Note: Descriptions are shown in the official language in which they were submitted.
1 332808
~olyester-based composition for the controlled release
of medicinal substances
The present invention relates to a pharma-
ceutical composition and more particularly to a com-
position permitting the sustained and controlled releaseof an effective dose of a given medicinal substance.
There are numerous examples of therapeutic
treatments in which it is desirable to achieve, by means
of a single administration, a sustained release of the
medicinal substance over a period of time and a controlled
release as regards the dose passing into the organism.
Various solutions have already been proposed in this
field, such as subcutaneous implants or injectable
suspensions of microparticles or microcapsules. Such
compositions are based on biocompatible and bio-
degradable polymers, for example polymers or copolymers
of D,L-lactic acid and/or glycolic acid (see e.g.
European patent applications A-0052510 published May 26,
1982 and A-0058481 published August 25, 1982.
In practice, interesting results have been
20 - obtained from therapeutic treatments with polypeptides,
such as LHRH or its analogues, used in the form of
injectable microcapsules or microparticles based on a
D,L-lactic acid/glycolic acid copolymer (approx. 50:50)
with an average molecular weight of the order of about
50 000. As this type of copolymer hydrolyzes relatively
easily in vivo, it is essential to use forms of high
molecular weight: the synthesis of such copolymers
requires the use of organometallic polymerization
catalysts and, when the reaction is complete, it is
imperative for all traces of these catalysts to be
removed for toxicological reasons. Operations of this
kind are often very lengthy and very expensive.
More generally, it is found that the techniques
of polymerization without the use of organometallic
catalysts are rather unsuitable for the preparation of
1 332808
-- 2
biodegradable polymers with an average molecular weight
of the order of 30 000 or more.
Moreover, in order to prevent this type of
polymer (lactide/glycolide copolymer) from being de-
graded too quickly by hydrolysis in vivo, one is forcedto prepare injectable microcapsules or microparticles
of relatively large mean size: when these are injected,
the tissues are very often observed to give an in-
flammatory response, which is sometimes extremely pain-
ful for the subject treated.
It has furthermore been found in some casesthat the uniformity of release of a pèptide-type
medicinal substance in the form of microparticles (see
e.g. European patent application A-0058481) gives rise
to problems, especially where the phenomenon of two-
stage release is to be avoided.
The pharmaceutical industry is therefore always
looking for biodegradable polymers which are capable of
being used as carriers for medicinal substances,
especially for a sustained and controlled release of
,
the active substance, and which do not have the above-
listed disadvantages inherent in the biodegradable
polymers recommended to date. The present invention
offers an advantageous solution to this problem, which
is defined in Claim 1.
In fact, certain polyesters or copolyesters are
known which are derived from carboxylic acids of the
Krebs cycle, such as, for example, succinic, malic,
fumaric or oxaloacetic acids, and from polyols such as
triols like glycerol, mannitol or sorbitol: according
to US patent 3,978,203 issued August 31, 1976, they can
be used inter alia as carriers for medicinal substances,
mainly steroids, in the form of matrices. However, the
polyesters described have a relatively high average
molecular weight of between about 20 000 and 200 000.
1 3~2808
-- 3
U.S. patent application A-4,481,353 recommends the
use of polyesters derived from acids of the Krebs cycle,
such as those mentioned above, and from C2 to C8
aliphatic diols in the preparation of surgical
requisites such as, for example, microtubes, ligatures
or sutures. In the said patent, however, there is no
mention or suggestion of the use of this type of poly-
ester as a carrier for medicinal substances.
The present invention relates to a well-defined
class of polyesters or copolyesters which can advan-
tageously be used for the stated purpose. More par-
ticularly, they are biodegradable polymers or co-
polymers or mixtures of biodegradable polymers and/or
copolymers derived from a dicarboxylic acid selected
from the acids of the Krebs cycle,and from an aliphatic
diol containing 4 carbon atoms or from cyclohexane-l,
4-dimethanol. Fumaric or succinic acid is preferably
used as the dicarboxylic acid of the Krebs cycle and
butane-1,4-diol or butane-2,3-diol is preferably used
as the C4 aliphatic diol, apart from cyclohexane-1,4-
dimethanol.
According to the invention, it is advantageously
possible to use a polymer such as poly-1,4-butylene
succinate, poly-1,4-butylene fumarate, poly-1,4-cyclo-
hexanedimethylene succinate or fumarate or else poly-
2,3-butylene succinate or fumarate. The above-mentioned
polyesters can be used in the pure state or in the form
of mixtures of at least two of the said polyesters.
According to the invention, it is also possible to use
a copolymer derived from fumaric and succinic acids and
from butane-1,4-diol or butane-2,3-diol, for example.
A copolymer derived from fumaric acid and from butane-
1,4-diol and butane-2,3-diol can also be used. Inte-
resting results have been obtained using poly-1,4-
butylene succinate, poly-1,4-cyclohexanedimethylene
1 332808
4 -
succinate and poly-2,3-butylene fumarate, although this
list does not imply a limitation.
In a particular embodiment of the invention,
a further possibility is to use one of the above-
mentioned polymers or copolymers mixed with a polymeror copolymer derived from an alpha-hydroxycarboxylic
acid such as D- or L-lactic acid and from glycolic acid.
Interesting results have been obtained using mixtures of
poly-1,4-butylene succinate and D,L-lactide/glycolide
copolymer.
The polymers, more precisely the polyesters,
used according to the present invention are characterized
by a relatively low average molecular weight which is
more generally between about 2000 and 50 000 and
preferably less than 10 000. This has a decisive
advantage when it comes to their synthesis, which can
be carried out without any need to use organometallic
polymerization catalysts. They can easily be obtained
by means of the customary techniques such as melt phase
polymerization in the presence of an organic esterifica-
tion catalyst (e.g. p-toluenesulphonic acid), or pearl
phase polymerization.
The polyesters obtained by these methods are
characterized by a lipophilic behaviour which is more
pronounced than that of the lactic or glycolic acid
polymers or copolymers known hitherto; they are also
less sensitive than the latter to degradation by
hydrolysis. This feature makes it possible easily to
achieve one of the stated aims, namely to prepare
injectable microcapsules or microparticles with very
small dimensions of the order of only a few microns or
tens of microns.
The polyesters mentioned above, or mixtures
thereof, are suitable for the preparation of any form
of carrier for medicinal substances: a matrix in which
the active substance is dispersed or solubilized can be
1 33280~
-- 5
considered for this purpose, examples being beads,
implants, microspheres or microparticles. These poly-
esters or mixtures thereof are particularly suitable
for carrying out the techniques of microencapsulation
of active substances, such as microencapsulation by
phase separation or microencapsulation by evaporation
(solvent evaporation microencapsulation). To obtain
the carriers in the appropriate form, it is also
possible to use processes such as spray drying or spray
congealing, which both produce microparticles containing
the active substance, or alternatively extrusion, which
makes it possible to prepare implants of predetermined
shape. These are known techniques: some of them will
be described in greater detail in the Examples below.
Microcapsules are preferably prepared using
polyesters with an average molecular weight of the order
of about 2000 to 5000, for example of the order of
about 2500. In a particular embodiment of the invention,
a polyester of this type is used in a mixture with a
D,L-lactic/glycolic acid copolymer (approx. 50:50) with
an average molecular weight of between about 35 000
and 60 000, preferably of the order of about 45 000.
However, this is not an exhaustive list.
Depending on the particular case, it is also
possible to incorporate into the polymer composition a
biocompatible hydrolysis modifier such as a carboxylic
acid, like citric acid, or else a salt such as sodium
chloride (neutral) or sodium carbonate (alkaline).
Despite their lipophilic character mentioned
earlier, the polyesters forming the subject of the
present invention have a sufficient affinity for
hydrophilic medicinal substances such as polypeptides.
Examples of medicinal substances which may be used are
natural or synthetic polypeptides containing from 3 to
60 amino acid units, or else a polypeptide derivative
1 332808
-- 6 --
such as a non-toxic salt of a polypeptide. For example,
it may be advantageous to use a decapeptide such as
luteinizing hormone/follicle-stimulating hormone releasing
hormone (LH/FSH-RH) or one of its natural or synthetic
analogues, or else thyrotropin releasing hormone (TRH),
insulin, somatostatin or one of its synthetic analogues,
human or animal calcitonin, human or animal growth
hormone, growth hormone releasing hormone (GHRH), a
cardiopeptide such as ANP (human 1-28) or a natural or
recombinant interferon. Such active substances are
suitable for the various microencapsulation techniques.
More generally, the medicinal substances which
can advantageously be used in the preparation of com-
positions according to the invention can be selected
from substances having an antiinflammatory, antitumoral,
immunosuppressive, antithrombotic, neuroleptic, anti-
depressant or antihypertensive effect or a non-toxic
salt of such substances. This is not an exhaustive
list.
As a general rule, the pharmaceutical composi-
tions according to the invention contain the chosen
medicinal substance in a proportion of about 0.5 to 20%
by weight, although these limits can be exceeded in
particular cases. One of the preferred forms of such
compositions consists of injectable microcapsules or
microparticles with a mean size of between about 1 and
500 microns, dispersed in a vehicle intended for
parenteral injection.
When administered in vivo or placed in an
aqueous environment of physiological type, the pharma-
ceutical composition according to the invention
releases the medicinal substance into the surrounding
medium at a constant rate over a period of at least
1 week.
The Examples below serve to illustrate the
1 3~280~
-- 7
present invention without thereby implying a limitation.
Example 1
Preparation of a succinic acid polyester
29.25 g (0.25 mol) of succinic acid were mixed
with 22.53 g (0.25 mol) of butane-1,4-diol, 0.43 g of
p-toluenesulphonic acid (1% by weight, based on the
theoretical yield of polyester) and 90 ml of toluene,
the mixture being placed in a reactor equipped with a
magnetic stirrer, a thermometer, a means for introducing
inert gas (N2) and a water separator. The reaction
mixture was heated to 110C and, after 10 hours of
heating, a first sample of polymer was taken in order
to determine its intrinsic viscosity (I.V.). Samples
were taken at regular intervals until the I.V. index
had reached 0.34 (measured at 25C in chloroform):
heating was stopped at that point and the reaction
mixture was left to cool to room temperature, with
stirring.
`Example 2
Preparation of a succinic acid polyester
47.24 g (0.40 mol) of succinic acid were mixed
with 60.57 g (0.42 mol) of cyclohexane-1,4-dimethanol,
the mixture being placed in a reactor equipped with a
magnetic stirrer, a thermometer and a distillation
bridge fitted to a means for introducing inert gas (N2)
and to a vacuum pump. With the reaction mixture placed
under an inert atmosphere, the temperature was gradually
raised to 130 to 170C over a period of 22 h and then
kept at 180C under a pressure of 1 mm Hg. After 72 h
of heating at this temperature and cooling to about
25C, the desired polymer was collected it had an I.V.
index of 0.27 (measured at 25C in chloroform).
1 33~808
-- 8
Example 3
Preparation of a fumaric acid polyester
34.83 g (0.3 mol) of fumaric acid were mixed
with 28.4 g (0.315 mol) of butane-2,3-diol and the
mixture was placed in a reactor identical to that
described in Example 2. With the reaction mixture
placed under an inert atmosphere, the temperature was
gradually raised to 130 to 180C over 6 h and then kept
at 170-180C for 20 h under a pressure of 5 mm Hg.
The desired polymer was thus colIected and had an
average molecular weight of about 2000 (measurement
of the vapour pressure by osmometry).
Example 4
Preparation of a polyester-based pharmaceutical
composition by microencapsulation
0.10 g of a decapeptide of the formula
(pyro)Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2
(hereafter called LHRH-D-Trp6) was suspended in a
solution of 2.0 g of poly-1,4-butylene succinate (I.V.
index 0.35; see Example 2) in 100 ml of methylene
chloride. The suspension obtained was then emulsified
with a solution of 1.35 g of methyl cellulose in 500 ml
of distilled water (rotation speed 1900 rpm) and the
organic solvent was then removed by rotary evaporation
(rotation speed 470 rpm) for 2 h at 40C under a
pressure of 380 mm Hg. The resulting microcapsules
were then filtered off, washed with cold H20 and finally
dried under vacuum.
Example 5
Preparation of a polyester-based pharmaceutical
composition by microencapsulation
0.037 g of LHRH-D-Trp6 was suspended in a
solution of 1.0 g of poly-1,4-butylene succinate (average
1 3S280~
_ 9
molecular weight 2600) in 36 ml of methylene chloride,
and 30 ml of silicone oil were then added gradually to
the suspension, at a rate of about 5 ml/min, at room
temperature. The resulting suspension, containing the
embryonic microcapsules, was then poured, with thorough
stirring, into 3000 ml of 1,1,2-trichlorotrifluoro-
ethane (FREON 113) kept at room temperature. After 5
min of stirring, the resulting microcapsules were
filtered off and then dried under vacuum.
Analysis of the microcapsules obtained by this
method showed that they were totally devoid of all
traces of residual solvent, especially FREON 113. By
way of comparison, a solvent residue of at least 5%
by weight is observed in the preparation of micro-
capsules from D,L-lactide/glycolide copolymer under
identical conditions.
Example 6
Preparation, by microencapsulation, of a pharma-
ceutical composition based on a mixture of
20 ` polymer and copolymer
0.037 g of LHRH-D-Trp6 was suspended in 36 ml
of methylene chloride containing the following mixture
in solution:
- 0.40 g of poly-1,4-butylene succinate (average
molecular weight approx. 2600) and
- 0.60 g of 50:50 D,L-lactide/glycolide copolymer
(average molecular weight approx. 45 000).
After undergoing the treatments described in Example 5,
the suspension obtained produced microcapsules having
the following characteristics: by means of a solubiliza-
tion treatment with dimethylformamide, it was demonstrated
that the D,L-lactide/glycolide copolymer formed the
core of the microcapsules and that the poly-1,4-butylene
* Trade-mark
1 332808
-- 10 --
succinate formed the outer wall of these microcapsules.
Furthermore, it was observed that the dried
microcapsules had a better flow property than comparable
microcapsules prepared either from D,L-lactide/
glycolide copolymer on its own or from poly-1,4-
butylene succinate on its own.
Comparable results were obtained using mixtures
containing 0.20 or 0.30 g of poly-1,4-butylene succinate
(average molecular weight approx. 2600) and 0.80 or,
respectively, 0.70 g of 50:50 D,L-lactide/glycolide
copolymer (average molecular weight approx. 45 000).
Example 7
Determination of the activity of a pharmaceutical
composition in the form of microcapsules
These experiments were carried out using micro-
capsules of LHRH-D-Trp6 prepared by the process of
Example 5 and appropriately dried and sterilized.
The microcapsules were injected into rats
- (laboratory subjects) at a rate of 300 micrograms/kg,
in the form of a sterile aqueous suspension (1% TWEEN/
2% NaCMC). The LHRH-D-Trp6 released and the testos-
terone were determined in the blood by radioimmunoassay
according to the standard techniques. The results
obtained are collated in the Table below (measurements
made on 4 subjects).
1 3~280~
11 --
Period LHRH-D-Trp6Testosterone
(days) (ng/ml) (ng/ml)
0 0.05 3.58
0.25 7.09not determined
2 1.53 7.15
4 0.32 1.25
7 0.28 1.13
11 0.23 1.07
14 0.07 1.40
18 0.06 1.72
21 0.07 1.55
0.07 2.40
After an initial stimulation phase (initial
burst effect), the LHRH-D-Trp6 is released continuously
and at a constant rate up to day 11 and even beyond.
The testosterone decreases and reaches a castration
level as from day 4; this castration level is maintained
,
up to day 21.
