GB2450608A - Use of a halogenated salicylanilide for the treatment of acne - Google Patents
Use of a halogenated salicylanilide for the treatment of acne Download PDFInfo
- Publication number
- GB2450608A GB2450608A GB0811139A GB0811139A GB2450608A GB 2450608 A GB2450608 A GB 2450608A GB 0811139 A GB0811139 A GB 0811139A GB 0811139 A GB0811139 A GB 0811139A GB 2450608 A GB2450608 A GB 2450608A
- Authority
- GB
- United Kingdom
- Prior art keywords
- salicylanilide
- pharmaceutically acceptable
- use according
- acceptable derivative
- halogenated
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- WKEDVNSFRWHDNR-UHFFFAOYSA-N salicylanilide Chemical class OC1=CC=CC=C1C(=O)NC1=CC=CC=C1 WKEDVNSFRWHDNR-UHFFFAOYSA-N 0.000 title claims abstract description 183
- 206010000496 acne Diseases 0.000 title claims abstract description 41
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 40
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 100
- 229950000975 salicylanilide Drugs 0.000 claims abstract description 86
- 238000009472 formulation Methods 0.000 claims abstract description 77
- 230000000699 topical effect Effects 0.000 claims abstract description 25
- JMPFSEBWVLAJKM-UHFFFAOYSA-N N-{5-chloro-4-[(4-chlorophenyl)(cyano)methyl]-2-methylphenyl}-2-hydroxy-3,5-diiodobenzamide Chemical compound ClC=1C=C(NC(=O)C=2C(=C(I)C=C(I)C=2)O)C(C)=CC=1C(C#N)C1=CC=C(Cl)C=C1 JMPFSEBWVLAJKM-UHFFFAOYSA-N 0.000 claims abstract description 23
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960001920 niclosamide Drugs 0.000 claims abstract description 23
- 229950004178 closantel Drugs 0.000 claims abstract description 22
- JYWIYHUXVMAGLG-UHFFFAOYSA-N oxyclozanide Chemical compound OC1=C(Cl)C=C(Cl)C=C1NC(=O)C1=C(O)C(Cl)=CC(Cl)=C1Cl JYWIYHUXVMAGLG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229950003126 oxyclozanide Drugs 0.000 claims abstract description 12
- NEMNPWINWMHUMR-UHFFFAOYSA-N rafoxanide Chemical compound OC1=C(I)C=C(I)C=C1C(=O)NC(C=C1Cl)=CC=C1OC1=CC=C(Cl)C=C1 NEMNPWINWMHUMR-UHFFFAOYSA-N 0.000 claims abstract description 11
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- 239000010703 silicon Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
- A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
- A01N37/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system having at least one carboxylic group or a thio analogue, or a derivative thereof, and one oxygen or sulfur atom attached to the same aromatic ring system
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/609—Amides, e.g. salicylamide
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Agronomy & Crop Science (AREA)
- Pain & Pain Management (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of a propionibacterial condition and/or of acne. The salicylanilide may in particular be a chlorinated salicylanilide such as niclosamide. Other preferred halogenated salicylanilides include closantel, rafoxanide, oxyclozanide and mixtures thereof. Other conditions associated with propionibacteria treatable using the invention include endophthalmitis, wounds, burns, ulcers and body odour. The formulation may be for topical or oral administration.
Description
New use 2450608
Field of the invention
This invention relates to the use of certain compounds as anti-acne agents.
Background to the invention
Certain types of salicylanilide, including halogenated salicylanilides, are known for use as anthelmintics and are used in particular to destroy or expel tapeworms in domestic animals.
Certain brominated salicylanilides are also known to have antibacterial and antifungal activities, and are used for example as disinfectants in medicated soaps: these include 4',5- dibromosalicylathuide (also known as dibromsalan, CAS #: 87-12-7); 3,5- dibromosalicylanilide (also known as metabromsalan, CAS #: 2577-72-2); and 3,4',S-tribromosalicylanilide (also known as tribromsalan, CAS #: 87-10-5) which is used as a bacteriostat in detergents.
FR-1.568.910 for example describes the use of halogenated (in particular brominated) salicylanilides as topical disinfectants. EP-l 362 581 mentions the use of tribromsalan as an antimicrobial agent, in combination with an anti-perspirant, in a pharmaceutical or cosmetic composition for topical application to the skin. EP-0 934 742 also refers to tribromsalan as an antimicrobial agent, for use in topical antimicrobial cleansers.
US-4,205,061 discloses an oral antimicrobial composition containing a synergistic combination of 3,5-dibromo-3'-trifluoromethyl salicylanilide and cetyl pyridinium chloride; the composition is intended to help prevent plaque and gingival diseases, without tooth staining.
Other halogenated salicylanilides are known for use as antimicrobial agents in certain contexts. For example, CH-506 292 discloses an oral health care composition, particularly for use against dental caries, which contains a halogenated trifluoromethyl salicylanilide and an alkali metal trimetaphosphate.
WO-02/288 19, meanwhile, describes the use of naphthyl-substituted salicylanilides as topical antibacterial and anti-inflammatory agents; the inclusion of the naphthyl group is said to confer activity against a range of bacteria.
Salicylanilides are also known as 2-hydroxy-N-phenylbenzamides or 2-hydroxybenzanilides. They have the following basic structure: Specific known halogenated salicylanilides include: * Closantel (CAS #: 57808-65-8), which is a halogenated salicylanilide also known as N-[S-chloro-4-[(4-chlorophenyl)cyanomethyl}-2-methylphenyl]2..
hydroxy-3,5-di-iodobenzamide, and is used as a veterinary anthelmintic. This is a broad spectrum antiparasitic agent used against several species and developmental stages of trematodes, nematodes and arthropods. The anti- trematode activity of closantel is mainly used against liver fluke. Its anti-nematode and anti-arthropod activity are especially used against species which feed on blood or plasma. The drug is widely used in sheep and cattle and can be used either parenterally (s.c. or i.m.) or orally for both prophylactic and therapeutic purposes. It is available as drench, bolus and injectable formulations. Closantel has also been combined with mebendazole and several other benzimidazoles in drench formulations for sheep and with levamisole in a bolus for cattle.
* Niclosaniide, which is another halogenated salicylanilide and is also known as S-ch1oro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenamjde. It is used as a veterinary anthelmintic against cestodes, and its ethanolaniine salt is also known for use as a molluscicide.
Rafoxanide (3 -chloro-4'-(p-chlorophenoxy)-3,5 -diiodosalicylanilide), which is known for veterinary use as a fasciolicide and anthelmintic.
* Oxyclozanide (3,31,5,5,6-pentachloro-2 -hydroxysalicylanilide), which again is known for veterinary use as an anthelmintic, primarily against trematodes.
It has now surprisingly been found that salicylanilides such as these can be antibacterially active, in particular against propionibacteria, and can therefore be used as anti-acne agents.
Statements of the invention
According to a first aspect of the present invention there is provided a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by (in particular caused or transmitted by) propionibacteria.
The propionibacteria are known to be implicated in acne. Thus, a second aspect of the invention provides a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use as an anti-acne agent (ie, for use in the treatment of acne or acne lesions).
Instead or in addition, the salicylanilide may be for use against an opportunistic infection which is caused, transmitted and/or exacerbated by (in particular caused by) propionibacteria, for instance an infection associated with an indwelling surgical device (a prosthetic joint, for example). It may be for use in treating an infected wound, bum or ulcer. It may be for use against any other infection or condition which involves or can involve propionibacteria, for example an eye infection such as endophthalmitis. In cases it may be used in the treatment of body odour, in particular in the axilla and/or feet, since this is a condition in which propionibactena can sometimes be implicated.
A halogenated salicylanilide is substituted at either or both of its phenyl rings with one or more halo groups. According to the present invention, however, the salicylanilide is not substituted with any bromo groups. A halo substituent may be selected from fluoro, chioro and iodo, in particular chloro and iodo.
In an embodiment, the salicylanilide is substituted with two or more halo groups, for example three or more.
The salicylanilide may also be substituted, at either or both of its phenyl rings, with one or more substituents selected from hydroxyl, nitro, cyano, phenoxy, optionally substituted C1-C4 alkyl (in particular methyl) and ether groups -OR. In an ether group -OR, R may be selected for example from optionally substituted C1-C4 alkyl and Substituents for substituted C 1-C4 alkyl groups may be selected for example from cyano (-CN), halo (other than bromo), hydroxyl, nitro, C1-C4 alkyl and optionally substituted phenyl, in particular cyano and optionally substituted phenyl.
Substituents for substituted phenyl groups may be selected for example from cyano, halo (other than bromo), hydroxyl, nitro, C1-C4 alkyl and optionally substituted phenyl, in particular halo and C1-C4 alkyl, more particularly halo.
The salicylanilide may for example be substituted with one or more chloro groups, for example two or more chloro groups (in other words, it may be a chlorinated salicylanilide). It may instead or in addition be substituted with one or more, for example two or more, iodine atoms.
Because the present invention does not extend to the use of brominated salicylanilides, the salicylanilide should not for example be dibromsalan, metabromsalan or tribromsalan.
In an embodiment of the invention, the salicyfanilide is selected from closantel, niclosa.mide, rafoxanide, oxyclozanide and mixtures thereof.
In an embodiment, the salicylanilide is selected from closantel, niclosamide and mixtures thereof. In another embodiment, the salicylanilide is niclosamide.
A "pharmaceutically acceptable derivative" of a halogenated salicylanilide may be a derivative which is acceptable for veterinary use. A "derivative" may for example be selected from salts, esters, solvates and also so-called "prodrug" forms or protected forms which revert to an active form of the relevant compound at an appropriate time on or after administration.
w In particular, the salicylanilide may be used in the form of a pharmaceutically acceptable salt, for example a metal salt or an anunonium salt (in particular the NH4 salt). Suitable metal salts include the alkali metal salts (for example the sodium or potassium salts, in particular the former) and the alkaline earth metal salts (for example the calcium salt). Other potential salts include substituted ammonium (for example Is alkanolammonium, in particular ethanolammonium) salts, and piperazine salts.
In particular where the salicylanilide is closantel, it may be used in the form of its sodium salt.
In particular where the salicylanilide is niclosamide, it may be used in the form of the free base, or of a salt such as the ethanolammonium or piperazine salt, and/or in the form of a hydrate such as a monohydrate.
The salicylanilide or derivative may in particular be for use against one or more bacteria associated with acne, more particularly the propionibacteria. It may for example be for use against one or more strains of Propionibacterium acnes and/or in some instances P. granulosum.
A third aspect of the present invention provides the use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament (typically a formulation) for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by (in particular caused or transmitted by) propionibactena.
A fourth aspect provides the use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament (typically a formulation) for use in the treatment of acne or acne lesions.
The salicylanilide or derivative is suitably used as an antibacterial, in particular an anti-propionibacterial, agent in the medicament. It is suitably used as an anti-acne agent (ie, as an agent which is active against acne (which includes against a symptom and/or a cause of acne) and/or against one or more micro-organisms associated with acne).
In the context of the present invention, treatment of a condition encompasses both therapeutic and prophylactic treatment, of either an infectious or a non-infectious condition, in either a human or animal but in particular a human. It may involve complete or partial eradication of the condition, removal or amelioration of associated symptoms, arresting subsequent development of the condition, and/or prevention of, or reduction of risk of, subsequent occurrence of the condition. It will typically involve use of the salicylanilide or derivative as a bactericide, in particular against propionibacteria.
Acne is a multifactorial disease of the pilosebaceous follicles of the face and upper trunk, characterised by a variety of inflamed and non-inflamed lesions such as papules, pustules, nodules and open and closed comedones. Its treatment can therefore encompass the treatment (which embraces prevention or reduction) of any of these symptoms, and references to use as an anti-acne agent may be construed accordingly.
The treatment of acne also encompasses the treatment and/or prevention of lesions and/or scarring associated with acne.
In general, the present invention will be used for the treatment of symptoms which are directly due to acne rather than for instance infections which may arise as a consequence of treating acne with other actives such as antibiotics, andlor secondary infections caused by opportunistic pathogens, which can arise in skin already affected by acne.
In accordance with all aspects of the invention, a mixture of two or more halogenated salicylanilides, or derivatives thereof, may be used as an antibacterial and/or anti-acne agent.
In embodiments of the invention, the salicylanilide or derivative is applied topically. It is preferably used in the form of a formulation which is suitable for topical application to, and/or contact with, the skin, in particular human skin. It is therefore preferably contained in a pharmaceutically acceptable vehicle which can safely be applied to, and/or contacted with, the skin and/or other epithelia.
A formulation which is "suitable for" topical application may also be adapted for Is topical application.
Suitable vehicles will be well known to those skilled in the art of preparing topical skin care or pharmaceutical preparations. The vehicle will typically be a fluid, which term includes a cream, paste, gel, lotion, foam, ointment or other viscous or semi-viscous fluid. The salicylanilide or derivative may be present in the form of a solution or suspension, the term "suspension" including emulsions, micellar systems and other multi-phase dispersions.
The salicylanilide or derivative may in general, however, be delivered by any appropriate route, whether local or systemic. It may for example be delivered orally, for instance in the form of a tablet, capsule, powder, granules, solution or suspension.
In this case the salicylanilide or derivative should be used in the form of a formulation which is suitable and/or adapted for oral ingestion. Again suitable vehicles for use in such formulations will be well known to those skilled in the art of preparing pharmaceutical preparations for oral delivery.
Alternatively the salicylanilide or derivative may be delivered transdermally, for instance via a skin patch.
The salicylanilide or derivative may be carried in or on a delivery vehicle which is suitable for targeting or controlling its release at the intended site of administration.
Such vehicles include liposomes and other encapsulating entities, for example niosomes, aspasomes, microsponges, microemulsions, hydrogels and solid lipid nanoparticles.
The antibacterial activity of the salicylanilide or derivative may be growth inhibitory activity or more preferably biocidal (ie, lethal to the relevant organism). In the context of this invention, activity against a particular species of bacterium may be taken to mean activity against at least one, preferably two or more, strains of that species.
Antibacterial activity may be or include the ability to disrupt and/or suppress biofilm formation by the relevant organism; thus, in accordance with the invention, the halogenated salicylanilide may be used to treat a condition which is caused, transmitted and/or exacerbated by microbial bioflim formation, in particular bioflim formation which is caused or exacerbated by, or which otherwise involves (in particular which is caused by), propionibacteria.
In the present context, the disruption of bioflim formation embraces any negative effect on the ability of a bacterium to form, maintain or exist in a biofilm, and/or on a bioflim already formed by the bacterium. Thus, it may involve reducing the amount of a previously formed biofllm, and/or impairing such a bioflim. It may involve killing or inhibiting sessile bacteria within a biofllm.
Suppression of bioflim formation embraces any degree of impairment (including complete prevention) of the ability of a bacterium to form, or more typically to co-aggregate with, a biofilm. It thus embraces total or partial impairment, including reducing the amount and/or strength of biofilm which the bacterium is able to form and/or the speed with which it is able to do so. It may involve preventing or reducing the growth or the rate of growth of an existing bioflim formed by the bacterium.
I
A formulation prepared or used according to the invention is preferably active against one or more propionibacteria which are wholly or partially resistant to one or more antibiotics, for instance those which are in common clinical use. For example, the formulation is ideally active against erythromycin-resistant, clindamycin-resistant andlor tetracycline-resistant P. acnes strains of bacteria, the term tetracycline here referring to the class of antibiotics including for example minocycline and doxycycline as well as the specific antibiotic known as tetracycline.
Antibacterial activity may be measured in conventional manner, for instance using the tests described in the examples below. Generally tests for activity involve treating a culture of the relevant bacterium with the candidate antibacterial compound, incubating the treated culture under conditions which would ordinarily support growth of the bacterium, and assessing the level of growth, if any, which can occur in the presence of the candidate compound.
Preferably the salicylanilide or derivative has a minimum inhibitory concentration (MIC), at least against propionibacteria, of 250 pg/ml or less, more preferably 100 or pg/mI or less, most preferably 25 or 15 or 10 or 5 or in cases 2 or even 1 or 0.5 pg/ml or less. Its corresponding minimum biocidal concentration (MBC) is preferably 250 pg/ml or less, more preferably 100 or 50 pg/mI or less, most preferably 25 or 15 or or 5 or in cases 2 or even I or 0.5 pg/mi or less. Suitably the ratio of its MIC to its MBC is from 0.01 to I or from 0.125 to 1, ideally from 0.5 to 1. More preferably the salicylanilide or derivative also exhibits such characteristics in the presence of at least one of, preferably both of, lipid and salt (sodium chloride) -these are species which can be present at the surface of the skin and hence performance in this context can be indicative of suitability for use in topical skin treatment formulations.
The concentration of the salicylanilide or derivative in a formulation prepared or used according to the invention, in particular a formulation for topical delivery, might suitably be 0.05 or 0.1 % w/v or greater, preferably 0.3 or 0.5 % w/v or greater. Its concentration might be up to 5 % w/v, for example up to 3 or 2 or 1.5 or I % w/v. Its concentration may for instance be from 0.05 to 2 % w/v or from 0.1 to 1.5 % w/v, for example about 1 % v/v.
For oral delivery, from about 50 mg to 2 g of the salicylanilide or derivative may be administered daily, whether as a single dose or as two or more divided doses. Thus the salicylanilide or derivative may be formulated in dosage forms -for example tablets or capsules -containing up to about 2 g, for instance from about 50 mg to 2g, of the active substance.
As discussed above, a formulation prepared or used according to the invention may be suitable for, and more preferably adapted for, topical administration to human skin. It may take the form of a lotion, cream, ointment, foam, paste, gel or any other physical form known for topical administration, including for instance a formulation which is, or may be, applied to a carrier such as a sponge, swab, brush, tissue, cloth, wipe, skin patch or dressing (which includes a bandage, plaster, skin adhesive or other material designed for application to a tissue surface, in particular to a wound) to facilitate its topical administration. It may be intended for pharmaceutical (which includes veterinary but is preferably human) use, and/or for cosmetic or other non-medical care purposes (for example, for general hygiene or skin cleansing).
In such cases the vehicle in which the salicylanilide or derivative is contained may be any vehicle or mixture of vehicles which is suitable for topical application; the type chosen will depend on the intended mode and site of application. Many such vehicles are known to those skilled in the art and are readily available commercially. Examples may for instance be found in Williams' "Transdermal and Topical Drug Delivery", Pharmaceutical Press, 2003, and other similar reference books. See also Date, A. A. Ct al, Skin Pharmacol. Physiot, 2006, 19(1): 2-16 for a review of topical drug delivery strategies.
As described above, the vehicle may be such as to target a desired site and/or time of delivery of the formulation. It may for instance target the formulation to the skin or hair follicles. It may delay or otherwise control release of the formulation over a particular time period. The salicylanilide or derivative may be microencapsulated, for instance in liposomes -particularly suitable liposomes, for topical use, are those made from stratum corneum lipids, eg, ceramides, fatty acids or cholesterol.
In some cases a polar vehicle may be preferred. Where the formulation is intended for use on the skin, the vehicle may be primarily non-aqueous, although in the case of an anti-acne treatment an aqueous vehicle may be used. The vehicle is suitably volatile.
In cases it may be alcohol-based or silicon-based.
By way of example, a lotion or gel formulation may contain a mixture of water, an alcohol such as ethanol or phenoxyethanol and a glycol such as propylene glycol.
The formulation may contain standard excipients and/or other additives known for use in pharmaceutical or veterinary formulations, in particular topical skin care formulations. Examples include emollients, perfumes, antioxidants, preservatives, stabilisers, gelling agents and surfactants; others may be found in Williams' "Transdermal and Topical Drug Delivery", supra. For the treatment of acne, however, it may be preferred for the formulation not to contain an emollient.
The formulation may contain additional active agents. It may for example contain one or more additional agents selected from anti-acne agents, keratolytics, comedolytics, agents capable of normalising keratinocyte and/or sebocyte function, anti-inflammatories, anti-proliferatives, antibiotics, anti-androgens, sebostatic/sebosuppressive agents, anti-pruritics, immunomodulators, agents which promote wound healing, additional antimicrobial (in particular antibacterial) agents and mixtures thereof. It may in particular contain one or more agents selected from anti-acne agents, keratolytics, comedolytics, sebostatic/sebosuppressive agents, anti-inflammatories and additional antibacterial agents. It may instead or in addition contain one or more agents selected from sunscreens, moisturisers and mixtures thereof.
An additional antimicrobial agent may for example be selected from the group consisting of biocides, disinfectants, antiseptics, antibiotics, bacteriophages, enzymes, anti-adhesins, immunoglobulins and mixtures thereof, it is preferably active as a bactericide, in particular against propionibacteria.
Generally speaking a formulation prepared or used according to the invention may contain one or more agents which enhance the activity of another active agent present
II
in the formulation, or reduce a side effect of such an active, or improve patient compliance on administration of the formulation.
It may however be preferred for the salicylanilide or derivative to be the only active agent in the formulation, or at least to be the only antimicrobially or antibacterially S active agent and/or the only anti-acne active agent.
In an embodiment of the invention, it may be preferred for the formulation not to contain a halogenated trifluoromethyl salicylanilide, for instance as described in CH-506 292.
In an embodiment, it may be preferred for the formulation not to contain an alkali metal trimetaphosphate, for instance as described in CH-506 292.
In an embodiment, it may be preferred for the formulation not to contain a naphthyl-substituted salicylanilide, for instance as described in WO-02/288 19.
In an embodiment, it may be preferred for the formulation not to contain an anti-perspirant, for instance as described in EP-1 362 581.
In an embodiment, it may be preferred for the formulation not to contain an anchoring agent of the type referred to in EP-0 934 742, in particular an anchoring agent selected from C3 to C6 polyols, adloses and ketoses, more particularly glycerin.
In an embodiment, it may be preferred for the formulation not to contain 3,5-dibromo- 3'-trifluoromethyl salicylanilide and/or cetyl pyridinium chloride, for instance as described in US-4,205,061.
In an embodiment, it may be preferred for the salicylanilide or derivative not to be for use against a bacterial infection within the oral cavity, in particular dental caries. It may be preferred for the salicylanilide or derivative not to be for use as a general skin disinfectant, such as in a hand or face wash or other general cleansing preparation. It may be preferred for the salicylanilide or derivative not to be for use as an anti-inflammatory agent. It may be preferred for the salicylanilide or derivative not to be for use against plaque and/or gingival diseases, and/or to reduce tooth staining.
In an embodiment, it may be preferred for the salicylanilide or derivative not to be applied topically within the oral cavity, and/or not to be adapted or intended for use in that way.
A formulation prepared or used according to the invention may be marketed with an indication that it has antibacterial and/or anti-acne activity, or enhanced antibacterial and/or anti-acne activity. The marketing of such a formulation may for example include an activity selected from (a) enclosing the formulation in a container or package that comprises the relevant indication; (b) packaging the formulation with a package insert that comprises the indication; (c) providing the indication in a publication that describes the formulation; and (d) providing the indication in a commercial which is aired for instance on the radio, television or internet. The antibacterial and/or anti-acne activity of the formulation may be attributed, in such an indication, at least partly to the presence of the halogenated salicylanilide or derivative.
The invention may involve assessing the antibacterial and/or anti-acne activity of the formulation during or after its preparation, for instance against one or more propionibacteria. It may involve assessing the antibacterial and/or anti-acne activity of the formulation both before and after incorporation of the salicylanilide or derivative, for example so as to confirm that it contributes to the antibacterial and/or anti- acne activity of the formulation.
A formulation prepared or used according to the invention may be incorporated into, and hence applied in the form of, another product such as a cosmetic, a skin or hair care preparation (for example a skin cleanser, toner or moisturiser, or a shampoo, conditioner, styling mousse or gel or hair spray), a deodorant or anti-perspirant, a cleansing preparation (for example a facial wash), a pharmaceutical (which includes veterinary) preparation, a cosmeceutical preparation, or a toiletry product (for instance a bath or shower additive or a soap).
A fifth aspect of the present invention provides a method for controlling the growth of a propionibacterium, the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, a halogenated salicylanilide (other than a brominated salicylanilide) or derivative thereof. The salicylanilide or derivative is suitably applied in a formulation of the type described above, for instance topically. It may in particular be applied to an area or surface which is infected with the relevant bacterium.
"Controlling the growth" of a bacterium embraces inhibiting or preventing its growth, whether completely or partially, as well as killing either completely or partially a culture of the organism. It also embraces reducing the risk of subsequent growth of the bacterium in the area or on the surface being treated. The method of the invention may thus be used to treat an existing occurrence of the bacterium or to prevent a potential subsequent occurrence.
Again the area or surface to which the salicylanilide or derivative is applied will typically be a surface such as human or animal tissue, in particular the skin, typically of a living human being. In this case the salicylanilide or derivative may be applied for therapeutic purposes or for non-therapeutic (eg, purely cosmetic) purposes.
Thus according to a sixth aspect of the invention, there is provided a method of treatment of a human or animal patient suffering from or at risk of suffering from a condition which is caused by, transmitted by and/or exacerbated by (in particular caused or transmitted by) propionibacteria, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a halogenatedsalicylanilide (other than a brominated salicylanilide) or a pharmaceutically acceptable derivative thereof. Again the salicylanilide or derivative may be administered by any appropriate route, for example orally or more preferably topically. It may be administered in a formulation of the type described above.
According to a seventh aspect there is provided a method of treatment of a patient suffering from or at risk of suffering from acne or acne lesions, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a halogenated salicylanilide (other than a brominated salicylanilide) or a pharmaceutically acceptable derivative thereof. The salicylanilide or derivative may be administered by any appropriate route, for example orally or more preferably topically. It may be administered in an anti-acne formulation of the type described above.
In accordance with the sixth and seventh aspects of the invention, the salicylanilide or derivative is suitably administered to a human patient. The patient is suitably suffering from the relevant condition, in particular acne.
According to an eighth aspect, the present invention provides an antibacterial or anti-acne formulation containing a halogenated salicylanilide (other than a brominated salicylanilide) or pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable vehicle, the formulation being adapted for topical application, in particular to human skin.
A ninth aspect provides an antibacterial or anti-acne formulation containing a halogenated salicylanilide (other than a brominated salicylanilide) or pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable vehicle, the formulation being adapted for oral delivery, in particular to a human patient.
The invention also provides, according to a tenth aspect, a product which incorporates an antibacterial or anti-acne formulation according to the eighth or the ninth aspect.
An eleventh aspect provides the use of a halogenated salicylanilide (other than a brominated salicylanilide), or a derivative thereof, as an anti-propionibacterial andlor anti-acne agent.
Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other moieties, additives, components, integers or steps.
Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
Preferred features of each aspect of the invention may be as described in connection with any of the other aspects.
Other features of the present invention will become apparent from the following examples. Generally speaking the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and drawings). Thus features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
Moreover unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.
The present invention will now be further described with reference to the following non-limiting examples.
Detailed description
Experimental tests were conducted to determine the anti-propionibacterial activity of formulations prepared according to the invention.
Test micro-organisms The primary test micro-organism used was a propionibacterial strain, Propionibacterium acnes NCTC 737. This is the type strain of the genus; it is fully susceptible to antibiotics.
The propionibacteria are clinically significant due to their involvement in acne. This is a very common, complex and multi-factorial skin disease in which P. acnes and other Propionibacterium spp. (for example P. granulosum) play key roles. They are also opportunistic pathogens in compromised hosts. Thus, activity observed against these micro-organisms is expected to be a good predictor of activity against acne.
Other propionibacterial strains were also tested, as described in Example 2 below.
These included certain antibiotic-resistant propionibacteria, such as the two P. acnes strains designated PRP-O10 and PRP-039 which are resistant respectively to macrolides-lincosamides-streptograminsketolides (MLSK) and to macrolides-lincosamides-streptogramins (MLS) and tetracycline -in other words, PRP-010 is resistant to erythromycin and clindamycin, and PRP-039 to erythromycin, clindamycin and tetracycline.
In addition, certain strains ofF. granulosum, another bacterium involved in acne, were also tested in Example 2.
The propionibacteria were cultured and maintained on Wilkins-Chaigren Anaerobe Medium (agar and broth) at pH 6.0; all cultures were incubated anaerobically at 37 C for 72 hours.
The following tests were carried out to assess antibacterial activity against the test organisms.
(a) Minimum inhibitory concentration (MIC) assay This is a standard international method for quantitatively assessing the antimicrobial activity of a compound in a liquid medium. The method used a sterile 96-well microtitre plate, capable of holding about 200 jil of liquid per well. The wells contained liquid culture medium and ranges of decreasing concentrations of the relevant test compound in doubling dilutions (eg, 1000, 500,250, 125. . . .tg/m1, etc..
down to 0.49 p.tg/ml). The culture medium was as described above.
The wells were inoculated with a liquid suspension of freshly grown micro-organism and incubated under the conditions described above. After incubation, the microtitre plate was examined visually (with the aid of a light box) for cloudiness in each well, which would indicate microbial growth. The MIC value was recorded as the lowest concentration of test compound required to inhibit microbial growth, ie, the lowest concentration for which the liquid in the well remained clear.
The assays were conducted in duplicate and included both negative (culture medium with no micro-organisms) and positive (culture medium plus diluting solvent plus micro-organism) controls.
Since inhibition does not necessarily indicate killing of microbial cells, merely that growth as visible to the naked eye has been inhibited, it is desirable to conduct a further test (the MBC assay described below) to establish the concentration of the test compound needed to kill the test organism.
(b) Minimum bactericidal concentration (MBC) assay This assay, normally carried out after an MIC assay, determines the minimum concentration of a compound that is lethal to the micro-organism being tested.
Following an MIC assay, a 5.tl sample was withdrawn from the first microtitre well that showed positive growth and from all the subsequent wells that showed no growth.
These samples were then individually sub-cultured on antibiotic-free agar medium, under the incubation conditions described above. Following incubation they were examined visually for microbial growth. The MBC was taken to be the lowest test compound concentration for which the incubated sample showed no growth.
The ratio of MIC to MBC should ideally be as close to 1 as possible. This facilitates selection of the lowest possible effective concentration of a test compound with a reduced risk of selecting a sub-lethal concentration which could promote resistance or allow the target microbial population to recover.
(c) Agar dilution MIC assay This is a standard international method for quantitatively assessing the antimicrobial activity of a compound in a solid medium. The test compound was prepared to 40x the highest concentration required (eg, 10 mg/ml for a final concentration of 250 .g/ml) and a series of doubling dilutions were performed in a suitable solvent. A set amount of these antimicrobial stock solutions was then added to molten agar medium (Ca 55 C), mixed thoroughly, poured into sterile Petri dishes and allowed to coollset.
The culture medium was as described above.
A MultipointTM Inoculator (AQS Manufacturing Ltd, UK) was used to inoculate the plates by spotting the inocula onto the surface of the agar, delivering approximately 1 to 2 1' per spot (yielding 1 5 CFU (colony forming units) per spot).
The plate(s) were then incubated under the conditions described above, following which they were examined visually for signs of bacterial growth. The MIC value was ascertained when there was a marked reduction in, or total loss of, growth on the test plate at the lowest concentration as compared to that of the growth on the control plate.
The assays were conducted in triplicate and included a positive control (culture medium, diluting solvent and inoculum).
(d) Disc diffusion assay (DDA) This is an internationally recognised standard method for qualitatively assessing the antimicrobial activity of a compound.
A sterile paper disc was impregnated with a sample of the test compound in a suitable solvent and 30 minutes allowed for the solvents to evaporate (where possible). The disc was then placed on an agar plate onto which the test micro-organism had been inoculated. The plate was then incubated under the conditions described above, following which it was examined visually for signs of microbial growth. If the test compound had antimicrobial activity, a circular zone of no growth would be obtained around the disc. The diameter of this zone of "inhibition" was measured using a Pr0t0COLTM automated zone sizer (Synbiosis, Cambridge, UK). In general, a greater diameter and/or area of the zone of inhibition indicates a greater antimicrobial activity in the relevant test compound, although other factors such as test compound mobility through the agar gel may also influence the result.
(e) Supplemented disc d4ffusion assays The DDA test may be carried out using an agar gel supplemented with lipid and/or salt to simulate some of the major components present in human skin and to assess whether these substances might affect the antimicrobial activity observed for the test compound. Performance under these conditions can provide a more reliable indication of activity on topical application. The supplement used in Example I below was sodium chloride (100 mM).
Example 1 -act ivitv against Propionibacterium spp The following experiments all used P. acnes NCTC 737 as the test organism.
MIC, MBC and DDA assays, as described above, were carried out using as the test compounds closantel, niclosamide, rafoxanide and oxyclozanide (all ex Sigma Aldrich, UK). The solvents used were DMSO for the closantel and niclosamide, and ethanol for the rafoxanide and oxyclozanide. All four actives were used in the form of their free bases rather than as salts.
Supplemented DDA assays were also carried out in the presence of sodium chloride, again as described above.
The results are shown in Table I below. All tests were conducted in triplicate.
Table 1
Test compound MIC MBC DDA DDA + ______________________ (pg/mi) (pg/mi) (mm) sail (mm) 29.79 27.92 Closantel 0.12 0.49 ( 0.18) ( 1.1) 43.44 41.98 Niclosamide 0.03 0.98 ( 1.36) ( 0.98) 21.46 22.92 Rafoxanide 0.12 0.98 ( 0.95) ( 3.34) 52.6 50.73 Oxyclozanide 0.49 1.95 ( 178) ( 1.41) It can be seen from Table 1 that all four compounds are highly active as antibacterial agents against P. acnes NCTC 737. This indicates their likely utility as anti-acne agents, the propionibacteria being implicated in acne.
This high level of activity appears to be maintained in the presence of salt.
Example 2-activity against other Propionibacterium spp The activities (MIC by agar dilution) of closantel and niclosamide were determined against a panel of different propionibacterium strains. DMSO was used as the solvent.
All tests were performed in triplicate.
The results are shown in Table 2 (closantel MICs) and Table 3 (niclosamide MICs) below; the resistance phenotype for each of the test species/strains is also indicated.
Table 2
Test organism Resistance MIC (/nil) _____________________________________ phenotype _____________ Propionibacterium acnes NCTC 737 None 0.12 P. granulosum NCTC 11865 None 0.49 P. acnes PRPOO2 TetJMLS 0.12 P. acnes PRPOO3 Tet 0.12 P. acnes PRP004 Tet 0.12 P. granulosum PRP-005 MLSK 0.25 P. granulosum PPR-006 MJJ 0.49 P. acnes PPR-007 Clin 0.12 P. acnes PRPOO8 Clin 0.12 P. acnes PRP-Ol0 MLSK 0.12 P. acnes PRP-017 MLS 0.12 P. granulosum PRP-019 MLSK 0.25 P. granulosum PRP-02 I MLS 0.49 P. acnes PRP-023 MLSK 0.12 P. acnes PRP-026 MLS 0.12 P. acnes PRP039 TetJMILS 0.12 P. granulosum PRP-043 MLS 0.25 P. granu/osum PRP-044 MLS 0.49 P. acnes PRP-046 None 0.12 Test organism Resistance MIC (pg/mi) _____________________________________ phenotype _____________ P. acnes P1053 TetIMLS 0.12 P. granulosum PRP055 None 0.12 P. .acnes PRP-059 rvlILs 0.12 P. acnes PRP068 Ery 0.12 P. acnes PRP101 TetJMLS 0.12 P. acnes PRP. 102 Tet/MLS 0.12 [Abbreviations: National Collection of Type Cultures (NCTC), Propionibacterium Panel Number (PRP), Tetracycline (Tet), Erythromycin (Ery), Clindamycin (Clin), Macrolide-Lincosamide-Streptogramin (MLS), Macrolide-Lincosamide-Streptogramin-Ketolide (MLSK).]
Table 3
Test organism Resistance MIC (pg/mi) ____________________________________ phenotype ____________ Propionibacterium acnes NCTC 737 None 0.03 P. granulosum NCTC 11865 None 0.06 P. acnes PRP002 Tet/MLS 0.03 P. acnes PRP003 let 0.03 P. acnes PRPOO4 Tet 0.03 P. granulosum PRP-005 4LSK 0.06 P. granulosum PPR-006 0.06 P. acnes PPROO7 Clin 0.03 P. acnes PRP008 Clin 0.03 P. acnes PRP-0 10 MLSK 0.03 P. acnes PRP-01 7 MLS 0.03 P. granulosum PRP-019 MLSK 0.06 P. granulosum PRP-02 I MLS 0.06 Test organism Resistance MIC (pg/mi) _____________________________________ phenotype _____________ P. acnes PRP-023 MLSK 0.03 P. acnes PRP-026 MLS 0.03 P. acnes PRP039 TetIMLS 0.03 P. granulosum PRP-043 MLS 0.06 P. granulosum PRP-044 MLS 0.06 P. acnes PRP-046 None 0.03 P. acnes PRPM53 TetIMLS 0.03 P. granulosum PRP055 None 0.03 P. acnes PRP-059 MLS 0.03 P. acnes PRP-068 Ery 0.03 P. acnes PRP-101 Tet/MLS 0.03 P. acnes PRPIO2 TetJMLS 0.03 [Abbreviations: National Collection of Type Cultures (NCTC), Propionibacterium Panel Number (PRP), Tetracycline (Tet), Erythromycin (Ery), Clindamycin (Clin), Macrolide-Lincosamide-Streptogramin (MILS), Macrolide-Lincosamide-Streptogramin-Ketolide (MLSK).] Both closantel and niclosamide can be seen to possess an excellent level of activity against the wide range of propionibacterium strains tested. l'his further indicates the utility of such halogenated salicylanilides either to treat or to prevent infections associated with such bacteria, in particular acne. The results are likely to be of particular clinical value for the antibiotic resistant test strains.
Example 3-topical anti-acne formulations The results from Examples 1 and 2 show that halogenated salicylanilides can be effective antibacterial agents against the bacteria associated with acne. This can be of use in preparing antibacterial formulations, in particular for topical application to the Is skin, for prophylactic or therapeutic use in any context where such bacteria are thought to be involved as possible sources of infection. More specifically, it can be of use in preparing anti-acne formulations, again suitably for topical use.
A topical formulation for use in treating acne may for example be prepared by formulating a halogenated salicylanilide such as closantel or niclosamide, or a S pharmaceutically acceptable salt thereof, in a suitable fluid vehicle and optionally together with conventional additives. Such vehicles and additives may be for instance as found in Williams' "Transdermal and Topical Drug Delivery", Pharmaceutical Press, 2003 and other similar reference books, and/or in Rolland A et al, "Site-specific drug delivery to pilosebaceous structures using polymeric microspheres", Pharm. Res. io 1993; 10: 1738-44; Mordon S et al, "Site-specific methylene blue delivery to pilosebaceous structures using highly porous nylon microspheres: an experimental evaluation", Lasers Surg. Med. 2003; 33: 119-25; and Alvarez-Roman Ret a!, "Skin penetration and distribution of polymeric nanoparticles", J. Controlled Release 2004; 99: 53-62.
The formulation may be prepared and administered using known techniques. It may for example take the form of a cream, lotion, ointment or gel.
The concentration of the salicylanilide or derivative may be in the ranges described above, and will be determined based on its antibacterial activity and the intended use of the formulation.
Claims (25)
- Claims 1. A halogenated salicylanilide (other than a brominatedsalicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by propionibacteria.
- 2. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of acne or acne lesions.
- 3. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 1 or claim 2, wherein the salicylanilide or derivative is topically applied.
- 4. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 1 or claim 2, wherein the salicylanilide or derivative is delivered orally.
- 5. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is substituted with one or more halogen atoms selected from chlorine and iodine atoms.
- 6. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 5, wherein the salicylanilide is a chlorinated salicylanilide.
- 7. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 6, wherein the salicylanilide is substituted with two or more chlorine atoms.
- 8. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is substituted with two or more iodine atoms.
- 9. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is selected from closantel, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.
- 10. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 9, wherein the salicylanilide is selected from closantel, niclosamide and mixtures thereof.
- 11. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 10, wherein the salicylanilide is niclosamide.
- 12. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation at a concentration of up to 5 % w/v.
- 13. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation at a concentration of 0.05 % w/v or greater.
- 14. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation which additionally contains one or more agents selected from anti-acne agents, keratolytics, comedolytics, agents capable of normalising keratinocyte and/or sebocyte function, anti-inflammatories, anti-proliferatives, antibiotics, anti-androgens, sebostatic/sebosuppressive agents, anti-pruritics, immunomodulators, agents which promote wound healing, additional antimicrobial agents and mixtures thereof.
- 15. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation which is in the form of a cream, paste, gel, ointment, lotion, foam or other viscous or semi-viscous fluid.
- 16. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of a condition which is caused by, transmitted by and/or exacerbated by propionibacteria, wherein the use is substantially as herein described.
- 17. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of acne or acne lesions, wherein the use is substantially as herein described.
- 18. Use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by propionibacteria.
- 19. Use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for use in the treatment of acne or acne lesions.
- 20. Use according to claim 18 or claim 19, wherein the medicament is a formulation which is suitable and/or intended and/or adapted for topical application.
- 21. Use according to claim 18 or claim 19, wherein the medicament is a formulation which is suitable and/or intended and/or adapted for oral delivery.
- 22. Use according to any one of claims 18 to 21, wherein the salicylanilide is substituted with one or more halogen atoms selected from chlorine and iodine atoms.
- 23. Use according to claim 22, wherein the salicylanilide is a chlorinated salicylanilide.
- 24. Use according to any one of claims 18 to 23, wherein the salicylanilide is selected from closantel, niclosamide, raloxanide, oxyclozanide and mixtures thereof.
- 25. Use according to any one of claims 17 to 24, wherein the medicament is substantially as herein described. * S. * S * * *. S.. m * S..IS.. .* * I ** * I * I25. Use according to claim 24, wherein the salicylanilide is niclosaniide.26. Use according to any one of claims 18 to 25, wherein the medicament is substantially as herein described.27. A method for controlling the growth of a propionibacterium, the method comprising applying, to an area or surface which is infected or suspected to be infected or capable of becoming infected with the bacterium, a halogenated salicylanilide (other than a brominated salicylanilide) or derivative thereof.28. A method according to claim 27, wherein the salicylanilide or derivative is applied topically.29. A method of treatment of a human or animal patient suffering from or at risk of suffering from a condition which is caused by, transmitted by andlor exacerbated by (in particular caused or transmitted by) propionibacteria, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a halogenated salicylanilide (other than a brominated salicylanilide) or a pharmaceutically acceptable derivative thereof.30. A method of treatment of a patient suffering from or at risk of suffering from acne or acne lesions, the method involving administering to the patient a therapeutically (which term includes prophylactically) effective amount of a halogenated salicylanilide (other than a brominated salicylanilide) or a pharmaceutically acceptable derivative thereof.31. A method according to claim 29 or claim 30, wherein the salicylanilide or derivative is administered topically.32. A method according to claim 29 or claim 30, wherein the salicylanilide or derivative is delivered orally.33. A method according to any one of claims 29 to 32, wherein the salicylanilide is selected from closantel, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.34. A method according to claim 33, wherein the salicylanilide is niclosamide.35. An antibacterial or anti-acne formulation containing a halogenated salicylanilide (other than a brominated salicylanilide) or pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable vehicle, the formulation being adapted for topical application.36. An antibacterial or anti-acne formulation containing a halogenated salicylanilide (other than a brominated salicylanilide) or pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable vehicle, the formulation being adapted for oral delivery.37. An antibacterial or anti-acne formulation according to claim 35 or claim 36, which is substantially as herein described.38. A product which incorporates an antibacterial or anti-acne formulation according to any one of claims 35 to 37.39. Use of a halogenated salicylanilide (other than a brominated salicylanilide), or a derivative thereof, as an anti-propionibacterial and/or anti-acne agent.40. Use according to claim 39, wherein the salicylanilide is selected from closantel, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.41. Use according to claim 40, wherein the salicylanilide is niclosaniide.mets to the claims have been filed as follows Claims I. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by propionibacteria.2. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use in the treatment of acne or acne lesions.3. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 1 or claim 2, wherein the salicylanilide or derivative is topically applied. * ** * S S *4. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim I or claim 2, wherein the salicylanilide or derivative p.....* : is delivered orally.* Se.. * *5. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is substituted with one or more halogen atoms selected from chlorine and iodine atoms.6. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 5, wherein the salicylanilide is a chlorinated salicylanilide.7. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 6, wherein the salicylanilide is substituted with two or more chlorine atoms.8. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is substituted with two or more iodine atoms.9. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide is selected from closantel, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.10. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 9, wherein the salicylanilide is selected from closantel, niclosamide and mixtures thereof.11. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to claim 10, wherein the salicylanilide is niclosamide. * S. * S 5 * 5,12. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide *.. S. * : is or derivative is used in a formulation at a concentration of up to 5 % w/v. * * S13. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation at a concentration of 0.05 % w/v or greater.14. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation which additionally contains one or more agents selected from anti-acne agents, keratolytics, comedolytics, agents capable of normalising keratinocyte and/or sebocyte function, anti-inflammatories, anti-proliferatives, antibiotics, anti-androgens, sebostatic/sebosuppressive agents, anti-pruritics, iminunomodulators, agents which promote wound healing, additional antimicrobial agents and mixtures thereof.15. A halogenated salicylanilide or pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the salicylanilide or derivative is used in a formulation which is in the form of a cream, paste, gel, ointment, lotion, foam or other viscous or semi-viscous fluid.16. A halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, for use according to any one of the preceding claims, wherein the use is substantially as herein described.17. Use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for use in the treatment of a condition affecting the human or animal body, which condition is caused by, transmitted by and/or exacerbated by propionibacteria. * *.18. Use of a halogenated salicylanilide (other than a brominated salicylanilide), or a pharmaceutically acceptable derivative thereof, in the preparation of a medicament for use in the treatment of acne or acne lesions. I.... * *I19. Use according to claim 17 or claim 18, wherein the medicament is a : formulation which is suitable and/or intended and/or adapted for topical application.20. Use according to claim 1 7or claim 18, wherein the medicainent is a formulation which is suitable and/or intended and/or adapted for oral delivery.21. Use according to any one of claims 17 to 20, wherein the salicylanilide is substituted with one or more halogen atoms selected from chlorine and iodine atoms.22. Use according to claim 21, wherein the salicylanilide is a chlorinated salicylanilide.23. Use according to any one of claims 17 to 22, wherein the salicylanilide is selected from closantel, niclosamide, rafoxanide, oxyclozanide and mixtures thereof.24. Use according to claim 23, wherein the salicylanilide is niclosamide.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GBGB0711957.1A GB0711957D0 (en) | 2007-06-21 | 2007-06-21 | Formulations |
Publications (3)
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GB0811139D0 GB0811139D0 (en) | 2008-07-23 |
GB2450608A true GB2450608A (en) | 2008-12-31 |
GB2450608B GB2450608B (en) | 2009-07-22 |
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GBGB0711957.1A Ceased GB0711957D0 (en) | 2007-06-21 | 2007-06-21 | Formulations |
GB0811139A Expired - Fee Related GB2450608B (en) | 2007-06-21 | 2008-06-18 | New use |
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GBGB0711957.1A Ceased GB0711957D0 (en) | 2007-06-21 | 2007-06-21 | Formulations |
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WO (1) | WO2008155535A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2456376A (en) * | 2008-12-22 | 2009-07-15 | Syntopix Ltd | Antibacterial/anti-acne formulations comprising a halogenated salicylanilide in combination with one or more anti-acne agents |
JP2019508463A (en) * | 2016-03-16 | 2019-03-28 | アンティバイオティクス・アー/エス | Non-aqueous topical composition comprising a halogenated salicylanilide |
US20200022931A1 (en) * | 2017-03-21 | 2020-01-23 | Supreet K. Deshpande | Therapeutic Agent For Phosphodiesterase Inhibition And Its Related Disorders |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG11201701928RA (en) | 2014-09-12 | 2017-04-27 | Antibiotx Aps | Antibacterial use of halogenated salicylanilides |
GB201509326D0 (en) | 2015-05-29 | 2015-07-15 | Antibio Tx Aps | Novel use |
CN105638690B (en) * | 2016-03-09 | 2017-10-24 | 安徽省农业科学院植物保护与农产品质量安全研究所 | A kind of composition pesticide containing emamectin benzoate and niclosamide ethanolamine salt |
GB201813876D0 (en) | 2018-08-24 | 2018-10-10 | Antibiotx As | Treatment |
WO2020089467A1 (en) | 2018-11-02 | 2020-05-07 | UNION therapeutics A/S | Dosage regimen |
CN113347977A (en) | 2018-11-02 | 2021-09-03 | 联合疗法公司 | Halogenated salicylanilides for the treatment of dermatitis symptoms |
US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
WO2020176067A1 (en) | 2019-02-25 | 2020-09-03 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with h. pylori using a halogenated salicylanilide |
Citations (5)
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US4310682A (en) * | 1979-02-28 | 1982-01-12 | Isao Ozawa | Halo-salicylanilide |
EP0487973A1 (en) * | 1990-11-26 | 1992-06-03 | Bayer Corporation | Topical lotion containing Niclosamide |
EP1129713A1 (en) * | 2000-02-29 | 2001-09-05 | New Pharma Research Sweden AB | Veterinary compositions for the treatment of parasitic diseases |
WO2004006906A2 (en) * | 2002-07-15 | 2004-01-22 | Combinatorx, Incorporated | Methods for the treatment of neoplasms |
GB2403905A (en) * | 2003-07-12 | 2005-01-19 | Norbrook Lab Ltd | Parasiticidal composition |
Family Cites Families (1)
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US7201914B2 (en) * | 2002-05-17 | 2007-04-10 | Xantech Pharmaceuticals, Inc. | Combination antiperspirant and antimicrobial composition |
-
2007
- 2007-06-21 GB GBGB0711957.1A patent/GB0711957D0/en not_active Ceased
-
2008
- 2008-06-18 GB GB0811139A patent/GB2450608B/en not_active Expired - Fee Related
- 2008-06-18 WO PCT/GB2008/002069 patent/WO2008155535A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4310682A (en) * | 1979-02-28 | 1982-01-12 | Isao Ozawa | Halo-salicylanilide |
EP0487973A1 (en) * | 1990-11-26 | 1992-06-03 | Bayer Corporation | Topical lotion containing Niclosamide |
EP1129713A1 (en) * | 2000-02-29 | 2001-09-05 | New Pharma Research Sweden AB | Veterinary compositions for the treatment of parasitic diseases |
WO2004006906A2 (en) * | 2002-07-15 | 2004-01-22 | Combinatorx, Incorporated | Methods for the treatment of neoplasms |
GB2403905A (en) * | 2003-07-12 | 2005-01-19 | Norbrook Lab Ltd | Parasiticidal composition |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2456376A (en) * | 2008-12-22 | 2009-07-15 | Syntopix Ltd | Antibacterial/anti-acne formulations comprising a halogenated salicylanilide in combination with one or more anti-acne agents |
JP2019508463A (en) * | 2016-03-16 | 2019-03-28 | アンティバイオティクス・アー/エス | Non-aqueous topical composition comprising a halogenated salicylanilide |
US20200022931A1 (en) * | 2017-03-21 | 2020-01-23 | Supreet K. Deshpande | Therapeutic Agent For Phosphodiesterase Inhibition And Its Related Disorders |
US11147779B2 (en) * | 2017-03-21 | 2021-10-19 | Supreet K. Deshpande | Therapeutic agent for phosphodiesterase inhibition and its related disorders |
AU2018238577B2 (en) * | 2017-03-21 | 2023-02-02 | Novalead Pharma Inc. | Therapeutic agent for phosphodiesterase inhibition and its related disorders |
US11786492B2 (en) | 2017-03-21 | 2023-10-17 | Novalead Pharma Inc | Therapeutic agent for phosphodiesterase inhibition and its related disorders |
Also Published As
Publication number | Publication date |
---|---|
GB2450608B (en) | 2009-07-22 |
GB0811139D0 (en) | 2008-07-23 |
WO2008155535A1 (en) | 2008-12-24 |
GB0711957D0 (en) | 2007-08-01 |
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