Title of Invention

"A PROCESS FOR PREPARATION OF MULTIPARTICULATE PHARMACEUTICASL FORM

Abstract The invention relates to a multiparticulate pharmaceutical form with delayed and pulsed release, enabling to obtain the onset of the availability of the active ingredient within 4 to 8 hours after the ingestion of the pharmaceutical form, and then a progressive release of the totality of the active ingredient within the 8 to 20 following hours, characterized by the fact that it is free of organic acid and that it is in the form of medicinal spheroids consisting of a neutral spherical core comprising a first coating based on a mixture of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer throughout which are uniformly distributed the constitutive particles of an active ingredient, the whole comprising a second coating based on at least two pH independent polymers presenting rates of permeability different from one another with respect to the gastric and intastinal mediums, optionally at Least one pH dependent polymer, at least one plasticizer and at least one inert carrier uniformly distributed throughout the said coating.
Full Text The invention relates to a process for preparation otmuitiparticuiate pharmaceutical form, with programmed and pulsed release.
Numerous pharmaceutical to forms with delated release for oral administration are available. The release of the active ingredient must be controlled as a function of the therapeutical purpose and of the phstmscologicfll properties of the active ingredient. In consequence, it is not always desirable dial the plasmatic rate be constant. On the contrary, in order to avoid any habituation and in order to limit the side effects provoked by the active ingredient, it "would be absolutely advariijigrotjs for the plasrnahr rate lo follow the metabolic rhyihrn and the specific needs of the patient during certain periods of the nvcthemcr. For instance, in order to diminish the nocturnal symptoms or the symptoms upon awakening in the case of certain chronic diseases such as ischemic heart disease. asthma and arthritis, the drugs should be administered such a way that the desired therapeutical plasmatic level is reached only at the desired moment, that is to say during sleep or just at the moment of awakening.
In the article "An Organic Acid-Induced Sigmoidal Release System for Oral Controlle.d-Release Preparations11, Pharmaceutical Research. Vol. 11. No. 1 (1994). is disclosed a pharmaceutical form wherein the release of the active ingredient is of the sismoidal type. However, it is indicated tn this article that the siqjnoidai rr.leJisr; of the active in;rrecltent ran be obtained onlv if an orcraiiu: ;icicl i:s ^dded!o the pharmaceutical form. However, due to the presence of an organic acid, such pharmaceutical forms may have an irritating ettect, which conotitxites a major drawback especially in the case of lone; lasting treatments. WO 98/17261 discloses n multiparticulate pharmaceutical form of controlled release, which comprises two kinds of medicinal spheriods, as well as its preparation process.
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Consequently, there does not exist at present a muitiparticulate pharmaceutical torm free of organic acid, capable of making available high concentrations of active ingredient at the moment at which the patient needs them the most, while maintaining the minimal therapeutical plasmatic concentration throughout the day.
The Applicants hove had the merit of findino-uneyocrerilv und snrnrisincrJv dial it is possible to obtain such pliaimaoeutical fumis which arc easy for administration and which do not present an irritating effect.
Thus, the Tnuil.tparliriifjile pharmaceutical lorrn according !o me invention wheretn the release of the-active ingredient is delayed ,and pulsed and which enables to obtain the onset of the availability of the active ingredient within 4 to 8 hours after the ingestion of the pharmaceutical form, and then a progressive release of the totality of the active ingredient within the 3 to 20 following hours, is characten2ed by the fact that it is free of organic acid and that it is in the form of microgranules or medicinal spheroids consisting of a neutral spherical core comprising a first coating based on a mixture of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer throughout which are uniformly distributed the constitutive particles of an arrive ingredient, the wholft comprising1 a second coating based on at least two pI I independent polymers presenting rates of permeability different trom one another with respect to the gastric and
inirslinal mrdiurns,, optionally at. 1ra:;l one: pH dr.prntlrni. polymer, at. \r.x'Al ont:
piasticizer and at least one ineit carrier uniformly distributed throughout the said coating..
The concentration of active ingredient is very high m the coating which envelops the neutral spherical core which makes it possible to obtain medicinal spheroids of

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reduced size and thus definite pharmaceutical forms of low size which are easier,.and more ploasant to be ingested by ths patient and which permit the administration of highe; dosages per administered drug unit.
According to an advantageous embodiment, this pharmaceutical form according to the invention is thu:; characterized by the fact that the active ingredient represents from 20 to 100% by weight of the coating which envelops a neutral spherical core, preferably from 60 to 90s by weight and still more preferably from 80 to 90% by we ight.
The hydrosoluble polymer which is part of this composition of the coating which envelops the neutral spherical core and which contains the active ingredient i:i selected from the group comprising especially poyvinylpyrrolidone, hydroxypropylmethyl cellulose, and thiair mixtures, and the non hydroso.Luble polymer is selected from the group comprising especially acrylic and/o meuhacrylic resins, cellulosic polyners, and their mixtures.
The weight ratio between the hydrosoluble polyme:: and the non hydrosoluble polyme is from 0.1 to 0.9 preferably from 0.3 to 0.7, and still more preferably froin 0.45 to 0.55.
The second coating of the pharmaceutical from according to the invention is based on at least two pH independent polymers which present permeability rates which are different from one another witn respect to the gastrio and the intestinal mediums, optionally at least one pU dependent polymer, at least one pla;ticizer and at least oni5 innrt carrier uniformly distributed throughout the said coating.
In this second coating, tha proportion between th-a polymer which presents the lowest permeability and th.= po! ymer which presents the highest permeability, is froin 97,3 to 80/20.

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It is necessary to respect these proportions betwesr the polymers of different permeability rates. As a matter oi faot, in the case of proportic ns of polymer of lov permeability higher than 97%, the release of the active-ingredient can be too much delayed; on the contrary, in th"s caise of proportions of polymer of low permeability lower than 80%, the release of the ac tive ingredient is not. sufficiently delayed.
The polymers of the second ooating are selected fron this group comprising especially acrylic and/or methacrylic reisins, cellulosic polymers, and their mixtures.
The inert carrier which is uniformly distributed throughout the second coating is selected from the group conprising especially talc, anhydrous colloidal silicon*; dioxide, magnesium stearate, morion tear ate of glycerol and thoir mixtures.
The plasticizer which is part of the constitution o:: thi? second coating must be pharmaceutically acceptable; it is selected from the group comprising especially jethylphthalate, triethylcitrate, dibutylsebacate, triacetine and their mixtures.
According to an advantagsous embodiment of the invention, the active ingredient is selected from the group conprising especially the molecules which are active on th cardio-vascular system, and more especially Diltiazem and Verapamil, the anti-inflammatories, the antiallergic^ and thfi antihistamines.
The pharmaceutical form according to the invention is administered at bed-time.
Thus, the availability oi1 the active ingredien1; becrins about 4 to 8 hours after ingsstion, that is to say a; thtj moment of awakening of the patient, i.e. the moment a: wh:.ch certain of the symptoms anong which the risks o: cardio-vascular accidents are the highest.
The release continues regularly throughout the

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foLlowing 8 to 20 hours.
The administration of the lext pharmaceutical forn being carried out several hours after the end of the tota._ release of the active ingredient-, the patient has the be.iefit of the minimal therapeutica. plasmatic concentration during the whole nycthemer.
The process according to the invention for this preparation of the pharmaceutical form according to thn invention is characterized by a sequence of step!! comprising:
- the introduction of neutral spherical cores into
a reaction vessel working on the pr .nciple of the fluidised-
bed,
- the spraying onto the said neutral spherical core:;
of particles of the active ing.redient suspended in a
solution of at least one hydroso.uble polymer and of at
least one non hydrosoluble polymer in an organic and/o::
aqueous solvent,
- the spraying on the coated particles obtained in
the preceding step of a coating suspension comprising at
least one inert carrier suspended in a solution of a mixture
of at least two polymers having permeabilities differsni:
from one another with respect to the gastric and tins
iniiestinal mediums,
- optionally the drying of the medicinal spheroid:?
thus obtained.
EXAMPLES
In the following exanples, the following pharmaceutical excipients are used:
- E1UDRAGIT RS 100: polyacrylic-poliTnethacrylic resin of low
permeability marketed by R6HM,
- 'SUDRAGIT RL 100: permeable polyazrylate-polymethaerylatta
resin marketed by R6HM,
- ?VP K 90: polyvinylpyrrolidone irarketed by BASF,

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- AEROSIL: silica gel marketed by DEGUSSA,
- Alcohol for pharmaceutical use,
- Talc for pharmaceutical use,
- Ethyl phthalate marketed by SOLVAY,
- Spherical neutral cores consisting of saccharose and o:
starch marketed by the Company VERNER's,
- INWITOR 900: glycerol monostearate marketed by the Company
UHLS,
- EUDRAGIT L 100: resin based on methacrylie acid and o.i
methyl methacrylate marketed by ROHM,
EXAMPLE 1
Preparation of medicinal sphero:.ds constituted of the pharmaceutical form according to the invention and whose ac :ive ingredient is Dilti&zftm.
0.7 kg of neutral spherical cores having a diameter from 300 to 400 urn are introduced in a tluidized air bed reaction vessel of the GPCGl typo and on the said core.5 th>3re is sprayed a suspension having the following composition:
EUDRAGIT RS 100 0.52 5 kg
PVP K 90 0.525 kg
Diltiazem 7,000 kg
Alcohol for pharmaceutical use . . 18.760 kg. Then, a coating suspensior is sprayed on the thu.s obtained particles, which suspension has the following composition:
EUDRAGIT RS 100 2.000 kg
EUDRAGIT RL 100 0.100 kg
Ethyl phthalate 0.192 kg
AEROSIL - . . 0.320 kg
Talc for pharmaceutica . use . . 0.400 kg Alcohol for pharmaceutical use 10.500 kg
Acetone 4,500 kg.
400 to 500 of the thus obtained medicinal spheroid.5

are introduced in. .hard gapjs:jles of gelatin having a
classical constitution.
A release test in vitro of the active ingredient is carried out as follows:
A conventional dissolu^eter equipped with pales is use:d; purified water Is used as dissolution medium,- the use conditions of the dissolumeter are 900 ml of purified watei and 100 rpm; the amount of introduced capsules corresponds to one therapeutical unit.
The amount of active ingredient released (expressed in percent by weight) with respect to the total amount of act.ive ingredient comprised in the introduced capsules is measured as follows: o
Sampling of the solution is carried out, every hour, frcm time 0 to 4 hours and then, every two hours, from the 4tt to the 16th hour. The released Diltiazem in the sample solutions is determined by way of an HPLC device equipped with an TJV detector at 240 nm.
The results obtained are collected in Table 1.
TABLE 1


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EXAMPLE 2
Proparation of medicinal spheroids constituted of the
pharmaceutical form according to the invention and whoso
active ingredient is Diltiazem.
Medicinal spheroids are prepared as indicated ir.
example 1 using as coating suspension a suspension havinc
th following composition:
EUDRAGIT RS 100 3.060 kg
EUDRAGIT RL 100 0.3 40 kg
Ethyl phthalate 0.340 kg
Inwitor 900 0.170 kg
Isopropanol 14.28 kg
Acetone i 9.52 kg.
According to the same way as in example 1, the
dissolution is measured. The result3 are collected in table
2 lereafter.
TABLE 2

EXAMPlE _3
Preparation of medicinal spheroils constituted of the pharmaceutical form according to t:he invention and whose act Lve ingredient is Diltiazem.
Medicinal spheroids are prepared as indicated in

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example 1 using as coating suspension a suspension having
ths following composition:
EUDRAGIT RS 100 3,612 kg
EUDRAGIT RL 100 0.638 kg
Ethyl phthalate 0,42 5 kg
Inwitor 900 0.213 kg
Isopropanol 17.850 kg
Acetone 11.900 kg
According to the same way as in example 1, the
dissolution is measured. The results are collected in tables
3 hereafter.
TABLE 3

EXAMPLE 4
Preparation of medicinal spheroids constituted of tho phe.rm&ceutical form according to the invention and whosti active ingredient is Verapamll.
Medicinal spheroids are prepared in the same way in example 1, Diltiazem being substituted as active ingredient by Verapamil, coating suspension consisting of a suspension having the following composition:

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EUDRAGIT RS 100 1.650 kg
EUDRAGIT RL 100 0 . 8? kg
EUDRAGIT L 100 0.063 kg
Ethyl phthalate 0.165 kg
AEROSIL 0.274 kg
Talc 0.3 43 kg
Alcohol for pharmaceutical use 9.000 kg
Acetone .... 3.857 kg.
According to the same was as in example 1, the disi solution is measured, the released Verapamil beinc determined by way of a spectrophotometer UV at 278 nm. The results are collected in table 4 hereafter,
TABLE 4


WE CLAIM:
i. A process for the preparation of a multiparticulate pharmaceutical form, comprising:
- the introduction of neutral spherical cores into a reaction vessel working on the
principle of the fluidised-bed,
- the spraying onto the said neutral spherical cores of particles of the active
ingredient suspended in a solution of at least one hydrosoiubie polymer and of at
least one non hydrosoiubie polymer in an organic and/or aqueous solvent,
the spraying on the coated particles obtained in the preceding step of a coating suspension comprising at least one inert currier suspended in a solution of a mixture of at least two polymers having permeabilities different from one another with respect to the gastric and the intestinal medium;*.
opi.ionnlly 'lit1, drying of llm rruj.t!ic.in;il spheroids thus obtained.
2. A process for the preparation of the multip articulate pharmaceutical form as
claimed in claim 1, wherein the active ingredient represents from 20% to iG0%,
preferably from 60 % to 90%, and more preferably from 80% to 90%, by weight
of the coating which envelops the neutral spherical core.
3. A process for the preparation of the mukiparticulate pharmaceutical form as
claimed in claims 1 or 2. wherein the weight ratio between the hydrosoiubie
polymer and the non hydrosoiubie polymer is from 0.1 to 0.9, preferably from 0.3
to 0.7, and more preferably from 0.45 to 0.55.
4. A process for the preparation of the multip articulate pharmaceutical form as
claimed in any one of claims 1 to 3, wherein the hydrosoiubie polymer ic selected
from the group comprising especially polyvinylpyrroiidone, hydroxy-propyimethyl
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cellulose and their mixtures, and the non hydrosoiubie polymer is seiected from the group comprising especially acrylic and/or mcthacrylic resins, ccllulosic polymers and their mixtures.
5. A process for the preparation of the multiparticulate pharmaceutical form-as
claimed in anv one of claims 1 to 4. wherein the nronorrion between the nolvmer
which presents the lowest permeability and the polymer "which presents the highest
permeability, ts from 97/3 to 80/20;-
6. A process for the preparation of the rnuitiparticulate phannaceuticai form
as claimed in any one of claims 1 to 5, wherein the polymers of the second coating
arc selected from the group comprising especially acrylic and/or mcthacrylic resins,
celiulosic polymers and their mixtures.
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7. A process for the preparation of the mnlfipsitttcutate phacroane'.!t"tcfll form ns
claimed in any one of claims i lo 6, whet em uic mcii caiiicr which is uinfoiinly
distributed throughout the second coating is selected from the group comprising
especially talc, anhydrous colloidal silicone dioxide, magnesium stearate,
fnonosltiarair of gtycttroi and ihwr nnxiutt^s.
8. A process for the preparation of the mui tip articulate pharmaceutical form as
claimed in any one of claims 1 to 7, wherein the active ingredient is selected from
the group comprising especially the molecules which are active on the
cardio vascular system, and more especially Diltiazem and Verapamil, the
anti-inflammatory, the antiallergics and trie antihistaniines.
The invention relates to a multiparticulate pharmaceutical form with delayed and pulsed release, enabling to obtain the onset of the availability of the active ingredient within 4 to 8 hours after the ingestion of the pharmaceutical form, and then a progressive release of the totality of the active ingredient within the 8 to 20 following hours, characterized by the fact that it is free of organic acid and that it is in the form of medicinal spheroids consisting of a neutral spherical core comprising a first coating based on a mixture of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer throughout which are uniformly distributed the constitutive particles of an active ingredient, the whole comprising a second coating based on at least two pH independent polymers presenting rates of permeability different from one another with respect to the gastric and intastinal mediums, optionally at Least one pH dependent polymer, at least one plasticizer and at least one inert carrier uniformly distributed throughout the said coating.

Documents:


Patent Number 207477
Indian Patent Application Number IN/PCT/2000/00528/KOL
PG Journal Number 24/2007
Publication Date 15-Jun-2007
Grant Date 14-Jun-2007
Date of Filing 20-Nov-2000
Name of Patentee ETHYPHARM
Applicant Address 21 RUE SAINT MATTHIEU, 78550 HOUDAN,
Inventors:
# Inventor's Name Inventor's Address
1 COUSIN GERARD 1, RUE DU GUE, 28210 LE MENSIL PONCEAU,
2 RAGOT FRANCOISE 6, RESIDENCE DE LA VALLEE, 28300 LEVES,
3 CLEE-BOUVET MARIE-CHRISTINE 3, RUE D' INBERNAIS, 28500 TREON
4 GENDROT EDOUARD 24 RUE DE DREUX, 28500 GARNAY
PCT International Classification Number A 61K 9/54
PCT International Application Number PCT/FR99/01201
PCT International Filing date 1999-05-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 98 06384 1998-05-20 France