COMPOSITION COMPRISING CAV2.2 CALCIUM CHANNEL BLOCKER AND

OPIOID

FIELD OF THE INVENTION

The invention relates to a novel pharmaceutical composition comprising a Ca _v 2.2 calcium channel blocker in combination with an opioid and to the uses of said composition in the treatment of pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions.

BACKGROUND OF THE INVENTION

Opioids are commonly used in the treatment of pain and typically refer to a chemical, such as morphine, that resembles opiates in their pharmacological effects. The painkiller effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. Opioids work by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids.

The side effects of opioids increase with dose and include sedation, constipation, a strong sense of euphoria and life threating respiratory depression. Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation. Morphine-like opioids are well known for their addictive properties, and for their ability to produce euphoria, motivating some to use opioids recreationally. Clinically, the side effects of opioids can occur at similar systemic exposures as the analgesic effects thereby limiting the use of opioids to the most severe pain conditions.

Chronic usage of opioids can also lead to tolerance which over time can result in the need for higher opioid doses to achieve the same analgesic effect. This can lead to decreased analgesic efficacy over time and/or increased risk of side effects as the dose is increased to compensate for the decreased analgesic efficacy.

Therefore, there is a great need for an effective medicament to reduce the requirement for the use of opioids in managing pain. This includes approaches that provide the analgesic efficacy of opioids with a more acceptable side effect profile as well as approaches that counteract opioid tolerance. SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided a pharmaceutical composition comprising a Ca _v 2.2 calcium channel blocker in combination with an opioid. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : Graph showing the effects of Compound 1 given p.o. and morphine given i.p. on CFA induced hyperalgesia in the rat.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect of the invention, there is provided a pharmaceutical composition comprising a Ca _v 2.2 calcium channel blocker in combination with an opioid.

Data is presented herein in Example 1 and Figure 1 which demonstrates that a combination therapy of a Ca _v 2.2 calcium channel blocker, such as Compound 1 , and an opioid, such as morphine, are likely to have additive/synergistic effects in the treatment of pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions.

Opioids

Examples of suitable opioids which may be used in the invention include: opium alkaloids such as phenanthrenes selected from codeine, morphine, thebaine and oripavine; esters of morphine such as diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), diacetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldesorphine and dibenzoylmorphine; ethers of morphine such as dihydrocodeine, ethylmorphine and heterocodeine; semi-synthetic alkaloid derivatives such as buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone and oxymorphone; synthetic opioids such as anilidopiperidines selected from fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl and ohmefentanyl; phenylpiperidines selected from pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodine and PEPAP, diphenylpropylamine derivatives selected from propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, levomethadyl acetate (LAAM), difenoxin, diphenoxylate and loperamide; benzomorphan derivatives selected from dezocine, pentazocine and phenazocine; oripavine derivatives selected from buprenorphine, dihydroetorphine and etorphine; morphinan derivatives selected from butorphanol, nalbuphine, levorphanol and levomethorphan; lefetamine; menthol (Kappa-Opioid agonist); meptazinol; mitragynine; tilidine; tramadol; tapentadol; and eluxadoline.

In one embodiment, the opioid is selected from morphine; esters of morphine selected from diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), diacetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldesorphine and dibenzoylmorphine; and ethers of morphine selected from dihydrocodeine, ethylmorphine and heterocodeine.

In a further embodiment, the opioid is selected from morphi

It will be appreciated that the Ca _v 2.2 calcium channel blocker of the present invention may be used in combination not only with existing opioid monotherapy but also existing opioid combination therapy. Thus, in one embodiment, the composition of the invention may additionally comprise one or more further therapeutic agents.

One example of an additional therapeutic agent includes an analgesic, such as a mild analgesic, in particular paracetamol. Thus, specific examples of such opioid combinations include: paracetamol and codeine; paracetamol and tramadol; paracetamol and oxycodone; and paracetamol and hydrocodone. Further examples of opioid and analgesic combinations are listed here: http://www.drugs.com/drug-dass/narcotic-analgesic-combinatio ns.html, the specific combinations of which are herein incorporated by reference.

One alternative example of an additional therapeutic agent includes a non-steroidal anti- inflammatory drug (NSAID), such as ibuprofen. Thus, specific examples of such opioid combinations include: ibuprofen and codeine; and ibuprofen and oxycodone.

Ca _v 2.2 calcium channel blockers

In one embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

m ^a and n ^a are independently selected from 0, 1 and 2;

where present, each R ^1a is independently selected from Ci _-4 alkyl, Ci _-4 alkoxy, C3-6 cycloalkyl, cyano, NR ^1aa R ^{1 ba} and halogen;

R ^1aa and R ^{1 ba} are independently selected from hydrogen, Ci _-4 alkyl, C3-6 cycloalkyl and a 4 to 6 membered heterocyclyl; or R ^1aa and R ^{1 ba} together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring;

where present, each R ^2a is Ci _-4 alkyl;

R ^3a is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

R ^4a is hydrogen or Ci _-4 alkyl;

R ^5a is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

R ^6a is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

such that at least 1 of R ^3a , R ^4a , R ^5a and R ^6a is a group other than hydrogen.

Compounds of formula (IA) are disclosed in WO 2010/007073 and Examples 1 -76 disclosed therein are herein incorporated by reference.

In a further embodiment, the compound of formula (IA) is: (2S)-2-Methyl-1-[(2-methyl-3- pyridinyl)carbonyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}p iperazine or a pharmaceutically acceptable salt thereof, such as (2S)-2-Methyl-1-[(2-methyl-3-pyridinyl)carbonyl]-4-{[4- (trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride (i.e. Example 2 from WO

2010/007073), hereinafter referred to herein as Compound 1 :

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (I B) or a pharmaceutically acceptable salt thereof:

(I B)

X ^b is nitrogen and Y ^b is carbon, or X ^b is carbon and Y ^b is nitrogen;

m ^b and n ^b are independently selected from 0, 1 and 2;

where present, each R ^{1 b} is independently selected from Ci _-4 alkyl, Ci _-4 alkoxy, C3-6 cycloalkyl, cyano, NR ^{1 ab} R ^{1 bb} and halogen;

R ^{1 ab} and R ^{1 bb} are independently selected from hydrogen, Ci _-4 alkyl, C3-6 cycloalkyl and a 4 to 6 membered heterocyclyl; or R ^{1 ab} and R ^{1 bb} together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring;

where present, each R ^2b is Ci _-4 alkyl;

R ^3b is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

R ^4b is hydrogen or Ci _-4 alkyl;

R ^5b is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

R ^6b is hydrogen, halogen, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

such that at least 1 of R ^3b , R ^4b , R ^5b and R ^6b is a group other than hydrogen. Compounds of formula (IB) are disclosed in WO 2010/007072 and Examples 1 -19 disclosed therein are herein incorporated by reference.

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (IC) or a pharmaceutically acceptable salt thereof:

(IC)

wherein R ^1c represents Ci _-4 alkyl;

n ^c represents an integer from 0 or 1 ;

m ^c represents an integer from 0 to 1 ;

R ^2c represents Ci _-4 alkyl;

R ^3c represents cyano, trifluoromethyl or trifluoromethoxy;

R ^4c represents hydrogen or methyl;

such that when R ^3c represents cyano, R ^4c represents a group other than hydrogen.

Compounds of formula (IC) are disclosed in WO 2010/007074 and Examples 1-8 disclosed therein are herein incorporated by reference.

In a further embodiment, the compound of formula (IC) is: 3-[((2S)-2-Methyl-4-{[4- (trifluoromethyl)phenyl]sulfonyl}-1-piperazinyl)carbonyl]pyr azolo[1 ,5-a]pyrimidine or a pharmaceutically acceptable salt thereof (i.e. Example 2 from WO 2010/007073), hereinafter referred to herein as Compound 2:

(2).

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (ID) or a pharmaceutically acceptable salt thereof:

(ID) wherein A ^d is selected from

(a) 2-quinolinyl,

(b) 5-quinolinyl,

(c) 7-quinolinyl,

(d) 8-quinolinyl, and

(e) isoquinolinyl;

and wherein A ^d is unsubstituted or substituted with 1 to 3 substituents independently selected from Ci _-4 alkyl;

m ^d is 0, 1 or 2;

where present, each R ^1d is Ci _-4 alkyl;

R ^2d is H, halogen, Ci _-4 alkyl, Ci- ₄ alkoxy, cyano, Ci _-4 haloalkyl or Ci- ₄ haloalkoxy;

R ^3d is H, halogen, Ci _-4 alkyl, Ci- ₄ alkoxy, cyano, Ci _-4 haloalkyl or Ci- ₄ haloalkoxy;

R ^4d is H, halogen, Ci _-4 alkyl, Ci- ₄ alkoxy, cyano, Ci _-4 haloalkyl or Ci- ₄ haloalkoxy;

R ^5d is H, halogen, Ci _-4 alkyl, Ci- ₄ alkoxy, cyano, Ci _-4 haloalkyl or Ci- ₄ haloalkoxy;

R ^6d is H, halogen, Ci _-4 alkyl, Ci- ₄ alkoxy, cyano, Ci _-4 haloalkyl or Ci _-4 haloalkoxy;

such that at least 1 of R ^2d , R ^3d , R ^4d , R ^5d and R ^6d is a group other than H.

Compounds of formula (ID) are disclosed in WO 201 1/086377 and Examples 1 -47 disclosed therein are herein incorporated by reference. In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (IE) or a pharmaceutically acceptable salt thereof:

(IE)

wherein

(a) A is N, B is CR ^{1 be} , D is CR ^1de and E is CR ^1ee ; or

(b) B is N, A is CR ^1ae , D is CR ^1de and E is CR ^1ee ; or

(c) D is N, A is CR ^1ae , B is CR ^{1 be} and E is CR ^1ee ; or

(d) E is N, A is CR ^1ae , B is CR ^{1 be} and D is CR ^1de ;

R ^1ae , R ^{1 be} , R ^1de and R ^1ee are independently selected from H and Ci- ₄ alkyl;

R ^2e is H or Ci-4 alkyl;

Y ^e is selected from

R ³ , R ^4e , R ^5e , R ^6e and R ^7e independently represent H, halogen, Ci _-4 alkyl, Ci-4 alkoxy, cyano, Ci-4 haloalkyl or Ci- ₄ haloalkoxy, such that at least 1 of R ^3e , R ^4e , R ^5e , R ^6e and R ^7e is a group other than H.

Compounds of formula (IE) are disclosed in WO 2012/098400 and Examples 1-203 disclosed therein are herein incorporated by reference.

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is a compound of formula (IF) or a pharmaceutically acceptable salt thereof:

(IF)

wherein

A ^f i is

R ^1f is hydrogen, methyl or chloro;

R ^2f is hydrogen, tnfluoromethyl, tnfluoromethoxy, chloro or cyano;

R ^3f is hydrogen, cyano, tnfluoromethyl, tnfluoromethoxy, difluoromethoxy, chloro, bromo, -S-CH ₃ , -S0 ₂ -Ci- ₃ alkyl or -SF ₅ ;

R ^4f is hydrogen, tnfluoromethyl, tnfluoromethoxy, chloro or cyano;

R ^5f is hydrogen, methyl or chloro;

wherein at least one of R ^1f , R ^2f , R ^3f , R ^4f or R ^5f is a group other than hydrogen;

X ^f is -CH2- , -CH2-CH2- or -CH(CH ₃ )-;

wherein when R ^1f is methyl, R ^5f is hydrogen or chloro, and when R ^5f is methyl, R ^1f is hydrogen or chloro;

wherein when R ^2f is chloro, R ^4f is hydrogen, tnfluoromethyl, tnfluoromethoxy or cyano, and when R ^4f is chloro, R ^2f is hydrogen, tnfluoromethyl, tnfluoromethoxy or cyano; R ^6f is hydrogen and R ^7f is C1-5 alkyl or C3-6cycloalkyl; or R ^6f and R ^7f together with the nitrogen atom to which they are attached form a saturated ring system B ^f , where B ^f is selected from

a) a 4 to 7 membered monocyclic heterocyclic ring,

b) a 5 to 10 membered fused bicyclic ring system;

c) a bridged 4 to 7 membered monocyclic heterocyclic ring system; and d) a 7 to 1 1 membered spiro ring system;

which ring system B ^f is unsubstituted or substituted with 1 to 3 substituents

independently selected from halogen, oxo, Ci-3alkyl, cyano, -S02-Ci-3alkyl, Ci- 3haloalkyl and -CO-Ci-3alkyl.

Compounds of formula (IF) are disclosed in WO 2012/004604 and Examples 1-147 disclosed therein are herein incorporated by reference.

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is any one of Compounds 1 to 53 disclosed in Lee, M. S. (2014) Progress in Medicinal Chemistry 53, 147-186, the compounds of which are herein incorporated by reference.

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is Z160, currently being developed by Zalicus.

In an alternative embodiment, the Ca _v 2.2 calcium channel blocker is ziconotide or T4 as disclosed in Swensen, A, M. et al (2014) European Journal of Pharmacology 745, 234-242, the compounds of which are herein incorporated by reference. Salts

References to the compounds of the invention also include ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof.

The compounds of formula (I A) to (IF) can exist in the form of a salt, for example an acid addition salt or, in certain cases a salt of organic and inorganic bases such as a carboxylate, sulfonate and phosphate salt. All such salts are within the scope of this invention, and references to compounds of formula (IA) to (IF) include the salt forms of these compounds.

The pharmaceutically acceptable salts of compounds of formula (IA) to (IF) are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate salts. For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; P L Gould, Int. J. Pharma., 33 (1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

The salts described herein can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic,

naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt. The compounds of the invention may exist as mono- or di-salts depending upon the pK _a of the acid from which the salt is formed. It will be appreciated that for use in medicine the salts of the compounds should be

pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. (1977) 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds described herein, and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

In one embodiment, the pharmaceutically acceptable salt thereof is selected from the hydrochloride salt.

Certain of the compounds described herein may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible

stoichiometric and non-stoichiometric forms.

Compositions

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

Since the compounds described herein are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are given on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the

pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprises one or more pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s). The carrier, diluent and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Pharmaceutical compositions of the invention can be prepared by intimately mixing the compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. These procedures may involve mixing, granulating and

compressing or dissolving the ingredients as appropriate to the desired preparation.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as

appropriate to the desired preparation.

The compounds or their pharmaceutically acceptable salts may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly, for administration to mammals including humans.

The compounds or their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation. A liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile vehicle, water being preferred, or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluoro-chloro-hydro-carbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment the composition is in unit dose form such as a tablet, capsule or ampoule.

Uses

According to a further aspect of the invention, there is provided a pharmaceutical composition as defined herein for use in therapy. In one embodiment, the therapy is co-therapy, adjunctive therapy or combination therapy, comprising administration of a Ca _v 2.2 calcium channel blocker and an opioid.

As used herein, the terms "co-therapy", "adjunctive therapy" and "combination therapy" shall mean treatment of a subject in need thereof by administering a Ca _v 2.2 calcium channel blocker and an opioid by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Thus, according to a further aspect of the invention there is provided a Ca _v 2.2 calcium channel blocker and an opioid for use in co-therapy, adjunctive therapy or combination therapy wherein the Ca _v 2.2 calcium channel blocker and opioid are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation. In one embodiment of this aspect of the invention, the Ca _v 2.2 calcium channel blocker and opioid are as defined hereinbefore for other aspects of the invention.

When administration is sequential, either compound may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

According to a further aspect of the invention, there is provided a pharmaceutical composition as defined herein for use in the treatment of pain.

Examples of pain include chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis);

musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.

In one embodiment, the composition of the invention is used in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch

(hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

According to a further aspect of the invention, there is provided a Ca _v 2.2 calcium channel blocker and an opioid for use in the treatment of pain, such as neuropathic pain, wherein the Ca _v 2.2 calcium channel blocker and opioid are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation. In one embodiment of this aspect of the invention, the Ca _v 2.2 calcium channel blocker and opioid are as defined hereinbefore for other aspects of the invention.

According to a further aspect of the invention, there is provided the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions.

According to a further aspect of the invention, there is provided a method of treating pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as defined herein.

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human adult, child or infant, who has been the object of treatment, observation or experiment. In one embodiment, the subject to be treated is a human.

It will be appreciated that references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and / or reduction of the severity of one or more of the symptoms of the disease or disorder being treated.

In the embodiment of co-therapy, adjunctive therapy or combination therapy, a

therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of a Ca _v 2.2 calcium channel blocker and an opioid would be the amount of a Ca _v 2.2 calcium channel blocker and an opioid that when taken together or sequentially have a combined effect that is therapeutically effective. Further, it will be recognized by one skilled in the art that in the case of co-therapy with a therapeutically effective amount, the amount of a Ca _v 2.2 calcium channel blocker and an opioid individually may or may not be therapeutically effective.

Thus, according to a further aspect of the invention there is provided a method of treating pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions, which comprises administering to a subject in need thereof a therapeutically effective amount of a Ca _v 2.2 calcium channel blocker and an opioid simultaneously, sequentially, separately or in a single pharmaceutical formulation. In one embodiment of this aspect of the invention, the Ca _v 2.2 calcium channel blocker and opioid are as defined hereinbefore for other aspects of the invention.

Data is presented herein in Example 1 and Figure 1 which demonstrates the effectiveness of a Ca _v 2.2 calcium channel blocker, such as Compound 1 , when dosed in conjunction with a sub-therapeutic dose of an opioid, for the reversal of hyperalgesia associated with an injury or inflammation.

Dosage

The dose of the compounds of the claimed invention, used in the treatment of the

abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However, as a general rule, suitable unit doses may contain from 0.1 % to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 1000 mg, for example from 1.0 mg to 500 mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be in the range of 50 mg to 1500 mg per day, for example 120 mg to 1000 mg per day. Such therapy may extend for a number of weeks or months.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of the compounds of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by

conventional techniques. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

Where the Ca _v 2.2 calcium channel blocker and opioid are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The Ca _v 2.2 calcium channel blocker and opioid may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral (i.e. peroral p.o.), intravenous (iv), intramuscular (im),

subcutaneous (sc), intranasal, transdermal, and rectal. Compounds may also be

administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventhcular, intrathecal, intracisternal, intraspinal and / or peri- spinal routes of administration by delivery via intracranial or intravertebral needles and / or catheters with or without pump devices. The Ca _v 2.2 calcium channel blocker and opioid may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms. Advantageously, the Ca _v 2.2 calcium channel blocker and opioid may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. The following studies illustrate the invention:

Example 1

Evaluation of Morphine and Compound 1 on Complete Freunds Adjuvant (CFA) induced hypersensitivity in rat assessed using weight bearing method

Background

Intraplantar injection of Complete Freunds adjuvant (CFA) causes an inflammatory reaction which induces hypersensitivity and oedema, and mimics some aspects of clinical inflammatory pain. These effects can be investigated using equipment to measure weight bearing.

Study details

Assessment of potential anti-hyperalgesic properties of test compound on CFA induced hypersensitivity using weight bearing measurements.

Weight bearing

Naive rats distribute their body weight equally between the two hind paws. However, when the injected (left) hind paw is inflamed and/or painful, the weight is re-distributed so that less weight is put on the affected paw (decrease in weight bearing on injured paw). Weight bearing through each hind limb is measured using a rat incapacitance tester (Linton Instruments, UK).

Rats were placed in the incapacitance tester with the hind paws on separate sensors and the average force exerted by both hind limbs was recorded over 4 seconds.

Procedure

Naive rats were acclimatised to the procedure room in their home cages, with food and water available ad libitum. Habituation to the incapacitance tester was performed over several days. Baseline weight bearing and paw volume recordings were taken prior to induction of insult. Inflammatory hypersensitivity was induced by intraplantar injection of CFA (100 μΙ_ of 1 mg/mL solution; Sigma 038K8726) into the left hind paw. A pre-treatment weight bearing measurement was taken to assess hypersensitivity 23 hours post-CFA. Animals were then ranked and randomised according to CFA window in a Latin square design.

Animals were treated with either Vehicle or Morphine 0.3 mg/kg i.p. (5 rnUkg dose volume) and either Vehicle or Compound 1 at 3 & 10 mg/kg p.o. (5 rnUkg dose volume) 24 hours post CFA. Weight bearing was measured at 1 , 2 and 4 hours post treatment.

Animals were culled by a schedule 1 method after the last assessment. Blood was taken from n=4 from all treatment groups other than Veh/Veh animals via cardiac puncture and placed into EDTA tubes.

The blood was then diluted 50:50 with Hepes buffer and frozen. Data were analysed by comparing treatment groups to the vehicle control group at each time point.

Animal details

Species: Rat

Strain: Sprague Dawley

Gender: Male

No animals /group: 10

Weight range at study start 218-274 g & 214-272 g

Environmental conditions: Housed in groups of 5, with standard conditions

Compound details

Compound Number/Name Morphine Hemi Sulphate

Appearance White Powder

Supplier Sigma Vehicle Saline

Base Equivalent Weight 1.33

Volume 5 mL/kg

Route i.p.

Compound Number/Name Compound 1

Appearance White powder

Supplier Prepared in accordance with

method described in Example

2 of WO 2010/007073

Vehicle 1 % Methylcellulose

Base Equivalent Weight n/a

Volume 5 mL/kg

Route p.o.

Compound 1 Preparation:

30 mg/kg @ 5 mL/kg = 6 mg/mL (108 mg in 18 mL of 1 % MC)

10 mg/kg @ 5 mL/kg = 2 mg/mL (100 mg in 50 mL of 1 % MC)

10 mg/kg

4,1 :3.3 Dilution

3 mg/kg 10 mL (10 mg/kg) + of 1 % MC

Appearance (solution/suspension): Cloudy suspension. Morphine Preparation:

3 mg/kg @ 5 mL/kg = 0.6 mg/mL stock BEW is 1.33 therefore 0.8 mg/mL (19.2 mg in 24 mL Saline)

3 mg/kg

41 :3 Dilution

1 mg/kg 8 mL (3 mg/kg) + 16 mL saline

41 :3.3 Dilution

0.3 mg/kg 6 mL (1 mg/kg) + 13.8 mL saline Appearance (solution/suspension): Clear solution.

Statistical analysis

Repeated measures ANOVA followed by Planned comparison test using InVivoStat

(invivostat.co.uk), (p<0.05 considered significant).

Results

The results of this study are shown in Figure 1 where *p<0.05, **p<0.01 and ***p<0.001 significant reversal of hyperalgesia when compared to the vehicle group at each time point.

A = Vehicle and Compound 1 3 mg/kg compared to 0.3 mg/kg morphine and Compound 1 3 mg/kg B = Vehicle and Compound 1 10 mg/kg compared to 0.3 mg/kg morphine and Compound 1 10 mg/kg

C = Vehicle and 0.3 mg/kg morphine compared to 0.3 mg/kg morphine and Compound 1 3 mg/kg

D = Vehicle and 0.3 mg/kg morphine compared to 0.3 mg/kg morphine and Compound 1 10 mg/kg The results shown in Figure 1 demonstrate a significant reversal of hypersensitivity using weight bearing with Compound 1 (30 mg/kg) at all time points. Morphine alone produced a dose-related reversal of the hypersensitivity response observed using weight bearing over the dose-range of 0.3-10 mg/kg. Overall, the effects of Compound 1 at the doses tested appeared to be at least additive to those of morphine (0.3 mg/kg) at the time points evaluated. These results demonstrate the effectiveness of a combination therapy of a Ca _v 2.2 calcium channel blocker, such as Compound 1 , and an opioid, such as morphine, are likely to have additive/synergistic effects in the treatment of pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions, resulting in a reduced dosage requirement for opiates in the management of clinical pain states.