Acids

Field of the invention

The present invention refers to joint mixtures of phenylbutyric acid or its ions and at least one D-amino acid, like organic salts of phenylbutyric acid, polymorphs, hydrates or solvates thereof and co-crystals of phenylbutyric acid with at least one D-amino acid, polymorphs, hydrates or solvates thereof, as well as their use in cancer therapy and other pharmaceutical applications.

Background of the invention

Phenylbutyric acid is a well known compound to which a number of medical uses has been ascribed in patent or scientific literature. In form of its sodium salt it is marketed as a drug in the USA and European Union. Sodium phenylbutyrate is an orphan drug, marketed by Ucyclyd Pharma (Hunt Valley, USA) under the trade name Buphenyl and by Swedish Orphan International (Sweden) as Ammonaps for the treatment of urea cycle disorders.

Over the years a number of salts of phenylbutyric acid has been described. Still, except for sodium phenyl butyrate none of them has - for various reasons - reached the market. On the other hand the marketed sodium phenylbutyrate can be - especially in the indication marketed for but also in other circumstances - quite disadvantageous. According to Summary of the Product Characteristics (ANNEX I published by the EMEA) under 4.4 (Special Warnings) it is stated:

"Each AMMONAPS tablet contains 62 mg (2.7 mmol) of sodium, corresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS should therefore be used with caution in patients with congestive heart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention with oedema. "

It was thus intended to identify a form of the active ingredient that would allow a favorable use in a slow-release formulation. Sodium phenylbutyrate is very well soluble in water. Even though this is in general a quite positive attribute, for this intention an API that is still water soluble but less so than sodium phenylbutyrate might have its advantageous, especially if easy to formulate due to its crystallinity.

In addition, it has been discussed in literature that Sodium phenylbutyrate or its salts are useful in the treatment of cancer. This has further been described and even exemplified in WO03/22253 especially for adenocarcinoma, prostate cancer or benign prostate hyperplasy. Even though such treatments had shown their effect, there had also been cases and reports in literature in which such a use of phenylbutyric acid or of its sodium salt were less effective or even showed no effect in the treatment of cancer.

Accordingly, it was the primary goal of this invention to identify ways of using phenylbutyric acid in an improved way in the treatment of various diseases, especially cancer or cancer subtypes such as prostate cancer. Such improvements would include improving the clinical results seen in patients after treatment with phenylbutyric acid or its salts or hydrates such as prolongation of survival time, reduction or even removal of cancer cells, allowing patients to be effectively treated that were not or only to a limited degree treatable before, reducing side-effects seen in patients suffering from cancer or increasing or decreasing levels of biomarkers used as parameters to indicate success in such a cancer treatment with these improvements being shown either in one or more of the above listed aspects. Such an improvement could further also include a reduction in dose of each treatment with phenylbutyric acid or its salts or hydrates, reducing the number of application per day of phenylbutyric acid or its salts or hydrates or even reducing any side effect possibly occurring during such a treatment (even though treatment with phenylbutyric acid is known to have close to no side effects).

In addition to that and following the first paragraphs, it was also a goal of this invention to identify alternative joint mixtures of phenylbutyric acid or its ions, especially like organic salts of phenylbutyric acid, polymorphs, hydrates or solvates thereof and co-crystals of phenylbutyric acid, polymorphs, hydrates or solvates thereof, to substitute the sodium in sodium phenylbutyrate, especially joint mixtures that are water soluble, though less so than sodium phenylbutyrate and/or joint mixtures that are crystalline. It has now been found that joined mixture of phenylbutyric acid or its inorganic salts and at least one D-amino acid, wherein the mixture is joined by intermolecular physically interacting forces, especially fitting salts or co-crystals are very advantageous and joining these compounds was effective and advantageous in the treatment of various diseases such as cancer.

Accordingly, the invention is drawn to a joined mixture of phenylbutyric acid or its inorganic salts and at least one D-amino acid, wherein the mixture is joined by intermolecular physically interacting forces.

"Joined mixture" or "joint mixture" according to the invention is defined as a mixture of the phenylbutyric acid or its inorganic salts and at least one organic molecule mixture in which it is not only a physical mixture without molecular interaction but is joined by intermolecular physically interacting forces, like ion-ion-interaction, van der Waals-Force, or a hydrogen bond. "Joined mixtures" or "joint mixtures" include a) a salt of phenylbutyrate with a positively charged ion of a D-amino acid including a respective polymorph, hydrate or solvate of the salt; b) a salt of phenylbutyrate with a positively charged ion of a D-amino acid; c) a polymorph of a salt of phenylbutyrate with a positively charged ion of a D-amino acid; d) a hydrate of a salt of phenylbutyrate with a positively charged ion of a D-amino acid; e) a solvate of a salt of phenylbutyrate with a positively charged ion of a D-amino acid; f) a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former, including a respective polymorph, hydrate or solvate of the co-crystal; g) a co- crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former; h) a polymorph of a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former; i) a hydrate of a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former; or j) a solvate of a co-crystal of phenylbutyric acid and at least one D- amino acid as co-crystal former.

"Intermolecular physically interacting forces" is defined in this application as forces that physically interact in the different parts of the joint mixture for example by ion-ion- interaction, van der Waals-Force, or a hydrogen bond. In a preferred embodiment of the invention the joined mixture according to the invention is a crystalline form of phenylbutyric acid or its ions and at least one D-amino acid.

In another preferred embodiment of the joined mixture according to the invention, the joined mixture is selected from

• a salt of phenylbutyrate with a positively charged ion of a D-amino acid, including a respective polymorph, hydrate or solvate of the salt;

• a salt of phenylbutyrate with a positively charged ion of a D-amino acid;

• a polymorph of a salt of phenylbutyrate with a positively charged ion of a D- amino acid;

• a hydrate of a salt of phenylbutyrate with a positively charged ion of a D- amino acid;

• a solvate of a salt of phenylbutyrate with a positively charged ion of a D- amino acid;

• a co-crystal of phenylbutyric acid and at least one D- amino acid as co- crystal former including a respective polymorph, hydrate or solvate of the co- crystal;

• a co-crystal of phenylbutyric acid and at least one D- amino acid as co- crystal former;

• a polymorph of a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former;

• a hydrate of a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former; or • a solvate of a co-crystal of phenylbutyric acid and at least one D-amino acid as co-crystal former.

"Polymorphs" in general are described in "Polymorphism in Pharmaceutical Solids", Harry G. Brittain (ed.) Drugs and the Pharmaceutical Sciences 192 (1999).

In a further preferred embodiment of the joined mixture according to the invention the D- amino acidis selected from proteinogenic or non-proteinogenic D-amino acids.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from non-polar, polar, acidic or basic D-amino acids.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from aliphatic, sulfur-containing, aromatic or neutral D-amino acids.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-alanine, D-valine, D-leucine, D-isoleucine, D-proline, D- methionine, D-phenylalanine and D-tryptophane.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-serine, D-threonine, D-asparagine, D-glutamine, D- cysteine and D-tyrosine.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-aspartic acid and D-glutamic acid.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-lysine, D-arginine and D-histidine.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-alanine, D-valine, D-Leucine and D-isoleucine. In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-cysteine and D-methionine.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-phenylalanine, D-tyrosine and D-tryptophane.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-serine, D-threonine, D-asparagine and D-glutamic acid.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from D-selenocysteine, D-selenomethionine, D-norleucine, D- norvaline D-ornithine, D-penicillamine, D-hydroxyproline, D-homoserine, D- homophenylalanine, D-homoleucine D-homonorleucine and D-homoarginine.

In a further preferred embodiment of the joined mixture according to the invention, the D- amino acid is selected from the group consisting of D-serine, D-alanine, D-lysine, D- arginine, D-glutamine, D-asparagine.

Preferably, in a further preferred embodiment of the joined mixture according to the invention, the D-amino acid is selected from

• D-alanine

• D-arginine

• D-aspargine

• D-aspartic acid

• D-cysteine

• D-glutamic acid

• D-glutamine

• D-histidine

• D-lsoleucine

• D-leucine

• D-ysine

• D-methionine

• D-phenylalanine

• D-proline

• D-serine

• D-threonine

• D-tryptophane

• D-tyrosine • D-valine

• D-selenocysteine

• D-selenomethionine

• D-norleucine

• D-norvaline

• D-ornithine

• D-penicillamine

• D-hydroxyproline

• D-homoserine

• D-homophenylalanine

• D-homonorleucine

• D-homoarginine. preferably the D-amino acid is selected from

• D-alanine,

• D-valine,

• D-leucine,

• D-isoleucine,

• D-proline,

• D-methionine,

• D-phenylalanine, and

• D-tryptophane;

more preferably the D-amino acid is selected from

• D-serine,

• D-alanine,

• D-lysine,

• D-arginine,

• D-glutamine, and

• D-asparagine;

most preferably the D-amino acid is

• D-alanine.

In a more preferred embodiment of the joined mixture according to the invention, the D- amino acid is D-alanine.

In certain embodiments of the joined mixture according to the invention, the D-amino acid is not D-carnitine or D-homocysteine.

In an alternative preferred embodiment of the joined mixture according to the invention the joined mixture is a hydrate or solvate. In an alternative preferred embodiment of the joined mixture according to the invention the joint mixture is present in crystalline form. In a preferred embodiment this joint mixture is a polymorph of this crystalline form.

In an alternative preferred embodiment of the joined mixture according to the invention the joint mixture is in amorphous form.

Preferably, in embodiments of the joined mixture according to the invention, the phenylbutyric acid is 4-phenylbutyric acid.

A further aspect of the invention refers to a pharmaceutical formulation comprising at least one joint mixture according to the invention and optionally at least one physiologically acceptable excipient.

A further aspect of the invention refers to a joint mixture according to the invention for use in the treatment of cancer, mucositis, amyotropic lateral sclerosis (ALS), skin/mucosal itching, degenerative diseases of the eye, neurodegenerative disorders, Huntington's disease, eating disorders, obesity, drug induced weight gain, pruritis, alcoholism, promyelocytic leukemia, especially acute promyelocytic leukemia, cardiac injury, especially adriamycin induced cardiac injury, epithelial damage, connective tissue damage, desmosis, Parkinson Disease, myelodysplastic syndrome, urea cycle disorder, fibrotic lung diseases, hepatic encephalopathies, thioredoxin mediated diseases, human papilloma virus (HPV) infections, autoimmune diseases, thalassemia, genetic disorders; or in the regulation of HDAC6 activity, the modulation of stem cells, the prevention of grey hair, the promotion of neuronal growth, the prevention of bone and joint diseases, or as adjuvant in cancer therapy. Also, the joint mixture according to the invention is for use in the treatment of a genetic disorder or epigenetic disorder which are selected from or manifests itself in symptoms or diseases selected from urea cycle disorders, thalassemia, cystic fibrosis, rheumatoid arthritis, Siogren' s syndrome, uveitis, polymyositis, and dermatomyositis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, affective disorders, systemic lupus erythematosus, immune response, varicosis, vaginitis, including chronic recurrent yeast vaginitis, depression or Sudden Infant Death Syndrome; especially in the treatment of cardiovascular disease like those being selected from arteriosclerosis, atherosclerosis, coronary heart disease, coronary artery disease, ischemic heart disease, angina, heart attack, heart failure, stroke and hypertension; or cystic fibrosis; or immune disease or autoimmune disease, like those being selected from rheumatoid arthritis, psoriatic arthritis, siogren's syndrome, uveitis, polymyositis, dermatomyositis, systemic lupus erythematosus, Crohn's disease, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, psoriasis, ulcerative colitis, vasculitis and ankylosing spondylitis; or neurological or neurodegenerative diseases like those being selected from Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntigton's disease, Parkinson's disease, amyotrophic lateral sclerosis and depression.

An alternative aspect of the invention refers to the use of a joint mixture according to the invention in the production of a medicament or pharmaceutical formulation for use in the treatment of cancer, mucositis, amyotropic lateral sclerosis (ALS), skin/mucosal itching, degenerative diseases of the eye, neurodegenerative disorders, Huntington's disease, eating disorders, obesity, drug induced weight gain, pruritis, alcoholism, promyelocyte leukemia, especially acute promyelocytic leukemia, cardiac injury, especially adriamycin induced cardiac injury, epithelial damage, connective tissue damage, desmosis, Parkinson Disease, myelodysplasia syndrome, urea cycle disorder, fibrotic lung diseases, hepatic encephalopathies, thioredoxin mediated diseases, human papilloma virus (HPV) infections, autoimmune diseases, thalassemia, genetic disorders; or for use in the regulation of HDAC6 activity, the modulation of stem cells, the prevention of grey hair, the promotion of neuronal growth, the prevention of bone and joint diseases, or as adjuvant in cancer therapy. This could include also the use of a joint mixture according to the invention in the production of a medicament or pharmaceutical formulation for use in the treatment of a genetic disorder or epigenetic disorder which are selected from or manifests itself in symptoms or diseases selected from urea cycle disorders, thalassemia, cystic fibrosis, rheumatoid arthritis, Siogren' s syndrome, uveitis, polymyositis, and dermatomyositis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, affective disorders, systemic lupus erythematosus, immune response, varicosis, vaginitis, including chronic recurrent yeast vaginitis, depression or Sudden Infant Death Syndrome; especially in the treatment of cardiovascular disease like those being selected from arteriosclerosis, atherosclerosis, coronary heart disease, coronary artery disease, ischemic heart disease, angina, heart attack, heart failure, stroke and hypertension; or cystic fibrosis; or immune disease or autoimmune disease, like those being selected from rheumatoid arthritis, psoriatic arthritis, siogren's syndrome, uveitis, polymyositis, dermatomyositis, systemic lupus erythematosus, Crohn's disease, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, psoriasis, ulcerative colitis, vasculitis and ankylosing spondylitis; or neurological or neurodegenerative diseases like those being selected from Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntigton's disease, Parkinson's disease, amyotrophic lateral sclerosis and depression.

For the medicament or pharmaceutical formulation according to the present invention or for a medicament or pharmaceutical formulation used in the use of the joint mixture according to the invention the medicament or pharmaceutical formulation can be of any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art. The medicament or pharmaceutical formulation can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002 y "The Theory and Practice of Industrial Pharmacy", Lachman L, Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are hereby incorporated by reference and form part of the disclosure. The composition of the medicament may vary depending on the route of administration.

The medicament or pharmaceutical formulation of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical excipients for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions. These medicaments or pharmaceutical formulation may for example be injected intramuscularly, intraperitoneally, or intravenously.

Medicaments or pharmaceutical formulation according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. The compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or modified or controlled release. The multiparticulate forms, such as pellets or granules, may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.

Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology", Wise,

D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery", Vol, I, Basic Concepts, Bruck, S.D. (Ed.), CRD Press Inc., Boca Raton (1983) y de Takada, K. and Yoshikawa, H., "Oral Drug Delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz,

E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., "Oral drug delivery, small intestine and colon", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are hereby incorporated by reference and form part of the disclosure.

Medicaments or pharmaceutical formulation according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament may pass the stomach undissolved and the respective salts or their respective crystalline form is liberated in the intestinal tract. Preferably the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.

Typically, the medicaments according to the present invention may contain 1-60 % by weight of one or more of the salts or their crystalline form as defined herein and 40-99 % by weight of one or more auxiliary substances (additives/excipients).

The joint mixture of the present invention may also be administered topically or via a suppository. The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans preferably is in the range of 10 to 2000 milligrams of active substance Qoined mixture according to the invention) to be administered during one or several intakes per day.

In a very preferred embodiment the medicament or pharmaceutical formulation of the invention is an oral pharmaceutical composition. Very suitable oral pharmaceutical compositions comprising 4-phenyl-butyric acid or a physiologically acceptable salt thereof are disclosed in EP1427396 (WO2003/22253), the content of which forming herewith part of the description/disclosure of the current invention. Accordingly, it is very preferred if such an oral pharmaceutical composition comprising a joint mixture according to the invention is formulated in an analoguous way to the formulation presented in EP1427396 (WO2003/22253). It is thus further very preferred if an oral medicament according to the invention especially a pharmaceutical composition comprises 100 to 2000 mg of the joined mixture according to the invention, preferably 200 to 1000 mg, most preferably approximately 500 mg or 250 mg of the joined mixture according to the invention.

In another alternative embodiment the joint mixture is formulated in a medicament or pharmaceutical formulation in form of a tablet wherein each gram of granulate contains 100 to 2000 mg of the joined mixture according to the invention, preferably 500 to 1000 mg of the joined mixture according to the invention. Preferably the granulate does further comprise microcrystalline cellulose, magnesium stearate and/or colloidal anhydrous silica.

In another alternative embodiment the joint mixture is formulated in a medicament or pharmaceutical formulation in form of a granulate containing 100 to 2000 mg of the joined mixture according to the invention, preferably 500 to 1000 mg of the joined mixture according to the invention. Preferably the granulate does further comprise calcium stearate and/or colloidal anhydrous silica.

Another aspect of the invention refers to a process for the production of a joint mixture according to the invention being either a salt or a co-crystal of 4-phenyl-butyric acid with D- amino acid with the following steps: a) 4-phenyl-butyric acid is dissolved in organic solvent 1 to form solution 1 ; b) the D-amino acid is dissolved in organic solvent 2 to form solution 2;

c) solution 1 and solution 2 are mixed;

d) in a first final step the organic solvents are removed from the mixture from step c) and a residue/joined mixture obtained.

In an embodiment of the process according to the invention the following steps are added after step d): e) the residue from step d) is dissolved in organic solvent 3;

f) the resulting mixture is stirred while the temperature is raised above room temperature followed by lowering of the temperature;

g) in a last final step the organic solvent is removed from the mixture from step f) and the joined mixture obtained,

In a preferred embodiment of the process according to the invention:

• the organic solvents 1 and 2 are the same organic solvent; and/or

• the organic solvents 1 and/or 2 is/are selected from EtOH, THF, or MeCN; and/or

• the organic solvent 3 is/are selected from toluene, TBME, heptane, or EtOAc; and/or

• where applicable - the temperature in step f) is raised to 25 to 35°C, preferably to approximately 30°C; and/or

• where applicable - the temperature in step f) is lowered to below 25°C, preferably to approximately 20°C; and/or

• in the first and/or the last final step the organic solvent is removed under gas flow.

"THF" is Tetrahydrofuran; "EtOH" is ethanol; "MeCN" is cyanomethan/acetonitril; "TBME" is tert.-butyl-methyl ether; and "EtOAc" is ethyl acetate.

In a very preferred embodiment and aspect of the invention, the joint mixture according to the invention is a salt of 4-phenyl-butyric acid with a salt-forming D-amino acid. In one embodiment the salt of 4-phenyl-butyric acid with the salt-forming D-amino acid is in amorphous or crystalline form, preferably is in crystalline form.

"Salt-forming D-amino acid" as used herein is defined as any D-amino acid which is able to become ionized and with which phenyl butyric acid or its derivative is able to form a salt. In an embodiment of the joined mixture according to the invention being a salt is an organic salt according to general formula I

Formula I

, wherein

A ⁺ is selected from positively charged ions of a salt-forming D-amino acid.

In a further embodiment this joint mixture according to the invention being a salt is a hydrate or solvate of a salt of 4-phenyl-butyric acid with a salt-forming D-amino acid.

"Hydrate" is defined as a substance/joint mixture according to the invention containing water. Thus, it may be a crystalline salt with one or more water molecules in the crystalline structure or also amorphous containing water molecules.

"Solvate" is defined as a substance/joint mixture according to the invention containing a further solvent. One most prominent example of the solvents is an alcohol like ethanol or methanol thus leading to methanolates or ethanolates. Thus, it may be a crystalline salt with one or more alcohol molecules in the crystalline structure or also an amorphous form containing alcohol molecules.

In another embodiment the joint mixture according to the invention being a salt is a polymorph of a salt of 4-phenyl-butyric acid with a salt-forming D-amino acid or of its hydrate or solvate. In a very preferred embodiment and aspect of the invention in this salt of 4-phenyl-butyric acid with a salt-forming D-amino acid according to the invention, the salt-forming D-amino acid is selected from

• D-alanine

• D-arginine

• D-aspargine

• D-aspartic acid

• D-cysteine

• D-glutamic acid

• D-glutamine

• D-histidine

• D-lsoleucine

• D-leucine

• D-ysine

• D-methionine

• D-phenylalanine

• D-proline

• D-serine

• D-threonine

• D-tryptophane

• D-tyrosine

• D-valine

• D-selenocysteine

• D-selenomethionine

• D-norleucine

• D-norvaline

• D-ornithine

• D-penicillamine

• D-hydroxyproline

• D-homoserine

• D-homophenylalanine

• D-homonorleucine

• D-homoarginine.

Another aspect of the invention refers to a pharmaceutical formulation comprising a salt or crystalline form thereof according to the invention being either generally a salt of 4-phenyl- butyric acid with a salt-forming D-amino acid and optionally at least one physiologically acceptable excipient.

Salts or crystalline forms thereof according to the invention being either generally a salt of 4-phenyl-butyric acid with a salt-forming D-amino acid for use in the treatment of cancer, mucositis, amyotropic lateral sclerosis (ALS), skin/mucosal itching, degenerative diseases of the eye, neurodegenerative disorders, Huntington's disease, eating disorders, obesity, drug induced weight gain, pruritis, alcoholism, promyelocytic leukemia, especially acute promyelocytic leukemia, cardiac injury, especially adriamycin induced cardiac injury, epithelial damage, connective tissue damage, desmosis, Parkinson Disease, myelodysplastic syndrome, urea cycle disorder, fibrotic lung diseases, hepatic encephalopathies, thioredoxin mediated diseases, human papilloma virus (HPV) infections, autoimmune diseases, thalassemia, genetic disorders; or in the regulation of HDAC6 activity, the modulation of stem cells, the prevention of grey hair, the promotion of neuronal growth, the prevention of bone and joint diseases, or as adjuvant in cancer therapy.

In a very preferred embodiment and aspect of the invention, the joint mixture according to the invention is a co-crystal of 4-phenyl-butyric acid (or derivative or salt thereof) with a co- crystal-forming D-amino acid. In an embodiment the molecular ratio between 4-phenyl- butyric acid (or anion thereof) and co-crystal forming D-amino acid is between 4:1 and 1 :4. In another embodiment the co-crystal does contain at least one further molecule being selected from water (a hydrate), solvents like alcohols (methanol, ethanol) (a solvate or alcoholate) or a cation. In an embodiment, any of these co-crystals according to the invention is existing in form of a polymorph.

"Molecular ratio" according to this invention as a whole is defined as the ratio - if comparing molecule with molecule - of the amount of molecules of phenyl-butyric acid (or its ion in a salt) as one molecule on one hand and the amount of the other organic molecules in the joint mixture on the other hand.

"Co-crystal" as used herein is defined as a crystalline material comprising two or more compounds at ambient temperature (20 to 25°C, preferably 20°C), of which at least two are held together by weak interaction, wherein at least one of the compounds is a co-crystal former. Weak interaction is being defined as an interaction, which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Waals forces, and S-S- interactions. Solvates or salts of phenyl butyric acid and an organic compound that do not further comprise a co-crystal former are not co-crystals according to the present invention. The co-crystals may however, include one or more solvate molecules in the crystalline lattice. Just for the sake of clarity the distinction between crystalline salt and a co-crystal has to be stressed here. An API bound to another compound forming a salt by means of ionic interaction can be considered as one "compound" according to the invention, but it cannot be considered as two compounds by itself.

In the scientific literature there is currently some discussion on the proper use of the word co-crystal (see for example Desiraju, CrystEngComm, 2003, 5(82), 466-467 and Dunitz, CrystEngComm, 2003, 5(91 ), 506). A recent article by Zaworotko (Zaworotko, Crystal Growth & Design, Vol. 7, No. 1 , 2007, 4-9) gives a definition of co-crystal which is in line with the definition given above.

"Co-crystal forming D-amino acid" as used herein is defined as any D-amino acid with which phenyl butyric acid or its salt is able to form co-crystals.

In a very preferred embodiment and aspect of the invention in this co-crystal of 4-phenyl- butyric acid with a co-crystal-forming D-amino acid according to the invention, the co- crystal-forming D-amino acid is selected from

• D-alanine

• D-arginine

• D-aspargine

• D-aspartic acid

• D-cysteine

• D-glutamic acid

• D-glutamine

• D-histidine

• D-lsoleucine

• D-leucine

• D-ysine

• D-methionine

• D-phenylalanine

• D-proline

• D-serine

• D-threonine

• D-tryptophane

• D-tyrosine

• D-valine

• D-selenocysteine

• D-selenomethionine

• D-norleucine

• D-norvaline

• D-ornithine • D-penicillamine

• D-hydroxyproline

• D-homoserine

• D-homophenylalanine

• D-homonorleucine

• D-homoarginine.

In a very preferred embodiment and aspect of the invention, in this co-crystal of 4-phenyl- butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid according to the invention, the co-crystal-forming D-amino acid is D-alanine. In an embodiment the molecular ratio between 4-phenyl-butyric acid (or anion thereof) and D-alanine is between 4:1 and 1 :4. In another embodiment the co-crystal does contain at least one further molecule being selected from water (a hydrate), solvents like alcohols (methanol, ethanol) (a solvate or alcoholate) or a cation. In an embodiment, any of these co-crystals according to the invention is existing in form of a polymorph.

Another aspect of the invention refers to a pharmaceutical formulation comprising a co- crystal according to the invention being either generally a co-crystal of 4-phenyl-butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid or a co-crystal of 4- phenyl-butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid being D-alanine, respectively and optionally at least one physiologically acceptable excipient.

Another aspect of the invention refers to a process for the production of a co-crystal according to the invention being a co-crystal of 4-phenyl-butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid being D-alanine with the following steps: a) 4-phenyl-butyric acid is dissolved in organic solvent 1 to form solution 1 ; b) the D-amino acid is dissolved in organic solvent 2 to form solution 2;

c) solution 1 and solution 2 are mixed;

d) in a first final step the organic solvents are removed from the mixture from step c) and a residue/joined mixture obtained.

Optionally, the following steps are added after step d): e) the residue from step d) is dissolved in organic solvent 3;

f) the resulting mixture is stirred while the temperature is raised above room temperature followed by lowering of the temperature; g) in a last final step the organic solvent is removed from the mixture from step f) and the Co-crystal is obtained.

Preferably, in that process:

• the organic solvents 1 and 2 are the same organic solvent; and/or

• the organic solvents 1 and/or 2 is/are selected from EtOH, THF, or MeCN; and/or

• the organic solvent 3 is/are selected from toluene, TBME, heptane, or EtOAc; and/or

• where applicable - the temperature in step i) is raised to 25 to 35°C, preferably to approximately 30°C; and/or

• where applicable - the temperature in step i) is lowered to below 25°C, preferably to approximately 20°C; and/or

• in the first and/or the last final step the organic solvent is removed under gas flow.

Co-crystal according the invention being either generally a co-crystal of 4-phenyl-butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid or a co-crystal of 4-phenyl-butyric acid (or derivative or salt thereof) with a co-crystal-forming D-amino acid being D-alanine, respectively for use in the treatment of cancer, mucositis, amyotropic lateral sclerosis (ALS), skin/mucosal itching, degenerative diseases of the eye, neurodegenerative disorders, Huntington's disease, eating disorders, obesity, drug induced weight gain, pruritis, alcoholism, promyelocytic leukemia, especially acute promyelocytic leukemia, cardiac injury, especially adriamycin induced cardiac injury, epithelial damage, connective tissue damage, desmosis, Parkinson Disease, myelodysplastic syndrome, urea cycle disorder, fibrotic lung diseases, hepatic encephalopathies, thioredoxin mediated diseases, human papilloma virus (HPV) infections, autoimmune diseases, thalassemia, genetic disorders; or in the regulation of HDAC6 activity, the modulation of stem cells, the prevention of grey hair, the promotion of neuronal growth, the prevention of bone and joint diseases, or as adjuvant in cancer therapy.

A further aspect of the invention would encompass a method of treatment of cancer, benign prostate hyperplasia, leukemias, cystic fibrosis, AIDS, kidney or liver diseases, thalassemia or urea cycle disorders; or

for the treatment of cancer, mucositis, amyotropic lateral sclerosis (ALS), skin/mucosal itching, degenerative diseases of the eye, neurodegenerative disorders, Huntington's disease, eating disorders, obesity, drug induced weight gain, pruritis, alcoholism, promyelocytic leukemia, especially acute promyelocytic leukemia, cardiac injury, especially adriamycin induced cardiac injury, epithelial damage, connective tissue damage, desmosis, Parkinson Disease, myelodysplastic syndrome, urea cycle disorder, fibrotic lung diseases, hepatic encephalopathies, thioredoxin mediated diseases, human papilloma virus (HPV) infections, autoimmune diseases, thalassemia, genetic disorders; or in the regulation of HDAC6 activity, the modulation of stem cells, the prevention of grey hair, the promotion of neuronal growth, the prevention of bone and joint diseases, or as adjuvant in cancer therapy by providing to a patient in need thereof a sufficient amount of the joined mixture according to the invention. Preferably the provision of the amount of the pharmaceutical combination according to the central aspect of the invention is done orally (e.g. in form of a tablet). Preferably the provision is done once or twice daily most preferably twice daily preferably in a dose range between about 100 to about 500 mg, preferably at about 125 to about 250 mg or at about 250 mg of phenylbutyic acid (or 4-phenyl butyric acid) in the joint mixture according to the current invention.

This method of treatment may apply also to the treatment of a genetic disorder or epigenetic disorder which are selected from or manifests itself in symptoms or diseases selected from urea cycle disorders, thalassemia, cystic fibrosis, rheumatoid arthritis, Sjogren's syndrome, uveitis, polymyositis, and dermatomyositis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, affective disorders, systemic lupus erythematosus, immune response, varicosis, vaginitis, including chronic recurrent yeast vaginitis, depression or Sudden Infant Death Syndrome; especially in the treatment of cardiovascular disease like those being selected from arteriosclerosis, atherosclerosis, coronary heart disease, coronary artery disease, ischemic heart disease, angina, heart attack, heart failure, stroke and hypertension; or cystic fibrosis; or immune disease or autoimmune disease, like those being selected from rheumatoid arthritis, psoriatic arthritis, siogren's syndrome, uveitis, polymyositis, dermatomyositis, systemic lupus erythematosus, Crohn's disease, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, psoriasis, ulcerative colitis, vasculitis and ankylosing spondylitis; or neurological or neurodegenerative diseases like those being selected from Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntigton's disease, Parkinson's disease, amyotrophic lateral sclerosis and depression.

The present invention is illustrated below with the help of the following examples. These illustrations are given solely by way of example and do not limit the invention.

EXAMPLES:

Example 1 : Use of the combination of 4-Phenylbutyrate-Sodium salt and D-alanine in a patient with elevated PSA Levels after prostate cancer

A patient born 1941 was diagnosed for cancer of the prostate. He was successfully treated and received orally twice daily 250 mg of sodium 4-phenylbutyrate. Even though

successfully treated with no further incidence, his PSA remained elevated (15 pg/l). In 201 1 he started treatment with orally twice daily 250 mg of sodium 4-phenylbutyrate together with 50 mg of D-alanine. His PSA became significantly reduced (1 1 pg/l), what was not achievable with a treatment with sodium 4-phenylbutyrate alone.