U.S. patent application number 10/332463 was filed with the patent office on 2004-02-05 for oral pharmaceutical composition with controlled release and prolonged absorption.
Invention is credited to Castan, Catherine, Legrand, Valerie, Meyrueix, Remi, Soula, Gerard.
Application Number | 20040022849 10/332463 |
Document ID | / |
Family ID | 8852353 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040022849 |
Kind Code |
A1 |
Castan, Catherine ; et
al. |
February 5, 2004 |
Oral pharmaceutical composition with controlled release and
prolonged absorption
Abstract
A galenic system with prolonged/controlled release of the
medicinal and/or nutritional active principle, for oral
administration. A composition including two controlled release
systems associated in series, namely: individualised coated
microcapsules of active principle forming an internal phase, the
coating including a film-forming polymer P.sub.1, a nitrogenous
polymer, a softener, and a lubricant, and an external phase of
functional carriers: polyelectrolytic hydrophilic polymer; neutral
hydrophilic polymer, and a gelling agent, the composition
spontaneously forming in the presence of water, a cohesive and
stable composite macroscopic solid, where the external continuous
phase is a gelled matrix including the active principle
microcapsules. The invention is useful for delayed oral galenic
formulation of metformin.
Inventors: |
Castan, Catherine;
(Orlienas, FR) ; Legrand, Valerie; (Lyon, FR)
; Meyrueix, Remi; (Lyon, FR) ; Soula, Gerard;
(Meyzieu, FR) |
Correspondence
Address: |
James C Lydon
Suite 100
100 Daingerfield Road
Alexandria
VA
22314
US
|
Family ID: |
8852353 |
Appl. No.: |
10/332463 |
Filed: |
January 9, 2003 |
PCT Filed: |
July 10, 2001 |
PCT NO: |
PCT/FR01/02224 |
Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61K 9/4858 20130101;
A61K 9/5073 20130101; A61K 9/2081 20130101; A61P 3/10 20180101;
A61K 9/4866 20130101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 009/22 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2000 |
FR |
0009047 |
Claims
1- . An oral pharmaceutical composition comprising at least one
active principle (AP) and excipients capable of conferring, on this
composition, properties of controlled release and of prolonged
absorption of the AP in the gastrointestinal tract, this
composition being of the type of those comprising: first, a
plurality of individual particles comprising AP and excipients,
and, secondly, a continuous external phase of excipients, in which
phase is dispersed this plurality of individual and coated
particles, characterized in that: -a- it comprises two systems for
the controlled release of the AP combined in series, namely:
individual and coated particles, first, and the continuous external
phase, secondly; -b- the individual and coated particles of AP are
microcapsules having the following characteristics: (i) their
coating film has the composition below: 1--at least one
film-forming polymer (P1) which is insoluble in the fluids of the
tract, present in a proportion of 50 to 90% by weight, preferably
50 to 80% by weight, on a dry basis with respect to the total mass
of the coating composition and composed of at least one
water-insoluble cellulose derivative, ethylcellulose and/or
cellulose acetate being particularly preferred; 2--at least one
nitrogenous polymer (P2), present in a proportion of 2 to 25% by
weight, preferably of 5 to 15% by weight, on a dry basis with
respect to the total mass of the coating composition and composed
of at least one polyacrylamide and/or one poly-N-vinylamide and/or
one poly-N-vinyllactam, polyacrylamide and/or polyvinylpyrrolidone
being particularly preferred; 3--at least one plasticizer, present
in a proportion of 2 to 20% by weight, preferably of 4 to 15% by
weight, on a dry basis with respect to the total mass of the
coating composition and composed of at least one of the following
compounds: glycerol esters, phthalates, citrates, sebacates, esters
of cetyl alcohol, castor oil, salicylic acid and cutin, castor oil
being particularly preferred; 4--and optionally at least one
surface-active agent and/or lubricating agent, present in a
proportion of 2 to 20% by weight, preferably of 4 to 15% by weight,
on a dry basis with respect to the total mass of the coating
composition and chosen from anionic surfactants, preferably alkali
metal or alkaline earth metal salts of fatty acids, stearic and/or
oleic acid being preferred, and/or from nonionic surfactants,
preferably polyoxyethylenated sorbitan esters and/or
polyoxyethylenated derivatives of castor oil, and/or from
lubricating agents, such as stearates, preferably calcium,
magnesium, aluminum or zinc stearate, or such as stearylfumarate,
preferably sodium stearylfumarate, and/or glyceryl behenate; it
being possible for said agent to comprise just one or a mixture of
abovesaid products; (ii) they have a particle size of between 50
and 1 000 microns, preferably between 100 and 750 microns and more
preferably still between 200 and 500 microns; -c- The continuous
phase of functional excipients comprises: (i) at least one
polyelectrolytic hydrophilic polymer (PEP) capable of gelling
and/or crosslinking, preferably an acrylic or cellulose polymer or
a polysaccharide and more preferably still an alginate; (ii) at
least one neutral hydrophilic polymer (NP), preferably chosen from
the group consisting of celluloses, more especially
hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC)
and their derivatives; (iii)and optionally a gelling/crosslinking
additive (ADD) for the PEP polymer, preferably a compound based on
a cation with a valency.gtoreq.2, preferably a calcium-based
compound and more preferably still calcium acetate; -d- the mixture
formed from the individual particles according to -b- and from the
continuous phase according to -c- above spontaneously forms, in the
presence of water in a dissolution test D, a composite macroscopic
solid comprising a continuous external phase in the gel form in
which is included a noncontinuous internal phase formed from the
individual and coated AP particles, this composite macroscopic
solid being formed spontaneously in a time of less than 30 minutes
and preferably of between 1 and 20 minutes.
2- . The composition as claimed in claim 1, characterized in that
it exhibits an in vitro dissolution curve in a test D having a
sigmoidal appearance defined in the following way: there exists a
point T on the dissolution curve, the tangent to which passes
through the origin without cutting the curve and the abscissa
t.sub.T of which is such that:t.sub.T.gtoreq.1 H20% of the AP is
released within a time t.gtoreq.1.5 H.
3- . The composition as claimed in claim 1 or 2, characterized in
that the polymer NP has a viscosity .eta. at 25.degree.
C..gtoreq.10 000 mPa.multidot.s at a concentration of 2% and
according to the conditions set by USP 2208.
4- . The composition as claimed in any one of claims 1 to 3,
characterized in that the composition of the coating film of the
discrete AP particles is as follows: 1-60 to 80% weight of
P1=ethylcellulose 2-5 to 10% weight of P2=PVP 3-5 to 10% weight of
plasticizer=castor oil 4-2 to 8% weight of
lubricant/surfactant=magnesium stearate
5- . The composition as claimed in any one of claims 1 to 3,
characterized in that the composition of the continuous external
phase is as follows: i--60 to 90% by weight, preferably from 70 to
90% by weight, of gelling/crosslinking polyelectrolytic hydrophilic
polymer PEP, advantageously of alginate; ii--5 to 40% by weight,
preferably from 10 to 30% by weight, of neutral hydrophilic polymer
NP, advantageously of HPMC; iii--1 to 5 by weight, preferably from
2 to 4% by weight, of a gelling/crosslinking additive ADD,
advantageously calcium acetate.
6- . The composition as claimed in any one of claims 1 to 5,
characterized in that it comprises: from 50 to 80% by weight,
preferably from 60 to 70% by weight, of continuous external phase,
and 50 to 20% by weight, preferably from 40 to 30% by weight, of
individual and coated particles of AP and of excipients.
7- . The composition as claimed in any one of claims 1 to 6,
characterized in that it is provided in the form of a pulverulent
mixture capable of being converted in the gastrointestinal tract
into a system comprising a gelled matrix based on the continuous
external phase including the individual and coated particles of AP
and of excipients.
8- . The composition as claimed in claim 7, characterized in that
it is present in a gelatin capsule which, in an in vitro
dissolution test D, spontaneously forms a cohesive solid which
maintains its cohesion in the test D for at least 3 h.
9- . The composition as claimed in any one of claims 1 to 8,
characterized in that it is provided in the form of a tablet
capable of being converted in the gastrointestinal tract into a
system comprising a gelled matrix based on the continuous external
phase including the individual and coated particles of
AP+excipients.
10- . The composition as claimed in any one of claims 1 to 9,
characterized in that the AP belongs to at least one of the
following families of active substances: antiulcer drugs,
antidiabetics, anticoagulants, antithrombics, hypolipemics,
antiarrhythmics, vasodilators, antianginals, antihypertensives,
vasoprotectants, fertility promoters, uterine labor inducers and
inhibitors, contraceptives, antibiotics, antifungals, antivirals,
antineoplastics, antiinflammatories, analgesics, antiepileptics,
antiparkinsonians, neuroleptics, hypnotics, anxiolytics,
psychostimulants, antimigraines, antidepressants, antitussives,
antihistaminics or antiallergics; and is preferably chosen from the
following compounds: metformin, pentoxyfylline, prazosin,
diltiazem, ketoprofen, metoprolol, captopril, atenolol, salbutamol,
ranitidine, quinidine, perindopril, morphine, verapamil and their
mixtures.
11- . The composition as claimed in any one of claims 1 to 10,
characterized in that the AP is present in a proportion of at least
10% by weight, preferably in a proportion of 15 to 50% by weight
and more preferably still in a proportion of 20 to 40% by
weight.
12- . A pharmaceutical dosage system, preferably in the form of a
gelatin capsule, characterized in that it comprises of the
composition as claimed in any one of claims 1 to 10, preferably in
an amount of between 300 and 1 000 mg, and more preferably still
between 400 and 700 mg.
13- . Use of the composition as claimed in any one of claims 1 to
12 in the preparation of pharmaceutical or dietary forms which are
preferably pulverulent and are present in gelatin capsules.
Description
[0001] The present invention relates to the technical field of
pharmaceutical dosage systems with prolonged and controlled release
of medicinal and/or nutritional active principles (AP), intended
for oral administration.
[0002] More specifically, the invention is targeted at a
pulverulent pharmaceutical composition which can be administered
per os and which comprises at least one active principle AP
absorbed in particular in the upper parts of the gastrointestinal
tract and excipients capable of conferring thereon properties of
prolonged absorption of the AP.
[0003] The oral route is the most convenient and the most widely
used administration route for medicinal and/or dietary active
principles. These systems have obvious advantages in terms of ease
of administration and of tolerance for the patients.
[0004] It is particularly advantageous to seek to develop oral
pharmaceutical dosage forms which provide therapeutic cover for the
patient over a nychthemeron (24 hours). Such an objective is
ambitious. This is because the majority of APs administered per os
are absorbed in the upper part of the gastrointestinal tract, which
constitutes a "window of absorption". The duration of passage of
the AP through this window is limited in time. Consequently, the
absorption time is itself limited. Thus, it is generally accepted
that residence times for ingested oral forms are of the order of
0.5 to 3 hours approximately in the stomach and of 2 to 4 hours
approximately in the small intestine, according to whether the
subject has eaten nothing or whether the ingested oral forms are
present in a sizeable food bolus. The duration of bioabsorption of
an AP administered per os and for which the absorption is limited
to the upper parts of the gastrointestinal tract (GIT) is therefore
only a few hours.
[0005] An additional condition to that of increasing the
bioabsorption time, which is the first objective of the
pharmaceutical dosage system of the present invention, is that of
maintaining the bioavailability of the AP at a satisfactory and
sufficient level.
[0006] The combination of an increase in the bioabsorption time and
the maintenance of the bioavailability at a satisfactory and
sufficient level is an object which is difficult to achieve. A
simple increase in the release time of the AP beyond the natural
duration of the transit through the GIT generally results only in
the release of a portion of the AP after the window of absorption
and therefore in the lowering of the bioavailability of the AP.
[0007] In practice, the bioabsorption time (Tabs) is deduced from
the plasma concentration profile (PCP) of the AP: this is the time
at the end of which the PCP enters a situation of pure
elimination.
[0008] The bioavailability is, for its part, evalued conventionally
by the ratio of the area under the curve of the PCP to the area
under the curve of the PCP of a reference immediate release
form.
[0009] Numerous technical proposals have appeared in attempting to
solve the problem set out above.
[0010] Taken as a whole, the prior technical proposals provide for
an increase in the transit time of the AP by providing three types
of pharmaceutical dosage systems, namely:
[0011] low-density floating systems, which float on the surface of
the liquid gastric contents, thus prolonging the time during which
the AP is present in the upper parts of the GIT;
[0012] bioadhesive systems, which adhere to the gastric and/or
intestinal mucous membranes;
[0013] swelling systems, which increase in volume once they are in
contact with the gastric fluids until dimensions are reached such
that they cannot cross the pylorus and are thus retained in the
stomach.
[0014] Some of the known systems can combine two or three of these
flotation, bioadhesion and swelling functionalities.
[0015] Patent application PCT WO-99/47128 provides a review of the
prior art relating to these three types of approach for the
development of gastroretentive pharmaceutical dosage forms having
properties of prolonged and controlled release of the AP.
[0016] This application PCT WO-99/47128 provides an oral
pharmaceutical dosage form suitable for active principles having
high solubility in water and exhibiting a window of absorption
limited to the upper part of the gastrointestinal tract
(metformin). For these highly soluble APs, this pharmaceutical
dosage form claims to solve the problem consisting in
simultaneously providing:
[0017] i) prolonged release without an initial "burst", and
[0018] ii) a prolonged gastric residence time.
[0019] This pharmaceutical dosage system with controlled release of
AP has two phases. It comprises:
[0020] a particulate internal phase formed of individual granules
charged with AP. The distinctive feature of these granules is that
of being uncoated and of comprising one or more excipients which
can be:
[0021] a hydrophobic polymer: copolymer of (meth)acrylic acid
(Eudragit.RTM.), ethylcellulose,
[0022] and/or a hydrophilic polymer: sodium carboxymethylcellulose
or sodium alginate,
[0023] and/or other hydrophobic compounds: waxes, fatty alcohols,
fatty acid esters,
[0024] and a solid continuous external phase in which the particles
of the internal phase are embedded, this solid continuous external
phase comprising:
[0025] one or more hydrophilic polymers:
[hydroxypropylmethylcellulose (HPMC) (with a viscosity of 5 cPs and
1.times.10.sup.5 cps), microcrystalline cellulose),
[0026] and/or one or more hydrophobic polymers,
[0027] and/or one or more other hydrophobic compounds (waxes, fatty
alcohols, fatty acid esters).
[0028] This pharmaceutical dosage system is preferably in the
tablet form. It is presented as having an increased residence time
in the upper part of the gastrointestinal tract (stomach/small
intestine) by an effect of increase in size, without, however,
reaching an upper limit leading to blockage.
[0029] One disadvantage of this pharmaceutical dosage form is that
it exhibits a variable gastric residence time, unlike a
microparticulate pharmaceutical dosage form, the residence time of
which is kept in balance by the large number of particles.
[0030] Furthermore, it is probable that this pharmaceutical dosage
system according to WO-99/47128 (preferably a tablet) has a low
mechanical strength in a gastric medium. Under such an assumption,
the release of the AP would no longer be controlled.
[0031] Patent application PCT WO-99/47125 provides a pharmaceutical
dosage form, the application of which is limited to
antihyperglycemics of very high solubility and more particularly
metformin. This form makes it possible to obtain therapeutic cover
over 24 hours after oral administration in the nourished state. It
is composed of a macroscopic tablet surrounded by a membrane which
is permeable to water but not to the AP. The core of the invention
is the development of a tablet which releases the AP by an osmotic
effect. The release of the AP is controlled by adjusting the
osmotic pressure by addition of a polymer which increases the
inflow of water and by adjusting the rate for departure of the AP
by inserting an orifice in the semipermeable membrane. The
bioavailability is maintained by adding an absorption promoter,
such as a bile salt, to the tablet.
[0032] The main disadvantage is the presence of this absorption
promoter, which can weaken the intestinal wall and can, on
prolonged administration, have undesirable side effects.
[0033] Another disadvantage is that this "tablet" form exhibits a
variable gastric residence time, unlike a microparticulate
pharmaceutical dosage form, the residence time of which is kept in
balance by the large number of particles.
[0034] U.S. Pat. No. 5,472,704 provides a controlled release system
which maintains the bioavailability of the AP by increasing the
residence time of the pharmaceutical dosage form passing through
the window of absorption of the AP in the (GIT). This bioadhesive
pharmaceutical dosage system is composed of a plurality of
individual particles, the largest dimension of which is at most 2
500 microns, in practice 300-600 microns. Each particle can
comprise a bioadhesive part formed of an acrylate copolymer and of
hydroxypropylmethylcellulose (HPMC) and a noncontinuous part
comprising coated AP granules (125-600 .mu.m) in which the AP is
combined with an excipient which is active with regard to the
prolonged and controlled release of said AP, this excipient not
having bioadhesive properties (castor oil and/or lactose and/or
polyvinyl alcohol and/or a vegetable oil and/or a calcium
hydrogenphosphate, and the like).
[0035] The bioadhesive part comprises, for example:
[0036] cellulose derivatives or a mixture of acrylic copolymer
(Carbopol) and of HPMC,
[0037] hydrophobic agents, such as stearic acid salts, hydrogenated
vegetable oils, polyethylene glycols, talc, and the like,
[0038] and disintegrating agents of the following types:
polyvinylpyrrolidone, starch functionalized by methyl and sodium
carboxylate groups, starch, alginic acid, calcium
carboxymethylcellulose, guar gum, silica, sodium alginate, gelatin,
pectin, and the like.
[0039] The coated AP granules with a diameter of 125-600 .mu.m are
mixed with the excipients intended to form the bioadhesive part.
This mixture is subsequently formed into tablets, which are
subsequently milled and sieved, so as to obtain a powder comprising
granules with a size of 300-600 .mu.m.
[0040] The targeted purpose of the pharmaceutical dosage system
according to U.S. Pat. No. 5,472,704 is the development of a
bioadhesive system. In point of fact, as taught in WO-99/47128
discussed above, bioadhesive systems have not demonstrated their
ability to increase the residence time in the upper parts of the
GIT. Consequently, there is nothing in this U.S. Pat. No. 5,472,704
which allows it to be supposed that the pharmaceutical dosage
system is capable of increasing the bioabsorption time of the
AP.
[0041] Another type of pharmaceutical dosage system is also known,
composed of a multiplicity of particles or microcapsules each
carrying AP coated with a layer of film coating based on
ethylcellulose, on polyvinylpyrrolidone, on magnesium stearate and
on castor oil, for example. Such a pharmaceutical dosage system is
disclosed in application PCT WO-96/11675. These reservoir
microcapsules benefit from their multiplicity, which benefit is a
more uniform and reproducible gastric emptying time. Furthermore,
their size, of between 50 and 1 000 .mu.m, and the characteristics
of their coating make it possible to increase their transit time in
the small intestine (between 8 and 24 hours) and, consequently, to
maintain the absorption of the AP throughout all or part of this
residence time in the small intestine.
[0042] As will be demonstrated clearly hereinbelow, the
multiparticulate pharmaceutical dosage system according to WO
96/11675 can be improved as regards the absorption time and the
bioavailability of active principles having a high solubility in
water and absorbed in the upper part of the GIT, such as, for
example, metformin.
[0043] In such a state of the art, one of the essential objectives
of the present invention is to provide a novel improved
pharmaceutical dosage system for the oral administration of active
principles APs, in particular of APs having a high solubility in
water and absorbed in the upper part of the GIT, this system having
to make it possible to obtain effective therapeutic cover over 24
hours.
[0044] Another essential objective of the invention is to provide a
gastroretentive pharmaceutical dosage system for the oral
administration of an AP having a high solubility in water and
absorbed in the upper part of the GIT, this system exhibiting an
increased bioabsorption time, while maintaining the bioavailability
of the AP at a sufficient and satisfactory level.
[0045] Another essential objective of the invention is to provide
an oral pharmaceutical dosage composition for the administration of
an AP having a high solubility in water, the in vitro release
profile for the AP of which has a sigmoidal shape.
[0046] Another essential objective of the invention is to provide
an oral pharmaceutical dosage composition of one dose per 24 hours
type which is effective therapeutically, which can be tolerated by
the patient, which is economic, which is easy to manufacture and in
which recourse has been had to a combination of conventional and
harmless pharmaceutical excipients.
[0047] Another essential objective of the invention is to provide a
pharmaceutical dosage system of the type of that mentioned above
which is provided in the form of gelatin capsules.
[0048] Another essential objective of the invention is to provide
for the use of the abovementioned oral pharmaceutical dosage system
or composition for the preparation of a medicament, in particular
of a medicament with an active principle which is very soluble in
water and more particularly still with an AP which is an
antidiabetic, such as metformin.
[0049] These objectives, among others, are achieved by the present
invention, which relates, first of all, to the oral pharmaceutical
composition comprising at least one active principle (AP) and
excipients capable of conferring, on this composition, properties
of controlled release and of prolonged absorption of the AP in the
gastrointestinal tract, this composition being of the type of those
comprising:
[0050] first, a plurality of individual and coated particles
comprising AP and excipients,
[0051] and, secondly, a continuous external phase of excipients, in
which phase is dispersed this plurality of individual and coated
particles, characterized in that:
[0052] -a- it comprises two systems for the controlled release of
the AP combined in series, namely: individual and coated particles,
first, and the continuous external phase, secondly;
[0053] -b- the individual and coated particles of AP are
microcapsules having the following characteristics:
[0054] i) their coating film has the composition below:
[0055] 1--at least one film-forming polymer (P1) which is insoluble
in the fluids of the tract, present in a proportion of 50 to 90% by
weight, preferably 50 to 80% by weight, on a dry basis with respect
to the total mass of the coating composition and composed of at
least one water-insoluble cellulose derivative, ethylcellulose
and/or cellulose acetate being particularly preferred;
[0056] 2--at least one nitrogenous polymer (P2), present in a
proportion of 2 to 25% by weight, preferably of 5 to 15% by weight,
on a dry basis with respect to the total mass of the coating
composition and composed of at least one polyacrylamide and/or one
poly-N-vinylamide and/or one poly-N-vinyllactam, polyacrylamide
and/or polyvinylpyrrolidone being particularly preferred;
[0057] 3--at least one plasticizer, present in a proportion of 2 to
20% by weight, preferably of 4 to 15% by weight, on a dry basis
with respect to the total mass of the coating composition and
composed of at least one of the following compounds: glycerol
esters, phthalates, citrates, sebacates, esters of cetyl alcohol,
castor oil, salicylic acid and cutin, castor oil being particularly
preferred;
[0058] 4--and optionally at least one surface-active agent and/or
lubricating agent, present in a proportion of 2 to 20% by weight,
preferably of 4 to 15% by weight, on a dry basis with respect to
the total mass of the coating composition and chosen from anionic
surfactants, preferably alkali metal or alkaline earth metal salts
of fatty acids, stearic and/or oleic acid being preferred, and/or
from nonionic surfactants, preferably polyoxyethylenated sorbitan
esters and/or polyoxyethylenated derivatives of castor oil, and/or
from lubricating agents, such as stearates, preferably calcium,
magnesium, aluminum or zinc stearate, or such as stearylfumarate,
preferably sodium stearylfumarate, and/or glyceryl behenate; it
being possible for said agent to comprise just one or a mixture of
abovesaid products;
[0059] (ii) they have a particle size of between 50 and 1 000
microns, preferably between 100 and 750 microns and more preferably
still between 200 and 500 microns;
[0060] -c- The continuous phase of functional excipients
comprises:
[0061] (i) at least one polyelectrolytic hydrophilic polymer (PEP)
capable of gelling and/or crosslinking, preferably an acrylic or
cellulose polymer or a polysaccharide and more preferably still an
alginate;
[0062] (ii) at least one neutral hydrophilic polymer (NP),
preferably chosen from the group consisting of celluloses, more
especially hydroxypropylmethylcellulose (HPMC) or
hydroxypropylcellulose (HPC) and their derivatives;
[0063] (iii) and optionally a gelling/crosslinking additive (ADD)
for the PEP polymer, preferably a compound based on a cation with a
valency.gtoreq.2, preferably a calcium-based compound and more
preferably still calcium acetate;
[0064] -d- the mixture formed from the individual particles
according to -b- and from the continuous phase according to -c-
above spontaneously forms, in the presence of water in a
dissolution test D, a composite macroscopic solid comprising a
continuous external phase in the gel form in which is included a
noncontinuous internal phase formed from the individual and coated
AP particles, this composite macroscopic solid being formed
spontaneously in a time of less than 30 minutes and preferably of
between 1 and 20 minutes.
[0065] In an entirely advantageous way, even before their discharge
from the matrix, the microcapsules make possible the controlled
release of the AP and its absorption in the upper part of the
gastrointestinal tract.
[0066] Furthermore, without wishing to be committed to a theory, it
may be imagined that, by virtue of its in situ initial mechanical
strength, this pharmaceutical dosage system makes possible gradual
release of the microparticles (microcapsules) of internal phase
into the stomach, as the gelled matrix is eroded by the gastric
fluids.
[0067] According to another characteristic of the invention, this
composition exhibits an in vitro dissolution curve in a test D
having a sigmoidal appearance defined in the following way:
[0068] a there exists a point T on the dissolution curve, the
tangent to which passes through the origin without cutting the
curve and the abscissa t of which is such that:
t.sub.T.gtoreq.1H
[0069] 20% of the AP is released within a time t.gtoreq.1.5 H.
[0070] This in vitro dissolution curve is given by a test D which
is defined as follows:
[0071] A gelatin capsule comprising the oral pharmaceutical dosage
composition in the powder form is stirred using a paddle at 100
revolutions/min in a simulated gastric medium at a temperature of
37.degree. C. This simulated gastric medium, a volume of 1 liter of
which is employed, initially has a pH=1.2. This medium comprises
0.034 mol/l of NaCl, 0.063 mol/l of HCl and 3.2 g/l of pepsin. The
pH is gradually brought to 4.5 by addition, to the medium of
pH=1.2, of KH.sub.2PO.sub.4 (12 g) and of 35% NaOH.
[0072] Examples of dissolution curves in accordance with the
invention are represented in the appended FIGS. 1 and 2.
[0073] It will be noted that the dissolution curves for the AP
present in the pharmaceutical dosage systems according to the
invention comprise a point T, the tangent to which passes through
the origin and the abscissa t.sub.T of which is .gtoreq.1 H,
preferably t.sub.T.gtoreq.1.5 H and more preferably still is:
1.ltoreq.t.sub.T.ltoreq.3 H.
[0074] In other words, this means that the dissolution curves, in
the test D, of the compositions according to the invention exhibit
a first part in which the release of the AP is initially slow and
for which the concavity is directed upward, followed by a part for
which the concavity is directed downward.
[0075] The pharmaceutical dosage composition according to the
invention makes it possible to increase the therapeutic cover of
the AP by an increase in the t.sub.max, while maintaining the
bioavailability at a sufficient and satisfactory level. The curves
giving the plasma concentrations of AP as a function of the time
following ingestion of the composition, respectively for an
immediate release AP (metformin) and for this same AP in a
pharmaceutical dosage composition according to the invention, are
shown in FIG. 3. The increase in the t.sub.max obtained by virtue
of the formulation according to the invention is obvious.
[0076] According to a preferred characteristic of the invention,
the composition of the coating film of the individual AP particles
is as follows:
1 1- 60 to 80% weight of P1 = ethylcellulose 2- 5 to 10% weight of
P2 = PVP 3- 5 to 10% weight of = castor oil plasticizer 4- 2 to 8%
weight of = magnesium stearate lubricant/surfactant
[0077] As regards the continuous external phase or matrix, it is
preferable for its composition to be as follows:
[0078] i--60 to 90% by weight, preferably from 70 to 90% by weight,
of gelling/crosslinking polyelectrolytic hydrophilic polymer (PEP),
advantageously of alginate;
[0079] ii--5 to 40% by weight, preferably from 10 to 30% by weight,
of neutral hydrophilic cellulose polymer (NP), advantageously of
HPMC;
[0080] iii--1 to 5 by weight, preferably from 2 to 4% by weight, of
a gelling/crosslinking additive (ADD), advantageously calcium
acetate.
[0081] The viscosity .eta. may possibly be a criterion for
selection of the PEP and NP polymers.
[0082] This viscosity .eta. is conventionally a viscosity measured
at 25.degree. C. for a polymer solution with an assay which can
vary, for example: 1.25 or 2%. The methodology used is that set by
the US pharmacopeia, namely USP 2208.
[0083] Thus, as regards the PEP polymer and more especially still
sodium alginate, the products are selected which have a viscosity
.eta. of:
[0084] between 300 and 1 000 mPa.multidot.s,
[0085] preferably between 600 and 900 mPa.multidot.s. for a 1.25%
solution in water.
[0086] As regards the neutral hydrophilic polymer NP, its viscosity
.eta. is .gtoreq.10 000 mPa.multidot.s,
[0087] preferably: 50 000 mPa.multidot.s.ltoreq..eta..ltoreq.150
000 mPa.multidot.s,
[0088] and more preferably still: 80 000
mPa.multidot.s.ltoreq..eta..ltore- q.120 000 mPa.multidot.s for a
2% solution in water.
[0089] Mention may be made, as other examples of gelling polyers
(PEP), of poly(acrylic acid)s, xanthan gums or
carboxymethylcellulose.
[0090] HPMC is not the only neutral hydrophilic polymer (NP)
capable of being suitable in the context of the invention. By way
of alternative, hydroxypropylcellulose (HPC) might also be
employed.
[0091] The gelling additives are specific to the polymers on which
they exert their action. By way of illustration, barium, strontium,
copper, nickel, zinc or manganese salts crosslink the alginate,
resulting in the formation of a gel.
[0092] To continue with regard to weight considerations, it should
be noted that the composition according to the invention has the
advantageous characteristic of comprising:
[0093] from 50 to 80% by weight, preferably from 60 to 70% by
weight, of continuous external phase,
[0094] and 50 to 20% by weight, preferably from 40 to 30% by
weight, of individual and coated particles of AP and of
excipients.
[0095] Without this being limiting, the oral composition according
to the invention is preferably pulverulent.
[0096] The oral composition according to the invention is a
pulverulent form present in a gelatin capsule which, in an in vitro
dissolution test D, spontaneously forms, in the presence of water,
a cohesive solid formed from a gel matrix based on the continuous
external phase and including the individual particles of AP coated
with excipients. This cohesive solid is formed in less than 30
minutes and preferably between 1 and 20 minutes. It maintains its
cohesion in the test D for at least 3 hours, thus providing, first,
for the formation of an object with a size such that it cannot be
expelled from the stomach during the time of the digestion during
which the pylorus is in the closed position. However, during this
phase, the AP is released into the system by virtue of the osmotic
pressure exerted by the active principle.
[0097] After a few hours, the object disintegrates, thus releasing
the microparticles, which can then migrate toward the small
intestine, where they will continue to release the AP, thus
increasing the absorption time for the AP in the body.
[0098] According to an alternative form, this pulverulent mixture
could be formed into tablets capable of being converted in the
gastrointestinal tract into a system comprising a gelled matrix
based on the continuous external phase including the individual and
coated particles of AP and of excipients.
[0099] As was seen above, the excipients selected and the way in
which they are arranged in the pharmaceutical dosage system are
essential characteristics of the invention. However, the
functionalities of these excipients will be all the better
expressed if the AP belongs to at least one of the following
families of active substances:
[0100] antiulcer drugs, antidiabetics, anticoagulants,
antithrombics, hypolipemics, antiarrhythmics, vasodilators,
antianginals, antihypertensives, vasoprotectants, fertility
promoters, uterine labor inducers and inhibitors, contraceptives,
antibiotics, antifungals, antivirals, antineoplastics,
antiinflammatories, analgesics, antiepileptics, antiparkinsonians,
neuroleptics, hypnotics, anxiolytics, psychostimulants,
antimigraines, antidepressants, antitussives, antihistaminics or
antiallergics;
[0101] this AP preferably being chosen from the following
compounds:
[0102] metformin, pentoxyfylline, prazosin, diltiazem, ketoprofen,
metoprolol, captopril, atenolol, salbutamol, ranitidine, quinidine,
perindopril, morphine, verapamil and their mixtures.
[0103] The active principles to which the invention also relates
could be nutritional and/or dietary supplements or their mixtures,
such as, for example, vitamins, amino acids, antioxidants or trace
elements, or their mixtures.
[0104] Vaccines can optionally constitute other medicinal APs.
[0105] At the quantitative level, the AP is present in a proportion
of at least 10% by weight, preferably in a proportion of 15 to 50%
by weight and more preferably still in a proportion of 20 to 40% by
weight.
[0106] According to a preferred characteristic of the invention,
the pharmaceutical dosage system to which it relates comprises the
composition as defined above, this composition being present,
preferably, in a gelatin capsule, for example made of gelatin,
preferably in an amount of between 300 and 1 000 mg, and more
preferably still between 400 and 700 mg.
[0107] According to another of its aspects, the invention relates
to the use of the composition as defined above in the preparation
of pharmaceutical or dietary forms which are preferably pulverulent
and are present in gelatin capsules.
[0108] As regards the preparation of the oral pharmaceutical dosage
composition according to the invention, it consists:
[0109] first, of the preparation of the noncontinuous internal
phase of individual and coated particles of AP,
[0110] and, secondly, of the preparation of a pulverulent mixture
of excipients forming the continuous external phase, after
hydration.
[0111] The two external and internal phases are subsequently mixed
and optionally converted into tablets.
[0112] Naturally, the pharmaceutical dosage system according to the
invention could comprise other nontoxic excipients used by a person
skilled in the art in gelatin capsule and tablet forms.
Preservatives, stabilizers, agents for combating adhesion and
taste-masking agents can also be employed.
[0113] As regards the preparation of the discrete coated particles
forming the internal phase, reference will be made to application
PCT WO-96/11675, which is entirely incorporated in the present
description by reference. More specifically, the coating of AP
particle is carried out by spraying the coating composition onto
the AP particles brought into motion, preferably by mechanical
stirring or by fluidization.
[0114] As regards the continuous external phase, this is a matter
of mixing powders, indeed even of mixing powders and solutions, and
of drying by any means known to a person skilled in the art.
[0115] The examples which follow will make possible a better
understanding of the invention and will make it possible to grasp
all its advantages, and also the alternative embodiments which can
be envisaged, without departing from the scope of the
invention.
EXAMPLES
DESCRIPTION OF THE FIGURES
[0116] FIGS. 1 and 2 represent the dissolution profile for an AP
(metformin), expressed by the % by weight of AP dissolved in the in
vitro test D as a function of the time in hours, for the
compositions of examples 2 and 3 respectively.
[0117] FIG. 2a represents the dissolution profile for an AP
(metformin), expressed by the % by weight of AP dissolved in the in
vitro test D as a function of the time in hours, for the
microparticles according to WO 96/11675, taken by themselves alone
and prepared according to the methodology described in point 1.2 of
example 1.
[0118] FIG. 3 represents the plasma concentration profiles of
metformin after administration per os as a single dose to the
subject:
[0119] (a): of 850 mg of metformin present in the Glucophage.RTM.
immediate release form
[0120] (b): of 1 000 mg of metformin present in the pharmaceutical
dosage form according to the present invention.
[0121] Reference should be made to example 5 for further
details.
Example 1
[0122] 1.1--Products Employed:
[0123] a--Active principle AP:
[0124] metformin/HCl, sold by Interchemical.
[0125] b--Excipient for coating the particles of internal
phase:
[0126] Ethylcellulose, characterized by an ethoxyl level of between
48 and 49.5% and a viscosity of between 6 and 8 cP, manufactured by
Dow and sold under the name Ethocel 7
[0127] Magnesium stearate, sold by Ackros
[0128] Polyvinylpyrrolidone, manufactured and sold by ISP under the
name Plasdone K29/32
[0129] Castor oil, sold by Garbit Huileries.
[0130] c--Excipient in the external phase:
[0131] Sodium alginate, characterized by a viscosity of between 600
and 900 cP, sold by Monsanto under the name Keltone HVCR
[0132] Hydroxypropylmethylcellulose, characterized by a viscosity
of between 80 000 and 120 000 cP, sold by Colorcon under the name
Methocel K 100 M Premium EP
[0133] Calcium acetate, manufactured by Dr. Paul Lohman, USP23
powder grade.
[0134] d--Gelatin capsule:
[0135] green opaque gelatin capsules with a size of 00,
manufactured and sold by Capsugel.
[0136] 1.2--Methodology
[0137] 1 kg of metformin.HCl, sieved between 200 and 500 .mu.m, was
film-coated in a fluidized air bed device (Niro, precision coater)
with an 8% (w/w) acetone/isopropanol (60/40 (%) (w/w) solution
composed of a mixture of ethocel 7, of plasdone K29/32, of castor
oil and of magnesium stearate (example of composition and of amount
of coating deposited in tables 1 and 2). These film-coated
metformin particles were subsequently dry blended in a cube mixer
with a mixture of sodium alginate powder,
hydroxypropylmethylcellulose powder and calcium acetate powder.
This mixture was finally introduced into gelatin capsules with a
size of 00. The release of metformin.HCl was tested in vitro by the
test D.
Example 2
[0138] A gelatin capsule comprising 142.9 mg of metformin HCl is
prepared; the level of coating deposited on the metformin.HCl
microparticles is 26%.
2TABLE 1 percentage composition of example 2 Percentage Unit
composition composition Components % (w/w) (mg) Metformin
.multidot. HCl 25.47 142.9 mg Ethocel 7 6.60 37.1 mg Magnesium
stearate 0.89 5.0 mg Castor oil 0.72 4.0 mg Plasdone K 29/32 0.72
4.0 mg Kelton HVCR 50.91 285.6 mg Methocel premium K 100M 13.12
73.6 mg Calcium acetate 1.57 8.8 mg
[0139] Quantitative data are collated in table 1 below.
[0140] FIG. 1 shows the dissolution profile obtained. It is
observed, with regard to this FIG. 1, that it comprises a point T,
the tangent to which passes through the origin and the abscissa T
of which is 5 H 20. Such a dissolution profile reveals a prolonged
and controlled release of the AP. This also shows that the
pharmaceutical dosage form according to the invention retains
mechanical integrity (weight-dimension-cohesion) for a relatively
long time (at least 4 h). The concavity of the first part of the
curve (0-4 H) is directed upward: the release kinetics are slow and
controlled.
[0141] This FIG. 1 also reveals the dissolution profile for the
pharmaceutical dosage system according to application PCT
WO-99/47128.
[0142] It is important to note the difference in appearance between
the two curves, which corresponds to significant differences with
respect to the in vivo behavior and thus to the absorption of the
AP.
Example 3
[0143] A gelatin capsule comprising 166.7 mg of metformin.HCl is
prepared; the level of coating deposited on the metformin.HCl
microparticles is 12%.
[0144] Quantitative data are presented in table 2 below.
3TABLE 2 percentage composition of example 3 Percentage Unit
composition composition Components % (w/w) (mg) Metformin
.multidot. HCl 30.31 166.7 mg Ethocel 7 3.06 16.8 mg Magnesium
stearate 0.41 2.3 mg Castor oil 0.33 1.8 mg Plasdone K 29/32 0.33
1.8 mg Kelton HVCR 50.87 279.8 mg Methocel premium K 100M 13.11
72.1 mg Calcium acetate 1.58 8.7 mg
[0145] The appended FIG. 2 shows the dissolution profile obtained.
Each point on this curve corresponds to a mean obtained with
respect to 16 gelatin capsules. The curve in FIG. 2, corresponding
to the composition according to the invention, comprises a point T,
the tangent to which passes through the origin and the abscissa
t.sub.T of which is 4 H.
[0146] The profile in FIG. 2 is of sigmoidal shape. It is clearly
distinguished from the dissolution profile obtained with the coated
microparticles alone (FIG. 2a) as obtained according to the
methodology described in point 1.2 above of example 1.
[0147] Comparison of FIGS. 2 and 2a also shows that the
pharmaceutical dosage form according to the invention retains
mechanical integrity (weight-dimension-cohesion) for a relatively
long time (at least 4 H). The concavity of the first part of the
curve (0-4 H) is directed upward.
Example 4
[0148] Mechanical Strength in a Simulated Gastric Medium of the
Composition According to the Invention Packaged in Gelatin
Capsules
[0149] Dissolution Conditions:
[0150] Dissolution at 37.degree. C., stirring with a paddle at 100
revolutions/min, dissolution volume=1 liter.
[0151] pH=1.2: this medium is composed of 0.034 mol/l of NaCl and
0.063 mol/l of HCl with 3.2 g/l of pepsin.
[0152] pH=4.5: addition to the medium of pH=1.2 of KH.sub.2PO.sub.4
(12 g) and of 35% NaOH.
[0153] The gelatin capsules tested have the composition described
in example 2 and are prepared according to the process described
example 1.
[0154] Quantitative data are collated in table 3 below:
4TABLE 3 quantitative data for mechanical strength with L the
length of the gel cylinder, 1 the diameter of the gel cylinder and
w the weight of the gel (gel .+-. internal water). L (mm) l (mm) w
(mg) 1 h at pH = 1.2 25.7 .+-. 0.5 10.7 .+-. 0.6 1501 .+-. 68 2 h
at pH = 4.5 27.7 .+-. 1.7 12 .+-. 1.4 2478 .+-. 214 4 h at pH = 4.5
22.3 .+-. 1.7 12.3 .+-. 1.7 1737 .+-. 229
[0155] It is apparent that, after 4 h in the medium with a pH of
4.5, L and l have not substantially varied. The gels formed, based
on the pharmaceutical dosage composition according to the
invention, have retained their integrity and their dimensions.
Example 5
[0156] 1 000 mg of metformin, distributed in 7 gelatin capsules
with a size of 00 each comprising 561 mg of the pharmaceutical form
according to the present invention, were administered to 6 healthy
subjects after taking a meal. The plasma concentration of metformin
is recorded as a function of the time between 0 and 36 hours after
administration.
[0157] In this pharmaceutical form according to the invention, the
metformin granules represent a fraction by weight of 25.5%, the
coating of the granules a fraction by weight of 8.9% and, finally,
the continuous external phase a fraction by weight of 65.6%.
[0158] The compositions are as follows:
5 For the metformin granule: Metformin 100% 142.9 mg For the
coating: Ethocel 7 74% 37.1 mg Magnesium stearate 10% 5 mg Plasdone
K 29/32 8% 4 mg Castor oil 8% 4 mg For the continuous phase:
Keltone HVCR 77.6% 285.6 mg Methocel K 100M 20.0% 73.6 mg Calcium
acetate 2.4% 8.8 mg
[0159] The mean plasma concentration profile with regard to 6
healthy subjects is represented in FIG. 3. For the purposes of
comparison, the mean plasma concentration profile resulting from
the administration to 24 healthy subjects, after a meal, of a
single dose of 850 mg of the immediate release form of metformin,
Glucophage.RTM., is also displayed. These data result from the FDA
(FOI) document: NDA 20-357, Metformin hydrochloride. Lipha
Pharmaceutical Inc.
[0160] The pharmacokinetic data extracted from these profiles are
listed in table 4 below:
6TABLE 4 pharmacokinetic data Formulation according to Parameter
the invention Glucophage .RTM. dose (mg) 1000 850 Cmax (ng/ml) 600
913 T max (h) 6 4 AUC (ng.h/ml) 5233 7980 T absorption (h) 10 4
[0161] It is thus clearly apparent that the pharmaceutical form
according to the invention: spectacularly increases the
bioabsorption time, also increases the Tmax and maintains the AUC
at more than 50% of the value corresponding to an immediate release
oral form.
* * * * *