TREATMENT OF INTERSTITIAL CYSTITIS

The present invention relates to the use of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid has the structure:

(3S,5R)-3-aminomethyl-5-methyloctanoic acid binds to the alpha-2-delta subunit of voltage-activated calcium channels. (3S,5R)-3-aminomethyl-5-methyloctanoic acid has been shown to have a selective affinity for the calcium channel alpha-2-delta subunit, with no or negligible affinity for common neurotransmitter receptors or ion channels. The affinity of (3S,5R)-3-aminomethyl-5-methyloctanoic acid is approximately 6 to 10 times higher than gabapentin for the calcium channel alpha-2-delta subunit.

Interstitial cystitis (IC) is a chronic condition affecting primarily the bladder and is of unknown origin. IC is characterized by symptoms of pain, such as pelvic pain, and lower urinary tract symptom(s) (LUTS), such as increased urinary frequency or urgency (particularly persistent urge). More recently terminology has evolved to include painful bladder syndrome (PBS) (MacDiarmid et al, Rev. Urol., 9(1 ), 9-16 (2007)) or bladder pain syndrome (BPS) (van der Merve et al, European Urology, 53, 60-67 (2008)), along with IC, that is IC/PBS/BPS to collectively describe this symptom complex.

Prevalence rates of IC/PBS/BPS vary from 67 to 230 per 100,000 women having clinically confirmed disease, although the number is likely higher than this due to under- or mis-diagnosis, commonly as endometriosis, recurrent urinary tract infection, overactive bladder or vulvodynia (Forrest J B et al, Clinical Courier 24(3), 1 -8 (2006)).

IC has a significant impact on quality of life, affecting travel, family relationships and employment (Slade et al, Urol., 49 (5A Suppl), 10-3(1997)), as well as being associated with depressive symptoms (Rothrock et al, J. Urol., 167, 1763-1767(2002)).

There are few well -performed, placebo-controlled, randomized trials of therapies aimed at IC and treatment often consists of a multimodal thal-and-error approach, as evidenced by one review of patients in the Interstitial Cystitis Data Base study which reported 183 different types of treatment (Rovner et al, J. Urol., 56, 940-5(2000)).

No single etiology has been identified, and it is most likely a multifactorial process with several urologic insults causing a self-perpetuating process of epithelial cell dysfunction, C-nerve fibre activation and proliferation of mast cells, leading to worsening tissue damage, scarring and fibrosis. The repetitive stimulation of C fibres from inflammation, and upregulation of sensory nerves in the bladder, ultimately leads to permanent alterations (centralization) resulting in central sensitization, hyperalgesia, chronic bladder pain and voiding dysfunction (Forrest et al, Clinical Courier, 24(3):1 -8 (2006)).

Although no consensus has been reached on the fundamental causes of IC, existing data have led to speculation that three pathophysiologic mechanisms may be implicated: epithelial dysfunction, mast cell activation and neurogenic inflammation (Nazif et al, Urol., 69 (Suppl 4A), 24-33(2007)).

There is a continuing need to provide a novel, effective treatment for a pain and/or a lower urinary tract symptom of interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome, without the adverse effects or limited efficacy of currently available therapies.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, and salts thereof, has been described in WO00/76958 for the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, arthritis, sleep disorders, irritable bowel syndrome or gastric damage. WO2004/054566 describes its use in the treatment of, for example, obsessive compulsive disorder, phobias, post-traumatic stress disorder, restless leg

syndrome, premenstrual dysphoric disorder, hot flashes, fibromyalgia or certain types of pain. WO2007/072159 describes methods for the preparation of (3S,5R)-3- aminomethyl-5-methyloctanoic acid incorporating an enzymatic, diastereoselective, hydrolysis step.

Southern Medical Journal, 93(2), 238-242 (February 2000) states "Two patients with interstitial cystitis improved functional capacity within their activities of daily living and received adequate pain control with the addition of gabapentin to their medication regimen".

Expert Opinion on Investigational Drugs, 10(3), 521-546 (2001 ) states that in a gabapentin study "Two IC patients were recently reported to improve functionally with reasonable pain control [36]. Any anecdotal reports from IC patients are hard to evaluate, especially since gabapentin is typically increased over time and the maximal appropriate dose has not been established for IC".

Pain Medicine, 2(1 ), 60-71 (2001 ) states that gabapentin "has been employed more recently for the treatment of IC pain" and that "Larger effectiveness trials in patients with IC are required to confirm its anecdotal clinical success in this population".

However, given the etiology of IC/PBS/BPS and poor mechanistic understanding of the condition, it cannot be easily predicted if any previously unindicated compound could be used for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

The present invention provides the use of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

In an aspect of the invention there is provided the use of (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for the

manufacture of a medicament for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

In another aspect of the invention there is provided a method for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome in a mammal comprising administration of an effective amount of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment. Preferably the mammal is a human being.

In a further aspect of the invention there is provided (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

Pain associated with IC, PBS or BPS comprises lower abdominal (pelvic) pain, bladder pain, suprapubic pain, vaginal pain, pain in the penis, testicles, scrotum or perineum, urethral pain, dyspareneuria, or pain, pressure or discomfort that may increase as the bladder fills.

Lower urinary tract symptoms comprise three groups of urinary symptoms, which may be defined as storage (irritative), voiding (obstructive) and post-micturition symptoms. Storage symptoms comprise urgency, frequency, nocturia, urgency incontinence and stress incontinence. Voiding symptoms comprise hesitancy, poor flow, intermittency, straining and dysuria. Post-micturition symptoms comprise terminal dribbling, post-void dribbling and a sense of incomplete emptying. The term 'urgency' is defined by the International Continence Society as the complaint of a sudden compelling desire to pass urine which is difficult to defer. This may be associated with a concern or fear of incontinence, a concern or fear of worsening pain, pressure or discomfort, or a concern or fear of onset or worsening of another unpleasant symptom related to the lower urinary tract. In some patients with interstitial cystitis / painful bladder syndrome /

bladder pain syndrome, this sensation of urgency may be accompanied by an increasing feeling of malaise and/or nausea.

The present invention provides, in a preferred aspect, (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, for inhibiting or blocking a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. In some embodiments, the pain and/or lower urinary tract symptom(s) is/are alleviated within about 24 hours after administering the compound. In some embodiments, the pain and/or lower urinary tract symptom(s) is/are alleviated within about 4 days after administering the compound. In some embodiments, the pain and/or lower urinary tract symptom(s) is/are alleviated before observing or in the absence of an indication of improvement of the condition in the individual.

In another aspect, the invention provides a pharmaceutical composition comprising

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier for use in the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

In a further aspect the invention provides a combination of (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, and a further therapeutically active entity, for the treatment of a pain and/or a lower urinary tract symptom(s) (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.

As used herein, "treatment" embraces curative, palliative and prophylactic treatment and is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement or alleviation of any aspect of a pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following:

lessening severity, alleviation of a pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome, including any aspect of pain (such as shortening duration of pain, reduction of pain sensitivity or sensation).

An "effective amount" of a compound or pharmaceutical composition is an amount sufficient to effect beneficial or desired results including clinical results such as alleviation or reduction in pain sensation. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to treat, ameliorate, reduce the intensity of and/or prevent a pain or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. In some embodiments, the "effective amount" may reduce pain at rest (resting pain) or mechanically-induced pain (including pain following movement), or both, and it may be administered before, during or after painful stimulus. As is understood in the clinical context, an effective amount of a compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

"Reducing incidence" of pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome means any of reducing severity (which can include reducing need for and/or amount of (e.g., exposure to) other drugs and/or therapies generally used for this conditions, including, for example, opiates), duration, and/or frequency (including, for example, delaying or increasing time pain in an individual). As is understood by those skilled in the art, individuals may vary in terms of their response to treatment, and, as such, for example, a "method of reducing incidence of pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome in an individual" reflects administering the compound based on a reasonable

expectation that such administration may likely cause such a reduction in incidence in that particular individual.

"Ameliorating" a pain and/or a lower urinary tract symptoms associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome means a lessening or improvement of one or more symptoms of pain and/or a lower urinary tract symptom(s) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome as compared to not administering the compound. "Ameliorating" also includes shortening or reduction in duration of a symptom.

"Palliative treatment" of a pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome means lessening the extent of one or more undesirable symptoms in an individual or population of individuals treated with the compound.

As used therein, "delaying" the development of pain means to defer, hinder, slow, retard, stabilize, and/or postpone progression of pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop pain. A method that "delays" development of the symptom is a method that reduces probability of developing the symptom in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.

"Pain" as used herein refers to pain of any etiology, including acute and chronic pain, and any pain with an inflammatory component. As used herein, "pain" includes nociception and the sensation of pain, and pain can be assessed objectively and subjectively, using pain scores and other methods well-known in the art. The pain can be primary or secondary pain, as is well-known in the art.

"Pain associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome" as used herein refers primarily to lower abdominal (pelvic) pain, bladder pain, suprapubic pain, vaginal pain, pain in the penis, testicles, scrotum or perineum, urethral pain, dyspareneuria or pain, pressure or discomfort that may increase as the bladder fills.

"Lower urinary tract symptoms associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome" as used herein primarily refers to three groups of urinary symptoms, which may be defined as storage (irritative), voiding (obstructive) and post-micturition symptoms. Storage symptoms comprise urgency, frequency, nocturia, urgency incontinence and stress incontinence. Voiding symptoms comprise hesitancy, poor flow, intermittency, straining and dysuria. Post-micturition symptoms comprise terminal dribbling, post-void dribbling and a sense of incomplete emptying. The term 'urgency' is defined by the International Continence Society as the complaint of a sudden compelling desire to pass urine which is difficult to defer. This may be associated with a concern or fear of incontinence, a concern or fear of worsening pain, pressure or discomfort, or a concern or fear of onset or worsening of another unpleasant symptom related to the lower urinary tract. In some patients with interstitial cystitis / painful bladder syndrome / bladder pain syndrome, this sensation of urgency may be accompanied by an increasing feeling of malaise and/or nausea.

An "individual" or "subject" is a mammal, more preferably a human. Mammals include, but are not limited to, farm animals (such as cows), sport animals (such as horses), pets (such as cats, dogs and horses), primates, mice and rats.

As used herein, "pharmaceutically acceptable excipient or carrier" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical excipients or carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline. Compositions comprising such carriers are formulated by well known conventional

methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).

Processes for the preparation of (3S,5R)-3-aminomethyl-5-methyloctanoic acid and pharmaceutically acceptable salts thereof have been described in WO00/76958, WO2004/054566 and WO2007/072159.

The following route, shown in the Scheme below, may be used to prepare (3S,5R)-3- aminomethyl-5-methyloctanoic acid.

NaBr, TBAB Toluene, H ₂ O

Q) (H)

1. KO ¹ Bu, Toluene, THF 2. aqueous HCl

(HI) (IV)

(VI) EtOH/H ₂ O

(VII)

(VIII)

(R)-2-methylpentanol (I) is reacted with methanesulphonyl chloride (1.05 mole equivalents) in the presence of triethylamine (1.1 mole equivalents) and in toluene as solvent, maintaining the temperature at from 0 to 25 ⁰ C, to provide a methanesulphonyloxypentane derivative (II). This is reacted with sodium bromide (1 mole equivalent) and tetrabutylammonium bromide (TBAB) (0.2 mole equivalents) in a mixture of toluene and water and at about 9O ⁰ C to provide the bromopentane derivative (III). The bromopentane derivative (III) and orthoester (IV) (1.2 mole equivalents) were combined in toluene as the solvent and this mixture was added slowly to a mixture of potassium t-butoxide (3.5 mole equivalents) in tetrahydrofuran (THF), maintaining the temperature at from -10 to O ⁰ C. The resulting intermediate orthoester is hydrolysed during work up under acidic conditions (using aqueous hydrochloric acid) to give the racemic cyanoester (V). Diastereoselective hydrolysis of this racemate with Amano (trade mark) lipase using Lipase PS-SD (20% w/w) at 45 ⁰ C, gave, after work-up using t- butyl methyl ether (t-BME), the optically pure cyanoester (Vl). Hydrolysis of this compound using aqueous sodium hydroxide, followed by reduction by catalytic hydrogenation in the presence of sponge nickel at 345 kPA (50psi) in water at 35 ⁰ C, provided, after pH adjustment using citric acid and isolation from aqueous ethanol, the required (3S,5R)-3-aminomethyl-5-methyloctanoic acid (VIII). This product is then recrystallised from aqueous ethanol to provide (3S,5R)-3-aminomethyl-5-methyloctanoic acid (VIIIA) of optimal purity, crystal habit and particle size.

Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of (3S,5R)-3-aminomethyl-5-methyloctanoic acid may be prepared by one or more of three methods:

(i) by reacting the compound with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic lactam precursor using the desired acid or base; or (iii) by converting one salt of the compound to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a

liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiomethc amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound

together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, X7_, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO-Na ⁺ or - COO-K ⁺ ) or non-ionic polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4 ^th Edition (Edward Arnold, 1970).

Hereinafter all references to (3S,5R)-3-aminomethyl-5-methyloctanoic acid include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

References herein to (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, include all polymorphs, crystal habits and prodrugs thereof and isotopically-labeled (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof.

As indicated, so-called 'prodrugs' of the (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, are also within the scope of the invention. Thus certain derivatives of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into (3S,5R)-3-aminomethyl-5-methyloctanoic acid having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as

'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

(i) with regard to the carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, is replaced by (Cr C ₈ )alkyl; and

(iii) with regard to the primary amino functionality (-NH ₂ ), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, is/are replaced by (Ci-Cio)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

The present invention includes all pharmaceutically acceptable isotopically-labelled forms of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, include isotopes of hydrogen, such as ² H and ³ H, carbon, such as

¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus, such as ³² P, and sulphur, such as ³⁵ S.

Certain isotopically-labelled forms of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled forms of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates include those wherein the solvent of crystallization may be isotopically substituted, e.g. D ₂ O, de-acetone, de-DMSO.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may be administered in combination with one or more other drugs (or as any combination thereof). (3S,5R)-3- aminomethyl-5-methyloctanoic acid, or a salt thereof, may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, for the treatment of a pain and/or a lower urinary tract symptom (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. For example, (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately, in combination with one or more agents selected from:

• an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

• a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

• a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental; • a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

• an Hi antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

• a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

• a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaphne, methocarbamol or orphrenadine;

• an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1 -piperidinyl]- 1 -hydroxyethyl-3,4-dihydro-2(1 H)-quinolinone;

• an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, terazosin, indoramin, alfuzosin, silodosin or 4- amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1 ,2,3,4-tetrahydroisoquinol-2- yl)-5-(2-pyhdyl)quinazoline;

• a tricyclic antidepressant, e.g. desipramine, imipramine, amithptyline or nortriptyline; • an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate;

• a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[1 ,4]diazocino[2,1 -g][1 ,7]-naphthyhdine-6-13-dione (TAK-637), δ-t^R.SS^-KI RJ-i -tS.δ-bisCtrifluoromethyOphenyllethoxy-S^-fluorophenylH- morpholinyl]-methyl]-1 ,2-dihydro-3H-1 ,2,4-thazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(thfluoromethoxy)phenyl]-methylamino]-2- phenylpiperidine (2S,3S);

• a muscarinic antagonist, e.g oxybutynin, tolterodine, fesoterodine, 5- hydroxymethyltolterodine, propivehne, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

• a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

• a coal-tar analgesic, in particular paracetamol;

• a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox,

asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

• a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);

• a beta-adrenergic such as propranolol; • a local anaesthetic such as mexiletine;

• a corticosteroid such as dexamethasone;

• a 5-HT receptor agonist or antagonist, particularly a 5-HT _{I B/I D} agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

• a 5-HT _2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1 -[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl- 4-(3-pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2- chloropyridine (ABT-594) or nicotine;

• Tramadol (trade mark); • a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1 -piperazinyl- sulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (sildenafil), (6R.12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2',1 ':6,1]-pyhdo[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1 -yl-1 -sulphonyl)-phenyl]-5-methyl- 7-propyl-3H-imidazo[5,1 -f][1 ,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3- pyridinyl)-3-ethyl-2-(1 -ethyl-3-azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3-c/]pyhmid in- 7-one, 5-(5-acetyl-2-propoxy-3-pyhdinyl)-3-ethyl-2-(1-isopropyl-3-a zetidinyl)-2,6- dihydro-7/-/-pyrazolo[4,3-c/]pyhmidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1 - ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dih ydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-

(hydroxymethyl)pyrrolidin-1 -yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5- carboxamide, 3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3- d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide; an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin,

(1 α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)- 3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic

acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3- chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1 R,5R,6S)-6- (aminonnethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl- cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1 -(1 H-tetrazol-5-yl methyl )- cycloheptyl]-methylannine, (3S,4S)-(1 -aminonnethyl-3,4-dinnethyl-cyclopentyl)- acetic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3R,4R,5R)-3-amino-4,5- dimethyl-heptanoic acid, (3R,4R,5R)-3-amino-4,5-dinnethyl-octanoic acid, (3S,5R)-3-aminonnethyl-6-cyclopropyl-5-nnethylhexanoic acid, (3S,5R)-3- anninonnethyl-6-cyclobutyl-5-nnethylhexanoic acid and (3S,5R)-3-aminonnethyl-6- cyclopentyl-δ-nnethylhexanoic acid;

• a cannabinoid;

• metabotropic glutamate subtype 1 receptor (mGluRI ) antagonist;

• a serotonin reuptake inhibitor such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cehclamine and trazodone;

• a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buprophon, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

• a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;

• an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1 - iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1 -iminoethyl)-amino]ethyl]-4,4- dioxo-L-cysteine, S-[2-[(1 -iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2- amino-2-methyl-7-[(1 -iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-3-amino-4- hydroxy-1 -(δ-thiazolyO-butyllthiol-δ-chloro-S-pyhdinecarbonitrile; 2-[[(1 R,3S)-3- amino-4-hydroxy-1 -(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino- 4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutan ol,

2-[[(1 R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile, 2-[[(1 R,3S)-3- amino-4-hydroxy- 1 -(5-thiazolyl)butyl]thio]-5- chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2- carboxamidine, or guanidinoethyldisulfide; • an acetylcholinesterase inhibitor such as donepezil;

• a prostaglandin E ₂ subtype 4 (EP4) antagonist such as λ/-[({2-[4-(2-ethyl-4,6- dimethyl-I H-imidazo^.S-clpyridin-i -ylJphenyllethylJanninoJ-carbonyl]^- methylbenzenesulfonamide or 4-[(1 S)-1 -({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid; • a leukotriene B4 antagonist; such as 1 -(3-biphenyl-4-ylmethyl-4-hydroxy- chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)- 3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,

• a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1 -methyl-2-quinolone (ZD-2138), or

2,3,5-thmethyl-6-(3-pyhdylmethyl),1 ,4-benzoquinone (CV-6504);

• a sodium channel blocker, such as lidocaine;

• a 5-HT3 antagonist, such as ondansetron;

• glycosaminoglycan layer replacer, such as pentosan polysulphate (Elmiron - trade mark);

• a beta-3 agonist, such as YM-178 (mirabegron or 2-amino-N-[4-[2-[[(2R)-2- hydroxy-2-phenylethyl]amino]ethyl]phenyl]- 4- thiazoleacetamide), solabegron, KUC-7483 (ritobegron or 2-[4-[2-[[(1 S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1 - methylethyl]amino]ethyl]-2,5-dimethylphenoxy]-acetic acid) or AK-134; • a nerve growth factor blocker or antibody, such as tanezumab, MNAC-13 or PG- 110 (alpha-D11 );

• an anti-histamine, such as hydroxyzine;

• a H ₂ -antagonist, such as cimetidine;

• silver nitrate; • a steroid;

• doxorubicin;

• chondroitin sulphate;

• disodium chromoglycate;

• oxychlorosene (Clorpactin - trade mark);

• an immunosuppressant, such as cyclosporine; and

• a beneficial agent for intravesical administration, e.g. dimethyl sulphoxide (Rimso-50) (intravesical), a hepahnoid (e.g. heparin or hyaluronic acid (Cystistat

- trade mark), capsaicin, resiniferatoxin, Bacillus Calmette-Guerin (BCG), lignocaine / lidocaine (alone or in combination with sodium bicarbonate and/or heparin) or oxybutinin:

and the pharmaceutically acceptable salts and solvates thereof.

Generally, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or

powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion on Therapeutic Patents, IJ. (6), 981-986, by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower al kyl -substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, is water-soluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Alternatively, (3S,5R)-3- aminomethyl-5-methyloctanoic acid, or a salt thereof, may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste- masking agents.

Films including (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations useful for (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1 -14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may also be administered directly into the blood stream, into muscle, or into an internal organ.

Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intravesical, intramuscular, intrasynovial and subcutaneous. Intravesical administration is particularly preferred. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, urinary catheters and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and semi-solids and suspensions comprising drug-loaded poly(c//-lactic- coglycolic)acid (PGLA) microspheres.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may also be administered topically, (intra)dermally, or transdermal^ to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams,

ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2- tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be

achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, per actuation and the actuation volume may vary from 1 μl to 10Oμl. A typical formulation may comprise (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a prefilled capsule, blister or pocket, or by a system that utilises a gravimetrically fed dosing chamber. Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 1 to 5000μg of (3S,5R)-3- aminomethyl-5-methyloctanoic acid, or a salt thereof. The overall daily dose will typically

be in the range of from 1 μg to 20mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Inasmuch as it may desirable to administer a combination of active compounds it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, may conveniently be combined in the form of a kit suitable for co-administration of the compositions.

Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains (3S,5R)-3-aminomethyl-5-methyloctanoic acid, or a salt thereof, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a salt thereof, is typically in the range of from 1 mg to 80mg depending, of course, on the mode of administration. For example, oral or intravenous administration may require a total daily dose of from 2mg to 60mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

Pain relief or relief from lower urinary tract symptoms may be characterized by time course of relief. Accordingly, in some embodiments, relief is observed within about 24 hours after administration of the compound. In other embodiments, relief is observed within about 36, 48, 60, 72 hours or 4 days after administration of the compound. In some embodiments, frequency and/or intensity of pain and/or lower urinary tract symptom is diminished, and/or quality of life of those suffering the disease is improved. In some embodiments, pain relief is provided for duration of at least about 7 days, at

least about 14 days, at least about 21 days, at least about 28 days, at least about 35 days, at least about 42 days, at least about 49 days, at least about 56 days, at least about 63 days, at least about 70 days, at least about 77 days, at least about 84 days, at least about 180 days, or longer after a single dose of the compound.

Pain relief or relief from lower urinary tract symptoms may be characterized by a validated patient-reported outcome measure such as a change in a pain numerical rating scale (NRS), a change in the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), a change in the O'Leary-Sant Interstitial Cystitis Problem Index (ICPI), a change in the Pelvic Pain and Urgency/Frequency (PUF) symptom score and/or changes in micturition variables including micturition frequency, nocturnal frequency, incontinence episode frequency, mean volume voided per micturition, mean interstitial cystitis pain severity per urinary event, urinary urgency episodes, average sleep disturbance score, average pain associated with sexual activity pain score, global response assessment, patient reported treatment impact assessment, treatment failure, biomarkers, safety endpoints, global response assessment and/or pharmacokinetic measures. Biomarkers may include NGF, glycoprotein-51 (GP-51 ), antiproliferative factor (APF) and HB- Epidermal growth factor (HB-EGF), amongst others.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.

Clinical study protocol

Patients with clinical diagnosis of IC can be treated with (3S,5R)-3-aminomethyl-5- methyloctanoic acid, or a pharmaceutically acceptable salt or solvate thereof, to confirm the safety and efficacy of the compound in treating one or more pain and lower urinary tract symptoms associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome. The patients to be treated will have moderate to severe interstitial cystitis as defined by a Pelvic Pain and Urgency/Frequency (PUF - Parsons et al, Urology, 60,573-578(2002)) score of at least 13 and an O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI - O'Leary et al, Urology, 49(Suppl 5A), 58-63(1997)) score of at least 7 at pre-treatment screening. Other inclusion criteria are to be met, including exclusion of confusable diseases in previous or current cystoscopy. At randomization, patients must have a mean worst daily pain score of 4 or greater calculated from the last 7 days of pain scores prior to randomization. Patients who do not meet all of the inclusion criteria or meet one or more exclusion criteria will be considered a screen failure and are not to be randomized into the study.

The efficacy of multiple doses of the compound compared to a placebo in the treatment of pain and/or lower urinary tract symptoms associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome is to be evaluated. The compound is to be administered orally to the patients for up to 12 weeks at doses of 15 or 30mg b.i.d.. All patients randomized to the compound will receive an initial dose of 15mg b.i.d. for the first 2 weeks of the 12 week dosing period.

The primary endpoint is to be analysed 12 weeks after dosing with the compound. Assessments at weeks 1 to 11 (inclusive) post-dose are to be included as secondary endpoints. Patients are to be evaluated in the clinic at weeks 2, 6 and 12 when their symptoms will be assessed. The primary endpoints will be a change in an 11 -point pain numerical rating scale (NRS) and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) score. Other secondary endpoints include O'Leary-Sant Interstitial Cystitis Problem Index (ICPI - O'Leary et al, Urology, 49(Suppl 5A), 58-63(1997)), ICSI plus ICPI, Pelvic Pain and Urgency/Frequency (PUF), micturition diary variables recorded by

the patient during the study period including including micturition frequency, nocturnal frequency, incontinence episode frequency, mean volume voided per micturition, mean interstitial cystitis pain severity per urinary event, urinary urgency episodes, average sleep disturbance score, average pain associated with sexual activity pain score, global response assessment, patient reported treatment impact assessment, treatment failure, safety endpoints and/or pharmacokinetic measures.

Administration of the compound is for the purpose of alleviating pain and/or a lower urinary tract symptom associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome in the patients to be treated as described above.

Example of an oral capsule formulation of (3S,5R)-3-aminonnethyl-5-nnethyloctanoic acid

Composition:

Preparation:

The above components are passed through a suitable screen in the following order: - microcrystalline cellulose (50% by weight of the required amount)

(3S,5R)-3-aminomethyl-5-methyloctanoic acid - sodium starch glycolate

- microcrystalline cellulose (50% by weight of the required amount).

The resulting mixture is then blended, screened and further blended. The blend is then encapsulated in gelatin capsules and polished. The capsules are stored at 2-8 ⁰ C.

Affinity of (3S,5R)-3-aminonnethyl-5-nnethyloctanoic acid for the alpha-2-delta calcium channel subunit

The binding affinity of (3S,5R)-3-aminomethyl-5-nnethyloctanoic acid for the alphas- delta subunit was determined by measuring the displacement of ³ [H]-gabapentin from membranes prepared from pig cerebral cortex and from HEK293 cells expressing the recombinant alpha-2-delta-1 or alpha-2-delta-2 subunits of voltage-gated calcium ion channels.

Membranes were prepared from porcine cerebral cortex and from HEK293 cells expressing either the recombinant porcine alpha-2-delta-1 or human alpha-2-delta-2 subunit. A scintillation proximity assay was performed with wheat germ agglutinin beads that examined the ability of the compounds to compete for ³ [H]-gabapentin binding to membranes. Non-specific binding was determined in the presence of 10 micromolar unlabelled (cold) pregabalin. The amount of bound ³ [H]-gabapentin was determined by liquid scintillation counting.

(3S,5R)-3-aminomethyl-5-methyloctanoic acid inhibited specific ³ [H]-gabapentin binding in the 3 membrane preparations. The affinities (K ₁ values) for inhibition of specific ³ [H]- gabapentin binding to membranes prepared from pig cortex and cells expressing alpha- 2-delta-1 or alpha-2-delta-2 are presented in Table 1 below and the results represented graphically in Figure 1 .

Table 1

Affinities of (3S,5R)-3-aminonnethyl-5-nnethyloctanoic acid for inhibiting specific ³ FHI- gabapentin binding

N= 3 to 5 experiments

FIGURE 1 : Displacement of [ ³ H]Gabapentin (30 nM) with (3S,5R)-3-aminomethyl-5- methyloctanoic acid (PD-0299685-0002) or gabapentin Using Membrane Proteins Prepared from HEK 293 Cells Expressing Recombinant Porcine alpha-2-delta-1 Subunits

0.0001 0.001 0.01 0.1 10 100

Gabapentin or PD 0299685-0002 (niM)

(3S,5R)-3-aminomethyl-5-methyloctanoic acid and gabapentin cause a complete and concentration-dependent inhibition of [ ³ H]gabapentin binding to membranes prepared from cells expressing the alpha-2-delta-1 subunit (values are the means +/- SEM; n=3 to 5 experiments).