CA2092074C

CA2092074C - Rapidly disintegratable multiparticulate tablet

Info

Publication number: CA2092074C
Application number: CA002092074A
Authority: CA
Inventors: Gerard Cousin; Etienne Bruna; Edouard Gendrot
Original assignee: Laboratories Prographarm SA
Current assignee: Ethypharm SAS
Priority date: 1991-07-22
Filing date: 1992-07-21
Publication date: 1998-05-19
Anticipated expiration: 2012-07-21
Also published as: JPH06502194A; ATE148339T1; HK1007414A1; DK0548356T3; WO1993001805A1; EP0548356A1; FR2679451A1; DE69217191T2; DE69217191D1; JP2820319B2; AU666666B2; CA2092074A1; EP0548356B1; AU2417192A; ES2099275T3; KR100197465B1; GR3023281T3; FR2679451B1

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.

Description

2~92~7~

RAPIDLY DISINT~GRATABLE MULTIP~RTICULATE TABLET

The invention relates to a rapidly disintegratable multiparticulate tablet, i.e. a pharmaceutical presenta-tion for oral administration whose disintegration rate issuch 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 suspen-sion easy to be swallowed.
The disin~egration 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 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 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 disin-tegration rate such as hereabove defined, the active substance in the form of coated or non-coated micro-crystals or ~icrogranules; 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 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, gastroresistance and controlled release of the active principle.

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Consequently, the rapidly disintegratable multipar-ticulate 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 disinte~
gration rate so that its disintegration in the buccal cavity 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 non-coated 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 carboxymethylcel-lulose type or insoluble reticulated PVP type, one or several swelling agents which may consist of a carboxy-methylcellulose, a starch, a modified starch, for instance a carboxymethylated starch, or a microcrystalline cellu-lose, 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 ~orm 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 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 3~ antiangorous agents, the drugs acting on the rhythm of the heart, the drugs used in the treatment of arterial hyper-2~2~7~

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 hematopoie-tical 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 brain-vasodilators, the anti-infectious agents, the antibiotics, the antiviral agents, the antiparasitic agents, the anti-cancerous 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 anti-spasmodic 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 clrugs, the antiasthmatic agents, the expectorants, the antitussive agents, the mucoregu-lators, the decongestants, the hypnotics, the antinauseous 2092~7A

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 espe-cially 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.
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 disintegra-tion 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 2~2~74 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 whieh is sometimes caused by certain pharmaeeutical presentations which are monolithic, especially when the patient sueeeeds in swallowing them with a little water or no water.
Another advantage of the tablet aeeording to the invention is that the said tablet has not the well-known drawbaeks of effervescent tablets as for instanee the taste whieh is very unpleasant to the child, the high sodium content whieh is disturbing to people whieh must follow a diet without sodium and finally the neeessity of having water and a glass for its administration.
Furthermore, it permits the formulation of eertain aetive prineiples which are not adapted to a previous extraeorporeal dissolution and which eonsequently ean be eontemplated only under a dry form, whieh prevents their use in effervescent tablets; consequently, the tablet aecording 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 pharmaceutieal form may contain if neeessary two or seYeral aetive prineiples whieh are usually ineompatible with one another and this without alteration of their stability.
Another advantage of the tablet aecording to the invention eonsists in the possibility of taking by the patient o~ doses of aetive prineiple whieh are more important than in the past. As a matter of fact as the said tablet is not to be swallowed under its inltial ~orm but after disintegration within the buccal cavity, its size might be greater than that of a elassieal 2~ 07~

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 non-modified 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 50 on.
Once obtained, these microgranules are coated if ne~essary in a pan or in a fluidized air bed.

2 ~ 3 r'~ ~

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.

Rapidly disinteqratable 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) . 530 mg direct compression sugar . . . . . . . . . . 160 mg microcrystalline cellulose . . . . . . . . . 90 mg reticulated polyvinylpyrrolidone . . . . . . 60 mg sodic carboxymethylcellulose . . . . . . . . 50 mg colloidal silica . . . . . . . . . . . . . . 6 mg lubricant ..................................... 4 mg sweetener . . . . . . . . . . . . . . . . . .25 mg aroma . . . . . . . . . . . . . . . . . . . .15 mg magnesium trisilicate . . . . . . . . . . .50 mg Total990 mg The said tablet is prepared as follows.
The paracetamol crystals are introduced in a fluidized air bed installation and a solution of ethylcel-lulose in an ethanol/acetone mixture is sprayed thereon.
The excipients are sieved and the coatedparacetamol 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.

2 ~ 7 ~ -The pressure is equal to 16 ~Newtons +1. 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 ~
Rapidly disinteqratable 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 Total1100 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 dr~ 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 +1. The hardness of the thus obtained tablets is 95 Newtons +10. The time of disintegration in the mouth is from 15 to 20 seconds.

Rapidly disinteqratable multiparticulate tablet based on coated crystals of paracetamol.
Tablets according to the invention composed as follows are prepared.
Formula:
complex of paracetamol-codeine (30 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 Total950 mg Eudragit is a copolymer of methacrylic acid.
This tablet is prepared as ~ollows.
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 ~1. The hardness of the thus obtained tablets is 35 Newtons ~5. The time of disintegration in the mouth is from 50 to 60 seconds.

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~apidly disinteqratable 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 1500l . . . . . . . . . . . . . 235 mg sweetener ................................. 48 mg aroma ~ . . . . . . . . . . . . . . . . . 52 mg magnesium stearate . . . . . . . . . . . 5 mg Total900 mg This tablet is prPpared as follows.
The crystals of ibuprofen are introduced in a fluidi~ed air bed installation and a solution of ethylcellulose in ethanol is sprayed thereon.
The excipients are sieved and the coated ibuprofen 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 15 KNewtons +1. The hardness of the thus obtained tablets is 50 Newtons ~5. The time of disintegration in the mouth is from 15 to 20 seconds.

Rapidly di~integratable multiparticulate tablet based on microgranules.
Formula:
microgranules with delayed release based on doxycycline monohydrate (with 100 mg of active principle) . . . . . . . . . . . . 225 mg 2~ 7ll 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 ~1. The hardness of the thus obtained tablets is 100 Newtons +10. The time of disintegration in the mouth is from 10 to 20 seconds.

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 manufacture 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 dosages, which did not previously exist, ~B6~2~

- 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) cons-titutes 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

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A rapidly disintegratable tablet for oral administration with or without the use of water, said tablet comprising an active substance and a mixture of excipients, wherein said active substance is multiparticulate and in the form of coated microcrystals, coated microgranules or uncoated microgranules and wherein said mixture of excipients comprises excipients which are responsible for the disintegration, said tablet being intended to be swallowed, said disintegration occuring in less than sixty seconds under the action of the excipients which are responsible for the disintegration and which are selected from the group consisting at least one disintegrating agent and at least one swelling agent.

2. The tablet of claim 1, wherein the active substance is in the form of coated microcrystals and is selected from the group consisting of gastrointestinal sedatives, antacids, analgesics, anti-inflammatory agents, coronary vasodilators, peripheral and brain-vasodilators, anti-infectious agents, antibiotics, antiviral agents, antiparasitic agents, anticancerous drugs, antianxiety agents, neuroleptic drugs, agents stimulating the central nervous system, antidepressant drugs, antihistaminic agents, antidiarrheal agents, laxatives, nutritional supplements, immunodepressant drugs, cholesterol lowering agents, hormones, enzymes, antispasmodic agents, antiangorous agents, drugs acting on the rhythm of the heart, drugs used in the treatment of arterial hypertension, anti-migraine agents, drugs acting on blood coagulability, antiepileptic agents, myorelaxing agents, drugs used in the treatment of diabetes, drugs used in the treatment of thyroidal dysfunctions, diuretical agents, anorexigenic drugs, antiasthmatic agents, expectorants, antitussive agents, mucoregulators, decongestants, hypnotics, anti-nausea agents, hematopoietical agents, uricosuric agents, plant extracts and contrast mediums.

3. The tablet of claim 1, wherein the active substance is in the form of coated microgranules and is selected from the group consisting of gastrointestinal sedatives, antacids, analgesics, anti-inflammatory agents, coronary vasodilators, peripheral and brain-vasodilators, anti-infectious agents, antibiotics, antiviral agents, antiparasitic agents, anticancerous drugs, antianxiety agents, neuroleptic drugs, agents stimulating the central nervous system, antidepressant drugs, antihistaminic agents, antidiarrheal agents, laxatives, nutritional supplements, immunodepressant drugs, cholesterol lowering agents, hormones, enzymes, antispasmodic agents, antiangorous agents, drugs acting on the rhythm of the heart, drugs used in the treatment of arterial hypertension, anti-migraine agents, drugs acting on blood coagulability, antiepileptic agents, myorelaxing agents, drugs used in the treatment of diabetes, drugs used in the treatment of thyroidal dysfunctions, diuretical agents, anorexigenic drugs, antiasthmatic agents, expectorants, antitussive agents, mucoregulators, decongestants, hypnotics, antinausea agents, hematopoietical agents, uricosuric agents, plant extracts and contrast mediums.

4. The tablet of claim 1, wherein the mixture of excipients comprises at least one disintegrating agent selected from the group consisting of carboxymethylcellulose, insoluble reticulated PVP type and at least one swelling agent selected from the group consisting of starch, modified starch and microcrystalline cellulose.

5. The tablet of claim 1, wherein the mixture of excipients comprises at least one disintegrating agent selected from the group consisting of carboxymethylcellulose, insoluble reticulated PVP, at least one swelling agent selected from the group consisting of starch, modified starch, microcrystalline cellulose and a direct compression sugar.

6. The tablet of claim 1, wherein the active substance is in the form of uncoated microgranules and is selected from the group consisting of gastrointestinal sedatives, antacids, analgesics, anti-inflammatory agents, coronary vasodilators, peripheral and brain-vasodilators, anti-infectious agents, antibiotics, antiviral agents, antiparasitic agents, anticancerous drugs, antianxiety agents, neuroleptic drugs, agents stimulating the central nervous system, antidepressant drugs, antihistaminic agents, antidiarrheal agents, laxatives, nutritional supplements, immunodepressant drugs, cholesterol lowering agents, hormones, enzymes, antispasmodic agents, antiangorous agents, drugs acting on the rhythm of the heart, drugs used in the treatment of arterial hypertension, anti-migraine agents, drugs acting on blood coagulability, antiepileptic agents, myorelaxing agents, drugs used in the treatment of diabetes, drugs used in the treatment of thyroidal dysfunctions, diuretical agents, anorexigenic drugs, antiasthmatic agents, expectorants, antitussive agents, mucoregulators, decongestants, hypnotics, antinausea agents, hematopoietical agents, uricosuric agents, plant extracts and contrast mediums.