WO2005051384A1

WO2005051384A1 - Stabilised pharmaceutical compositions

Info

Publication number: WO2005051384A1
Application number: PCT/IB2004/003743
Authority: WO
Inventors: Elena Razzano
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 2003-11-25
Filing date: 2004-11-12
Publication date: 2005-06-09

Abstract

The present invention relates to the use of calcium carbonate as a stabilising agent in solid pharmaceutical compositions comprising an amino acid as the pharmaceutically active agent, to the stabilised pharmaceutical compositions resulting therefrom and processes for their preparation.

Description

Stabilised Pharmaceutical Compositions

Background The development of solid pharmaceutical compositions of active compounds containing amino acid functional groups has proven challenging due to dosage form stability issues, which in some cases can preclude the development of a commercially viable product. For example, dosage forms of active compounds containing amino acid functional groups have shown high levels of instability due to the formation of undesired degradation products as a result of inherent degradation pathways of the amino acids. For example, suitable amino acids such as, in particular, γ- and δ-amino acids may spontaneously cyclise to give γ- and δ-lactams. These lactams may be thermodynamically more stable than the amino acids under the conditions prevailing in the formulated composition. Several approaches have been undertaken to minimise amino acid degradation and the resulting detrimental impact on pharmaceutical composition stability, however little success has been achieved to date.

Summary of the invention.

We have surprisingly found that the inclusion of calcium carbonate in solid pharmaceutical compositions comprising an amino acid as the pharmaceutically active agent provides a number of advantages:

(a) The reactivity of the active compound containing the amine and acid functional groups is considerably reduced,

(b) The presence of degradation products is substantially reduced and in particular, lactam formation is minimised, and (c) The combination of microciystalline cellulose (e.g. Avicel) and calcium carbonate provide an excellent diluent system for tablet manufacture.

According to a first aspect, the present invention relates to a stabilised solid pharmaceutical composition comprising an amino acid as the pharmaceutically active agent and calcium carbonate as the stabilising agent.

Preferably, the composition is for oral administration.

Preferably, the amino acid is a γ- or δ-amino carboxylic acid.

In one aspect of the present invention the amino acid is a compound of formula A-(l) as described in published international patent application WO 02/14285, which is hereby incorporated by reference in its entirety:

wherein: X is N or CH n is 0 to 3 R¹ is: a) Ci-β alkyl, straight chain or branched chain, b) Ci_-6 alkenyl, straight chain or branched chain, c) C-ι-₆ alkynyl, straight chain or branched chain, d) Heterocycle, e) Aromatic heterocycle, f) Aryl; g) hydrogen; said groups (a), (b) and (c) optionally further substituted by: C₃-₇ cycloalkyl, aryl, aromatic heterocycle, heterocycle, OR¹¹, NR¹¹R¹², S(0)_pR¹¹, OC(0)R¹¹, CO₂R¹¹, CONR¹¹R¹², S0₂NR¹¹R¹², halo and NHS0₂R¹¹, where R¹ may be attached at any position on the imidazole ring,

R² and R³ are each independently selected from hydrogen, Ci-₆ alkyl, optionally further substituted by OR¹¹ , halo; or wherein R² and R³ may be joined to form a link, said link is C₂-₆ alkylene,

R⁴ is hydrogen, Cι_-6 alkyl, optionally further substituted by C_3-7 cycloalkyl, aryl,

OR¹¹, halo and R¹¹; or wherein R⁴ and R¹⁰ may be joined to form a link, wherein said link is C₁.₄ alkylene, optionally further substituted by OR¹¹, halo and R¹¹,

R and R are selected from: hydrogen- aryl, Cι_-6 alkyl, said alkyl optionally further substituted by C_3-7 cycloalkyl, aromatic heterocycle, heterocycle, aryl, OR¹¹, R¹¹ and halo; or wherein R¹⁰ and either of R⁵ or R⁶ may be joined to form a link, wherein said link is a C₁-₃ alkylene, optionally further substituted by OR¹¹, halo, R¹¹ and aryl; or wwhheerreeiinn I R⁵ and R⁶ may be joined to form a link, wherein said link is C₂-₆ alkylene,

R⁷ and R⁸ are independently selected from: hydrogen, Cι_-6 alkyl, optionally further substituted by OR¹¹, halo, aryl and R¹¹; or wherein R⁷ and R⁸ may be joined to form a link, wherein said link is C₂-₆ alkylene,

R⁹ and R ⁰ are independently selected from: hydrogen, C(NR¹¹)NR¹¹R¹², C_1-6 alkyl, said alkyl optionally substituted by OR¹¹, halo, aryl and R¹¹; or wherein R⁹ and R¹⁰ may be joined to form a link, wherein said link is C₂-e alkylene, R¹¹ and R¹² are each independently selected from hydrogen or Cι_-6 alkyl; or when forming a NR¹ R¹² moiety, R¹¹ and R¹² may also be joined to form a link wherein said link is C_2-6 alkylene,

p is 0, 1 or 2

wherein:

Aryl is defined as a 6-14 membered aromatic carbocycle, optionally further substituted by R¹¹, halo, OR¹¹, NR¹¹R¹², NR¹¹C0₂R¹², C0₂R¹¹, NR¹¹S0₂R¹², CN, haloalkyl, O(haloalkyl), S(0)_pR¹¹, OC(0)R¹¹, S0₂NR¹¹R¹², C(0)NR¹¹R¹²,

Aromatic heterocycle is defined as a 5 to 7 membered ring, containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said heterocycle group optionally substituted by OR¹¹, NR¹¹R¹², C0₂R¹¹, NR¹¹C0₂R¹², R¹¹, halo, CN, haloalkyl, O(haloalkyl), S(0)_pR¹¹, OC(0)R¹¹, NR¹¹S0₂R¹², S0₂NR¹¹R¹², C(0)NR¹¹R¹²,

Heterocycle is defined as a 3-8 membered ring containing from 1-3 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, said heterocycle group optionally substituted by OR¹¹, NR¹¹R¹², C0₂R¹\ NR¹¹C0₂R¹², R¹¹, halo, CN, haloalkyl, O(haloalkyl), S(0)_pR¹¹, OC(0)R¹¹, NR¹¹S0₂R¹², S0₂NR¹¹R¹², C(0)NR¹¹R¹²,

a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the compound of formula A-(l) is selected from:

(+)-5-Amino-2-[(1 -n-propyl-1 --imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-[(1 -π-butyl-1 H-imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-[(1 -n-propyl-1 H-imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-(1 H-imidazol-4-ylmethyl)pentanoic acid, (2S)-2-[(2-Aminoethyl)amino]-3-(1 -n-propyl-1 H-imidazol-4-yl)propanoic acid, (2S)-2-[(2-Aminoethyl)amino]-3-(1 -n-butyl-1 H-imidazol-4-yl)propanoic acid,

(2S)-2-[(2-Aminoethyl)amino]-3-(1- isobutyl-1 H-imidazol-4-yl)propanoic acid, and (2S)-2-[(2-Aminoethyl)amino]-3-(1- isopentyl-1 H-imidazol-4-yl)propanoic acid.

More preferably, the compound of formula A-(l) is:

(+)-(2S)-5-Amino-2-[(1-n-propyl-1 H-imidazol-4-yl)methyl]pentanoic acid, which is disclosed as Example 7 of WO 02/14285.

In another aspect of the present invention the amino acid is a compound of formula B-(l) as described in published international patent application WO 03/061652, which is hereby incorporated by reference in its entirety:

wherein: n is 0, 1 , 2 or 3;

R¹ is selected from an optionally substituted straight chain or branched chain Cι_-6 alkyl group, an optionally substituted straight chain or branched chain C_2-6 alkenyl group, an optionally substituted straight chain or branched chain C_2-6 alkynyl group, Aryl,

Aromatic heterocycle,

Heterocycle, and hydrogen; where the optional substituents in groups (a), (b) and (c) above are selected from: C_3-7 cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR¹⁰, NR¹⁰R¹¹,

S(0)pR¹⁰, OC(0)R¹¹, C0₂R¹°, CONR¹⁰R¹¹, SO₂NR¹⁰R¹¹, halo and NHSO₂R¹⁰ ₍ and where p is 0, 1 or 2; R², R³, R⁴, R⁶, R⁷ and R⁹ are each independently selected from hydrogen and straight chain or branched chain Ci-e alkyl optionally substituted by OR¹⁰ or halo; R⁵ and R⁸ are each independently selected from hydrogen and straight chain or branched chain Cι_-6 alkyl optionally substituted by OR¹⁰ or halo, or together are a C-₂-₆ alkylene chain;

R¹⁰ and R¹¹ are each independently selected from hydrogen and straight chain or branched chain Ci-6 alkyl;

Aryl is a 6-14 membered aromatic monocyclic or fused polycyclic carbocyclic group optionally substituted with one or more groups selected from R¹², halo, OR¹³, NR¹³R¹⁴, NR¹³C0₂R¹², C0₂R¹³, NR¹³S0₂R¹², CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0₂R¹², OC(0)R¹³, S0₂NR¹³R¹⁴, C(0)NR¹³R¹⁴, C₃-₇ cycloakyl, 0(C_3-7 cycloalkyl), R¹⁵ and OR¹⁵, where R¹² is straight chain or branched chain C₁-₆ alkyl, R¹³ and R¹⁴ are each independently selected from hydrogen and straight chain or branched chain Cι_-6 alkyl, and R¹⁵ is phenyl optionally substituted by R¹², OR¹³, halo or haloalkyl;

Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being optionally substituted with one or more groups selected from OR¹³, NR¹³R¹⁴, C0₂R¹³, NR¹³C0₂R¹², R¹², halo, CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0 R¹². OC(0)R¹³, NR¹³S0₂R¹², S0₂NR¹³R¹⁴ and C(0)NR¹³R¹⁴; and

Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, said ring further being optionally substituted with one or more groups selected from OR¹³, NR¹³R¹⁴, C0₂R¹³, NR¹³C0₂R¹⁴, R¹², halo, CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0₂R¹², OC(0)R¹³, NR¹³S0₂R¹², S0₂NR¹³R¹⁴ and C(0)NR¹³R¹⁴,

Preferably, the compound of formula B-(l) is selected from: (2S)-(-)-2-(2-aminoethoxy)-3-(1 -phenyl-1 -/-imidazol-4-yl)propanoic acid, (2S)-2-{[(1 r?)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-cyclohexylethyl)-1 H-imidazol-4- yljpropanoic acid, (2S)-2-{[(1 fl)-2-amino-1 -methylethyl]oxy}-3-(1 -phenyl-1 H-imidazol-4-yl)- propanoic acid,

(2S)-2-{[(2S)-2-aminopropyl]oxy}-3-[1-(2-cyclohexylethyl)-1 H-imidazol-4-yl]- propanoic acid, (2S)-2-(2-aminoethoxy)-3-(1 H-imidazol-4-yl)propanoic acid,

(2S)-2-{[(1 R)-2-amino-1-methylethyl]oxy}-3-(1 H-imidazol-4-yl)propanoic acid, and

(2S)-2-{[(1 R)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-pyridinyl)-1 H-imidazol-4-yl]- propanoic acid.

In another aspect of the present invention the amino acid is a compound of formula C-(l) as described in United States patent, US 4,024,175, which is hereby incorporated by reference in its entirety:

wherein n is 2, 3 or 4, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the compound of formula C-(l) is

1-(aminomethyl)cyclohexaneacetic acid, otherwis known as Gabapentin:

In another aspect of the present invention the amino acid is S-(+)-4-amino-3-(2-methylpropyl)butanoic acid, otherwise known as Pregabalin:

as described in European patent, EP 0,641 ,330, which is hereby incorporated by reference in its entirety.

In another aspect of the present invention the amino acid is a compound of formulae D-(l) - D-(XVII) as described in published international patent application WO 02/085839, which is hereby incorporated by reference in its entirety:

D-(l) D-(ll) D-(lll) D-(IV)

D-(V) D-(VI) D-(VII) D-(VIII)

D-(X) D-(XI) D-(XII)

D-(XXIII) DD--((XXXXIIVV)) D-(XXV) wherein R¹ and R² are each independently selected from hydrogen, straight or branched alkyl of 1 -6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and benzyl, subject to the proviso that except in the case of a tricyclooctane compound of formula D-(XVII) R¹ and R² are not simultaneously hydrogen, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the amino acid is the compound of formula D-(IX): [(1 R, 5R, 6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, which is disclosed as Example 1 C of WO 02/085839:

D-(IX)

In another aspect of the present invention the amino acid is a compound of formulae E-(l) - E-(IV) as described in published international patent application WO 01/28978, which is hereby incorporated by reference in its entirety:

wherein n is an integer of from 1 to 4, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the amino acid is (1 ,3 ,5α)(3-Aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid.

In another aspect of the present invention the amino acid is a compound of formulae F-(l) - F-(ll) as described in published international patent application WO 99/21824, which is hereby incorporated by reference in its entirety:

F-(l) F-(ll)

wherein R¹ to R¹⁴ are each independently selected from hydrogen, straight or branched chain alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -CO₂H, C0₂R¹⁵, -CH₂C0₂H, CH2CO2R¹⁵, OR¹⁵ whereion R¹⁵ is a straight or branched alkyl of from 1 to 6 carbons, phenyl or benzyl, and R¹ to R⁸ are not simultaneously hydrogen, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the amino acid is

(3S, 4S)-(1-aminomethyI-3,4-dimethylcyclopentyl)acetic acid.

In another aspect of the present invention the amino acid is a compound of formulae G-(l) as described in published international patent application WO 00/76958, which is hereby incorporated by reference in its entirety:

G-(l)

wherein R¹ is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl: R² is straight or branched alkyl of from 1 to 8 carbons, stright or branched alkenyl of from 2 to 8 carbons, cycloalkyl of from 3 to 7 carbons, alkoxy of from 1 to 6 carbons, alkylcycloalkyl, alkylalkoxy, alkyl OH, alkylphenyl, alkylphenoxy, phenyl or substituted phenyl; and

R¹ is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R² is methyl a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

Preferably, the amino acid is (3S, 5R)-3-aminomethyl-5-methyloctanoic acid.

In another aspect of the present invention the amino acid is a compound of formula H-(l) as described in published international patent application WO 04/039367, which is hereby incorporated by reference in its entirety:

H-(l)

wherein either X is O, S, NH or CH₂ and Y is CH₂ or a direct bond, or Y is O, S or NH and X is CH₂; and R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, where any ring may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl, C C₆ alkyl, C C₆ alkenyl, C C₆ alkynyl,

Cι-C₆ alkoxy, hydroxyC C₆ alkyl, C C₆ alkoxyd-C₆ alkyl, perfiuoro d-C₆ alkyl, perfluorod-Ce alkoxy, d-C₆ alkylamino, di- Cι-C₆ alkylamino, aminod-C₆ alkyl, C C₆ alkylaminoCι-C₆ alkyl, di-d-ds alkylaminoCrC₆ alkyl, d-C₆acyl, CrC₆acyloxy, Cι-C₆acyloxyCrC6 alkyl, Cι-C₆ acylamino,

Cι-C₆ alkylthio, d-C₆ alkylthiocarbonyl, C C₆ alkylthioxo, CrC₆ alkoxycarbonyl,

Cι-C₆ alkylsulfonyl, d-Cβ alkylsulfonylamino aminosulfonyl, Cι-C₆ alkylaminosulfonyl, di-Cι-C₆ alkylaminosulfonyl,

3-8 membered cycloalkyl, 4-12 membered heterocycloalkyl, phenyl and monocyclic heteroaryl, or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

Preferably, R is an optionally substituted cyclohexyl, dihydrobenzofuranyl, isoquinolinyl or phenyl group. More preferably, R is an optionally substituted phenyl group.

Preferably, R is optionally substituted by one or two groups selected from halogen, hydroxy and (Cι-C₆)alkoxy. More preferably, R is substituted by one or two groups selected from methoxy, fluoro, chloro and bromo.

Preferably, X is O, S, NH or CH₂ and Y is CH₂ or a direct bond, or X is CH₂ and Y is O. More preferably, -Y-X- is an oxy, thio, amino, methylene, methylenethio, methyleneoxy or oxymethylene link. Yet more preferably, -Y-X- is an oxy, methylene or oxymethylene link

Particularly preferred compounds are those of general formulae H-(la), H-(lb) and H-(lc):

H-(la) H-(lb) H-(lc)

wherein

R^a and R^b are independently selected from hydrogen, halogen, hydroxy, (d-Ce)alkoxy, cyano, nitro, amino, hydroxycarbonyl, d-Ce alkyl, C C₆ alkenyl, C C₆ alkynyi,

Cι-C₆ alkoxy, hydroxyd-Ce alkyl, Cι-C₆ alkoxyd-C₆ alkyl, perfiuoro d-C₆ alkyl, perfluoroCrC6 alkoxy, d-Ce alkylamino, di- d-Ce alkylamino, aminod-Ce alkyl, d-d. alkylaminoCrCe alkyl, di-Cι-C₆ alkylaminoCrCe alkyl,

CrC₆acyl, CrC₆acyloxy, CrC₆acyloxyCrC6 alkyl, CrC₆ acylamino, d-Ce alkylthio, CrC₆ alkylthiocarbonyl, CrC₆ alkylthioxo, CrC₆ alkoxycarbonyl,

CrC₆ alkylsulfonyl, CrC₆ alkylsulfonylamino aminosulfonyl, CrC₆ alkylaminosulfonyl, di-CrC₆ alkylaminosulfonyl, 3-8 membered cycloalkyl, 4-12 membered heterocycloalkyl, phenyl and monocyclic heteroaryl, or a pharmaceutically acceptable salt, solvate or pro-drug thereof, provided that, for a compound of formula H-(la) or H-(lb), R^a and R^b cannot both be hydrogen and when R^b is a para substituent, R^a cannot be hydrogen, for a compound of formula H-(la), when R^a is methylthio, R^b cannot be hydrogen, and for a compound of formula H-(lb), when R^a is methoxy, R^b cannot be hydrogen.

Highly preferred compounds are:

(2S, 4S)-4-(3-chlorophenoxy)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(3-fluorobenzyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(2,3-difluorobenzyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(2,5-difluorobenzyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(cyclohexylmethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(3-fluorophenoxymethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(3,6-difluorophenoxymethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(2,3-difluorophenoxymethyl)pyrrolidine-2-carboxylic acid and (2S, 4S)-4-(3-methoxyphenoxymethyl)pyrrolidine-2-carboxylic acid; or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

In another aspect of the present invention the amino acid is selected from:

5-amino-2-[(1-benzyloxycarbonylamino-2- methylpropyl)hydroxyphosphinoyloxy]pentanoic acid, and

5-amino-2-{[1-(2-benzyloxycarbonylamino-3-phenylpropionylamino)-2- methylpropyl]hydroxyphosphinolyloxy}pentanoic acid, as described in published international patent application WO 00/66550, which is hereby incorporated by reference in its entirety.

In another aspect of the present invention the amino acid is selected from: 5-amino-2-(1 H-imidazol-4-yl)pentanoic acid,

7-amino-2-(1 H-imidazol-4-yl)heptanoic acid,

6-methylamino-2-(1 H-imidazol-4-yl)hexanoic acid, and

6-amino-2-(1-isopentyl-1 -/-imidazol-4-yl)hexanoic acid, as described in published international patent application WO 03/013526, which is hereby incorporated by reference in its entirety.

Methods for preparing the amino acid compounds of the invention described above are disclosed in the above-cited patent applications. All of the hereinabove and below cited references, U.S. patent applications, published European patent applications and published PCT International patent applications are hereby incorporated by reference herein in their entireties. The pharmaceutical compositions of the present invention of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, or powders, lozenges, chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco- adhesive), ovules. Liquid formulations may also be prepared by the reconstitution of a solid formulation, for example, from a sachet. Such formulations typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.

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

For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.

The calcium carbonate may make up from 1 wt% to 80 wt% of the dosage form, preferably, from 5 wt% to 60 wt% of the dosage form and most preferably, from 15 wt% to 50 wt% of the dosage form.

Preferably, the ratio (w/w) of amino acid to calcium carbonate is from 20:1 to 1 :100. More preferably, the ratio (w/w) of amino acid to calcium carbonate is from 5:1 to 1 :50. Most preferably, the ratio (w/w) of amino acid to calcium carbonate is from 2:1 to 1 :25.

The invention further provides a solid pharmaceutical composition comprising an amino acid as the pharmaceutically active agent and calcium carbonate, wherein the amino acid is as defined above, said composition comprising less than 10% of lactam formed from cyclisation of the amino acid.

Preferably, the composition comprises less than 5%, most preferably less than 2%, of lactam formed from cyclisation of the amino acid.

In addition, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

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

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

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

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Tablet blends may be compressed directly to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

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

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

Table 1 discloses the preferred excipients commonly used in tablet technology

Table 1

The following examples are for the purpose of illustration only and are not intended in any way to limit the scope of the instant invention.

Compound 1 is (+)-(2S)-5-Amino-2-[(1-r?-propyl-1 H-imidazoI-4- yl)methyl]pentanoic acid, which is disclosed as Example 7 of WO 02/14285.

Compound 2 is [(1 R, 5R, 6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, which is disclosed as Example 1C of WO 02/085839

EXAMPLE 1

The following compositions A and C represent stabilised compositions in accordance with the instant invention in white tablet form, whereas composition B does not contain the stabiliser of the instant invention. In detail, the weight ratio of the active component, Compound 1 , to the stabiliser in composition A is

1 to 1.4 and the weight ratio of the microcrystalline cellulose and the stabiliser is

2 to 1. In composition B the stabiliser has been substituted by dicalcium phosphate anhydrous, whilst maintaining unaltered the other composition ingredients. In composition C the weight ratio of the active component, Compound 1 , to the stabiliser is 1 to 1 and the weight ratio of microcrystalline cellulose and the stabiliser is 1 to 1. Amount (mg)

Ingredient A B C

Compound 1 31.13^a 31.13^a 31.13^a

Microcrystalline cellulose 43.08 43.08 32.31

Dicalcium phosphate — 21.54 — anhydrous

Calcium carbonate 21.54 32.31

Croscarmellose sodium 3.00 3.00 3.00

Magnesium stearate 1.25 1.25 1.25

Total 100.00 100.00 100.00

^a corresponding to 25mg of active ingredient, based on an activity of 80.3%

Tablet preparation

Tablets have been manufactured according to the compositions in Example 1 at the batch size of 300 g.

Blend preparation A dry blend of the above ingredients, with the exception of magnesium stearate, is prepared using a turbula blender. After 10 minutes of blending, the mixture is deagglomerated through a 500 micron screen and it is further blended using the turbula blender for 10 minutes, to ensure content homogeneity. The blend is then lubricated by addition of 40% of the required amount of magnesium stearate followed by additional mixing using the turbula blender for 5 minutes.

Granule Preparation

The blend is compacted into ribbons using the Freund roller compactor. The resultant ribbons are milled into granules using the L1A Fitzmill, knives forward milling equipment, fitted with a 1.65 mm screen, at the speed of 1900 rpm. The resultant granules are lubricated by the addition of 60% of the required magnesium stearate (in accordance with the amount of granules produced) and followed by mixing using the turbula blender for 5 minutes.

Compression of the granules

The granules are compressed into tablets on a single station tablet press (Manesty F3 tablet press), using normal round concave tooling of 6 mm of diameter. The target tablet weight is 100mg.

Packaging of the tablets

The resultant tablets are placed into HDPE bottles, with standard closure (20 tablets per bottle) and stored according to a stability protocol.

Tablet analytical method

High performance liquid chromatography (HPLC) is used to separate compound 1 from potential process-related impurities, degradation products and formulation excipients. Quantification of Compound 1 is achieved by comparison of the UV response of test samples against external standard solutions. Identity is confirmed on the basis of retention time. Quantification of Compound 1 related substances is achieved by area normalisation.

This method is suitable for the identity, assay, purity and stability assessment of Compound 1 in Compound 1drug substance as well as drug products containing Compound 1.

Chromatographic conditions are detailed in Table 2

Table 2

* An in-line C18 cartridge should be attached to the 20 mM dipotassium hydrogen orthophosphate (pH 6.0) line to minimise system peaks (e.g. Sep- Pak).

EXAMPLE 2

To demonstrate the effectiveness of the stabiliser of the instant invention against temperature and added moisture, the following results have been obtained when, the compositions of Examples 1A-1C where stored at 40° C and 75% of relative humidity for 12 weeks:

Assay o //o Lactam % Total number of impurities

Example 1A 97.4 0.1 3

Example 1 B 97.0 0.4 4

Example 1 C 98.9 0.1 3 EXAMPLE 3

To demonstrate the effectiveness of the stabiliser of the instant invention against temperature, the following results have been obtained when the compositions of Examples 1A-1C where stored at 50° C and 20% of relative humidity for 12 weeks:

Assay % Lactam % Total number of impurities

Example 1A 97.5 1.7 2

Example 1 B 63.4 30.5 12

Example 1C 100.5 0.7 1

EXAMPLE 4

The following compositions B and C represent stabilised compositions in accordance with the instant invention in white compact form, whereas compositions A and D do not contain the stabiliser of the instant invention. In detail, the weight ratio of the active component, Compound 2, to the stabiliser in composition B and C is 1 to 23. In compositions A, B, C and D the weight ratio of microcrystalline cellulose /starch to the stabiliser/ dicalcium phosphate is 1 to 1.

Amount (mg)

Ingredient A B D

Compound 2 5.03 ^a 5.03 ' 5.03 ^a 5.03 ^! Microcrystalline 113.74 113.74 cellulose

Starch 113.74 113.74

Dicalcium phosphate 113.73 — — 113.73 anhydrous

Calcium carbonate — 113.73 113.73 —

Sodium starch glycollate Type A 12.50 — 12.50 —

Croscarmellose 12.50 12.50 sodium

Magnesium stearate 5.00 5.00 __

Sodium stearyl — 5.00 5.00 fumarate

Total 250.00 250.00 250.00 250.00

^a corresponding to 5mg of active ingredient, based on an activity of 99.5%

Compact preparation Compacts have been manufactured according to the compositions in Example 5 at the batch size of 25 g.

Blend preparation

A dry blend of the above ingredients, with the exception of magnesium stearate, is prepared using a turbula blender. After 10 minutes of blending, the mixture is deagglomerated through a 500 micron screen and it is further blended using the turbula blender for 10 minutes, to ensure content homogeneity. The blend is then lubricated by addition of the required amount of lubricant followed by mixing using the turbula blender for 5 minutes.

Compact preparation

The blend is compacted into compacts of 250mg of weight using an IR press (5 station, 8mm die). Compacts are individually placed into an open HDPE container and stored according to a stability protocol.

Compact analytical method

Achiral high performance liquid chromatography (HPLC) is used to separate Compound 2 from potential process-related impurities, degradation products and formulation excipients.

Compound 2 and all other chromatographic peaks present in the test chromatography are reported by % area normalisation of main band after subtraction of system related peak. Peak areas of the lactam formed from Compound 2 are corrected for lactam moiety RRF of 13.2, prior to calculating total peak area and individual area normalisation values.

Chromatographic conditions are detailed in Table 3

Table 3

EXAMPLE 5

To demonstrate the effectiveness of the stabiliser of the instant invention against temperature and added moisture, the following results have been obtained when the compositions of Examples 4A-4D where stored at 40° C and 75% of relative humidity for 13 weeks:

Assay % Lactam %

Example 4A 96.02 0.16

Example 4B 97.87 0.10

Example 4C 93.34 0.07

Example 4D 97.27 0.17

EXAMPLE 6

To demonstrate the effectiveness of the stabiliser of the instant invention against temperature, the following results have been obtained when the compositions of Examples 4A-4D where stored at 50° C and 20% of relative humidity for 13 weeks:

Assay % Lactam % Example 4A 96.83 0.88

Example 4B 97.46 0.46

Example 4C 94.14 0.42

Example 4D 96.42 0.72

Claims

1. A stabilised solid pharmaceutical composition comprising an amino acid as the pharmaceutically active agent and calcium carbonate as the stabilising agent.

2. A stabilised composition according to claim 1 wherein the composition is for oral administration.

3. A stabilised composition according to either claim 1 or claim 2 wherein the amino acid is a γ- or δ-amino carboxylic acid.

4. A stabilised composition according to either claim 1 or claim 2 wherein the amino acid is a compound of formula A-(l)

wherein:

X is N or CH n is 0 to 3

R¹ is: a) C-i-e alkyl, straight chain or branched chain, h) C-i-e alkenyl, straight chain or branched chain, i) Ci-₆ alkynyl, straight chain or branched chain, j) Heterocycle, k) Aromatic heterocycle,

I) Aryl; m) hydrogen; said groups (a), (b) and (c) optionally further substituted by: C_3-7 cycloalkyl, aryl, aromatic heterocycle, heterocycle, OR¹¹, NR¹¹R¹², S(0)_pR¹¹, OC(0)R¹¹, C0₂R¹¹,

CONR¹¹R¹², S0₂NR¹ R¹², halo and NHS0₂R¹¹, where R¹ may be attached at any position on the imidazole ring,

R² and R³ are each independently selected from hydrogen, d_-6 alkyl, optionally further substituted by OR¹¹, halo; or wherein R² and R³ may be joined to form a link, said link is C₂-₆ alkylene,

R⁴ is hydrogen, Cι_-6 alkyl, optionally further substituted by C₃-₇ cycloalkyl, aryl,

OR¹¹, halo and R¹¹; or wherein R⁴ and R¹⁰ may be joined to form a link, wherein said link is d- alkylene, optionally further substituted by OR¹¹, halo and R¹¹,

R⁵ and R⁶ are selected from: hydrogen, aryl, d_-6 alkyl, said alkyl optionally further substituted by C_3-7 cycloalkyl, aromatic heterocycle, heterocycle, aryl, OR¹¹, R¹¹ and halo; or wherein R¹⁰ and either of R⁵ or R⁶ may be joined to form a link, wherein said link is a C-ι-3 alkylene, optionally further substituted by OR¹¹, halo, R¹¹ and aryl; or wwhheerreeiinn R⁵ and R⁶ may be joined to form a link, wherein said link is C₂-₆ alkylene,

R⁷ and R⁸ are independently selected from: hydrogen, Cι_-6 alkyl, optionally further substituted by OR¹¹, halo, aryl and R¹¹; or wherein R⁷ and R⁸ may be joined to form a link, wherein said link is C₂-e alkylene,

R⁹ and R¹⁰ are independently selected from: hydrogen, C(NR¹¹)NR¹¹R¹², C_1-6 alkyl, said alkyl optionally substituted by OR¹¹, halo, aryl and R¹¹; or wherein R⁹ and R¹⁰ may be joined to form a link, wherein said link is C_2-e alkylene, R¹¹ and R¹² are each independently selected from hydrogen or d_-6 alkyl; or when forming a NR¹¹R¹² moiety, R¹¹ and R¹² may also be joined to form a link wherein said link is C₂-₆ alkylene,

p is 0, 1 or 2

wherein:

Aromatic heterocycle is defined as a 5 to 7 membered ring, containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said heterocycle group optionally substituted by OR¹¹, NR¹¹R¹², C0₂R¹¹, NR¹¹C0₂R¹², R¹¹, halo, CN, haloalkyl, O(haloalkyl), S(0)_pR¹¹, OC(0)R¹¹, NR ¹S0₂R¹², S0₂NR¹¹R¹², C(0)NR¹¹R¹²,

Heterocycle is defined as a 3-8 membered ring containing from 1-3 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, said heterocycle group optionally substituted by OR¹¹, NR¹¹R¹², C0₂R¹¹, NR¹¹C0₂R¹², R¹¹, halo, CN, haloalkyl, O(haloalkyl), S(0)_pR¹¹, OC(0)R¹¹, NR¹¹S0₂R¹², S0₂NR¹¹R¹², C(0)NR¹¹R¹²,

5. A stabilised composition according to claim 4 wherein the compound of formula A-(l) is selected from:

(+)-5-Amino-2-[(1 -π-propyl-1 H-imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-[(1 -π-butyl-1 rV-imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-[(1 -π-propyl-1 H-imidazol-4-yl)methyl]pentanoic acid, (+)-(2S)-5-Amino-2-(1 H-imidazol-4-ylmethyl)pentanoic acid, (2S)-2-[(2-Aminoethyl)amino]-3-(1 -n-propyl-1 -/-imidazol-4-yl)propanoic acid, (2S)-2-[(2-Aminoethyl)amino]-3-(1 -n-butyl-1 H-imidazol-4-yl)propanoic acid, (2S)-2-[(2-Aminoethyl)amino]-3-(1-isobutyl-1 H-imidazol-4-yl)propanoic acid, and (2S)-2-[(2-Aminoethyl)amino]-3-(1 -isopentyl-1 H-imidazol-4-yl)propanoic acid.

6. A stabilised composition according to claim 5 wherein the compound of formula A-(l) is (+)-(2S)-5-Amino-2-[(1-n-ρropyl-1 H-imidazol-4- yl)methyl]pentanoic acid.

7. A stabilised composition according to either claim 1 or claim 2 wherein the amino acid is a compound of formula B-(l)

wherein: n is 0, 1 , 2 or 3; R¹ is selected from an optionally substituted straight chain or branched chain Ci-6 alkyl group, an optionally substituted straight chain or branched chain C_2-6 alkenyl group, an optionally substituted straight chain or branched chain C_2-6 alkynyl group, Aryl,

Aromatic heterocycle, Heterocycle, and hydrogen; where the optional substituents in groups (a), (b) and (c) above are selected from: C_3-7 cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR¹⁰, NR¹⁰R¹¹, S(0)_pR¹⁰, OC(0)R¹¹, C0₂R¹⁰, CONR¹⁰R¹¹, SO₂NR¹⁰R¹¹, halo and NHS0₂R¹°, and where p is 0, 1 or 2;

R², R³, R⁴, R⁶, R⁷ and R⁹ are each independently selected from hydrogen and straight chain or branched chain Cι_-6 alkyl optionally substituted by OR¹⁰ or halo; R⁵ and R⁸ are each independently selected from hydrogen and straight chain or branched chain Ci-β alkyl optionally substituted by OR¹⁰ or halo, or together are a C_2-e alkylene chain;

R¹⁰ and R¹¹ are each independently selected from hydrogen and straight chain or branched chain C_1-6 alkyl;

Aryl is a 6-14 membered aromatic monocyclic or fused polycyclic carbocyclic group optionally substituted with one or more groups selected from R¹², halo, OR¹³, NR¹³R¹⁴, NR¹³C0₂R¹², C0₂R¹³, NR¹³S0₂R¹², CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0₂R¹², OC(0)R¹³, S0₂NR¹³R¹⁴, C(0)NR¹³R¹⁴, C₃-₇ cycloakyl, 0(C_3-7 cycloalkyl), R¹⁵ and OR¹⁵, where R¹² is straight chain or branched chain C-ι-₆ alkyl, R¹³ and R¹⁴ are each independently selected from hydrogen and straight chain or branched chain Cι_-6 alkyl, and R¹⁵ is phenyl optionally substituted by R¹², OR¹³, halo or haloalkyl;

Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being optionally substituted with one or more groups selected from OR¹³, NR¹³R¹⁴, C0₂R¹³, NR¹³C0₂R¹², R¹², halo, CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0₂R¹², OC(0)R¹³, NR¹³S0₂R¹², S0₂NR¹³R¹⁴ and C(0)NR¹³R¹⁴; and Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, said ring further being optionally substituted with one or more groups selected from OR¹³, NR¹³R¹⁴, C0₂R¹³, NR¹³C0₂R¹⁴, R¹², halo, CN, haloalkyl, O(haloalkyl), SR¹³, S(0)R¹², S0₂R¹², OC(0)R¹³, NR¹³S0₂R¹², S0₂NR¹³R¹⁴ and C(0)NR¹³R¹⁴,

8. A stabilised composition according to claim 7 wherein the compound of formula B-(l) is selected from:

(2S)-(-)-2-(2-aminoethoxy)-3-(1 -phenyl-1 H-imidazol-4-yl)propanoic acid,

(2S)-2-{[(1 fl)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-cyclohexylethyl)-1 H-imidazol-4- yljpropanoic acid,

(2S)-2-{[(1 f?)-2-amino-1 -methylethyl]oxy}-3-(1 -phenyl-1 H-imidazol-4-yl)- propanoic acid,

(2S)-2-{[(2S)-2-aminopropyl]oxy}-3-[1-(2-cyclohexylethyl)-1 H-imidazol-4-yl]- propanoic acid,

(2S)-2-(2-aminoethoxy)-3-(1 H-imidazol-4-yl)propanoic acid,

(2S)-2-{[(1 f?)-2-amino-1 -methylethyl]oxy}-3-[1 -(2-pyridinyl)-1 H-imidazol-4-yl]- propanoic acid.

9. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is a compound of formula C-(l)

10. A stabilised composition according to claim 9 wherein the compound of formula C-(l) is

1 -(aminomethyl)cyclohexaneacetic acid.

11. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is S-(+)-4-amino-3-(2-methylpropyl)butanoic acid.

12. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is a compound of any of the formulae D-(l) - D-(XVII):

D-(l) D-(ll) D-(lll) D-(IV)

D-(V) D-(VI) D-(VII) D-(VIII)

D-(X) D-(XI)

D-(XIII) D-(XIV) D-(XV) D-(XVI) D-(XVII)

D-(XXI)

D-(XXII) D-(XXIII) D-(XXIV) D-(XXV) wherein R¹ and R² are each independently selected from hydrogen, straight or branched alkyl of 1 -6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and benzyl, subject to the proviso that except in the case of a tricyclooctane compound of formula D-(XVII) R¹ and R² are not simultaneously hydrogen, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

13. A stabilised composition according to claim 12 wherein the amino acid is the compound of formula D-(IX)

D-(IX)

14. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is a compound of any of the formulae E-(l) - E-(IV):

15. A stabilised composition according to claim 14 wherein the amino acid is (1 α,3 ,5 )(3-aminomethylbicyclo[3.2.0]hept-3-yl)acetic acid.

16. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is a compound of either of the formulae F-(l) - F-(ll):

F-(l) F-(ll)

wherein R¹ to R¹⁴ are each independently selected from hydrogen, straight or branched chain alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -C0₂H, - C0₂R¹⁵, -CH₂C0₂H, CH₂C0₂R¹⁵, OR¹⁵ whereion R¹⁵ is a straight or branched alkyl of from 1 to 6 carbons, phenyl or benzyl, and R¹ to R⁸ are not simultaneously hydrogen, a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.

17. A stabilised composition according to claim 16 wherein the amino acid is (3S, 4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.

18. A stabilised composition according to any one of claims 1 to 3 wherein the amino acid is a compound of any of the formula G-(l) :

G-(l)

wherein R¹ is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl:

R² is straight or branched alkyl of from 1 to 8 carbons, stright or branched alkenyl of from 2 to 8 carbons, cycloalkyl of from 3 to 7 carbons, alkoxy of from

1 to 6 carbons, alkylcycloalkyl, alkylalkoxy, alkyl OH, alkylphenyl, alkylphenoxy, phenyl or substituted phenyl; and

19. A stabilised composition according to claim 18 wherein the amino acid is (3S, 5R)-3-aminomethyl-5-methyloctanoic acid.

20. A stabilised composition according to either claim 1 or claim 2 wherein the amino acid is a compound of formula H-(l):

H-(l)

wherein either X is O, S, NH or CH₂ and Y is CH₂ or a direct bond, or Y is O, S or NH and X is CH₂; and

R is a 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, aryl or heteroaryl, where any ring may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, nitro, amino, hydroxycarbonyl,

CrCe alkyl, d-Ce alkenyl, C C₆ alkynyl,

CrC₆ alkoxy, hydroxyCrC₆ alkyl, CrC₆ alkoxyd-Cβ alkyl, perfiuoro CrC₆ alkyl, perfluorod-Ce alkoxy, d-C-₆ alkylamino, di- CrC₆ alkylamino, aminoCrC₆ alkyl, d-di alkylaminoCrCe alkyl, di-d-d alkylaminoCrC₆ alkyl,

CrC₆acyl, Crdacyloxy, CrC₆acyloxyCrC6 alkyl, CrC₆ acylamino, d- i alkylthio, CrC₆ alkylthiocarbonyl, d-ds alkylthioxo, d-C-₆ alkoxycarbonyl,

CrC₆ alkylsulfonyl, d-d. alkylsulfonylamino aminosulfonyl, Crd alkylaminosulfonyl, di-d-Cβ alkylaminosulfonyl,

21. A stabilised composition according to claim 20 wherein the amino acid is selected from:

(2S, 4S)-4-(3-chlorophenoxy)pyrrolidine-2-carboxylic acid;

(2S, 4S)-4-(3-fluorobenzyl)pyrrolidine-2-carboxylic acid;

(2S, 4S)-4-(2,3-difluorobenzyl)pyrrolidine-2-carboxylic acid;

(2S, 4S)-4-(2,5-difluorobenzyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(cyclohexylmethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(3-fluorophenoxymethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(3,6-difluorophenoxymethyl)pyrrolidine-2-carboxylic acid; (2S, 4S)-4-(2,3-difluorophenoxymethyl)pyrrolidine-2-carboxylic acid and (2S, 4S)-4-(3-methoxyphenoxymethyl)pyrrolidine-2-carboxylic acid; or a pharmaceutically acceptable salt, solvate or pro-drug thereof.

22. A stabilised composition according to either claim 1 or claim 2 wherein the amino acid is selected from:

5-amino-2-[(1-benzyloxycarbonylamino-2- methylpropyl)hydroxyphosphinoyloxy]pentanoic acid, 5-amino-2-{[1-(2-benzyloxycarbonylamino-3-phenylpropionylamino)-2- methylpropyl]hydroxyphosphinolyloxy}pentanoic acid, 5-amino-2-(1 H-imidazol-4-yl)pentanoic acid, 7-amino-2-(1 H-imidazol-4-yl)heptanoic acid, 6-methylamino-2-(1 H-imidazol-4-yl)hexanoic acid, and 6-amino-2-(1-isopentyl-1 H-imidazol-4-yl)hexanoic acid.

23. A stabilised composition according to any one of claims 1 to 22 wherein the ratio (w/w) of amino acid to calcium carbonate is from 20:1 to 1 :100.

24. A stabilised composition according to claim 23 wherein the ratio (w/w) of amino acid to calcium carbonate is from 5:1 to 1 :50.

25. A stabilised composition according to claim 24 wherein the ratio (w/w) of amino acid to calcium carbonate is from 2:1 to 1 :25.

26. The use of calcium carbonate for the stabilisation of a solid pharmaceutical composition comprising an amino acid as the pharmaceutically active agent wherein the amino acid is as defined in any one of claims 1 to 22.

27. A solid pharmaceutical composition comprising an amino acid as the pharmaceutically active agent and calcium carbonate, wherein the amino acid is as defined in any one of claims 1 to 22, said composition comprising less than 10% of lactam formed from cyclisation of the amino acid.

28. A composition according to claim 27 comprising less than 5% of lactam formed from cyclisation of the amino acid.