WO2006056874A1

WO2006056874A1 - Salt form

Info

Publication number: WO2006056874A1
Application number: PCT/IB2005/003550
Authority: WO
Inventors: Neil Feeder; Matthew Neil Johnson; Philip Charles Levett
Original assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Ltd Great Britain; Pfizer Corp SRL
Priority date: 2004-11-25
Filing date: 2005-11-18
Publication date: 2006-06-01
Anticipated expiration: 2007-05-25

Abstract

The present invention provides the benzenesulphonate salt of (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid which has the following structural formula (II).This compound is particularly suitable as a drug substance and is useful in the treatment of pain, epilepsy and other conditions.

Description

Salt form

The present invention relates to the benzenesulphonate salt of (1α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid and to pharmaceutical compositions comprising and to processes for making such a benzenesulphonate salt. The invention further relates to the use of the salt and its compositions in the treatment of various conditions, particularly in the treatment of neuropathic and visceral pain and gastrointestinal disorders.

The compound (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid, having the structural formula (I):

(0

its hydrochloride salt and processes for the manufacture of both, are disclosed in WO-A-01 /28978 (see Table 1 , page 8, Example 6 and Methods 2A to 2C, 4A, 4B and 5). This compound is described as being useful in the treatment of epilepsy and other conditions. Its use in the treatment of visceral pain and gastrointestinal disorders is disclosed in WO-A-02/058680.

If a compound is to be developed as a drug, it is important to provide a form of that compound (commonly known as a drug substance) which can be reliably prepared and purified on a large scale and which does not degrade on storage. Such characteristics are normally found in a drug substance which is crystalline and of high melting point; a high-melting point crystalline solid tends to be easy to purify by re-crystallisation and stable on storage. Furthermore, the drug substance must be suitable for formulation in a dosage form chosen according to the intended route of administration. The most popular kind of pharmaceutical formulation is a tablet or capsule, such a dosage form being easily and conveniently administered via the oral route. For formulation as a tablet or capsule, a drug substance should be non-hygroscopic and compressible. Hygroscopicity can lead to problems with processing and a short shelf life. It should also possess a solubility and rate of dissolution that leads to rapid bioavailability on exposure to the gastric environment.

Neither the free base of (1 α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid (which actually exists as a zwitterion), nor its hydrochloride salt, possesses the requisite combination of such favourable properties; neither of these compounds is therefore an entirely suitable drug substance. In particular, the free base shows instability in the presence of certain excipients commonly used in the manufacture of tablets, forming a lactam impurity and is also hygroscopic, absorbing moisture to form a monohydrate. Such monohydrate formation is enhanced by compression which is particularly undesirable. The hydrochloride salt is even more unstable to atmospheric moisture, absorbing enough water to eventually form a solution (a process known as deliquescence).

There therefore exists a need to provide a form of (1α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid which is a suitable drug substance. Many unsuccessful experiments have been performed to this end and, in particular, salt forms other than the hydrochloride have been studied. Unfortunately, many salt forms of (1 cc,3α,5α)-

[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid do not readily form or are not crystalline. The citrate, sulphate, hydrogensulphate, olamine, tromethamine, L- tartrate, L-lactate, L-lysine, calcium, potassium, magnesium and ammonium salts all fall into this category. Of those salts of (1 α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid which are crystalline, many fail to meet one or more other criteria as set out above. For instance, the hydrobromide salt, in common with the hydrochloride salt, is deliquescent. The fumarate salt has a tendency to transform into another form thought to be a solvate. The phosphate salt also seems to transform into other solvated forms. These results demonstrate the difficulties encountered in providing a suitable form of (1 α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid and the unpredictable nature of such research. Unexpectedly, we have now found that the benzenesulphonate (besylate) salt of (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid is a suitable drug substance and possesses a highly favourable combination of properties. It is stable, both to degradation and hydration, and can be stored for long periods without deterioration, either with or without formulation excipients. It is a crystalline solid with a high melting point and is easily formulated with standard excipients. It crystallizes as long needles and laths, with no changes to crystallinity, polymorph or hydration state on milling or compaction. Compaction does not affect the hygroscopicity of the salt. Furthermore, it has acceptable dissolution and solubility characteristics.

The present invention therefore provides the benzenesulphonate salt of (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid which has the following structural formula (II):

OD

(1 α,3α,5α)-[3-(Aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate (II) may be prepared by treating the free base (see formula (I) above) with benzenesulphonic acid. The reaction is preferably carried out as a solution in a mixture of water and isopropyl alcohol (IPA).

The free base of formula (I) may itself be prepared by treating the hydrochloride salt of formula (III):

(III) with aqueous sodium hydroxide.

The hydrochloride salt of formula (III) may be prepared by treating the lactam of formula (IV):

with aqueous hydrochloric acid as described in WO-A-01 /28978 and WO-A- 02/058680.

A further, and more advantageous method for preparing (1 α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate comprises the direct reaction of the lactam of formula (IV) with benzene sulphonic acid. In a typical procedure, a solution of the compound of formula (IV) in a suitable solvent (e.g. aqueous dimethylacetamide) is treated with benzene sulphonic acid and heated, typically to about 11 O⁰C.

The present invention includes all polymorphic and pharmaceutically acceptable isotopically-labelled forms of (1α,3α,5α)-

[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate. In an isotopically-labelled form, one or more atoms are replaced by an atom or 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.

Suitable isotopes include isotopes of hydrogen, such as ²H and ³H; carbon, such as ¹¹C, ¹³C and ¹⁴C; nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵0, ¹⁷O and ¹⁸O; and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds, such as those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, 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. ²H, 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 ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Since (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid is an alpha- 2-delta ligand it may be used, in the form of the benzenesulphonate salt disclosed by the present invention and otherwise, in the treatment of a variety of conditions, particularly in the treatment of pain (especially neuropathic pain).

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1 -164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post¬ surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141 -S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (Gl) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro¬ esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.

Other types of pain include:

• pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non- articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis; • heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia; • head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and

• orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

Apart from pain, other conditions that may be treated with the besylate salt provided by the present invention include any condition for which an alphas- delta ligand may be prescribed. Alpha-2-delta ligands are particularly useful in the treatment of epilepsy and may also be useful in the treatment of overactive bladder, premature ejaculation, burning mouth syndrome, bladder disorders, faintness attacks, fibromyalgia, hypokinesia, cranial disorders, hot flashes, essential tremor, chemical dependencies and addictions, withdrawal symptoms associated with dependencies or addictions, addictive behaviours, spasticity, arthritis, inflammatory disorders (e.g. rheumatoid arthritis, osteoarthritis, psoriasis), diuresis, premenstrual syndrome, premenstrual dysphoric disorder, tinnitus, gastric damage, Down's syndrome, demyelinating diseases (e.g. multiple sclerosis and amylolateral sclerosis), cerebral vascular disorders due to acute or chronic cerebrovascular damage (e.g. cerebral infarction, subarachnoid haemorrhage or cerebral oedema), head trauma, spinal cord trauma and neuronal damage that occurs, for instance, during stroke, in cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest and in status epilepticus. Alpha-2-delta ligands may also be useful in the treatment of delirium, dementia and amnestic and other cognitive or neurodegenerative disorders (e.g. Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, memory disorder, vascular dementia). They may be useful in the treatment of movement disorders such as akinesias, dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, palsys, akinetic- rigid syndrome and extra-pyramidal movement disorders. They may also be useful in the treatment of sleep disorders, mood disorders, depression, depressive disorders, bipolar disorders, anxiety disorders, borderline personality disorder, schizophrenia, psychotic disorders, behavioural disturbances associated with mental retardation, autistic disorder and conduct disorders. (1 α,3α,5α)-[3-(Aminomethyl)bicyclo[3.2.0]hθpt-3-yl]acetic acid benzenesulphonate (henceforth referred to as the compound of the invention) may be administered alone but will generally 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 the compound of the invention. 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 the compound of the invention 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).

The compound of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.

The use of a hard gelatine capsule for oral administration is particularly preferred with the compound of the invention. Examples of blends suitable for filling into gelatine capsules are (a) a mixture of the compound of the invention and talc (e.g. a 85:15 mixture, respectively, by weight); and (b) a mixture of the compound of the invention, lactose monohydrate, maize starch and talc (e.g. a 74.5:10.6:7.45:7.45 mixture, respectively, by weight). Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules 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.

The compound of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the compound of the invention 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, 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 alkyl- 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 also 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 tablet ingredients include anti-oxidants, colouring agents, 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 compaction 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).

The compound of the invention may also be orally administered in the form of a consumable oral film for human or veterinary use. Such a film is typically a pliable water-soluble or water-swellable thin film dosage form which may be rapidly dissolving or mucoadhesive and typically comprises the compound of the invention, 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.

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 film ingredients include anti-oxidants, colouring agents, 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 in accordance with the invention 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 vacuum drying.

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

Suitable modified release formulations for the purposes of the invention 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-A-00/35298.

The compound of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Such parenteral administration may be via the intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous route. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors 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 non-aqueous 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.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release. Thus compound of the invention may be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted depot providing modified release of the compound of the invention.

Examples of such formulations include drug-coated stents and poly(c/Alactic- coglycolic)acid (PGLA) microspheres.

The compound of the invention may also be administered topically to the skin or mucosa, i.e. dermally or transdermally. 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. ScL, 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™) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release.

The compound of the invention 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 or 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. 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 of the invention 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 of the invention, 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 the compound of the invention per actuation and the actuation volume may vary from 1 μl to 10Oμl. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavouring agents, 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 includes delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

The compound of the invention may be administered rectally or vaginally, in the form, for example, 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 includes delayed, sustained, pulsed, controlled, targeted and programmed release.

The compound of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methyl cellulose or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted, or programmed release.

The compound of the invention may be combined with a soluble macromolecular entity, such as a cyclodextrin or a suitable derivative thereof or a polyethylene glycol-containing polymer, in order to improve its 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 WO-A-91/11172, WO- A-94/02518 and WO-A-98/55148.

For administration to human patients, the total daily dose of the compound of the invention will typically be in the range 0.01 mg/kg to 100 mg/kg depending, of course, on the mode of administration. 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. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

The compound of the invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, the compound of the invention 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, cyclobenzaprine, 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, or 4-amino-6,7-dimethoxy-2-(5-methane- sulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

• a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline 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]- naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]- methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]- methylamino]-2-phenylpiperidine (2S.3S); • a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, 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_{1 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®;

• 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]ρyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2- methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2^l,1 ':6,1]-pyrido[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-7H-pyrazolo[4,3-Gdpyrimidin-7-one, 5-(5-acetyl-2- propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-c/]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1- ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-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, (1α,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-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3- (1 -aminomethyl-cyclohexylmethylMH-p ,2,4]oxadiazol-5-one, C-[1 -(1 H- tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1 -aminomethyl- 3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl- octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-

5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

• a cannabinoid;

• metabotropic glutamate subtype 1 receptor (mGluRI) antagonist; • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

• a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, 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 -(5-thiazolyl)-butyl]thio]-5-chloro-3- pyridinecarbonitrile; 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-thiazolebutanol, 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 E₂ subtype 4 (EP4) antagonist such as Λ/-[({2-[4-(2-ethyl- 4,6-dimethyl-1 H-imidazo[4,5-c]pyhdin-1-yl)phenyl]ethyl}amino)-carbonyl]- 4-methylbenzenesulfonamide or 4-[(1 S)-1-({[5-chloro-2-(3- fluorophenoxyjpyridin-s-yllcarbonyljaminojethyljbenzoic 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-trimethyl-6-(3-pyridylmethyl),1 ,4-benzoquinone (CV- 6504);

• a sodium channel blocker, such as lidocaine;

• a 5-HT3 antagonist, such as ondansetron;

and the pharmaceutically acceptable salts and solvates thereof.

A combination with a PDE5 inhibitor, such as sildenafil or a pharmaceutically acceptable salt thereof, for the treatment of neuropathic pain, is worthy of specific mention, as is a combination with a 5-HT_{I B/I}D agonist such as eletriptan, or a pharmaceutically acceptable salt thereof, for the treatment of migraine. 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 the compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains the compound of the invention, 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.

Such a kit is particularly suitable for administering different dosage forms, for example, oral and parenteral dosage forms, 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.

The following examples illustrate the preparation of (1α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate.

Example 1

Preparation of (1α.3α.5αH3-(Aminomethyl)bicvclor3.2.0l hept-3-yli acetic acid

(1 α,3α,5α)-[3-(Aminomethyl)bicyclo[3.2.0]hept-3-yl] acetic acid hydrochloride salt

(380.0 g, see WO-A-01 /28978) was dissolved in water (1520 ml). The solution was filtered and adjusted to pH 7.5 using a 20 weight % aqueous solution of sodium hydroxide (353 ml). The resultant suspension was stirred for 1 hour at about 0-4⁰C. The precipitate was filtered and washed with iced water (500 ml). The filter cake was then slurried in 2-propanol (2.5 litres) and heated to reflux. After cooling to room temperature, the solid was filtered and washed with 2- propanol (250 ml). The filter cake was then further slurried in 2-propanol (2.5 litres) and again heated to reflux. After cooling to room temperature, the product was filtered, washed with 2-propanol (250 ml) and dried in vacuo at 50⁰C to constant weight to give the title compound (277 g).

When analysed by differential scanning calorimetry (measured using a TA Instruments Q1000), the zwitterion shows a sharp endothermic melting peak around 203⁰C.

Example 2

Preparation of (1α,3α,5α)-[3-(aminomethyl)bicvclor3.2.01hept-3-yllacetic acid benzenesulphonate

(1α,3α,5α)-[3-(Aminomethyl)bicyclo[3.2.0]hept-3-yl] acetic acid (7 kg; 38.2 mol) was added to a mixture of isopropanol (21 litres) and water (10 litres). The reaction mixture was heated to 4O⁰C and stirred for 20 minutes. A 70 weight % solution of benzene sulphonic acid in water (8.64 kg of acid; 38.2 mol) was then added over 40 minutes. Water (1.41 litres) was added and the mixture was stirred for a further 20 minutes. The reaction mixture was concentrated under vacuum until 10 litres of solvent remained. Isopropanol (24.5 litres) was added and the reaction mixture was again concentrated under vacuum to until 10 litres of solvent remained. This process was repeated a further five times until all water had been removed. The slurry obtained was cooled to 2O⁰C and stirred overnight. The product was collected by filtration and dried in a vacuum oven at 50⁰C overnight to yield the title compound (12.4 kg). ¹H-NMR (400 MHz, D₂O): δ = 7.68 (d, 2H), 7.50 (m, 3H), 2.82 (s, 2H), 2.64 (s, 4H), 2.20 (m, 2H), 1.90 (dd, 2H), 1.60 (m 4H).

When analysed by differential scanning calorimetry (DSC) (measured using a Perkin Elmer Diamond DSC with a sample size of 2.991 mg at a heating rate of 2O⁰C per minute in an aluminium pan with a hole in the lid), the benzenesulphonate salt shows a sharp endothermic melting peak around 182°C followed by an exothermic recrystallisation event around 184⁰C and a second endothermic melting peak around 190⁰C. The DSC trace is shown in Figure 1. The peak at around 182⁰C is due to the initial melting of the benzenesulphonate salt (Form A) and the peak at around 190⁰C is due to the melting of a separate high-temperature polymorph (Form B) of the benzenesulphonate salt. This high- temperature polymorph reverts rapidly to the stable low-temperature crystalline form on cooling.

When characterised by powder X-ray diffraction (PXRD), the benzenesulphonate salt (Form A) gives the pattern shown in Figure 2. The main characteristic peaks are given in Table 1 below.

Table 1 - Characteristic PXRD peaks for Form A

When characterised by powder X-ray diffraction (PXRD), the benzenesulphonate salt Form B gives the pattern shown in Figure 3. The main characteristic peaks are given in Table 2 below. Table 2 - Characteristic PXRD peaks for Form B

The powder X-ray diffraction patterns were determined using a Bruker-AXS Ltd. D4 powder X-ray diffractometer fitted with an automatic sample changer, a theta- theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The sample was prepared for analysis by packing the powder into 12mm diameter, 0.25mm deep cavity that had been cut into a silicon wafer specimen mount. The specimen was rotated whilst being irradiated with copper K-alphai X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 40kV/40mA. The analyses were performed with the goniometer running in continuous mode set for a 5 second count per 0.02° step over a two theta range of 2° to 55° The peaks obtained for Form A were aligned against a silicon reference standard.

2-Theta Angles, d spacings and relative intensities were calculated from the single crystal structure of the benzenesulphonate salt form A using the "Reflex Powder Diffraction" module of Accelrys Materials Studio™ [version 2.2]. Pertinent simulation parameters were in each case:

Wavelength = 1.540562 A (Cu Ka); Polarisation Factor = 0.5; and Pseudo-Voigt Profile (U = 0.01 , V = -0.001 , W = 0.002).

The calculated pattern is shown in Figure 4. The main characteristic peaks are given in Table 3 below.

Table 3 - Characteristic PXRD peaks from the calculated pattern for Form A

Example 3

Preparation of πα.3α.5αH3-(aminomethvObicvclor3.2.01hept-3-yllacetic acid benzenesulphonate

(1α,3α,5α)-Spiro[bicyclo[3.2.0]heptane-3,3'-pyrrolidin]-5'-one (10 g, 60.5 mmol, see WO-A-01 /28978) was added to a mixture of water (36.2 ml) and N₁N- dimethylacetamide (1.5 ml). A 70wt% solution of benzene sulphonic acid in water (28.7 g, 182 mmol) was then added. The reaction mixture was heated under reflux and stirred for 48 hours. The reaction was cooled to 80°C and washed with toluene (2x50 ml). The aqueous layer was stirred overnight at room temperature. The crude product was collected by filtration and dried in a vacuum oven at 50°C overnight. The crude product was then suspended water (34 ml) at room temperature and stirred overnight. The product was collected by filtration and dried in a vacuum oven at 50°C for 24 hours to yield the title compound (14.3 g). ¹H-NMR (400 MHz, D₂O): δ = 7.68 (d, 2H), 7.50 (m, 3H), 2.82 (s, 2H), 2.64 (s, 4H), 2.20 (m, 2H), 1.90 (dd, 2H), 1.60 (m 4H).

Some of the advantages of the benzenesulphonate salt provided by the present invention are demonstrated by the experimental data presented below.

Chemical stability in the presence of standard excipients

The free base (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid and its benzenesulphonate salt were formulated with three key tablet/capsule excipients Aerosil (colloidal silicon dioxide), Avicel PH102 (microcrystalline cellulose) and 200 mesh talc. In each case a 1 :1 binary mixtures of drug (500mg) and excipient (500mg) were prepared. Six aliquots (62.5 mg) of each blend were weighed into pre-cleaned 4 dram glass vials, which were sealed with black screw top lids. Duplicate samples of each blend were then stored at the following conditions: (a) 25°C/60%RH for seven days; (b) 40°C/75%RH for seven days; and (c) 25°C/60%RH for six days and 90⁰C over 24 hours. The screw top lids on the samples stored at 40°C/75%RH were replaced with muslin during the storage period to maximise the exposure of the blends to this high humidity condition and allow ingress of moisture to the sample vials. Following storage, 5 ml of diluent was added to each of the samples, which were then extracted and analysed by gradient reverse phase HPLC for purity.

The benzenesulphonate salt of (1 α,3α,5α)-

[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid was found to be more chemically stable than the free base, showing lower levels of degradation under identical stress conditions. In general, the free base samples contained a higher number of significant impurities and a higher total level of degradation. The levels of the main degradant (lactam of formula IV) are presented in Table 4 (RT = room temperature, RH = relative humidity). The levels of this impurity were, in general, higher in the free base samples, especially at higher temperature.

Table 4 - Stability data

Thermogravimetric analysis

Thermogravimetric Analysis (TGA) was performed on (1 α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate using a Perkin Elmer Pyris TGA3 apparatus with a sample size of 8.234mg in a platinum pan heated at 2O⁰C per minute. The results are shown in Figure 5. The sample analysed shows a total weight loss of 0.43% from when heated from room temperature to 200⁰C. This will include losses during melt through to degradation. There is no evidence of any hydration or solvation.

Dynamic vapour sorption

Dynamic Vapour Sorption (DVS) was performed on (1 α,3α,5α)- [3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid benzenesulphonate using an SMS DVS 1000 apparatus, in the range 0-90-0% relative humidity, in 15% steps, at 30⁰C. The results are shown in Figure 6. The fluctuations seen are due to noise at the baseline level. The total increase in weight at 90% relative humidity is around 0.01 % of dry weight, demonstrating that the sample is non-hygroscopic and shows no evidence of hydration.

Claims

1. The benzenesulphonate salt of (1 α,3α,5α)-

[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid which has the following structural formula (II):

(II)

2. A pharmaceutical composition comprising the benzenesulphonate salt claimed in claim 1 and a pharmaceutically acceptable excipient.

3. The benzenesulphonate salt claimed in claim 1 , for use as a medicament.

4. The use of the benzenesulphonate salt claimed in claim 1 for the manufacture of a medicament for the treatment of pain.

5. A method of treating pain comprising administering to a mammal in need of such treatment, an effective amount of the benzenesulphonate salt claimed in claim 1.

6. A combination of the benzenesulphonate salt claimed in claim 1 and a second pharmacologically active substance.

7. A process for preparing the benzenesulphonate salt claimed in claim 1 comprising the reaction of a compound of formula (I)

(I) (I)

with benzenesulphonic acid.

8. A process for preparing the benzenesulphonate salt claimed in claim 1 comprising the reaction of a compound of formula (IV)

(IV)

with benzenesulphonic acid.