U.S. patent application number 10/522234 was filed with the patent office on 2006-12-07 for microcapsules with modified release of active principles with low solubility for oral delivery.
Invention is credited to Catherine Castan, Florence Guimberteau, Remi Meyrueix, Gerard Soula.
Application Number | 20060275376 10/522234 |
Document ID | / |
Family ID | 30011527 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060275376 |
Kind Code |
A1 |
Guimberteau; Florence ; et
al. |
December 7, 2006 |
Microcapsules with modified release of active principles with low
solubility for oral delivery
Abstract
The invention concerns microcapsules for reliably modified
release and adapted to industrial reproduction of an active
principle hardly water-soluble, other than anti-hyperglycemia
agents Each of said microcapsules comprises a core of hardly
soluble active principle and a coating film applied on the core.
Their mean diameter is less than 1000 microns. The coating film
contains a film-forming polymer (P1) insoluble in gastrointestinal
tract fluids, a water-soluble polymer (P2), a plasticizer (PL), and
optionally a lubricating surfactant (TA). Said coating film
represents at least 4% p/p of dry mraner of their total weight. and
its components P1, P2. PL satisfy the following characteristics:
dry weight mass fraction of PI relative to the total coating weight
ranging between 40 and 90%; dry matter weight fraction of PL/P1+P2
ranging between 15 and 60%: dry matter weight fraction of PL/P1+P2
ranging between 1 and 30%. The invention also concerns the uses of
said microcapsules in galenic formulation.
Inventors: |
Guimberteau; Florence;
(Montussan, FR) ; Castan; Catherine; (Orlienas,
FR) ; Meyrueix; Remi; (Lyon, FR) ; Soula;
Gerard; (Meyzieu, FR) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Family ID: |
30011527 |
Appl. No.: |
10/522234 |
Filed: |
July 28, 2003 |
PCT Filed: |
July 28, 2003 |
PCT NO: |
PCT/FR03/02384 |
371 Date: |
June 9, 2006 |
Current U.S.
Class: |
424/490 |
Current CPC
Class: |
A61K 9/5047 20130101;
A61K 9/5026 20130101; A61K 9/5015 20130101 |
Class at
Publication: |
424/490 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 9/16 20060101 A61K009/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 26, 2002 |
FR |
02/09530 |
Claims
1. A microcapsule for the modified release of at least one AP with
low water solubility, with the exclusion of blood glucose-lowering
agents, intended to be administered orally and of the type of
those: each consisting of a core comprising at least one active
principle and of a coating film applied onto the core and
controlling the modified release of the AP(s), the mean diameter of
which is less than 1000 microns, preferably between 800 and 50
microns, and even more preferably between 600 and 100 microns, in
which the coating film of each microcapsule contains the following
components: -I--at least one film-forming polymer (P1) insoluble in
gastrointestinal tract fluids, -II--at least one water-soluble
polymer (P2), -III--at least one plasticizer (PL), -IV--and,
optionally, at least one lubricating surfactant (TA); with the
exclusion of coating films consisting of enteric compositions and
of coating films having the composition below: 1--at least one
film-forming polymer (P1) insoluble in the fluids of the tract,
present in a proportion of 50 to 90, preferably 50 to 80% by weight
on a dry basis relative to the total mass of the coating
composition and consisting of at least one water-insoluble
derivative of cellulose, i.e. ethylcellulose and/or cellulose
acetate; 2--at least one nitrogenous polymer (P2) present in a
proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis
relative to the total mass of the coating composition and
consisting of at least one polyacrylamide and/or one
poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e.
polyacrylamide and/or polyvinylpyrrolidone; 3--at least one
plasticizer present in a proportion of 2 to 20, preferably 4 to 15%
by weight on a dry basis relative to the total mass of the coating
composition and consisting of at least one of the following
compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl
alcohol esters, castor oil, salicylic acid and cutin; 4--and at
least one surfactant and/or lubricant, present in a proportion of 2
to 20, preferably 4 to 15% by weight on a dry basis relative to the
total mass of the coating composition and chosen from anionic
surfactants, i.e. alkali metal salts or alkaline-earth metal salts
of fatty acids, stearic acid and/or oleic acid being preferred,
and/or from nonionic surfactants, i.e. polyoxyethylenated sorbitan
esters and/or polyoxyethylenated castor oil derivatives, and/or
from lubricants such as calcium stearate, magnesium stearate,
aluminum stearate or zinc stearate, or such as sodium stearyl
fumarate and/or glyceryl behenate; it being possible for said agent
to comprise just one or a mixture of the abovementioned products;
characterized: in that their coating film represents at least 3%
dry weight/dry weight, preferably at least 5% dry weight/dry weight
of their total mass, and in that the components P1, P2 and PL of
the coating film satisfy the following characteristics: mass
fraction by dry weight of P1 relative to the total mass of the
coating of between 40 and 90%, and preferably of between 50 and
80%; mass fraction by dry weight P2/P1+P2 of between 15 and 60%,
and preferably of between 15 and 55%; mass fraction by dry weight
PL/P1+PL of between 1 and 30%, and preferably of between 5 and
25%.
2. The microcapsule as claimed in claim 1, without the exclusion
relating to blood glucose-lowering agents and without the exclusion
relating to coating films consisting of enteric compositions and to
coating films having the composition 1, 2, 3 and 4 as defined in
claim 1.
3. The microcapsule as claimed in claim 1 or 2, characterized in
that the coating film comprises component TA in a proportion of 2
and 20%, and preferably of between 4 and 15% of the total mass of
the dry coating.
4. The microcapsule as claimed in any one of claims 1 to 3,
characterized in that P1 is selected from the group of products
below: water-insoluble derivatives of cellulose, preferably
ethylcellulose and/or cellulose acetate, acrylic derivatives,
poly(vinyl acetates), and mixtures thereof.
5. The microcapsule as claimed in any of one of claims 1 to 4,
characterized in that P2 is selected from the group of products
below: water-soluble derivatives of cellulose, polyacrylamides,
poly-N-vinylamides, poly(N-vinyl lactams), polyvinyl alcohols
(PVAs), polyoxyethylenes (POEs), polyvinylpyrrolidones (PVPs) (the
latter being preferred), and mixtures thereof.
6. The microcapsule as claimed in any one of claims 1 to 5,
characterized in that PL is selected from the group of products
below: glycerol and esters thereof, preferably from the following
subgroup: acetylated glycerides, glyceryl mono-stearate, glyceryl
triacetate, glyceryl tributyrate, phthalates, preferably from the
following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl
phthalate, dioctyl phthalate, citrates, preferably from the
following subgroup: acetyl tributyl citrate, acetyl triethyl
citrate, tributyl citrate, triethyl citrate, sebacates, preferably
from the following subgroup: diethyl sebacate, dibutyl sebacate,
adipates, azelates, benzoates, plant oils, fumarates, preferably
diethyl fumarate, malates, preferably diethyl malate, oxalates,
preferably diethyl oxalate, succinates, preferably dibutyl
succinate, butyrates, cetyl alcohol esters, salicylic acid,
triacetin, malonates, preferably diethyl malonate, cutin, castor
oil (this being particularly preferred), and mixtures thereof.
7. The microcapsule as claimed in any one of claims 1 to 6,
characterized in that TA is selected from the group of products
below: anionic surfactants, preferably from the subgroup of alkali
metal salts or alkaline-earth metal salts of fatty acids, stearic
acid and/or oleic acid being preferred, and/or nonionic
surfactants, preferably from the following subgroup:
polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated
castor oil, polyoxyethylene-polyoxypropylene copolymers,
polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil
derivatives, stearates, preferably calcium stearate, magnesium
stearate, aluminum stearate or zinc stearate, stearyl fumarates,
preferably sodium stearyl fumarate, glyceryl behenate, and mixtures
thereof.
8. The microcapsule as claimed in any one of claims 1 to 7,
characterized in that the APs with low solubility are chosen from
at least one of the major varieties of active substances below:
antiulcer agents, antidiabetic agents, anticoagulants,
antithrombics, blood lipid-lowering agents, anti-arrhythmics,
vasodilators, antiangina agents, anti-hypertensives, vasoprotective
agents, fertility promoters, inducers and inhibitors of uterine
labor, contraceptives, antibiotics, antifungal agents, anti-viral
agents, anticancer agents, anti-inflammatories, analgesics,
antiepileptics, antiparkinsonian agents, neuroleptics, hypnotics,
anxiolytics, psychostimulants, antimigraine agents,
antidepressives, antitussives, antihistamines or antiallergic
agents.
9. The microcapsule as claimed in claim 8 characterized in that the
AP(s) with low solubility is (are) chosen from the following
compounds: prazosine, acyclovir, nifedipine, naproxen, ibuprofen,
ketoprofen, fenoprofen, indomethacine, diclofenac, sulpiride,
terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine,
ganciclovir, spironolactone, acetylsalicyclic acid, quinidine,
morphine, amoxicillin, paracetamol, metoclopramide, verapamil and
mixtures thereof.
10. A medicinal product comprising the microcapsules as claimed in
any one of claims 1 to 9.
11. The medicinal product as claimed in claim 10, characterized in
that it is in solid form, preferably: tablet, gelatin capsule or
powder, or in liquid form, preferably: an aqueous suspension.
12. The use of microcapsules for the modified release of at least
one AP with low water solubility, with the exclusion of blood
glucose-lowering agents, intended to be administered orally, these
microcapsules having the following characteristics: they each
consist of a core comprising at least one active principle and of a
coating film applied onto the core and controlling the prolonged
release of the AP(s), their mean diameter is less than 1000
microns, preferably between 800 and 50 microns, and even more
preferably between 600 and 100 microns, their coating film contains
the following components: -I--at least one film-forming polymer
(P1) insoluble in gastrointestinal tract fluids, -II--at least one
water-soluble polymer (P2), -III--at least one plasticizer (PL),
IV--and, optionally, at least one lubricating surfactant (TA);
components P1, P2 and P1 of the coating film satisfying the
following characteristics: mass fraction by dry weight of P1
relative to the total mass of the coating of between 40 and 90%,
and preferably of between 50 and 80%; mass fraction by dry weight
P2/P1+P2 of between 15 and 60%, and preferably of between 15 and
55%; mass fraction by dry weight PL/P1+PL of between 1 and 30%, and
preferably of between 5 and 25%; and this coating film represents
at least 4% w/w, preferably at least 5% w/w of their total mass;
with the exclusion of coating films consisting of enteric
compositions and of coating films having the composition below:
1--at least one film-forming polymer (P1) insoluble in the fluids
of the tract, present in a proportion of 50 to 90, preferably 50 to
80% by weight on a dry basis relative to the total mass of the
coating composition and consisting of at least one water-insoluble
derivative of cellulose, i.e. ethylcellulose and/or cellulose
acetate; 2--at least one nitrogenous polymer (P2) present in a
proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis
relative to the total mass of the coating composition and
consisting of at least one polyacrylamide and/or one
poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e.
polyacrylamide and/or polyvinylpyrrolidone; 3--at least one
plasticizer present in a proportion of 2 to 20, preferably 4 to 15%
by weight on a dry basis relative to the total mass of the coating
composition and consisting of at least one of the following
compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl
alcohol esters, castor oil, salicylic acid and cutin; 4--and at
least one surfactant and/or lubricant, present in a proportion of 2
to 20, preferably 4 to 15% by weight on a dry basis relative to the
total mass of the coating composition and chosen from anionic
surfactants, i.e. alkali metal salts or alkaline-earth metal salts
of fatty acids, stearic acid and/or oleic acid being preferred,
and/or from nonionic surfactants, i.e. polyoxyethylenated sorbitan
esters and/or polyoxyethylenated castor oil derivatives, and/or
from lubricants such as calcium stearate, magnesium stearate,
aluminum stearate or zinc stearate, or such as sodium stearyl
fumarate and/or glyceryl behenate; it being possible for said agent
to comprise just one or a mixture of the abovementioned products;
for producing a medicinal product based on at least one AP with low
solubility which can be administered orally, which can be readily
swallowed, and which is released in vivo in a controlled, prolonged
and, optionally, delayed manner.
13. The use as claimed in claim 12, without the exclusion relating
to blood glucose-lowering agents and without the exclusion relating
to coating films consisting of enteric compositions and to coating
films having the composition 1, 2, 3 and 4 as defined in claim 12.
Description
[0001] The field of the present invention is that of systems with
modified release of medicinal and/or nutritional active principles
(APs), intended to be administered orally.
[0002] The present invention also relates to microcapsules intended
to be administered per os and containing at least one AP with low
solubility.
[0003] The invention also relates to the medicinal products
containing these microcapsules mentioned above and to the use of
the latter for producing medicinal products.
[0004] In the present disclosure, the expression "modified release"
denotes without distinction a release of the active principle(s)
beginning as soon as the pharmaceutical form has been brought into
contact with its dissolving medium (in vivo or in vitro) or else a
release of the active principle(s) beginning only after a
predetermined period of time ranging, for example, from 0.5 to
several hours. Thus, for the purpose of the invention, a prolonging
of the release corresponds to a release time for 50% of the active
principle(s) which is typically several hours and which can extend
from 0.25 to 20 hours, for example.
[0005] The expression "low solubility" relates to active principles
the water-solubility of which is less than 10 g/l at 25.degree.
C.
[0006] More precisely, the invention relates to pharmaceutical
formulations with prolonged release of active principles with low
solubility, this formulation consisting of a plurality of
microcapsules consisting of a core containing the active principle
of low solubility and coated with a layer of polymer which controls
the release of the AP.
[0007] Among the various modified-release systems, pharmaceutical
systems with modified release consisting of a plurality of
microcapsules of the reservoir type with an average diameter of
less than 1000 microns are particularly advantageous. In fact, in
these systems, the dose of active principle(s) to be administered
is distributed among a large number of microcapsules (typically 10
000 for a dose of 500 mg and a diameter of 400 microns) and this
type of system, as a result, has the following intrinsic
advantages: [0008] the use of a mixture of microcapsules having
different modified-release profiles makes it possible to produce
release profiles exhibiting several waves of release or providing,
by means of appropriate regulation of the various fractions, a
constant plasma concentration level of the AP; [0009] the
sensitivity to the variability of gastric emptying is lower, since
the emptying, which takes place here with respect to a large number
of particles, is statistically more reproducible; [0010] contact of
the tissues with a high dose of AP, "dose dumping", is avoided.
Each microcapsule in fact contains only a very low dose of active
principle(s). The risk of tissue deterioration through local
overconcentration of aggressive active principle(s) is thus
avoided; [0011] it is possible to combine several pharmaceutical
forms (immediate and/or delayed and/or prolonged release)
comprising one or more active principles, in these
"multimicrocapsular" systems; [0012] it does not induce any
degradation of the AP; [0013] the amount of time spent by the
microcapsules in the upper parts of the tract can be prolonged,
which ensures an increase in the amount of time spent by the active
principle(s) in passing in front of the absorption windows and thus
maximizes the bioavailability of the active principle(s).
[0014] However, when the solubility of the AP is low, the
production of a microparticulate modified-release form comes up
against a substantial difficulty.
[0015] The diffusion of the active principle through the coating
film surrounding each microcapsule takes place under the action of
the dissolved AP concentration gradient between the inside and the
outside of the microcapsule. In other words, it is the difference
in osmotic pressure of the AP between the inside and the outside of
the microcapsule which drives the release. The internal
concentration of AP is the saturation concentration. The external
concentration of AP is, for its part, negligible under usual
conditions (termed "sink"). The driving of release is therefore
directly linked to the saturation concentration of the AP, i.e. to
its solubility.
[0016] For APs with low solubility, the saturation concentration of
AP is relatively low and the diffusion of the AP to the outside is
therefore, a priori, very slow, even for coating films that are not
very thick.
[0017] Furthermore, in any case, for thin coating films, the
following difficulties are then encountered: [0018] (a) The
depositing of a very thin coating film is not even: there are gaps
next to areas that are too thick, and the release of the AP is not
prolonged. [0019] (b) The industrial control of the process for a
very thin deposit becomes very difficult and relatively
unreproducible.
[0020] Moreover, for thicker coating films, the release of the AP
is extremely slow, or even nonexistent.
[0021] This technical problem is all the more difficult to solve in
that it must not be down to the detriment of the other
specifications required for a pharmaceutical system for oral
administration of AP, which are, inter alia, cumulatively and for a
wide range of APs, as follows: [0022] slow transit in the upper
parts of the gastrointestinal tract, reflected by an in vivo
absorption profile which is over a period of time notably longer
than that permitted by the natural transit (3 h.+-.1), [0023]
absence of irritation of the mucosa, [0024] limited mass of the
pharmaceutical form corresponding to a dose, [0025] low cost
price.
[0026] The difficulty in modifying the release of an AP with low
solubility explains the small number of technical solutions which
have been proposed to date.
[0027] As regards the solid, multimicrocapsular pharmaceutical
systems, those consisting of a multiplicity of particles or
microcapsules each carrying active principle(s) coated with a
film-coating layer based on ethylcellulose, on
polyvinylpyrrolidone, on magnesium stearate and on castor oil, for
example, are known. Such a pharmaceutical system is disclosed in
PCT application WO 96/11675. These microcapsule reservoirs obtain
an advantage from their multiplicity, which is a more even and
reproducible gastric emptying time. In addition, their size is
between 50 and 1000 .mu.m and also the characteristics of their
coating make it possible to increase their transit time in the
upper parts of the gastrointestinal tract and, consequently, to
maintain absorption of the active principle(s) for all or part of
this time spent in the small intestine.
[0028] However, the multimicrocapsular pharmaceutical system
according to WO 96/11675 is perfectable as regards APs with low
solubility that can be administered orally, since it does not
propose any solution to the problem of the diffusion of such an AP
with low solubility through a coating film of sufficiently large
thickness, for example of several microns.
[0029] In the field of microcapsules with modified release of blood
glucose-lowering active principles, mention should be made of
French patent application FR-A-2 816 840 which discloses
microcapsules in which the core consists of metformin crystals
coated with a membrane for controlling the release of the
metformin, comprising stearic acid (50%) or castor oil (10%) and
ethylcellulose (respectively 50 and 90%). This pharmaceutical
system, for the oral administration of blood glucose-lowering
active principles, should make it possible to obtain an effective
therapeutic coverage over 24 hours by overcoming the problems of
by-pass of the absorption window and of massive localized release
of active principle. This technical problem remains perfectible,
insofar as it does not solve the problem of the low-solubility APs
mentioned above.
[0030] As regards the prior art on microcapsules with modified
release of active principles with low solubility, mention should
first of all be made of PCT patent application WO 99/49846 which
describes a pharmaceutical preparation composed of submicronic
(0.05 to 10 .mu.m) particles combining an active principle with low
solubility with a phospholipid compound, a surface charge-modifying
compound and a block polymer. The aim of this preparation is to
improve the bioavailability and the stability of the active
principle and it finds its applications in injectable forms or
alternatively in forms intended to be administered ocularly or
nasally. A prolonged-release form is only obtained in the case of
intramuscular injection.
[0031] PCT patent application WO 00/18374 describes an invention of
the same type as the previous one: the active principle in the form
of submicronic (<1000 nm) particles is stabilized by a compound
associated at the surface of the particles and mixed with a
polymer. This mixture can then be formulated into granules or
pellets and, optionally, into tablets. The active principle is
rapidly dissolved and it is the increase in bioavailability
obtained by virtue of the decrease in size which makes it possible
to have an effective plasma concentration over a prolonged
period.
[0032] Patent application GB-2 202 143 describes spheroids of
diameter greater than 0.5 mm, and preferably greater than 0.8 mm,
containing the poorly soluble active principle dispersed in 70 to
99.5% of microcrystalline cellulose. This matricial form requires
no coating controlling the release of the active principle.
[0033] Patent application JP-8073345 describes a controlled-release
system composed of a film-coated granule. The granule contains an
active principle with low solubility at neutral pH and inorganic
acids. This system therefore proposes a solution that is only
suitable for the case of basic active principles with low
solubility.
[0034] Finally, European patent EP-B-0 249 587 concerns a solid
preparation for the slow release of an active substance with low
solubility (<0.1% by weight). This controlled-release
preparation can be provided in the form of gelatin capsules
comprising capsules consisting of coated granules. The granules
comprise the active principle with low solubility and a
solubilizing agent consisting of the commercial product
Cremophor.RTM. RH 40 (polyoxyethylenated hydrogenated castor oil:
40 ethylene oxide units), and also other additives such as
polyvinylpyrrolidone, cellulose, starch and lactose. These granules
of size of between 700 and 1120 .mu.m are covered with an
ethylcellulose coating layer for controlling release. The
ingredients of the granules, namely polyvinylpyrrolidone,
cellulose, cornstarch and lactose, appear to be the elements of the
hydrophilic gel system specific to the pharmaceutical form
according to EP-B-0 249 587. These capsules therefore comprise a
single constituent (ethylcellulose) in their coating layer, which
limits its capacities in terms of modification of the release of
the active principle. In particular, it is doubtful whether a
coating layer composed only of ethylcellulose (known to form
impermeable films) would allow the release of an AP with low
solubility in a controlled and industrially reproducible manner
over a period of several hours, for example.
[0035] None of these patent applications describes microparticles
of the reservoir type or microcapsules for which the prolonged
release of the active principle with low solubility is controlled
by means of its diffusion through a membrane that is sufficiently
thick to ensure a controlled and industrially reproducible
permeability. Neither do they teach the manner in which such a
system can be successfully achieved.
[0036] In the face of this vacuity of the prior art, one of the
essential objectives of the present invention is to propose a form
with modified release of AP(s) with low solubility consisting of a
plurality of microcapsules, each formed by a core containing the AP
and coated with a coating film.
[0037] Another objective of the present invention is to provide a
plurality of reservoir-type microcapsules of AP of low solubility,
for oral administration of the latter, the coating film of these
microcapsules being sufficiently thick to ensure a controlled and
industrially reproducible permeability.
[0038] Another essential objective of the present invention is to
provide a plurality of microcapsules of AP(s) with low solubility,
less than 1000 .mu.m in size.
[0039] Another objective of the present invention is to propose an
oral pharmaceutical form consisting of a large number (for example
of the order of several thousand) of microcapsules, this
multiplicity ensuring, statistically, good reproducibility of the
kinetics of transit of the AP in the entire gastrointestinal tract,
such that better control of the bioavailability and therefore
better effectiveness result therefrom.
[0040] Another essential objective of the present invention is to
provide a plurality of microcapsules of AP(s) with low solubility,
for oral administration of the latter according to a prolonged
and/or optionally delayed release profile, such that the
half-release time, t.sub.1/2, is between 0.25 and 20 hours.
[0041] Another essential objective of the present invention is to
provide an oral form with modified release in which the AP(s) is
(are) in the form of a plurality of particles individually coated
to form microcapsules, and in which it is possible to mix several
active principles in multimicrocapsular form, that are released
according to different respective release times.
[0042] Having set themselves all the above objectives among others,
the inventors have, to their credit, developed a multimicrocapsular
pharmaceutical system with prolonged release of AP(s) with low
solubility, by oral administration, which, besides the properties
targeted in the aims above, has, cumulatively and for a wide range
of APs, the following specifications, inter alia: [0043] absence of
irritation of the mucosa, [0044] high AP content, [0045] low cost
price, [0046] which makes it possible to adjust the AP half-release
time to between 0.25 and 20 hours, [0047] which is reproducible and
easy to implement industrially by virtue of a ratio of the mass of
the coating film to the mass of the particle of greater than 3% dry
weight/dry weight, preferably greater than 5% dry weight/dry
weight, and even more preferably of between 3 and 40% dry
weight/dry weight.
[0048] To do this, the inventors have, to their credit, discovered,
after many trials, microcapsules with a particular structure which
make it possible to satisfy the objectives recalled above, among
others.
[0049] To this end, a subject of the present invention is a
pharmaceutical system made up of microcapsules for the modified
release of at least one AP with low water solubility, with the
possible exclusion of blood glucose-lowering agents, intended to be
administered orally and of the type of those: [0050] a each
consisting of a core comprising at least one active principle and
of a coating film applied onto the core and controlling the
prolonged release of the AP(s), [0051] the mean diameter of which
is less than 1000 microns, preferably between 800 and 50 microns,
and even more preferably between 600 and 100 microns, [0052] in
which the coating film of each microcapsule contains the following
components: [0053] -I--at least one film-forming polymer (P1)
insoluble in gastrointestinal tract fluids, [0054] -II--at least
one water-soluble polymer (P2), [0055] -III--at least one
plasticizer (PL), [0056] -IV--and, optionally, at least one
lubricating surfactant (TA); [0057] with the possible exclusion of
coating films consisting of enteric compositions and of coating
films having the composition below: [0058] 1--at least one
film-forming polymer (P1) insoluble in the fluids of the tract,
present in a proportion of 50 to 90, preferably 50 to 80. by weight
on a dry basis relative to the total mass of the coating
composition and consisting of at least one water-insoluble
derivative of cellulose, i.e. ethylcellulose and/or cellulose
acetate; [0059] 2--at least one nitrogenous polymer (P2) present in
a proportion of 2 to 25, preferably 5 to 15% by weight on a dry
basis relative to the total mass of the coating composition and
consisting of at least one polyacrylamide and/or one
poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e.
polyacrylamide and/or polyvinylpyrrolidone; [0060] 3--at least one
plasticizer present in a proportion of 2 to 20, preferably 4 to 15o
by weight on a dry basis relative to the total mass of the coating
composition and consisting of at least one of the following
compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl
alcohol esters, castor oil, salicylic acid and cutin; [0061] 4--and
at least one surfactant and/or lubricant, present in a proportion
of 2 to 20, preferably 4 to 15% by weight on a dry basis relative
to the total mass of the coating composition and chosen from
anionic surfactants, i.e. alkali metal salts or alkaline-earth
metal salts of fatty acids, stearic acid and/or oleic acid being
preferred, and/or from nonionic surfactants, i.e.
polyoxyethylenated sorbitan esters and/or polyoxyethylenated castor
oil derivatives, and/or from lubricants such as calcium stearate,
magnesium stearate, aluminum stearate or zinc stearate, or such as
sodium stearyl fumarate and/or glyceryl behenate; it being possible
for said agent to comprise just one or a mixture of the
abovementioned products; characterized: [0062] in that their
coating film represents at least 3% dry weight/dry weight,
preferably at least 5% dry weight/dry weight of their total mass,
[0063] and in that the components P1, P2 and PL of the coating film
satisfy the following characteristics: [0064] mass fraction by dry
weight of P1 relative to the total mass of the coating of between
40 and 90%, and preferably of between 50 and 80%; [0065] mass
fraction by dry weight P2/P1+P2 of between 15 and 60%, and
preferably of between 15 and 55%; [0066] mass fraction by dry
weight PL/P1+PL of between 1 and 30%, and preferably of between 5
and 25%.
[0067] To the applicant's credit, it has developed, entirely
surprisingly and unexpectedly, such a pharmaceutical system that
allows diffusion of the AP with low solubility through a
sufficiently thick coating film for the microcapsules, and without
putting a strain on the cost price.
[0068] The choice of an amount of coating greater than or equal to
3% by weight on a dry basis relative to the total mass of the
microcapsule is a particularly inventive provision which goes
against the technical opinion commonly held in this field.
[0069] The same is true as regards the quantitative data for P1, P2
and PL.
[0070] According to a particularly preferred embodiment of the
invention, the coating film represents 3 to 40% w/w on a dry basis
of the total mass of the microcapsules.
[0071] Preferably, P1 is selected from the group of products below:
[0072] water-insoluble derivatives of cellulose, preferably
ethylcellulose and/or cellulose acetate, [0073] acrylic
derivatives, [0074] poly(vinyl acetates), [0075] and mixtures
thereof.
[0076] Preferably, P2 is selected from the group of products
below:
[0077] water-soluble derivatives of cellulose, [0078]
polyacrylamides, [0079] poly-N-vinylamides, [0080] poly(N-vinyl
lactams), [0081] polyvinyl alcohols (PVAs), [0082] polyoxyethylenes
(POEs), [0083] polyvinylpyrrolidones (PVPs) (the latter being
preferred), [0084] and mixtures thereof.
[0085] Preferably, PL is selected from the group of products below:
[0086] glycerol and esters thereof, preferably from the following
subgroup: [0087] acetylated glycerides, glyceryl mono-stearate,
glyceryl triacetate, glyceryl tributyrate, [0088] phthalates,
preferably from the following subgroup: [0089] dibutyl phthalate,
diethyl phthalate, dimethyl phthalate, dioctyl phthalate, [0090]
citrates, preferably from the following subgroup: [0091] acetyl
tributyl citrate, acetyl triethyl citrate, tributyl citrate,
triethyl citrate, [0092] sebacates, preferably from the following
subgroup: [0093] diethyl sebacate, dibutyl sebacate, [0094]
adipates, [0095] azelates, [0096] benzoates, [0097] plant oils,
[0098] fumarates, preferably diethyl fumarate, [0099] malates,
preferably diethyl malate, [0100] oxalates, preferably diethyl
oxalate, [0101] succinates, preferably dibutyl succinate, [0102]
butyrates, [0103] cetyl alcohol esters, [0104] salicylic acid,
[0105] triacetin, [0106] malonates, preferably diethyl malonate,
[0107] cutin, [0108] castor oil (this being particularly
preferred), [0109] and mixtures thereof.
[0110] According to an advantageous variant, the coating film
comprises component TA in a proportion of 2 and 20%, and preferably
of between 4 and 15% of the total mass of the dry coating.
[0111] Preferably, TA is selected from the group of products below:
[0112] anionic surfactants, preferably from the subgroup of alkali
metal salts or alkaline-earth metal salts of fatty acids, stearic
acid and/or oleic acid being preferred, [0113] and/or nonionic
surfactants, preferably from the following subgroup: [0114]
polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated
castor oil, [0115] polyoxyethylene-polyoxypropylene copolymers,
[0116] polyoxyethylenated sorbitan esters, [0117]
polyoxyethylenated castor oil derivatives, [0118] stearates,
preferably calcium stearate, magnesium stearate, aluminum stearate
or zinc stearate, [0119] stearyl fumarates, preferably sodium
stearyl fumarate, [0120] glyceryl behenate, [0121] and mixtures
thereof.
[0122] Advantageously, the microcapsules are designed so as to be
able to spend at least approximately 5 hours, preferably at least
approximately 8 hours, in the upper parts of the gastrointestinal
tract, and thus allow absorption of the AP for a prolonged period
of time.
[0123] According to a particular embodiment of the microcapsules
containing APs with low solubility according to the invention, and
according to another quantitative mode of expression, the coating
film comprises from 35 to 75% of ethylcellulose P1, from 20 to 50%
of polyvinylpyrrolidone P2, from 5 to 15% of PL.
[0124] This preparation according to the invention makes it
possible to produce a multimicrocapsular form with modified release
of APs with low solubility, it being possible for the AP
half-release time to be adjusted to between 0.25 and 20 hours in a
reproducible manner through the use of a coating film, that can be
described as a diffusion coating film, which is sufficiently
thick.
[0125] Moreover, for APs with low solubility for which the
absorption window is limited, such a plurality of microcapsules
(typically 10 000 for a dose of 500 mg and a mean diameter of 400
microns) has the following intrinsic advantages: [0126] The use of
a mixture of microcapsules having different delayed- and
controlled-release profiles makes it possible to produce release
profiles exhibiting several waves of release or providing, by means
of adequate regulation of the various fractions, a constant plasma
concentration level of the AP. [0127] The variability of gastric
emptying is lower, since the emptying, which takes place here with
respect to a large number of particles, is statistically more
reproducible. [0128] Contact of the tissues with a high dose of AP,
"dose dumping", is avoided. Each microcapsule in fact contains only
a very low dose of AP. The risk of tissue deterioration through a
local overconcentration of aggressive AP is thus avoided. [0129]
The amount of time spent by the microcapsules in the upper parts of
the tract can be prolonged, which ensures an increase in the amount
of time spent by the AP in passing in front of the absorption
windows and thus maximizes the bioavailability of the AP.
[0130] The APs with low solubility used for preparing the
modified-release, preferably controlled-release, microcapsules
according to the invention can be chosen from at least one of the
major varieties of active substances below: antiulcer agents,
antidiabetic agents, anticoagulants, antithrombics, blood
lipid-lowering agents, anti-arrhythmics, vasodilators, antiangina
agents, anti-hypertensives, vasoprotective agents, fertility
promoters, inducers and inhibitors of uterine labor,
contraceptives, antibiotics, antifungal agents, anti-viral agents,
anticancer agents, anti-inflammatories, analgesics, antiepileptics,
antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics,
psychostimulants, antimigraine agents, antidepressives,
antitussives, antihistamines or antiallergic agents.
[0131] Preferably, the AP(s) is (are) chosen from the following
compounds: prazosine, acyclovir, nifedipine, naproxen, ibuprofen,
ketoprofen, fenoprofen, indomethacine, diclofenac, sulpiride,
terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine,
ganciclovir, spironolactone, acetylsalicyclic acid, quinidine,
morphine, amoxicillin, paracetamol, metoclopramide, verapamil and
mixtures thereof.
[0132] According to one variant, the AP consists of at least one
nutritional and/or dietetic supplement, preferably chosen from
vitamins, amino acids, trace elements, antioxidants and mixtures
thereof.
[0133] As regards the preparation of the microcapsules according to
the invention, this goes back to micro-encapsulation techniques
accessible to those skilled in the art, the principles of which are
summarized in the article by C. Duverney and J. P. Benoit in
"L'actualitechimique" [Current use in chemistry], December 1986.
More precisely, the technique under consideration is
microencapsulation by film-coating, resulting in individualized
"reservoir" systems as opposed to matricial systems.
[0134] For further details, reference will be made to patent EP-B-0
953 359.
[0135] The AP particles of desired mean particle size necessary for
preparing the microcapsules according to the invention may be
crystals of pure AP and/or AP that has undergone a pretreatment by
one of the conventional techniques in the field, such as for
example granulation, in the presence of at least one conventional
binding agent and/or of an agent for modifying the intrinsic
solubility characteristics of the AP.
[0136] The present invention is also directed toward a medicinal
product comprising the microcapsules as defined above.
[0137] This medicinal product may be in solid form: tablet, gelatin
capsule, powder, etc, or a in liquid form, for example an aqueous
suspension.
[0138] In accordance with the invention, it is also proposed, as a
solution to the problems mentioned at the beginning of the present
disclosure, namely: modified, preferably prolonged, release of APs
with low solubility, in a pharmaceutical form that can be readily
swallowed, all this in a perspective of long, effective and safe
therapeutic coverage, to use a plurality of microcapsules for the
modified release of at least one AP with low water solubility, with
the possible exclusion of blood glucose-lowering agents, intended
to be administered orally, these microcapsules having these
following characteristics: [0139] they each consist of a core
comprising at least one active principle and of a coating film
applied onto the core and controlling the prolonged release of the
AP(s), [0140] their mean diameter is less than 1000 microns,
preferably between 800 and 50 microns, and even more preferably
between 600 and 100 microns, [0141] their coating film contains the
following components: [0142] -I--at least one film-forming polymer
(P1) insoluble in gastrointestinal tract fluids, [0143] -II--at
least one water-soluble polymer (P2), [0144] -III--at least one
plasticizer (PL), [0145] -IV--and, optionally, at least one
lubricating surfactant (TA); [0146] components P1, P2 and PL of the
coating film satisfying the following characteristics: [0147] mass
fraction by dry weight of P1 relative to the total mass of the
coating of between 40 and 90%, preferably of between 50 and 80%;
[0148] mass fraction by dry weight of P2/P1+P2 of between 15 and
60%, and preferably of between 15 and 55%; [0149] mass fraction by
dry weight PL/P1+PL of between 1 and 30%, and preferably of between
5 and 25%, [0150] and this coating film represents at least 3% dry
weight/dry weight, preferably at least 5% dry weight/dry weight of
their total mass; [0151] with the possible exclusion of coating
films consisting of enteric compositions and of coating films
having the composition below: [0152] 1--at least one film-forming
polymer (P1) insoluble in the fluids of the tract, present in a
proportion of 50 to 90, preferably 50 to 80% by weight on a dry
basis relative to the total mass of the coating composition and
consisting of at least one water-insoluble derivative of cellulose,
i.e. ethylcellulose and/or cellulose acetate; [0153] 2--at least
one nitrogenous polymer (P2) present in a proportion of 2 to 25,
preferably 5 to 15% by weight on a dry basis relative to the total
mass of the coating composition and consisting of at least one
polyacrylamide and/or one poly-N-vinyl-amide and/or one poly
(N-vinyl lactam), i.e. polyacrylamide and/or polyvinylpyrrolidone;
[0154] 3--at least one plasticizer present in a proportion of 2 to
20, preferably 4 to 159 by weight on a dry basis relative to the
total mass of the coating composition and consisting of at least
one of the following compounds: glyceryl esters, phthalates,
citrates, sebacates, cetyl alcohol esters, castor oil, salicylic
acid and cutin; [0155] 4--and at least one surfactant and/or
lubricant, present in a proportion of 2 to 20, preferably 4 to 15%
by weight on a dry basis relative to the total mass of the coating
composition and chosen from anionic surfactants, i.e. alkali metal
salts or alkaline-earth metal salts of fatty acids, stearic acid
and/or oleic acid being preferred, and/or from nonionic
surfactants, i.e. polyoxyethylenated sorbitan esters and/or
polyoxyethylenated castor oil derivatives, and/or from lubricants
such as calcium stearate, magnesium stearate, aluminum stearate or
zinc stearate, or such as sodium stearyl fumarate and/or glyceryl
behenate; it being possible for said agent to comprise just one or
a mixture of the abovementioned products; [0156] for producing a
medicinal product based on at least one AP with low solubility
which can be administered orally, which can be readily swallowed,
and which is released in vivo in a controlled, prolonged and,
optionally, delayed manner.
[0157] According to yet another of its objects, the present
invention relates to a method of therapeutic treatment, in which
use is made of a medicinal product as defined above as a product
per se or as a product obtained by means of the method described
above.
[0158] The invention will be understood more fully, in terms of its
composition and the properties and obtaining thereof, on reading
the examples below, given only by way of illustration and making it
possible to highlight the variants of implementation and the
advantages of the invention.
DESCRIPTION OF THE FIGURES
[0159] FIG. 1 represents the curve of the percentage dissolution (%
D) of the active principle AP, as a function of the time (t) in
hours (H), of the microcapsules of example 1, in the dissolving
test described in the following examples.
[0160] FIG. 2 represents the curve of the percentage dissolution (%
D) of the active principle AP, as a function of the time (t) in
hours (H), of the microcapsules of example 2, in the dissolving
test described in the following examples.
EXAMPLES
Example 1
Preparation of Acyclovir Microcapsules:
[0161] Step 1: Granule
[0162] 970 g of Acyclovir and 30 g of Povidone (Plasdone.RTM.
K29/32) are dry-mixed beforehand in the tank of a high-shear
granulator (Lodige.RTM. M5MRK) for 5 minutes. This pulverulent
mixture is then granulated with water (200 g). The granules are
dried at 40.degree. C. in a ventilated oven, and then sized on a
500 .mu.m screen. The 200-500 .mu.m fraction is selected by
sieving.
[0163] Step 2: Coating
[0164] 700 g of granules obtained above are coated, in a Glatt.RTM.
GPCG1 fluidized airbed device, with 50.65 g of ethylcellulose
(Ethocel.RTM. 7 Premium), 50.65 g of Povidone (Plasdone.RTM.
K29/32), 12.35 g of magnesium stearate and 9.88 g of castor oil
dissolved in an acetone/isopropanol (60/40 m/m) mixture.
TABLE-US-00001 Microcapsule composition: Production Ingredients %
by mass formula (in g) Acyclovir granules 85.0 700.0 L Plasdone
.RTM. K29/32 (2.55) Acyclovir (82.45) Coating 15.0 123.5 Ethocel
.RTM. 7 Premium (6.15) Plasdone .RTM. K29/32 (6.15) magnesium
stearate (1.50) castor oil (1.20)
Test:
[0165] The kinetics of release of the Acyclovir are determined by
means of a dissolving test (type II device according to the
European pharmacopoeia, 3rd edition, phosphate buffer medium, pH
6.8, volume 900 ml, temperature 37.degree. C., 100 rpm paddle
agitation, UV detection at 268 nm).
Result:
[0166] The attached FIG. 1 shows the dissolution profile obtained
by means of these microcapsules.
[0167] The microcapsule composition described above makes it
possible to obtain a dissolution profile characterized by 80% of
Acyclovir released at 3 hours.
Example 2
Preparation of Amoxicillin Microcapsules:
[0168] Step 1: Granule
[0169] 970 g of amoxicillin trihydrate and 30 g of Povidone
(Plasdone.RTM. K29/32) are dry-mixed beforehand in the tank of a
high-shear granulator (Lodige.RTM. M5MRK) for 5 minutes. This
pulverulent mixture is then granulated with water (200 g). The
granules are dried at 40.degree. C. in a ventilated oven and then
sized on a 500 .mu.m screen. The 200-500 .mu.m fraction is selected
by sieving.
[0170] Step 2: Coating
[0171] 700 g of granules obtained above are coated, in a Glatt.RTM.
GPCG1 fluidized airbed device, with g of ethylcellulose
(Ethocel.RTM. 7 Premium), g of Povidone (Plasdone.RTM. K29/32) and
0.96 g of castor oil dissolved in an acetone/isopropanol (60/40
m/m) mixture. TABLE-US-00002 Microcapsule composition Production
Ingredients % by mass formula (in g) Amoxicillin granules 82.0
700.0 Plasdone .RTM. K29/32 (0.45) Amoxicillin trihydrate (14.55)
Coating 18.0 153.6 Ethocel .RTM. 7 Premium (12.60) Plasdone .RTM.
K29/32 (4.14) Castor oil (1.20)
Test:
[0172] The kinetics of release of the amoxicillin are determined by
means of a dissolving test (type II device according to the
European pharmacopoeia, 3rd edition, phosphate buffer medium, pH
6.8, volume 900 ml, temperature 37.degree. C., 100 rpm paddle
agitation, UV detection at 240 nm).
Result:
[0173] The attached FIG. 2 shows the dissolution profile obtained
for these microcapsules.
[0174] The microcapsule composition described above makes it
possible to obtain a dissolution profile characterized by 80% of
amoxicillin released at 4 hours.
* * * * *