ORAL ANTI-CANCER COMPOSITIONS

Abstract: An orally-administrable pharmaceutical composition for the treatment of cancer comprising a coordination com­ pound of platinum having the general formula (A)(B)Pt(X) (Y)trans(Z)₂ in which A and B are the same or different and are each selected from ammine abd alkylamines or together represent a diaminocycloalkane, X and Y are the same or different and are selected from halide and pseudohalide or together represent cycloalkanedicarboxylate, with the pro­ visos that when X and Y together represent cycloalkanedicar­ boxylate A and B do not represent ammine and/or alkyl­ amine and when A and B together represent a diamino­ cyclohexane X and Y do not represent halide and/or pseudohalide, and the Z moieties are optional and are selected from halide and hydroxy, in association with a pharmaceutically-acceptable orally-administrable carrier therefor.

Description: ORAL COMPOSITIONS This invention relates to orally-administrable pharmaceutical compositions for the treatment of cancer. It is known to treat various forms of cancer or malignant tumour by administering certain coordination compounds of platinum, in particular the compound cis-dichloro-diammineplatinum(II), known gerçrically as -cisplatin", Hitherto, such compounds have been administered parenterally, for example intravenously. Although parenteral administration of platinum-based drugs is beneficial for the clinician, in that dosage levels are easily r-termined and monitored, the availability of an orally-administrable composition would be beneficial to the patient provided that, to counteract patient-to-patient variation, the active compound was absorbed into the systemic circulation at a reasonably high level and that there was a low incidence of emesis or diarrhoea. However, despite various unsubstantiated claims in the literature to oral administrability in connection with certain such compounds, it has hitherto been found that those compounds which were investigated failed due to showing insignificant activity and in consequence it has been believed that oral administration of platinum-based drugs was not a practical proposition. For example, the compound cis- [diammine-( 1, 1-cyclobutanedicarboxylato)platinum(II) 1, referred to in British patent no GB 1380228, was found to have insignificant activity when administered orally against both P388 lymphocytic leukaemia and ADJ/PC6A plasmacytoma, the therapeutic index for the latter being 2.4 compared with a value of 12.4 for the same compound against ADJ/PC6A when administered parenterally. We have found that, despite indications to the contrary, certain coordination compounds of platinum do give promising results when administered orally. According to the present invention, an orallyadministrable pharmaceutical composition for the treatment of cancer comprises a coordination compound of platinum having the general fornila:- EMI3.1 in which A and B are the same or different and are each selected from ammine and alkylamflnes or together represent a diaminocycloalkane, X and Y are the same or different and are selected from halide and pseudohalide or together represent cycloalkanedicarboxylate, vith the provisos that when X and Y together represent cycloalkanedicarboxylate A and B do not represent ammine and/or alkylamine, when A and B together represent a diaminocyclohexane X and Y do not represent halide and/or psezdohalide, and when A represents ammine B does not represent ethylamine, isopropyöamine or cyclopentylamine, and the Z moieties are optional and are selected from halide and hydroxy, in association with a pharmaceutically-acceptable orally-administrable carrier therefor. Preferably X and E are the same and are both halide, for example chloride. The oxidation state of the platinum is +2 if the Z moieties are absent or +4 if the Z moieties are present. The alkylamine which may constitute A and/or B may be a primary, secondary, tertiary or cyclic alkylamine. Primary alkylamines have the formula nxH2x+1NH2 where x is an integer preferably from 3 to 9 inclusive, secondary and tertiary alkylamines have the formula CyH2y+1NH2 where y is an integer preferably from 3 to 9 inclusive excluding y=3 when A is ammine and cyclo-alkylamines have the general formula either cyclo-CzH2z-1NH2 or, where A and B together represent a diaminocycloalkane, cyclo-C2H2z-2(NH2)2 where z is an integer preferably from 3 to 7 inclusive, excluding z=5 where A is ammine. Preferred compounds for use in compositions according to the invention either have cycloalkanedicarboxylate and diaminocycloalkane ligands or have cis-dichloro, ammine and primary, secondary, tertiary or cyclic alkylamine ligands, especially cycloalkylamine ligands where the cycloalkyl moiety has an even number of carbon atoms, particularly C4 and C6. where the compound contains cycloalkanedicarboxylate and diaminocycloalkane ligands, it is preferred to have cyclobutanedicarboxylate and diaminocyclohexane respectively. Where the oxidation state of the platinum is +4, the Z moieties are preferably hydroxy or chloride, A and B are the same or different selected from ammine, secondary and cyclic alkylamines and X and Y are both chloride. By way of example, particular coordination compounds of platinum which may be used in compositions according to the present invention include the following cis-diamminedichloroplatinum(II) (1) EMI5.1 cis-amminecichlorocyclohexylamineplatinum(II) (2) EMI5.2 (1,1-cxclobutanedicarboxylatol)1,2-diaminocyclohexaneplatinum(ll) .......(3) EMI5.3 cis-dichloro-trans-dihydroxobis(isopropylamine)platinum(IV)..(4) EMI6.1 and cis-amminetetrachlorocyclohexylamineplatinum(IV) (5) EMI6.2 Of these coordination compounds, compounds 1, 2, 4 and 5 are known per se and their preparation is well documented in the literature. Compound 3 is a novel compound. Accordingly, the invention also includes a coordination compound of platinum having the formula (3) above. Compound 3 may be prepared by the reaction of cyclobutanedicarboxylate (CBDCA) with the aquo complex formed from Pt[C12(1,2dac)] (dac-diaminocyclohexane) and aqueous silver nitrate, according to the following method given by way of example: - PtEC12(1,2 dac)] (50g) was added grsdually to a solution of AgN03 (41g) in B20 (900ml). The flurry was allowed to stir overnight in total darkness. After this time the AgCl precipitate was filtered off and the resultant yellow filtrate was charcoaled and filtered. A solution of CBDCA (6.36g in E20) was neutralised with 2.4g of KOR and this was added to 300ml of the filtrate prepared as above. The mixture was allowed to stir overnight. A white solid formed and was filtered off. The mother liquid was concentrated and more solid precipitated. Pharmaceutical compositions according to the invention may be made in dosage form by combining a suitable coordination compound of platinum 4n an amount sufficient to produce anti-tumour activity when administered orally with a standard orally-administrable pharmaceutical farrier according to combination procedures known in the pharmaceutical art. The pharmaceutical carrier is preferably solid - that is, it provides a solid pharmaceutical composition - although liquid carriers may be used. By "solid" is meant soft capsules containing the compound formulated as a liquid or oil, as well as compressed tablets, dry filled capsules and the like, as distinct from a syrup or suspension or other bulk liquid form. It is preferred that compositions according to the invention contain in unit dosage form about 10 mg to ig of active compound. The following substances are representative of tne carriers, together with optional ingredients such as binders, lubricants and flavouring agents, which may be used for preparing pharmaceutical compositions in various forms suitable for oral administration: edible oils such as wheat germ oil, sunflower seed oil, peanut oil - for filling soft gelatine capsules; water-soluble vitamins such as those of the B complex or derivatives thereof, for example niacinamide and calcium pantothenate - for incorporation into dry filled capE-les or compressed tablets; lactose, glucose, magnesium s;phate, magnesium stearate and zinc sulphate - for use as binders or other excipients in the preparation of compressed tablets. In order to produce anti-tumour activity following oral administration, it is necessary for the active ingredient of the composition - that is, the platinum coordination compound - to be absorbable to a sufficient extent into the systemic circulation. In order to establish that such absorption takes place, pharmacokinetic determinations are made, following administration, of the concentration of platinum in the blood, urine and faeces. Determinations of the anti-tumour activity are also made. To determine such results for selected test compounds, the compounds were administered orally via a stomach tube as a suspension in arachis oil. Dosage levels were 50mg/kg body weight. The compounds were tested for anti-tumour activity against the ADJ/PC6A plasmacytoma grown subcutaneously in female Balb C mice, according to the protocol as published in Chemical Biological Interactions, vol.11, pp. 145-161 (1975). Experimental results are set out by way of example below. The designation of the compounds is shown in Table 1. Absorption screening (i.e. pharmacokinetic) data for certain compounds are given in Table 2. Anti-tumour results are quoted in Table 3. In the absorption screening data, maximum blood levels are achieved 1 to 4 hours after administration. The excretion data indicates that the compounds are absorbed to an appreciable extent in to the systemic circulation. However, it is impossible to draw any corclusions or to predict, from the solubility data alone, the extent of absorption. Thus, while it may be thought that a high aqueous solubility would imply a high solubility in the stomach and that a high octanol solubility would imply good absorption through the stomach wall, and thus that high figures for both would be reflected by a high figure for blood levels, this is seen not to follow. For example, compound II has solubility figures in both aqueous and octanol solvents approximately five times those for compound VII and yet the blood level figures are almost identical. Even more surprising is the observation that the compound with the higher solubility (compound II) required four hours to attain its peak blood level whereas compound VII, with its lower solubility, required only one hour. In the anti-tumour tests, the LDso figures (the dose level causing 30Z deaths) and the ED90 figures (the dose level causing a 90% regression in tumour size) are determined by administering dosage levels ranging from lethal to non-tumour inhibitory. The therapeutic index (T.I.) is the ratio LD50/ED90 and is a measure of the selectivity of the compound as an anti-tumour agent when administered orally. It is seen that compound I (the comparative compound) gave a TI of 7.3 against the ADJ/PC6 tumour, whereas the compound with the lowest TI (4.2) was compound XI and the compound with the highest TI (16) was compound X. It is to be observed that compounds VII and VIII - the evenllumbered C4 and C6 analogues respectively of compound I - gave surprisingly high values of TI, at 14.7 and 12.7, that is, approximately twice that for the C5 analogue the use of which for oral administration has already been proposed. TABLE 1 EMI12.1 <tb> Compound <SEP> Formula <SEP> <tb> <SEP> I <SEP> cis-tPtC12(NE3)(c-C5 <SEP> N <SEP> NH2) <SEP> <tb> <SEP> II <SEP> cis-fFtCl2(NE3)2] <SEP> <tb> <SEP> III <SEP> cis-[Pt:Cl2(NH3)(n-C3H7NH2)] <tb> <SEP> IV <SEP> cis-[Pt:Cl2(NH3)(i-C4H9NH2)] <tb> <SEP> V <SEP> cis-[Pt:Cl2(NH3)(i-C5H11NH2)] <tb> <SEP> VI <SEP> cis-[Pt:Cl2(NH3)(t-C4H9NH2)] <tb> <SEP> VII <SEP> cis-[Pt:Cl2(NH3)(c-C4H7NH2)] <tb> <SEP> VIII <SEP> cis-[Pt:Cl2(NH3)(c-C6H11NH2)] <tb> <SEP> IX <SEP> cis-[Pt:Cl2(i-C4H9NH2)(c-C6H11NH2)] <tb> <SEP> X <SEP> [Pt(1,2-dac)(CBDCA)] <tb> <SEP> XI <SEP> cis,trans-[Pt:Cl2(OH)2(i-C3H7NH2)2] <tb> Footnotes to Table 1: Compound I is a comparative example. dac represents the diaminocyclohexylamine ligand. CBDCA represents the 1,Icyclobutanedicarboxylate ligand. TABLE 2 EMI13.1 <tb> COMPOUND <SEP> SOLUBILITY <SEP> BLOOD <SEP> OEVEL <SEP> AUC, <SEP> 48h <SEP> EXCRETION <tb> <SEP> (Pt <SEP> mg/ml) <SEP> (Pt <SEP> g/ml) <SEP> Ptug.h/ml) <SEP> (% <SEP> dose,48h) <tb> <SEP> AQ <SEP> OCT <SEP> URINE <SEP> FAECES <tb> <SEP> I <SEP> 1.1 <SEP> 0.07 <SEP> 1.6 <SEP> (1) <SEP> 52 <SEP> 20 <SEP> 74 <tb> <SEP> II <SEP> 1.2 <SEP> 0.05 <SEP> 1.6 <SEP> (4) <SEP> 55 <SEP> 15 <SEP> 63 <tb> <SEP> III <SEP> 2.0 <SEP> 0.03 <SEP> 0.6 <SEP> (4) <SEP> 15 <SEP> 23 <SEP> 64 <tb> <SEP> IV <SEP> 0.97 <SEP> 0.08 <SEP> 0.9 <SEP> (4) <SEP> 27 <SEP> 15 <SEP> 66 <tb> <SEP> V <SEP> 0.18 <SEP> 0.05 <SEP> 1.0 <SEP> (4) <SEP> 31 <SEP> 16 <SEP> 69 <tb> <SEP> VI <SEP> 1.8 <SEP> 0.05 <SEP> 1.1 <SEP> (2) <SEP> 34 <SEP> 24 <SEP> 65 <tb> <SEP> VII <SEP> 0.28 <SEP> 0.01 <SEP> 1.8 <SEP> (1) <SEP> 55 <SEP> 14 <SEP> 68 <tb> <SEP> VIII <SEP> 0.19 <SEP> 0.06 <SEP> 0.6 <SEP> (1) <SEP> 25 <SEP> 15 <SEP> 59 <tb> <SEP> X <SEP> 0.77 <SEP> 0.07 <SEP> 0.72 <SEP> 25 <SEP> 9 <SEP> 89 <tb> <SEP> XI <SEP> 8.6 <SEP> 0.16 <SEP> 1.5 <SEP> 39 <SEP> 15 <SEP> 82 <tb> Footnotes to Table 2: Solubility is quoted for demineralised water (AQ) and octan-l-ol (OCT) solvents. Blood level figures are the peak figures recorded; the figures in parentheses represent the hours, after administration, that the peak figure was attained. AUC (Area Under Curve) figures represent the availability of platinum compound in the blood during the 48 hours following administration of the compound and are quoted in microgram-hours of platinum per ml. of blood. TABLE 3 EMI14.1 <tb> <SEP> TUMOUR <SEP> COMPOUND <SEP> LD <SEP> 50 <SEP> ED <SEP> 90 <SEP> TI <tb> <SEP> (mg/Kg) <SEP> (mg/Kg) <tb> ADJ/PC6 <SEP> I <SEP> 70 <SEP> 9.6 <SEP> 7.3 <tb> <SEP> II <SEP> 140 <SEP> 24 <SEP> 5.8 <tb> <SEP> III <SEP> 71 <SEP> 12 <SEP> 6 <tb> <SEP> lV <SEP> 119 <SEP> 12 <SEP> 9.9 <tb> <SEP> V <SEP> 142 <SEP> 21 <SEP> 6.8 <tb> <SEP> VI <SEP> 71 <SEP> 12 <SEP> 5.9 <tb> <SEP> VII <SEP> 140 <SEP> 9.5 <SEP> 14.7 <tb> <SEP> VIII <SEP> 140 <SEP> 11 <SEP> 12.7 <tb> <SEP> IX <SEP> < 200 <SEP> <tb> <SEP> X <SEP> 1600 <SEP> 100 <SEP> 16 <tb> <SEP> XI <SEP> 290 <SEP> 68.5 <SEP> 4.2 <tb>

Claims: CLAMS 1. An orally-admitistrable pharmaceutical composition for the treatment of cancer comprising a coordination compound of platinum having the general formula:- EMI15.1 in which A and B are the same or different and are each selected from ammine and alkylamines or together represent a diaminocycloalkane, X and Y are the same or different and are selectee from halide and pseudohalide or together represent cycloalkanedicarboxylate, with the provisos that when X and Y together represent cycloalkanedicarboxylate A and B do not represent ammine and/o- alkylamine, when A and B together represent a diaminocycloexane X and Y do not represent halide and/or pseudohalide, anc when A represents ammine B does not represent ethylamine, isopropylamine or cyclopentylamine and the Z moieties are optional and are selected from halide and hydroxy, in association with a pharmaceutically-acceptable orally-administrable carrier therefor. 2. A composition according to claim 1 in which the oxidation state of the platinum is +2 and in which A and B together represent a diaminocycloalkane and X and Y together represent cycloalkanedicarboxylate. 3. A composition according to claim 2 in which the diaminocycloalkane is diaminocyclohexane and the cycloalkanedicarboxylate is cyclobutaned-carboxylate. 4. A composition according to claim 1 in which the oxidation state of the platinum is +2 and in which X and Y are both halide, A is ammine and B is a primary, secondary, tertiary or cyclo alkylamine. 5. A compositiom according to claim 4 in which B is a cycloalkyl moiety having an even number cf carbon atoms. 6. A composition according to claim 5 in which the cycloalkyl moiety is cyciobutyl or cyclohexyl. 7. A composition according to claim 1 in which the oxidation state of the platinum is +4 and in which X and Y are Y are both chloride, A and B are the same or different and are selected from ammine, secondary and cyclic alkylamine, and the Z moieties are selected from chloride and hydroxy. 8. A composition according to claim 7 in which the compound is cisdichloro-transdihydroxo-bis(isopropylamine) platinum(IV). 9. A composition according to claim 7 in which the compound is cis-amminetetrachlorocyclohexylamineplatinum (IV). 10. A composition according to any of claims 1 to 9 in unit dosage form. 11. A composition according to claim 10 in which the platinum coordination compound is present in an amount of from lOmg to 1g per unit dosage. 12. A composition according to claim 10 formulated as a solid. 13. A composition according to any of claims 1 to 12 in which the platinum coordination compound is absorbable into the systemic circulation to an extent sufficient to produce anti-t=mour activity following oral administration. 14. A coordination compound of platinum having the formula EMI18.1

Inventors: BARNARD, CHRISTOPER FRANCIS JAMES
Applicants: JOHNSON MATTHEY PUBLIC LIMITED COMPANY
Application year: 1984
Main classification: A61K31
IPC codes: A61K31, A61P35, C07F15