NABUMETONE POWDERS

Abstract: The use of a powder formulation of nabumetone for the manufacture of a medicament for the treatment or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome in mammals.

Description: NABUMETONE POWDERS The present invention relates to the treatment of inflammation by the administration of a powder formulation. UK Patent No. 1474377 discloses pharmaceutical compositions which comprise compounds of formula (I) : wherein X is a chlorine or bromine atom or a methoxy, methylthio or al yl group or 1 to 4 carbon atoms; Y is a -CHR 1 CH2*- or -CR 1 =CH- group where R- j _ is a hydrogen atom or a methyl group a A is a CHOH or CO group. One particular compound which falls within the scope of the abovementioned patent and specifically is mentioned therein is nabumetone: which has been found to be a particularly good antiflammatory agent and is especially useful for treating the inflammation associated with rheumatoid or oesteo arthritis, sports injuries e.g. sprains, strains or impact injuries which cause bruising and swelling. Nabumetone has previously been formulated as tablets and it has now been unexpectedly found that a powder presentation of nabumetone possesses certain advantageous properties. Accordingly the present invention provides the use of a powder formulation of nabumetone for the manufacture of a medicament for the treatment or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome in mammals, including humans. The invention further provides a method of treatment and/or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome which comprises administering an effective and/or prophylactic amount of a powder formulation of nabumetone to a sufferer in need thereof. The present invention also provides a pharmaceutical composition for use in the treatment and/or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome in mammals including humans which comprises nabumetone admixed with a conventional excipient to form a powder formulation. It will be appreciated that powder formulations of nabumetone are prepared by admixing a therapeutically effective amount of nabumetone with conventional excipients such as lactose, sugar, maize starch, calcium phosphate, sorbital, colloidal silica or hydroxy propylmethyl cellulose and those described in the British Pharmacopea. Preferred excipients include colloidal silica and hydroxypropylmethyl cellulose. Powder formulations of nabumetone are suitably in unit dose form and unit dosages are suitably packaged in sachets or other suitable receptacle. A therapeutically effective amount of nabumetone will depend upon the severity of the disorder being treated and the weight of the sufferer. A unit dose powder formulation may contain from lOmg to 5000mg, preferably lOOmg to 2000mg, more preferably 500mg to lOOOmg, and most preferably lOOOmg. A number of unit doses may be taken by a sufferer in any 24 hr period, for example 1 to 4 unit doses may be taken. Preferably a single unit dose in a 24 hr period is taken by the sufferer. It will be appreciated that the powder formulation of nabumetone may be admixed with a suitable liquid to facilitate ease of administration. A suitable liquid is water. The following clinical data demonstrate the present invention. Clinical Data A bioequivalence study of two oral preparations of RELIFEX (nabumetone being the active compound) , rapid release tablets of l,000mg and granular powder of l,000mg was carried out as described below. The composition of the two preparations is as follows: ( g) (mg) Composition Tablet Powder Active compound 1,000 1,000 Nabumetone * Official pharmacopea STUDY PROTOCOL Ten healthy Caucasian subjects ranging in age from 19 to 28 years were studied. The characteristics of the volunteers are summarized in Table 1. The drug preparations were given early in the morning in two occasions separated by one week washout period; the subjects were fasted overnight. The sequence of administrations, rapid release tablets (T) and granular powder (P) , was randomly defined for each subject. Blood samples were withdrawn at 0,1,2,3,4,6,12,24,48, and 72h after oral dosing. Three female volunteers were using effective contraceptive methods. No other drugs were allowed before (3 days) and during the study. During the entire study, none of the subjects reported side-effects. DRUG MEASUREMENT Nabumetone and its active metabolite, 6-methoxy-2- naphthylacetic acid (6-MNA) , were measured in plasma samples by high pressure liquid chromatography (HPLC) according to the methods described by Daigneault et al [Am J. Med. 1987; 83 (Suppl 4B) : 11-14], Ray et al [J. Chrom 1984, 336: 234- 236] and Broquaire et al [J Chrom 1981,224:43-49)], with modifications. Naproxen was used as internal standard. Nabumetone, 6-MNA and naproxen were extracted in diethyl ether at acid pH and the organic phase was evaporated to dryness under a stream of nitrogen. The residue was dissolved in 200μl of acetonitrile and injected into the HPLC instrument. The column (reverse phase C-18) effluent was monitored spectrophotometrically at 280nm. Calibration curves, run in parallel with samples, were linear (r=0.99). The inter-assay coefficients of variation of replicate analysis of solutions of 6-MNA (7.5 and 30mg 1 _1 ) in A.V.I.S. plasma were 6.9% for 7.5mg 1 _1 (n=12) and 9.6 for 30mg 1 _1 (n=14) . PHARMACOKINETIC AND STATISTIC ANALYSIS Standard non-compartmental pharmacokinetic methods have been used for calculation of the following pharmacokinetic parameters: β - elimination rate constant calculated by regression analysis of log drug concentration over the elimination phase of the plasma concentration-time curve (h -1 ) . t 1/2 = elimination half-life (h) . AUC = area under the plasma concentration-time curve (mg l "1 h) . F rel - relative bioavailability. Calculation formula: t 1/2 = In 2/β AUC = calculated by the trapezoidal rule with extrapolation to infinity (AUC Q > «** <*) AUC (P) F rel = AUC (T) c max ( maχ -**- mum observed plasma concentration and t maχ (time of C maχ ) , calculated on the theoretical curve by non-linear regression analysis using the NLFIT package (HP-85) . The results are mean ± standard deviation (s.d.) The data were compared using paired Student's test RESULTS Nabumetone was not measurable in plasma at any time. Figures 1 to 10 Table 2 show plasma concentration-time 5 curves of nabumetone metabolite, 6-MNA, after oral dosing of two nabumetone preparation (T and P) . Pharmacokinetic parameters are summarized in Table 3. Mean plasma concentration-time curve of 6-MNA afte oral dosing of nabumetone preparations (T and P) are shown in Figure 11.. 10 1. Marked interindividual variability was observed in the profile of plasma concention-time curves. More than on peak was found in several instances. 152. Drug absorption was slow and time T maχ variable (from 3 to 24h) . 3. Elimination half-life of 6-MNA was between 18 and 41h, the mean being 30 ± 6 h after T dosing and 26 ± 20 2 h after P dosing (the difference was not statistically significant) . The elimination half- life variability after T dosing was higher than that after P dosing, possibly due to differences in T maχ . 25 4. Absorption was slower after T dosing than after P dosing: a) τ max after T significantly higher than after P (p<0.05) b) C maχ after T was significantly lower than after 30 P (ρ<0.01) . 5. Relative bioavailability was 114 ± 25% and it was higher than 100% in 6 out of 10 volunteers. 6. At 24h, plasma concentration of 6-MNA was significantly lower after T than after P dosing (p<0.05).

Claims: CLAIMS: 1. The use of a powder formulation of nabumetone for the manufacture of a medicament for the treatment or prophylaxis of inflammation and/or cancer pain and/or 5 myofacial pain syndrome in mammals. 2. A use according to claim 1 in which the excipients in the powder formulation of nabumetone are selected from the group consisting of colloidal silica and 10 hydroxypropylmethyl cellulose. 3. A use according to claim 1 or 2 in which the powder formulation of nabumetone is in unit dose form. 154. A use according to claim 3 in which the powder formulation of nabumetone in unit dose form is packaged in a sachet. 5. A use according to claim 3 or 4 in which the powder 20 formulation of nabumetone contains 1000 mg of nabumetone. 6. A use according to any one of claims 3 to 5 in which the powder formulation of nabumetone is admixed with 25 water to facilitate ease of administration. 7. A method of treatment and/or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome which comprises administering an effective 30 and/or prophylactic amount of a powder formulation of nabumetone to a sufferer in need thereof. 8. A method of treatment according to claim 7 in which the powder formulation is as defined in any one of claims 2 to 6. 9. A pharmaceutical composition for use in the treatment and/or prophylaxis of inflammation and/or cancer pain and/or myofacial pain syndrome in mammals which comprises nabumetone a<dmixed with a conventional excipient to form a powder formulation. 10. A pharmaceutical composition according to claim 9 in which the powder formulation is as defined in any one of claims 2 to 6.

Inventors: FRANCESE FRANCO, OLDANI DIEGO, VERCESI GIANPIERO, FRANCESE, FRANCO, OLDANI, DIEGO, VERCESI, GIANPIERO
Applicants: ZAMBELETTI SPA L, DR LO ZAMBELETTI S.P.A.
Application year: 1992
Main classification: A61K47
IPC codes: A61K9, A61K31, A61K47, A61P25, A61P29