AU666666B2 - Rapidly disintegratable multiparticulate tablet - Google Patents

Abstract

A rapidly disintegratable multiparticulate tablet having a mixture of excipients which is suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in an extremely short time, particularly in less than sixty seconds. The tablet is characterized in that the active substance is present in the form of coated microcrystals or optionally coated microgranules.

Description

OPI DATE 23/02/93 AOJP DATE 29/04/93, APPLN. ID 24171/92I 111II 111li111 11111111li ii PCT NUMBER PCT/FR92/00715I1111iihhli iiDi ii111liiii AU9224 171 DEMANDE iiAEtr. ur- iuKtVt I Z (51) Classification internationale des brevets 5 (11) Numn6ro de publication internationale: 'WO 93/01805 A61K 9/20 Al (43) Date de publication internationalc: 4 f~vrier 1993 (04.02.93) (21) Numiro de la demnande intcrnationale: PCT/FR92/00715 (74) Mandataires: KOCH, Gustave etc. ;Cabinet Plasseraud, 84, rue d'Amsterdam, F-75009 Paris (FR).

(22) Date de dep6t international: 21 juillet 1992 (21.07.92) (81) Etats di~signis: AT, AU, BB, BG, BR, CA, CH, CS, DE, Donnies relatives i Ia priorit6: DK, ES, Fl, GB, HU, JP, KP, KR, LK, LU, MG, MN, 91/09245 22juillet 1991 (22.07.91) FR MW, NL, NO, PL, RO, RU, SD, SE, US, brevet europ~en (AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LU, MC, NL, SE), brevet OAPI (BF, BJ, CF, CG, Cl, CM, (71) D~posant (pour tous les Etats d~sign~s sauf US): LABORA- GA, GN, ML, MR, SN, TD, TG).

TOIRES PROGRAPHARM [FR/FR]; Z.1. Saint-Arnoult, F-28 170 Ch~teauneuf-en-Thymerais (FR).

Publi&e (72) Inventeurs; et Ai'ec rapport de recherche internaional'.

Inventeurs/Diposants (US setileinent) :COUSIN, Gerard [FR/FR]; 4, impasse de la Man~e, F-28320 Gallardon BRUNA, Etienne [FR/FR]; 9, place Jean-Moulin, Residence des Carneaux, F-28000 Chartres GEN DROT, Edouard [FR/FR]; 24, rue de Dreux, Garnay, F-6 28500 Vernouillet 6 6 6 (54) Title: RAPIDLY DISI NTEGRATAB LE MULTI PARTICULATE TABLET (54)Titre: COMPRIME MULTI PARTICULAI RE A DELITEMENT RAPIDE (57) Abstract A rapidly disintegratable multiparticulate tablet having a mixture of excipients which is suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in an extremely short time, particularly in less than sixty seconds, The tablet is characterized in that the active substance is present in the form of coated microcrystals or optionally coated microgranules.

(57) Abr~g6 Comprim6 multiparticulaire A d&litement rapide dont le melange d'excipients est propre 4 conf~rer une vitesse de d~litement telle que sa. d~sagr~gation dans Ia cavit& buccale se produit en un temps extr~mement court et notamment inf~rieur A 60 secondes, caract~ris par le fait que Ia substance active est pr~sente sous Ia forme de microcristaux enrob~s ou de microgranules enrobes ou non, RAPIDLY DISINTEGRATABLE MULTIPARTICULATE TABLET The invention relates to a rapidly disintegratable multiparticulate tablet, i.e. a pharmaceutical presentation for oral administration whose disintegration rate is such that, when it is placed into the buccal cavity and particularly on the tongue, it disintegrates in less than sixty seconds providing with the saliva present a suspension easy to be swallowed.

More specifically a rapidly disintegratable multiparticulate tablet comprising an excipient and an active substance which are mixed with one another, the thus obtained mixture being then tabletted after addition of a lubricant, the said excipient which is selected from the group comprising one or several disintegrating agents and/or one or several swelling or soluble agents, being suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in less than sixty seconds, the said tablet being characterized by the fact that the active substance is present in the form of coated microcrystals or coated microgranules.

The disintegration rate is obtained due to a mixture of excipients or vehicles which comprises generally a disintegrating agent which may consist of a carboxymethylcellulose and a swelling agent which may consist of modified S starch.

The active substance or principle is mixed with the abovesaid vehicles, the mixture then being tabletted after addition of a lubricant such as, for "j example, magnesium stearate. The Applicants have had the merit of having found that it was possible, unexpectedly and surprisingly, to introduce into a multiparticulate tablet with high disintegration rate such as hereabove defined, the active substance in the I c form of coated or non-coated microcrystals or microgranules; thus, the physician has at his disposal a rapidly disintegratable multiparticulate tablet proper to facilitate the taking by the patient of most diversified active substances and especially of those whose taste is particularly unpleasant, the said tablet permitting the taking of the said active substances with as diversified features as gastroresistance and controlled release due to the fact that the said coated or 1 7. 0 1 1 Ila non-coated microcrystals and microgranules preserve, after having been shaped in the form of a multiparticulate tablet, their initial properties amongst which masking of taste, gastro resistance and controlled release of the active principle.

at, *C9999 9 a tro 999 99 9 99 S. 4 9. 9 Cs. C 5 99 99 t 9 9 2 C 9 C 9 C~ e

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_L L" 'ntM *hn i irifCACi irii' Consequently, the rapidly disintegratable multiparticulate tablet according to the invention, which can be used for human beings and for animals,, the excipient mixture of which is such as to provide it with a disintegration rate so that its disintegration in the buccal Scavity occurs in an extremely short time and especially shorter than sixty seconds, is characterized by the fact that the active substance is in the form of coated or noncoated microcrystals or microgranules with modified action or non-modified action.

According to an advantageous embodiment of the abovesaid tablet, the mixture of excipients comprises one or several disintegrating agents of the carboxymethylcellulose type or insoluble reticulated PVP type, one or several swelling agents which may consist of a carboxymethylcellulose, a starch, a modified starch, for instance a carboxymethylated starch, or a microcrystalline cellulose, and possibly a direct compression sugar consisting for example of 92% of dextrose.

According to an advantageous embodiment, the tablets according to the invention, wherein the active substance is in the form of coated microcrystals, comprise as active substance at least one of those of the group comprising the gastrointestinal sedatives, the antacids, the analgesics, the anti-inflammatory agents, the coronary vasodilators, the peripheral and brain-vasodilators, the anti-infectious agents, the antibiotics, the antiviral SI agents, the antiparasitic agents, the anticancerous drugs, the antianxiety agents, the neuroleptic drugs, the agents stimulating the central nervous system, the antidepressant drugs, the antihistaminic agents, the antidiarrheal agents, the laxatives, the nutritional supplements, the immunodepressant drugs, the cholesterol lowering agents, the hormones, the enzymes, the antispasmodic agents, the antiangorous agents, the drugs acting on the rhythm of the STR, heart, the drugs used in the treatment of arterial hyper- I'T ~ll -T 1 tension, the anti-migraine agents, the drugs acting on blood coagulability, the antiepileptic agents, the myorelaxing agents, the drugs used in the treatment of diabetes, the drugs used in the treatment of thyroidal dysfunctions, the diuretical agents, the anorexigenic drugs, the antiasthmatic agents, the expectorants, the antitussive agents, the mucoregulators, the decongestants, the hypnotics, the antinauseous agents, the hematopoietical agents, the uricosuric agents, the plant extracts, the contrast mediums.

According to another advantageous embodiment, the tablets according to the invention, wherein the active substance is present in the form of coated or non-coated microgranules with modified action or non-modified action, comprise as active substance at least one of those of the group comprising the gastrointestinal sedatives, the antacids, the analgesics, the anti-inflammatory agents, the coronary vasodilators, the peripheral and brainvasodilators, the anti-infectious agents, the antibiotics, the antiviral agents, the antiparasitic agents, the anticancerous drugs, the antianxiety agents, the neuroleptic drugs, the agents stimulating the central nervous system, the antidepressant drugs, the antihistaminic agents, the antidiarrheal agents, the laxatives, the nutritional supplements, the immunodepressant drugs, the cholesterol lowering agents, the hormones, the enzymes, the antispasmodic agents, the antiangorous agents, the drugs acting on the rhythm of the heart, the drugs used in the treatment of arterial hypertension, the anti-migraine agents, the drugs acting on blood coagulability, the antiepileptic agents, the myorelaxing agents, the drugs used in the treatment of diabetes, the drugs used in the treatment of thyroidal dysfunctions, the diuretical agents, the anorexigenic drugs, the antiasthmatic agents, 35 the expectorants, the antitussive agents, the mucoregu- S lators, the decongestants, the hypnotics, the antinauseous .1 0 9_ INTERNATIONAL SEARCH REPORT International application No.

PCT/FR 92/00715 A. CLASSIFICATION OF SUBJECT MATTER A61K9/20 iI 4 agents, the hematopoietical agents, the uricosuric agents, the plant extracts, the contrast mediums.

The use of the tablet according to the invention is especially advantageous due to the fact that it may be very easily used by any users. The said tablet can be taken in any condition (when working, when travelling and so on), without a glass and without water. It constitutes an "ambulatory" pharmaceutical presentation which can advantageously be used instead of numerous pharmaceutical presentations such as sachets, effervescent tablets, drinkable ampoules, capsules, traditional tablets and so on.

Its very easy facility of administration is especially interesting when it is necessary that young children or old people take therapeutical substances, i.e.

populations which often have swallowing difficulties, i.e.

populations which keep the drug in the mouth and which are unable to swallow it. Contrary to the traditional tablet or to the capsule, the tablet according to the invention offers in connection with such populations an advantage of security as, as soon as it is introduced in the mouth, it provides a therapeutical protection.

zL. On the other hand, it is important to emphasize that, even directly swallowed with a little water for example, the said tablet preserves its rapid disintegration rate within the stomach. This type of administration will again raise no security problem.

Furthermore, the tablet according to the invention provides a further big advantage with respect to tablets or simple capsules. In fact until today, people who need to swallow a tablet or a capsule under the above-mentioned conditions (during working, during travelling, without water and without a glass), swallowed the said tablet or capsule without water and that could be dangerous as the tablet or capsule can block in the esophagus and provide thus an important delay as far as absorption of the active -T 1, principle is concerned or even an ulceration at the level of the esophagus. Similarly, the fact that, on the one hand, the active principle is coated and, on the other hand, that it is present in the form of a multiparticulate tablet, prevents agressive active principles causing ulcerations of the esophagial or gastric mucous membranes, phenomenon which is sometimes caused by certain pharmaceutical presentations which are monolithic, especially when the patient suceeeds in swallowing them with a little water or no water.

Another advantage of the tablet according to the invention is that the said tablet has not the well-known drawbacks of effervescent tablets as for instance the taste which is very unpleasant to the child, the high sodium content which is disturbing to people which must follow a diet without sodium and finally the necessity of having water and a glass for its administration.

Furthermore, it permits the formulation of certain active principles which are not adapted to a previous extracorporeal dissolution and which consequently car. be contemplated only under a dry form, which prevents their use in effervescent tablets; consequently, the tablet according to the present invention has all the advantages of the dry forms, i.e. the stability as well as the facility of packaging and storage.

On the other hand, this new pharmaceutical form may contain if necessary two or several active principles which are usually incompatible with one another and this without alteration of their stability.

Another advantage of the tablet according to the invention consists in the possibility of taking by the patient of doses of active principle which are more important than in the past. As a matter of fact as the said tablet is not to be swallowed under its initial form but after disintegration within the buccal cavity, its size might be greater than that of a classical pharmaceutical form which must be adapted to be swallowed without disturbing the taking of the drug.

Finally, the tablet according to the invention has all the advantages of coated particles which permit to obtain especially a taste-masking, a gastroresistance, a delayed release as well as all the advantages of the multiparticulate forms with modified action or nonmodified action, i.e. a great exchange surface, the dispersion, less inter- and intra-individual variations, a very reduced gastric empting influence, a very reduced intestinal transit time influence as well as reduced pH influence in the digestive tract, reduced influence of the viscosity and consequently of food and of the position of the body, without local toxic manifestation.

The preparation of the rapidly disintegratable multiparticulate tablets according to the invention is as follows or similar.

When the active principle is in the form of coated microcrystals, it is possible to proceed as follows.

The microcrystals are coated by way of a process known by itself such as, for example, the fluidized air bed, the coacervation and the microencapsulation.

The mixture of excipients is then prepared by the dry- or wet-granulation method.

Then, the coated microcrystals are mixed under dry conditions with the mixture of excipients before compression.

The preparation of the tablet according to the invention wherein the active principle is in the form of coated or non-coated microgranules, may be as follows.

The active principle is put in the form of microgranules by way of a method known by itself such as, for example, extrusion-spheronisation, manufacture in pan, fluidized air bed and so on.

Once obtained, 'these microgranules are coated if necessary in a pan or in a fluidized air bed.

ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIFA LA DEMANDE INTERNATIONALE NO. FR 9200715 SA 63061 The mixture of excipients is then prepared by the dry- or wet-granulation method.

Then, the coated or non-coated microgranules are mixed under dry conditions with the mixture of excipients before compression.

The invention may even be better understood by way of the following non-limitating examples which relate to advantageous embodiments of the invention.

EXAMPLE 1 Rapidly disintegratable multiparticulate tablet based on coated crystals of paracetamol.

Tablets according to the invention are prepared whose composition is as follows.

Formula: coated paracetamol (with 6% ethylcellulose) direct compression sugar microcrystalline cellulose reticulated polyvinylpyrrolidone sodic carboxymethylcellulose colloidal silica lubricant sweetener aroma magnesium trisilicate 530 mg 160 mg 90 mg 60 mg 50 mg 6 mg 4 mg 25 mg 15 mg 50 mg Total 990 mg The said tablet is prepared as follows.

The paracetamol crystals are introduced in a fluidized air bed installation and a solution of ethylcellulose in an ethanol/acetone mixture is sprayed thereon.

The excipients are sieved and the coated paracetamol is homogeneized with the excipients inside a mixing .device under dry conditions.

Distribution and tabletting are carried out on a compressing machine fitted with punches having a diameter equal to 15 mm and a radius of curvature equal to 20 mm.

L

ii^ 1 ::d The pressure is equal to 16 KNewtons The hardness of the thus obtained tablets is equal to 100 Newtons ±10. The time of disintegration in the mouth is from 35 to 45 seconds.

EXAMPLE 2 Rapidly disintegratable multiparticulate tablet based on coated cimetidine crystals.

Tablets according to the invention are prepared whose composition is as follows.

Formula: coated cimetidine (with 15.25% of Eudragit E) 944 mg reticulated polyvinylpyrrolidone 89 mg magnesium stearate 5 mg sweetener 50 mg aroma 12 mg i Total 1100 mg The said tablet is prepared as follows.

The cimetidine crystals are introduced in a fluidized air bed installation and a solution of a copolymer of dimethyl-aminoethyl-methacrylate and of neutral esters of methacrylic acid known under the trademark "Eudragit E" in alcohol is sprayed thereon.

The excipients are sieved and the coated cimetidine is homogeneized with the excipients inside a mixing apparatus under dry conditions.

Distribution and tabletting are executed on a compressing machine equipped with punches having a diameter equal to 16 mm and a radius of curvature equal to 20 mm.

The pressure is 20 KNewtons The hardness of the thus obtained tablets is 95 Newtons ±10. The time of disintegration in the mouth is from 15 to 20 seconds.

EXAMPLE 3 Rapidly disinteMatable multiparticulate tablet based on coated crystals of paracetamol.

Tablets according to the invention composed as follows are prepared.

Formula: complex of paracetamol-codeine mg of codeine and 18.4% of Eudragit*) 627.5 mg reticulated polyvinylpyrrolidone 90 mg sodium carboxymethylcellulose 70 mg starch commercialized under the trademark "STARCH 1500" 100 mg sweetener. 40 mg aroma 22.5 mg Total 950 mg Eudragit is a copolymer of methacrylic acid.

This tablet is prepared as follows.

The crystals of paracetamol are introduced in a fluidized air bed installation and the codeine dissolved in a solution of Eudragit E and Eudragit NE 30D (neutral polymer of esters of polymethacrylic acid) is sprayed thereon.

The excipients are sieved and the coated paracetamol is homogeneized with the excipients in a mixing apparatus under dry conditions.

Distribution and tabletting are carried out on a compressing machine equipped with punches having a diameter equal to 16 mm and a radius of curvature equal to 20 mm.

The pressure is 21 KNewtons The hardness of the thus obtained tablets is 35 Newtons The time of disintegration in the mouth is from 50 to 60 seconds.

EXAMPLE 4 Rapidly disintegratable multiparticulate tablet based on coated crystals of ibuprofen.

Tablets according to the invention and whose composition is as follows are prepared.

Formula: ibuprofen (with 10% of ethylcellulose) 440 mg reticulated polyvinylpyrrolidone 120 mg starch commercialized under the trademark "STARCH 1500" 235 mg sweetener 48 mg aroma .52 mg magnesium stearate 5 mg Total 900 mg This tablet is prepared as follows.

The crystals of ibuprofen are introduced in a fluidized air bed installation and a solution of ethylcellulose in ethanol is sprayed thereon.

The excipients are sieved and the coated ibuprofe' i is homogeneized with the excipients in a mixing apparatus: j under dry conditions.

Distribution and tabletting are carried out on a compressing machine equipped with punches having a diameter equal to 16 mm and a radius of curvature equal to mm.

The pressure is 15 KNewtons The hardness of the thus obtained tablets is 50 Newtons The time of disintegration in the mouth is from 15 to 20 seconds.

EXAMPLE Rapidly disintegratable multiparticulate tablet based on microgranules.

Formula: microgranules with delayed release based on doxycycline monohydrate (with 100 mg of active principle) 225 mg 11 microcrystalline cellulose 142 mg starch commercialized under the trademark "SEPPISTAB ST 500" 98 mg aspartam 20 mg aroma 15 mg Total 500 mg The microgranules are prepared in a pan by coating a neutral sugar sphere with doxycycline according to the classical technology, the microgranules being then coated with Eudragit E also in coating pan.

The tablet is prepared by sieving of the excipients, followed by homogeneization of the microgranules of doxycycline with the excipients in a mixing apparatus under dry conditions, followed by distribution and tabletting in a rotary compressing machine equipped with punches having a diameter equal to 12 mm and radius of curvature is equal to 11 mm.

The pressure is 20 KNewtons The hardness of the thus obtained tablets is 100 Newtons ±10. The time of disintegration in the mouth is from 10 to 20 seconds. i As a result of which we have a rapidly disintegratable multiparticulate tablet, the constitution and method of manufacture of which are sufficiently disclosed above, such that it would be useless to repeat this subject and about which it is recalled that it consists of a tablet which combines a high level technology (control of release, of gastroresistance, of taste-masking of the active principle) with a high security of use due to its multiparticulate form by way of the coating during the process of :anufacture and to the fact that its disintegration occurs in the mouth, it constitutes an ambulatory form which can be adapted to a great number of active principles and to high i e dosages, which did not previously exist, A;n oil it offers a high facility of use, as the same pharmaceutical form can be disintegrated within the mouth, in a glass of water or in liquid or semi-liquid food, as for example, in yoghourt for children or infants, or in food for animals in connection with its use in the veterinary field, it consists of a single and same pharmaceutical form which can be prescribed to people requiring different strengths; thus, it can be used in connection with an active principle given at its maximum dose and manufactured in a divisible shape at one or several scored places in such a manner that it can be administered in totality or according to the age or the symptoms of the patient, in the form of a divisible part depending upon the shape of the punch, it being emphasized that it was not obvious to obtain a divisible multiparticulate tablet, it consequently consists of a pharmaceutical form which is suitable to everybody because it offers a great variety of means for administration and of dosages, which represents a definite economical advantage.

The fact that a single product permits, on the one hand, ways of administration normally permitted by several pharmaceutical forms and that, on the other hand, it gives rise to several posologies normally obtained by the creation of various strengths (tablets or capsules of different concentrations for example) constitutes an economical advantage of primary importance.

In fact from the industrial point of view, this means a single line production instead of several lines production each corresponding to each strength selected and to each pharmaceutical form selected.

Claims (6)

1. Rapidly disintegratable multiparticulate tablet comprising an excipient and an active substance which are mixed with one another, the thus obtained mixture being then tabletted after addition of a lubricant, the said excipient which is selected from the group comprising one or several disintegrating agents and/or one or several swelling or soluble agents, being suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in less than sixty seconds, the said tablet being characterized by the fact that the active substance is present in the form of coated microcrystals or coated microgranules.

2. Tablet according to claim 1, characterized by the fact that the mixture of excipients comprises one or several disintegrant agents of the carboxymethylcellulose or insoluble reticulated PVP type, one or several swelling agents of the starch, modified starch or microcrystalline cellulose type and possibly a direct compression sugar. 4*

3. Tablet according to one of claims 1 or 2, characterized by the fact that it can be disintegrated in the mouth, in a glass of water or in liquid or semi-liquid food, as for example, in yoghourt, in connection with its use in the paediatric field, or in food for animals in connection with its use in the veterinary field. Tablet according to one of claims 1 to 3, characterized by the fact that it 4,4 comprises, in the form of coated microcrystals, at least one of the active S substances of the group comprising the gastrointestinal sedatives, the antacids, the analgesics, the anti-inflammatory agents, the coronary vasodilators, the :O peripheral and brain-vasodilators, the anti-infectious agents, the antibiotics, the antiviral agents, the antiparasitic agents, the anticancerous drugs, the antianxiety agents, the neuroleptic drugs, the agents stimulating the central nervous system, the antidepressant drugs, the antihistaminic agents, the 14 antidiarrheal agents, the laxatives, the nutritional supplements, the immunodepressant drugs, the cholesterol lowering agents, the hormones, the enzymes, the antispasmodic agents, the antiangorous agents, the drugs acting on the rhythm of the heart, the drugs used in the treatment of arterial hypertension, the anti-migraine agents, the drugs acting on blood coagulability, the antiepileptic agents, the myorelaxing agents, the drugs used in the treatment of diabetes, the drugs used in the treatment of thyroidal dysfunctions, the diuretical agents, the anorexigenic drugs, the antiasthmatic agents, the expectorants, the antitussive agents, the mucoregulators, the decongestants, the hypnotics, the antinauseous agents, the hematopoietical agents, the uricosuric agents, the plant extracts the contrast mediums. Tablet according to one of claims 1 to 3, characterized by the fact that it comprises, in the form of coated microgranules, at least one of the active substances of the group comprising the gastrointestinal sedatives, the antacids, the analgesics, the anti-inflammatory agents, the coronary vasodilators, the peripheral and brain-vasodilators, the anti-infectious agents, the antibiotics, the antiviral agents, the antiparasitic agents, the anticancerous drugs, the antianxiety agents, the neuroleptic drugs, the agents stimulating the central nervous system, the antidepressant drugs, the antihistaminic agents, the antidiarrheal agents, the laxatives, the nutritional supplements, the immunodepressant drugs, the cholesterol lowering agents, the hormones, the enzymes, the antispasmodic agents, the antiangorous agents, the drugs acting on the rhythm of the heart, the drugs used in the treatment of arterial Sr hypertension, the anti-migraine agents, the drugs acting on blood coagulability, the antiepileptic agents, the myorelaxing agents, the drugs used in the treatment of diabetes, the drugs used in the treatment of thyroidal dysfunctions, the O diuretical agents, the anorexigenic drugs, the antiasthmatic agents, the expectorants, the antitussive agents, the mucoregulators, the decongestants, the (f: hypnotics, the antinauseous agents, the hemnatopoletical agents, the uricosuric agents, the plant extracts, the contrast mediums.

DATED this 12th day of December, 1995. LABORATOIRES PROG2RAPHARM WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA CJH:JGc:BB AU2417192.WPC DOC 6 t S S S 555 S t

5-5 C St I C S C S C 15- 55 5- I 5- 51115~ 5 5- RAPIDLY DISINTEGRATABLE MULTIPARTICULATE TABLET ABSTRACT Rapidly disintegratable multiparticulate tablet the excipient mixture of which is suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in an extremely short time, notably in less than sixty seconds, characterized by the fact that the active substance is present in the form of coated microcrystals or coated or uncoated microgranules. No figure. c g 1 i:~.illiill i_ I( IIIII( ~FIIRn*II~-II-- INTERNATIONAL SEARCH REPORT International application No. PCT/FR 92/00715 A. CLASSIFICATION OF SUBJECT MATTER IPC 5 A61K9/20 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No, X EP,A,O 281 200 (GIST BROCADES 1-6 7 September 1988 see claims 1,11,14 see page 4, line 17 line 19 see page 4, line 43 page 5, line 2 see page 5, line 13 line 17 see page 5, line 31 line 39 X EP,A,O 408 273 SQUIBB &SONS) 1-6 16 January 1991 see claims 1,3 see page 3, line 6 line see page 4 X EP,A,0 255 002 (ALFA FARMACEUTICI 1-6 3 February 1988 see claims 1,3,5 -see page 3. line 1 line S Further documents are listed in the continuation of Box C. O See patent family annex. Special categories of cited documents: later document published after the international filing dae or priority A" document defining the generalstateof the art which i date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention to be of particular relevance e earlier document but published on orafter the international filing date document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance: the claimed invention cannot be document referring to an oral disclosure, use. exhibition or other considered to involve an inventive step when the document is means combinedwith oneormoreothersuch documents.such comoination document published prior to the international filing date but later than being obvious toa person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 08 October 1992 (08.10.92) 29 October 1992 (29.10.92) Name and mailing address of the ISA' Authorized officer EUROPEAN PATENT OFFICE Facsimile No. Telephone No. Form PCT/ISA/210 isecond sheet) (July 1992Y ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR SA 9200715 63 061 Ibis annex fists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP ile on The European Patent Office is in no way liable for these particulars which ame merely given for the purpose of information. 08/10/92 Paetdcument PbiainPatent family Publication cited in search report date rmmer(s) date EP-A-0281200 07-09-88 AU-B- 603870 29-11-90 AU-A- 1252088 01-09-88 JP-A- 63301820 08-12-88 US-A- 4950484 2 1-08-90 EP-A-0408273 16-01-91 CA-A- 2019324 10-01-91 JP-A- 3048623 01-03-91 US-A- 5006344 09-04-91 EP-A-0255002 03-02-88 DE-A- 3778781 11-06-92 JP-A- 63054316 08-03-88 US-A- 4888178 19-12-89 ZA-A- 8704577 19-01-88 4' I w For more details About this Annex see Official journal of the European Patent Office, No. 12/32 mi RAPPORT DE RECHERCHE INTERNATIONALE Demands Internationals Ni PCT/FR 92/00715 1, CLASSEMENT DE L'INVENTION (sl plusilurs symboles do classification sont applicables, Its Iodiquef t0lis 7 Scion la classafli-:'4n internatonale des brevets Cll) cii a I, fois scion la classification nationals at la CIB CIB 5'A61K9/20 U. DOMAINES SUR LESQUELS LA RECHERCHEI A PORTE Documentation mlinihic comwilt&0 3 Syste de classificadon jSymboles de classiflition CIB 5 A61K Documentation consult** esicre quo I& documentation minimale dans I& mesure oia de tels documeits font partie des domaines sur lesquelsl a recherche a port'# Ml. DOCUMtENTS CONSIDERES COMMdE PERTINENTS 10 CatakOfleo Identification des docum~ents citis, ayec: indication, si ncessaLr,2 No. des revendicatons X EP,A,0 281 200 (GIST BROCADES 1-6 7 Septembre 1988 voir revendications 1,11,14 voir page 4, ligne 17 ligne 19 voir page 4, ligne 43 page 5, ligne 2 voir page 5, ligne 13 ligne 17 voir page 5, ligne 31 ligne 39 X EP,A,0 408 273 SQUIBB SONS) 1-6 16 Janvier 1991 voir revendications 1,3 voir page 3, ligne

6 Higne voir page 4 X EP,A,0 255 002,(ALFA FARMACEUTICI 1-6 3 Flivrier 1988 voir revendications 1,3,5 voir page 3, ligne 1 ligne oCatkgories spicales do documents aiti t IT document ultiileur publik postirieutement i la date de diot A dcumnt ifiluat rwt iafal o atecniqe, onInternational ou A I& date do pniorti at n'appeartalinant Ps ,,dcun d om. ss culreet p& o e chn ique no i tat do la technique posanent, mals citt pour coniprmdre consdir coma prciulitessnt prtientIs princip ou ii thioris constituent asbase do LI'nvention document antirieur, maLs publik i la date do dipat intern- document pariimalfroent pertinent; l'nvention revendi- tional ou, apriks cette date quie no pom eve considiri. comma. Douvallo ou comma IL document pouvant later un dnuto sir uno r,*.'dicafion do ImpliqUat tine aCtl~itk Inventive priouitk o ci ti pour diteisiner la date do publication d'une IY document particuliroist Pertinent; I'lnvat ien autre citation oni pour Una raison spfriale (tells qteindlqui) diqUlo no pout fts. conjjd~zte comma impliquant Uoo '0 document $e rfkrsat i Uo divulgadion orals, i un usge, i activitt Inventive Iorsquo 1. document est associk i tin cii Une exposition cm tout xama maens phuseurs autres documents do mime nature, awe? combi- PF document publik avant In date do d4p6t Itnational, nmis nalson &tat ividente pour tine pomoonne dui m~ler. postenieurement i a date do piontt bevendiqule 1&1 document qul fait pario do Is. mime famlls do bret IV. CERTIFICATION Administration charge de a recherchie Internationals I OFFICE EUROPEEN DES BREVETS ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALEF RELATIF -A LA DEMANDE INTERNATIONALE NO. FR9200715 SA 63061 La presentc ancxe indiquc les menibres de In falle de brevets relatift aux doazments brcvets citis dans le rapport dc recherche internationale vise ci-dessus. Lesdits menibres sont contenus au fishier informatique de l'Olllcc curopea dcs brevets i In date du Lcs renstignemants fournis sont donnis i titre indicatif et n'cngagetit pasIn. responsabiliti de 'OHficc curopen des brevets. 08/ 10/92 Doctument brevet dti Date dc Membre(s) dc la Date de mu rapport de recberchc publication famdUle de brevet(s) publicntion EP-A-0281200 07-09-88 AU-B- 603870 29-11-90 AU-A- 1252088 01-09-88 JP-A~ 63301820 08-12-88 US-A- 4950484 2 1-08-90 EP-A-0408273 16-01-91 CA-A- 2019324 10-01-91 JP-A- 3048623 01-03-91 US-A- 5006344 09-04-91 EP-A-0255002 03-02-88 DE-A- 3778781 11-06-92 JP-A- 63054316 08-03-88 US-A- 4888178 19-12-89 ZA-A- 8704577 19-01-88 0 l. Pour tout renseignement eonernaut ceft munce voir Journal Officielid fice Occuropeen des brevts, No.11/32