WO2018077889A1

WO2018077889A1 - Compositions comprising linsitinib

Info

Publication number: WO2018077889A1
Application number: PCT/EP2017/077188
Authority: WO
Inventors: Jordi RIUS CAPALVO; Jacob Gonzalez Rodriguez
Original assignee: Almirall, S.A.
Priority date: 2016-10-24
Filing date: 2017-10-24
Publication date: 2018-05-03

Abstract

The present invention relates to a compound which is an insulin-like growth factor inhibitor or a pharmaceutically acceptable salt thereof for use in the topical treatment of dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer. The invention also relates to pharmaceutical compositions comprising the compound.

Description

Compositions comprising linsitinib

The present invention relates to the use of linsitinib in treating acne, and to pharmaceutical compositions comprising linsitinib.

Background to the Invention

Acne is a complex chronic skin disease characterized by seborrhoea, the formation of open and closed comedones (black and white heads respectively), erythematous papules and pustules and in more severe cases nodules and deep pustules. Acne typically starts in early puberty, and it appears early in girls than boys (which correlates with early puberty onset in females), but more boys are affected in mid-teenage years. By 20-25 years tendency is to resolve slowly, however in a considerable number of people acne persists in adulthood. Alterations in the normal function of the pilosebaceous unit are the main pathophysiological features in acne and include follicle hyperkeratinisation, abnormal sebum production, P. acnes infection and innate and acquired immune activation. Genetic, hormonal and diet- related factors are also related with this pathology. Complications of acne lesions can lead to permanent scarring. Scarring usually follows deep-seated inflammatory lesion but may also occur as a result of more superficial inflamed lesions in scar-prone patients.

Acne is also associated to significant physiological morbidities such as poor self-image, depression and anxiety. Comparison with other chronic illnesses has shown that acne patients have levels of social, physiological and emotional disability similar to patients with asthma, epilepsy, diabetes or arthritis.

Conventional treatments for acne include topical and systemic therapies. The most used topical treatments are based in retinoids, antibiotics, benzoyl peroxide (BPO), azelaic acid, and dapsone or combinations of retinoids with BPO or retinoids with antibiotiocs. Oral retinoids, specially isotretinoin, and oral antibiotics are usually indicated for moderate to severe acne patients. Oral treatments can be combined with topical therapies in order to increase efficacy. Insulin-like growth factor 1 receptor (IGF-1 R) is a tyrosine protein kinase receptor activated by insulin growth factor-1 (IGF-1 ), a pleiotropic trophic factor involved in the growth and maintenance of several tissues. It has now surprisingly been found that an insulin-like growth factor inhibitor, particularly linsitinib, has efficacy in reducing sebum production and/or skin cell proliferation when applied topically, which would be useful for treating dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer; more preferably selected from acne, actinic keratosis and seborrheic dermatitis; most preferably the dermatological disease is acne. The topical administration of an insulin-like growth factor inhibitor, particularly linsitinib, avoids the occurrence of the side-effects which would result from oral administration.

Summary of the Invention

The present invention therefore provides an insulin-like growth factor inhibitor, particularly linsitinib, or a pharmaceutically acceptable salt thereof, for use in the topical treatment of dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer, more preferably selected from acne, actinic keratosis and seborrheic dermatitis; in particular for use in the topical treatment of acne.

The present invention also provides a topical pharmaceutical composition comprising an insulin-like growth factor inhibitor, particularly linsitinib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for use in treating

dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer, more preferably selected from acne, actinic keratosis and seborrheic dermatitis; in particular for use in the topical treatment of acne. Also provided is the use of an insulin-like growth factor inhibitor, particularly of linsitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above, in the manufacture of a medicament for the topical treatment of dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer, in particular of acne ; and a method of treating dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer; more preferably selected from acne, actinic keratosis and seborrheic dermatitis; in particular a method of treating acne in a patient; which method comprises topically administering to the patient an insulin- like growth factor inhibitor, particularly linsitinib, or a pharmaceutically acceptable salt thereof, or a composition as defined above.

In a particularly preferred embodiment of the invention, the insulin-like growth factor inhibitor is selective, i.e. it has not a significant activity on any other receptor, enzyme or

pharmacological target.

Detailed Description of the Invention Linsitinib is cis-3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1 ,5-a]pyrazin-3-yl]-1 - methylcyclobutanol. It has the structure:

The present invention provides linsitinib and pharmaceutical acceptable salts thereof for use in treating dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer, more preferably selected from acne, actinic keratosis and seborrheic dermatitis; in particular acne. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in

Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds for use in this invention include addition salts with a pharmaceutically acceptable acid such as such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Other salts may be formed with a pharmaceutically acceptable base. Suitable such pharmaceutically acceptable salts include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts, and meglumine salts.

In a preferred embodiment of the invention the compound for use is linsitinib.

As described herein the term "acne" also designates comedonic acne, papulopustular acne, papulocomedonic acne, nodulocystic acne, acne conglobata, cheloid acne of the nape of the neck, recurrent miliary acne, necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, solar acne and medication-related acne.

As described herein the term "skin cancer" includes squamous cell carcinoma, basal cell carcinoma, malignant melanoma.

Typically the patient to be treated is a mammal. Preferably the patient is a human.

Typically, the linsitinib, the pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is applied topically to the face of a patient.

Pharmaceutical compositions according to the invention are suitable for topical

administration.

For topical administration the pharmaceutical compositions of the present invention may take the form of any formulation normally used for topical administration, in particular solutions, lotions, emulsions of liquid consistency, emulsions of semi-liquid consistency, emulsions of semi-solid consistency, emulsions of solid consistency, creams, gels or ointments.

Preferably the compositions of the present invention may take the form of a gel, a lotion or a cream; more preferably a lotion or a cream; still more preferably a cream.

The emulsions are obtained by dispersion of an oil phase in water (O/W) or a water phase in oil (W/O). Preferred pharmaceutical compositions for topical administration contain an oil phase. In a preferred embodiment, the pharmaceutical compositions of the present invention are water-in-oil emulsions (i.e. emulsions wherein the water is the dispersed phase and the oil in the dispersion medium). In another preferred embodiment, the pharmaceutical compositions of the present invention are oil-in-water emulsions (i.e. emulsions wherein the oil is the dispersed phase and the water in the dispersing medium). Compositions for topical use in accordance with the invention may also contain one or more emollients, emulsifiers, thickeners and/or preservatives.

The emollients are typically long chain alcohols, such as cetyl alcohol, stearyl alcohol and cetearyl alcohol; hydrocarbons such as petrolatum and light mineral oil; or acetylated lanolin. The total amount of emollient in the formulation is preferably about 10% to about 20%, and more preferably about 5% to about 10% by weight based on the total weight of the formulation. The emulsifier is typically a nonionic surface active agent, e.g., polysorbate 60 (available from Sigma Aldrich), sorbitan monostearate, polyglyceryl-4 oleate, and

polyoxyethylene(4)lauryl ether or trivalent cationic. Generally the total amount of emulsifier is preferably about 2% to about 14%, and more preferably about 2% to about 6% by weight based on the total weight of the formulation.

Pharmaceutically acceptable thickeners, such as Veegum.TM.K (available from R. T.

Vanderbilt Company, Inc.), and long chain alcohols (i.e. cetyl alcohol, stearyl alcohol or cetearyl alcohol) can be used. The total amount of thickener present is preferably about 3% to about 12% by weight based on the total weight of the formulation.

Preservatives such as methylparaben, propylparaben and benzyl alcohol can be present in the formulation.

Optionally, an additional solubilizing agent such as benzyl alcohol, lactic acid, acetic acid, stearic acid or hydrochloric acid can be included in the formulation.

Optionally, the formulation can contain a humectant such as glycerin and skin penetration enhancers such as butyl stearate. It is known to those skilled in the art that a single ingredient can perform more than one function in a composition, i.e., cetyl alcohol can serve both as an emollient and as a thickener.

The oil phase in an emulsion may be any oil phase normally used in emulsions for topical administration. Such oil phases include, for example, hydrocarbon bases such as such as hard paraffin, soft paraffin, ceresine and microcrystalline wax, absorption bases such as lanolin and beeswax, emulsifying bases such as emulsifying wax and cetrimide, and vegetable oils such as olive oil, coconut oil, sesame oil, almond oil and peanut oil. Other oil phases useful in accordance with the invention are mineral oil, liquid petroleum, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol and 2-octyldodecanol.

Those skilled in the art will understand that by varying the ratio of water to oil in an emulsion, the result could be deemed a lotion, a cream, or an ointment, by order of increasing proportion of oil. An emulsion comprising similar proportions of oil phase and water phase is usually deemed a cream, whereas an ointment will generally contain a substantially higher proportion of oil phase compared to water phase, for example greater than 60 wt. % oil phase, preferably greater than 70 wt. % oil phase, more preferably greater than 80 wt. % oil phase, based on the total weight of the oil phase and the water phase. A lotion will generally contain a lower proportion of oil phase than a cream, for example under 25 wt. % oil phase, under 20 wt. % oil phase, under 15 wt. % oil phase, under 10 wt. % oil phase or under 5 wt. % oil phase, based on the total weight of the oil phase and the water phase.

Generally, a cream for use according to the invention comprises an oil phase and a water phase mixed together to form an emulsion. Preferably, the amount of water present in a cream of the invention is about 45% to about 95% by weight based on the total weight of the cream, more preferably about 55 wt. % to about 90 wt. %, even more preferably about 65 wt. % to about 80 wt. %.

Where the composition is an ointment a pharmaceutically acceptable ointment base will be used. Examples of ointment bases include hydrocarbon bases such as such as hard paraffin, soft paraffin, ceresine and microcrystalline wax, absorption bases such as lanolin and beeswax, water-soluble bases such as polyethylene glycols (e.g. polyethylene glycol 200, 300, 400, 3350, 4000 or 6000), propylene glycol and polypropylene glycols, emulsifying bases such as emulsifying wax and cetrimide, and vegetable oils such as olive oil, coconut oil, sesame oil, almond oil and peanut oil. Mixtures of ointment bases can of course be used. The amount of ointment base present in an ointment of the invention is preferably about 60% to about 95% by weight based on the total weight of ointment, more preferably about 70 wt. % to about 90 wt. %, still more preferably about 75 wt. % to about 85 wt. %.

The pharmaceutical composition for use in accordance with the present invention may also be a lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.

In the compositions for use according to the invention, the linsitinib or pharmaceutically acceptable salt thereof is present at a concentration of between 0.001 and 20% by weight (expressed as linsitinib free base), relative to the total weight of the composition, preferably between 0.01 and 10%, more preferably between 0.1 and 10% by weight, in particular 0.1 %, 0.25%, 0.5%, 0.75%, 1 %, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.50%, 8.75%, 9%, 9.25%, 9.5%, 9.75% or 10%.

Claims

1 . A compound which is an insulin-like growth factor inhibitor or a pharmaceutically acceptable salt thereof for use in the topical treatment of dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer.

2. The compound for use according to claim 1 wherein the compound is linsitinib.

3. The compound for use according to claims 1 or 2 wherein the dermatological disease is selected from acne, actinic keratosis and seborrheic dermatitis.

4. The compound for use according to claims 1 to 3 wherein the dermatological disease is acne.

5. A pharmaceutical composition for topical administration comprising (a) an insulin-like growth factor inhibitor or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier or diluent, for use in treating dermatological diseases selected from acne, psoriasis, actinic keratosis, seborrheic dermatitis and skin cancer.

6. A pharmaceutical composition for use according to claim 5 wherein the insulin-like growth factor inhibitor is linsitinib.

7. A pharmaceutical composition for use according to claims 5 or 6 wherein the

dermatological disease is selected from acne, actinic keratosis and seborrheic dermatitis.

8. A pharmaceutical composition for use according to claims 5 to 7 wherein the

dermatological disease is acne.

9. A pharmaceutical composition for use according to claims 5 to 8, wherein the

composition is a gel, a lotion or a cream.

10. A pharmaceutical composition for use according to claims 5 to 9, wherein the insulinlike growth factor inhibitor or pharmaceutically acceptable salt thereof is present at a concentration of between 0.001 and 20% by weight, expressed as free base, relative to the total weight of the composition.

1 1 . Use of a compound which is an insulin-like growth factor inhibitor or a

pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 5 to 10 in the manufacture of a medicament for the topical treatment of dermatological diseases as defined in any of claims 1 , 3 or 4.

12. Use of a compound according to claim 1 1 wherein the insulin-like growth factor inhibitor is linsitinib.

13. A method of treating dermatological diseases in a patient, which method comprises administering to the patient an insulin-like growth factor inhibitor or a

pharmaceutically acceptable salt thereof, or a composition as defined in any one of claims 5 to 10, wherein the dermatological diseases are as defined in any of claims 1 , 3 or 4.

14. A method according to claim 13 wherein the insulin-like growth factor inhibitor is linsitinib.