WO2009068876A1 - Compositions pour le traitement d'affections cutanées - Google Patents

Compositions pour le traitement d'affections cutanées Download PDF

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Publication number
WO2009068876A1
WO2009068876A1 PCT/GB2008/003953 GB2008003953W WO2009068876A1 WO 2009068876 A1 WO2009068876 A1 WO 2009068876A1 GB 2008003953 W GB2008003953 W GB 2008003953W WO 2009068876 A1 WO2009068876 A1 WO 2009068876A1
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WO
WIPO (PCT)
Prior art keywords
receptor antagonist
muscarinic receptor
sebum secretion
antibacterial
acne
Prior art date
Application number
PCT/GB2008/003953
Other languages
English (en)
Inventor
Alan Geoffrey Roach
Nigel Blackburn
Jonathon Mark Tinsley
Fancis Xavier Wilson
Paul Goldsmith
Original Assignee
Summit Corporation Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0723589A external-priority patent/GB0723589D0/en
Priority claimed from GB0723587A external-priority patent/GB0723587D0/en
Priority claimed from GB0723588A external-priority patent/GB0723588D0/en
Application filed by Summit Corporation Plc filed Critical Summit Corporation Plc
Publication of WO2009068876A1 publication Critical patent/WO2009068876A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 use of muscarinic receptor antagonists as antibacterial agents.
  • the invention relates to the use of certain muscarinic receptor antagonists that have dual antibacterial and anti-sebum secretion activity in the treatment of various skin disorders, including acne.
  • the invention also relates to the use of muscarinic receptor antagonists as anti-sebum agents.
  • the invention relates to the use of certain muscarinic receptor antagonists that have dual antibacterial and anti-sebum secretion activity in the treatment of various skin disorders, including acne.
  • the invention also relates to cosmetic compositions for use in reducing facial shine and to cosmetic methods based thereon.
  • Sebum is an oily secretion from sebaceous glands in the skin and serves many functions. Sebum is involved in the development of 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.
  • seborrhoeic dermatitis may be also referred to as "sebopsoriasis”, “seborrhoeic eczema”, “dandruff” and "pityriasis capitis”.
  • 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 secretion.
  • 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.
  • Bacteria most importantly Propionibacterium 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 various categories, including comedonal, inflammatory, nodulocystic and conglobate acne.
  • Conglobate acne describes a condition where there is a merging of deep abscesses to produce scarring channels in the skin.
  • Nodulocystic acne is characterised by the appearance of hard lumps. 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 lesions is currently treated with topical antibiotics and antimicrobial agents (clindamycin, erythromycin, tetracycline, and azelaic acid).
  • Moderate to severe inflammatory and nodulocystic acne are generally treated with oral antibiotics and retinoids. Severe side effects are associated with high dose retinoids and therefore treatment with these agents is often limited.
  • Non-responsive acne include acne that has not responded to standard treatment with oral antibiotics and topical medicines (referred to herein as "non-responsive acne") including post-retinoic acne (acne which develops after treatment with retinoic acids, such as isotretinoin (Roaccutane®)).
  • retinoic acne acne which develops after treatment with retinoic acids, such as isotretinoin (Roaccutane®)
  • Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all five muscarinic receptor subtypes and centrally-mediated side effects have been reported, particularly with scopolamine.
  • the older generation non-selective compounds are a mixture of compounds that enter the brain, and those that contain a quaternary ammonium function and therefore do not readily penetrate the blood brain barrier. Examples of compounds that contain a quaternary amine function are propantheline, methylscopolamine, homatropine methylbromide, poldine, ipratropium, trospium and glycopyrrolate.
  • muscarinic receptor antagonists which possess some selectivity for and preferentially block muscarinic M3 receptors relative to the other M receptor subtypes have been introduced or are currently being developed for the treatment of bladder disorders.
  • newer M3 muscarinic compounds are darifenacin, solifenacin, fesoterodine, zamifenacin, imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2- phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • Oxybutynin is not a new generation muscarinic antagonist but it displays modest activity for M1 and M3 receptors over the other subtypes. It is used extensively to treat overactive bladder disorders. However, compounds with differing selectivity profiles at muscarinic receptors have been developed to treat chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • WO01/10427 discloses the use of certain anti-muscarinic agents having a dipole moment greater than 4D and having a defined degree of epithelial cell antiproliferative activity for the treatment of various forms of skin disorders including acne.
  • certain anti-muscarinic agents may act to suppress sebum secretion or have antibacterial activity.
  • preferred antimuscarinic agents disclosed in WO01/10427 do not possess such properties: the present inventors have shown that the quaternary amine glycopyrrolate does not, for example, exhibit antibacterial activity.
  • Healthy skin is coated with a thin film of lipids composed of triglycerides, diglycerides, fatty acids, wax esters, squalene, sterols, sterol esters and phospholipids known as sebum.
  • Sebum is secreted by the sebaceous glands. These are most numerous on the face (where they typically occur at a density of 400-800 glands/cm 2 ).
  • the film of sebum is usually at least 4 ⁇ m thick and it functions to prevent undue water loss through the skin, protect against sunburn, maintain the dermal microflora and deliver antioxidants to the skin surface.
  • Facial shine is considered to be aesthetically unattractive, imparting the appearance of unclean greasiness suggestive of poor hygiene and/or health.
  • a demographic study showed that facial shine is a common concern of 70% of the US female population and 62% of the Japanese female population (see e.g. Draelos et al. (2006) Journal of Cosmetic and Laser Therapy 8: 96-101).
  • Sebum control is therefore a goal of many over-the-counter (non-prescription) skin care products.
  • most currently available products function by absorbing sebum from the face rather than modulating its production and/or secretion. This can lead to problems associated with residue build-up and the need for daily facial scrubbing, as well as requiring frequent application in cases where sebum secretion rates are high.
  • muscarinic receptor antagonists exhibit antibacterial activity (e.g. against Propionibacterium spp. (e.g. P. acnes)). This discovery is both surprising and of great significance, since bacteria, particularly propionibacteria, are implicated in many skin disorders (including acne).
  • the antibacterial muscarinic receptor antagonists may also exhibit anti- sebum secretion and/or production activity.
  • Such dual action muscarinic receptor antagonists are particularly useful in the treatment of skin disorders which have both bacterial and seborrhoeic components, including in particular acne.
  • the invention contemplates the use of a muscarinic receptor antagonist for the manufacture of a medicament for the treatment or prevention of a bacterial skin infection.
  • the invention contemplates the use of a muscarinic receptor antagonist for the manufacture of a medicament for use: (a) in antibacterial sebum suppression therapy; or (b) as a sebum secretion suppressing antibacterial agent; or (c) as sole active ingredient in dual antibacterial/sebum secretion reduction therapy.
  • the antibacterial sebum suppression therapy preferably comprises the simultaneous reduction of skin sebum secretion and antibacterial activity (e.g. against Propionibacterium spp. (e.g. P. acnes)).
  • the invention contemplates the use of a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity for the manufacture of a medicament for the treatment of a skin disease or disorder in a human.
  • the disease or disorder may be one which is associated with excess sebum production.
  • the disease or disorder may be seborrhoea or seborrhoeic dermatitis, for example seborrhoea in Parkinson's patients.
  • Particularly preferred is the treatment of acne.
  • any of the various types of acne may be treated according to the invention, but the invention finds particular application in the treatment of: (a) comedonal acne with inflammatory lesions; (b) nodulocystic acne; (c) conglobate acne; and (d) non-responsive acne.
  • Any suitable muscarinic receptor antagonist may be used according to the invention. Preferred are preferential M3 receptor antagonists. Also preferred are tertiary amine muscarinic receptor antagonists.
  • muscarinic antagonists selected from: darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide, trospium, imidafenacin (KRP-197/ONO- 8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-penteny!)piperidin-4-yl]-2-cyclopentyl-2- hydroxy-2-phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • muscarinic antagonists which exhibit dual antibacterial and anti-sebum secretion activity, for example a tertiary amine selected from oxybutynin and darifenacin.
  • the medicament may be administered by the topical route to the infected areas. In such embodiments it may be formulated as a solution, gel, lotion, cream, shampoo or a spray.
  • Preferred are water-based solutions, gels, lotions, creams, shampoos or sprays, since such formulations do not necessarily contain oily excipients which can support or promote bacterial growth on or in the skin and so exacerbate the effects of infection by contributing to the levels of oil on the skin.
  • muscarinic receptor antagonists which are sufficiently water soluble to permit formulation in an aqueous (e.g. oil-free) excipient, since such antagonists may be formulated in oil-free excipients which do not support or promote bacterial growth and so exacerbate the effects of skin infection by contributing to the levels of oil on the skin.
  • the medicament may also be administered orally.
  • it may be formulated as a tablet, troche, lozenge suspension, dispersible tablet, powder or granules, emulsion, capsules, syrup or elixir.
  • the patient to be treated according to the invention may also be administered: (a) an antifungal or an antiproliferative; and/or (b) benzoyl peroxide, azelaic acid, adapalene, a retinoid, salicyclic acid, nicotinamide, a histone deacetylase inhibitor or an antibacterial agent; and/or (c) a retinoid, an anti-androgen, a histone deacetylase inhibitor, or an antibiotic agent.
  • the adjunctive antiproliferative agent may be an antiproliferative anti- muscarinic agent having a dipole moment greater than 4D and having a defined degree of epithelial cell antiproliferative activity as defined in WO01/10427.
  • the bacterial skin infection treated according to the invention may be mediated by any bacterium, but preferred are infections in which Propionibacterium spp. (e.g. P. acnes) is implicated.
  • the invention also contemplates a method for the treatment or prevention of a bacterial skin infection comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist.
  • the invention contemplates a method of antibacterial sebum suppression therapy comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist.
  • the invention contemplates a method of dual antibacterial/sebum secretion reduction therapy comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist as sole active ingredient.
  • the invention contemplates a method for treating acne comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity.
  • the invention contemplates a muscarinic receptor antagonist for the treatment or prevention of a bacterial skin infection.
  • the invention contemplates a muscarinic receptor antagonist for use: (a) in antibacterial sebum suppression therapy; or (b) as a sebum secretion suppressing antibacterial agent; or (c) as sole active ingredient in dual antibacterial/sebum secretion reduction therapy.
  • the invention contemplates a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity for the treatment of a skin condition, for example acne, in a human.
  • muscarinic receptor antagonists exhibit anti-sebum secretion and/or production activity. This discovery is both surprising and of great significance, since high levels of sebum secretion is implicated in many skin disorders (including acne). The discovery is of great practical importance, because the present inventors have also discovered that the antibacterial muscarinic receptor antagonists may also exhibit antibacterial activity (e.g. against Propionibacterium spp. (e.g. P. acnes)). Such dual action muscarinic receptor antagonists are particularly useful in the treatment of skin disorders which have both bacterial and seborrhoeic components, including in particular acne.
  • the invention contemplates the use of a muscarinic receptor antagonist for the manufacture of a medicament for the reduction of sebum secretion (e.g. facial sebum secretion).
  • sebum secretion e.g. facial sebum secretion
  • the invention contemplates the use of a muscarinic receptor antagonist for the manufacture of a medicament for use: (a) in antibacterial sebum suppression therapy; or (b) as a sebum secretion suppressing antibacterial agent; or (c) as sole active ingredient in dual antibacterial/sebum secretion reduction therapy.
  • the antibacterial sebum suppression therapy preferably comprises the simultaneous reduction of skin sebum secretion and antibacterial activity (e.g. against Propionibacterium spp. (e.g. P. acnes)).
  • the invention contemplates the use of a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity for the manufacture of a medicament for the treatment of a skin disease or disorder in a human.
  • the disease or disorder may be one which is associated with excess sebum production.
  • the disease or disorder may be seborrhoea or seborrhoeic dermatitis, for example seborrhoea in Parkinson's disease patients.
  • Particularly preferred is the treatment of acne.
  • any of the various types of acne may be treated according to the invention, but the invention finds particular application in the treatment of: (a) comedonal acne with inflammatory lesions; (b) nodulocystic acne; (c) conglobate acne; and (d) non-responsive acne.
  • muscarinic receptor antagonist Any suitable muscarinic receptor antagonist may be used according to the invention. Preferred are preferential M3 receptor antagonists. Also preferred are tertiary amine muscarinic receptor antagonists. Particularly preferred are muscarinic antagonists selected from: darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide, trospium, imidafenacin (KRP- 197/ONO-8025), OrM3/J- 10429 (2R)-N-[I -(4-methyl-3- pentenyl)piperidin-4-yI]-2-cycIopentyl-2-hydroxy-2-phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • muscarinic antagonists which exhibit dual antibacterial and anti-sebum secretion activity, for example a tertiary amine selected from oxybutynin and darifenacin.
  • the medicament may be administered by the topical route to the infected areas.
  • it may be formulated as a solution, gel, lotion, cream, shampoo or a spray.
  • Preferred are water-based solutions, gels, lotions, creams, shampoos or sprays, since such formulations do not necessarily contain oily excipients which can exacerbate the effects of excess sebum secretion by contributing to the levels of oil on the skin.
  • muscarinic receptor antagonists which are sufficiently water soluble to permit formulation in an aqueous (e.g. oil-free) excipient, since such antagonists may be formulated in oil-free excipients which do not exacerbate the effects of excess sebum secretion by contributing to the levels of oil on the skin.
  • the medicament may also be administered orally.
  • it may be formulated as a tablet, troche, lozenge suspension, dispersible tablet, powder or granules, emulsion, capsules, syrup or elixir.
  • the patient to be treated according to the invention may also be administered: (a) an antifungal or an antiproliferative; and/or (b) benzoyl peroxide, azelaic acid, adapalene, a retinoid, salicyclic acid, nicotinamide, a histone deacetylase inhibitor or an antibacterial agent; and/or (c) a retinoid, an anti-androgen, a histone deacetylase inhibitor, or an antibiotic agent.
  • the adjunctive antiproliferative agent may be an antiproliferative anti- muscarinic agent having a dipole moment greater than 4D and having a defined degree of epithelial cell antiproliferative activity as defined in WO01/10427.
  • the bacterial skin infection treated according to the invention may be mediated by any bacterium, but preferred are infections in which Propionibacterium spp. (e.g. P. acnes) is implicated.
  • the invention also contemplates a method for reducing sebum secretion (e.g. facial sebum secretion) comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist.
  • the invention contemplates a method of antibacterial sebum suppression therapy comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist.
  • the invention contemplates a method of dual antibacterial/sebum secretion reduction therapy comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist as sole active ingredient.
  • the invention contemplates a method for treating acne comprising administering to a patient in need thereof an effective amount of a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity.
  • the invention contemplates a muscarinic receptor antagonist for reducing sebum secretion (e.g. facial sebum secretion).
  • sebum secretion e.g. facial sebum secretion
  • the invention contemplates a muscarinic receptor antagonist for use: (a) in antibacterial sebum suppression therapy; or (b) as a sebum secretion suppressing antibacterial agent; or (c) as sole active ingredient in dual antibacterial/sebum secretion reduction therapy.
  • the invention contemplates a muscarinic receptor antagonist having dual antibacterial and anti-sebum secretion activity for the treatment of a skin condition, for example acne, in a human.
  • the invention provides a cosmetic composition (e.g. a topical cosmetic composition) comprising a muscarinic receptor antagonist.
  • a cosmetic method for the reduction of facial shine said method comprising the application of a muscarinic receptor antagonist to facial sebocytes thereby to reduce facial sebum secretion.
  • the invention contemplates the use of a muscarinic receptor antagonist as a cosmetic to reduce facial shine.
  • Any muscarinic receptor antagonist may be used according to the invention. They may be of the tertiary or quaternary amine structural class. They may be selective or non-selective M3 muscarinic receptor antagonists. Selective M3 muscarinic receptor antagonists may be preferred since they do not cause the extensive side-effects associated with blockade if all the muscarinic receptors (such as bladder outflow problems, eye accommodation abnormalities, confusion and hallucinations).
  • the muscarinic antagonist is selected from: darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide, poldine, ipratropium, tiotropium, trospium, glycopyrrolate, imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4- methyl-S-pentenyOpiperidin ⁇ -yl ⁇ -cyclopentyl ⁇ -hydroxy ⁇ -phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • darifenacin solifenacin
  • tolterodine tolterodine
  • fesoterodine zam
  • a reference to a particular anti-m ⁇ scarinic agent herein is intended to include ionic, salt, solvate, isomers, tautomers, ester, prodrugs, isotopes, derivatives, analogues and protected forms thereof.
  • Any suitable formulation may be used to deliver the muscarinic receptor antagonist: preferred are formulations selected from solutions, gels, lotions, creams, shampoos or a sprays.
  • water-based solutions e.g. oil-free
  • gels e.g. oil-free
  • lotions e.g. lotions
  • creams e.g., shampoos or a sprays
  • oily excipients which can contribute to facial shine.
  • muscarinic receptor antagonists which are sufficiently water soluble to permit formulation in an aqueous excipient (e.g. oil-free), since such antagonists may be formulated in oil-free excipients which do not contribute to facial gloss.
  • acne includes all forms of acne, including acne vulgaris, comedonal, inflammatory and nodulocystic acne.
  • the terms “combined” and “combining” in this context are to be interpreted accordingly.
  • dual antibacterial/sebum secretion reduction therapy is used herein to define a form of therapy in which a single active ingredient acts to: (1) reduce sebum secretion; and (2) exert an antibacterial effect.
  • association of the two or more compounds/agents in a combination may be physical or non-physical.
  • physically associated combined compounds/agents include: • compositions (e.g. unitary formulations) comprising the two or more compounds/agents in admixture (for example within the same unit dose);
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by cross linking, molecular agglomeration or binding to a common vehicle moiety); • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);
  • non-physically associated combined compounds/agents examples include:
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents
  • material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;
  • material comprising at least one of the two or more compounds/agents in an amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds/agents.
  • references to “combination therapy”, “combinations” and the use of compounds/agents "in combination” in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen.
  • the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately).
  • a "pharmaceutical composition” is a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.
  • Pharmaceutical compositions are typically sterile and/or non-pyrogenic.
  • non-pyrogenic as applied to the pharmaceutical compositions of the invention defines compositions which do not elicit undesirable inflammatory responses when administered to a patient.
  • the term "pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging.
  • dosing means e.g. measuring device
  • delivery means e.g. inhaler or syringe
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical kit may optionally further comprise instructions for use.
  • the term "pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging.
  • pharmaceutical packs comprising a combination of two or more compounds/agents
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical pack may optionally further comprise instructions for use.
  • patient pack defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment.
  • Patient packs usually contain one or more blister pack(s).
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • the co-efficient of variation (or CV.) as applied to the dose units of the pharmaceutical compositions of the invention is term of art defining a key statistic of the quality of batches of a formulated pharmaceutical composition. Specifically, the CV. is the standard deviation divided by the mean multiplied by 100.
  • the term batch defines a plurality of dose units intended to have uniform character and quality, within specified limits, produced in the same manufacturing run. The term covers plural dose units produced by both batch manufacturing processes and continuous manufacturing processes.
  • the dose units may take any physical form. They may for example be individual pills, capsules etc (in the case of formulations for oral use), or a quantity of the drug dispensed into individual containers (e.g. tubes, jars or bottles) in the case of liquid, gel or paste formulations for topical application.
  • anti-sebum activity defines the ability to reduce sebum secretion by sebaceous glands (for example, by facial sebaceous glands/sebocytes).
  • references herein to any particular muscarinic receptor antagonist include pharmaceutically acceptable derivatives (e.g. salts) and analogues (e.g. metabolites) thereof.
  • references herein to oxybutynin and darifenacin are to be interpreted to cover oxybutynin and darifenacin metabolites and pharmaceutically acceptable salts thereof (e.g. oxybutynin chloride or darifenacin hydrobromide).
  • references to any particular muscarinic receptor antagonist are to be interpreted to encompass racemic mixture of diastereoisomers, individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers.
  • a reference to oxybutynin is to be interpreted to cover: (a) (S)- oxybutynin; (b) (R)-oxybutynin and (c) racemic mixtures thereof.
  • Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family comprising at least five receptor sub-types (M1 , M2, M3, M4 and M5). They are activated by the neurotransmitter acetylcholine. The receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The receptor subtypes are distributed in a tissue/organ specific manner: for example, the M3 subtype is located predominantly on smooth muscle and salivary glands.
  • Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all five muscarinic receptor subtypes and centrally-mediated side effects have been reported, particularly with scopolamine.
  • the older generation non-selective compounds are a mixture of compounds that enter the brain, and those that contain a quaternary ammonium function and therefore do not readily penetrate the blood brain barrier. Examples of compounds that contain a quaternary amine function are propantheline, methylscopolamine, homatropine methylbromide, poldine, ipratropium, trospium and glycopyrrolate.
  • muscarinic receptor antagonists which possess some selectivity for and preferentially block muscarinic M3 receptors relative to the other M receptor subtypes have been introduced or are currently being developed for the treatment of bladder disorders.
  • newer M3 muscarinic compounds are darifenacin, solifenacin, fesoterodine, zamifenacin, imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2- phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • Oxybutynin is not a new generation muscarinic antagonist but it displays modest selectivity for M1 and M3 receptors over the other subtypes. It is used extensively to treat overactive bladder disorders. However, compounds with differing selectivity profiles at muscarinic receptors have been developed to treat chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Preferred muscarinic receptor antagonists for use in the invention are darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide, trospium,midafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-pentenyl)piperidin-4-yl]-2- cyclopentyl-2-hydroxy-2-phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • Preferential M3 muscarinic receptor antagonists such as imidafenacin (KRP- 197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-pentenyl)piperidin-4-yl]-2- cyclopentyl-2-hydroxy-2-phenylacetamide (J-10429), CHF 5407, aclidinium bromide (LAS- 34273), darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin and Ro- 3202904 (PSD-506), are particularly preferred.
  • Darifenacin as also preferred.
  • Oxybutynin is particularly preferred.
  • the advantage of using preferential M3 muscarinic receptor antagonist is that they do not cause the extensive side-effects associated with blockade of all the muscarinic receptor subtypes (such as bladder outflow problems, eye accommodation abnormalities, confusion and hallucinations).
  • Muscarinic receptor antagonists for use according to the invention preferably exhibit dual antibacterial and anti-sebum secretion activity.
  • Such antagonists (which may be referred to herein as “muscarinic receptor antagonists having dual antibacterial and anti-sebum secretion activity") may be readily identified by determining the minimum inhibitory concentration (MIC) and/or minimum bactericidal concentration (MBC) using any of a wide variety of standard techniques known to those skilled in the art (and described in general terms in the Study, below).
  • the muscarinic receptor antagonists for use according to the invention are tested for antibacterial activity against Propionibacterium spp. (e.g. P. acnes).
  • antibacterial activity is used herein to define the ability to destroy bacteria or inhibit or prevent bacterial growth or metabolism.
  • Those skilled in the art will be aware of many different tests for detecting and/or quantifying antibacterial activity, including for example cup plate or paper disc bioassays based on the detection/measurement of zones of inhibition in seeded agar plates.
  • the antibacterial muscarinic receptor antagonists for use according to the invention may be bacteriocidal or bacteriostatic.
  • Antibacterial activity may be expressed in terms of the minimum inhibitory concentration (MIC) of the test compound required to produce a bacteriostatic effect in vitro.
  • MIC values of less than 1000 mg/L (or 500 mg/L or less) define thresholds that identify antibacterial activity.
  • the in vitro tests typically involve serial dilution and liquid culture or the impregnation of absorbent discs with various concentrations of test agent followed by zone clearing tests with the discs on solid media. In the former case, the tests are typically broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards (NCCLS) method using RPMI 1640 as the test medium or its
  • the assay format typically involves a series of agar plates, each having the test compound incorporated at a particular concentration. The plates are then inoculated with a standard culture of, for example, a propionibacterium and the plates then incubated for 48 hours at 37 ° C. The plates are then examined for the presence or absence of growth of the bacterium. Both of these assay formats are common general knowledge in the art.
  • Preferred antibacterial muscarinic receptor antagonists for use according to the invention have MIC values of less than 1000 mg/L (preferably 500 mg/L or less) in broth microdilution tests against at least one species of Propionibacterium.
  • anti-sebum secretion activity is used herein to define the ability to reduce serum secretion by sebaceous glands (e.g. facial sebaceous glands/sebocytes).
  • Muscarinic receptor antagonists having anti-sebum secretion activity may be identified using any of a wide variety of standard techniques known to those skilled in the art (and described in general terms in the Study, below), for example by measuring skin sebum excretion rates with a Sebumeter®.
  • tertiary amine muscarinic receptor antagonists such as oxybutynin and darifenacin may exert an antibacterial effect by promoting the production of free radicals in or on the skin or in (or near) a comedone.
  • tertiary amine muscarinic receptor antagonists such as oxybutynin and darifenacin
  • oxybutynin and darifenacin may be preferred for use according to the invention, and particularly preferred are selective
  • M3 tertiary amine muscarinic receptor antagonists such as oxybutynin and darifenacin.
  • selective M3 tertiary amine muscarinic receptor antagonists are those which exhibit dual antibacterial and anti-sebum secretion activity as defined herein and identified according to the teachings set out herein.
  • the muscarinic receptor antagonists 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. They may be administered by known means, in any suitable formulation, by any suitable route.
  • the muscarinic receptor antagonist 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.
  • 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 0.001 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 activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the condition to be treated.
  • the active agent is administered at a frequency of 1 to 4 times per day.
  • a typical daily dosage is 1 to 1000 ⁇ g, e.g. 10 to 500 ⁇ g.
  • compositions for oral administration include known pharmaceutical forms for such administration, for example lozenges, pastilles, dispersible tablets, powders or granules or as a liquid for spraying into the mouth.
  • 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 corn 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.
  • the composition may be in any form that will release the active agent, when held in the mouth, whether for a short time or for a matter of hours. It may be malleable and non-disintegrating, and/or chewable or dispersible. Preferred examples of such compositions are gums, as well as wafers and dispersible tablets (described above).
  • a flavorant will typically be included. It is particularly desirable if the flavorant has mucolytic properties. An example of such a flavorant is menthol.
  • 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 agents.
  • 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.
  • Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family comprising at least five receptor sub-types (M1 , M2, M3, M4 and M5). They are activated by the neurotransmitter acetylcholine. The receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The receptor subtypes are distributed in a tissue/organ specific manner: for example, the M3 subtype is located predominantly on smooth muscle and salivary glands.
  • Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all five muscarinic receptor subtypes and centrally-mediated side effects have been reported, particularly with scopolamine.
  • the older generation non-selective compounds are a mixture of compounds that enter the brain, and those that contain a quaternary ammonium function and therefore do not readily penetrate the blood brain barrier. Examples of compounds that contain a quaternary amine function are propantheline, methylscopolamine, homatropine methylbromide, poldine, ipratropium, trospium and glycopyrrolate.
  • muscarinic receptor antagonists which possess some selectivity for and preferentially block muscarinic M3 receptors relative to the other M receptor subtypes have been introduced or are currently being developed for the treatment of bladder disorders.
  • newer M3 muscarinic compounds are darifenacin, solifenacin, fesoterodine, zamifenacin, imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I ⁇ (4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2- phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • Oxybutynin is not a new generation muscarinic antagonist but it displays modest activity for M1 and M3 receptors over the other subtypes. It is used extensively to treat overactive bladder disorders. However, compounds with differing selectivity profiles at muscarinic receptors have been developed to treat chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Preferred muscarinic receptor antagonists for use in the invention are darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide, poldine, ipratropium, tiotropium, trospium, glycopyrrolate, imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2- phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273).
  • Preferential M3 muscarinic receptor antagonists such as darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, revatropate and Ro-3202904 (PSD-506), imidafenacin (KRP-197/ONO-8025), OrM3/J-10429 (2R)-N-[I -(4-methyl-3- pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (J-10429), CHF 5407 and aclidinium bromide (LAS-34273) are particularly preferred.
  • Oxybutynin is further preferred.
  • preferential M3 muscarinic receptor antagonist are those that they do not cause the extensive side-effects associated with blockade if all the muscarinic receptors (such as bladder outflow problems, eye accommodation abnormalities, confusion and hallucinations).
  • the muscarinic receptor antagonists 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. They may be administered by known means, in any suitable formulation, by any suitable route.
  • the muscarinic receptor antagonist 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.
  • 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.
  • Cosmetically 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.
  • the active compound is administered at a frequency of 1 to 4 times per day.
  • compositions for topical administration are suitable for use in the invention.
  • the cosmetically active compound or combination of compounds may be dispersed in a cosmetically 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 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 cosmetic forms for such administration, for example tablets, troches, lozenges, aqueous 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 cosmetic 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 cosmetically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic cosmetically 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 corn 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.
  • 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 cosmetic 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, flavouring and colouring agents.
  • the cosmetic 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 anaerobic cutaneous propionibacteria e.g. Propionibacterium acnes are implicated in the pathogenesis of acne vulgaris.
  • the test organism Propionibacterium acnes is classified as a 'Type' strain for the species.
  • This study examined the minimum inhibitory concentration (MIC) and, minimum bactericidal concentration (MBC) of P. acnes NCTC 737 to oxybutynin chloride and darifenacin hydrobromide, both muscarinic acetylcholine receptor antagonists.
  • MIC determinations were carried out using a standard 96-well plate broth micro-dilution assay. Wilkins-Chalgren anaerobe broth at pH6 and pH 7.1 ⁇ 0.2 was used for P. acnes.
  • the MIC range for the test compounds was 1.95 - 1000 mg/L in doubling dilutions, the diluting solvent acted as the positive control.
  • the test range for the control compounds varied depending on known activity levels.
  • the MBC was determined by sub-culturing 5 ⁇ l of the first well that shows positive growth and all the subsequent wells indicating no growth on to Wilkins-Chalgren (pH 6 or pH 7.1+0.2) agar plates.
  • Benzoyl peroxide and erythromycin were used as control compounds in P. acnes assays. Benzoyl peroxide and erythromycin were both dissolved in ethanol.
  • Table 1 MIC and MBC date of test compounds and controls at pH 6.
  • Test assays indicate that oxybutynin chloride and darifenacin hydrobromide demonstrate some moderate antimicrobial activity against P. acnes at pH 6.
  • Table 2 MIC and MBC data of test compounds and controls at pH 7.1 ⁇ 0.2
  • Test assays again indicate that oxybutynin chloride and darifenacin hydrobromide demonstrate some moderate antimicrobial activity against P. acnes at pH 7.1+0.2.
  • the study examined the effects of oxybutynin on sebum secretion in 18 volunteers with greater than normal sebum secretion. This was double-blind, randomised, placebo-controlled crossover (3 x 4 day periods) study with a minimum 7 day washout between study periods. Sebum excretion measured over 6 hours following t 0 dose on each study day by Sebumeter SM810. The AUC sebum excretion rate is shown in Figure 1. The results show that oxybutynin significantly reduced sebum excretion in humans.
  • Sebocytes derived from normal human chest midline were cultured in serum-free media (DMEM High glucose and Ham's F-12 media (1 :1). Differentiated sebocytes displayed prominent cytoplasmic lipid droplets. For compound treatment 1OmM stock solutions were freshly made and the appropriate dilutions made for each experiment. The oxybutynin for testing was dissolved in complete media. Complete media with no oxybutynin was used in control experiments. In lipid experiments shown below cells were also treated with carbachol, a muscarinic agonist. 2. Nile Red staining
  • Intracellular lipid content was measured by nile red staining. After incubation with various concentrations of oxybutynin, cells were washed three times with PBS. 100 ⁇ l of Nile Red (10 ⁇ g/ml) was added to the wells and mixed. The plate was incubated for 10 minutes and the fluorescence measured (ex 485nm : em 535nm) using a multiplate reader.
  • Nile Red staining studies were initiated on 7 day old sebocyte primary cultures, whereby cells were cultured alone (control) or with different concentrations of oxybutynin (0.1-100 ⁇ M) in triplicate for 120 hours. At the end of treatment, the 12 day old culture was stained with Nile Red and the results are shown in the table below.
  • Lipid analysis was done by thin layer chromatography on 20 * 20 cm TLC pre-coated silica gel plates. Separation of neutral and polar lipids was done by developing half-way in polar solvent using methyl acetate/isopropanol/ chloroform/methanol/0.25% KCI (aqueous) 25:25:25:10:9 (vol/vol) followed by three runs in the following neutral solvents: (i) toluene/ diethyl ether/ethanol/acetic acid 60:40:1 :0.23 (vol/vol), (ii) hexane/diethyl ether 96:4 (vol/vol), and (iii) hexane alone. The separated lipid classes were visualized by spraying the plates with 3% cupric acetate in 8% orthophosphoric acid followed by heating in an oven at 1600C for 15 minutes. The lipid classes were quantified densitometrically.
  • HPLTC studies were performed with 7 day old sebocyte primary cultures, whereby cells were cultured alone (control), with 100 ⁇ M of oxybutynin or 100 ⁇ M carbachol. At the end of the treatment period, the 12 day old culture were extracted with various different solvents for estimation of squalene, wax, cholesterol, triglyceride and phospholipids. The solvent fractions were run on HPTLC and were analyzed through densitometry scan. The mean areas of the peaks were estimated for each lipid type with or without treatments. The results of treatments compared to control on the amounts of various lipids in sebum are shown in the table below.
  • the data set outlined above show that the muscarinic receptor antagonist oxybutynin reduces the accumulation of all classes of lipids analysed in cultured sebocytes whereas the muscarinic agonist carbachol produced opposite effects and increased lipid levels in the sebocytes.

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Abstract

L'invention porte sur des antagonistes des récepteurs muscariniques pour une utilisation en tant qu'agents antibactériens, et, en particulier, sur l'utilisation de certains antagonistes des récepteurs muscariniques qui ont une activité double de sécrétion antibactérienne et anti-sébum dans le traitement de diverses affections cutanées, comprenant l'acné. L'invention porte également sur l'utilisation d'antagonistes des récepteurs muscariniques en tant qu'agents anti-sébum et dans des compositions cosmétiques destinées à être utilisées pour réduire la brillance du visage, et sur des procédés cosmétiques basés sur ces antagonistes.
PCT/GB2008/003953 2007-11-30 2008-11-27 Compositions pour le traitement d'affections cutanées WO2009068876A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0723587.2 2007-11-30
GB0723589A GB0723589D0 (en) 2007-11-30 2007-11-30 Antibacterial compositions
GB0723588.0 2007-11-30
GB0723587A GB0723587D0 (en) 2007-11-30 2007-11-30 Cosmetic compositions
GB0723588A GB0723588D0 (en) 2007-11-30 2007-11-30 Anti-sebum compositions
GB0723589.8 2007-11-30

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150408A2 (fr) * 2008-06-13 2009-12-17 Summit Corporation Plc Formulations antimuscariniques topiques
WO2016173817A1 (fr) 2015-04-28 2016-11-03 Unilever Plc Composés de n-aralkylcarbonyle-pipérazine et n-aralkylcarbonyle-homopipérazine et compositions de soins personnels les comprenant
WO2018154495A1 (fr) * 2017-02-24 2018-08-30 Ftf Pharma Private Limited Composition pharmaceutique de solution orale d'antagoniste muscarinique
US10307355B2 (en) 2015-04-28 2019-06-04 Conopco, Inc. N-aralkylcarbonyldiamine compounds and personal care compositions comprising the same
US11179393B2 (en) 2014-05-06 2021-11-23 Anthony G. Visco Methods of treating or preventing preterm labor
EP4072535A4 (fr) * 2019-12-13 2024-01-17 Free State Pharma Inc. Compositions et procédés de régulation de la production de cérumen

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150408A2 (fr) * 2008-06-13 2009-12-17 Summit Corporation Plc Formulations antimuscariniques topiques
WO2009150408A3 (fr) * 2008-06-13 2010-05-06 Summit Corporation Plc Formulations antimuscariniques topiques
US11179393B2 (en) 2014-05-06 2021-11-23 Anthony G. Visco Methods of treating or preventing preterm labor
WO2016173817A1 (fr) 2015-04-28 2016-11-03 Unilever Plc Composés de n-aralkylcarbonyle-pipérazine et n-aralkylcarbonyle-homopipérazine et compositions de soins personnels les comprenant
US10155733B2 (en) 2015-04-28 2018-12-18 Conopco, Inc. N-aralkylcarbonyl-piperazine and -homopiperazine compounds and personal care compositions comprising the same
US10307355B2 (en) 2015-04-28 2019-06-04 Conopco, Inc. N-aralkylcarbonyldiamine compounds and personal care compositions comprising the same
WO2018154495A1 (fr) * 2017-02-24 2018-08-30 Ftf Pharma Private Limited Composition pharmaceutique de solution orale d'antagoniste muscarinique
EP4072535A4 (fr) * 2019-12-13 2024-01-17 Free State Pharma Inc. Compositions et procédés de régulation de la production de cérumen

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