U.S. patent application number 09/775782 was filed with the patent office on 2001-06-21 for composition with sustained release of active principle, capable of forming a microemulsion.
Invention is credited to Barthelemy, Philippe, Benameur, Hassan.
Application Number | 20010004459 09/775782 |
Document ID | / |
Family ID | 9529608 |
Filed Date | 2001-06-21 |
United States Patent
Application |
20010004459 |
Kind Code |
A1 |
Barthelemy, Philippe ; et
al. |
June 21, 2001 |
Composition with sustained release of active principle, capable of
forming a microemulsion
Abstract
The invention concerns a composition comprising a microemulsion
forming system by contact with a hydrophilic phase brought, after
ingestion, by the physiological fluid, said microemulsion forming
system comprising: at least an active principle; a lipophilic
phase; a surfactant (TA); a co-surfactant (CoTA) . The invention is
characterized in that said composition further comprises an inert
polymeric matrix which cannot be ionised at physiological pH,
dispersed in the microemulsion forming system before ingestion,
said polymeric matrix being capable, after ingestion, of forming on
contacting the physiological fluid, a gelled polymeric matrix
enabling to release by diffusion, in continuous and prolonged
manner the already microemulsified active principle.
Inventors: |
Barthelemy, Philippe;
(Mions, FR) ; Benameur, Hassan; (Genas-Azieu,
FR) |
Correspondence
Address: |
HESLIN & ROTHENBERG, PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
|
Family ID: |
9529608 |
Appl. No.: |
09/775782 |
Filed: |
February 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09775782 |
Feb 2, 2001 |
|
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PCT/FR99/10889 |
Jul 30, 1999 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61K 9/4858 20130101; A61K 9/4866 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 7, 1998 |
FR |
98.10313 |
Claims
1. Composition intended to be ingested, comprising a system which
is self-microemulsifying on contact with a hydrophilic phase
provided, after ingestion, by the physiological fluid, the said
self-microemulsifying system comprising: at least one active agent,
a lipophilic phase consisting of a mixture of mono-, di- and
triglycerides and of C.sub.8-C.sub.18 fatty acids and of
polyethylene glycol monoesters and diesters with a
hydrophilic/lipophilic balance (HLB) of less than 16; a
glyceride-based surfactant (SA) with an HLB of less than 16, chosen
from the group comprising saturated C.sub.8-C.sub.10
polyglycosylated glycerides and oleic esters of polyglycerol; a
co-surfactant (CoSA) chosen from the group comprising fatty acid
esters of propylene glycol, oleic esters of polyglycerol, and ethyl
diglycol; the SA-CoSA ratio being between 0.5 and 6; characterized
in that the said composition also comprises an inert polymer
matrix, representing from 0.5% to 40% relative to the weight of the
total composition, which is not ionizable at physiological pH,
dispersed in the self-microemulsifying system before ingestion, the
said polymer matrix being capable, after ingestion, of forming, in
contact with physiological fluid, a gelled polymer matrix making it
possible to release the thus microemulsified active agent in a
continuous and sustained manner by diffusion.
2. Composition according to claim 1, characterized in that the
co-surfactant is chosen from the group comprising lauric esters of
propylene glycol, capric esters of propylene glycol and palmitic
esters of propylene glycol.
3. Composition according to either of the preceding claims,
characterized in that the polymer matrix is chosen from the group
comprising cellulose polymers.
4. Composition according to claim 3, characterized in that the
molecular weight of the polymer matrix is less than one
million.
5. Composition according to claim 4, characterized in that the
molecular weight of the polymer matrix is between 80,000 and
800,000.
6. Composition according to one of claims 2 to 5, characterized in
that the polymer matrix is hydrophilic and chosen from the group
comprising hydroxypropylcellulose, hydroxypropylmethylcellulose and
methylcellulose, alone or as a mixture.
7. Composition according to one of claims 2 to 5, characterized in
that the polymer matrix is hydrophobic and consists of
ethylcellulose.
8. Composition according to either of claims 1 and 2, characterized
in that the polymer matrix is chosen from the group comprising
acrylic polymers which are capable of swelling on contact with an
aqueous phase.
9. Composition according to either of claims 1 and 2, characterized
in that the polymer matrix is chosen from the group comprising
non-cellulose polysaccharides.
10. Composition according to claim 9, characterized in that the
inert polymer matrix represents from 5% to 25% relative to the
weight of the total composition.
11. Process for manufacturing the composition which is the subject
of claims 1 to 10, in which: a self-microemulsifying system is
first prepared by mixing, if necessary while heating, with
stirring, the active agent, a lipophilic phase, a surfactant and a
co-surfactant; the polymer matrix in powder form is then gradually
dispersed, while still stirring, in the said self-microemulsifying
system.
12. Gel capsule incorporating the composition which is the subject
of one of claims 1 to 10.
Description
[0001] The invention relates to a composition with sustained
release of active principle which can be administered orally in
particular, for pharmaceutical or cosmetic use, which is capable of
forming a microemulsion with an external hydrophilic phase, for
example physiological fluid or water, while at the same time
gradually releasing the active agent it contains in situ. The
invention also relates to the process for manufacturing the said
composition.
[0002] As is known, a microemulsion is a homogeneous, fluid, stable
solution consisting of four major constituents, a hydrophilic
phase, a lipophilic phase, at least one surfactant (SA) and at
least one co-surfactant, respectively. Microemulsions are
distinguished from emulsions and micellar solutions in particular
by the size of the droplets of which they are formed. Specifically,
the droplet size of a microemulsion is between 10 and 200
nanometers (nm) whereas it is less than 10 nm for a micellar
solution and greater than 200 nm for an emulsion. Moreover, in
contrast with emulsions, which are unstable, microemulsions, which
necessarily comprise a co-surfactant, are stable. Furthermore, a
microemulsion is characterized by its more or less pronounced
transparency due-to the proportion of reflected light transmitted
by a light beam, the intensity of the light beam which is passed
through being less than that of the incident beam. Since the
reflected light is richer in blue and violet radiation, finely
dispersed microemulsions have a bluish appearance. This is the
so-called Tyndall effect described in particular in the book
"Emulsions, micro-mulsions, mulsions multiples [Emulsions,
microemulsions and multiple emulsions]" by Jean Por.
[0003] In document EP-A-0 670 715, the Applicant disclosed a
composition formed of a vector system of self-microemulsifiable
active agent known by the expression SMEDDS.TM., a trademark
registered by the Applicant, meaning Self Micro Emulsifying Drug
Delivery System. These systems are disclosed at length in the
abovementioned document and essentially comprise:
[0004] an active agent,
[0005] a lipophilic phase consisting of a mixture of mono-, di- and
triglycerides and of C.sub.8-C.sub.18 fatty acids and of
polyethylene glycol monoesters and diesters with a
hydrophilic/lipophilic balance (HLB) of less than 16;
[0006] a glyceride-based surfactant (SA) with an HLB of less than
16, chosen from the group comprising saturated C.sub.8-C.sub.10
polyglycosylated glycerides and oleic esters of polyglycerol;
[0007] a co-surfactant (CoSA) chosen from the group comprising
lauric esters of propylene glycol, oleic esters of polyglycerol,
ethyl diglycol and polyethylene glycol;
[0008] the SA-CoSA ratio being between 0.5 and 6.
[0009] Certain products sold by the Applicant, consisting of
saturated and/or unsaturated fatty acids and of esters of these
fatty acids, may be used as lipophilic phase, surfactant and
co-surfactant, such as, for example, the combination of Gelucire
44/14, Labrafac CM10 and Lauroglycol, respectively, disclosed in
Examples 1 and 2 of the abovementioned document.
[0010] The SMEDDS.TM.s may be in solid or liquid form at room
temperature, depending on the actual nature of the fatty substances
of which they are composed. Thus, if at least one of the fatty
substances constituting the SMEDDS has a melting point which is
greater than room temperature (about 25.degree. C.), then the
SMEDDS.TM. will be semi-solid at room temperature. On the other
hand, if at least one fatty substance constituting the SMEDDS.TM.
has a melting point of less than about 25.degree. C., then the
SMEDDS.TM. is liquid at room temperature.
[0011] Consequently, the SMEDDS.TM.s may be incorporated into gel
capsules in liquid form, optionally while warm, and then, depending
on the nature of their constituents, remain liquid or become
semi-solid at room temperature.
[0012] Due to the formation of the microemulsion in situ,
SMEDDS.TM.s make it possible to dissolve the active principle and
consequently to increase the bioavailability of the microemulsified
active agent(s) they convey. However, the formation of the
microemulsion gives the composition properties of immediate release
of microemulsified active agent.
[0013] In other words, the problem which the invention proposes to
solve is that of providing a composition of the SMEDDS.TM. type
which is capable of gradually releasing the active agent(s) it
conveys, and of doing so whatever the consistency, solid or liquid,
of the SMEDDS.TM. at room temperature.
[0014] To solve this problem, the invention proposes a composition
with sustained release of the active principle, for pharmaceutical
or cosmetic use, which is intended to be ingested, comprising a
system which is self-microemulsifying on contact with a hydrophilic
phase provided, after ingestion, by the physiological fluid, the
said self-microemulsifying system comprising:
[0015] at least one active agent,
[0016] a lipophilic phase consisting of a mixture of mono-, di- and
triglycerides and of C.sub.8-C.sub.18 fatty acids and of
polyethylene glycol monoesters and diesters with a
hydrophilic/lipophilic balance (HLB) of less than 16;
[0017] a glyceride-based surfactant (SA) with an HLB of less than
16, chosen from the group comprising saturated C.sub.8-C.sub.10
polyglycosylated glycerides and oleic esters of polyglycerol;
[0018] a co-surfactant (CoSA) chosen from the group comprising
fatty acid esters of propylene glycol, oleic esters of
polyglycerol, ethyldiglycol and polyethylene glycol;
[0019] the SA-CoSA ratio being between 0.5 and 6.
[0020] The composition of the invention is characterized in that it
also comprises an inert polymer matrix which is not ionizable at
physiological pH, dispersed in the self-microemulsifying system
before ingestion, the said polymer matrix being capable, after
ingestion, of forming, in contact with physiological fluid, a
gelled polymer matrix making it possible to release the thus
microemulsified active agent in a continuous and sustained manner
by diffusion.
[0021] In the description hereinbelow and in the claims, the
expression "microemulsified active agent" denotes the active agent
dissolved in the microemulsion, i.e. in its hydrophobic zone.
[0022] Similarly, the expression "physiological fluid" denotes the
physiological medium in vivo, as is found after ingestion of the
composition and the pH of which will vary as a function of the
state of the gastrointestinal tract.
[0023] However, at the experimental stage, i.e. without ingestion
of the composition, the physiological fluid is replaced with water
or a physiological medium reconstituted in vitro. In this case, the
microemulsion will be formed on simple contact with the aqueous
phase.
[0024] Hereinbelow in the description and in the claims, the
expression "polyglycosylated glycerides" denotes a mixture of
mono-, di- and triglycerides and of polyethylene glycol (PEG) mono-
and diesters with a molecular weight preferably of between 200 and
600, optionally of glycerol and of free PEG, the HLB value of which
is controlled by the chain length of the PEG and the melting point
of which is controlled by the chain length of the fatty acids, of
the PEG and of the degrees of saturation of the fatty chains, and
thus of the starting oil.
[0025] Similarly, the expression "C.sub.8 to C.sub.18 fatty acids",
also written C.sub.8-C.sub.18 fatty acids, denotes mixtures in
significant and variable proportions of caprylic (C.sub.8) acid,
capric (C.sub.10) acid, lauric (C.sub.12) acid, myristic (C.sub.14)
acid, palmitic (C.sub.16) acid and stearic (C.sub.18) acid, when
these acids are saturated, and the corresponding C.sub.8-C.sub.18
unsaturated acids.
[0026] It is recalled that the proportions of these fatty acids may
vary as a function of the starting oils.
[0027] In one preferred embodiment of the invention, the
co-surfactant is chosen from the group comprising lauric esters of
propylene glycol, capric esters of propylene glycol and palmitic
esters of propylene glycol.
[0028] In other words, the invention consists in incorporating an
inert polymer matrix into a self-microemulsifying system. The said
self-microemulsifying system thus forms a microemulsion after
ingestion, on contact with physiological fluid, thus making it
possible, by diffusion through the matrix which has thus become
gelled on contact with the physiological fluid, to gradually,
continuously and uniformly release the microemulsified active
agent(s).
[0029] In practice, when the composition of the invention is
formulated as gel capsules, after ingestion, the gel capsule
dissolves on contact with the digestive fluids, resulting in
parallel in the formation of a small fraction of microemulsion,
since the water gradually comes into contact with the SMEDDS.TM..
The result of this is that a small proportion of the active
principle is thus microemulsified, and the microemulsified active
principle is then released.
[0030] Concomitantly, the polymer gradually becomes hydrated, then
gels, resulting in the formation of a viscous layer, the volume of
which increases gradually to form a matrix from which the
microemulsion is released by diffusion. The gelled barrier thus
formed therefore counters the rapid release of the microemulsified
active principle and, by controlling the penetration of water from
the outside inwards, makes it possible gradually to release the
said microemulsified active principle.
[0031] Moreover, when the SMEDDS.TM. comprises fatty substances
with an HLB value >10, it has been found, entirely surprisingly,
that the polymer matrix is gelled only after ingestion, i.e. in
contact with physiological fluid, whereas it might have been
expected that the gelation would have taken place before ingestion
merely on contact with the constituents of the SMEDDS.TM., the very
high HLB value of which (>10) would have resulted in salvation
of the polymer, and thus have led to the formation of a gel.
[0032] Furthermore, it was not obvious that the rate of release of
active agent would not change as a function of the hydrodynamic
conditions, i.e. as a function of the intestinal motility, in
particular by erosion of the matrix, as occurs for monolithic
systems. On the contrary, the composition according to the
invention has the advantage of being independent of the
hydrodynamic conditions, since the matrix on contact with
physiological fluid swells and forms a continuous network, allowing
release of the micelles forming the microemulsion.
[0033] In a first embodiment of the invention, in order for the
polymer matrix to form a hydrated network and thus a gel on contact
with physiological fluid, the polymer matrix is chosen from the
group comprising cellulose polymers.
[0034] According to this embodiment, the polymer matrix has a
molecular weight of less than one million.
[0035] For a molecular weight of greater than one million, the
viscosity of the composition is too high and the release of the
SMEDDS.TM. is improved.
[0036] The molecular weight of the polymer matrix is advantageously
between 80,000 and 800,000.
[0037] In a second embodiment of the invention, the polymer matrix
is chosen from the group comprising acrylic polymers. Any acrylic
polymer capable of swelling on contact with an aqueous phase may be
suitable.
[0038] In a third embodiment of the invention, the polymer matrix
is chosen from the group comprising non-cellulose polysaccharides,
for example gums.
[0039] When it is desired to incorporate a hydrophobic active agent
into the SMEDDS.TM., a hydrophilic polymer matrix chosen from the
group comprising hydroxypropylcellulose,
hydroxypropylmethylcellulose and methylcellulose, alone or as a
mixture, is used.
[0040] Similarly, when it is desired to incorporate a hydrophilic
active agent into the SMEDDS.TM., a hydrophobic polymer matrix such
as ethylcellulose is used.
[0041] The composition of the invention thus makes it possible to
use hydrophilic active agents independently of their water
solubility, since the release of the active agent does not take
place as a function of its water solubility, but by diffusion of
micelles, the active agent being presented beforehand in a form of
SMEDDS.TM..
[0042] To bring about gelation of the polymer matrix on contact
with physiological fluid, while at the same time ensuring the
formation of the microemulsion, the inert polymer matrix represents
from 0.5% to 40% relative to the weight of the total
composition.
[0043] For a concentration of less than 0.5%, no gelation of the
matrix is observed on contact with physiological fluid. In
contrast, for a matrix concentration of greater than 40%, the
solution becomes too viscous.
[0044] The concentration of polymer matrix is advantageously
between 5% and 25% relative to the total weight of the
composition.
[0045] The invention also relates to the process for manufacturing
the composition.
[0046] According to this process:
[0047] a self-microemulsifying system is first prepared by mixing,
if necessary while heating, with stirring, the active agent, the
lipophilic phase, the surfactant and the co-surfactant;
[0048] the polymer matrix in powder form is then gradually
dispersed, while still stirring, in the said self-microemulsifying
system.
[0049] The composition of the invention, which is in liquid or
semi-solid form at room temperature depending on the nature of the
constituents of the SMEDDS.TM., will be formulated in the form of
gel capsules.
[0050] In this case, these capsules will be filled with the
composition of the invention in liquid form, optionally preheated,
which liquid, during cooling and depending on the composition of
the SMEDDS.TM., may solidify at room temperature.
[0051] The invention thus also relates to the sustained-release gel
capsule incorporating the SMEDDS.TM. described above.
[0052] The invention and the advantages following therefrom will
emerge more clearly from the embodiment below in support of the
attached figures.
[0053] FIG. 1 is a diagrammatic representation of the system for
releasing the active agent from the composition of the
invention.
[0054] FIG. 2 is a representation of the dissolution curves of
indomethacin at pH 1.2 for indomethacin alone, indomethacin
formulated in the form of SMEDDS.TM. as disclosed in document
EP-A-0 670 715 and indomethacin formulated in the form of
sustained-release SMEDDS.TM. as disclosed in the present
invention.
Example 1
[0055] As already stated, FIG. 1 shows the functioning of the
polymer matrix dispersed in a formulation of SMEDDS.TM. type, the
composition obtained being in the form of a gel capsule.
[0056] FIG. 1a represents a gel capsule (1) containing a polymer
matrix (2) distributed homogeneously and in dry form in the bulk
and a self-microemulsifying system (3) or SMEDDS.TM..
[0057] As shown in FIG. 2a, on contact with the hydrophilic phase,
i.e. physiological fluid, the gel capsule (1) is dissolved, which
allows the physiological fluid to enter the mixture of polymer and
SMEDDS.TM..
[0058] On contact with water, the polymer matrix gradually forms by
structuring a gelled barrier (4).
[0059] As shown in FIG. 1c, the polymer matrix gradually becomes
destructured, thus allowing the SMEDDS.TM. to be released
slowly.
Example 2
[0060] The test below was carried out in a laboratory using water
as physiological medium.
[0061] Manufacture of the Composition of the Invention in the Form
of a Gel Capsule
[0062] In this example, a SMEDDS.TM. is prepared, the composition
of which is as follows:
1 surfactant Labrasol 43.40% co-surfactant Plurololeic 14.40%
lipophilic phase Labrafil WL2609BS 38.40% active principle
Indomethacin 4%
[0063] In a known manner, the constituents of the SMEDDS.TM. are
mixed together at room temperature with stirring of between 60 and
100 rpm.
[0064] The polymer matrix consisting of
hydroxypropylmethylcellulose (HPMC) representing 20% of the final
composition is then gradually dispersed, while still stirring.
[0065] A liquid preparation is obtained which is then formulated in
the form of gel capsules.
[0066] Dissolution Curves
[0067] FIG. 2 represents the dissolution curves for indomethacin
when the active agent is alone (curve 1), in the form of
immediate-release SMEDDS.TM. (curve 2) , or in the form of
sustained-release SMEDDS.TM. according to the invention (curve
3).
[0068] As shown in this figure, the indomethacin, which is known to
be insoluble at acidic pH (curve 3), can be made fully available
when it is incorporated in a SMEDDS.TM. (curves 1 and 2).
[0069] As shown in curve 2, the composition of the invention has
sustained-release characteristics, despite the fact that the
SMEDDS.TM. is in liquid form at room temperature.
[0070] Characterization of the Microemulsion Formed by the
Composition of the Invention
[0071] Tyndall Effect
[0072] The microemulsion obtained in vitro has a bluish appearance
which corresponds to the Tyndall effect.
[0073] Size of the Droplets Forming the Microemulsion.
[0074] The size of the droplets of the microemulsion obtained in
vitro when the composition of the invention is placed in contact
with an aqueous phase was measured by photon correlation
spectroscopy.
[0075] The mean droplet size obtained is 25 nanometers.
[0076] The advantages of the invention clearly emerge from the
description above.
[0077] The possibility of incorporating SMEDDS.TM.s into
sustained-release forms will be noted in particular, thus making it
possible to increase the bioavailability of the active agent.
[0078] It will also be noted, entirely surprisingly, that the
composition of the invention has a structure such that it allows
gradual release of the active principle in vivo, even if the
SMEDDS.TM. is in liquid form at room temperature.
* * * * *