ZA200506028B - Composition comprising a mixture of active principles, and method of preparation - Google Patents

Description

COMRPOSITION COMPRISING A MIXTURE OF ACTIVE PRINCIPLES,

ANDs METHOD OF PREPARATION

Thea present invention relates to coated particles comprising two active principles, to the method of preaparation thereof and to the multiparticulat e tablets comprising said particles.

Pharmaceutical forms comprising two active p rinciples al r-eady exist, in unit forms such as gelatin capsules or tablets.

In these pharmaceutical forms, a first al ternative corsists in formulating each active principle individually.

The two populations are tlmen either compresse-d without a prior mixing step, in the form of bilayer tablets, tecchnically complex to set up and requiring as specific ma®erial for the compress ion, or mixed, bef-ore being cormnpressed, placed in gelat-in capsules or in s-achets.

A second alternative consists in simul_taneously formulating the two active principles, for e xample by mizxing, followed by a granulation step, the resulting prcoduct possibly then being compressed, laced in gelatin capsules or in sachets.

The=se mixtures are often complicated to cont_rol since thesy bring together several populations of active pr dnciples and of ex cipients of heterogeneous re spective size, mass and form. There ensues therefrom . an increased risk of segregation, leading to a gradual demnixing of the two populations of active particles du ring the mixing itself or the pharmaceutical ) op erations following thes mixing, for ex=nmple the coguwpression or the placirig in gelatin caps ules. The £1i nal unit form contains a highly variable content of ea ch of the two active primciples.

- 2 = ’ Choos ing the populations of active principles and of excip ients needs great care but is not, however, . suffi cient to completely eliminate this risk.

In th e case of a mixture of active principles, the risk of se=gregation, already high due to the presence of an addit ional population, becomes even more unfavorable when the dose ratio between the active principle prese nt at the highest dose and that present at the lowes t dose 1s high, in particular when it becomes equal to or greater than 5, preferably equal to or great-er than 10.

To compensate for this unfavorable dose ratio and to maint.ain a ratio of the respective masses of each fraction close to 1, a diluent is usually added to the fract—ion present at the lowest dose with which said active principle is granulated.

The =mddition of the diluent to the particle formulation leadss to an increase in the unit size and weight of the pharmaceutical form to be administered tc the patient, whicla creates an additional obstacle to be overcome in formutalating the medicinal product, and makes it more diffi cult to administer to patients who have difficulty in swrallowing.

A second problem appears in the case of combinations of active principles in which at least one of the active principles, or even both, require (s) a coating to mask its « their) unpleasant taste. . In this case, the size of the particles is increased by the polymeric coating layer masking the taste.

WO» 2004/069135 PCT/EP2004/0508035 ’ It would therefore be advantageous t=o have a composition which is such that the risks of . heterogeneity in terms of mass and of size= and, where appropriate, of contemt, set out above. would be avoided, and which iss suitable for any subsequent formulating, for exarmple compression, placing in gelatin capsules or coating.

To solve this problem, the Applicant ha s developed coated particles comloining two active principles different in nature, respectively a f—irst active principle which is a constituent of all or part of the core and a second active principle wwhich is a constituent of all or part of the coating.

In the remainder of +he description, the expression “coating” denotes a c cating comprising at least one coating layer. Should the coating consist of several layers, each layer would have the same composition, applied in practice by spraying onto the co re. However, it should be noted that, since one of thes aims is to obtain coated particles as small as possilole in size, the particle will ad-vantageously be coated with a single layer. The coating applied around th _e core is to be distinguished from the additional func tional layer to which reference will subsequently be mad_e, and which denotes an additional. layer applied to- the basic coating.

In other words, and a&ccording to the in~vention, the same particle combines two different activ—e principles making it possible to solve the problerms mentioned . above relating to the population heterogemneity of the particles used, in terms of size and shape.

: The .dnvention therefore relates to an active principl _e- based coated particle in which both the core and tthe . coat ding contain active principle, wherein the coore cont-ains a first active principle while the coatXng cont-ains a second active principle, which is different in nature.

The Applicant has presented, in patent applicatzon

WO 0 2739981, a substantially spherical microgranuale cons isting of a core coated with at least one coat—ing laye r, the core and said coating layer each contain=ing betw een 80 and 95% by weight of active principle, “the rest up to 100% consisting of at least one bind=ing agen t. According to that document, the active principole cons tituting the core is the same as that contained in the coating layer. In addition, the set of examples desc_ribes only embodiments based on a single act_dve prin ciple.

To solve the problem of the heterogeneity of content of acti_ve principle in cases, therefore, where the two acti ve principles have a differrent concentration in ~—the coat_ed particle, the core contains the active princimple pressent at the highest dose, while the coating conta.ins the active principle present at the lowest dose.

In =n advantageous embodiment, the dose ratio betw een the active principle present at the highest dose (fi rst acti_ve principle) and that present at the lowest d ose (second active principle) is equal to or greater t han 5, preferably equal to or greater than 10. . The coated particle comprises two active princip-les which can be chosen from any family of compounds, for example from gastrointestinal sedatives, antaci ds, ’ anal _gesics, anti-inflammatories, coronary vasodilato-rs, peri _pheral and cerebral vasodilators, anti-infecti ous agerts, antibiotics, antiviral agents, antiparasi.tic agerats, anticancer agents, anxiolytics, neurolepti cs,

! central nervous system stimulants, antidepressants, antihistamines, antidiarrheal agents, laxatives, . nutrient supplemnents, immunosuppress ants, blood cholesterol -reduci ng agents, hormone s, enzymes, antispasmodics, armti-angina agents, medicinal products affecting cardiac rhythm, medicinal products used in the treatment of arterial hypertension, antimigraine agents, medicirmal products affecting blood coagulability, =Antiepileptics, muscle relaxants, medicinal products used in the treatment= of diabetes, medicinal products used in the treatmemmt of thyroid dysfunctions, di uretics, anorectic a_gents, anti- asthmatics, expect.orants, antitussives, m.ucoregulators, decongestants, hypnotics, antinaussea agents, hematopoietic agerxts, uricosuric agents, plant extracts and contrast agents, or any other family of compounds, the active principles combined in the tablet possibly being chosen froml the same family or f=rom different families.

Combinations, which concern medicinal pizoducts of the same family or of different families, ar e particularly studied by the pharmaceutical industry for treating serious pathological conditions requiring the prescription of several specialty products in conjunction, since they make it possib le to improve adherence to treatments by decreasing the number of units to be taken by the patient, and sometimes make it possible to obtaira a synergy of effects.

Combinations of active principles are of particular use in the field of armalgesia, when a synergi stic effect on . the treatment of pain 1s sought by combining two reasonably powerf-ul analgesics, such as. for example, oxycodone and paracetamol, hydrocodone an.d paracetamol, ’ paracetamol and t ramadol, or combination s combining an opioid analgesic, for example oxycodone, with an opioid receptor antagonisst, such as naloxone or naltrexone, so

~— 6 —- ’ as to -avoid incorrect use of medicinal products by d rug addicts.

In the field of antiulcer agents, prefer red combin<ations combine an antacid with an antiul cex agent, for example antacids and omeprazole or lansop razole, antacids and famotidine or ranitidine.

In thee field of blood cholesterol -reducing agents and antidi abetic agents, preferred «combinations comb ine fenofibrate with metformin or fenofibrate w-ith simvas tatin.

Other domains are particularly studied, such as th ose of medicinal products effective against the AIDS vi rus or ant icancer agents.

Accord_ing to the invention, the composition of the coated. particles will vary as a fumction of the size= of the pamrticles of the active princi ples used and of the conten t of each active principle in the final coasted partic le.

In a first embodiment, the core contains 100% by wei _ght of time first active principle, while the coat=ing contains from 60 to 99% by weight of the second active princi ple, advantageously from 80 to 99% by weight, the rest —up to 100% consisting of at least one bincding agent and optionally an antistatic agent.

In th-is first embodiment, the rest up to 100% of the coatirag can also consist exclusively of binding agen t.

In a second embodiment, the core contains from 60 to 29% by weight of the first active principle, advant-ageously from 80 to 99% by weight, while the coatirag contains from 60 to 99% by weight of the second actives principle, advantageously from 80 to 95% by weightz, the rest up to 100% of the core and of the

’ coatin.g consisting of at lea st one binding acgent and option.ally an antistatic agent=.

In th is second embodiment, the rest up to 100% by 5) weight. of the core and of the coating can consist exclus:=ively of a binding agermt, which may be i dentical or difT ferent.

As alr—eady mentioned, in all cases, the addition of an antist-atic agent to the suspemnsion or the solut ion used for tme coating may be envisaged.

The clmoice of the binding agemt will be determi ned as a functi_on not only of its abil ity to bind the p articles of ac®ive principle to one another within the coated core, but also of the functio.mal characteristic s of the desire=d coated core, whether =—in the presence or absence of swubsequent functional coating. The ex pression “funct— ional characteristic” d_.enotes in particullarx, but in a nonlimiting manner, —the properties o f taste maskirmg and of modified or winmodified release= of the actives principle.

In practice, the binding agen—t is chosen from t he group compri sing in particular cel lulosic polymers, acrylic polyme=rs, povidones, copovidsones, polyvinyl a.lcohols, algini.c acid, sodium alginat e, starch, pregel atinized starclm, sucroses and deriva tives thereof, guaar gum, polyetz-hylene glycols, and mixtures thereof.

At time time of production of the core or of the coatirmag, the binding agent is sprayed in a solvent = choserm from the group compxising water and organic solvermts, such as ethanol, isopropanol or acetone, alone or as a mixture.

. As already mentioned, the core and the coating comprise an antista tic agent which is present, in principle, in . proportionss possibly ranging up to 10% by weight, preferably up to 3% by weight, relatDdve to the weight of the core and up to 10% by weight, preferably up to 3% by weicgght, relative to the weight of the coating, and which can be chosen from the group comprising micronized or nonmicronized talc, colloidal silica (RAerosil®2 00), treated silica (Pnerosil®RS72) or precipitated silica (Syloid®FP244) , and mixtures thereof.

By virtue of their structure consistirag of a core which is itself coated with a layer which gives it a substantiallly spherical shape, the particles of the invention may advantageously then be coated with an additional functional layer, the composition of which is chosen as a function of the desired characteristics of taste masking and/or of release of the active principles — i The compos ition of the additional fumctional layer is chosen ass a function of the physicochemical characteristics of each active principle, and consists of at least= one coating polymer.

The coatineg polymer is advantageously” chosen from the group compxising cellulosic polymers, acrylic polymers and mixtures thereof.

Among cellulosic polymers, ethylcel lulose, hydroxy- propylcellwualose (HPC) and hydroxypropylmethylcellulose (HPMC), alcone or as a mixture, will advantageously be chosen. : Among acrylic peclymers, ammonio metha crylate copolymer (Eudragit® RL and RS), polyacrylate (Eudragit® NE) and polymethacr—ylate (Eudragit® E) will advantageously be chosen, Euc3ragit® being a trademark re gistered by ROHM.

The additional func tional layer is applied by spraying . a solution, or a suspension, or else a colloidal dispersion, of the coating polymer in a solvent or a mixture of solventss, so as to form a con tinuous film covering the entire surface of each partic le, whatever its surface finish, in an amount sufficien t to obtain, for example, a masking of taste which is effective at the time the medici_ nal product is taken amd throughout the time the coated particles remain in the buccal cavity.

The thickness of th e film, which is general ly between 5 and 75 pm, most commonly depends on the solubility of the active principle contained in the coa ting (second active principle) &t the pH of saliva and on the more or less pronounced mature of the bitterness thereof.

The polymer of the additional functional layer is applied to the sur=face of the coated part icles of the invention in propo rtions possibly ranging up to 40%, preferably up to 20%, calculated as weight gain relative to the mas s to be coated.

The solvent chosera for spraying the coa ting polymer contained in the additional functional l.ayer may be water, an organic s olvent, such as ethanol, isopropanol or acetone, or a mi xture of solvents.

The additional Functional layer also optionally comprises a plasti.cizer, a surfactant, an antistatic agent, a lubricant.

- 10 =~ ' The plasticizer is used in a proportion o=f at most 40%, preferably betwesen 15 and 30%, expres=sed by weight . relative to the dry weight of polymer, a nd chosen from the group compr ising triethyl citrate, acetyltributyl citrate, triacsetine, tributyl citr ate, diethyl phthalate, poly ethylene glycols, polyscorbates, mono- and diacetylated glycerides, and mixtures thereof.

The surfactant is chosen from aniomic, cationic, nonionic and amp hoteric surfactants.

The antistatic a.gent is used in a proport=ion of at most 10% by weight, preferably between 0 and 3%, preferably less than 1%, by® weight, calculated relat—ive to the dry weight of the polymer, and chosen from the group comprising micronized or nonmicronized t alc, colloidal silica (Rerosil®200), treated silica (Ae rosil®R972) or precipitated s ilica (Syloid®FP244), and mixtures thereof.

The lubricant iss used in a proportion of at most 10% by weight, preferaloly between 0 and 3%, p referably less than 1%, by we=ight, calculated relatixse to the dry weight of the polymer and 1s chosen f£rom the group comprising magn.esium stearate, stearic acid, sodium stearyl fumarat—e, poly(oxyethylene glyscols), sodium benzoate and mix=tures thereof.

The size of tke coated particles is conventionally between 50 um and 2 mm, preferably between 100 and 800 pm, even mo re preferably between 200 and 500 um, and is determined by conventional methods, for example , using a set of sieves of calibrated messh size, or by laser diffractiocon.

A subject of the present inventiora is also a pharmaceutical or cosmetic composition containing said coated particless.

WO) 2004/069135 PCT/EP2004/050035 : The coated particles, possibly coverexd with an additional functional layer, may be used im any type of . formulation intended for oral administrat ion, but are particularly suital>le when the pharmaceutical form => chosen involves br inging the coated pa rticles into contact with saliva.

Particularly preferred pharmaceutical forms are powders intended for oral administration, packaged in the form of sachets, or of drinkable suspensions ira liquid form or to be reconstituted by extemporaneous &ddition of a certain volume of water, or else tablets, Dn particular multiparticulate tablets which are orodi spersible or . dispersible in a small volume of water.

Orodispersible tablets define tablets intended to disintegrate or to solubilize in the rmwouth without chewing, upon contact with saliva, in ess than 60 seconds, preferably less than 40 secondss, forming a suspension of particles, which may or may not be 2(0 coated, which is easy to swallow.

The disintegration time corresponds to t he amount of time between the moment at which the tablet is placed in the mouth in cormtact with saliva and the moment at 255 which the suspension resulting from the d isintegration or the dissolving without chewing of tke tablet in contact with saliva is swallowed.

This type of tablet is, for example, described in 3(D documents EP 548356, EP 636364, EP 1003484 , EF 1058538,

WO 98/46215, WO 00/ 06126, WO 00/27357 and WO 00/51568, but the particle of the invention can alsso be used in , any other formulation equivalent to those described in the documents mentioned.

Initially, the coatesd particles are rel eased into the buccal cavity afters the tablet has disintegrated or ] dissolved by the action of the sali-va, then they release the active principle rapidly ®&n the gastro- 5} intestinal tract, in the stomach or in time duodenum.

The orodispersible t—ablet consists of the particles of the invention and of a mixture of excipiesnts comprising at least one disinte=gration agent, a soluwable diluent, a lubricant and, op=tionally, a swelling agent, a permeabilizing agent , sweeteners and flavorings.

The proportion of excipient mixture relative to the coated particles is conventionally betwe en 0.4 and 10, preferably between 1 and 5, parts by weig ht.

The disintegration agent is chosen from the group comprising in parti cular crosslinked s odium carboxy- methylcellulose den oted in the trade by the term croscarmellose, crospovidone and mixtures thereof.

The disintegration agent is used in a proportion of between 1 and 20% b y weight, preferably between 5 and 15% by weight, irm the case of a mixture, each disintegrating agent being between 0.2% and 15% by weight, preferably between 5 and 10% by weight, calculated relative to the weight of the tablet.

The diluent may be chosen from the groupe comprising in particular soluble agents with bindirag properties, preferentially polycsls of less than 13 carbon atoms, lactose, cellulose derivatives and preferentially microcrystalline cellulose.

The preferred polyol of less than 13 carbon atoms is ) chosen from mannitol, xylitol, sorbitol amd maltitol.

Tre diluent is used in a proportion of betweeen 20 and 90% by weight, preferably between 30 and 50% I>y weight, } calculated relative to the weight of the table-t.

Tre soluble diluent is in the form of a directly compressible product the mean diameter of the particles off which is from 100 to 500 pm, or in the #Form of a powder the mean diameter of the particles of which is le=ss than 100 um, said powder being used alone= cor as a mi.xture with the directls compressible product .

Im a preferred embodiment, the polyol is use=d in the form of the directly compressible product.

Im a second preferred embodiment, a directly compressible polyol and a polyol in the form of a powder are mixed, the polyol in this «ca se being icdentical or different, the respective propo—xtions of di rectly compressible polyol and of powdered polyol be=ing from 99/1 to 20/80, preferably from 80/20 to 20 /80.

The lubricant is chosen from the group c¢ comprising ma_gnesium stearate, stearic acid, sodium stearyl fumarate, poly(oxyethylene glycols), sodium benzoate an d mixtures thereof.

Th e lubricant is used in a proportion between 0.02 and 2% by weight, preferably between 0.5 and 1% bw weight, ca lculated relative to thie weight of the tablet=.

Th e lubricant is dispersed in the mixzture of cogupression excipients sprayed at the surfaces of the tablet at the time of compression, comple=tely or pa rtially.

Thee swelling agent is chosen from the group comprising miecrocrystalline cellulose, starches and modified starches.

The swell ing agent is used in & proportion of between 1.0 and 15% by weight, calculated relative to the . weight of the tablet.

The permueabilizing agent is <hosen from the group comprisirag in particular silicas having great affinity for aqueous solvents, such as pr-ecipitated silica, more well-known under the trademark <Syloid®, maltodextcrins,

B-cyclode=xtrins and mixtures the-reof.

The permeabilizing agent is us ed in a proportieon of between O.5 and 5.0% by weight, calculated relative to the weight of the tablet.

The anti static agent may be chosen from the group comprisirig micronized or nonmic ronized talc, colloidal silica (Perosil®200), treated s dilica (Rercsil®R9772) or precipitated silica (Syloid® FP244), and mi=xtures thereof.

The antisstatic agent is used in a proportion of between 0.5 and 5.0% by weight, calculated relative t o the weight oF the tablet.

The swee tener may be chosen freom the group compxising in parti cular aspartame, potasssium acesulfane, =sodium saccharirate, neohesperidire dihydrocha Jdcone, sucralose, monoammonium glycyrir—hizinate, and mizxtures thereof.

The flavorings and dyes are th ose conventionally used in pharmacy for preparing tablet=s.

The inve ntion also relates to t—he method for preparing the coated particles described &bove.

’ The met—hod in accordance with the invention comprisses the fol lowing steps: . - pr eparing a core comprissing the first active principle, - co-ating the core thus o btained by spraying a so-liution or suspension comprising the second ac.-tive principle and at least one binding agent, - dr-vying.

In a first preferred embodiment, the particles =are prepare d according to the followring steps: - granulation of the first active principle in tthe fo=rm of a powder, using a binding agent in the foerm of an aqueous or organic solution or a somlvent mixture, and then drying, - comating of the core thus obtained by spraying t=he scmlution or the suspensiom comprising the second ac=tive principle and at le=st cone binding agent, - drying.

In a second preferred embodiment, the particles are prepare=d according to the following steps: - gr-anulometric selection of microcrystals of be=tween 50 Mm and 400 um =n size constituting tthe fi rst active principle, - cemating of the microcrysstals by spraying fhe sce lution or the suspensiom comprising the second ac=tive principle and at le=st one binding agent, - dr-ying.

Accordi_ng to this embodiment, t—he steps may be carrzed out in different devices or in the same device.

For tlme granulation, a high energy granulator, a planeta ry mixer or a flu idized air bed are advanta.geously used.

In the case of granulation in a fluidized a=ir bed, the m ixture of powder conta-ining the active primciple, and . optionally the diluent and the antistatic agent, is 1 ntroduced into the devi. ce, before being gramulated, by spraying onto said mix ture of powder a ssolution or s uspension of excipierats comprising at least one b inding agent.

W hen the two active pr inciples are incompatible with o ne another, such that accelerated degradat_ion of one o f them is observed, it 1s possible to applly, between t he core comprising the first active princirpole and the c coating comprising the second active pri nciple, an

Oo ptional polymer layer: separating the ®&,wo active p rinciples. Said layer t—hen consists of a po_lymer which c an be used as a binding agent, ideally= the same p olymer as that used as binding agent in orae or other o f the steps for prepardng the particle, the amount of p olymer applied not exceeding 15%, pref-erably not e xceeding 5%, calculated as weight gain rela—tive to the m ass to be coated.

I £f the organoleptic claaracteristics of thee particle m ake it necessary, an &dditional step of coating the c oated cores thus obtai ned is carried out koy spraying a n additional functional layer which masks the taste, f ollowed by drying.

A ll the steps of the method in accordance= with the i nvention can be carried out in a sugar-~coat—ing pan or a perforated pan or in a fluidized air bed. . I.n a preferred embodiment of the method in accordance w ith the invention, alll the steps for presparing the c cated core and for coating with the additional layer a re carried out in a flu idized air bed.

’ The fluidized air bed 1s equ ipped with a spray rozzle, the spray direction and position of which czan be . chossen.

Thiss choice makes it possible to control the kA3netics of cgrowth of the particles and to avoid phenommena of sticking, related to the nature of the active priraciple, to the compositiora of the sprayed binding or coat-ing composition, and to the various paramet ers of the method (temperature, a ir pressure for example, solution flow rate).

According to an advantageou s embodiment, the Ibinding agerat used to prepare the pamticle and the polymer used to mask the taste of said parcticle are identical.

The invention also relates t o the method for preparing the multiparticulate tabletts comprising the coated partzicles.,

The method in accordance with the invention comprises the following steps: - dry mixing of the particles, obtained according to the method described aloove, with the compmession excipients, - compressing of the mixtumre to obtain a unit form. y

The compression of the mixturre may be carried out= on an alternating or rotary compresssion machine.

The constraints exerted durirag the compression step may . rancge from 5 kN to 50 kN, preferably from 5 kN to 15 kN. ’ The hardness of these tabletzs is preferably bet—ween 1 and 10 kp, more preferentially between 1 and 5 kp, meassured according to the method of the Euaropean

Pharmacopoeia (2.9.8), 1 kp kreing equal to 9.8 N.

) Preferably, the hardness of the multipparticulate tablet is suitable for obtaining a friability, measured - according to tthe method of the European Pharmacopoeia, of less than 2%, while at the same time conserving a dissolution pxofile identical to th-at of the coated particles alorme and for the multipar—ticulate tablets, and permitting a disintegration time for the tablet in the mouth of less than or equal to 60 seconds, preferably les s than or equal to 40 se=conds.

The tablets may have a diameter of between 6 mm and 17 mm. They may be round, oval or oblecong in shape, have a flat or concave surface, and optionally have grooves.

In the case of orodispersible tablets, “polo”-shaped punches may al so be used.

The tablets have .a mass of betwee en 0.1 gram and 2.0 grams.

The invention will be understood more clearly by means of the examples of preparation of the coated particles and of the mu ltiparticulate tablets =n accordance with the invention. These examples are given only by way of illustrations and of advantageous emmbodiments of the invention and in no way constituate a limitation thereof.

MATERIALS AND ANALYTICAL METHODS

Excipients used mannitol: Pear litol®200SD marketed by ROQUETTE. microcrystalline cellulose: Avicel® PH102 marketed by . FMC colloidal sili_ca: Syloid® 244FP marketed by BASF

HPMC: Pharmaccoat® 603 marketed by SHIIN-ETSU methacrylate copolymer: Eudragit®E100 marketed by ROHM aspartame: marketed by Nutrasweet.

Method for dissolving pH 1.2 3 device: USP type II . — blade speed: 50 rpm — volume: 500 ml — temperature: 37.0°C+0.5°C — detection: UV spectrophotometry at 210 nm for hydrocodone bitartrate, 280 nm for oxyccodone hydrochloride, 298 nm for paracetamol. — dissolving medium: 0.1N HCl

EXAMPLE 1: Coated particles combining oxycodone Thydro- chloride and paracetamol

An aqueous solution containing 30.8 grams of oxy=codone

HCl (“oxycodone”) and 8.0 gxams of hydroxypropylm-ethyl- cellulose (“HPMC”) as binding agent (25% by ~weight relative to oxycodone) is sprayed onto 1000 gre=ams of paracetamol crystals having a mean size of 350 um , in a fluidized air bed of the GPCG-3 type, equipped with a

Wirster nozzle (“bottom spray”). 1038 grams of the particles obtained after the as sembly step described above are coated, in a GLATT GPCG-3 fluidized air bed equipped with a Wirster inser—t, by spraying an alcohol solution of Eudragit(R®E100, comprising 10% by weight of colloidal s ilica, calculated relative to the dry weight of polymer.

A total amount of Eudragit®E100 corresponding t=o 20% calculated in weight gain relative to the st arting particle mass 1s applied to the particles. . The final formulation of the coated particles a ppears in table 1:

’ Table 1 . . % (w/w) 0.6 n6.5 1.6 w/a

EXAMPLE 2: Orodispersible tabletss containing 325 mcy of paracetamol and 10 mg of oxycodone hydrochloride

The coated particles obtained ir Example 1 are m ixed with excip ients, according to tab_le 2, the mixture thus obtained is then compressed on an SVIAC PR6 p ress equipped w ith 6 round, flat punclaes 15 mm in diame ter, so as to obtain an average unit dose of 325 mg of paracetamo 1 and 10 mg of oxycodone.

The final formulation of the tzablets thus obta.ined i appears in table 2: Table 2

TOTAL

Claims (18)

1. —- 25 J ’ CLAIMS

   , 1. An active principle-based coated particle in whi ch both the core and the coating contain active principle, wherein the core contains a fir st active principle while the coating contains a second active principle, which is different in nature.
2. 2. The coated particle as cl aimed in claim 1, where_in the core contains the active principle present at the highest dose while the coating contains the active principle present at the lowest dose.
3. 3. The coated particle as claimed in claim 2, characterized in that the dose ratio between tT he first active principle and the second acti ve principle is equal to or greater than 5, preferably equal to or greater than 10.
4. 4. The coated particle as cl aimed in claim 1, where in the core contains 100% by weight of the fir st active principle, while the coating contains fr om 60 to 99% by weight of the second acti ve principle, advantageously from 80 to 99% by weight, the rest up to 100% consisting of at lea st one binding agent and «optionally an antistat ic agent.
5. 5. The coated particle as cl aimed in claim 1, where in the core contains from 60 to 99% by weight of t he first active principle, advantageously from 80 to 99% by weight, while the coating contains from 60 to 99% by weight of the second active principl e, advantageously from 80 to 95% by weight, the re st ’ up to 100% of the core and of the coati ng consisting of at least one binding agent a nd optionally an antistatic agent.
6. 6. The coated particle as claimed in either of claims 4 or 5, wherein the rest to 100% of the coating , and, where appropriate, of the core c=onsists exclusively of a binding agent, which may be identical or different.
7. 7. The particle as claimed in one of claims =4 to 6, wherein the binding agent is chosen from th_e group comprising cellulosic polymers, acrylic polymers, povidones, copovidones, pelyvinyl al _cohols, alginic acid, sodium alginate, starch, pregelatinized starch, sucroses and deri _vatives thereof, guar gum and polyethylene glycols , alone or as a mixture.
8. 8. The coated particle as claimed in claim 1, wherein the core and/or the coating also contain a t least one antistatic agent in proportions ranging respectively up to 10% by weight, preferabl y up to 3% by weight, relative to the weight of t he core and up to 10% by weight, preferably up to 3% by weight, relative to the weight of the coating.
9. 9. The coated particle as claimed in claim 1 , which comprises, in addition to the coatimg, an additional functional layer, the compositzion of which 1s chosen as a function of the desired characteristics of taste masking and/or of release of active principle.
10. 10 . The particle as claimed in claim 9, wherein the additional functional layer ccnsists of at least

    . one coating polymer chosen from the group comprising cellulosic polymers and acrylic polymers, alone or as a mixture.

    WwVO 2004/069135 PCT/EP2004/0S0035 :
11. 11. The particle as claimed in clazim 1, which comprises, betwzeen the core and the coating, an . intermediate la yer based on a polyme r chosen from the group comproising cellulosic polymers, acrylic polymers, pov~idones, copovidones , polyvinyl alcohols, algiraic acid, sodium algi nate, starch, pregelatinized starch, sucroses ancl derivatives thereof, guar «gum and polyethylene glycols, alone or as a mixture .
12. 12. A pharmaceut® cal or cosmetic composition comprising the coated particles wkiich are the subject of one «of claims 1 to 11.
13. 13. The composition. as claimed in claim 12, which is in the form of tablets, in part=Scular multi- particulate talolets which are orod_dspersible or dispersible.
14. 14. 2A method for producing a particle coated with active principle, the core of which contains a first active pr-inciple while the coating contains a second active principle, cormprising the following steps : - preparing th e core comprising the first active principle, - coating the core thus obtained IDy spraying a solution or suspension comprisin g the second active prin ciple and at least one binding agent, - drying. :
15. 15. The method as claimed in claim 14 , wherein the step for preparing the core consists of granulation of the first active primciple in the ) form of a powder, using a binding agent in the form of an acueous or organic solution or a solvent mixture , and then drying.

    . :
16. 16. The method as claimed in claim 14, wherein the preparation of the core consists of granulometric : selection of microcrystals of betwee=n 50 pm and 400 pm in size, <«onstituting the first active principle.
17. 17. The method as claimed in claim 14, wZhich contains an additional step of coating with &=n additional functional layer, the composition of which is chosen as a function of t—he desired ‘characteristics of *aste masking and/eor of release of an active principle.
18. 18. The method as claimed in claim 14, wherein the binding agent is ch osen from the growip comprising cellulosic polymers , acrylic polymers, povidones, copovidones, polyvAnyl alcohols, alginic acid, sodium alginate, ss tarch, pregelatin ized starch, sucroses and derivatives thereof, «guar gum and polyethylene glycolss, alone or as a mi_xture.