The present invention concerns cocrystals of finasteride and a carboxylic acid, a method of their preparation and a pharmaceutical formulation comprising said cocrystals. In addition the invention relates said cocrystals and said formulation for use in the treatment of benign prostatic hyperplasia and androgenetic alopecia.

Finasteride is a 5a-reductase inhibitor and is regarded as a synthetic steroid. Due to its similar structure compared with testosterone, finasteride is reported to irreversibly inhibit 5a-reductase and, thus, prevents testosterone from being converted into dihydro testosterone (DHT). Currently a specific kind of hair follicle is reported to reduce its anagen-phase (growth-phase) when brought into contact with DHT. By preventing the formation of DHT, the growth phase of the hair follicle can be enhanced and the beginning of androgenetic alopecia can be postponed for years. However, this treatment has to be applied continuously since in case the finasteride administration is abandoned, the level of DHT rises and the grown hairs fall out again. Further, finasteride can be used in the treatment of benign prostatic hyperplasia (BPH) also known as enlarged prostate, wherein it eases the symptoms associated with BPH such as difficulty urinating, having to get up during the night to urinate, hesitation at the start of urination and decreased urinary flow.

The IUPAC name of finasteride is (lS,3aS,3bS,5aR,9aR,9bS, l laS)-N-tert-butyl- 9a, 1 la-dimethyl-7-oxo- l,2,3,3a,3b,4,5,5a,6,9b,10, l l-dodecahydroindeno[5,4-f] quinoline- l-carboxamide and the compound is represented by the following chemical Formula (I)

Formula (I) Finasteride for the treatment of alopecia is marketed under the brand name "Propecia" and is administered 1 mg once daily. Further, finasteride is marketed under the brand name "Proscar" and administered 5 mg once daily for the treatment of benign prostatic hyperplasia.

Finasteride is reported to be present in at least three different polymorphic forms. As known in the art, depending on the environmental conditions polymorphic forms can convert into each other. The properties of the corresponding polymorphic forms, such as solubility and/or permeability, can significantly differ. Thus, for regulatory reasons alone it is desirable to have one stable form with known properties.

Finasteride is reported to be neither protonated nor deprotonated with pharmaceutically acceptable acids or bases. Thus, pharmaceutical salts of finasteride are rather unknown. Further, finasteride Form I melts at a rather high temperature of 257°C. Several properties are said to relate to the melting point of an active pharmaceutical ingredient not being in the form of a salt. Usually, the higher the melting point, the lower the dissolution rate, the release and/or permeability. Thus, it might become necessary to further process the active pharmaceutical ingredient, for example by milling/micronizing, to achieve the above-mentioned properties to an acceptable extent.

Further, there are some finasteride solvates known in the art, for example finasteride acetic acid solvate. However, these solvates still seem to be improvable with regard to their properties such as stability and/or dissolution rate.

Thus, it was an object of the present invention to overcome the above-illustrated drawbacks. In particular, it was an object of the invention to provide finasteride in a stable form and having a good dissolution rate. In particular it was an object to provide a stable form of finasteride with a good dissolution rate, wherein the desirable properties of finasteride in its free form, such as good crystallinity and low hygroscopicity, are maintained. Preferably, such properties should be achieved without micronization. Further, finasteride should be provided in a form which can be produced in a simple way and/or which can be advantageously processed into formulations.

The objects of the present invention have been unexpectedly solved by cocrystals comprising finasteride and a specific carboxylic acid and a method for preparing said cocrystals.

The inventors found out that the cocrystals of the present invention unexpectedly allow the enhancement of the dissolution rate of finasteride. In addition, finasteride can be provided in a stable form. Further, the cocrystals show a crystallinity and low hygroscopicity being substantially the same as the ones of finasteride in its free form.

Summary of the Invention

This invention provides cocrystals comprising finasteride and carboxylic acid having 3 to 11 carbon atoms.

In addition a method for the preparation of the cocrystals according to the invention is provided wherein the method comprises the steps of

(i) suspending finasteride and carboxylic acid having 3 to 11 carbon atoms in a solvent,

(ii) allowing the formation of a cocrystal

(iii) isolating the cocrystals according to the present invention.

Further, this invention relates to a pharmaceutical formulation comprising the cocrystals according to the present invention and a pharmaceutical excipient. Finally, a subject of the present invention is the cocrystal or the pharmaceutical formulation of the present invention for use in the treatment of benign prostatic hyperplasia and/or androgenetic alopecia.

Detailed Description of the Invention

A cocrystal can be regarded as a solid being a crystalline single phase material and being composed of two or more different molecular and/or ionic compounds. Preferably, all compounds of the cocrystal are in solid state. Contrary, in case that at least one of the other compound(s) is/are liquid, the corresponding product is reported to be a solvate. Within the teaching of the present invention solvates preferably should not be regarded as cocrystals.

Finasteride is referred to as the compound according to above Formula I.

A carboxylic acid is referred to as a substance bearing at least one carboxy group, which is also referred to as a carboxyl group. A carboxy group is regarded as a group which can be represented by a carbon atom connected by a covalent double bond to one oxygen atom and by a further bond to another oxygen atom further otherwise bonded to a hydrogen atom. The carboxy group can also be referred to as a carboxylic acid functional group when the carbon bonded to the two oxygen atoms is further bonded to a carbon atom.

A carboxylic acid is an organic compound which can be generally represented by the following structure:

wherein R _ca is an aliphatic or aromatic residue.

The carboxylic acid comprised by the cocrystal of the present invention has 3 to 11 carbon atoms. It is preferred that the carboxylic acid having 3 to 11 carbon atom is a solid at 25°C and 1013 mbar. That is to say, the melting point of the carboxylic acid has to be at least 25 °C at 1013 mbar. The melting temperature is defined as the temperature at which a substance converts from its solid state to a liquid state. The melting temperature can for example be determined by DSC (differential scanning calorimetry).

An aromatic residue includes at least one ring system predominately containing carbon, nitrogen, sulphur or oxygen atoms, wherein said ring system comprises, according to the Hiickel-Rule, a number of 4n+2 (n=0,l ,2,...) delocalized electrons in conjugated double bonds, free electron pairs or unoccupied p-orbitals. In a preferred embodiment the aromatic residue can be substituted with one or more substituents.

Substituents can preferably be selected independently from one or more of the following substituents: alkyl groups with 1 to 4 carbon atoms, halogen, nitro, nitrile, carboxylic group, carboxylic esters and carboxylic amide, methoxy and ethoxy.

Examples for aromatic residues are phenyl and tolyl.

More preferably, the carboxylic acid can be a carboxylic acid having a substituted or non-substituted aliphatic residue, i.e. R _ca is an aliphatic residue and the carboxylic acid wherein the corresponding carboxylic acid can be referred to as an aliphatic carboxylic acid An aliphatic residue can be a saturated residue which is joined by single bonds or an unsaturated residue joined by double bonds or triple bonds. The aliphatic residue can have a linear, branched or cyclic carbon skeleton and the carbon atom might be replaced by a heteroatom such as oxygen, sulfur or nitrogen. The aliphatic residue might be substituted by one or more substituent(s) at any position, i.e. the carbon skeleton can be bound to an atom or a group being different from hydrogen.

Examples of substituents are halogen, such as fluoride (-F), chloride (-C1), bromide (-Br) and iodide (-1), hydroxy (-OH), alkoxy, such as methoxy (-OCH ₃ ) and ethoxy -OC ₂ H ₅ , cyano (CN), mercapto (-SH), carboxylic acid (-COOH), carboxylic esters, such as carboxylic methyl ester (-COOCH ₃ ), carboxylic ethyl ester (-COOC ₂ H ₅ ), and carboxamides, such as carboxamide (-CONH ₂ ), methyl- carboxamide (-CONHCH ₃ ), dimethylcarboxamide (-CON(CH ₃ ) ₂ ).

Examples for aliphatic carboxylic acid suitable for the formation of cocrystals can be malonic acid, tartaric acid and hexanoic acid (caproic acid).

In a more preferred embodiment the carboxylic acid can preferably be a carboxylic acid having a substituted or non-substituted aromatic residue, i.e. the carboxylic acid can be referred to as an aromatic carboxylic acid.

An aromatic residue includes at least one ring system predominately containing carbon atoms, wherein said ring system comprises, according to the Hiickel-Rule, a number of 4n+2 (n=0,l ,2,...) delocalized electrons in conjugated double bonds, free electron-pairs or unoccupied p-orbitals. Apart from carbon atoms the ring system can further comprise nitrogen, sulphur and/or oxygen. As far as the possible substituents are concerned the same applies as described above with regard to substituents of the aliphatic residues.

Examples of substituents for aromatic residues are alkyl, such as methyl (-CH ₃ ), ethyl (-C ₂ H ₅ ), isopropyl (-CH(CH ) ₂ ) and the substituents as mentioned above with regard to substituents of the aliphatic residues, preferably methyl, methoxy and hydroxy, in particular hydroxy.

Examples for aromatic residues are phenyl, tolyl, naphthyl, indolyl, indeneyl, hydroxyphenyl, dihydroxyphenyl. Preferred are phenyl, hydroxyphenyl and dihydroxyphenyl, in particular hydroxyphenyl and dihydroxyphenyl.

In a particularly preferred embodiment of the invention the carboxylic acid having 3 to 11 carbon atoms is 3-hydroxy benzoic acid. In an alternatively particularly preferred embodiment of the invention the carboxylic acid having 3 to 11 carbon atoms is 2,4-dihydroxy benzoic acid.

It is further preferred that the cocrystals of the present invention comprise finasteride and the carboxylic acid in a molecular ratio of 2.0 : 1.0 to 1.0 : 2.0, preferably 1.50 : 1 to 1 : 1.50, more preferably 1.30 : 1 to 1 : 1.30, especially 1.15 : 1 to 1 : 1.15, in particular 1.05 : 1 to 1 : 1.05. In an especially preferred embodiment it is preferred that the cocrystal of the present invention comprises finasteride and the carboxylic acid in a molecular ratio of 1 : 1. A cocrystal of the present invention can be characterized by analytical data/methods such as powder X-ray diffraction. As is known in the art, any analytical data may be subject to small variations, e.g. in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity.

Nonetheless, the skilled person would readily be capable of comparing analytical data, such as the signal in a powder X-ray diffractogram, with corresponding analytical data generated for an unknown crystal form and confirm whether the two sets of data characterize the same crystal or cocrystal, respectively.

A cocrystal may be referred to herein as being characterized by data selected from two or more different data groupings. For example, the skilled person may characterize a cocrystal form using a group of five characteristic powder XRD peaks and supplement that characterization with one or more additional features observed in the powder X-ray diffractogram, e.g. an additional peak, a characteristic peak shape, a peak intensity or even the absence of a peak at some position in the powder XRD pattern. Alternatively, the skilled person may in some instances characterize a crystal form using a group of five characteristic powder XRD peaks and supplement that characterization with one or more additional feature(s) observed using another analytical method, such as NMR or DSC thermogram.

Unless indicated otherwise, XRPD peaks are recorded as described in the experimental section. Further, unless indicated otherwise, XRPD peaks are reported as degrees 2 theta values with a standard error of + 0.2 degrees 2 theta. A preferred embodiment of the present invention is a cocrystal comprising finasteride and 3-hydroxy benzoic acid having characteristic X-ray powder diffraction peaks at 8.7, 15.9, 18.3, 19.3 and 24.35 degrees 2Θ (+ 0.2 degrees 2Θ).

In a preferred embodiment the cocrystal comprising finasteride and 3-hydroxy benzoic acid can be characterized by one or more further XRPD diffraction peak(s) at 7.1, 12.0, 15.6, 16.4, 17.59 and/or 20.9 degrees 2Θ (+ 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention the cocrystal comprising finasteride and 3-hydroxy benzoic acid can be characterized by the XRPD diffraction as shown in Figure 1.

A preferred embodiment of the present invention is a cocrystal comprising finasteride and 2,4-dihydroxy benzoic acid having characteristic X-ray powder diffraction peaks at 10.7, 14.8, 16.3, 16.9, and 20.4 degrees 2Θ (+ 0.2 degrees 2Θ). In a preferred embodiment the cocrystal comprising finasteride and 2,4-dihydroxy benzoic acid can be characterized by one or more further XRPD diffraction peak(s) at 14.2, 18.3 and/or 23.3 degrees 2Θ (+ 0.2 degrees 2Θ). In an alternatively further preferred embodiment of the present invention the cocrystal comprising finasteride and 2,4-dihydroxy benzoic acid can be characterized by the XRPD diffraction as shown in Figure 7.

Further the present invention relates to a pharmaceutical formulation comprising or being prepared by using the cocrystals of the present invention.

In a preferred embodiment the pharmaceutical formulation can be present in a liquid form. Examples of liquid pharmaceutical formulations can be a solution or an emulsion.

In a preferred embodiment of the invention the pharmaceutical formulation is in form of a solution. The solution can preferably be prepared by dissolving, preferably completely dissolving, the cocrystals of the present invention in a solvent or a mixture of solvents. Suitable solvents are for example water, aliphatic mono- or divalent or trivalent alcohols having 2 to 6 carbon atoms or mixtures thereof. Suitable alcohols are for example ethanol, propanol, isopropanol, 1,2-propandiol or 1,3-propandiol, preferably ethanol and isopropanol. Ethanol is particularly preferred. The volume ratio of water to alcohol can preferably be between 8: 1 and 1 :8, more preferably between 4: 1 and 1 :4, in particular between 2: 1 and 1 : 1.5. This applies especially in regard with a mixture of water and ethanol. In a preferred embodiment the formulation of the present invention, preferably in form of a solution can comprise one or more additives. The formulation, preferably in form of a solution, can comprise additive(s) in an amount of 0.01 wt.% to 40 wt.%, preferably 0.01 wt.% to 35 wt.%, more preferably 0.1 wt.% to 30 wt.%, in particular 0.5 wt.% to 20 wt.%.

Additives are for example active pharmaceutical ingredients, conditioning agents, preservatives, dyes, perfume substances, care substances, pH-regulators and penetration enhancers. Each single additive can be present in an amount of 0.001 wt.% to 10 wt.%, in particular 0.01 wt.% to 5 wt.%.

The term "active pharmaceutical ingredients" means that besides finasteride a further substance having a pharmacological effect is contained in the formulation. Active substances can preferably be selected from the extracts of plants, synthetically produced substances corresponding to extracts and analogous derivatives thereof, vitamins as well as substances that influence the skin and mixture thereof.

Extracts of plants are, for example, those of ylang ylang, pine needles, cypress, thyme, mint, limes, oranges, grapefruit, mandarin oranges, juniper, valerian, lemon balm, eucalyptus, thyme, palmarosa, rosemary, lavender, rosewood, lemon grass, spruce needles, pine needles, ginger, currant, linden blossom, calendula, magnolia, algae, aloe vera, pineapple, guava, echinacea, ivy leaf, birch leaf, calendula, hibiscus, burdock root, witch hazel, hydrocotylidis herba, quince, water lily, cinnamon, or mixtures thereof.

Suitable vitamins are, for example, vitamins A, B, E, C or suitable derivatives thereof, such as esters, e.g. palmitate, acetate or phosphate.

Other suitable active substances that influence the skin are minerals and trace elements such as copper, zinc, magnesium or their derivatives, particularly salts, such as Zincidone ^® (zinc PCA), zinc gluconate or copper gluconate.

Further, astringent and sebum-regulating substances, such as hydroxydecanoic acid, pyridoxine, niacinamide, glycerin, caproyl collagen amino acids, sebacic acid, cinnamonum zeylanicum, or cooling/soothing active substances such as menthyl lactate or sodium hyaluronate, wheat germ extract, saccharomyces cerevisiae extract can be preferably be used.

Furthermore, active substances can preferably be active substances that promote blood circulation. Examples are nicotinic acid derivatives such as methyl nicotinate or tocopheryl nicotinate, alphahydroxy and betahydroxy acids and their derivatives.

Furthermore, substances having an antioxidant effect or a cell-protection effect, such as polyphenols, flavonoids, or isoflavones. Other active substances can preferably be UV filters such as UVB, UVA, and broadband filters, as they are generally known, e.g. cinnamic acid esters, salicylates, or inorganic UV filters. Further, active substances that can preferably be used are biotin, allantoin, panthenol, niacinamide, urea and inositol. Depending on the purpose of use, active substances that are soluble in oil or water can also be used or combined for cosmetic and/or dermatological/pharmaceutical purposes.

Dermatologically/pharmaceutically active substances can be, in particular, anti- microbially active substances (antibiotics; antimycotics, antiviral substances), hormones or hormonally active substances such as sex hormones, wound cleansing agents, analgesics, cytokins, cytostatics, anti-acne agents, immune suppressives, pigmentation regulators, agents against photodermatoses, or the vasoactive/antiphlogistic substances named above, or combinations thereof. In contrast, strongly oxidative substances such as hydrogen peroxide are preferably not used.

Examples of conditioning agents can be acrylamides; polysaccharide such as xanthan gum; cellulose and its derivatives such as methyl cellulose, ethyl cellulose hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose; carmellose-Na; starch and mixtures thereof.

Furthermore, complexing agents such as EDTA, compounds such as citric acid, soda lye, solvents such as propylene glycol or alcohols, salts such as NaCl, starch or starch derivatives, or mixtures thereof, can be contained as conditioning agents. Other conditioning agents are monoalkyl and dialkyl phosphates or glyceryl stearate.

A preservative is a substance that can be added to the emulsion of the present invention to protect the emulsion and its ingredients from disadvantageous reactions such as oxidation or damage caused by microorganisms. A preservative can be a natural or synthetic substance.

Example of suitable preservatives are imidazolidinyl urea, glutaraldehyde, formaldehyde, 2-phenoxyethanol, l-phenoxy-propan-2ol, undec-10-enoic acid iodo- propynyl butyl carbamate, DMDM hydantoin, phenoxyethanol and other commonly used preservatives, such as sorbic acid and dehydracetic acid, and their salts, methyl dibromoglutarononitrile or combinations thereof; or other acids such as benzoic acid, propionic acid or salicylic acid, or benzyl alcohol or esters such as p-hydroxy benzoic acid esters, e.g. methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, or climbazol or suitable combinations of the stated substances. Dyes can preferably be naturally occurring and synthetically produced colouring agents. Examples are Acid Blue 7, disodium salt of l-(3-sulfo- l-phenylazo)-2- naphthol-6-sulfonic acid (Food Orange 2), disodium salt of l-(4- sulfo-l-phenylazo)-2- naphthol-6-sulfonic acid (Food Orange 3), Acid Orange 10 (Food Orange 4) or derivatives thereof, trisodium salt of l-(4-sulfo-l-naphthylazo)- 2-naphthol-6,8- disulfonic acid (Acid Red), trisodium salt of l-(4-sulfo-l-naphthyl- azo)-2-naphthol- 3,6-disulfonic acid (Acid Red 27), tetrasodium salt of l-(4-sulfo-l- naphthylazo)-2- naphthol-3,6,8-disulfonic acid (Acid Red 41), quinophthalonedisul- fonic acid or suited combinations thereof. Suitable perfume substances are, for example, the ether oils named under active substances or commercially available perfume mixtures.

Particularly suitable care substances are phytosterols (essentially mixtures of β- sitosterol, campesterol, and stigmasterol or ethoxylated derivatives thereof), such as those from canola oil. Also lecithin (e.g. soybean lecithin), phosphatidyl choline, phosphatidyl serine or diethanolamine, or mixtures thereof with the aforementioned phytosterols can preferably be used.

Furthermore, silicone oils such as dimethicones or silicone (co)polymers, e.g. di- cyclomethicone or di vinyl dimethicone/dimethicone copolymers, CI 2- 13 pareth-3/C12- 13 pareth-23) can preferably be used.

Other care substances can be moisturizing agents such as glycerin, propylene glycol, or polyethylene glycols, propylene glycol, butylene glycol, sorbitol, or polymers, e.g. polyquaternium types such as polyquaternium 39, collagen or its hydrolysates, amino acids, urea, polysaccharide (biosaccharide gum 1), glucosaminoglycanes, e.g. hyaluronic acid or sulfated glucosaminoglycanes such as chondroitin sulfate, dermatane sulfate, keratane sulfate, heparane sulfate or mixtures thereof. Substances to adjust the pH-value of the emulsion can be referred to as pH regulators. A pH regulator can preferably selected from indifferent und less irritated salts such as calcium chloride, barium chloride; or from acids, especially organic acids, such as acetic acid, citric acid, salicylic acid, lactic acid and other alpha hydroxy acids as well as inorganic acids such HC1, from buffering substances such as phosphate buffer, lactate buffer or citric buffer, or from salts such as NaOH and KOH and from other bases. These regulators are used in amounts sufficient to provide the desired pH value of the composition of the invention. In a preferred embodiment the pH value of the claimed formulation is between 3 and 7, and more preferably between 4.5 and 5.5.

Penetration enhancers can be chosen amongst polyvalent alcohol(s) and derivatives thereof preferably esters, such as glycerol alone or with its esters or suitable combinations thereof; mono- or polyvalent glycols or derivatives thereof, such as propylene glycol, ethoxydiglycol, preferably Transcutol ^® , or azacycloheptanone, preferably 1-dodecyl azacycloheptan-2-one as in Azone ^® .

In a preferred embodiment the pharmaceutical formulation of the present invention may be contained in and released from devices commonly used for solutions or emulsions. Discharge and application in/with air leads to the finely distributed product on the skin with fine air bubbles or in the form of a foam as described above. In a preferred embodiment the pharmaceutical formulation can preferably be present as foamable composition which can be applied in form of a foam. To this end, it may e.g. be contained in a foam dispenser with a suitable pumping mechanism or together with a suitable propellant in an aerosol device. In this case, the product is obtained directly as a foam and is not post-foaming as described in the prior art discussed above. The aerosol device may comprise a compressed gas container containing foaming agent, a distribution device with a valve, spray nozzle as well as the composition.

Commercially available gasses or mixtures of gasses, like C0 ₂ , N ₂ , N ₂ 0, or mixtures thereof, like C0 ₂ :N ₂ 0 1: 1 to 0.5: 1, are suitable as propellant. Particularly preferred are gasses such as butane/propane/isobutane or mixtures thereof as commonly used for aerosols, e.g. 3-5:20-25:65-73 as available e.g. as Drivosol ^® (35a). The gas may be present in compressed form in amounts of 2 to 20%, preferably 3- 13%, in particular 4-8%, based on the finished product. These amounts may, however, be varied depending on the total amount of the product and/or the size of the container. Suitable devices for administering the inventive composition as aerosol as well as for application without propellant are known. To this end, e.g. mechanical foam dispensers working according to the principle of air pumps may be used, such as Squeeze Foamer (F2 Finger Pump Foamer, commercially available), Rieke Dispensing by Englass or foamers made by Airspray, wherein the finished emulsion is filled in in a suitable manner. Preferably, the composition is provided in common dispensers. In particular it is dispensed from a foam dispenser or a aerosol container filled with a propellant. In a preferred embodiment of the invention the pharmaceutical formulation is in form of an emulsion.

The emulsion can preferably be prepared by emulsifying, preferably completely emulsifying, the cocrystal of the present invention in a solvent or a mixture of solvents in the presence of an emulsifier.

Suitable solvents for emulsifying can be preferably the same as described above with regard to the solution. As emulsifier generally emulsifiers known in the art can be used. Examples of emulsifiers are alkylglycosides (glucose- or alkyl-glucose-) ethers of saturated, partially unsaturated or unsaturated alcohols of C8-C20-fatty acids such as decyl-, stearyl-, palmityl-, lauryl-, oleyl, caprylic, caprinic, myristyl acid, CioCu- glucosidic ethers such as decylglucoside, which is commercially available under the trade name Plantacare ^® 2000 UP, Plantacare ^® 818 UP, sugar esters, such as esters of C8-C20--fatty acids and sugars like glucose, saccharose, alkyl glucose such as methyl glucose.

In an embodiment alkyl glucosides can be selected from sugar (glucose- or alkyl - glucose-) ethers of saturated, partially unsaturated or unsaturated, C8-C20--fatty alcohols (such as decyl-, stearyl-, palmityl-, lauryl-, oleyl alcohol and the like). A further group of emulsifiers according to another embodiment of the invention may be selected from hydrated lecithins, such as hydrated phosphatidylcholine, Probiol N03031. Yet, in another embodiment emulsifiers can be selected from one or more of lecithins such as phosphatidylcholin or phosphatidylserin to enhance good skin compatibility and penetration enhancing effect. As far as the additives optionally contained in the emulsion are concerned substantially the same as described above applies. Further, the emulsion can be contained in the same container as well as applied therefrom for example as a foam as described above.

In an alternatively preferred embodiment the pharmaceutical formulation of the present invention (comprising the cocrystal of the present invention) can be in form of a semi-solid composition. As used herein, the term semi-solid composition means a preparation which is not liquid, but which contains one or more liquid components. Preferably, the major liquid component is water. Optionally, the semi-solid composition may further comprise other liquid components, such as pharmaceutically acceptable organic solvents, cosolvents, viscosity regulation polymers and emulsifiers. Examples of such other liquid components are ethanol, glycerol, propylene glycol, and polyethylene glycol. Such water-miscible organic solvents may be incorporated for example in order to solubilize a poorly water-soluble ingredient, such as a lipophilic substance. The term semi-solid composition includes gels, creams and ointments which can be regarded as an inert carrier into which the cocrystals of the present invention may be incorporated. An ointment in which the active ingredient has not been incorporated yet can be regarded as ointment base. The same applies to a gel or a cream.

An example for an ointment base can be petrolatum, optionally stiffened with wax. Another type of ointment base contains lanolin, which can absorb water and aqueous emulsions or dispersions, such that a "water-in-oil type" emulsion is formed. Water-soluble ointment bases are often derived from polymers of ethylene glycol (PEGS); these will absorb water and ingredients dissolved in the water.

In comparison to a liquid composition these semi-solid formulations are not freely flowing. The viscosity of semi-solid compositions may be controlled by a viscosity enhancing polymer or by a combination of such polymers, like natural gums like xanthan gum, cellulose derivates like cellulose ester or ether, lecithin poloxamer, polyethylene glycols, polymethacrylates, polyvinyl alcohol, polyvinyl pyrrolidone, sodium starch glycolate starch, pregelatinised starch or derivatives thereof. In an alternatively preferred embodiment of the invention the pharmaceutical formulation comprising the cocrystal of the present invention can be in form of an oral dosage form such as a peroral tablet, a capsule, an effervescent tablet or an orally disintegrating tablet.

Further, the present invention relates to the cocrystal of the present invention or the pharmaceutical formulation of the present invention for use in the treatment of benign prostatic hyperplasia or androgenetic alopecia. In a preferred embodiment the pharmaceutical formulation of the present invention can be used in a topical treatment, in particular a topical treatment of androgenetic alopecia. This preferably applies in cases in which the pharmaceutical formulation is present in liquid form, such as a solution or emulsion, or in semi-solid form, such as an ointment, cream or gel.

In an alternative embodiment the pharmaceutical formulation of the present invention can be used in a parenteral or oral treatment, in particular a systemic treatment of benign prostatic hyperplasia or androgenetic alopecia. More preferred is a systemic treatment of benign prostatic hyperplasia. This preferably applies in cases in which the pharmaceutical formulation is present in a solid form, such as a tablet.

A further subject of the invention is the method for preparing the cocrystal of the invention comprising the steps of

(i) suspending finasteride and carboxylic acid having 3 to 11 carbon atoms in a solvent,

(ii) allowing the formation of a cocrystal, and

(iii) isolating the cocrystals of the present invention.

In step (i) finasteride and carboxylic acid having 3 to 11 carbon atoms are suspended in a solvent. In an alternatively preferred embodiment of step (i) finasteride and carboxylic acid having 3 to 1 1 carbon atoms can be dissolved, preferably completely dissolved, in solvent. Finasteride can be finasteride according to Formula (I) as shown above. Further, in line with the method of the present invention finasteride also refers to any polymorphic form of finasteride as well as to solvates of finasteride. As far as the carboxylic acid having 3 to 1 1 carbon atoms is concerned the same as described above applies.

A solvent is defined herein as a liquid substance being able to at least partially dissolve a solid substance, wherein in the present case finasteride and the carboxylic acid having 3 to 11 carbon atoms are considered both as solid substances. The solvent can preferably be liquid at room temperature and normal pressure, i.e. at 23°C and 1013 mbar.

In a preferred embodiment the solvent can be a liquid substance selected from water, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl- l- propanol, 2-methyl-2-propanol, ketones such as acetone, tert. butyl methylketone, methyl ethylketone, ethers such as diethylether, tetrahydrofuran and dioxane, dimethyl formamide, acetonitrile, carboxylic acid esters such as ethyl acetate and isopropyl acetate and mixtures thereof. Preferred solvents are methanol, ethanol, acetonitrile, ethyl acetate and isopropyl acetate and mixtures thereof, in particular methanol.

In a preferred embodiment of the invention the weight ratio of solvent to the sum of finasteride and carboxylic acid having 3 to 11 carbon atoms is from 30 : 1 to 1 : 5, more preferably from 20 : 1 to 1 : 4, even more preferably from 10 : 1 to 1 : 3, in particular from 2.5 : 1 to 1 : 2.5.

Step (i) can be preferably carried out under mechanical treatment such as stirring or ultrasonic treatment. Stirring can be preferably carried out at a stirring speed of 100 to 600 rpm (rotations per minute). Generally, ultrasonic treatment can be carried out by immersing the mixture of step a) into an ultrasonic device, for example an ultrasonic bath.

Further, further step (i) can preferably be carried out at an elevated temperature. An elevated temperature as used herein can be a temperature which is above room temperature and below the boiling point of the solvent at standard pressure. Room temperature and a temperature of 23 °C can be used interchangeably. In a preferred embodiment step (i) can be carried out at a temperature between 30°C and 60°C, preferably between 35°C and 55°C, in particular between 40°C and 50 °C.

In step (ii) the formation of a cocrystal is allowed. It is preferred that the start of the formation of a cocrystal can be recognized by the appearance of a precipitate or by the formation of a slurry.

In step (ii) a solvent can preferably be added to the mixture from step (i). The solvent added to the mixture of step (ii) can be the same solvent or a different solvent as the one used in step (i). Preferably, the solvent added in step (ii) is different from the solvent used in step (i). Examples of solvents that can be added in step (ii) are ketones such as acetone, tert. butyl methylketone, methyl ethylketone, carboxylic acid esters such as ethyl acetate and isopropyl acetate, and mixtures thereof, preferably carboxylic acid esters, in particular isopropyl acetate.

The amount of solvent added in step (ii) can preferably be from one-fifth to the five times, preferably from one-third to the three times, in particular from halve to the twice the amount of the solvent used in step (i). Especially preferred the amount of solvent added in step (ii) and the amount of the solvent used in step (i) can be about the same.

Step (ii) can be preferably carried out at a temperature of 0°C to 23°C, preferably 5°C to 20°C, more preferably 10°C to 15°C. Thus, in case that step (i) is carried out at an elevated temperature, the mixture of step (i) can be cooled, for example, in a substep of step (ii) the mixture from step (i) can preferably be cooled to the temperature at which step (ii) can preferably be carried out. In a preferred embodiment in a first substep of step (ii) the mixture from step (i) can preferably be cooled to a temperature of 0 to 23°C, for example by ice-bath cooling. Further, step (ii) can preferably include a seeding of a few crystals of finasteride, or carboxylic acid having 3 to 1 1 carbon atoms or the corresponding cocrystal.

Step (ii) can preferably be carried out under mechanical treatment such as stirring. In a preferred embodiment step (ii) can be carried until out a slurry is formed or a precipitate occurs. The duration of step (ii) can be preferably from 2 minutes to 240 minutes, preferably from 5 minutes to 60 minutes, in particular from 10 minutes to 30 minutes.

In step (iii) the cocrystals of the present invention can preferably be isolated. The isolation of the cocrystal of the present invention can preferably comprise separating the solid from the liquid of the mixture from step (ii). In a preferred embodiment step (iii) can comprise filtering the mixture from step (ii). Filtering can for example be carried out through a glass sinter filter funnel or over filter paper. Further filtering is preferably carried out under suction, such as suction from a water jet pump or a rotary vane pump. Filtering can preferably be conducted under protection of an inert gas such as nitrogen.

After filtering in a preferred embodiment step (iii) can comprise washing the obtained solid with a solvent. Examples of solvents that are suitable for washing the solid can be the ketones such as acetone, tert. butyl methylketone, methyl ethylketone, carboxylic acid esters such as ethyl acetate and isopropyl acetate and mixtures thereof, preferably carboxylic acid esters, in particular isopropyl acetate.

The resulting solid, the cocrystal of the present invention, can preferably be dried. Drying can preferably be carried out under reduced pressure of 0.5 to 200 mbar, in particular 10 to 150 mbar. Drying can be preferably carried out at a temperature of 20°C to 90°C, more preferably 30°C to 80°C. Drying can for example be carried out in a drying chamber or compartment dryer. Drying can also be conducted by applying a combination of the above drying condition, for example drying in a drying chamber at 40°C under 20 mbar.

Drying can preferably be carried out until weight stability of the corresponding cocrystal of the present invention is obtained. Alternatively drying can last 2 to 24 hours, preferably 6 to 12 hours.

As the final product the cocrystal of the present invention, preferably in anhydrous or unsolvated form is obtained.

The invention should illustrated by the following examples. Further, the following analytical methods have been used. Analytical methods:

1. X-Ray Powder Diffraction (XRPD) X-ray powder diffraction patterns were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), θ - 2Θ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The instrument is performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analyzed and presented using Diffrac Plus EVA v 15.0.0.0.

Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was gently packed into a cavity cut into polished, zero- background (510) silicon wafer. The sample was rotated in its own plane during analysis. The data was collected using two separate settings, one for the screening samples and the other for the standard data collection.

The details of the data collection for standard method (7 minute method) are: · Angular range: 2 to 42° 2Θ

Step size: 0.05° 2Θ

• Collection time: 0.5 s/step

2. Proton Nuclear Magnetic Resonance (1H-NMR)

NMR spectra were collected on a Bruker 400MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin vl .3 using the standard Bruker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone. Samples were prepared in DMSO-<i<5, unless otherwise stated. Off-line analysis was carried out using ACD Spectrus Processor 2014.

3. Differential Scanning Calorimetry (DSC)

DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to the temperature just below the samples degradation point, determined from its TGA analysis. A purge of dry nitrogen at 50 ml/min was maintained over the sample.

The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.

4. Thermo-Gravimetric Analysis (TGA)

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. The instrument was temperature calibrated using certified Alumel and Nickel. Typically 5- 10 mg of each sample were loaded onto a pre- tared aluminium DSC pan and heated at 10°C/min from ambient temperature to 350°C. A nitrogen purge at 60 ml/min was maintained over the sample. The instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.

5. Polarised Light Microscopy (PLM)

Samples were studied on a Leica LM/DM polarized light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil and covered with a glass slip, the individual particles being separated as well as possible. The sample was viewed with appropriate magnification and partially polarized light, coupled to a λ false-color filter. 6. Chemical Purity Determination by HPLC

Purity analysis was performed on an Agilent HPl lOO series system equipped with a diode array detector and using ChemStation software vB.04.03 using the method detailed below: Table 1 : HPLC method for chemical purity determinations

7. Gravimetric Vapour Sorption (GVS)

Sorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software vl .0.1.2 (or v 1.0.1.3). The sample temperature was maintained at 25°C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100% RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy +0.005 mg). Typically 5- 20 mg of sample were placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25°C (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans giving 1 complete cycle). The standard isotherm was performed at 25 °C at 10% RH intervals over a 0-90% RH range. Data analysis was carried out using Microsoft Excel using DVS Analysis Suite v6.2 (or 6.1 or 6.0). Table 2: Method for SMS DVS intrinsic experiments

The sample was recovered after completion of the isotherm and re-analyzed by XRPD.

8. Thermodynamic Solubility in Various Solvents

Aqueous solubility was determined by suspending sufficient compound for a maximum final concentration of ca. 40 mg/ml of the free form. Suspensions were equilibrated at 25°C / 750 rpm for 24 hrs after which the pH-values of the saturated solutions were measured and the appearance of the sample solutions noted. Samples were then filtered through the 96 well-block (Glass 'C fibre filter, particle retention size 1.2 μιη) before injection for quantitation by HPLC.

Solubility in various solvents was performed by suspending the sample at a maximum final concentration of > 50 mg/ml of the free form. Suspensions were equilibrated at 25°C / 750 rpm for 24 hrs and the appearance of the sample solutions was then noted. Samples were then centrifuged at 13400 rpm for 10 mins, and the neat supernatant diluted as appropriate with IPA before injection for quantitation by HPLC.

Quantitation was by HPLC with reference to a standard solution of approximately 0.15 mg/ml in 1 : 1 ACN/H20. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. Table 3: Method for solubility measurements

Analysis was performed on Agilent HPl lOO series system equipped with a diode array detector and using ChemStation software vB.04.03.

Examples

Example 1: Cocrystal of Finasteride and 3-Hydroxybenzoic acid

1.1. Test: To a solution of anhydrous finasteride (100 mg; 0.268 mmol) in methanol (0.5 ml) 3-hydroxybenzoic acid (37 mg; 0.268 mmol) was added. The mixture was stirred at 50°C for 15 minutes and then was cooled to 5°C at 0.1°C/min and left overnight. The clear solution was placed for slow evaporation, followed by the addition of isopropyl acetate (0.08 ml) and stirred for 10 minutes at 23°C, wherein a thick white suspension occurred. The suspension was centrifuged and the liquid discarded. The white solid was dried at 23°C overnight. 1.2. Scale-up: Finasteride (2.3 g; 6.2 mmol) and 3-hydroxybenzoic acid (0.86 g; 6.2 mmol) were dissolved in methanol (2 ml) under stirring at 50°C resulting in a clear solution. Under stirring, isopropyl acetate (2ml) was added and the almost clear solution was left at ambient temperature overnight, resulting in a thick white precipitate. The sample was left for maturation (eight hours heat/cool cycle between 23°C/50°C) for 48 hours. To the samples seeds of the corresponding cocrystal were added and the mixture was left at room temperature under stirring. The mixture was filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at 40°C in vacuum oven (20 mbar) to yield 1.88 g (59.5%) of finasteride - 3-hydroxybenzoic acid cocrystal.

Analysis of the product of Examples 1.1 and 1.2 XRPD as shown in Figure 1

NMR-data:

¾-NMR (400 MHz, DMSO-d6), 0[ppm j : 0.51-0.60 (m, Ml ). 0.80-0.88 (m, 3H), 0.90-1.09 (m, 3H), 1.16(br, dd, .7=11 ,81, 5.75Hz, lH), 1.24 (s, 9H), 1.27- 1.46 (m, 4H), 1.46-1.65 (m, 4H), 1.68-1.80 (m, 2H), 1.92-2.06 (m, 1H), 2.09-2.20 (m, 1H), 3.12-3.22 (m, I H ). 3.27-3.40 (m, 2H), 5.56-5.66 (m, 1H), 6.78-6.85 (m, 1 H ). 6.86- 6.93 (m, IH), 6.95-7.02 (m, IH), 7.24-7.39 (m, 11 ). 7.41 (d, 7= 1 . 2 Hz, IH), 9.53- 9.96 (m, IH), 12.63- 13.00 (m, IH) Figure 2 shows PLM images of the cocrystal comprising finasteride and 3-hydroxybenzoic acid.

Figure 3 shows the characteristics in the DSC and TGA analysis. As can be seen from Figure 3 the melting point of the cocrystal comprising finasteride and 3-hydroxybenzoic acid (about 172°C) is advantageously lower than the melting point of finasteride (257°C).

Figure 4 GVS-isotherms

The isotherms show the reproducibility of the low hygroscopicity, for example a mass change of about 1% at 80% relative humidity in every cycle.

As can be seen from Figure 5, the XRPD of the cocrystal comprising finasteride and 3-hydroxybenzoic acid after storing at 25°C and 97% relative humidity shows substantially the same peaks as the one of Figure 1. Thus, the cocrystal is stable under these conditions.

As can be seen from Figure 6, the cocrystal comprising finasteride and 3-hydroxybenzoic acid is present in pure form and contains only finasteride and the conformer, 3-hydroxybenzoic acid, as components.

Example 2: Cocrystal of Finasteride and 2,4-Diydroxybenzoic Acid

2.1. Test: To a solution of anhydrous finasteride (100 mg; 0.268 mmol) in methanol (0.5 ml) 2,4-dihydroxybenzoic acid (41 mg; 0.268 mmol) was added. The mixture was stirred at 50°C for 15 minutes and then was cooled to 5°C at 0.1°C/min and left overnight. The clear solution was placed for slow evaporation, followed by the addition of isopropyl acetate (0.08 ml) and stirred for 10 minutes at 23°C, wherein a thick white suspension occurred. The suspension was centrifuged and the liquid discarded. The white solid was dried at 23°C overnight.

2.2. Scale-up: Finasteride (0.5 g, 1.3 mmol) and 2,4-dihydroxybenzoic acid (0.21 g; 1.3 mmol) were added to methanol (0.45 ml) under stirring at 23°C resulting in a clear solution. After cooling to 23°C under stirring, a white slurry was formed. Further, under stirring, isopropyl acetate (0.45 ml) was added and the mixture was filtered under suction, washed with cold isopropyl acetate (0.6 ml) and dried at 23°C in vacuum oven (20 mbar) to yield finasteride 2,4-dihydroxybenzoic acid cocrystal.

2.3. Scale-up: Finasteride (2.3 g; 6.2 mmol) and 2,4-dihydroxybenzoic acid (0.95 g; 6.2 mmol) were added to methanol (2 ml) under stirring at 23°C, wherein a thick white suspension was obtained. Under further stirring, isopropyl acetate (2 ml) was added and the mixture was filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at 23°C in a vacuum oven (20 mbar) to yield 2.05 g (63%) of finasteride 2,4-dihydroxybenzoic acid cocrystal.

Analysis of the product of Examples 2.1 to 2.3 Table 5: XRPD as shown in Figure 7

NMR-data:

Ή-NMR (400 MHz, DMSO-D6), dfppm j : 0.51 -0.60 (m, 3H), 0.80-0.87 (m, Ml ). 0.87- 1.19 (m, 4H), 1.21- 1.26 (m, 91 1 ). 1.27- 1.65 (m, 8H), 1.67- 1.79 (m, 2H), 1.92- 2.06 (m, I H ). 2.08-2.20 (m, 1H), 2.79-2.80 (m, I H), 3.17 (dd, .7= 1 2. 1 , 3.41 Hz, 1H), 5.56-5.65 (m, 1 1 1 ). 6.21 -6.28 (m, 1H), 6.30-6.38 (m, 1 H i. 6.78-6.85 (m, 1H), 6.86-6.93 (m, 1H), 7.37-7.45 (m, 1H), 7.55-7.66 (m, 1H), 7.61 (d, .7=8.72 Hz, 1H), 10.34 (s, 1H)

Figure 8 shows PLM images of the cocrystal comprising finasteride and 2,4-dihydroxybenzoic acid.

Figure 9 shows the characteristics in the DSC and TGA analysis. As can be seen from Figure 1 1 the melting point of the cocrystal comprising finasteride and 2,4-dihydroxybenzoic acid (about 216°C) is advantageously lower than the melting point of finasteride (257°C).

Figure 10 shows GVS isotherms

The isotherms show the reproducibility of the low hygroscopicity, for example a mass change of below 0.1 % at 80% relative humidity in every cycle.

As can be seen from Figure 1 1 , the XRPD of the cocrystal comprising finasteride and 2,4-dihydroxybenzoic acid after storage at 25 °C and 97% relative humidity shows substantially the same peaks as the one of Figure 7. Thus, the cocrystal is stable under these conditions.

As can be seen from Figure 12, the cocrystal comprising finasteride and 2,4-dihydroxybenzoic acid is present in pure form and contains only finasteride and the conformer, 2,4-dihydroxybenzoic acid, as components.