HK1113092A - Use of reboxetine for the treatment of pain - Google Patents

Description

Use of reboxetine for the treatment of pain

Technical Field

The present invention relates to some novel uses of (S, S) -or racemic reboxetine (reboxetine) for pain.

Background

U.S. Pat. No. 4,229,449 discloses the compound (RR, SS) -2- [ alpha- (2-ethoxyphenoxy) benzyl ] morpholine and pharmaceutically acceptable salts thereof, which have useful antidepressant effects. This compound is also known as racemic reboxetine.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the chiral center of the molecule. For a particular chemical structure, each of a pair of enantiomers is identical, except that they are non-coincident mirror images of the other. Particular stereoisomers may also be referred to as enantiomers, and 1: 1 mixtures of these isomers are often also referred to as enantiomeric or racemic mixtures.

When two chiral centers are present in a molecule, they can have four stereoisomers: (R, R), (S, S), (R, S), and (S, R). Of these isomers, (R, R) and (S, S) are examples of one pair of enantiomers (mirror images of each other), which generally have the same chemical nature and melting point as the other enantiomer pairs. However, the mirror images of (R, R) and (S, S) do not coincide with (R, S) and (S, R). This relationship is called diastereoisomerism.

Chemically, racemic reboxetine has two chiral centers, defined as the (R, R) and (S, S) enantiomer pairs. Currently, reboxetine is only commercially available as a racemic mixture of enantiomers, with the ratio of (R, R) to (S, S) being 1: 1, and reference to the generic name "reboxetine" herein refers to such an enantiomeric or racemic mixture. Reboxetine with EDRONAX^TM、PROLIFT^TM、VESTRA^TMAnd NOREBOX^TMThe trade name of (2) is marketed.

(S, S) -reboxetine and related compounds are disclosed in GB-A-2167407, which is incorporated by reference in its entirety.

Reboxetine does not function as well as most antidepressants. Unlike tricyclic antidepressants, even selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), reboxetine does not work in the 8-OH-DPAT hypothermia test, indicating that reboxetine is not an SSRI. See Brian E.Leonard, "Noradrenaline in basic modules of expression," European neuropsychoharmacol, 7suppl.1 pp.S11-6 and S71-3(April1997), which are incorporated herein by reference in their entirety. (S, S) -reboxetine is a selective norepinephrine reuptake inhibitor with only marginal 5-hydroxytryptamine reuptake inhibitory activity, and no dopamine reuptake inhibitory activity. Reboxetine showed no anticholinergic binding activity and essentially no monoamine oxidase (MAO) inhibitory activity in different animal models.

It is known that (S, S) -reboxetine has a greatly improved selectivity for norepinephrine reuptake compared to 5-hydroxytryptamine reuptake. Thus, WO 01/01973 discloses a method for selectively inhibiting norepinephrine reuptake comprising the step of administering to an individual a therapeutically effective amount of a composition comprising para-5-hydroxytryptamine (K)_i) Noradrenaline (K)_i) A compound having a pharmaceutical selectivity of at least about 5000. This document further discloses some novel uses of (S, S) -and racemic reboxetine, including the treatment of chronic pain, peripheral neuropathy, fibromyalgia and other somatic diseases, and migraine.

Treatment to ameliorate the symptoms of many types of pain is an important medical need. We have now surprisingly found that (S, S) -and racemic reboxetine can be further used to treat pain conditions other than those disclosed above.

An α -2- δ receptor ligand is any molecule that is capable of binding to any subset of the human calcium ion channel α -2- δ subunit. The alpha-2-delta subunit of the calcium channel comprises a number of receptor subclasses, which have been described in the literature: see, for example, n.s.gee, j.p.brown, v.u.disananayake, j.offord, r.thurlow, and g.n.woodruff, J-Biol-Chem 271 (10): 5768-76, 1996, (type 1); gong, j.hang, w.kohler, z.li, and T-z.su, j.membr.biol.184 (1): 35-43, 2001, (types 2 and 3); e.marais, n.klugbauer, and f.hofmann, mol.pharmacol.59 (5): 1243-1248, 2001, (types 2 and 3); and n.qin, s.yagel, m.l.momplaisir, e.e.codd, and m.r.d' andrea.mol.pharmacol.62 (3): 485- "496, 2002, (type 4). They are also known as GABA analogs.

A number of indications have been described for alpha-2-delta ligands. The most recognized alpha-2-delta ligand, gabapentin (gabapentin, Neurontin)) 1- (aminomethyl) -cyclohexylacetic acid, was first described in patent family publications including US-A-4024175. The compounds are approved for the treatment of epilepsy and neuropathic pain.

The second α -2- δ ligand, pregabalin (pregabalin), (S) - (+) -4-amino-3- (2-methylpropyl) butanoic acid, is described in EP- ｃA-641330 as an anticonvulsant for the treatment of epilepsy and in EP- ｃA-934061 for the treatment of pain.

The α -2- δ ligands are further described in the following documents.

International patent application No. WO-A-01/28978 describes A series of novel bicyclic amino acids having the following structural formulA:

wherein n is an integer from 1 to 4. When stereocenters are present, each center can be independently R or S, and preferred compounds are those of the above formulas I-IV, wherein n is an integer from 2 to 4.

International patent application No. WO-A-02/85839 describes α -2- δ ligands having the following structural formulA for use in the treatment of A number of indications, including pain:

wherein R is¹And R²Each independently selected from the group consisting of H, straight or branched chain alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl and benzyl, with the proviso that R is other than in the tricyclic octane compounds of formula (XVII)¹And R²Not hydrogen at the same time.

International patent application No. WO-A-03/082807 describes A compound having the following structural formulA I:

wherein R is₁Is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₂is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group; or

R₁And R₂Taken together with the carbon atom to which they are attached form a three to six membered cycloalkyl ring;

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-n (h) -, or pyridyl-n (h) -, wherein each of the foregoing alkyl moieties may be optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms, wherein said phenyl and said pyridyl and said phenyl- (C) are substituted with one or more fluorine atoms₁-C₃) Alkyl and said pyridyl- (C)₁-C₃) The phenyl and pyridyl moieties of the alkyl group, may optionally be substituted with 1 to 3 substituents, preferably 0 to 2 substituents, respectively, independently selected from chloro, fluoro, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) Alkyl, and optionally substituted1 to 3 fluorine atoms substituted (C)₁-C₃) An alkoxy group;

R₄is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₅is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group; and is

R₆Is hydrogen or (C)₁-C₆) An alkyl group.

International patent application No. WO-A-04/039367 describes A compound having the following structural formulA (I), or A pharmaceutically acceptable salt thereof:

wherein X is O, S, NH or CH₂And Y is CH₂Or a direct bond, or Y is O, S or NH and X is CH₂(ii) a And is

R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, wherein any ring may be optionally substituted with one or more substituents independently selected from the group consisting of:

halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₁-C₆Alkoxy, hydroxy C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl, perfluoro C₁-C₆Alkyl, perfluoro C₁-C₆Alkoxy radical, C₁-C₆Alkylamino radical, di-C₁-C₆Alkylamino radical, amino radical C₁-C₆Alkyl radical, C₁-C₆Alkylamino radical C₁-C₆Alkyl, di-C₁-C₆Alkylamino radical C₁-C₆Alkyl radical, C₁-C₆Acyl radical, C₁-C₆Acyloxy, C₁-C₆Acyloxy C₁-C₆Alkyl radical, C₁-C₆Acylamino group, C₁-C₆Alkylthio radical, C₁-C₆Alkylthio carbonyl group, C₁-C₆Alkylthio radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylsulfonyl radical, C₁-C₆Alkylsulfonylamino, aminosulfonyl, C₁-C₆Alkylaminosulfonyl, di-C₁-C₆Alkylaminosulfonyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl.

International patent application No. WO-A-05/030700 describes compounds having the following structural formulA (I):

wherein R is₁Is a hydrogen atom or is optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₂is a hydrogen atom or is optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group; or

R₁And R₂Taken together with the carbon atom to which they are attached form a three to six membered cycloalkyl ring;

R₃is a hydrogen atom, (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl, or pyridyl- (C)₁-C₃) Alkyl, wherein the alkyl and cycloalkyl moieties or substituents are optionally substituted with 1 to 5 fluorine atoms, preferably 0 to 3 fluorine atoms, and phenyl and pyridyl substituents and phenyl- (C)₁-C₃) Alkyl and pyridyl- (C)₁-C₃) The phenyl and pyridyl moieties of the alkyl substituents are optionally substituted with 1 to 5 substituents, preferably 0 to 2 substituents, independently selected from chloro, fluoro, amino, nitro, cyano, hydroxy, (C)₁-C₃) Alkylamino, optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) Alkyl, and (C) optionally substituted by 1 to 3 fluorine atoms₁-C₃) An alkoxy group;

R₄is a hydrogen atom or is optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₅is a hydrogen atom or is optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₄and R₅Together with the carbon atom to which they are attached form a 3-to 6-membered cycloalkyl ring; and is

R₆Is a hydrogen atom or (C)₁-C₆) An alkyl group;

with the proviso that R₁、R₂、R₃、R₄、R₅And R₆Not simultaneously hydrogen atoms.

Further specific alpha-2-delta ligands include gabapentin, pregabalin, 3-methyl gabapentin, [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (1 alpha, 3 alpha, 5 alpha) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (2S, 4S) -4- (3-fluoro-phenoxymethyl) -pyrrolidine-2-carboxylic acid, (2S, 4S) -4- (2, 3-difluorobenzyl) -pyrrolidine-2-carboxylic acid, (2S, 4S) -4- (3-fluorobenzyl) proline, (2S, 4S) -4- (3-chlorophenoxy) proline, proline, (3R, 4R, 5R) -3-amino-4, 5-dimethyl-heptanoic acid and (3R, 4R, 5R) -3-amino-4, 5-dimethyl-octanoic acid, or a pharmaceutically acceptable salt thereof.

Gabapentin has been successfully used to treat pain in a large number of patients. For example, M.Backonja et al, JAMA, 280, 1831-1836(1998) report on the efficacy and safety of gabapentin in relieving pain due to diabetic peripheral neuropathy. Patients treated with gabapentin noted a statistical significance in both the primary efficacy index of pain and a number of secondary efficacy indices compared to those receiving placebo. It is noted that in patients with Global Impression Change (this is on the order of 1 to 7, where 1 represents a significant improvement in symptoms, 2 represents a moderate improvement, 3 represents a small improvement, 4 represents no Change, 5 represents a small deterioration, 6 represents a moderate deterioration, and 7 represents a significant deterioration of symptoms), approximately 60% of patients receiving gabapentin have at least a moderate improvement (i.e. 1 or 2 points). See "A randomized, placebo-controlled tertiary", R.H. Dworkkin et al, Neurology 60, 1274-.

As can be seen from the above studies, a proportion of patients suffering from pain, in particular neuropathic pain, still do not respond to treatment with α -2- δ ligands such as gabapentin for a number of reasons which are not yet understood. For the purposes of the present invention, a "patient who does not respond to treatment" is defined as a patient who has little or no improvement in the change in the patient's overall impression, i.e. a score of 3 or more.

Simpson, Journal of Clinical neurological Disease, 3(2), 53-62(2001) reported that gabapentin was effective in the treatment of painful diabetic neuropathy. This document further discloses that patients receiving gabapentin plus venlafaxine (venlafaxine, which is a potent inhibitor of 5-hydroxytryptamine and norepinephrine reuptake, and also a weak inhibitor of dopamine reuptake) show significant improvements in pain relief, mood disorders and quality of life. The authors conclude that additional treatment with venlafaxine is effective in patients who do not respond to gabapentin monotherapy.

We have surprisingly found that a highly selective norepinephrine reuptake inhibitor, (S, S) -reboxetine is effective for the treatment of pain in patients who do not respond to treatment with an alpha-2-delta ligand such as gabapentin. This is contrary to the results expected based on the teachings of the prior art, and it is believed that there is a need for a compound having both 5-hydroxytryptamine and norepinephrine reuptake inhibitory activity, so that it is effective for treating pain in persons who are non-responders to gabapentin.

We have also surprisingly found that (S, S) -and racemic reboxetine show efficacy as psychotropic and mood-enhancing agents.

Disclosure of Invention

According to a first aspect of the present invention there is provided the use of (S, S) -or racemic reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a pain condition selected from the group consisting of: neuropathic pain (defined as pain caused by damage or dysfunction of the nervous system, including diabetic neuropathy, postherpetic neuralgia, cancerous neuropathy, HIV neuropathy, trigeminal neuralgia, phantom limb pain, carpal tunnel syndrome, neuropathic pain caused by chronic alcoholism, hypothyroidism, uremia or vitamin deficiency, central post-stroke pain, and pain caused by multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy), nociceptive pain (including moderate to severe acute nociceptive pain), cancer pain (including tumor-associated pain, such as bone pain, headache and facial pain, visceral pain, pain associated with cancer therapy, such as post-chemotherapy syndrome, chronic post-operative pain syndrome, post-radiation syndrome, and acute pain syndrome associated with cancer, such as those caused by therapeutic interactions, such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy), back pain (including back pain due to herniated or ruptured spinal disc or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or posterior longitudinal ligaments), inflammatory pain (including arthritic pain, rheumatoid disease, rheumatoid arthritis and symptomatic osteoarthritis), musculoskeletal disorders (including myalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, muscular dystrophy (dystrophiy), glycogenolysis, polymyositis and pyomyositis), visceral pain, such as cardiac and vascular pain (including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, raynaud's phenomenon, scleroderma (sclerodoma), and skeletal muscle ischemia), and pain caused by gastrointestinal dysfunction (including digestive visceral pain, digestive pain, muscle pain caused by abnormal muscle function, and muscle weakness, Non-digestible visceral pain, Functional Bowel Disorder (FBD), Inflammatory Bowel Disease (IBD), gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS), Functional Abdominal Pain Syndrome (FAPS), crohn's disease, ileitis, and ulcerative colitis, pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis), pain caused by overexertion/sprain, post-operative pain (pain occurring after any type of surgical procedure), post-traumatic pain, burns, renal colic, acute pain, central nervous system trauma, headaches (including cluster headaches), and oromandibular facial pain (including dental pain and temporomandibular fascia pain).

In a second aspect, the invention includes a method of treating a pain condition in a mammal, including a human, said pain condition being selected from the group consisting of: neuropathic pain (defined as pain caused by damage or dysfunction of the nervous system, including diabetic neuropathy, postherpetic neuralgia, cancerous neuropathy, HIV neuropathy, trigeminal neuralgia, phantom limb pain, carpal tunnel syndrome, neuropathic pain caused by chronic alcoholism, hypothyroidism, uremia or vitamin deficiency, central post-stroke pain, and pain caused by multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy), nociceptive pain (including moderate to severe acute nociceptive pain), cancer pain (including tumor-associated pain, such as bone pain, headache and facial pain, visceral pain, pain associated with cancer therapy, such as post-chemotherapy syndrome, chronic post-operative pain syndrome, post-radiation syndrome, and acute pain syndrome associated with cancer, such as those caused by therapeutic interactions, such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy), back pain (including back pain due to herniated or ruptured spinal disc or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or posterior longitudinal ligaments), inflammatory pain (including arthritic pain, rheumatoid disease, rheumatoid arthritis and symptomatic osteoarthritis), musculoskeletal disorders (including myalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, muscular dystrophy, glycogenolysis, polymyositis and pyomyositis), visceral pain, such as cardiac and vascular pain (including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, raynaud's phenomenon, scleroderma and skeletal muscle ischemia), and pain caused by gastrointestinal dysfunction (including digestive visceral pain, visceral pain, Non-digestible visceral pain, Functional Bowel Disorder (FBD), Inflammatory Bowel Disease (IBD), gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS), Functional Abdominal Pain Syndrome (FAPS), crohn's disease, ileitis, and ulcerative colitis, pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis), pain caused by overexertion/sprain, post-operative pain (pain occurring after any type of surgical procedure), post-traumatic pain, burns, renal colic, acute pain, central nervous system trauma, headache (including cluster headache), and oromandibular facial pain (including toothache and temporomandibular fascia pain); the method comprises administering to the mammal an effective amount of (S, S) -or racemic reboxetine, or a pharmaceutically acceptable salt thereof.

In a third aspect, the present invention provides the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine for the manufacture of a medicament for the treatment of pain in a patient resistant to an α -2- δ ligand.

The invention further provides in a fourth aspect a method of treating pain in a patient who is resistant to an α -2- δ ligand, the method comprising administering to a patient in need of such treatment an effective amount of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, that is substantially free of (R, R) -reboxetine.

The invention also provides in a fifth aspect the use of (S, S) -or racemic reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a mental performance or mood enhancer.

The invention also provides in a sixth aspect a method of improving mental performance or mood, which method comprises administering to a patient in need of such treatment an effective amount of (S, S) -or racemic reboxetine or a pharmaceutically acceptable salt thereof.

Other advantages and preferred aspects of the invention are described below.

Detailed Description

The use and method of the present invention can employ optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, said compound being substantially free of (R, R) -reboxetine. The phrases "optically pure (S, S) -reboxetine" and "substantially free of (R, R) -reboxetine" as used herein refer to compositions that contain a greater proportion of (S, S) -reboxetine relative to (R, R) -reboxetine. In a preferred embodiment, the phrase refers to a composition that is at least 90 wt.% of (S, S) -reboxetine and 10 wt.% or less of (R, R) -reboxetine. In a more preferred embodiment, the phrase means that the composition contains at least 97 wt.% of (S, S) -reboxetine and 3 wt.% or less of (R, R) -reboxetine. In a further preferred embodiment, the phrase means that the composition contains at least 99 wt.% of (S, S) -reboxetine and 1 wt.% or less of (R, R) -reboxetine. In a most preferred embodiment, the phrases "optically pure (S, S) -reboxetine" and "substantially free of its (R, R) stereoisomer" as used herein means that the composition contains more than 99 wt.% of (S, S) -reboxetine. The preceding percentages are based on the total amount of reboxetine present in the composition.

The first and second aspects of the invention comprise the use of (S, S) -or racemic reboxetine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition selected from the group consisting of the pain conditions listed above.

It is to be understood that the term "treatment" as used herein refers to therapeutic, prophylactic and palliative treatment.

(S, S) -and racemic reboxetine contain a base and can therefore be converted to pharmaceutically acceptable salts by reaction with an acid.

Suitable acid addition salts can be formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzylbenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, sucrose, stearate, succinate, citrate, dihydrogenphosphate, stearate, fumarate, salicylate, and the like, Tartrate, tosylate and trifluoroacetate salts. Preferred examples of the salt include methanesulfonate, fumarate and succinate, with succinate being particularly preferred.

For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use "(Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of (S, S) -or racemic reboxetine can be readily prepared in a conventional manner by suitably mixing (S, S) -or racemic reboxetine with the desired acid. The salt may be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to almost unionized.

The (S, S) -or racemic reboxetine can be administered as a crystalline or amorphous product. They can be obtained as solid fillers, powders or films by processes such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying may be used for this purpose.

(S, S) -or racemic reboxetine can be administered alone or in combination with one or more other drugs (or any combination thereof). Typically, they are administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient will depend in large part 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 (S, S) -or racemic reboxetine, and methods for their preparation, will be apparent to those skilled in the art. These compositions and their preparation are described, for example, in Remington's Pharmaceutical Sciences, 19 th edition (MackPublishing Company, 1995).

According to the invention, (S, S) -or racemic reboxetine can be administered orally. Oral administration may involve swallowing, whereby the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed whereby the compound passes directly from the mouth into the bloodstream.

Dosage forms suitable for oral administration include solid dosage forms such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid-filled), chewables, multi-and nano-particles, gels, solid solutions, liposomes, films (including mucoadhesive), ovules, sprays and liquid dosage forms.

Liquid dosage forms include suspensions, solutions, syrups and elixirs. Such dosage forms may be employed as fillers in soft or hard gelatin capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid dosage forms can also be prepared by reconstitution of a solid, for example from sachets.

(S, S) -or racemic reboxetine can also be used in fast-dissolving, fast-disintegrating dosage forms, as described by Liang and Chen in Expert Opinion in Therapeutic Patents, 11(6), 981-986 (2001).

For tablet dosage forms, depending on the dosage, the drug may constitute from 1 wt% to 80 wt%, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant constitutes from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

Binders are commonly used to provide binding properties to the tablets. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. 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.

The tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise 0.2 wt% to 5 wt% of the tablet and the glidant may comprise 0.2 wt% to 1 wt% of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant typically comprises 0.25 wt% to 10 wt%, preferably 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste masking agents.

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

The tablet blend may be directly compressed or formed into tablets by rolling. The tablet blend or partial blend may be wet, dry, or melt-granulated, melt congealed, or extruded prior to tableting. The final dosage form may comprise one or more layers, and may be coated or uncoated; and can even be encapsulated.

Formulations of tablets are described in "Pharmaceutical Dosage Forms: tablets, Vol.1 ", H.Lieberman and L.Lachman, Marcel Dekker, N.Y., N.Y., 1980(ISBN 0-8247-6918-X).

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

Suitable modified release formulations for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable delivery techniques, such as high energy dispersions and osmotic and coated particles, can be found in Pharmaceutical Technology On-line, 25(2), 1-14(2001), Verma et al. The use of chewing gum to achieve controlled release is described in WO 00/35298.

(S, S) -or racemic reboxetine can also be administered directly into the bloodstream, muscle, or into internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably at a pH of 3-9), but for some applications they may be more suitably formulated as sterile non-aqueous solutions, or in dry form for use in conjunction with a suitable carrier such as sterile pyrogen-free water.

Parenteral formulations are prepared under sterile conditions, for example by freeze-drying, which can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of (S, S) -or racemic reboxetine used in preparing the parenteral solution can be increased by using suitable formulation techniques, such as the addition of a solubilizing agent.

Formulations for parenteral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and sequential release. The compounds of the present invention may thus be formulated as solids, semisolids, or thixotropic liquids for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug coated stents (stents) and PGLA microspheres.

The (S, S) -or racemic reboxetine can 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, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may also be incorporated-see, for example, J Pharm Sci, 88(10), 955-958 by Finnin and Morgan (October 1999).

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

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

(S, S) -or racemic reboxetine can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture, e.g., a dry blend with lactose, or as a mixed component particle, e.g., mixed with a phospholipid such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, nebulizer (spray), atomizer (preferably using an electrohydrodynamic atomizer to produce a fine mist), or nebulizer (nebuliser), with or without the use of a suitable propellant, e.g., 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive, such as chitosan or cyclodextrin.

A pressurized container, pump, nebulizer (spray), atomiser, or nebuliser (nebuliser) contains a solution or suspension of (S, S) -or racemic reboxetine including, for example, ethanol, aqueous ethanol, or a suitable alternative for dispersing, dissolving or prolonged release of the active, a propellant as a solvent and optionally a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for inhalation delivery (typically less than 5 microns). This can be accomplished by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (e.g. made from gelatin or HPMC), effervescent agents and cartridges for use in an inhaler or insufflator may be formulated to contain a mixture of (S, S) -or racemic reboxetine, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable solution formulations for nebulizers using electro-hydraulic dynamics to produce a fine mist may contain 1 μ g to 20mg (S, S) -or racemic reboxetine per actuation and the actuation volume may be 1 μ l to 100 μ l. Typical formulations may include (S, S) -or racemic reboxetine, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

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

Formulations for inhalation/intranasal administration may be formulated for immediate and/or modified release using, for example, poly (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and sequential release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by providing a metered number of valves. The units according to the invention are typically arranged to be administered in measured doses or "blisters

(S, S) -or racemic reboxetine can also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, crystals and granular or vesicular systems, such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymers such as gellan gum (gelan gum), may be incorporated with preservatives such as benzalkonium chloride. The formulation may also be delivered by iontophoresis.

Formulations for ocular/otic administration may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or sequential release.

If desired, a daily dose (e.g., tablet, sachet, or capsule) of the composition contains from about 0.1 to about 10mg of (S, S) -or racemic reboxetine. More preferably, the composition contains from about 0.5 to about 10mg of the active ingredient- (S, S) -or racemic reboxetine per dose. Such dosage forms may be administered in one or two oral doses for a full day dosage of about 0.5 to about 2.5 mg. This will result in a tablet containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5mg of (S, S) -or racemic reboxetine.

According to the invention, (S, S) -or racemic reboxetine is used to treat pain in patients resistant to alpha-2-delta ligands. For the purposes of the present invention, a "patient resistant to an α -2- δ ligand" is defined as a patient who has little or no improvement in the change in the patient's overall impression when treated with an α -2- δ ligand, i.e. a score of 3 or less.

In one embodiment, the α -2- δ ligand is gabapentin or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, that is substantially free of (R, R) -reboxetine, in the manufacture of a medicament for the treatment of pain in a patient that is non-responsive to gabapentin or a pharmaceutically acceptable salt thereof (in other words, a patient that has little or worse improvement in patient global impression variation, i.e. a score of 3 or less, when treated with gabapentin or a pharmaceutically acceptable salt thereof).

In another embodiment, the α -2- δ ligand is pregabalin or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, that is substantially free of (R, R) -reboxetine, in the manufacture of a medicament for the treatment of pain in a patient that is non-responsive to pregabalin, or a pharmaceutically acceptable salt thereof (in other words, a patient that has little or worse improvement in patient global impression variation, i.e. a score of 3 or less, when treated with pregabalin, or a pharmaceutically acceptable salt thereof).

In another embodiment, the α -2- δ ligand is [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo- [3.2.0] hept-6-yl ] acetic acid or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine, for the manufacture of a medicament for the treatment of pain in a patient who is non-responsive to [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo- [3.2.0] hept-6-yl ] acetic acid or a pharmaceutically acceptable salt thereof (in other words, a patient who is improved by little or worse change in the patient' S overall impression, i.e. a score of 3 or less, when treated with [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo- [3.2.0] hept-6-yl ] acetic acid or a pharmaceutically acceptable salt thereof).

In another embodiment, the α -2- δ ligand is (1 α, 3 α, 5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine, for the manufacture of a medicament for the treatment of pain in a patient who is non-responsive to (1 α, 3 α, 5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a pharmaceutically acceptable salt thereof (in other words, a patient who is improved by little or worsening in the change of the patient' S overall impression, i.e. a score of 3 or less, when treated with (1 α, 3 α, 5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid or a pharmaceutically acceptable salt thereof).

In another embodiment, the α -2- δ ligand is (2S, 4S) -4- (3-chlorophenoxy) proline or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine, in the preparation of a medicament for the treatment of pain in a patient who is non-responsive to (2S, 4S) -4- (3-chlorophenoxy) proline or a pharmaceutically acceptable salt thereof (in other words, a patient who has little or worse improvement in patient global impression variation, i.e. a score of 3 or worse, when treated with (2S, 4S) -4- (3-chlorophenoxy) proline or a pharmaceutically acceptable salt thereof).

In another embodiment, the α -2- δ ligand is (2S, 4S) -4- (3-fluorobenzyl) proline or a pharmaceutically acceptable salt thereof. Thus, in a preferred embodiment, the invention comprises the use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine, in the manufacture of a medicament for the treatment of pain in a patient who is non-responsive to (2S, 4S) -4- (3-fluorobenzyl) proline or a pharmaceutically acceptable salt thereof (in other words, a patient who has little or worse improvement in patient global impression variation, i.e. a score of 3 or worse, when treated with (2S, 4S) -4- (3-fluorobenzyl) proline or a pharmaceutically acceptable salt thereof).

(S, S) -or racemic reboxetine according to the present invention can be used to treat neuropathic pain. The activity of (S, S) -or racemic reboxetine in the treatment of neuropathic pain can be determined according to the following protocol.

Animals: male Sprague Dawley rats (200-. All animals were kept in a 12h white/day cycle (lights on at 07h 00 min), with ad libitum access to food and water. All trials were conducted by observers blinded to drug treatment.

CCI surgery in rats

Animals were anesthetized with isoflurane. Sciatic nerves were ligated as previously described by Bennett and Xie, 1988. The animals were placed in a thermostatted enclosure during the procedure. After the surgical preparation is completed, the common sciatic nerve (common sciatic nerve) is exposed to the center of the thigh by blunt dissection through the biceps femoris. Proximal to the sciatic trigeminal branch (trifurcation), approximately 7mm of the nerve was free from the adherent tissue (adhering tissue), around which the 4 ligatures (4-0 silk) were loosely tied, leaving a gap of approximately 1 mm. The incisions were closed layer by layer and the wounds were treated locally with antibiotics.

Assessment of allodynia

Static allodynia was determined using Semmes-Weinstein von Frey hair (Stoelting, Illinois, u.s.a.). The animal is placed in a cage with a wire mesh at the bottom so that the underside of its paw can be brought into contact with the wire mesh. The animals were familiarized with the environment prior to starting the experiment. Static allodynia was detected by contacting the plantar surface of the right hind paw of the animal with von Frey hairs for 6 seconds in increasing force sequences (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g). Once the evasive response is established, the paw is retested and the next decreasing force of von Frey hairs is applied until no response occurs. The maximum force 29g may cause the paw to lift and cause a response, thus representing a cut-off point. The minimum force required to elicit a response is recorded as PWT (grams).

Dynamic allodynia was assessed by tapping the plantar surface of the hind paw with a cotton swab. This procedure was carefully performed in inactive rats completely familiar with the environment to avoid recording general motor activity. At least three measurements were made at each time point, the mean of which represents Paw Withdrawal Latency (PWL). If no response is shown within 15s, the procedure is terminated and the animal is assigned this paw withdrawal time. Thus, 15s represents virtually no avoidance. Avoidance reactions are often accompanied by repeated paw withdrawal or licking. If the animal responded to the swab stimulus before tapping for 8s, dynamic allodynia was considered to be present.

According to the invention, (S, S) -and racemic reboxetine can also be used to treat nociceptive pain. The activity of (S, S) -and racemic reboxetine in the treatment of nociceptive pain can be determined according to the following protocol.

Hot plate

The test method comprises the following steps: charles River male Sprague Dawley rats (75-200g) were placed on a hot plate (Ugo Basile, Italy) and maintained at 55. + -. 5 ℃. The time between placing the animal on the hot plate and the occurrence of licking the fore or aft foot, shaking or jumping on the surface is measured. Baseline measurements were taken and animals after dosing were re-evaluated. The off-time of the hot plate latency was set to 20 seconds to prevent tissue damage.

Ovariohysterectomy (OVX)

The test method comprises the following steps: charles River female Sprague Dawley rats (175-₂The mixture was anesthetized. Anesthesia is maintained during the procedure through the nasal cone. A midline incision (2cm long) was made on the white line and OVX was performed while the animals were placed on a heat blanket. Using the single clamp technique, the ovarian ligaments and cervix are ligated with 5-0 silk thread. The ovaries and uterus were then removed. The abdominal wall was closed with 4 simple intermittent sutures and the skin was closed with 4 wound clips. Immediately after surgery the animals were placed in a separate plexiglas chamber. Once the animals recovered from anesthesia, abdominal morphology was recorded at various time points within 30 minutes of the box. The scored postures were kyphosis, abdominal muscle contraction associated with hind limb inward movement, body extension and lower abdominal pressure towards the floor. Each of these behaviors is recorded as a gesture.

Brennan

The test method comprises the following steps: charles River male Sprague Dawley rats (125-₂The mixture was anesthetized. During surgery, anesthesia is maintained through the nasal cone. The plantar surface of the right hind foot was cleaned with 50% ethanol. A longitudinal 1cm long incision was made through the skin and plantar fascia of the foot using a 11 gauge blade, starting 0.5cm from the proximal edge of the heel and extending to the toes. The metatarsus muscle is lifted up using forceps and is cut longitudinally, the muscle is initiatedAnd the insert portion remains intact. After hemostasis by gentle pressure, the skin was closed by simple suturing with braided silk for 2 times.

Behavioral endpoint measurement

Punctate allodynia

The test method comprises the following steps: prior to assessment of allodynia, animals were familiarized with a wire-bottomed test cage. Punctate allodynia was assessed by applying increasing force (0.6, 1, 1.4, 2, 4, 6,8, 10, 15 and 26g) on the plantar surface of the hind foot using von Frey hair (Stoelting, Wood Dale, Illinois, u.s.a.). Each von Frey hair was applied to the paw for a maximum of 6 seconds, or until an evasive reaction occurred. Once the evasive response to von Frey hair had formed, the paw was retested, starting with the filament below the one that produced paw withdrawal, and then with the remaining filaments in a decreasing force sequence until paw withdrawal did not occur. The maximum force 26g lifts the paw and causes a response, thus representing a cut-off point. Both hind paws of each animal were tested in this way. The minimum force required to elicit a response is recorded as the Paw Withdrawal Threshold (PWT) (grams). If the animal responds to a stimulus of less than 4g, which is unresponsive in normal rats, then punctate allodynia is prescribed.

Dynamic allodynia

The test method comprises the following steps: dynamic allodynia was assessed by tapping the plantar surface of the hind paw with a cotton swab. This procedure was carefully performed in inactive rats completely familiar with the environment to avoid recording general motor activity. At least two measurements were made at each time point, the mean of which represents Paw Withdrawal Latency (PWL). If no response is shown within 15s, the procedure is terminated and the animal is assigned this paw withdrawal time. Thus, 15s represents virtually no avoidance. Avoidance reactions are often accompanied by repeated paw withdrawal or licking. If the animal responded to the swab stimulus before starting the flick for 8s, dynamic allodynia was considered to be present.

Radiation thermal shrinkage claw

The test method comprises the following steps: the heat-shrinkable paw was evaluated using the rat plantar test (Ugo Basile, Italy) according to Hargreaves et al, modified 1988. Rats were familiarized with a device consisting of three individual plexiglas boxes on a raised glass table. A moving radiant heat source was positioned under the table and focused on the rear paw, recording the Paw Withdrawal Latency (PWL). The automatic cut-off point was 22.5s to prevent tissue damage. PWLs were taken 2-3 times for both hind paws of each animal, the mean of which represents the baseline for the right and left hind paws. The device was calibrated and the resulting PWL was approximately 10 s.

Bearing

The test method comprises the following steps: animals were examined for hypersensitivity using an "incapacitive tester" (Lintoninstruments, Diss, Norfolk, U.K.) in a weight-bearing test. The forelimbs of the rats were placed on an plexiglass ramp and the weight distribution of the hind limbs was measured under each hind paw via a force sensor. Each animal was placed in the apparatus, noting the weight load exerted by the hind paw. The difference in weight bearing was calculated by subtracting the value of the ipsilateral (injured) foot from the contralateral (normal) foot, which constitutes the raw data.

According to the invention, (S, S) -and racemic reboxetine can also be used to treat inflammatory pain. The activity of (S, S) -and racemic reboxetine in the treatment of inflammatory pain can be determined according to the following protocol.

CFA-induced rat weight bearing deficit

Male 7-week-old SD rats were fasted overnight. CFA (300. mu.g M.tuberculosis H37 RA (Difco laboratories) in 100. mu.L liquid paraffin (Wako)) was injected into the right hind footpad of the rat. Changes in hindfoot weight distribution between the left (ipsilateral) and right (contralateral) limbs were measured 2 days after CFA administration using a Linton incapacititation tester (Linton Instrumentation, UK) as an index of pain. The test compound suspended in 0.1% mc (wako) was administered orally in a volume of 1mL per 100g body weight. Each animal was placed in the device and the weight load applied to the hind paw was measured before dosing, 1, 2 and 4 hours after dosing.

Carrageenan-induced mechanical hyperalgesia in rats

Male 4-week-old SD rats were fasted overnight. Hyperalgesia was induced by intraplantar injection of lambda-carrageenan (0.1ml of 1% w/v saline solution, Zushikagaku). The test compound (1ml of 0.1% methylcellulose per 100g of body weight) was administered orally 5.5 hours after carrageenan injection. Paw withdrawal thresholds (grams) were measured by an analgesia meter (Ugo Basile) at 3.5, 4.5, 6.5 and 7.5 hours after carrageenan injection. (Randall L.O. & Selitto I.J., Arch.Iht. Pharmacodyn.111, 409-

Carrageenan-induced thermal hyperalgesia in rats

Male 4-week-old SD rats were fasted overnight. Hyperalgesia was induced by intraplantar injection of lambda-carrageenan (0.1ml of 1% w/v saline solution, Zushikagaku) into the right hind paw of the rat. The test compound (1ml of 0.1% methylcellulose per 100g of body weight) was administered orally 5 hours after the carrageenan injection. The rat is placed in a plastic cage of a plantar detection device (Ugo Basile) and a moving radiant heat source is focused on the right hind foot of the rat. The heat-shrinkable paw latency (seconds) was measured before injecting carrageenan and at 3, 4, 6 and 7 hours after injection.

According to the invention, (S, S) -and racemic reboxetine can also be used to treat visceral pain. The activity of (S, S) -and racemic reboxetine in the treatment of visceral pain was determined according to the following experimental protocol.

Several models can be used to determine whether (S, S) -and racemic reboxetine are effective in the treatment of visceral dysfunction. These models include the LPS model (Eutamene H et al, JPharmacol Exp Ther 2000295 (1): 162-7), the TNBS model (Diop L. et al, Gastroenterology 1999, 116, 4 (2): A986), the IBD model (Clemett D, Markhama, Drugs 2000 Apr; 59 (4): 929-56), the pancreatic pain model (Isla AM, Hosp Med2000 Jun; 61 (6): 386-9), and the visceral non-digestible pain model (Boucher M et al, J Urol 2000 Jul; 164 (1): 203-8).

TNBS-induced chronic visceral allodynia in rats

In a colonic distension test model in conscious rats, trinitrobenzene sulfonic acid (TNBS) is first injected into the proximal colon, reducing the visceral pain threshold.

Materials and methods: male Sprague-Dawley rats weighing 340-400g were used. 3 animals were housed per cage in a conditioned environment (20. + -.1 ℃, 50. + -.5% humidity, 8:00am to 8:00pm light). On day 0, TNBS (50mg/kg in 30% ethanol) was injected under anesthesia (ketamine 80mg/kg intraperitoneally; acepromazine 12mg/kg intraperitoneally), or saline (1.5ml/kg) was injected into control rats, entering the proximal colon wall (1 cm from the cecum). After surgery, animals were housed individually in polypropylene cages and kept in a conditioned environment (20. + -. 1 ℃, 50. + -. 5% humidity, 8:00am to 8:00pm light) for 7 days. 7 days after TNBS administration, a balloon (5-6cm long) was inserted through the anus and the catheter was fixed in place by anchoring it at the base of the tail (5 cm from the anus at the tip of the balloon). Test compounds were administered orally 1h prior to the colonic dilatation cycle: the balloon was progressively inflated at a rate of 5mm Hg (0.667kPa) each time, from 0 to 75mm Hg, each inflation lasting 30 s. Each colon expansion cycle is controlled by a standard barostat. The threshold (mm Hg) corresponds to the pressure that produces the first abdominal contraction, and then the expansion cycle is stopped. Colon thresholds were determined after four cycles of expansion in the same animal.

LPS-induced rectal hypersensitivity in rats

Intraperitoneal injection of bacterial Lipopolysaccharide (LPS) has been shown to induce rectal hyperalgesia in conscious rats.

Materials and methods: animals were prepared for surgery for electromyography: rats were anesthetized with peritoneal injection of acepromazine (0.6mg/kg) and ketamine (120 mg/kg). Three sets of three electrodes were embedded in the extraabdominal oblique muscle tissue just above the inguinal ligament. The electrodes are withdrawn from the back side of the neck and protected by a glass tube attached to the skin. Animals were housed individually in polypropylene cages and kept in a temperature controlled chamber (21 ℃). Food (UAR pellets, epicy, France) and water ad libitum.

Electromyographic recordings began 5 days after surgery. The electrical activity of the abdominal striated muscle was recorded with an electronic electroencephalograph (Mini VIII Alvar, Paris, France) using a very short time constant (0.03s) to remove low frequency signals (< 3Hz) and a paper feed speed of 3.6 cm/min. The peak blast (spike burst) was recorded as the abdominal contraction index.

And (3) an expansion process: rats were placed in plastic tunnels (6cm diameter x 25cm long) so that they could not move, escape or turn around to prevent damage to the balloon. Animals were habituated to this procedure for 4 days prior to rectal dilatation to minimize stress during the experiment. The balloon used for dilation was an arterial embolectomy catheter (Fogarty, Edwards Laboratories Inc.). Rectal dilation was performed by inserting a balloon (2mm diameter x 2cm long) into the rectum, 1cm from the anus, and fixing the catheter at the root of the tail. The sequential dilation with warm water is carried out at 0.4ml each time, from 0 to 1.2ml each time for 5 min. To detect possible leaks, the syringe is completely withdrawn at the end of the expansion cycle to check the volume of water entering the balloon.

Test protocol: rats were injected intraperitoneally with LPS (1mg/kg (Escherichia coli, serotype O111: B4), Sigma-Aldrich Chemical Co., St Louis, Mo.), or its vehicle, and rectal distension was performed 9 and 12h after this administration while abdominal contractions were recorded by electromyography. To determine the anti-pain properties of (S, S) -or racemic reboxetine under hyperalgesic conditions, the test compound or vehicle (NaCl 0.9% 0.3 ml/rat) was administered orally 1h before rectal distension, before LPS injection (1mg/kg i.p.) (12 h).

Medicine preparation: all compounds were dissolved in sterile NaCl (0.9% isotonic saline) immediately prior to use.

Examples

The following study was conducted to evaluate the effect of (S, S) -reboxetine in treating patients with postherpetic neuralgia (PHN) who did not respond to Gabapentin (GBP) treatment.

The study population is as follows: patients, male or female, 18 years or older, still have pain for more than 3 months after healing of herpes zoster and are also ineffective in GBP treatment. There is no upper limit on the duration of the PHN. GBP invalidation is defined as follows: patients who show little or no improvement in Patient Global Impression Change (PGIC) after 2 weeks of treatment with GBP (1800 mg/day) or who are unable to tolerate GBP doses of less than or equal to 1800 mg/day.

Research and design: randomized, double-blind, placebo-controlled, two-treatment (placebo and active drug) age-staged studies were performed in PHN patients aged 18 years or older. The study consisted of phase 3: (i) a 7-week screen comprising 4 weeks GBP treatment, (ii)5 weeks randomized treatment, and (iii) a 1-week follow-up period.

All patients who met the entry criteria began a 1-week lead-in period during which daily pain was kept recorded. Thereafter, if the severity of the pain meets the relevant criteria included in the study, the patient enters a 4 week period during which he will receive GBP treatment. Subsequently, patients entered a 2-week washout period prior to randomization. At the end of the GBP treatment period, patients identified as treatment-ineffective and meeting the randomization criteria after a 2-week elution period were randomized to either placebo or (S, S) -reboxetine for a period of 5 weeks based on age-staged randomization.

GBP dosing regimens are shown in the table below.

Sky	1	2	3-6	7-9	10-12	13-28
							Mg/day	300	600	900	1200	1500	1800
Scheme(s)	OD	BID	TID	TID	TID	TID

OD-once a day; BID twice daily; TID three times a day

Randomization of (S, S) -reboxetine or placebo was age-staged for patients with an age of less than 75 (< 75, non-elderly) or 75 or older (> 75, elderly). The groups of both age groups received medication in the following manner.

Tian (treatment)	1-7	8-14	15-21	22-28	29-35
						Non-elderly dosage (mg/day)	2	4	6	4 or 6	4 or 6
Dosage for the elderly (mg/day)	1	2	3	2.3 or 4	2.3 or 4
						Scheme(s)	OD	OD	OD	OD	OD

Non-elderly patients

Non-elderly patients characterized by a well-tolerated dose of 6 mg/day, which is maintained for the remainder of double-blind treatment. In the case of poor tolerability in these patients, it is prescribed to reduce the dose from 6 mg/day to 4 mg/day at the end of treatment weeks 3 and 4. This is the only case in this study that allowed for dose reduction.

Elderly patients

For patients characterized by good tolerance to a dose of 3 mg/day, the dose may be routinely increased to 4 mg/day at the end of week 3 (V6). In the case of poor tolerability, it is permissible to reduce the dose in one step in the following manner: (i) from 3 to 2 mg/day at the end of week 3, (ii) from 4 to 3 mg/day or from 3 to 2 mg/day at the end of week 4. Patients therefore received doses of 2, 3 or 4 mg/day.

Terminal point

Primary end point:	● change from baseline in the weekly mean pain score. Pain intensity on a scale of 0-10 was rated according to the daily pain record.
		Secondary endpoint:	● responder rate (30% average pain score from baseline to endpoint)&50% ofDecrease). ● mean weekly sleep disturbance score from daily sleep records. ● SF-McGill pain questionnaire. ● patient global impression changes. ● clinical global impression changes. ● patient reported the results. ● SF-36. ● Hospital anxiety depression Scale.

Claims (14)

1. Use of (S, S) -or racemic reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a pain condition selected from the group consisting of: neuropathic pain, nociceptive pain, cancer pain, back pain, inflammatory pain, musculoskeletal disorders, visceral pain, pain caused by exertion/sprain, post-operative pain, post-traumatic pain, burns, renal colic, acute pain, central nervous system trauma, headache, and oromandibular facial pain.
2. 2. The use according to claim 1, wherein the pain condition is neuropathic pain.
3. 3. The use according to claim 1, wherein the pain condition is nociceptive pain.
4. 4. The use according to claim 1, wherein the pain condition is cancer pain.
5. 5. The use according to claim 1, wherein the pain condition is inflammatory pain.
6. 6. The use according to claim 1, wherein the pain condition is visceral pain.
7. 7. A method of treating a pain condition in a mammal, including a human, said pain condition being selected from the group consisting of: neuropathic pain, nociceptive pain, cancer pain, back pain, inflammatory pain, musculoskeletal disorders, visceral pain, pain caused by exertion/sprain, post-operative pain, post-traumatic pain, burns, renal colic, acute pain, central nervous system trauma, headache, and oromandibular plane pain, the method comprising administering to a mammal an effective amount of (S, S) -or racemic reboxetine, or a pharmaceutically acceptable salt thereof.
8. 8. Use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, substantially free of (R, R) -reboxetine, in the manufacture of a medicament for treating pain in a patient resistant to an α -2- δ ligand.
9. 9. Use according to claim 8 wherein the pharmaceutically acceptable salt of (S, S) -reboxetine is the succinate salt.
10. 10. Use according to claim 8 or 9, wherein the pain is neuropathic pain.
11. 11. The use according to claim 10, wherein the neuropathic pain is postherpetic neuralgia.
12. 12. A method of treating pain in a patient resistant to an α -2- δ ligand, said method comprising administering to a patient in need of such treatment an effective amount of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, said compound being substantially free of (R, R) -reboxetine.
13. Use of (S, S) -or racemic reboxetine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a mental performance or mood enhancer.
14. 14. A method of improving mental performance or mood, comprising administering to a patient in need thereof an effective amount of (S, S) -or racemic reboxetine or a pharmaceutically acceptable salt thereof.