LU85943A1 - PHARMACEUTICAL TABLETS FOR THE EASY ADMINISTRATION OF PELLETS, THEIR PREPARATION AND THEIR USE - Google Patents

Description

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. f * "Pharmaceutical tablets allowing the easy administration of pellets, their preparation and their use".

The present invention relates to pharmaceutical tablets for oral administration, allowing easy administration of medicinal substances when presented in pellets or microgranules, their preparation and their use.

The present invention relates more particularly to tablets comprising pellets, which have the characteristic of releasing these pellets in a very short time, after they have been brought into contact with a certain quantity, even very small, and of the order a few milliliters, of an aqueous liquid.

It is currently accepted in medicine that the administration of an active principle in the form of pellets or microgranules allows in many cases the optimization of the therapeutic effect thanks, in particular, to the better distribution of these pellets in the digestive tract compared to a whole tablet [H. Bechgaard, A / S Alfred Benzon, Copenhagen V - Acta Pharmaceutica Technologica 28 (2) 1982)].

Currently, when a drug is presented in the form of pellets, these are enclosed in capsules, which makes it impossible for the user to fractionate the dose and therefore obliges the producer to prepare as many units of doses. that there are dosages necessary for the therapeutic 25-This presentation in capsules does not facilitate the administration of drugs in people (children, adults, the elderly) who find it difficult to swallow solid preparations of a some quail.

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Estevenel, TheJy and Coulon (US Patent No. 3,922.33S) have developed a process for compressing pellets without breaking them, using a triple layer compression technique because , they say, "direct compression of the microcapsules, whether or not of the coated type, has the effect of destroying the internal and external structure of the capsules, and the tablets thus obtained lose the properties of these microcapsules. ratio between the thickness of the sum of the two outer layers and that of the inner layer is preferably between 1 and 2.4 ". However, the disintegration time of this type of tablet is long, since, as indicated, it is of the order of at least 35 minutes.

The production of such triple-layer tablets requires special equipment which is expensive and difficult to adjust. 1 ^ In addition, as specified in this patent, the amount of active pellets that can be incorporated is very low given the height ratio of the different layers.

As just mentioned above, the pharmaceutical forms consisting of pellets are, therefore, dosed either in hard gelatin capsules, or in sachets containing the unit dose, or in the form of multilayer tablets. Any other possible presentation, such as "loose" pellets contained in bottles has the disadvantage of making the dosage imprecise by the patient himself using any 2 ^ any measuring system.

The object of the present invention is to remedy the drawbacks of the prior art, by providing single-layer tablets, which may or may not be scored, containing pellets which can be released, in a very short time, when these ccmpri- * 2 Λ, y mes are brought into contact with even a very small amount of aqueous liquid, the integrity of the structure and properties of the pellets being moreover preserved during the manufacturing phase pro- * 3 fi take called the tablet, that is ie during the compression phase.

To this end, according to the invention, the tablet ή is of the monolayer type, rapidly disintegrating and each of the 5 pellets which it contains, comprising at least one active principle in combination with at least one pharmaceutically acceptable excipient, comprises a film of outer protective coating, highly lubricated, non-sticky, so that the pellet can be released quickly enough when the tablet which contains the pellets 10 is brought into contact with an aqueous liquid, even of very small volume.

Advantageously, the outer protective coating film of the pellets comprises a mixture of a polymer of the acrylic or cellulosic type and of a lubricant, the polymer of the cellulosic type preferably being chosen from the group comprising sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl * methylmethylcellulose, hydroxybutylmethylcellulose and mixtures of at least two of these substances, the lubricant being preferably chosen from the group comprising stearic acid, aluminum, calcium, magnesium and zinc stearates and talc.

According to a particularly advantageous embodiment of the invention, the lubricant content relative to the acrylic or cellulosic type polymer content of the outer coating film of the pellets is of the order of 5 to 2 cc'c by weight , and preferably of the order of 10 to 150 ^ by weight.

According to another particularly advantageous embodiment of the invention, the pellets each comprise at least one internal coating film making it possible to modify the kinetics of release of the active principle which they contain, this internal coating iiim comprising one or more several polymers chosen from the group comprising polymers of the acrylic type, polymers of the methacrylic type, polymers of the cellulosic type

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and polymers of the polyvinylpyrrolidone type.

According to a particularly advantageous embodiment of the invention, the external protective coating of each pellet constitutes from 1 to 75% by weight, and preferably from $ to 50% by weight, of the weight of this coat.

The invention also relates to the preparation of these pharmaceutical tablets as well as to their method of use, which consists in the oral administration of said tablet in therapeutically effective doses, in whole or in the form of one or more. several of its fragments.

As already mentioned previously, the tablet of the invention is capable of releasing the pellets which it contains in an extremely short time and in only a few milliliters of aqueous liquid, such as for example the content of a teaspoon or tablespoon. This therefore leaves the choice to the user of the drug either to absorb it as it is in its tablet form, or in the drinkable form of the pellets in the liquid used to obtain the disintegration of the tablet.

The absorption in this form of microgranules 20 mixed with a little liquid makes possible the easy administration of the drug in many people: children, adults, old people who experience sometimes insurmountable difficulties in swallowing drugs in the form of tablets, dragees, capsules, capsules or the like, when the dissolution, spraying or disintegration of these forms is difficult, impossible or even prohibited.

This technique therefore brings together the advantages of the precise dosage of the active ingredients thanks to the presentation in comorimates and of the swallowing facilitated thanks to the microgranuie form.

We know that the structure of? micro-granules is relatively fragile; however, the pellets released by deuteration of the tablet of the invention retain, in a substantially unmodified manner, their characteristics before compression. However, t the tablet obtained must have sufficient hardness so that it does not crumble during the various manipulations of manufacturing and packaging as well as transport.

As mentioned above. -5 one of the major drawbacks of the dosage forms based on pellets currently available on the market is the impossibility of dividing the dose to adapt it to the needs of the patient, which on the one hand obliges the manufacturer to make available to the the medical profession, several different unit packages and, on the other hand, greatly limits the use of such drugs in pediatrics, given the large number of dosages which would be necessary to adapt the dosage to the differences and variations in ages and weights characteristic of childhood.

In order to overcome this important problem, provision is also made, according to the present invention, of pellets tablets which can be broken into several fragments according to engraved guides, the various fractions of which have the same qualitative properties * as those of the whole tablet, and each fragment of which additionally contains a known amount of active substance.

The pellets used to obtain the tablets of the present invention may have different compositions and release characteristics of the active substance.

They can consist of one or more active ingredients and one or more excipients chosen from diluents, wetting agents, densifiers, acids, bases, emulsifiers, disintegrants or any other pharmaceutically acceptable substance.

In order to hide - if necessary. the taste of certain substances and / or to solve these problems of incompatibility of 50 active ingredients with one another or of active ingredient-excipient or for any other purpose, the pellets used can be coated so as to give them, for example, release properties fast / 6 in the stomach, enteric release and / or prolonged in time, gu or the active ingredients they contain.

A mixture of peiiets whose composition varies either by the active ingredient (s) they contain, or by one or more of the excipients they deny, or by the nature of the coating used, or by characteristics different from release of one or more active ingredients, can be used for the form of tablets according to the present invention.

The pellets used in the present invention can be obtained by extrusion and subsequent spheronization of a plastic mixture formed by the excipient (s), the active ingredient (s) and the solvent or mixture of granulation solvents.

For extrusion, various types of equipment, such as the ALEX ANDER WERK (Alexanderwerk, Germany) or the XTRUDER (Fuji Paudal, Japan) can be used, and the diameter of the holes in the dies or sieves through which the dough is extruded must be between 0.1 mm and 2 mm, preferably between 0.5 mm and 1 mm.

The small cylinders obtained after extrusion are then made spherical using, for example, a spheroniser of the CALEVA (GB) or MARUMERIZER (Japan) type.

The pellets can also be obtained by different techniques, such as spraying and / or dusting of suitable cores in coating turbines or by means, for example, of the CF Granulator System of the firm Freund Industrial Co (Japan) or also by simple mixing in a planetary type mixer.

The pellets thus obtained are dried by any means such as, for example, an oven or a fluidized ht and then calibrated to the desired diameter through suitable sieves.

The pellets of the present invention may have a diameter of between 0.05 mm and 2 mm and preferably between 0.1 and 0.9 mm.

The active ingredients which go into the composition of the pellets can be any and their particle size must be equal to or less than half the average diameter of the finished pellets, bare, that is to say without coating. As examples of active principles, mention may be made of gastrointestinal sedatives such as metoclopramide and propanthelm bromide, antacids such as the triple aluminosilicate, aluminum hydroxide, sucralfa- ^ 0 te and cimetidine, anti-inflammatory drugs such as phenylbutazon, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodilators such as trinitrine, isosorbide dinitrate , isosorbide mononitrate and pentaerythrityl tetramtrate, peripheral and cerebral vasodilators such as suloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and = acid nicotinic, anti-infectives such as erythromycin and its derivatives, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, amoxycillin, flucloxacillin sodium, mandelate methenamine, methenamine hippurate, neuroleptics such as fluazepam, diazepam, temaze-pam, amitriptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, 25 fluphenazm, piperothiazine, haioperidci, maprotilme hydrochloride, imipramine and desipramine. central nervous system stimulants such as methylpnididate, ephedrine, adrenaline, isoprenaline, amphetamine sulfate ex amphetamine hydrochloride, antihistamines like cimenhy drinate, diphenyipyraime, chlorphenamine and bropheniramme, antidiarrheals such as diphenoxyiate. laxatives such as bisacodyi, magnesium sulfate, sodium dioctylsulfosuccinate, nutritional supplements such as ascorbic acid, alpha-tocopherol, thiamine and pyndoxine, antispasmodics such as dicycloverine and diphenoxylate, drugs which influence the heart rate such as verapamil, nifedipi-3 ne, dilthiazem, i procainamide, disopyramide, brethylium tosylate, ie quinidine sulfate and quinidine gluconate, drugs used in the treatment of hypertension arterial, such as prqxanolol hydrochloride, guanethidine sulfate, methyldopa, oxprenolol hydrochloride. Captopril and hydralazine, antimigraine drugs such as ergotamine, drugs that influence blood coagulability, such as epsilonami-nocaproic acid and protamine sulfate, pain relievers such as acetylsalicylic acid, paracetamol , codeine phosphate, codeine sulfate, oxvcodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine , buprenorphine, scopolamine and mefenamic acid, antiepileptics such as sodium phenytoin, sodium valproate and lysine valproate, a muscle relaxant such as dantrolene sodium, used in the treatment of diabetes, such as tolbutamide, chlorpropamide, glucagon and insulin, drugs used to treat thyroid dysfunctions, such as triiodothyronine, thyroxine and propylthiouracil, di uretics such as furosemide, chlorta-25 lidone, hydrochlorothiazide, Spironolactone and triamterene, uterine muscle relaxant ritodrine, anorectics such as diethylpropion hydrochloride, anti asthmatics such as aminophylii-ne, theophylline, salbutamol, orciprenaline sulfate and terbutaline sulfate, expectorants such as guaiphenesin, 30 cough suppressants such as dextromethorpr.ane and noscapine, mucoregulators such as carbocysteme and lysine N-acetyicysteine, decongestants such as phenylpropanolamine and pseudoephedrine, hypnotics such as dichloralphenazone 9 and nitrazepam. anti-nausea drugs such as promethazine theoclate, hematopoietic agents such as ferrous sulfate, folic acid and calcium gluconate, uricosurics such as ia sulpfinpyra-zone, allopurinol and probénéciae, extracts of plants such as, for example, extracts of Prunus Africana. this Valerian, from Crataegus, Belladonna, Licorice, etc. However, it is understood that the invention is not limited to the drugs cited above by way of examples.

Among the excipients which can be used in the manufacture of the pellets according to the present invention, mention may be made, for example, of diluents, such as lactose, sucrose, xylitol, milk powder, microcrystalline celluloses (such as avicels pH 101, 102, RC 5S1 , CL 611), talc, kaolin, magnesia, agglutinants, such as dextrmes, carboxymethylcellulose, carbo \ vax, gelatin, poiyvinylpyrrolidone ^ and gums, wetting agents, such as sodium laurvlsulfate, stearate and oleate of tr 1 st thano ne, polyethylene lenegl ycol s, disintegrants, such as starches and their derivatives, aerosil., crosslinked poiyvinylpyrrolidone, acidifiers, such as citric and tartaric acids, alkalisanxs, such as calcium carbonate, sodium citrate, gluconate calcium, densifiers, such as barium sulfate, as well as any other pharmaceutically acceptable substance. However, it is understood that the invention is not limited to the aforementioned excipients. The particle size of the excipients used must be less than or at most equal to half the average diameter of the finished pellets, bare, that is to say without coating.

As granulating liquid, there can be used - any liquid and in particular water, methane !, ethanol, isopropanol. I methylene chloride, ie chloroform. Γ acetate or ethyl acetate, buty acetate, acetone, methyliscbutyicetone, methyl ethyl ketone. these liquids being used alone or as a mixture of two or more of them.

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In order to give the pellets thus obtained particular properties, such as modification of the kinetics of release of the active principle (s), protection with respect to the external environment and / or certain portions or digestive tract, various films or so-called coatings "interiors" can be applied to them.

These interior coating films may be such that the kinetics of release of the active ingredient (s) is rapid, ient or sustained and / or delayed over time.

A film providing rapid release kinetics upon arrival in the stomach can be used either to mask the taste of certain components of the pellet, or to protect, for example, the esophagus from the irritant effect of certain active ingredients, or to solve a problem of incompatibility between various types of pellets, or to increase stability by preserving. 15 pellets from attacks from the outside environment. Kinetics of slow or sustained release of the active ingredient (s) can be used to obtain pharmaceutical preparations whose therapeutic effect will be prolonged and taken less frequently; 20 time-delayed kinetics can be used to avoid the release of the principle (s) in certain portions of the digestive tract, such as, for example, by the use of an enteric film. These interior coating films can be deposited on the pellets using well known techniques, such as spraying in a turbine or in a fluidized bed.

These films can consist of polymers or mixtures of polymers of these acrylic types (Eudragit). cellulosic [Methocel, Klucels, Metoicse, cellulose derivatives such as cellulose acetates and ethyiceiiuiosiques {Aquaccat, EtroceDjoj '30 of the polyvinylpyrrolidone type such as poJvvir.vjovrroiidc-ne (vinylpyrrolidone copolymers) acetates. co-polymers of vinyl methyl ethers and maleic anhydride for example, associated with one or more plasticizers, such as triacetin, ie i {il dibutylsébaçate, poiyléthvlènes glycols, poîyvinylpyrrolidone, with one or more colored pigments or not, such as l titanium oxide and iron oxides, to one or more release agents, such as talc, magnesium stearate, to one or more defoamers, such as silicone oils, to one or more wetting agents , such as tweens, spans, sodium lauryl sulphate as well as one or more pharmaceutically acceptable agents useful for making the film and / or obtaining the desired characteristics. One could, for example, use as gastro-resistant film substances such as cellulose acetophthalate, Eudragits types L 100 and / or L 30 D, polyvinyipyrrolidone acetophthalates.

The pellets, bare or already coated with a film known as an internal coating, which gives them one or more of the above-mentioned particular properties, are then covered with a film or coating, an external protective coating, not sticky, consisting of one or more polymers such as , for example, acrylics, cellulosics (or derivatives of cellulosics) such as, for example, hydroxypropylmethylcelluloses (Methocel, Klucels, Sepifilm 002) ^ carboxymethylcel sodium julose, ethylcellulose, methylcellulose, hydroxyethyiceilulose, hydroxypropylceliulose and hydroxybutylmethylceliulose, containing a high proportion of lubricant, or of a mixture of lubricants, such as, for example, talc, stearic acid or its aluminum salts, calcium, magnesium, zinc. The ratio between the quantity of lubricant and dry film-forming agent must be between 5% and 200% and preferably between 10% and 150%. This protective material may also contain one or more substances which, by virtue of their pressure deformability properties, protect the integrity of the structure of the pellets and / or act as disintegrants by virtue of their swelling properties. presence of an aqueous liquid. As disintegrants of this type, it is possible to use, for example, starches or derivatives thereof, derivatives of polyvinylpyrrolidone. colloidal microorisisiul celluloses ί •? or not, natural anionic polymers such as gum adragan-te, alginates, agar-agar. Plasticizers could also be used, such as triacetin, dibutylphthalate, dioctylphthalate, diethylphthalate. polyvinylpyrrolidone, polvpropylènegly-5 cols, polyethyienegiycois, pigments, such as titanium oxide, iron oxides, bulking agents such as barium sulphate, kaolin, antistatic agents, such as colloidal aluminum oxide and wetting agents, such as tweens, spans.su-croesters.

The weight of this exterior coating film constitutes between 1% and 75% and preferably between 5% and 50% of the weight of the pellet.

The finished pellets are then mixed by any suitable means such as, for example, a cubic mixer, with the compression powder, which may have been previously granulated, in whole or in part, and may or may not contain a or active ingredients.

Advantageously, this powder comprises, as excipient, one or more substances chosen from the group comprising starch, lactose, xylose, xylitol, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, ethylcellulose , methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose. According to the invention, this powder can also comprise disintegrants, such as crosslinked polyvinylpyrrolidone, modified celluloses, such as those known under the name Ac-Di-Sol. natural or modified starches, for example that known under the name of Explotab, lubricants, such as magnesium, aluminum, zinc stearates, stearic acid, ooiv-30 ethylene glycols, agents of 'flow, such as aerosii. antistatic agents, such as colloidal aluminum oxide, etc.

The homogeneous mixture of pellets and powder and / or granule for compression is introduced into the feed device 13 of a tableting machine adjusted so that the tablets obtained have a suitable weight and a hardness which allow handling. and trouble-free transportation.

The tablets obtained can have any shape and have, when they are scored, engravings serving as a guide for fractionation.

The examples described below are intended to explain the present invention further and cannot in any way limit it.

10 'Example n ° 1.

Long-acting theophylline pellet tablets.

5.10 kg theophylline hydrate 0.15 kg sugar 15 0.18 kg polyvinyl pyrrolidone "0.69 kg avicel pH 102 0.15 kg polylethylene glycol 6000 - After mixing the powders for 5 minutes, Add 1.6 liters of water and continue mixing for 30 to 20 minutes. The wet mixture thus obtained is extruded in an XTRUDER device fitted with a sieve whose hole diameter is 0.5 mm and then spheronized in a CALEVA spheronizer. After having dried for 24 hours in an oven heated to 60-70 ° C, the pellets are coated twice and in portions of 600 g in a STREA 1 fluidized bed apparatus from the firm AEROMATIC. Coating n ° l. for 600 g of bare pellets

Magnesium stearate 5.S3 g Titanium oxide 5.20 g 30 Polyethylene glycol 6000 8.33 g

Water 110.32 g

Eudragit E 30 D 199.43 g i c i; i * r

Coating n ° 2.

On 500 g of pellets having received coating No. 1, the following solution is sprayed, using the same apparatus:

Sepifilm 502 43.40 3 Magnesium stearate 21.75

Water 435.03

After drying for 24 hours in an oven, mix:

Coated pellets 400 g 15 Granulated starch 400 g

Crosslinked polyvinylpyrrolidone 390 g

Magnesium stearate 10 g The tablets are obtained by compression I1 2 3 4 5 using a type 27 compression machine from the company COURTOY. s Characteristics of the tablets:

Cylindrical tablets, divisible into 4 equal parts Diameter 10 mm Weight 475 mg 25 Hardness 4.5 to 5.5 Kp

Disaggregation time 15 to 20 seconds MEASUREMENT OF THEOPHYLLIN RELEASE SPEED. Amount expressed as% of theophvlline released.

Time 2-5 (h) Before compression After compression 6.36 7.33 2 12.19 14.60 3 4 24.30 26.99 4 30 6 33.96 37.14 5 41.20 43.09 10 43 , 99 45.20 15

Example 2.

, Enteric-coated base erythromycin pellet tablets.

The bare pellets are obtained by proceeding as in Example No. 1 starting from 5 Erythromycin base 7.5 kg

Polyvinylpyrrolidone 0.5 kg

Avicel pH 101 2.0 kg

Water for granulating, approximately 3.6 liters The pellets with a particle size of between 0.1 and 0.8 mm are then coated with an enteric coating consisting of the film obtained by spraying in a coating turbine of the following mixture : for 500 g of pellets

Cellulose acetophthalate 120 g 15 Dibutyl phthalate 12 g; - Ethyl acetate 460 g

Ethanol 4 ^ 0 g: “After drying, the pellets are coated with a second film identical in quality and quantity to the film nc2 of Example 20 1.

The pellets are then compressed on a rotary press type R100 (COURTOY) after mixing with the following ingredients:

Pellets 500 g 25 Granulated lactose 30 g

Granulated starch 100 g

Ac-Dî "Sol 7C g; Magnesium stearate 5 g

Cherry flavor 0.0: g 30 Stearic acid 1.5 g

Characteristic of the tablet.

Biconvex tablets, diameter 15 mm, divisible into 4 equal parts.

*] 6 ί

Weight: 1250 mg.

Hardness: 6 to 6.5 Kp

Disaggregation time. ‘Less than one minute Cherry aroma 5 Example n ° 3

"Fast" release doxycycline pellet tablets

By operating as in example l from:

Doxycycline hyclate 2,100 kg 10 Methocel E5 0.100 kg

Polyvinylpyrrolidone 0.020 kg

Avicel pH 101 0.1S0 kg

Sodium lauryl sulfate 0.030 kg

Starch 0.100 kg 15 Lactose 0.450 kg

Water, sufficient quantity to granulate: approximately 6 liters.

The pellets thus obtained, calibrated between 0.1 mm and 0.9 mm are then coated in a coating pan with a film of rapid disintegration in the stomach and the composition of which is as follows: per 600 g of pellets

12.5% Eudragit E solution in Isopropanol / acetone 60/40 400 g

Talc 5 g 25 Magnesium stearate 5 g

Isopropanol 590 g

The protective film, the formula of which is identical to film No. 2 of Example No. 1, is then applied to the pellets thus coated. The following mixture is then prepared to be compressed:

Pellets 600 g Aerosil 20 g

Crosslinked polyvinylavrrolidone 60 g 17 i, t

Expiotab 50 g

Granulated starch 200 g

Poiyvinylpyrrolidone 50 g

Magnesium stearate 2ûg 5 The compression is then done on an alternative type 27 compression machine (COURTOY).

Characteristics of the tablets obtained.

Oblong tablets divisible into 2 equal parts Weight; 600 mg 10 Hardness: 5 to 5.5 Kp

Disintegration time: 30-35 seconds Example n ° * f.

Very fast release amoxicillin pellet tablets.

The pellets are produced as in Example 15 No. 1 by means of the mixture, the composition of which is as follows: Amoxicillin S, 0 kg

Avicel CL 611 2.0 kg

Water for granulating, approximately 2.00 liters The fraction of pellets thus obtained, the granulometry of which is between 0.1 and 0.9 mm in diameter, is then coated in a coating pan with 15% (expressed in dry weight film compared to the weight of the pellets) of the following film: Methocel E5 5 parts

Talc 0.5 parts 25 Magnesium stearate 0.5 parts

Aquacoat 5 parts

Water S9 parts

After drying the pellets, the following mixture is prepared for compression: 30 pellets 700 g

Xylitol 50 g

Granulated lactose 100 g

Ac-Di-Sol they g

Polyethylene glycol 600 2 g i jr

iS

The tablets are obtained by compression of the powder on a rotary tableting machine (COURTOY R100).

Characteristics of the tablets.

5 obiongs tablets divisible into 4 equal parts

Weight: 1030 mg Hardness 5 to 6 Kp

Decay time: less than 1 minute.

Example 3.

10 Densified pellet tablets of indomethacin with rapid disintegration and prolonged release of the active ingredient.

1. Manufacturing of pellets Mix, in a planetary mixer:

Indomethacin 1.175 kg dd Polyvmylpyrrolidone 1.175 kg

Barium sulfate 1.90 kg

Avicel pH 101 0.75 kg

Water to granulate, approximately 1.3 liters 20 Extrude the wet mixture, spheronize the fragments and dry the pellets in an oven at 60 ° C. Keep the fraction of pellets between 0.3 mm and 0.5 mm in diameter.

2. Coating n ° 1 of the pellets:

In a fluidized bed apparatus, coat the pellets 25 with 10 ° o (calculated by dry weight) of the following film intended to provide a sustained release of the active principle:

Magnesium stearate 17.5 g

Titanium dioxide 10.0 g

Polyethvlènegyicol 6000 15.0 2 30 Poiyvinyipyrrohdone 15.0 g

Indomethacin 32.5 g

Water 389.5 g

Euaragn E 30 D 515.5 g 19 3. Coating n ° 2 of the pellets

The pellets covered with film No. 1 are coated, in a fluidized bed apparatus with 10% (calculated by dry weight) of the following protective film: 5

Hydroxypropylmethylceliulose (SEPIFILM 002) 65 g

Magnesium stearate 20 g

Talc 30 g

Wheat starch 50 g ^ Polyvinylpyrrolidone 10 g

Water S25 g k. Pellet compression

The following mixture is compressed on a K27 type press (COURTOY): ^ Coated pellets 1 + 2,600.0 g

Avicel pH 102 granulated 203.0 g

Magnesium stearate ¢, 0 g

Crosslinked polyvinylpyrrolidone 116.0 g Aerosil 1.6 g ΛΑ υ 5. Characteristics of the tablets obtained:

Oblong tablet divisible into 2 equal parts Weight: 600 mg Hardness: 6 - 7 Kp

Disaggregation time: less than 1 minute 25 6. Measured kinetics of dissolution of indomethacin (rotary vane method)% of dissolved indetethacme 30

Time (h) Before compression After compression 1 3.3 ¢, 1 2 6.5 7.0 * 18.3 17.2 x 20 9o of dissolved indomethacin (continued)

Time (h) Before comoression After comoression 5 6 61.7 62.3

S 62.0 60, S

SI, 5, 83.0 ^ It should be understood that the present invention is in no way limited to the above embodiments and that many modifications can be made thereto without departing from the scope of this patent.

15 20 25 30

Claims (26)

21 CLAIMS. 1. Pharmaceutical tablet containing pellets, characterized in that it is of the monolayer type, rapidly 'disintegrable and in that each of the pellets, comprising at least 5 an active principle in combination with at least one pharmaceutically acceptable excipient, comprises an outer protective coating, highly lubricated, non-sticky, so that the pellet can be released quickly enough when the tablet which contains the pellets is brought into contact with an aqueous liquid, even of very small volume. 2. Tablet according to claim 1, characterized in that the above-mentioned outer protective coating film of the pellets comprises a mixture of a polymer of the acrylic or cellulosic type and of a lubricant. 3. Tablet according to claim 2, characterized in that the polymer of the cellulosic type is chosen from the group comprising sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose. , hydroxypropylmethylcellulose, hydroxybutylmethylcellulose and mixtures of at least two of these substances. 4. Tablet according to either of claims 2 and 3, characterized in that the lubricant is chosen from the group comprising stearic acid, aluminum, calcium, magnesium and zinc stearates and talc. 5. Tablet according to any one of claims 2 to 4, characterized in that the lubricant content relative to the content of polymer of acrylic or cellulosic type in the outer coating film of the pellets is of the order of 5 at 200% by weight. 6. A tablet according to claim 5. characterized in that the lubricant content relative to the content of polymer of acrylic or cellulosic type is of the order of 10 to 150% by weight. 22 7. Tablet according to any one of the claims 2-6, characterized in that the outer protective coating film contains at least one plasticizer, such as triacetin, dibutylphtaiate. dioctyjphthalate. diethylphthalate, polyvinyl-5 pyrrolidone, glycois polypropylenes, polyethylene glycols and / or at least one disintegrating agent, such as starch, microcrystalline or colloidal celluloses and / or at least one pigment, such as oxide of titanium, iron oxides and / or at least one filler, such as barium sulphate, kaolin and / or an antistatic agent, such as colloidal aluminum oxide and / or at least one wetting, such as tweens, spans, sucroesters. S. Tablet according to any one of claims 1 to 7, characterized in that each of the pellets comprises, as excipient, at least one substance chosen from group 1-5 comprising lactose, sucrose, xylitol, powder of milk, c microcrystalline celluloses, talc, kaolin, magnesia, dextrins, carboxymethylcellulose, carbowax, gelatin, polyvinylpyrrolidone, gums, sodium lauryl sulphate, stearate and very oleate thano 1 friend ne, polyethyleneglycols, starches and their derivatives, aerosil, crosslinked polyvinylpyrrolidone, citric and tartaric acid, calcium carbonate, sodium citrate, sodium gluconate and barium sulfate. 9. Tablet according to any one of claims 1 to 7, characterized in that each of the pellets comprises, as active principle, at least one substance chosen from the group comprising gastrointestinal sedatives, antacids, anti-inflammatories , coronary vasodilators, peripheral and cerebral vasodilators, amies, neuroieptics, central nervous system stimulants, antihistamines, antidiarrheals, laxatives, nutritional supplements, 23 4 * »antispasmodics, drugs influencing the heart rate, drugs used in the treatment of high blood pressure, antimigraine drugs, drugs influencing blood coagulation, antieepiieptics, muscle relaxants, drugs used in the treatment of diabetes, drugs used in the treatment of thyroid dysfunctions, diuretics, appetite suppressants, amiasthmatic ies, ex pectorants, antitusives, decongestants, hypnotics, anti-nausea, hematopoietics, uricosurics and extracts of plants. 10. Tablet according to any one of claims 1 to 9, characterized in that the pellets each comprise at least one internal coating film making it possible to modify the kinetics of release of the active principle which they contain. 11. A tablet according to claim 10, characterized in that said inner coating film is used to obtain rapid, slow or sustained release of the active ingredient that the pellets contain. 12. A tablet according to claim 10, character-ized in that said inner coating film is used to obtain a delayed release of the active ingredient that the pellets contain. 13. Tablet according to either of claims 11 and 12, characterized in that the interior coating film comprises at least one polymer chosen from the group comprising polymers of the acrylic type. Polymers of the methacrylic type, polymers of the cellulosic type and polymers of the polyvinyl-pyrrolidone type. 14. Tablet according to claim 13, characterized in that the abovementioned interior coating film comprises at least one substance chosen from plasticizers, pigments, antiadherents; anti-foaming agents and wetting agents. 15. Tablet according to any one of claims 1 to 14. characterized in that the protective outer coating * <1 "3 / · laughter of each pellet constitutes from 1 to 75% by weight of the weight of this pellet. · . 16. A tablet according to claim 15, character-ized in that the protective outer coating of the pellet constitutes "ae 5 to 50% by weight of the weight thereof. 17. Tablet according to any one of claims 1 to 16, characterized in that the pellets have a diameter of about 0.05 to 2 mm. 18. Tablet according to claim 17, character-ized in that the diameter of the pellets is of the order of 0.1 to 0.9 mm. 19. Tablet according to either of claims 17 and 18, characterized in that the active principle and pharmaceutically acceptable excipient of the pellets have a particle size which does not exceed half the average diameter of these pellets, "not taking into account their external coating and their possible internal coating. 20. Tablet according to any one of claims 1 to 19, characterized in that the release time of the pellets is less than two minutes. 21. Tablet according to any one of claims 1 to 20, characterized in that the volume of aqueous liquid in which the tablet is placed to obtain its disintegration is equal to or greater than the volume of the tablet itself. 75. , 22. A tablet according to any one of claims 1 to 21, characterized in that it comprises a powder for compression comprising, as excipient, at least one substance chosen from the group comprising starches, lactose, xvlose, xylitol , microcrystalline cellulose, hydroxypropyimethyl cellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylmethylceilulose. -. % 25 * * 23. Tablet according to claim 22, character-ized in that the compression powder comprises at least one substance chosen from disintegrants, gelling agents, flavoring agents and coloring agents. - 5 24. Tablet according to either of claims 22 and 23, characterized in that the compression powder comprises at least one active principle. 25. Tablet according to any one of claims 1 to 24, characterized in that it comprises on one of its 190 faces at least one groove serving as a guide for its fractionation. 26. A method of preparing the tablet according to any one of claims 1 to 25, characterized in that each pellet is coated with the above-mentioned outer protective film, this outer coating constituting from 1 to 75%, and preferably 15 of 5 at 50% by weight of the weight of the pellet, the powder for compression is mixed with the pellets thus coated and the mixture thus obtained is compressed to obtain a tablet of desired weight and hardness. 27. The method of claim 26, characterized in that each pellet is coated beforehand with the above-mentioned inner film. 28. Method according to either of claims 26 and 27, characterized in that the powder for compression is at least partially granulated. 29. Method of using the tablet according to any one of claims 1 to 25, characterized in that it is administered orally in therapeutically effective doses, in whole or in the form of one or more of its fragments. 30 - ’Ü ·· '. .Z O .... 53cer · · '·; f ------ · "* 5 ·