine, ipratropium, tiotropium, trospium or glycopyrrolate.
5. Use according to any preceding claim, wherein the medicament is to be administered by the topical route to affected areas.
6. Use according to claim 5, wherein the medicament is formulated as a solution, gel, lotion, cream, shampoo or a spray.
7. Use according to claim 3, wherein the anti-muscarinic is to be administered by the oral route. 8. Use according to claim 7, wherein the anti-muscarinic agent is darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro- 3202904 (PSD-506), propantheline, methscopolamine, homatropine methylbromide, poldine, trospium or glycopyrrolate. 9. Use according to any preceding claim, wherein the condition is seborrhoea. 10. Use according to any of claims 1 to 8, wherein the condition is seborrhoeic dermatitis.
I 1. Use according to any of claims 1 to 8, wherein the condition is acne.
12. Use according to claim 9 or claim 10, wherein the medicament is to be administered by the topical route and wherein the patient to be treated is also administered an antifungal, an antiproliferative, cyclopirox, terbinafine, selenium sulphide, coal tar, lithium succinate, benzoyl peroxide or a corticosteroid.
13. Use according to claim 11 , wherein the medicament is to be administered by the topical route and wherein the patient to be treated is also administered benzoyl peroxide, azelaic acid, adapalene, a retinoid salicyclic acid, nicotinamide, a histone deacetylase inhibitor or an antibacterial agent.
Applications Claiming Priority (2)
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GB0611241.1 | 2006-06-07 | ||
GBGB0611241.1A GB0611241D0 (en) | 2006-06-07 | 2006-06-07 | The treatment of increased sebum production |
Publications (1)
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WO2008059190A1 true WO2008059190A1 (en) | 2008-05-22 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/GB2007/002101 WO2008059190A1 (en) | 2006-06-07 | 2007-06-07 | Treatment of excess sebum production |
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GB (1) | GB0611241D0 (en) |
WO (1) | WO2008059190A1 (en) |
Cited By (8)
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EP2526943A1 (en) * | 2006-02-13 | 2012-11-28 | Orient Pharma (Samoa) Co, Ltd | Liquid formulation comprising an alpha-2 receptor agonist (e.g. clonidin) and oxybutynin (anti-muscarinic agent) for the treatment of sialorrhoea |
US20130072532A1 (en) * | 2010-01-08 | 2013-03-21 | Recro Pharma, Inc. | Topical transdermal dexmedetomidine compositions and methods of use thereof |
EP3093017A1 (en) * | 2010-11-16 | 2016-11-16 | Allergan, Inc. | Pharmaceutical composition comprising (s)-(3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl)methanol for use in treating mammalian conditions |
US9795559B2 (en) | 2011-12-11 | 2017-10-24 | Recro Pharma, Inc. | Intranasal dexmedetomidine compositions and methods of use thereof |
US10772871B2 (en) | 2013-10-07 | 2020-09-15 | Teikoku Pharma Usa, Inc. | Dexmedetomidine transdermal delivery devices and methods for using the same |
US10874642B2 (en) | 2013-10-07 | 2020-12-29 | Teikoku Pharma Usa, Inc. | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
US10987342B2 (en) | 2013-10-07 | 2021-04-27 | Teikoku Pharma Usa, Inc. | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
US11331306B2 (en) | 2011-11-21 | 2022-05-17 | Allergan, Inc. | Pharmaceutical compositions comprising 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole derivatives for treating retinal diseases |
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2526943A1 (en) * | 2006-02-13 | 2012-11-28 | Orient Pharma (Samoa) Co, Ltd | Liquid formulation comprising an alpha-2 receptor agonist (e.g. clonidin) and oxybutynin (anti-muscarinic agent) for the treatment of sialorrhoea |
US8481583B2 (en) | 2006-02-13 | 2013-07-09 | Orient Pharma (Samoa) Co., Ltd. | Combination of alpha-2 receptor agonist (clonidin) and anti-muscarinic agent (oxybutynin) for the treatment of sialorrhoea |
US8658683B2 (en) | 2006-02-13 | 2014-02-25 | Orient Pharma (Samoa) Co., Ltd | Combination of alpha-2 receptor agonist (clonidin) and anti-muscarinic agent (oxybutynin) for the treatment of sialorrhoea |
US20130072532A1 (en) * | 2010-01-08 | 2013-03-21 | Recro Pharma, Inc. | Topical transdermal dexmedetomidine compositions and methods of use thereof |
EP3093017A1 (en) * | 2010-11-16 | 2016-11-16 | Allergan, Inc. | Pharmaceutical composition comprising (s)-(3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl)methanol for use in treating mammalian conditions |
US11331306B2 (en) | 2011-11-21 | 2022-05-17 | Allergan, Inc. | Pharmaceutical compositions comprising 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole derivatives for treating retinal diseases |
US9795559B2 (en) | 2011-12-11 | 2017-10-24 | Recro Pharma, Inc. | Intranasal dexmedetomidine compositions and methods of use thereof |
US10682311B2 (en) | 2011-12-11 | 2020-06-16 | Baudax Bio, Inc. | Intranasal dexmedetomidine compositions and methods of use thereof |
US10772871B2 (en) | 2013-10-07 | 2020-09-15 | Teikoku Pharma Usa, Inc. | Dexmedetomidine transdermal delivery devices and methods for using the same |
US10874642B2 (en) | 2013-10-07 | 2020-12-29 | Teikoku Pharma Usa, Inc. | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
US10987342B2 (en) | 2013-10-07 | 2021-04-27 | Teikoku Pharma Usa, Inc. | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
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