NZ286432A

NZ286432A - Pharmaceutical compositions comprising 3-substituted-2-oxoindole-carboxamide derivatives and method of inhibition by photodecomposition thereof

Info

Publication number: NZ286432A
Application number: NZ286432A
Authority: NZ
Inventors: Willard C Newlin; Sharon M Laughlin
Original assignee: Pfizer
Priority date: 1995-04-24
Filing date: 1996-04-23
Publication date: 1998-05-27
Also published as: UA42739C2; SK51296A3; CN1053667C; HUP9601057A2; AP607A; IL117969A0; KR960037656A; AU692378B2; JPH10506635A; FI973988A; CN1139110A; FI973988A0; SG64924A1; AP9600787A0; HU216544B; NO961622D0; HU9601057D0; WO1996033701A1; IS4339A; NO961622L

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £86432 New Zealand No. International No. 286432 PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 24.04.1995; Complete Specification Filed: 2.J.04.1998 Classification:^) A01K31/405; A61K9/20.48 Publication date: 27 May 1998 Journal No.: 1428 Title of Invention: Inhibiting photodecomposition of 3-substituted-2-oxindoles Name, address and nationality of applicant(s) as in international application form: PFIZER INC., a Delaware corporation of 235 East 42nd Street, New York, New York 10017, United States of America NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 286432 NEW ZEALAND PATENTS ACT, 1953 No: Date: N.Z. PATENT OFFICE 2 3 APR 1996 RECEIVED COMPLETE SPECIFICATION INHIBITING PHOTODECOMPOSITION OF 3-SUBSTITUTED-2-OXINDOLES We, PFIZER INC., a corporation organized under the laws of the State of Delaware, United States of America of 235 East 42nd Street, New York, New York 10017, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: • -1 - (followed by page la) 28 6W ■1? INHIBITING PHOTODECOMPOSITION OF 3-SUBSTITUTED-2-OXINDOLES Field of the Invention This Invention relates to the Inhibition of photodecomposition of certain 3-sub8tituted-2-oxlndole-1 -carboxamldes of the formula 10 and the pharmaceutically-acceptable base salts thereof wherein X is H, CI or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F. Background of the Invention 15 U.S. 4,569,942 discloses certain 2-oxlndole-1-carboxamldes of the formula 20 •0 Y 0=C-NH-R2 wherein X is H, fluoro, chloro, bromo, (C,-C4)alkyl, (C3-C7)cycloali<yl, (C,-C4)alkoxy, (C,-C4)alkyHhio, trifluoromethyi, (C,-C4)alkylsulfinyl, (C1-C4)aikyisulfony1, nitro, phenyl, (C2-C4)alkanoyl, benzoyl, thenoyl, (C,-C4)alkanamido, benzamido or 25 N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said aikyls; Y is, H, fluoro, chloro, bromo, (C,-C4)alkyl, (C,-C7)cycloalkyl, (C,-C4)alkoxy, (C,-C4)alkylthio and trifluoromethyi; R1 is (C,-C8)alkyl, (C3-C7)cycloaIkyI, (C4-C7)cycloalkenyt, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 30 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo- [2.2.1 ]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -(CH2)„-Q-R; n is zero, 1 or 2; Q is a divalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 28 6432 -2- 1,2,6-thladlazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothlopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]-thiophene; and Ra is (C,-Ce)alkyl, (C,-C7)cycloalkyl, benzyl, furyl, thienyt, pyridyl or where R3 and R4 are each H, fluoro, chloro, (C^CJalkyl, (CrC4)alkoxy or trifluoromethyi. That patent also discloses that said 2-oxindoie-1-carboxamldes are inhibitors of cyciooxygenase and lipoxygenase, possess analgesic activity In mammals 10 and are useful in treatment of pain and alleviation of symptoms of chronic diseases such as Inflammation and pain associated with rheumatoid arthritis and osteoarthritis. U.S. Patent 4,556,672 discloses certain 3-acyl substituted- 2-oxindole-1-carboxamides of the formula 20 wherein X, Y and R1 are as described above for the compounds of U.S. Patent No. 4,569,942. y v U.S. Patent No. 4,861,794 discloses thwise of compounds of the formula 0 5 0 15 Y o=c—nh2 li C—R 25 0^ ^nh£ 30 and the pharmaceutically-acceptable base salts thereof wherein X is H, CI or F, Y is H or CI and R is benzyl or thienyl to inhibit biosynthesis of interleukin-1 (IL-1) and to treat IL-1 mediated disorders and dysfunctions. 286432 Summary of the Invention This Invention relates to a method for reducing the rate of degradation, by inhibiting photodecomposition, of a compound of the formula o \\ (T^C^NH2 and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein 10 X is H, C1 or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F; said photodecomposition resulting from light emanating from a light source; which comprises: bringing a light absorbing material into intimate contact with said compound by admixture therewith coating thereof, or incorporation into a dosage form therefor, whereby said light from said light source is substantially prevented from 15 impinging upon said compound. In a preferred method of this invention said light absorbing material is a dye selected from the group consisting of yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3. In a further preferred method of this invention said light absorbing material is 20 yellow #6. ■ In another aspect this invention relates to a tablet comprising: (A) a therapeutically active ingredient comprising a compound of the formula , and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein: X is H, CI or F; Y is H or C l; and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and 286432 (C) a coating on said tablet containing a light absorbing material comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3 in sufficient amount to inhibit photodecomposition of said therapeutically active ingredient by light from a light source impinging upon said compound. In a preferred aspect this invention comprises a coated tablet wherein said coating contains yellow dye #6 in sufficient amount to inhibit photodecomposition of 5 said pharmaceutical^ active ingredient. In another preferred aspect this invention provides a capsule comprising: (A) A therapeutically active ingredient comprising a compound of the formula: and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein X is H, CI or F: Y is H or C1: and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and 2o (C) each shell of said capsule containing a light absorbing material comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3 in sufficient amount to inhibit photodecomposition of said therapeutically active ingredient by light from a light source impinging upon said compound. In still a further aspect, the present invention provides a pharmaceutical composition comprising: (A) a therapeutically active ingredient comprising a compound of the formula: 0 10 \\ 2 25 0 \\ - 4a - 286432 and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein X is H, C1 or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and (C) a light absorbing material in intimate contact with said compound comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3 in sufficient amount to inhibit photodecomposition of said therapeutically active ingredient by light from a light source impinging upon said compound. Detailed Description of the Invention . Compounds of the formula 0 O^Cxnh2 286432 -5- and the enol form: 0^NH2 and the pharmaceutically-acceptable base salts thereof wherein X is H, CI or F; Y is H or CI; and R is benzyl or thienyl optionally substituted with CI or F and the preparation 10 thereof are disclosed in U.S. Patent Nos. 4,556,672 and 5,290,802 the teachings of which are incorporated herein by reference. These compounds have been found to be photosensitive and are decomposed by light. This invention concerns methods for preventing photodecomposition of the compounds of Formula I and its enol form by Inhibiting light from contacting said compounds. 15 As used within this document, "light source" means solar light or any artificial light source which produces light of wave lengths less than 600 nm. "Ught absorbing materialmeans materials which block all or most wave lengths of light such as opaque glass or metals; or materials which absorb light with wave lengths of less than 600 nm such as ultra violet stabilizers or dyes. 20 The light absorbing material may be used in packaging materials such as/ blister packages, sachets or bottles. Chemical light absorbing materials such as ultraviolet stabilizers may be incorporated in packaging material including blister packages, sachets or bottles or are preferably incorporated in capsule shells or tablet coatings. Chemical light absorbing materials may also be mixed directly with the active/ ingredient 25 prior to tableting or placing in a capsule shell. "Inhibition of photodecomposition* means a statistically significant reduction in formation of light induced degradation products described herein below. Of the methods of inhibiting photodecomposition described below, preferred therein are those where the compound employed is of the Formula I above wherein X 30 is CI, Y is H and R is thienyl; those wherein X is F, Y is CI and R is thienyl or 4-chlorothien-2-yl; those wherein X is F, Y is CI and R is 2-thienyl; and those wherein X is H, Y is CI and R is benzyl. Particularly preferred are methods whereii^X^s CI, Y is \ *8> X 286432 -6- H and R is 2-thienyl. The compounds of Formula I may exist in an enol form; all such enol forms and salts thereof are contemplated in this invention. As disclosed in U.S. 4,556,672 and 5,290,802, the compounds protected by this invention are acidic and form base salts. All such base salts are within the scope of 5 this invention and can be formed as taught by these patents. Such suitable salts, within the scope of this invention, include both the organic and inorganic types and include, but are not limited to, the salts formed with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal 10 carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of bases which form such base salts include ammonia, primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzyiamine, p-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamlne, diethanolamine, N-methylglucamine, N-methylaniline, morphollne, 15 pyrrolidine and piperidine; tertiary amines, such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hydroxides, such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate. Preferred salts are those of sodium, 20 potassium, ammonium, ethanolamine, diethanolamine and triethanolamine. Particularly preferred are the sodium salts. The compounds to which this invention is applicable include solvates such as the hemihydrates and monohydrates of the compounds hereinabove described. Light-induced degradation of 3-substituted-oxindole-1 -carboxamldes occurs 25 primarily at wave lengths of light less than 600 nm producing as decomposition products mainly benzoic orthenoic acid and oxindole-1-carboxamide. This degradation may be avoided by preventing light of wave lengths less than 600 nm from contacting the 3-substituted oxindole-1-carboxamide. Red and yellow dyes have been found effective in preventing contact of light and 30 the associated light-induced degradation of 3-substituted oxindole-1-carboxamldes. Preferred dyes are FD&C red #40, FD&C red #3 and FD&C yellow #6. Yellow #6 is especially preferred. The dyes are effective in preventing light-induced degradation of 3-substituted-oxindole-1 -carboxamides when mixed with the oxindole, applied to a 286432 -7- preformed tablet in a coating, or in a gelatin capsule containing the oxindole. The preferred method is the coating of tablets. Rim coating of pharmaceutical tablets is well known in the art and is described, for example, In United States Patents 4,828,841; 3,981,948; and 3,802,896 which are hereby incorporated by reference. Rim coating materials such as white Opadry, Opadry II, Surelease, Aquacoat and Eudragit which are suitable for formulation with the selected dye are commercially available from Colorcon, West Point, PA; FMC Corp., Philadelphia, PA; Rohm Pharma, Welterstadt, Germany respectively. Dyes may also be formulated into gelatin capsules which are then filled with the oxindole. The technology for preparing capsules is well known to those of ordinary skill in this art. Capsules incorporating selected dyes are available commercially from Elanco Shinogi, Indianapolis, IN and Capsugel, Greenwood, SC. U.S. patent no. 3,784,684 describes the incorporation of opacifers and dyes In gelatine capsule shells. The amount of dye in the coating or capsule shell is not critical except that sufficient dye must be incorporated to absorb any incident light. We have found that 1.2-2.8 mg/tablet of yellow #6 prevented decomposition while In capsule shells 0.28 to 0.5 mg/capsule afforded light stability. A typical formulation of the coated tablets of this invention may be prepared as follows: 286432 -8- COMPONENT mg/TABLET Oxlndole-1 -carboxamide 21.74 Klucal EF 6.00 Lactose, Anhydrous 122.26 5 Ac-Di-Sol 6.00 Avicel PH102 40.00 Magnesium Stearate 3.60 Sodium Laurvl Sulfate 0.40 Total Weight (Core) 200.00 10 White Opadry (YS-5-7068)' 10.00 Distilled Water Yellow #6 Lake f39% PuritvV> _L15 Total Weight (Rim coated tab) 211.15 • For the lots which will be film coated. 15 b For the lot which will contain dye. The following Examples are presented to illustrate, but not to limit the invention which is defined by the claims. EXAMPLE 1 Coated Tablet? 20 Tablet cores of 5-chloro-2,3-dlhydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- IndoleM -carboxamide (600 g) were prepared using the formulation described above. Orange Opadry, containing yellow dye #6 obtained from Colorcon, West Point, PA (144 g) was suspended in 816 ml water. Tablet cores were changed to a Hi Coater HCT30 coating machine and held at 42°C while the orange Opadry suspension was 25 applied. Two coated and one uncoated lot of 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H-indole-1 -carboxamide (Formula I, X = CI, Y = H) tablets were heated to 30°C and 50°C and held in a light cabinet for 6 weeks. Tablet cores were identical for all three lots. The coated tablets differ only in the amount of yellow 30 #6 in the film coat. The intensity of the light cabinet was 400 foot candles (FC) in the center and 300 FC on the sides of the cabinet which was maintained at room temperature. 28 6432 -9- Appearances of the samples stored at 30°C and 50°C were not different from the appearance of the samples stored at 5°C. Raking of the film coat was not observed for any tablets. The following visual observations were made on samples stored in the light cabinet for 6 weeks: 5 Lot 1 (core): Slightly darkened, brown spots (compared to 6°C control) Lot 2 (coated): Slightly faded (compared to 5°C control) Lot 3 (coated): Slightly faded (compared to 5°C control) The LC assay results for these lots are summarized in the table below. All 10 samples were analyzed in triplicate. Assay values for the uncoated tablets were close to the intended 100 mg/g. Levels of thiophene-2-carboxylic acid, 6-chloro-1 H-quinazoline-2,4-dione, thiophene-2-carboxylic acid 1 -carbamoyl-5-chloro-2-oxo-2,3-dihydro 1 H-indol-3-yl ester, 6-chloro-2-hydroxy-quinazoline-4-carboxylic acid and unknown #3 for the uncoated tablets increased significantly in the light cabinet 15 (compared to 5°C control). No significant degradation was observed for the tablet cores stored at 5°C, 30°C or 50°C. No significant degradation was observed for the coated tablets stored at 5°C, 30°C, 50°C or in the light cabinet. After 6 weeks, the levels of degradation in the light cabinet samples was approximately the same for both the coated tablet lots. Results 20 of the above tests are shown in the table below. 286432 -10- 40 mg 5-chloro-2,3-dihydro-3-(hydroxy-2-thlenylmethylene)-2-oxo-1 H-indole-1 - fl carboxamide (Formula I, X = CI, Y = H) Stability, 6 Weeks* \ LOT 1 (tablet core) | 6 weeks: 6°C 30° C 50°C LC | 5-chloro-2,3-dlhydro-3-(hydroxy-2-| thienylmethylene)-2-oxo-1 H-indole-1 -I carboxamide (Formula I, X = CI, Y = H) (mg/Tab) 39.4 39.7 39.8 38.7 5-chloro-2,3-dlhydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1 H-indole-1 • carboxamide (Formula I, X = CI, Y = H) (mg/g) 99.0 99.8 100.8 97.8 % Thiophene-2-carboxylic acid 0.01 0.02 0.04 0.28 % 6-Chloro-1H-quinazoline-2,4-dione ND ND <0.01 0.06 % Thiophene-2-carboxylic acid 1-carbamoyl-6-chloro-2-oxo-2,3-dihydro 1 H-indol-3-yl ester 0.01 0.03 0.02 0.19 % 6-Chloro-2-hydroxy-quinazoline-4-carboxylic acid 0.01 0.03 0.04 0.29 1 % Unknown #3** ND ND ND 0.03 LOT 2 (coated tablets, 1.35 mg yellow #6) 6 weeks 5°C 30°C LC 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1 H-indole-1 -carboxamide (Formula 1, X = CI, Y = H) (mg/Tab) 39.5 39.4 38.7 5-ch1oro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1 H-indole-1 -carboxamide (Formula 1, X = CI, Y = H) (mg/g) 92.7 93.1 91.2 % Thiophene-2-carboxylic acid 0.02 0.01 0.03 % 6-Chloro-1H-quinazoline-2,4-dione 0.02 0.02 0.02 % Thlophene-2-carboxyllc acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1 H-indol-3-yl ester 0.01 0.01 0.01 % 6-Chloro-2-hydroxy-quinazoline-4-carboxylic acid 0.03 0.02 0.04 28 6432 -11- 10 LOT 3 (coated tablets, 0.9 mg yellow #6) 6 weeks 5°C 30°C 50 °C LC | 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylnr»ethylene)-2-oxo-1 H-indole-1 -carboxamide (Formula I, X = CI, Y = H) (mg/Tab) 39.5 39.6 39.0 39.0 | 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylnr»ethylene)-2-oxo-1 H-indole-1-carboxamide (Formula 1, X = CI, Y = H) (mg/g) 94.9 94.8 94.3 93.3 I % Thiophene-2-carboxylic acid 0.01 0.03 0.04 0.04 % 6-Chloro-1H-quinazoline-2,4-dlone 0.01 0.01 0.01 0.01 % Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro 1H-lndol-3-yl ester 0.01 0.02 0.02 0.02 % 6-Chloro-2-hydroxy-quinazoline-4-carboxylic acid 0.02 0.04 0.05 0.05 * Stability comparisons should be made against the 5°C control. [ ** Area percent. | 15 20 EXAMPLE 2 Capsules A formulation of a compound of Formula i where X is CI, Y is H and R is thieny) was prepared from the following components: 25 30 Compound of Formula I Sodium Lactose, anhydrous Pregelatinized Starch Croscormellose Sodium Magnesium Stearate ma/unit 128.205 159.795 112.500 9.000 9.000 The above ingredients were mixed and a portion roller compacted, then milled and reblended with the remaining Ingredients, lubricated and encapsulated In gelatin capsules obtained from Capsugel, a division of Warner-Lambert Company. A preferred </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 286432 -12- lubricant is sodium laurel sulfate. The capsules contained FD&C yellow dye 0.2661% of total dry weight in the capsule body and 0.1768% in the cap. Capsules prepared in this manner were found to afford light stability to the compound of Formula I. -13- WHAT WE CLAIM IS: 286432 I. A method for reducing the rate of degradation, by inhibiting photodecomposition, of and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein X is H, CI or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F; said photodecomposition resulting from light emanating from a light source; which comprises: bringing a light absorbing material into intimate contact with said compound by admixture therewith, coating thereof, or incorporation into a dosage form therefor, whereby said light from said light source is substantially prevented from impinging upon said compound.
2. A method according to claim 1 wherein X is CI; Y'is H; and R is thienyl.
3. A method according to claim 2 wherein R is 2-thienyl.
4. The method according to claim 3 wherein the pharmaceutically-acceptable base salt is sodium.
5. A method according to claim 1 wherein X is F; Y is C1; and R is thienyl or 4-chlorothien-2-yl.
6. The method according to claim 5 wherein R is 4-chlorothien-2-yl.
7. The method according to claim I wherein X is H; Y is CI; and R is benzyl.
8. A method of any one of the preceding claims wherein said light absorbing material is a dye selected from the group consisting of yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3.
9. A method of claim 8 wherein said light absorbing material is yellow dye #6. compound of the formula 0 0^C^NH2
10. A tablet comprising: (A) a therapeutically active ingredient comprising a compound of the formula 14- 286432 , and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein: X is H, CI or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and (C) a coating on said tablet containing a light absorbing material comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3 in sufficient amount to inhibit photodecomposition of said therapeutically active ingredient by light from a light source impinging upon said compound.
11. A tablet of claim 10 wherein said coating contains yellow dye #6.
12. A capsule comprising: (A) A therapeutically active ingredient comprising a compound of the formula: 0 V-R x^° I and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein X is H, CI or F; Y is H or C1; and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and (C) each shell of said capsule containing a light absorbing material comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake ufficient amount to inhibit photodecomposition of said therapeutically active ihjpe&^Jjy light from a light source impinging upon said compound. 28 6 4 5 Z
13. A capsule of claim 12 wherein said capsule shell contains yellow dye #6.
14. A pharmaceutical composition comprising: (A) a therapeutically active ingredient comprising a compound of the formula: and the enol form thereof or a pharmaceutically-acceptable base salt thereof, wherein X is H, CI or F; Y is H or CI; and R is benzyl or thienyl, each optionally substituted with CI or F; (B) a pharmaceutical^ acceptable carrier for said active ingredient; and (C) a light absorbing material in intimate contact with said compound comprising one or more members independently selected from the group consisting of dyes yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3 in sufficient amount to inhibit photodecomposition of said therapeutically active ingredient by light from a light source impinging upon said compound.
15. A pharmaceutical composition as claimed in claim 14 wherein said light absorbing material comprises yellow dye #6.
16. A method as defined in claim 1 for inhibiting photodecomposition of a compound of formula I defined therein and the enol form thereof or a pharmaceutically-acceptable base salt thereof substantially as herein described with reference to any example thereof.
17. A tablet as defined in claim 10 substantially as herein described with reference to any example thereof.
18. A capsule as defined in claim 12 substantially as herein described with reference to any example thereof.
19. A pharmaceutical composition as defin in 0 \\ O-S^NHj described with reference to any example therei By the authorised ageM& °c By the authorised AJ PARK & SON END OF CLAIMS </div>