Title of Invention

FAST DISINTEGRATING TABLET COMPRISING COATED ACTIVE PRINCIPLE AND A MIXTURE OF EXCIPIENTS

Abstract The invention concerns an improved multiparticulate tablet disintegrating in the mouth in contact with saliva in less than 40 seconds. The invention is characterised in that it is based on particles of coated active principle, said particles having intrinsic compression properties and a mixture of carriers, the proportion of carrier mixture relative to coated active principle particles being 0.4 to 6 parts by weight, the carrier mixture comprising: a disintegrating agent; a diluting soluble agent with binding properties; a lubricant; a permeabilizing agent; and advantageously lubricants, sweeteners, flavouring and colouring agents, the proportion of disintegrating agent and soluble agent relative to the tablet mass being 1 to 15 wt.% for the former and 30 to 90 wt.% for the latter.
Full Text The invention relates to fast disintegrating tablet ccxnprising
coated active principle and a mixture of excipients, particularly
where the tablet disintegrate in the mouth in less than 40 seconds
and the active principle have intrinsic characteristics.
Ibuprofen, paracetamol and aspirin may be mentioned as examples of active
principles which can be used 10 produce the tablets according to the invention.
Tablets based on ibuprofen are already known
Thus patent US 5.215.755 describes chewing tablets in which the ibuprofen
is present in the form of granules having a coating based on hydroxyethyl cellulose
or a hydroxyethyl cellulose/hydroxypropyl methyl cellulose mixture. This coating
was chosen to overcome the observed deficiencies of the coatings of the prior art
based on ethyl cellulose only
The object of the invention is to provide tablets obtained with the aid of
particles of coated active principle which not only disintegrate rapidly in the mouth
in less than 40 seconds, but also have a pleasant palatability, together with
satisfactory hardness characteristics enabling them to be manufactured industrially,
and which keep sufficiently well under normal storage conditions to enable them to
be handled by the patient, these tablets also optimizing the bioavailability of the
active principle.
The tablet according to the invention is characterized in that it is based on
particles of coated active principle which have intrinsic compression characteristics,
and on a mixture of excipients, the ratio of excipient mixture to coated active
principle being 0 4 to 6 parts by weight, preferably 1 to 4 parts by weight, the
mixture of excipients comprising
- a disintegration agent.
- a soluble diluent agent with binding properties which consists of a polyol
having less than 13 carbon atoms and being either in the form of the directly
compressible product with an average panicle diameter of 100 to 500 mm, or in the
form of a powder with an average panicle diameter of less than 100 mm, this polyol
preferably being selected from the group comprising mannitol, xylitol, sorbitol and
maltitol, it being understood that sorbitol cannot be used alone and that, in the case
where there is only one soluble diluent agent with binding properties, it is used in
the form of the directly compressible product, whereas in the case where there are
at least two soluble diluent agents with binding properties, one is present in the
directly compressible form and the other is present in powder form, it then being
possible for the polyols to be the same, the ratio of directly compressible polyol to
powder polyol being 99/1 to 20/80, preferably 80/20 to 20/80;
- a lubricant;
- a permeabilizing agent; and
- advantageously sweeteners, flavourings and colours,
the proportion of disintegrating agent being 1 to 15% by weight, preferably 2 to 7%
by weight, and the proportion of soluble agent being 30 to 90% by weight,
preferably 40 to 70% by weight, based in each case on the weight of the tablet.
The soluble diluent agent with binding properties consists of a polyol having
less than 13 carbon atoms and being either in the form of the directly compressible
product with an average particle diameter of between 100 and 500 micrometres, or
in the form of a powder with an average particle diameter of less than 100
micrometres, this polyol preferably being selected from the group comprising
mannitol, xylitol, sorbitol and maltitol, it being impossible to use sorbitol alone.
If there is a single soluble diluent agent with binding properties, therefore
different from sorbitol, it is used in the form of the directly compressible product.
If at least two soluble diluent agents with binding properties are used, one is
present in the form of the directly compressible product and the other, which can
consist of the same polyol, is present in the form of a powder in which the average
diameter of the constituent particles is less than 100 micrometres, the ratio of
directly compressible polyol to powder polyol being 99/1 to 20/80, preferably 80/20
to 20/80.
The disintegration agent is selected from the group comprising especially
crosslinked sodium carboxymethyl cellulose (known in the profession as
croscarmellose), crospovidone and mixtures thereof. By virtue of the choice and
proportion of this disintegration agent, the tablet retains an acceptable hardness for
normal handling conditions when tablets are kept in leaktight packaging up to
temperatures of at least 30°C.
The chosen proportions of disintegration agent and soluble agent for
constituting the excipient are 1 to 15% by weight and 30 to 90% by weight,
respectively, based in each case on the weight of the tablet.
The lubricant preferably used in this mixture of excipients is selected from
the group comprising magnesium stearate, sodium stearyl fumarate, stearic acid,
micronized polyoxyethylene glycol (micronized Macrogol 6000) and mixtures
thereof. It can be used in a proportion of 0.05 to 2%, based on the total weight of
the tablet.
The permeabilizing agent used is a compound selected from the group
comprising especially silicas with a high affinity for aqueous solvents, such as the
precipitated silica better known by the trade mark Syloid®, maltodextrins, b-
cyclodextrins and mixtures thereof.
The permeabilizing agent allows the creation of a hydrophilic network which
facilitates the penetration of the saliva and hence assists the disintegration of the
tablet.
In one highly advantageous embodiment of the tablets according to the
invention, the permeabilizing agent is the precipitated silica better known by the
trade mark Syloid® FP244. In fact, this silica not only assists the disintegration of
the tablets, but also, through its properties as a flow promoter, favours the
rearrangements of the particles during compression, and it makes it possible on the
one hand to reduce the amount of hydrophobic lubricant needed to ensure optimum
manufacturing conditions, and on the other hand to reduce the intensity of the
compression force needed to produce a tablet which can be handled under these
industrial conditions.
The proportion of permeabilizing agent is between 0.5 and 5% by weight,
based on the weight of the tablet.
A sweetener and optionally a flavouring and a colour are also included in the
mixture of excipients forming part of the composition of the tablets according to the
invention.
The sweetener can be selected from the group comprising especially
aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydro-
chalcone and mixtures thereof.
The flavourings and colours are those conventionally used in pharmacy for
the preparation of tablets.
Compared with the already existing tablets of the type in question, the
tablets according to the invention have an improved palatability and particularly an
improved taste and texture, and can allow a reduction in the ratio of tablet weight
to active principle dose.
They have a satisfactory hardness, enabling them to be handled under
standard operating conditions without special operating precautions. By way of
indication, it is pointed out that hardnesses which satisfy these conditions are
generally between 20 and 70 Newtons.
The tablets according to the invention can be prepared in the following
manner or by any other appropriate process. Particles of coated active principle
which have intrinsic compression characteristics are added to a mixture of
excipients containing a disintegration agent, a soluble diluent agent with binding
properties, a permeabilizing agent and advantageously a lubricant, sweeteners,
flavourings and colours, in the proportions indicated above. The mixture obtained
in this way is homogenized in a dry mixer and then subjected to a compression force
which gives the resulting tablet a satisfactory hardness, enabling it to be
manufactured industrially and handled under normal conditions without special
operating precautions; by way of indication, it is pointed out that hardnesses which
satisfy these conditions are generally between 20 and 70 Newtons.
EXAMPLES
EXAMPLE 1: Tablet containing 200 mg of ibuprofen
Table I shows the unit formula and the centesimal formula of this tablet.
This tablet is prepared as indicated below.
The excipients identified in Table I are sieved on a grid with a mesh size of
1000 mm.
The different constituents are weighed in separate containers of appropriate
capacity.
The coated ibuprofen particles (having the formulation given in Table II
below), the granulated mannitol, the pulverulent mannitol, the croscarmellose, the
aspartame, the potassium acesulfame, the precipitated silica and the flavourings are
introduced into a rotating mixer.
A homogeneous mixture is prepared.
The mixer is stopped, the magnesium stearate is added and the mixing
operation is continued for 1 to 5 min, according to the weight of mixture.
The mixture obtained is compressed on a rotary machine to give tablets with
the following characteristics:
- average weight of between 665 mg and 735 mg;
- breaking strength of between 20 and 50 N; and
- average disintegration time in the mouth of less than 40 seconds.
This disintegration time corresponds to the time between the moment when
the tablet is placed in contact with the saliva in the mouth and the moment when the
suspension resulting from the disintegration of the tablet in contact with the saliva is
swallowed.
The tablets are prepared in the same way as in Example 1 with the aid of
coated granules having the formula given in Table IV below.
The tablets are prepared in the same way as in Example 1 with the aid of
coated granules having the formula given in Table VI below.
WE CLAIM:
1. Improved multiparticulate tablet which disintegrates in contact with the
saliva in the mouth in less than 40 seconds, wherein it is based on particles of
coated active principle which have intrinsic compression characteristics, and on
a mixture of excipients, the ratio of excipient mixture to coated active principle
particles being 0.4 to 6 parts by weight, preferably 1 to 4 parts by weight, the
mixture of excipients comprising:
a disintegration agent;
a soluble diluent agent with binding properties which consists of a polyol
having less thasn 13 carbon atoms and being either in the form of the directly
compressible product with an average particle diameter of 100 to 500 mm, or in
the form of a powder with an average particle diameter of less than 100 mm, this
polyol preferably being selected from the group comprising mannitol, xylitol,
sorbitol and maltitil, it being understood that sorbitol cannot be used on its own
and that, in the case where there is only one soluble diluent agent with binding
properties, it is used in the form of the directly compressible product, whereas in
the case where there are at least two soluble diluent agents with binding
properties, one is present in the directly compressible form and the other is
present in powder form, it then being possible for the polyols to be the same, the
ratio of directly compressible polyol to powder polyol being 99/1 to 20/80,
preferably 80/20 to 20/80;
a lubricant;
a permeabilizing agent; and
advantageously lubricants, sweeteners flavourings and colours, the
proportion of disintegration agent being 1 to 15% by weight, preferably 2 to 7%
by weight, and the proportion of soluble agent being 30 to 90% by weight,
preferably 40 to 70% by weight, based in each case on the weight of the tablet.
2. Tablet according to claim 1, wherein the active principle is selected from
the group comprising especially aspirin, paracetamol and ibuprofen.
3. Tablet according to claims 1 or 2, wherein the disintegrating agent is
selected from the group comprising especially croscarmellose, crospovidone
and mixtures thereof.
4. Tablet according to one of claims 1 or 3, wherein the permeabilizing
agent is selected from the group comprising affinity for aqueous solvents, such
as precipitated silica, maltodextrins, P-cyclodextrins and mixtures thereof;
5. Tablet according to one of claims 1 to 4, characterized in that the
permeabilizing agent is precipitated silica;
6. Tablet according to one of claims 1 to 5, wherein the proportion of
permeabilizing agent is 0.1 to 10%, preferably 0.5 to 5%, based on the weight of
the tablet.
7. Tablet according to any one of claims 1 to 6. characterized in that the
lubricant is selected from the group comprising especially magnesium stearate,
sodium stearyl fumarate, stearic acid, micronized polyoxyethylene glycol and
mixtures thereof;
8. Tablet according to one of claims 1 to 7, characterized in that the
sweetener is selected from the group comprising especially aspartame,
potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone and
mixtrures thereof.
The invention concerns an improved multiparticulate tablet
disintegrating in the mouth in contact with saliva in less than 40 seconds. The
invention is characterised in that it is based on particles of coated active
principle, said particles having intrinsic compression properties and a mixture
of carriers, the proportion of carrier mixture relative to coated active principle
particles being 0.4 to 6 parts by weight, the carrier mixture comprising: a
disintegrating agent; a diluting soluble agent with binding properties; a
lubricant; a permeabilizing agent; and advantageously lubricants, sweeteners,
flavouring and colouring agents, the proportion of disintegrating agent and
soluble agent relative to the tablet mass being 1 to 15 wt.% for the former and
30 to 90 wt.% for the latter.

Documents:

IN-PCT-2001-00454-FORM-27.pdf

IN-PCT-2001-454-KOL-CORRESPONDENCE 1.1.pdf

IN-PCT-2001-454-KOL-CORRESPONDENCE.pdf

IN-PCT-2001-454-KOL-FORM 27 1.1.pdf

IN-PCT-2001-454-KOL-FORM 27.pdf

IN-PCT-2001-454-KOL-FORM-27.pdf

in-pct-2001-454-kol-granted-abstract.pdf

in-pct-2001-454-kol-granted-claims.pdf

in-pct-2001-454-kol-granted-correspondence.pdf

in-pct-2001-454-kol-granted-description (complete).pdf

in-pct-2001-454-kol-granted-examination report.pdf

in-pct-2001-454-kol-granted-form 1.pdf

in-pct-2001-454-kol-granted-form 18.pdf

in-pct-2001-454-kol-granted-form 2.pdf

in-pct-2001-454-kol-granted-form 26.pdf

in-pct-2001-454-kol-granted-form 3.pdf

in-pct-2001-454-kol-granted-form 5.pdf

in-pct-2001-454-kol-granted-form 6.pdf

in-pct-2001-454-kol-granted-pa.pdf

in-pct-2001-454-kol-granted-priority document.pdf

in-pct-2001-454-kol-granted-reply to examination report.pdf

in-pct-2001-454-kol-granted-specification.pdf


Patent Number 223910
Indian Patent Application Number IN/PCT/2001/454/KOL
PG Journal Number 39/2008
Publication Date 26-Sep-2008
Grant Date 23-Sep-2008
Date of Filing 23-Apr-2001
Name of Patentee LABORATORIES DES PRODUITS ETHIQUES ETHYPHARM S.A.
Applicant Address 21, RUE SAINT MATTHIEU, 78550 HOUDAN
Inventors:
# Inventor's Name Inventor's Address
1 NOURI NOURREDINE 10, BOULEVARD DE LA REPUBLIQUE, 06400 CANNES
2 BARBERO MARYVONNE LES COMORES PLAISANCE-ANJOUAN, 521, CHEMIN DU PUY, 06600 ANTIBES
3 CHAUVEAU CHARLES 2, RUELLE DES BRUYERES, 06560 VALBONNE
4 ZUCCARELLI JEAN-MARC RESIDENCE CLOS LAMARTINE, 126 CHEMIN DE LA PAROUQUINE, 06600 ANTIBES
PCT International Classification Number A61K 9/00, 9/20
PCT International Application Number PCT/FR1999/02681
PCT International Filing date 1999-11-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 98 14034 2001-11-06 France