|Title of Invention||
TABLET FOR INSTANT AND PROLONGED RELEASE OF ONE OR MORE ACTIVE SUBSTANCES.
|Abstract||The invention relates to a multilayer tablet for the instant and then prolonged release of active substances comprising at least two superposed layers, characterized in that, a first outer layer is composed of a mixture of excipients and of a first active substance, the said first layer allowing immediate release of the said first active substance; a second layer, arranged in contact with the said first layer, consists of a nonbiodegradable, inert porous polymeric matrix in which a second active substance is dispersed.|
The Invention relates to solid galenic forms of the controlled release tablet type for the Instant and then prolonaed release of one or more active substances.
The importance of such galenic forms is undeniable. The immediate release of an active substance wilt ensure its practically instant bioavailability, which is particularly desirable in the case of patients suffering from acute conditions.
However, In the case of active substances having a short half-LIFE, the therapeutic activity is only temporary. Now, a continuous and regular supply of active Ingredient is often necessary for an effective therapy. To this end, numerous immedlate-and prolonged-release systems have been developed.
Reference may be made, for example, to the following patents and applications of the state of the art: WO 96/03111, US 4,990,335, EP 352 190, BE 905 282, EP 106 443, EP 36 350, EP 615 444 and EP 220 670.
However, in the prior art systems, the kinetics of release of the active ingredient depend on many factors, such as the enzymatic activity and the pH conditions which vary substantially from one individual to another and for the same individual, depending on whether they are on an empty stomach or not Furthermore, the pH conditions vary all along the gastrointestinal tract. Thus, it is difficult to predict in vivo, with precision, the profile for the release of a given substance after administration of the prior art instant and prolonged-release systems.
The present Invention alms to solve this problem by providing tablets which preserve their characteristics for the release of active substances regardless of the conditions of administration In vivo.
The tablets of the Invention provide an excellent reproduclbillty of the results, while allowing an Increased control of the rates of release during the phase of prolonged release of the active
ingredient. By using the tablets of the invention, it becomes
possible to optimize the supply of the active ingredients in the
body white taking into account both the subject's tolerance to the active ingredient and the pharmacokinetic and metabolic profiles of the active ingredient
Tablets of the invention are, moreover, advantageous from the point of view of the formulation of the active Ingredients since a Judicious choice of the exciplents leads to tablets with high concentrations of active ingredients.
Thus, It Is possible to produce tablets with very high doses, having an acceptable size for oral administration.
More precisely, the invention relates to multilayer tablets for the Instant and then prolonged release of active substances comprising at least two superposed layers, characterized In that: a first outer layer is composed of a mixture of excipients and of a first active substance, the said first layer allowing immediate release of the said first active substance;
a second layer, arranged in contact with the said first layer, consists of a nonblodegradable, inert porous polymeric matrix in which a second active substance is dispersed.
The second layer, which is arranged in contact with the first layer, is either completely enveloped by the first layer, or only partially covered by It
In the first case, the two layers are concentric.
In the second case, only one of the surfaces of the second layer Is In contact with the first layer: In the text which follows, this type of tablet Is designated as containing parallel layers" and the shape of the tablet Is unimportant and is In particular ovoldal. It should be understood that In this case, the two layers have one outer surface, their other surface being h contact with one another.
The tablets of the invention are preferably bilayered. However, the invention also encompasses multilayer tablets, as long as they; comprise the combination of the first and second layers defined above.
For some active ingredients, problems of stability of the active Ingredient Included In the prolonged-release matrix may exist. In this case, It is advantageous to opt for the preparation of tablets containing concentric layers.
The kinetics of release of the active Ingredient depend, In each case, on the exact composition of the layer considered. Zt Is by adapting the nature and the quantity of the exclpients constituting the two layers that the kinetics of release can be modulated.
One characteristic of the first layer Is that It disintegrates rapidly at the site of administration. In contrast, the second layer is not
biodegradable. Its matrix is inert in the sense that it does not react with the surrounding medium. The matrix of the second layer retains its physical and chemical integrity throughout, the prolonged release of the active ingredient, regardless of the pH variations.
Since the first layer disintegrates instantly upon contact with an aqueous medium such as a physiological medium, It Is easy to understand why the release of the first active substance Is immediate.
In the case of the second layer and since the matrix constituting It Is Inert (it does not become eroded and does not swell in an aqueous medium), the release of the second active substance occurs by lixlviation and diffusion. The surrounding aqueous medium gradually penetrates Into the Inert porous matrix and then progressively, this aqueous medium dissolves the active substance dispersed in the inert matrix. The mechanism of diffusion being slow in essence, it can be understood why the release of the active ingredient is prologned in this case.
Whereas the mechanism of disintegration of the first layer does not, or not to any great extent, depend on the nature of the active substance, it is dear that the more or less hydrophilic character of the active substance of the second layer can influence the kinetics of lixiviation/diffusion.
However, the invention is not limited as to the nature of the active substances. Each layer may contain a different active Ingredient.
However, according to a specific embodiment of the invention, the first and second layers comprise the same active substance.
The active substances may be chosen In particular from any of the following groups (to designate the active substances, the International nonproprietary names have been adopted):
Medicaments which are active In asthma such as 2-ethoxymethyl-4 (3H)-pteridinone and bronchodilators such as theophylline, and/or some anti-inflammatory agents or antihistaminics of the ketotifen type;
medicaments which are active in the treatment of diabetes and its
related complications of the neurological, nephrological, ocular or
vascular type. By way of example, there may be mentioned
metformin, hypolipidaemic agents such as fenofibrate or
pravastatin and anti-atheromatous agents in general;
medicaments which are active in the treatment of alcoholism, such
peripheral analgesics, for example para-aminophenol derivatives
such as paracetamol, salicylated derivatives such as aspirin,
dlflunlsal, proplonlc add derivatives such as ibuprofen, fenoprofen,
ketoprofen, amlnoqulnollne derivatives such as floctafenlne,
pyrazolone derivatives such as noramidopyrlne;
central analgesics such as dextropoxyphene, codeine, morphine,
pethldlne, dextromoramlde, buprenorphlne, nalbuphlne,
antlspasmodics such as tfemonlum, dlfemerine, phlorogluclnol,
trimebutine, pinaverium, prifinium;
nonsteroidal anti-infiammatory agents and, for example:
arylproplonlc derivatives such as ketoprofen, Ibuprofen, naproxen,
fiurbiprofen, alminoprofen, tiaprofenic acid,
aryiacetic derivatives such as dlclofenac, fentiazac, aryicarboxyiic
derivatives such as fenbufen and etodolac,
anthranliic derivatives or fenamates such as niflumic acid and
idole derivatives such as indometacin and oxametacin,
oxicams such as piroxicam, tenoxicam,
pyrazole-contalnlng derivatives such as phenylbutazone,
lndene derivatives such as sullndac;
steroidal anti-inflammatory agents such as corticoids of the
prednlsone, prednlsolone and methylprednisolone type;
antibiotics of the beta-lactam type, such as penicillins,
of the cephalosporin type, such as cefuroxime axetll, of the beta-
lactamase inhibitor type, such as clavulanic acid,
of the amlnoglycoslde type, such as neomydn,
of the macrolide type, such as splromydn, erythnomydn,
of the tetracycllne type, such as mlnocydlne and doxycycllne,
of the sulfamide type, such as sulfediazine,
of the quinolone type, such as pefloxacin;
antituberculous agents such as Isonlazld rffamplcln, ethambutol,
central analgesics such as dextropoxyp;hene, codeine, morphine,
pethldine, dextromoramide, buprenorphine, nalbuphine,
antispasmodics such as tiemonlurn, difemerine, phloroglucinol,
trimebutine, pinaveritum, prifinium;
nonsteroidal anti-inflammatory agents and, for example :
arylproplonlc derivatives such as ketoprofen, Ibuprofen, naproxen,
flurbtprofen, atmlnopnofen, daprofenic add,
aryiacetic derivatives such as diclofenac, fentiazac,
arylcarboxytlc derivatives such as fenbufen and etodolac,
anthranlllc derivatives or fenamates such as nlflumlc add and
Indole derivatives such as Indometacln and oxametacln,
oxlcams such as plroxlcam, tenoxkam,
pyrazote-contalning derivatives such as phenylbutazone,
Indene derivatives such as sullndac;
steroidaf anti-inflammatory agents such as corticoids of the
prednisone, prednisolone and methytprednisolone type;
polyenic antifungal agents such as amphotericin B, nystalin,
imadazole-containing antifungat agents such as miconazole^
ketoconazole, fluconazole, flucytosine, griseofulvin;
antiviral agents of the type including zidovudine, aciclovir,
adamantane such as rimantadine, amantadlne, and moroxydine;
beta-blockers such as acebutolol, celiprolol, atenolol, betaxolol,
metoprolol, bisoprolol, propanoiol, nadolol, timoiol, tertatolol,
sotalol, plndolot, penbutolol, carteolol, oxyprcnotol, labetatol;
nitrated derivatives such as Isosorblde dintrate, Isosorblde
mononitrate, pentaerythrityl tetranitrate, erythrityl tetranltrate;
antlanglnals of the sydnonlmlne type, such as molsldomlne and
cardlotonics such as orclprenallne, or alternatively of the dlgitalln
type, such as dlgoxin, dtgltoxln,
diuretics such as furosemlde, bumetanlde, clopamlde, of the
thlazlde type such as hydrochlorothlazlde, xlpamide, of the ttenlltc
acid type, Indapamlde, clcletamne, splronolactone, canrenone
conversion enzyme inhibitors such as captopril, enalapril, lisinopril,
perindopril, quinalapril, ramipril, benazepril;
calcium inhibitors such as nifedipine, nicardipine, nilrendipine,
diltiazem, verapamH, bepridil;
antihypertensfves such as rilmenidine, clonidine, methytdopa,
dihydralazine, prasozine, uradipil, minoxidil;
antiantiythmlcs such as qunldlne, dlsopyramlde, clbenzollne,
propafenone, fiecalnlde, aprindlne, nadoxolol, mexlleUne,
antilschaemlcs such as nafldrofuryl, trimetazldine, pentoxyfllline,
nlcergoltne, buflomedll, dlhydroergotoxlne, dlhydroengocrtsflne,
dihydroergocryptlne, moxisylyte, raubaslne, vincamlne,
papaverine, nlfotlnlc add;
venotonlcs such as vitamin P;
hypotension correctors such as heptamlnol,
hormones such as thyroid hormones of the levothyroxine sodium
medicaments stimulating gastroduodenat motor function, such as
antiemetics such as metoclopramide, metopimazine, aiiprazide,
antiulcer agents such as ranitidine, famotidine, nizatidine,
cimetidine, omeprazole, of the antiulcer prostaglandtn type such as
misoprostol, sucralfate, aluminium hydroxide;
antidlarrhoeals such as loperamide, diphenoxylate, medicaments
promoting bacterial flora and those promoting yeast flora;
intestinal antiseptics such as nitrofuran;
contraceptives such as oestroprogestogens;
antlanaemtc agents such as iron;
antihlstamtntcs such as phenothlazlne;
vitamins such as thlamlne, nlcotlnamlde, pyridoxlne, biotln,
ascorbic acid, cyanocobalamlne, retinol, colecalclferol;
antleplleptics such as valproic acid, phenytoin, carbamazeptne,
ethosuximlde, progablde, vigabatrin;
antimigraine agents such as oxetorone, indoramine, ergotamine,
erot of the rye derivatives such as dihydroergotamine,
methysengide, tricyclic derivatives such as pizotifen;
anticoagulants such as antivitamin K agents;
antiparkinsonians such as levodopa, selegiline, lisurtde,
bromocriptine, biperiden, orphenadrine, pnocyclidine, tropatepin,
anxiotytics derived from benzodiazepines such as clotiazepam,
toflsopam, oxazepam, alprazolam, torazepam, bromazepam,
prazepam, busplrone, alpldem, hyderoxyzlne, mepnobamate,
antldepressants such as qulnupramlne, deslpramlne, Imlpramlne,
domlpramlne, amltriptyllne, vlioxazlne, amlneptine, fluvoxamlne,
fluoxetlne, tianeptlne, oxaflozane, maprotlllne, mlansertn,
trazodone, medifoxarrtne, totoxatone, IMAOs;
hypnotics such as zoplclone, zolpldem, and benzodlazeplne
derivatives such as fiunltrazepam, nltrazepam, triazolam,
phenotlazlne derivatives such as nlaprazlne,doxytamlne,
barbiturate derivaties such as butobarbital, amobarbital,
normothuymics such as lithium, vaipromide;
neuroleptics such as thioxanthen, pimozide, loxapine,
carpipramine, phenothiazine derivatives such as chlorpromazine,
thioridazine, fluphenazine, butyrophenone derivatives such as
haloperidol, penfluridoi, pipamperonse, benperidol, benzamide
derivatives such as sulpiride, amisulpiride, tiapride, sultopride;
antJmetabolites such as methotrexate, metxaptopuiine,
fluorouradi, cytarablne, hydroxo-urea, asparaglnase;
alkylating agents such as busulfan, pipobroman, procarbazine,
nitrogen mustard derivatives such as chlorambucll,
cyclophosphamlde, estramustine, melphalan, lomustine,
antlcancer steroids such as methoxyprogesterone, gestonorone,
norethlsterone, dlethylstilbestrol, dlenesfrol;
and more generally peptides having a therapeutic activity.
A pharmaceuticafiy acceptable salt of any one of the sallfiable active ingredients listed above may also be selected as active ingredient.
The content of active ingredient in the first layer will be determined according to the pathology to be treated.
This content may be high, it being possible for the active substance to represent up to 99.0% of the total weight of the first layer, and for example from 1 to 99.0% by weight, preferably from 85 to 95% of the total weight of the first layer.
The second layer may contain up to 98.55 by weight of active ingredient, for example from 1 to 95% by weight, better still from 60 to 80%.
Numerous Immediate-release compositions are known In the art and persons skilled In the art may thereby be freely Inspired for the production of the first layer.
Persons skilled In the art will choose In particular the constituents of the first layer so as to ensure rapid disintegration thereof upon contact with water or with a physioloical fluids.
Zt is in particular known to incorporate into this type of layer a disinterating agent whose role is to cause the disintegration of the tablet in the presence of water or of physiological fluids.
These disintegrating agents are normally included in the said layer in an amount of from 0 to 15% by weight, preferably from 2 to 5% by weight.
Examples of such disintegrating agents are: alglnlc add carboxymethylcellulose calcium, carboxymethylcellulose sodium, anhydrous colloidal silica, croscarmellose sodium, crospovfdone, guar gum, magnesium and aluminium silicate, methyl cellulose, mlcrocrystatllne cellulose, potassium polacrllln, cellulose, pregelatinlzed starch, sodium alglnate, starch sodium glycolate, starch and the effervescent mixtures known In the art for their disintegrating action.
The effervescent mixtures form part of the substances capable of rapidly causing the disintegration of the first layer, especially when
the latter comes Into contact with the gastric adds. These mixtures generally contain alkali metal or alkaline-earth metal, carbonates or bicarbonates or sodium gfycine carbonate.
Other additives may be incorporated into the immediate-release layer, such as diluents, binders, lubricants, antioxidants, colourings, sweeteners, flavourings and acidulants, wetting agents, hydrophilizing agents such as sorbito! and cyclodextrines, osmotic agents such as mannltol, pH correctors, stabilizing agents such as tnehalose and mannltol, adsorbants, chelating and sequestering agents and gastroresistant film-coating excipients of the type Including cellulose acetylphthalate and polymethacrylates.
By way of example, there may be chosen any one of the following diluents or alternatively a combination thereof: calcium carbonate, calcium sulfate, sucrose, dextrates, dextrin, dextrose, dlcalclum phosphate dlhydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose, mlcracrystalllne cellulose, soifcltol, starches, pregelatinized starch, talc, tricaldum phosphate and lactose.
Among the binders, there may be mentioned: gum arable, gum-tragacanth, guar gum, alginic add, sodium alginate, sodium cartooxymethylcellulose, dextrin, gelatin, hydroxyethylcellulos, hydroxypropylceltulose, liquid gtuycose, magnesium and aluminium silicate, maitodextrin, povidone, pregelatinized starch, starch and zein.
The lubricants are glidants (such as anhydrous colloidal silica, magnesium trfslllcate, magnesium silicate, cellulose, starch, talc or trtcalclum phosphate) or alternatively antifriction adhering agents (such as calcium stearate, glyceryl monostearate, glyceryt palmltostearate, hydrogenated vegetable oils, paraffin, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, fumaric add, stearic acid or zinc stearate and talc).
As examples of antioxldants, persons skilled in the art may select any of the following compounds :
acorblc add, ascorbyt palmltate, fumaric add, propyt gallate, sodium ascorbate and sodium metabisulfite, alpha-tocopherol, malic acid, BHA and BTH.
Preferred wetting agents are :
sodium docusate and sodium lauryi sulfate which are anionic
benzalkoniumchloride, benzethonium chloride and cetrimide which
are cationic surfactants;
glyceryi monooleate, fatty acid esters of polyoxyethylene sorbitan,
poly(vinyt alcohol) and sorbitans, which are nonionic surfactants.
Among the pH regulators, there arc acidifying agents of the type including citric add, hydrochloric add, lactic add, tartaric add, as well as alkallnlzing agents of the type Including monoethanolamlne, dlethandamlne and triethanolamlne, potassium citrate, sodium bicarbonate, sodium citrate dlhydrate.
Examples of adsorbants are bentonlte, anhydrous colloidal silica, kaolin, magnesium and aluminium silicate, mlcrocrystalllne cellulose and cellulose.
As chelating and sequestering agents, there may be used citric acid monohydrate, edetic acid, disodfum phosphate, monosodium phosphate, potassium citrate, tartaric acid and sodium citrate dihydrate.
The quantities of these additives are those normally used in the art. Generally, the binder may represent from 0.5 to 25% by weight, better still from 2 to 5% by weight of the said first layer.
The lubricants are preferably incorporated into this first layer in an amount of 0.01 to 10% by weight.
As a guide, the quantity of gastroreslstant film coating recipients varies between 0,5 and 9% by weight.
It will be noted that all the abovementioned additives, with the ex exception of the disintegrating agents may also be added to the prolonged-release layer in similar proportions. The prolonged-
release layer may, in addition, contain diluents chosen from glyceryl palmitostearate, hydrogenated vegetable oils, polymethacrylates, potassium chloride and sodium chloride.
Moreover, binderes such as carbomer, ethyl cellulose, hydrogenated vegetable oils, hydroxyproplymethytcellulose, methyl cellulose and polymethacrylates may be incorporated Into the prolonged-release layer.
However, the essential constituents of the second prolonged-release layer are polymeric materials which confer on Its Inert and nonblodegradable character. According to the Invention, the polymeric materials In question are polymers or copotymers insoluble in water (but not forming a gel either upon Immereslon In an aqueous medium) which are discharged intact by the body.
These polymers may play the role of binder in the composition of the second layer.
Such materials are in particular polyviny! chlorides, vinyl acetate/vinyl chloride copolymers, acrylonitrile/vinylidene cNoride copolymers, polydimethylsiloxanes and copolymers derived from (meth) acrylic acids.
The copolymers derived from (meth) acrylic adds comprise the copolymers of derivatives of methacrylic acid and the copotymers of derivatives of acrylic add and of derivatives of methacrylic add. As derivatives of (meth) acrylic acids, esters are preferred.
According to a preferred embodiment of the Invention, the nonblodegradable Inert polymeric material Is chosen from the groups consisting of ethyl acrylate and methyl methacrytate copolymers, ethylammonlum methacrytate and methyl acrylate copolymers, ethylammonlum methacrylate and ethyl acrylate copolymers, ethylammonlum methacrylate and methyl methacrytate copolymers, ethylammonlum methacrylate and ethyl methacrylate copolymers, methacrylic acide and ethyl acrylate copolymers, methacrylic acid and methyl methacrylate copotymers.
According to the invention, "ethylammonlum" Is understood to mean a radical chosen from the ammonloethyl, (C1-C4) alkylammonloethyf, dl (C1-C4) dkyiammonloethyl and tri (C1-C4) alkyl-arnmonloethyl and til (C1-C4) alkyiammonloethyl groups. Preferably, ethytammonium designates a trimethylammonioethyl radical.
Such materials are commercially available, for example, from the company Rohm.
There may be mentioned, purely as a guide : the copolymers Eudragit RL 30 D®, Eudragit RS 30 D®, Eudragit RL PO® and Eudragit RS PO®, Eudragit RL 12.5®, Eudragit RS 12.5®, Eudragit RL 100® and Eudragit RS 100®, which are copolymers of esters of acrylic acid and of esters of methacrytic add, with a low content of ammonium groups. These polymers have as recurring unit:
in which R1 Is a hydrogen atom or a methyl group and R2 Is the methyl or ethyl group;
the copolymer Eudragit NE 30 D® which Is a neutral copolymer of ethyl acrylate and methyl methacrylate, in which the recurring unit has the formula:
The copolymers Euderagit L 30 D-55® and Eudragit 1100-55® which are copolymers of methacryflc add and ethyl acrylate, In which the recurring unit has the formula :
the copoiyrners Eudraglt L 100®, Eudraglt L 12.5®, Eudraglt S 100® which arc copolymers of methacryllc acid and methyl1 methacryiate in which the recurring unit has the formula :
Among these polymers, the copotymer NE 30 D® has proved particularly advantageous. In general, the copolymers of esters of methacryllc acid and of esters of acrylic add are used In preference to any other type of Inert matrix.
The molecular mass of the polymeric material used may vary to a large extent depending on the nature of the monomers constituting the material.
In the case of the copolymers derived from acrylic and/or methacrylic acid mentioned above, the average molecular mass is between 100,000 and 1,000,000, preferably between 130,000'and 800,000.
It is desirable that the quantity of inert polymeric materials does not exceed 25% of the total weight of the second layer, and is not less than 1% of the total weight of this layer. Preferably, the quantity cf polymeric materials varies between 2.5% and 12% of the total weight of the second layer.
The whole tablet may be coated with a gastroreslstant or enterosofuble polymeric film, such that the active ingredient Is released only In the duodenal tract.
The polymeric substances generally used for the production of the gastroreslstant systems are cellulose acetophthatate, cellulose acetopnopionate, cellulose trimellitate or polymers and copolymers of (meth) acrylic acids.
The tablets of the Invention are conventionally prepared by a method including the steps of granulation, followed by compression.
More precisely, the method of preparation, which is the subject of the invention, comprises the steps consisting in :
a) preparing a granule of a first active substance from a
pulverulent mixture of the said first active substance, a
disintegrating agent and one or more additives suitable for
the preparation of a layer for the immediate release of the
said active substance;
b) preparing a granule of a second active substance from a
pulverulent mixture of the said second active substance,
from one or more nonblodegradable Inert polymeric
materials and from one or more additives suitable for the
preparation of a layer for the prolonged release of the said
c) combining, by compressing, in a manner known per se, the ¦ two types of granule obtained in steps a) and b) above so as to obtain tablets in which the first layer, affording immediate release, results from the compression of the granule obtained in step a), and, having a second layer arranged in contact with the said first layer, the said second layer resulting from the compression of the prolonged-release granule obtained in step b).
The first step (step a) is designed to provide a granule based on the first active substance, which will lead, through compression, to foe first layer, called Immediate-release layer.
The second step (step b) Is designed to provide a granule based on the same active substance or on a different active substance, which will lead, through compression, to the second layer, called prolonged-release layer. The constituents of this layer are those of the nonbiodegradable inert polymeric matrix defined above.
Step c) leads to the formation of the tablet through successive compression of the granules obtained in the preceding steps and); and b).
Steps a) and b) involve the granulation of powders of amorphous or crystallized particles. This granulation is carried out in a manner known per se and, for example, by a wet granulation method.
The method of granulation comprises five essential steps : 0) dry-mixing of its various constituents, (ii) wetting, (ill) granulation proper, (iv) drying, and then (v) sizing.
The dry-mixing consists In mixing the pulverulent exclpients entering into the composition of the granule.
The wetting consists In adding to the pulverulent mixture various constituents, a wetting liquid which may be water, a (C1-C4) alkanol, an aqueous solution of binder or an alcoholic solution of binder.
According to the invention, the expression "alcoholic solution of binder" includes both the alcoholic and aqueous-alcoholic solutions in which the solvent Is a mixture of one or more (C1-C4) alkanots or a mixture of water and of one or more (C1-C4) alkanols. A preferred (C1-C4) alkanol Is Isopropanol. It Is carried out in a kneading, planetary, mixing pan, projection or whirling-type mixer-blender or a rapid-type mixer-granulator.
In step a), the appropriate wetting liquid Is water, a (C1-C4) alkanol, an aqueous solution of binder or an alcoholic solution of binder as defined above, and as generally recommended In the art
In step b), it Is possible to use an aqueous dispersion or an organic solution of the nonblodegradable polymeric material (s) as wetting liquid. Better homogeneity of distribution of the matrix Is thus obtained. "Organic solution" Is understood according to the
invention to mean a solution of the nonbiodegradable polymeric materials) in an organic solvent which is either a mixture of one or more (C!-C4) alkanols, or a mixture of one or more ((C1-C4) alkyl) ((C1 -C4)alkyl) ketones and of one or more (C1-C4) alkanols. According to the Invention, Isopropanol Is the preferred (C1-C4) alkanol. Likewise, when a mixture of ketone(s) and of alkanoi(s) is used, the mixture of isopropanol and acetone is preferred.
When the polymeric material Is a copotymer derived from acrylic and/or methacrylic acide, the dispersion or the solution will preferably have a viscosity of between 10 and 300 mPa.s, better still between 15 and 200 mPa.s.
According to a preferred embodiment of the Invention, the sizing Is carried out by passing over a screen with a mesh opening of between 03 and 1.5 mm, preferably of between 0.8 and 1.5 mm.
The preferred value of the mesh opening is 1.25 mm in each of steps a) and b).
However, the Invention Is not limited to carrying out a wet granulation method. Thus, persons skilled in the art will also be able to use the other existing granulation methods, such as the dry granulation method.
The last step (step c) leads to the formation of the tablet. The combination of the granules is carried out in a conventional manner using the granules obtained in steps a) and b).
In the case of bllayer tablets, containing concentric layers, this step involves (i) compression, in a first compression chamber, of the entire prolonged-release granule obtained In step b) for the production of a core tablet; (II) the compression, In a second compression chamber, of a portion, preferably 50% by weight, of the Immediate-release granule obtained In step a) above; (III) the Introduction and the positioning of the core tablet resulting from step (I) above In the said second compression chamber; (Iv) the application of a gentle compression with centring of the core In the
said second compression chamber; (v) the addition of the remainder of the immediate-release granule to the said second granulation chamber; and (vi) the conjoint compression of the immediate -release granule on the tablet formed in step iv) above.
In the case of bllayer tablets, containing parallel layers, step c) comprises : (I) a gentle compression of the entire prolonged-release granule in a compression chamber; and then (ii) the addition of the entire Immediate-release granule to the said compression chamber and Its positioning on the tablet resulting from step I) above; and (III) the final compression of the tablet.
The respective proportions of the Immediate-release and prolonged-release granules are not critical according to the Invention.
The tablets of the invention may be administered by the oral or vaginal route. They allow the immediate release of a first active substance, and then the release of a second active substance, which is optionally identical to the first, over a period of 2 to 12 h.
The multilayer tablets of the invention are particularly advantageous since their method of preparation is simple, the exdplents constituting them being customary. Further, It is possible, by appropriately selecting the nonblodegradable Inert polymeric materials, to vary the dissolution profiles to a very large extent and with precision, depending on the needs.
According to the preferred embodiment of the Invention, the polymeric materials belong to the Eudraglt series marked by the Company Rohm, which are copolymers derived from methacryllc and/or add. Because of the diversity of the properties of these copolymers, It Is possible to obtain modulation of the release profile of the active ingredients.
In addition, these copolymers confer on the resulting tablets excellent formulation capacity (possibility of incorporating high levels of active ingredients) and compression capacity.
The choice of such copolymers offers, in addition, the possibility of film-coating the tablets with excipients of the Eudragit type in order to obtain a gastroresistant coating.
On the other hand, these copolymers are absolutely Inert In relation to the body, which ensures release of the active ingredient independently of the Influence of the body (and In particular of pH variations) and therefore reliability, safety, quality, reproduclblllty and better tolerance of the effects linked to the administration of the tablets of the Invention.
The examples provided In the text which follows Illustrates the invention more dearly. Reference will be made to the accompanying Figures 1 and 2.
a) Preparation and formulation of the Immediate-release granule.
The active ingredient is 2-ethoxymethyi-4(3H) - pteridlnone, designated as EMP in the text which follows.
The constituents for the preparation of the immediate-release granule, designated as GLM in the text which follows, were used In the following proportions by weight:
Polyvlnylpyrrolidone 30 2.94%
Cross-linked carboxymethyicellulose 2.94%
The active Ingredient, polyvinylpyrrolldone 30, and the carboxymethylcellulose arc Introduced into a mlxer-granulator for a 3-minute mixing.
The wetting liquid, osmosed water, is then introduced into the mixer-granulator until well-formed grains and agglomerates are obtained. Next; the whole is dried (oven or fluidized air bed) and sized on a screen with a mesh opening of 1.25mm.
b) Preparation and formulation of the prolonged-release granule
The active ingredient is that used in Example 1.
The nonblodegradable polymeric material used is Eudraglt NE 30 D® marketed by the company Rohm.
The constituents for the preparation of the prolonged-release granule, designated as GLP-1 In the text which follows, were used In the following proportions by weight:
Rne lactose powder 17.20%
Eudraglt NE 30 D® 8.80%
Magnesium stearate 1,20%
The active Ingredient and the lactose are Introduced Into a mixer-granulator for a 3-minute mixing.
The Eudragit NE 30 D®, which is an aqueous dispersion of a neutral copolymer of ethyl acrytate and methyl methacrylate, Is then gradully Introduced Into the mixture, as wetting liquid. Purified water Is added, If necessary, In order to obtain well-formed granules comprising agglomerates. Next the granule Is dried In a fluldized air bed and sized on a screen with a mesh opening of 1.25 mm. The lubricants (talc and magnesium stearate) are then mixed with the granule obtained above for 40 seconds.
c) Preparation of tablets containing concentric layers and of so-called tables containing parallel layers
The following tablets containing parallel layers A to D are obtained using the following steps by means of a compressing machine provided with ovoid dies :
(I) by gentle compression, In a compression
chamber, of the entire prolonged-release granule
of Example lb); and
(II) by addition, In the same compression chamber,
of the entire Immediate-release granule of
Example la) over the tablet obtained In step 0);
Oil) by subsequent compression of the whole consisting of the Immediate-release granule of Example la) and of the tablet obtained In step (I) above.
The following tablet containing concentric layers E was obtained using the following steps :
(a) the compression, in a first compression chamber, of the
entire prolonged-release granule of Example 1b) for the
production of a core tablet;
(b) the compression of a fraction of the immediate-release
granule of Example la) in a second compression chamber
(c) the transfer of the tablet resulting from step (a) Into the
second compression chamber;
(d) the application of a gentle compression with centring of
the tablet of step (a) In the said second compression
(e) the addition of the remainder of the Immediate-release
granule of Example la) to the second compression
(f) the conjoint compression of the immediate-release
granule of Example la) and of the tablet resulting from
step (d) above.
Table 1 below Indicates, for each tablet, the respective quantities of granules used.
Dissolution profiles for the tablets manufactured accordng to the procedure of Example 1
The dissolution profiles for the tablets manufactured in the preceding example were determined by UV spectrometry.
The tablet to be tested is introduced into a reactor previously changed with one litre of osmosed water, at 37°C, and provided with a temperature-regulating system and with an effective stirring system.
During the whole experiment, the reactor is kept stirring at 37°C.
At regular Intervals of time t, samples of the medium contained In the reactor are collected, filtered on a filter with a porosity of 0.45?m, and analysed by UV spectrometry.
Conditions for analysis by UV spectrometry:
The optical density of the samples collected, diluted In a known volume of osmosed water, Is measured at 313 nm.
The quantity of active Ingredient q present In the sample Is determined by comparison with the optical density of a control
solution of the active ingredient, EMP, of known concentration. A simple calculation makes it possible to find the total quantity of active ingredient released in the reactor at the Instant t
The dissolution profile for a tablet tested is obtained by plotting, on a curve, the calculated quantities of active ingredient as a function of the time of collection.
The accompanying Fiures 1 and 2 show the dissolution profiles plotted In the cases of tablets A to E above.
By following the operating protocol described In Example 1, the tablets containing parallel layers F to I In the following Table 2 are prepared:
The formation of the Immediate-release granules, GLI-2 Is given
Polyvlnylpyrrolldone 30 4.0%
Cross-linked carboxymethylcellulose 4.0%
Magnesium stearate 0.5%
These granules are prepared using the operating protocol of
The formulations of the prolonged-release granules are given below:
Rne lactose powder 16 %
Eudraglt RSPO 10 %
Magnesium stearate 1.2%
Fine lactose powder 17.2%
Eudragit RS30D 8.8%
Magnesium stearate 1.2%
Rne lactose powder 17.2%
Eudragit RSPO 8.8%
Magnesium stearate 1.2%
These granules are prepared using the operating protocol of Example 1b).
48 EXAMPLE 4
The dissolution curves for tablets F to I were plotted using the operating protocol described in Example 2.
These curves are presented in Figures 3 to 6.
1. Multilayer tablet for the instant and then prolonged release
of active substances comprising at least two superposed,
layers, characterized in that:
- a first outer layer is composed of a mixture of
excipients and of a first active substance, the said first
layer allowing Immediate release of the said first active
- a second layer arranged in contact with the said first
layer, consists of a nonblodegradabfe, Inert porous
polymeric matrix In which a second active substance Is
2. Tablet as claimed In claim 1, wherein the second active
substance Is identical to the first active substance.
3. Tablet as claimed in any one of the preceding claims,
wherein the nonbiodegradable inert polymeric matrix
contains one or more nonbiodegradable inert polymeric
materials chosen from polyvinyl chlorides, vinyl acetate/vinyl
chloride copolymers, copolymers derived from acrylic and/or
methacrylic adds, acrylonitrile/vinylidene chloride
copolymers and polydimethylsiloxanes.
4. Tablet as claimed in claim 3, wherein the copolymers derived
from methacrylic and/or acrylic acids are chosen from the
groups consisting of copolymers of esters of ethyl acrylate
and methyl metehacrylate, ethytammonlum methacrylate
and methyl acrylate copolymers, ethylarnmonturn
methacrylate and ethyl acrylate copolymers, ethylarnrnonlum
methacrylate and methyl methacrylate copolymers,
ethylammonlum methacrylate and ethyl methacrylate
copolymers, methacrylic aclde and ethyl acrylate copolymers,
methacrylic acid and methyl methacrylate copotymers.
5. Tablet as claimed in any one of claims 3 and 4, wherein the
nonbiodegradable inert polymeric materials are present in
the said second layer in an amount of 1 to 25% by weight.
6. Tablet as claimed in any one of the preceding claims,
wherein the porous polymeric matrix comprises from 1 to
95% by weight of the said second active substance.
7. Tablet as claimed In any one of the preceding claims,
wherein for immediate release of said first active substance
said first layer comprises one or more disintegrating agents
chosen from alglnlc add, carboxymethylcellulose calcium,
carboxymethylceliulose sodium, anhydrous colloidal silica,
croscarmellose sodium, crospovldone, guar gum,
magnesium and aluminium silicate, methyl cellulose,
mlcrocrystalllne cellulose, potassium polacrilin, cellulose,
pregetatlnlzed starch, sodium alglnate, starch sodium
glycoiate, starch and the effervescent mixtures known in the
art for their disintegrating action.
8. Tablet as claimed In any one of the preceding claims,
wherein the said first layer comprises from I to 99.0% by
weight of the said first active substance.
9. Bilayer tablet as claimed in any one the preceding claims,
wherein the said second layer has a top surface and a
bottom surface, only one of the said surfaces being in
contact with the said first layer.
10. Bilayer tablet as claimed In any one of the preceding claims,
wherein the said first layer and the said second layer are
11. Method for preparing a tablet as claimed In any one of claims
1 to 10, comprising the steps consisting In :
a) preparing a granule of a first active substance from a pulverulent mixture of the said first active substance, a disintegrating agent and one or more additives suitable for the preparation of a layer for the immediate release of the said active substance;
b) preparing a granule of a second active substance from a
pulverulent mixture of the said second active substance,
from one or more nonblodegradable inert polymeric
materials and from one or more additives suitable for the
preparation of a layer for the prolonged release of the said
c) combining, by compressing. In a manner known per se, the
two types of granule obtained in steps a) and b) above so
as to obtain tablets in which the first layer, affording
Immediate release, results from the compression of the
granule obtained in step a), and, having a second layer
arranged In contact with the said first layer, the said second
layer resulting from the compression of the granule
obtained In step b).
12. Tablet as claimed in any one of claims 1 to 10, wherein the said second layer comprises, as active substances, 2-ethoxymethyl-4 (3H) -pteridinone.
The invention relates to a multilayer tablet for the instant and then prolonged release of active substances comprising at least two superposed layers, characterized in that, a first outer layer is composed of a mixture of excipients and of a first active substance, the said first layer allowing immediate release of the said first active substance; a second layer, arranged in contact with the said first layer, consists of a nonbiodegradable, inert porous polymeric matrix in which a second active substance is dispersed.
in-pct-2000-00088-kol letters patent.pdf
in-pct-2000-00088-kol reply f.e.r.pdf
in-pct-2000-88-kol-granted-reply to examination report.pdf
|Indian Patent Application Number||IN/PCT/2000/88/KOL|
|PG Journal Number||02/2008|
|Date of Filing||19-Jun-2000|
|Name of Patentee||MERCK PATENT GMBH.|
|Applicant Address||FRANKFURTER STRASSE 250 64293 DARMSTADT|
|PCT International Classification Number||A61K 9/20|
|PCT International Application Number||PCT/EP98/08100|
|PCT International Filing date||1998-12-11|