WO2022243430A1 - Treatment of acne - Google Patents

Treatment of acne Download PDF

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Publication number
WO2022243430A1
WO2022243430A1 PCT/EP2022/063570 EP2022063570W WO2022243430A1 WO 2022243430 A1 WO2022243430 A1 WO 2022243430A1 EP 2022063570 W EP2022063570 W EP 2022063570W WO 2022243430 A1 WO2022243430 A1 WO 2022243430A1
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Prior art keywords
inhibitor
substance
nki
acne
pharmaceutical composition
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PCT/EP2022/063570
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French (fr)
Inventor
Manuel Vicente SALINAS-MARTIN
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Plus Vitech, S.L.
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Publication of WO2022243430A1 publication Critical patent/WO2022243430A1/en

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    • 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
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • the present invention relates to the treatment of acne using (a) an NK1 inhibitor, and /or (b) an Substance P release inhibitor.
  • Acne is a skin disease, which results in blackheads and/or whiteheads, pimples, oily skin and, in some cases, scarring. Acne generally arises when hair follicles are clogged with dead skin cells and oil from the skin, and thus tends to affect areas of the skin with a relatively high number of oil glands, such as the face, upper chest and back.
  • Treatments applied directly to the affected skin such as azelaic acid, benzoyl peroxide, and salicylic acid, are commonly used.
  • antibiotics are sometimes prescribed, either in formulations that are applied directly to the skin and or in formulations taken by mouth.
  • therapeutic approaches using antibiotics are increasingly undesirable and/or ineffective.
  • Treatments derived from retinoic acid are also available, but these have many adverse effect.
  • currently available treatments for acne are ineffective and/or effective only for a limited time period and/or are associated with undesirable side effects.
  • Acne is estimated to affect over 600 million people globally. As well as the primary symptoms described above, the resulting damage to the patient’s appearance can lead to anxiety, reduced self-esteem, depression and (in some cases) thoughts of suicide. The disease is especially prevalent in adolescence and youth, and can thus causes life-long aesthetic and emotional damage. There therefore remains a need for new safe and effective treatments for acne.
  • NKi neurokinin 1 receptor inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting.
  • Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer.
  • Substance P The main agonist of the NKi receptor is the so-called Substance P.
  • a number of Substance P release inhibitors are known, including pregabalin, gabapentin and capsaicin.
  • Pregabalin is currently authorized for the treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD) in adults.
  • GAD generalized anxiety disorder
  • both NKi inhibitors and Substance P release inhibitors are able to inhibit the growth of Cutibacterium acnes.
  • the combination of an NKi inhibitor and a Substance P release inhibitor was found to provide greater inhibition of the growth of Cutibacterium acnes than either component alone: the NKi inhibitor and Substance P release inhibitor thus interact synergistically to provide a very high level of inhibition of the growth of Cutibacterium acnes
  • Cutibacterium acnes has a well-established role of acne (see Sutcliffe J, McLaughlin R, Webster G, Read AF, Drlica K, Elliott R, Stuart I. Susceptibility of Cutibacterium acnes to topical minocycline foam. Anaerobe. 2020 Apr;62: 102169. doi: 10.1016/j.anaerobe.2020.102169. Epub 2020 Jan 28. PMID: 32058277). It follows that substances that can inhibit the growth of Cutibacterium acnes , such as NKi inhibitors and/or Substance P release inhibitors, will be effective in treating patients with acne. NKi inhibitors and/or Substance P release inhibitors can therefore provide an effective and non toxic treatment of acne, whilst avoiding the problems of antibiotic resistance that occur with existing antibiotic-based therapies.
  • the present invention provides pharmaceutical composition which comprises: an NKi inhibitor; and/or a Substance P release inhibitor; for use in treating acne.
  • the invention further provides: ⁇ an NKi inhibitor, for use in treating acne, optionally by co-administration with a
  • a Substance P release inhibitor for use in treating acne optionally by co administration with an NKi inhibitor
  • a method of treating acne in a patient which method comprises administering to said patient an NKi inhibitor, and which method optionally comprises co administration with a Substance P release inhibitor
  • a method of treating acne in a patient which method comprises administering to said patient a Substance P release inhibitor, and which method optionally comprises co-administration with an NKi inhibitor;
  • a method of treating acne in a patient which method comprises administering to said patient a pharmaceutical composition which comprises an NKi inhibitor and a Substance P release inhibitor;
  • a product comprising (a) a NKi inhibitor, and (b) a Substance P release inhibitor, as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of a patient suffering from acne;
  • kits which comprises (a) a pharmaceutical composition comprising a NKi inhibitor; and (b) a pharmaceutical composition comprising a Substance P release inhibitor.
  • the present invention is concerned with the treatment of acne using (a) an NKi inhibitor, and /or (b) a Substance P release inhibitor.
  • NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention.
  • the NKi inhibitor is aprepitant, fosaprepitant, maropitant, netupitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017, L-733,060, L- 732,138, L -703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760735, CP-122721, L-758 298, L-741 671, L-742694, CP-99994 or T- 2328, or a pharmaceutically acceptable salt of any thereof.
  • the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.
  • the NKI inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, or a pharmaceutically acceptable salt of any thereof.
  • the NKI inhibitor is aprepitant, fosaprepitant, maropitant, or a pharmaceutically acceptable salt of any thereof
  • the NKI inhibitor is aprepitant or its prodrug fosaprepitant, or a pharmaceutically acceptable salt of either thereof.
  • the NKI inhibitor is aprepitant or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g.
  • Aprepitant has the following structure: Aprepitant is not typically formulated in the form of a pharmaceutically acceptable salt. Thus, in a preferred aspect of the invention the NKi inhibitor is aprepitant.
  • Fosaprepitant is prodrug of aprepitant and has the following structure:
  • Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:
  • the NKi inhibitor is fosaprepitant dimeglumine.
  • compositions comprising fosaprepitant are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.
  • aqueous solvent such as saline
  • Fosaprepitant is converted in vivo to aprepitant.
  • fosaprepitant is converted to aprepitant.
  • Maropitant is the compound (2S,3S)-2-Benzhydryl-N-(5-tert-butyl-2- methoxybenzyl) quinuclidin-3 -amine, and has the following structure:
  • Maropitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the citrate salt.
  • the NKi inhibitor is maropitant citrate.
  • Substance P release inhibitors are a well-known class of drug, and any suitable Substance P release inhibitor can be used in the present invention.
  • the ability of a given compound to inhibit the release of Substance P can be assessed by routine techniques, such as those described in Fehrenbacher et al , Pain, vol 105, 1-2, September 2003, pages 133- 141.
  • the Substance P release inhibitor is a grrawa-aminobutyric acid derivative of formula (I), or a pharmaceutically acceptable salt thereof: wherein
  • Ri is a Ci- 6 alkyl, phenyl, or C3-6 cycloalkyl group
  • R.2 is a hydrogen or methyl group
  • R 3 is a hydrogen, methyl, or carboxyl group.
  • Ci- 6 alkyl group may be a straight-chain or branched-chain alkyl group.
  • Ci- 6 alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • an alkyl or cycloalkyl group is unsubstituted.
  • Ri is a Ci-6 alkyl group, more preferably a -(CH 2 )o- 2 -iC 4 H 9 group and most preferably an -1C 4 H 9 group (i.e., an isobutyl group).
  • R 2 is hydrogen.
  • R 3 is hydrogen.
  • a particularly preferred compound of formula (I) is one in which Ri is an -iC 4 H 9 group and R 2 and R 3 are both hydrogen.
  • a particularly preferred gamma- aminobutyric acid derivative is the compound of formula (I) in which Ri is an -1C 4 H 9 group and R 2 and R 3 are both hydrogen.
  • Compounds of formula (I) can contain one or several asymmetric carbon atoms.
  • the invention includes the individual diastereomers or enantiomers, and the mixtures thereof.
  • the individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
  • the compound of formula (I) is pregabalin, i.e. (3S)-3- (aminomethyl)-5-methylhexanoic acid, or a pharmaceutically acceptable salt thereof.
  • Pregabalin has the following structure:
  • the compound of formula (I) is gabapentin or a pharmaceutically acceptable salt thereof.
  • Gabapentin has the following structure:
  • the Substance P release inhibitor may be a capsaicinoid of formula (II), or a pharmaceutically acceptable salt thereof: wherein R 4 represents a C 6 to C 12 alkyl or alkenyl moiety preferably a Cx to C 10 alkyl or alkenyl moiety.
  • An alkyl or alkenyl moiety may be a straight-chain or branched-chain alkyl group.
  • the Substance P release inhibitor is capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsacicin, homodihydrocapsaicin, or nonivamid, or a pharmaceutically acceptable salt of any thereof.
  • the Substance P release inhibitor is capsaicin.
  • Capsaicin has the following structure:
  • Dihydrocapsaicin has the following structure:
  • Nordihydrocapsaicin has the following structure:
  • Homocapsacicin has the following structure:
  • Homodihydrocapsaicin has the following structure:
  • Nonivamid has the following structure:
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, hydrosulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, mandelic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
  • the patient to be treated in the present invention is suffering from acne.
  • Acne is also known as acne vulgaris.
  • the patient to be treated is a mammal.
  • the patient is a human.
  • the patient is a human between 10 and 40 years old, typically between 13 and 25, for example a teenage human.
  • Acne can easily be diagnosed using routine diagnostic techniques known to those of skill in the art.
  • a successful treatment can identified by a reduction in, or an absence of symptoms of acne, or using routine diagnostic techniques.
  • the acne to be treated in the present invention is mild, moderate or severe acne.
  • the acne to be treated in the present invention is moderate or severe acne.
  • Mild acne is generally defined by the presence of clogged skin follicles (known as comedones) limited to the face with occasional inflammatory lesions.
  • Moderate acne is generally said to occur when a higher number of inflammatory papules and pustules occur on the face, compared to mild cases of acne, and when the papules and pustules are found on the trunk of the body.
  • Severe acne arises when nodules (painful bumps lying under the skin) are the characteristic facial lesions and involvement of the trunk is extensive.
  • patient to be treated exhibits excessive growth of Cutibacterium acnes, generally on the areas of skin affected by the acne.
  • the active ingredient(s) treat the acne by inhibiting the grown of Cutibacterium acnes , generally on the areas of skin affected by the acne.
  • the active ingredient(s) are typically not treating the acne by addressing other skin complaints, such as pruritus/itching.
  • the Cutibacterium acnes is an therapy-resistant or recurrent despite therapy.
  • the patient may have previously been treated with antibiotics and developed antibiotic resistance during that treatment.
  • an NK1 inhibitor, and/or a Substance P release inhibitor provides an alternative approach for treating the acne, by inhibiting the grown of Cutibacterium acnes.
  • Treatment may be curative or palliative in nature, i.e. it may aim at curing the patient, achieving complete or partial remission, alleviating or managing symptoms and/or side effects of the disease (without curing the patient).
  • compositions The present invention provides a pharmaceutical composition that comprises an
  • compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition comprises both the NKi inhibitor and a Substance P release inhibitor, and typically does not comprise any other active ingredients.
  • the pharmaceutical composition comprises the NKi inhibitor, but does not comprise the Substance P release inhibitor and typically does not comprise any other active ingredients.
  • the pharmaceutical composition comprises the Substance P release inhibitor, but does not comprise the NKi inhibitor and typically does not comprise any other active ingredients.
  • the present invention extends to situations where the active ingredients discussed above are co-administered.
  • the active ingredients can be present either in a single pharmaceutical composition or in separate pharmaceutical compositions, including in separate pharmaceutical compositions optimized for administration either by the same mode or a different mode.
  • the active ingredients may both be administered topically, either in a single pharmaceutical composition or in separate pharmaceutical compositions.
  • the product comprising (a) a NKi inhibitor, and (b) a Substance P release inhibitor, as a combined preparation for simultaneous, concurrent, separate or sequential use, the product may comprise either a single pharmaceutical composition that comprises both (a) and (b) (i.e. a unit dosage form) or alternatively a first pharmaceutical composition that comprises (a) and a second (i.e., separate) pharmaceutical composition that comprises (b).
  • Co-administration of the active ingredients according to the present invention includes simultaneous, separate and sequential administration.
  • administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), topical (as a cream, lotion, solution, emulsion, gel, ointment, etc) by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.).
  • Oral and topical administration are generally preferred.
  • Topical administration is typically to at least part of the area of the patient’s skin affected by the acne.
  • aprepitant is preferably delivered orally or topically
  • fosaprepitant is preferably administered parenterally, although it can be administered topically.
  • the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glyco
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • compositions of the invention may take the form of, for example, creams, lotions, solutions, emulsions, gels or ointments prepared by conventional means with suitable pharmaceutically acceptable excipients.
  • Compositions for topical use may also contain one or more emollients, emulsifiers, thickeners and/or preservatives, of which suitable examples are well known to those of skill in the art.
  • the pharmaceutical compositions typically take the form of an aqueous injectable solution.
  • suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler.
  • the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant.
  • Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes.
  • compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art.
  • Topical administration is generally preferred, as it tends to increase the exposure of the Cutibacterium acnes to the active ingredients.
  • topical administration will generally result in reduce systemic side effects.
  • compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
  • additional active ingredients such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
  • the compositions of the invention do not contain any further active ingredients, and only contain (a) an NKi inhibitor, and/or (b) a Substance P release inhibitor.
  • Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations. Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.
  • NKi inhibitors such as aprepitant and fosaprepitant, and pharmaceutically acceptable salts thereof, are currently approved for use in treating nausea and vomiting in patients, including those suffering from cancer who may also be suffering from nausea and vomiting as a result of chemotherapy and/or surgery. It is thus preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating nausea and vomiting, but instead is prescribed and/or administered to the patient for treating acne. It is also preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating pruritus/itching, but instead is prescribed and/or administered to the patient for treating acne.
  • Substance P release inhibitors in particular pregabalin, are currently approved treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD). It is thus preferred in the present invention that the Substance P release inhibitor is not prescribed and/or administered to the patient for the purpose of treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD), but instead is prescribed and/or administered to the patient for treating acne.
  • the NKi inhibitor and/or Substance P release inhibitor is administered 1 to 5 time per day, for example 3 times per day.
  • the NKi inhibitor is administered orally, it is administered at a dose of 1 to 10 mg/kg of body weight per day (corresponding to approximately 40 to 500 mg per day). Alternatively, if the NKi inhibitor is administered topically, it is typically administered at a dose of 1 to 50 mg per day.
  • the Substance P release inhibitor is administered orally, it is administered at a dose of 1 to 10 mg/kg of body weight per day (corresponding to approximately 40 to 500 mg per day). Alternatively, if the Substance P release inhibitor is administered topically, it is typically administered at a dose of 1 to 50 mg per day. Determination of the proper dosage for particular situations is within the skill of the person skilled in the art.
  • the plates used were ASA (Agar Sangre Anaerobios; Reference: 1007 - Placa de Petri 90) by MAIM.
  • BD GasPak EZ was used as a gas generation bag system, for anaerobic incubation.
  • ASA plates were prepared in which bacteria exposed only to DMSO were seeded, as a growth control for plates in which the bacteria were exposed to Aprepitant and Maropitant.
  • ASA plates were prepared in which bacteria exposed only to physiological saline were seeded, as a growth control for plates in which the bacteria were exposed to Fosaprepitant.
  • Example 2 effect of Substance P release inhibitors Pregabalin, Gabapentin and Capsaicin alone or in combination with NK1 inhibitors on Cutibacterium acnes
  • the material and method used in this example was similar to that explained in
  • TheNKl inhibitors Aprepitant (1 mg/ml), Maropitant (1 mg/ml) dissolved in DMSO and Fosaprepitant (1 mg/ml) dissolved in physiological serum were tested.
  • the Substance P release inhibitors Pregabalin (5mg / ml), Gabapentin (5mg / ml), Capsaicin (5mg / ml) were tested. Combinations of the NK1 inhibitors and the Substance P release inhibitors were also tested.
  • Tables 2 A to 21 below shows the percentage of bacterial proliferation in reference to the control (mean +/- standard deviation).
  • the cell proliferation count was performed by counting the Colony Forming Units (CFU) in each plate. Counting on each plate was performed with an inverted microscope.
  • Example 1 shows that NKi inhibitors, such as aprepitant, fosaprepitant and maropitant, inhibit the growth of Cutibacterium acnes. Further, increasing the concentration of the NKi inhibitors increases the inhibition of growth of Cutibacterium acnes. In view of the well-established role of Cutibacterium acnes in acne, it follows that NKi inhibitors will be useful in treating acne in patients.
  • NKi inhibitors such as aprepitant, fosaprepitant and maropitant
  • Example 2 shows that Substance P release inhibitors, such as pregabalin, gabapentin and capsaicin, inhibit the growth of Cutibacterium acnes.
  • Substance P release inhibitors will be useful in treating acne in patients.
  • Example 2 also shows that a surprising synergistic enhancement of the effect is observed when NKi inhibitors are co-administered with Substance P release inhibitors.
  • a synergistic increase in the inhibition of growth of Cutibacterium acnes is observed, meaning that the combination of an NKi inhibitor with a Substance P release inhibitor will be particularly effective in treating acne in patients.

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Abstract

The present invention relates to the treatment of acne using (a) an NK1 inhibitor, and /or (b) a Substance P release inhibitor.

Description

TREATMENT OF ACNE
FIELD OF THE INVENTION
The present invention relates to the treatment of acne using (a) an NK1 inhibitor, and /or (b) an Substance P release inhibitor.
BACKGROUND TO THE INVENTION
Acne is a skin disease, which results in blackheads and/or whiteheads, pimples, oily skin and, in some cases, scarring. Acne generally arises when hair follicles are clogged with dead skin cells and oil from the skin, and thus tends to affect areas of the skin with a relatively high number of oil glands, such as the face, upper chest and back.
Although genetics is thought to be the primary cause of acne in around 80% of patients, and increased production of sebum triggered by androgens appears to be part of the underlying mechanism, in many cases excessive growth of the bacterium Cutibacterium acnes on the skin is implicated.
There are many available treatment options for acne, ranging from changes in lifestyle to medications and medical procedures. Treatments applied directly to the affected skin, such as azelaic acid, benzoyl peroxide, and salicylic acid, are commonly used. In cases where excessive growth of the bacterium Cutibacterium acnes are implicated, antibiotics are sometimes prescribed, either in formulations that are applied directly to the skin and or in formulations taken by mouth. However, given the rising problem of antibiotic resistance, therapeutic approaches using antibiotics are increasingly undesirable and/or ineffective. Treatments derived from retinoic acid are also available, but these have many adverse effect. Overall, currently available treatments for acne are ineffective and/or effective only for a limited time period and/or are associated with undesirable side effects.
Acne is estimated to affect over 600 million people globally. As well as the primary symptoms described above, the resulting damage to the patient’s appearance can lead to anxiety, reduced self-esteem, depression and (in some cases) thoughts of suicide. The disease is especially prevalent in adolescence and youth, and can thus causes life-long aesthetic and emotional damage. There therefore remains a need for new safe and effective treatments for acne.
Aprepitant and its prodrug fosaprepitant are neurokinin 1 (NKi) receptor inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting. Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer.
The main agonist of the NKi receptor is the so-called Substance P. A number of Substance P release inhibitors are known, including pregabalin, gabapentin and capsaicin. Pregabalin is currently authorized for the treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD) in adults. SUMMARY OF THE INVENTION
It has now surprisingly been found that both NKi inhibitors and Substance P release inhibitors are able to inhibit the growth of Cutibacterium acnes. Moreover, the combination of an NKi inhibitor and a Substance P release inhibitor was found to provide greater inhibition of the growth of Cutibacterium acnes than either component alone: the NKi inhibitor and Substance P release inhibitor thus interact synergistically to provide a very high level of inhibition of the growth of Cutibacterium acnes
Cutibacterium acnes has a well-established role of acne (see Sutcliffe J, McLaughlin R, Webster G, Read AF, Drlica K, Elliott R, Stuart I. Susceptibility of Cutibacterium acnes to topical minocycline foam. Anaerobe. 2020 Apr;62: 102169. doi: 10.1016/j.anaerobe.2020.102169. Epub 2020 Jan 28. PMID: 32058277). It follows that substances that can inhibit the growth of Cutibacterium acnes , such as NKi inhibitors and/or Substance P release inhibitors, will be effective in treating patients with acne. NKi inhibitors and/or Substance P release inhibitors can therefore provide an effective and non toxic treatment of acne, whilst avoiding the problems of antibiotic resistance that occur with existing antibiotic-based therapies.
Accordingly, the present invention provides pharmaceutical composition which comprises: an NKi inhibitor; and/or a Substance P release inhibitor; for use in treating acne.
The invention further provides: · an NKi inhibitor, for use in treating acne, optionally by co-administration with a
Substance P release inhibitor;
• a Substance P release inhibitor for use in treating acne, optionally by co administration with an NKi inhibitor; • a method of treating acne in a patient, which method comprises administering to said patient an NKi inhibitor, and which method optionally comprises co administration with a Substance P release inhibitor;
• a method of treating acne in a patient, which method comprises administering to said patient a Substance P release inhibitor, and which method optionally comprises co-administration with an NKi inhibitor;
• use of an NKi inhibitor, in the manufacture of a medicament for the treatment of acne, optionally by co-administration with a Substance P release inhibitor;
• use of a Substance P release inhibitor, in the manufacture of a medicament for the treatment of acne, optionally by co-administration with an NKi inhibitor;
• a pharmaceutical composition which comprises an NKi inhibitor and a Substance P release inhibitor;
• a method of treating acne in a patient, which method comprises administering to said patient a pharmaceutical composition which comprises an NKi inhibitor and a Substance P release inhibitor;
• use of a pharmaceutical composition which comprises an NKi inhibitor and a Substance P release inhibitor, in the manufacture of a medicament for the treatment of acne;
• a product comprising (a) a NKi inhibitor, and (b) a Substance P release inhibitor, as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of a patient suffering from acne; and
• a kit which comprises (a) a pharmaceutical composition comprising a NKi inhibitor; and (b) a pharmaceutical composition comprising a Substance P release inhibitor.
DETAILED DESCRIPTION
The present invention is concerned with the treatment of acne using (a) an NKi inhibitor, and /or (b) a Substance P release inhibitor.
NKi inhibitors
NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention. Typically, the NKi inhibitor is aprepitant, fosaprepitant, maropitant, netupitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017, L-733,060, L- 732,138, L -703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760735, CP-122721, L-758 298, L-741 671, L-742694, CP-99994 or T- 2328, or a pharmaceutically acceptable salt of any thereof.
Preferably, the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.
More preferably, the NKI inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, or a pharmaceutically acceptable salt of any thereof.
Still more preferably, the NKI inhibitor is aprepitant, fosaprepitant, maropitant, or a pharmaceutically acceptable salt of any thereof
Still more preferably, the NKI inhibitor is aprepitant or its prodrug fosaprepitant, or a pharmaceutically acceptable salt of either thereof. Most preferably, the NKI inhibitor is aprepitant or a pharmaceutically acceptable salt thereof
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines. Aprepitant has the following structure:
Figure imgf000005_0001
Aprepitant is not typically formulated in the form of a pharmaceutically acceptable salt. Thus, in a preferred aspect of the invention the NKi inhibitor is aprepitant.
Fosaprepitant is prodrug of aprepitant and has the following structure:
Figure imgf000006_0001
Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:
Figure imgf000006_0002
Thus, in a preferred aspect of the invention, the NKi inhibitor is fosaprepitant dimeglumine.
Pharmaceutically acceptable salts of fosaprepitant, such as fosaprepitant dimeglumine, are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.
Fosaprepitant is converted in vivo to aprepitant. Thus, when administered to a patient, typically intravenously, fosaprepitant is converted to aprepitant.
Maropitant is the compound (2S,3S)-2-Benzhydryl-N-(5-tert-butyl-2- methoxybenzyl) quinuclidin-3 -amine, and has the following structure:
Figure imgf000007_0001
Maropitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the citrate salt. Thus, in a preferred aspect of the invention, the NKi inhibitor is maropitant citrate.
Substance P release inhibitors
Substance P release inhibitors are a well-known class of drug, and any suitable Substance P release inhibitor can be used in the present invention. The ability of a given compound to inhibit the release of Substance P can be assessed by routine techniques, such as those described in Fehrenbacher et al , Pain, vol 105, 1-2, September 2003, pages 133- 141.
Typically, the Substance P release inhibitor is a grrawa-aminobutyric acid derivative of formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0002
wherein
Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group;
R.2 is a hydrogen or methyl group; and R3 is a hydrogen, methyl, or carboxyl group.
An Ci-6 alkyl group may be a straight-chain or branched-chain alkyl group. Ci-6 alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl. C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably an alkyl or cycloalkyl group is unsubstituted. Preferably Ri is a Ci-6 alkyl group, more preferably a -(CH2)o-2-iC4H9 group and most preferably an -1C4H9 group (i.e., an isobutyl group). Preferably R2 is hydrogen. Preferably R3 is hydrogen. A particularly preferred compound of formula (I) is one in which Ri is an -iC4H9 group and R2 and R3 are both hydrogen. A particularly preferred gamma- aminobutyric acid derivative is the compound of formula (I) in which Ri is an -1C4H9 group and R2 and R3 are both hydrogen.
Compounds of formula (I) can contain one or several asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
Most preferably the compound of formula (I) is pregabalin, i.e. (3S)-3- (aminomethyl)-5-methylhexanoic acid, or a pharmaceutically acceptable salt thereof. Pregabalin has the following structure:
Figure imgf000008_0001
Alternatively, the compound of formula (I) is gabapentin or a pharmaceutically acceptable salt thereof. Gabapentin has the following structure:
Figure imgf000008_0002
Synthetic methods for preparing compounds of formula (I) and pharmaceutically salts thereof are well known in the art. For example, suitable methods are described in WO 98/003167, the contents of which are herein incorporated by reference in their entirety.
Alternatively, the Substance P release inhibitor may be a capsaicinoid of formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0001
wherein R4 represents a C6 to C12 alkyl or alkenyl moiety preferably a Cx to C10 alkyl or alkenyl moiety. An alkyl or alkenyl moiety may be a straight-chain or branched-chain alkyl group. Preferably, the Substance P release inhibitor is capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsacicin, homodihydrocapsaicin, or nonivamid, or a pharmaceutically acceptable salt of any thereof. Preferably the Substance P release inhibitor is capsaicin.
Capsaicin has the following structure:
Figure imgf000009_0002
Dihydrocapsaicin has the following structure:
Figure imgf000009_0003
Nordihydrocapsaicin has the following structure:
Figure imgf000009_0004
Homocapsacicin has the following structure:
Figure imgf000010_0001
Homodihydrocapsaicin has the following structure:
Figure imgf000010_0002
Nonivamid has the following structure:
Figure imgf000010_0003
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, hydrosulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, mandelic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
Treatment of acne
The patient to be treated in the present invention is suffering from acne. Acne is also known as acne vulgaris.
Typically the patient to be treated is a mammal. Preferably the patient is a human. Generally, the patient is a human between 10 and 40 years old, typically between 13 and 25, for example a teenage human. Acne can easily be diagnosed using routine diagnostic techniques known to those of skill in the art. Similarly, a successful treatment can identified by a reduction in, or an absence of symptoms of acne, or using routine diagnostic techniques.
Typically, the acne to be treated in the present invention is mild, moderate or severe acne. Preferably, the acne to be treated in the present invention is moderate or severe acne. Mild acne is generally defined by the presence of clogged skin follicles (known as comedones) limited to the face with occasional inflammatory lesions. Moderate acne is generally said to occur when a higher number of inflammatory papules and pustules occur on the face, compared to mild cases of acne, and when the papules and pustules are found on the trunk of the body. Severe acne arises when nodules (painful bumps lying under the skin) are the characteristic facial lesions and involvement of the trunk is extensive.
Typically, patient to be treated exhibits excessive growth of Cutibacterium acnes, generally on the areas of skin affected by the acne.
Typically, the active ingredient(s) treat the acne by inhibiting the grown of Cutibacterium acnes , generally on the areas of skin affected by the acne. Thus, the active ingredient(s) are typically not treating the acne by addressing other skin complaints, such as pruritus/itching.
Typically, the Cutibacterium acnes is an therapy-resistant or recurrent despite therapy. Thus, in some cases, the patient may have previously been treated with antibiotics and developed antibiotic resistance during that treatment. In such case, an NK1 inhibitor, and/or a Substance P release inhibitor provides an alternative approach for treating the acne, by inhibiting the grown of Cutibacterium acnes.
Treatment may be curative or palliative in nature, i.e. it may aim at curing the patient, achieving complete or partial remission, alleviating or managing symptoms and/or side effects of the disease (without curing the patient).
Pharmaceutical compositions The present invention provides a pharmaceutical composition that comprises an
NKi inhibitor and/or a Substance P release inhibitor (the “active ingredient(s)”), typically for use in treating acne. Pharmaceutical compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers. In some preferred instances, the pharmaceutical composition comprises both the NKi inhibitor and a Substance P release inhibitor, and typically does not comprise any other active ingredients.
In other preferred instances, the pharmaceutical composition comprises the NKi inhibitor, but does not comprise the Substance P release inhibitor and typically does not comprise any other active ingredients.
In other preferred instances, the pharmaceutical composition comprises the Substance P release inhibitor, but does not comprise the NKi inhibitor and typically does not comprise any other active ingredients. The present invention extends to situations where the active ingredients discussed above are co-administered. When the active ingredients are co-administered they can be present either in a single pharmaceutical composition or in separate pharmaceutical compositions, including in separate pharmaceutical compositions optimized for administration either by the same mode or a different mode. For example, the active ingredients may both be administered topically, either in a single pharmaceutical composition or in separate pharmaceutical compositions.
For the avoidance of doubt, in the product comprising (a) a NKi inhibitor, and (b) a Substance P release inhibitor, as a combined preparation for simultaneous, concurrent, separate or sequential use, the product may comprise either a single pharmaceutical composition that comprises both (a) and (b) (i.e. a unit dosage form) or alternatively a first pharmaceutical composition that comprises (a) and a second (i.e., separate) pharmaceutical composition that comprises (b).
Co-administration of the active ingredients according to the present invention includes simultaneous, separate and sequential administration. In general, administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), topical (as a cream, lotion, solution, emulsion, gel, ointment, etc) by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.). Oral and topical administration are generally preferred. Topical administration is typically to at least part of the area of the patient’s skin affected by the acne.
The preferred route of administration will depend upon the specific active ingredient to be delivered, and a skilled person can easily choose an appropriate route. For example, aprepitant is preferably delivered orally or topically, whereas fosaprepitant is preferably administered parenterally, although it can be administered topically.
For oral administration, the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
For topical administration, the pharmaceutical compositions of the invention may take the form of, for example, creams, lotions, solutions, emulsions, gels or ointments prepared by conventional means with suitable pharmaceutically acceptable excipients. Compositions for topical use may also contain one or more emollients, emulsifiers, thickeners and/or preservatives, of which suitable examples are well known to those of skill in the art.
For administration by injection, the pharmaceutical compositions typically take the form of an aqueous injectable solution. Examples of suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
For administration by inhalation, the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler. Alternatively, the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant. Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes.
Pharmaceutical compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art. Topical administration is generally preferred, as it tends to increase the exposure of the Cutibacterium acnes to the active ingredients. In addition, topical administration will generally result in reduce systemic side effects.
Pharmaceutical compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects. However, it is generally preferred that the compositions of the invention do not contain any further active ingredients, and only contain (a) an NKi inhibitor, and/or (b) a Substance P release inhibitor. Dosages and dosage regimens
Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations. Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.
NKi inhibitors, such as aprepitant and fosaprepitant, and pharmaceutically acceptable salts thereof, are currently approved for use in treating nausea and vomiting in patients, including those suffering from cancer who may also be suffering from nausea and vomiting as a result of chemotherapy and/or surgery. It is thus preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating nausea and vomiting, but instead is prescribed and/or administered to the patient for treating acne. It is also preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating pruritus/itching, but instead is prescribed and/or administered to the patient for treating acne.
Substance P release inhibitors, in particular pregabalin, are currently approved treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD). It is thus preferred in the present invention that the Substance P release inhibitor is not prescribed and/or administered to the patient for the purpose of treatment of peripheral and central neuropathic pain in adults, for the treatment of partial seizures with secondary generalization, and for the treatment of generalized anxiety disorder (GAD), but instead is prescribed and/or administered to the patient for treating acne. Typically, the NKi inhibitor and/or Substance P release inhibitor is administered 1 to 5 time per day, for example 3 times per day.
Typically, if the NKi inhibitor is administered orally, it is administered at a dose of 1 to 10 mg/kg of body weight per day (corresponding to approximately 40 to 500 mg per day). Alternatively, if the NKi inhibitor is administered topically, it is typically administered at a dose of 1 to 50 mg per day.
Typically, if the Substance P release inhibitor is administered orally, it is administered at a dose of 1 to 10 mg/kg of body weight per day (corresponding to approximately 40 to 500 mg per day). Alternatively, if the Substance P release inhibitor is administered topically, it is typically administered at a dose of 1 to 50 mg per day. Determination of the proper dosage for particular situations is within the skill of the person skilled in the art.
The present invention is explained in more detail in the following by referring to the Examples, which are not to be construed as limiting.
EXAMPLES
Example 1 - effect of NKi inhibitors on Cutibacterium acnes
The bacteria used in this experiment was Cutibacterium acnes Scholz and Kilian (ATCC® 6919™) [deposited as Corynebacterium acnes (Gilchrist) Eberson by ATCC, strain designation NCTC 737 [VPI 0389] see http://www.lgcstandards- atcc . org/ products/ all/6919. aspx? geo_country=es] .
The plates used were ASA (Agar Sangre Anaerobios; Reference: 1007 - Placa de Petri 90) by MAIM. BD GasPak EZ was used as a gas generation bag system, for anaerobic incubation.
Concentration solutions of Aprepitant (lmg / ml, 5mg / ml, lOmg / ml, 20mg / ml) and Maropitant (lmg / ml, 5mg / ml, lOmg / ml, 20mg / ml) dissolved in DMSO and Fosaprepitant (lmg / ml, 5mg / ml, lOmg / ml, 20mg / ml) dissolved in physiological serum were tested. On the plates in each ASA plate 10,000 bacteria were seeded. In the different plates, the bacteria were exposed to Aprepitant, Fosaprepitant, Maropitant at the different concentrations. ASA plates were prepared in which bacteria exposed only to DMSO were seeded, as a growth control for plates in which the bacteria were exposed to Aprepitant and Maropitant. ASA plates were prepared in which bacteria exposed only to physiological saline were seeded, as a growth control for plates in which the bacteria were exposed to Fosaprepitant.
Plates were incubated under anaerobic conditions in BD GasPak EZ containers at 37 ° C for 72 hours. After 72 hours, the growth reading was performed. All experiments were done in triplicate. Table 1 below shows the percentage of bacterial proliferation in reference to the control (mean +/- standard deviation). The cell proliferation count was performed by counting the Colony Forming Units (CFU) in each plate. Counting on each plate was performed with an inverted microscope.
Figure imgf000016_0001
Figure imgf000017_0001
Example 2 - effect of Substance P release inhibitors Pregabalin, Gabapentin and Capsaicin alone or in combination with NK1 inhibitors on Cutibacterium acnes The material and method used in this example was similar to that explained in
Example 1.
TheNKl inhibitors Aprepitant (1 mg/ml), Maropitant (1 mg/ml) dissolved in DMSO and Fosaprepitant (1 mg/ml) dissolved in physiological serum were tested. The Substance P release inhibitors Pregabalin (5mg / ml), Gabapentin (5mg / ml), Capsaicin (5mg / ml) were tested. Combinations of the NK1 inhibitors and the Substance P release inhibitors were also tested.
Tables 2 A to 21 below shows the percentage of bacterial proliferation in reference to the control (mean +/- standard deviation). The cell proliferation count was performed by counting the Colony Forming Units (CFU) in each plate. Counting on each plate was performed with an inverted microscope.
Figure imgf000017_0002
Table 2A
Figure imgf000017_0003
Table 2B
Figure imgf000018_0001
Table 2C
Figure imgf000018_0002
Figure imgf000018_0003
Table 2E
Figure imgf000018_0004
Table 2F
Figure imgf000018_0005
Table 2G
Figure imgf000018_0006
Figure imgf000019_0001
Table 2H
Figure imgf000019_0002
Table 21
Conclusions from Examples 1 and 2
Example 1 shows that NKi inhibitors, such as aprepitant, fosaprepitant and maropitant, inhibit the growth of Cutibacterium acnes. Further, increasing the concentration of the NKi inhibitors increases the inhibition of growth of Cutibacterium acnes. In view of the well-established role of Cutibacterium acnes in acne, it follows that NKi inhibitors will be useful in treating acne in patients.
Example 2 shows that Substance P release inhibitors, such as pregabalin, gabapentin and capsaicin, inhibit the growth of Cutibacterium acnes. In view of the well- established role of Cutibacterium acnes in acne, it follows that Substance P release inhibitors will be useful in treating acne in patients. Example 2 also shows that a surprising synergistic enhancement of the effect is observed when NKi inhibitors are co-administered with Substance P release inhibitors. Thus, a synergistic increase in the inhibition of growth of Cutibacterium acnes is observed, meaning that the combination of an NKi inhibitor with a Substance P release inhibitor will be particularly effective in treating acne in patients.

Claims

1 A pharmaceutical composition which comprises:
(a) an NKi inhibitor; and/or
(b) a Substance P release inhibitor; for use in treating acne.
2 The pharmaceutical composition for use according to claim 1, wherein the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition for use according to claim 2, wherein the NKi inhibitor is aprepitant, fosaprepitant or maropitant, or pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition for use according to any one of the preceding claims, wherein the Substance P release inhibitor is a garwwa-aminobutyric acid derivative of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000020_0001
wherein
Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group;
R.2 is a hydrogen or methyl group; and R3 is a hydrogen, methyl, or carboxyl group.
5. The pharmaceutical composition for use according to claim 4, wherein the Substance P release inhibitor is pregabalin or gabapentin, or a pharmaceutically acceptable salt thereof.
6 The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the Substance P release inhibitor is a capsaicinoid of formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000021_0001
wherein R4 represents a C6 to C12 alkyl or alkenyl moiety preferably a Cx to C10 alkyl or alkenyl moiety, and preferably wherein the Substance P release inhibitor is capsaicin or a pharmaceutically acceptable salt thereof.
7. The pharmaceutical composition for use according to any one of the preceding claims, wherein the acne exhibits excessive growth of Cutibacterium acnes.
8 The pharmaceutical composition for use for use according to claim 7, wherein Cutibacterium acnes is antibiotic-resistant Cutibacterium acnes.
An NKi inhibitor as defined in any one of claims 1 to 3, for use in treating acne as defined in any one of claim 1, 7 and 8, optionally by co-administration with a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6.
10 A Substance P release inhibitor as defined in any one of claims 1 and 4 to 6, for use in treating acne as defined in claim 1, 7 or 8, optionally by co-administration with an NKi inhibitor as defined in any one of claims 1 to 3
11 A method of treating acne as defined in any one of claims 1, 7 and 8 in a patient, which method comprises administering to said patient an NKi inhibitor as defined in any one of claims 1 to 3, and which method optionally comprises co administration with a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6.
12 A method of treating acne as defined in any one of claims 1, 7 and 8 in a patient, which method comprises administering to said patient a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6, and which method optionally comprises co-administration with an NKi inhibitor as defined in any one of claims 1 to 3.
13. Use of an NKi inhibitor as defined in any one of claims 1 to 3, in the manufacture of a medicament for the treatment of acne as defined in any one of claims 1, 7 and 8, optionally by co-administration with a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6.
14. Use of Substance P release inhibitor as defined in any one of claims 1 and 4 to 6, in the manufacture of a medicament for the treatment of acne as defined in any one of claims 1, 7 and 8, optionally by co-administration with an NKi inhibitor as defined in any one of claims 1 to 3.
15. A pharmaceutical composition which comprises an NKi inhibitor as defined in any one of claims 1 to 3 and a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6.
16. A method of treating acne as defined in any one of claims 1, 7 and 8 in a patient, which method comprises administering to said patient a pharmaceutical composition as defined in claim 15.
17. Use of a pharmaceutical composition as defined in claim 15, in the manufacture of a medicament for the treatment of acne as defined in any one of claims 1, 7 and 8
18. A product comprising (a) a NKi inhibitor as defined in any one of claims 1 to 3, and (b) a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6, as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of a patient suffering from acne as defined in any one of claims 1, 7 and 8.
19. A kit which comprises:
(a) a pharmaceutical composition comprising a NKi inhibitor as defined in any one of claims 1 to 3; and
(b) a pharmaceutical composition comprising a Substance P release inhibitor as defined in any one of claims 1 and 4 to 6.
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