CONTROLLED AND DELAYED RELEASE ORAL PHARMACEUTICAL COMPOSITION

COMPOSITION PHARMACEUTIQUE A LIBERATION CONTROLEE ET RETARDEE POUR ADMINISTRATION PAR VOIE ORALE

English Abstract

ABSTRACT
The present invention provides an oral pharmaceutical
composition adapted for the controlled delayed release of an
active substance and comprising said active substance and a
carrier or coating material, wherein said carrier or coating
material comprises a material selected from biodegradable cyclic
carboxylic acid esters, polymers thereof, and mixture of said
esters or polymers. The invention also provides processes for
preparing such compositions.

Claims

22
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An oral pharmaceutical composition adapted for the
controlled delayed release of an active substance and comprising
said active substance and a carrier or coating material, wherein
said carrier or coating material comprises a material selected
from biodegradable cyclic carboxylic acid esters, polymers
thereof, and mixture of said esters or polymers.
2. A composition according to claim 1 in the form of a
tablet, a capsule, a pellet or granules.
3. A composition as claimed in claim 1 or 2 wherein said
carrier or coating material comprises a material selected from
oligomers, co-oligomers and co-polymers of said biodegradable
cyclic carboxylic acid esters.
4. A composition as claimed in claim 1 or 2, wherein said
carrier or coating material comprises a material selected from the
group comprising cyclic carboxylic acid esters of formulae I, II,
III and IV, oligomers, co-oligomers and co-polymers thereof
<IMG>
I II III
and/or
<IMG>
IV

23
(wherein R1, R2, R3, R4, R5 and R6, which may be the same or
different, each represents a hydrogen atom, a C3-6 cycloalkyl or
C1-12 branched or unbranched alkyl, alkenyl or alkynyl group
optionally substituted by a halogen atom or by a hydroxy, a
branched or unbranched C1-4 alkoxy, a C1-5 acyl, a carboxyl, an
amino, or an alkylamino-, dialkylamino- or quaternary amino group,
a C1-5 acyl group with 1 to 5 carbon atoms, a branched or
unbranched (C1-5 alkoxy) carbonyl group or an optionally
substituted aryl or heteroaryl group having 6 to 12 carbon atoms
in the ring system, and n may represent any one of the integers
from 2 to 10), polymers thereof and mixtures of said esters and/or
said polymers.
5. A composition as claimed in 1 or 2, wherein said carrier
coating material comprises a material selected from glycolide,
lactide, oligomers and co-oligomers thereof with molecular weights
of up to 3000, polymers and co-polymers thereof with molecular
weights of up to 1.2 million, and mixtures of two or more of the
said materials.
6. A composition as claimed in claim 1 or 2, wherein said
carrier coating material is selected from the group comprising
glycolide, L-lactide, D-lactide, D,L-lactide, meso-lactide, poly-
L-lactide, poly-D-lactide, poly-D,L-lactide, poly (L-lactide-co-
glycolide), poly(D,L-lactide-co-glycolide) and combinations
thereof.

24
7. A composition as claimed in claim 1 or 2 further
containing one or more pharmaceutical carriers or excipients.
8. A composition as claimed in claim 3 further containing
one or more pharmaceutical carriers or excipients.
9. A composition as claimed in claim 4 further containing
one or more pharmaceutical carriers or excipients.
10. A composition as claimed in claim 5 further containing
one or more pharmaceutical carriers or excipients.
11. A composition as claimed in claim 6 further containing
one or more pharmaceutical carriers or excipients.
12. A composition as claimed in claim 1 or 2 further
containing one or more pharmaceutically acceptable water-soluble
additives or excipients.
13. A composition as claimed in claim 3 further containing
one or more pharmaceutically acceptable water-soluble additives or
excipients.
14. A composition as claimed in claim 4 further containing
one or more pharmaceutically acceptable water-soluble additives or
excipients.
15. A composition as claimed in claim 5 further containing

one or more pharmaceutically acceptable water-soluble additives or
excipients.
16. A composition as claimed in claim 6 further containing
one or more pharmaceutically acceptable water-soluble additives or
excipients.
17. A composition as claimed in claim 1 or 2 additionally
comprising a water-swellable or water-soluble polymer or
copolymer.
18. A composition as claimed in claim 3, additionally
comprising a water-swellable or water-soluble polymer or
copolymer.
19. A composition as claimed in claim 4, additionally
comprising a water-swellable or water-soluble polymer or
copolymer.
20. A composition as claimed in claim 5, additionally
comprising a water-swellable or water-soluble polymer or
copolymer.
21. A composition as claimed in claim 6, additionally
comprising a water-swellable or water-soluble polymer or
copolymer.
22. A process for the preparation of an oral pharmaceutical

26
composition as claimed in claim 1 or 2, which process comprises:
a) Dissolving or suspending a said carrier or coating
material and a said active substance in a volatile solvent, drying
a film of the solution or suspension thereby obtained, grinding
the dried film thereby obtained to a particle size of 10 to 500
micrometers, and formulating the granulate obtained thereby,
optionally together with one or more pharmaceutical carriers or
excipients, into oral dosage units, or
b) Compressing into tablet form a mixture of a said carrier
or coating material and a said active substance, optionally after
the granulation of said mixture or of one or more of the
components thereof, said mixture optionally further containing one
or more pharmaceutical carriers or excipients, or
c) Applying to granules or pellets comprising a said active
substance a retardant coating comprising a said carrier or coating
material whereby to yield coated granules or pellets of which the
retardant coating constitutes from 3 to 30% of the total weight,
d) Admixing a said active substance and a said carrier or
coating material, optionally together with one or more
pharmaceutical carriers or excipients, and extruding the mixture
obtained.
23. A process as claimed in claim 22 (a) wherein the
quantity of said active substance dissolved or suspended in said
solvent is 0.1 to 20% of the quantity of said carrier or coating
material dissolved or suspended in said solvent.
24. A process as claimed in claim 22(b) wherein from 40 to

27
90% by weight of said mixture is comprised by said active
substance.
25. A process as claimed in claim 22(d) wherein as said
carrier or coating material is used a finely divided polymer
material.
26. An oral pharmaceutical composition comprising a
pharmaceutically active substance in association with a carrier or
coating material, wherein said carrier or coating material
comprises a material selected from biodegradable cyclic carboxylic
acid esters, polymers thereof and mixtures of said esters or
polymers.
27. A composition according to claim 26 wherein said
pharmaceutically active substance which is coated with said
carrier or coating material and is in the form of particles whose
size is in the range of 10 to 500 micrometers.
28. A composition according to claim 27 wherein said
pharmaceutically active substance which is coated with said
carrier or coating material and is in the form of granules or
pellets whose size is about 1.0 to 1.5 mm.

Description

1 32q767
-- 1 ~
NI 52-472
CONTROLLED AND DELAYED RELEASR ORAL
PHARMACEUTICAL COMPOSITION
~
The present invention relates to controlled and
delayed release oral pharmaceutical compositions.
Oral pharmaceutical compositions having a polymeric
5 carrier for the active substance and including
some such compositions which provide delayed release
of the active substance, have been described in
a number of patent specifications. The polymeric
carriers that have been used include, for example,
polymers based on acrylic acids and celluloses,
inter alia. A disadvantage is that the majority
of carrier materials are non-physiological substances,
that is to say substances which do not occur naturally
in the body, and thus have to undergo stringent
tests for toxicological safety. However, polymers
(including oligomers and copolymers) of lower hydroxy-
carboxylic acids, particularly glycolic and lactic
acids, are broken down in the body by the natural
metabolic cycle and are toxicologically harmless.
Stitches and implants based on these polymers have
been successfully used in surgery for some time.
Parenteral pharmaceutical compositions made using
copolymers of lactic and glycolic acid have been
disclosed, for example, in EP-A-26 599 and also
in DE-A-20 51 580. These two publications describe
pharmaceutical compositions comprising these polymers,
which compositions have the property of releasing
the active substance over a lengthy period of time,
i.e. between 14 days and a year. This is desirable
in the case of parenteral delayed-release compositions;
however due to the slow rate of active substance
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1 329767
-- 2 ---
release, polymers of lactic and glycolic acid would
appear to be totally unsuitable for use in oral
pharmaceutical compositions.
It is an objective of the present invention to
provide an oral pharmacuetical composition caPable
of permitting controlled delayed release o~ an
active substance by the use of a physiologically
acceptable (e.g. toxicologically safe) polymeric
carrier material.
In one aspect the present invention provides an
oral pharmaceutical composition adapted for the
controlled delayed release of an active substance
and comprising said active substance and a carrier
or coating material, wherein said carrier or coating
material comprises a material selected from biodegradable
cyclic carboxylic acid esters, polymers thereof,
and mixtures of said esters or polymers. The oral
composition of the invention ~onveniently may be
in the form of a tablet, a powder, granules, a
capsule or a pellet and preferably is adapted to
permit continuous release of active substance within
a period of 24 hours. ~he polymers of the bio-
deqradable cyclic carboxylic acid esters, usefulas carrier or coating materials include the oligomers,
co-oligomers, homopolymers and copolymers thereof.
Suitable carrier or coating materials for this
purpose include 1,3~dioxan-2-ones of formula I
R
R32 ~O~o
~R 6
1 4()
;` r
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1 3297~7
- 3 -
l,4-dioxan-2-ones of formula II
R o
R2~ .6
R ~O'\R5
.
lactides of formula III
R
R ~ ~ R Y
O
~ 15
:, and lactones of formula IV
O O
( C ~R~I
.
In form~lae I,II,III and IV
Rl, R2, R3, ~4, R5 and R6, which may be the same
or different, each represents
a hydrogen atom,
a C3_6 cycLoalkyl or Cl_l2 (preferably Cl 4) branched
or unbranched alkyl, alkenyl or alkynyl group optionally
substituted by a halogen atom or by a hydroxy, a
branched or unbranched Cl_~ alkoxy, a Cl_5 acyl, a
. carboxyl, an amino, or an alkylamino-, dialkylamino-
l 35 or q~aternary amino group (which alkylamino-, dialkylamino-,
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-4- 27400-87
1 32~767
or quaternary amino group preferably has 1 to ~ carbon atoms),
A Cl 5 acyl group with 1 to 5 carbon atoms, a branched or
unbranched (Cl_5 alkoxy) carbonyl group or an optionally sub-
stituted aryl or heteroaryl group having 6 to 12 carbon atomsin the ring system;
and n represents any one of the integers from 2 to 10.
In the lactones of formula (IV) there will be present from 2
to 10Rl's and from 2 to 10R 's. Each of these ~l's and R2's
can be the same as or different from other Rl's and R2's.
Useful as halogen atoms in the compounds of formulae I to IV
are fluorine, chlorine, bromine and iodine atoms and unless
stated otherwise the preferred alkyl moieties in these com-
pounds and their polymers are preferably methyl, ethyl, propyl,
isopropyl, butyl, or tert.-butyl groups, and aryl moieties
ara preferably phenyl or substituted phenyl groups~
The above-mentioned lactones (i.e. the compounds of formulae
I to IV) and their polymers, e.g. the oligomers and co-
oligomers thereof having number average molecular weights
of up to 3000 and the polymers and copolymers thereof having
number average molecular weights of up to 1.2 million, are
particularly subitable for use as the carrier or coating
`~ material in the compositions of the invention. Other suitable
carrier and coating materials include mixtures of the above-
mentioned lactone-, the oligomers and co-oligomers, polymers
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1 329767
-4a- 27400-87
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and co-polymers thereof.
Also suitable as carrier or coating materials are mixtures
of the lactones described above or polymers thereof with
other polymers such as for example polyacrylates,
polymethacrylates, polyesters 3 polyamides, celluloses and
starches.
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1 329767
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Some of the lactones described above and the polymers
prepared therefrom have centres of asymmetry.
The starting materials for preparing the carrier
or coating materials may be the dextrorotatory
forms, the laevorotatory forms, the opticaLly inactive
racemic forms, the optically inactive meso forms
and any desired mixtures of these individual forms.
Co-oligomers and copolymers of the lactones described
may, if desired, be prepared so that the diferent
monomer units occur randomly distributed or in
blocks of different lengths in the polymer chain.
Both random co-oligomers and copolymers and also
block co-oligomers and copolymers are suitable
carrier materials.
The oligomers, co-oligomers, polymers and copolymers
may be prepared by various methods. A number of
patent specifications describe methods based on
the condensation of hydroxycarboxylic acids, whilst
other patent specifications describe methods based
I on the ring-opening polymerisation of lactones,
`1 for example:
~ ~5
:`
HO- C--COOH 2 ~ O-C-C ~ ~ R ~ ~ R~
3 o R~ R~ m O O
:~ R
'`.
,
..
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~i .
The method of manufacture of the above-mentioned
oligomers, co-oligomers, polymers and copolymers
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1 32~767
-- 6 --
is generally not critical for their use as carrier
or coating material for the pharmaceutical compositions
of the invention. The oligomers, co-oligomers,
polymers and copolymers can all be used according
to the invention, irrespective of whether they
are prepared by condensation from hydroxy acids
and their derivatives or by polymerisation from
lactones. In the interests of simplicity, the
oligomers, co-oligomers, polymers and copolymers
of the lactones, may be referred to herein as polymers
without thereby referring to the method of production~
degree of polymerisation or other properties.
Preferred as carrier or coating materials are polymers
(homo- and copolymers) of glycolide, L-lactide,
D,L-lactide, D-lactide, 1,4-dioxanone and caprolactone.
The copolymers may be synthesised from two or more
comonomers. The amount of each comonomer may conveniently
vary between 1 and 99%.
Particularly preferred lactones are
glycolide,
L-lactide,
D-lactide,
; 25 D,L-lactide (racemate), and
meso~lactide.
`~ Particularly preferred polymers are
poly-L-lactide,
poly-D-lactide,
poly-D,L-lactide,
poly (L-lactide-co-glycolide) with 55 mol-%
- glycolide, and
poly (D,L-lactide-co-glycolide) with 55 mol-%
glycolideO
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1 329767
- 7 -
By suitable selection of the coating or carrier
material, desired rates of active substance release
from the pharmaceutical com~osition of the invention
may be achieved. The biodegradable carrier or
coating material used in the preparation of the
compositions may thus allow active substance release
; rates to be varied within a wide range.
In order to achieve the desired rate of active
substance release, the pharmaceutical compositions
according to the invention may, for example, be
- prepared by the following processes which themselves
represent further aspects of the invention.
,;
Thus in another aspect the present invention provides
a process for the preparation of an oral pharmaceutical
composition according to the invention, which process
comprises dissolving or suspending a said carrier
or coating material and a said active substance
in a volatile solvent, dryin~ a film of the solution
or suspension thereby obtained, grinding the dried
film thereby obtained to a particle size of 10
to 500 micrometers, and formulating the granulate
obtained thereby, optionally together with one
or more pharmaceutical carriers or excipients,
into oral dosage units, e.g. by filling into capsules
or by compressing into tablets.
~A In this Process, the carrier or coatinq material,
e.g. a polymer or copolymer as defined hereinbefore
is dissolved or suspended in a volatile solvent,
such as dichloromethane, and mixed with the active
substance. In this process therefore the polymers
or copolymers and the volatile solvent used will
suitably be such that the selected polymer or copolymer
- dissolves or adequately swells in the selected
solvent. It may be noted that the solubility of
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1 32~767
a copolymer of glycolide and lactide is reduced
as its glycolide content increases. Copolymers
containing more than 55~ of glycolide do not generally
dissolve in the volatile solvents in question.
The solution or suspension obtained by this process
may be poured out to form a film from which the
solvent is eliminated. The film thus formed is
- then ground to a screened particle size in the range from
10 to 500, e.g. 50 ~o 500, micrometers conveniently
at a temperature below the glass temperature o~
the polymer in question. The rate of release of
active ~ubstance from the final product can be
varied by varying the particle size. The powder
thus obtained may be compressed directly to form
tablets or packed into capsules. The ratio of
polymer to active substance is non-critical within
wide limits and the active substance may conveniently
be present at between 0.1 and 20%, preferably between
0O5 and 5% by weight relative to the weight of
the carrier or coating material. If desired, adjuvants
conventionally used in pharmaceuticals, such as
corn starch, lacto~e and the like, may be added
during the production of the pharmaceutical composition,
e.g. during the cold grinding or the tablet compression.
i 25 During the cold grinding, the mass ratio of polymer
containing the active substance to excipient may
vary within wide limits and may conveniently be
from about 10:1 to 1:4.
A preferred polymer for use in this process is
. a poly-D,L-lactide with a degree of polymerisation
i! of between 4 and 6. Other preferred polymers are
~ poly-L-lactide with a numher average molecular
i~ weight of about 2000, poly-L-lactide (number average
molecular weight of about 43,000), poly-D,L-lactide
(number average molecular weight about 363,000),
copolymer ~,L-lactide/glycolide 50/50 ~number average
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1 329767
molecular weight about 8000) and a copolymer of
~,L-lactide/glycolide 75/25 ~7ith a number average
molecular ~eight of about 19,000.
S In the case of an oral pharmaceutical composition
prepared by this process in tablet form, virtually
no drug is released during the retention time in
the stomach, even though the tablet very rapidly
breaks up into individual particles in the stomach.
The active substance is only released during the
passage through the intestines, i.e. in a neutral
medium, and there it is released continuously over
a period of 3 to 12 hours. The properties described
open up the possibility of achieving a p~-dependent
release of active substance, i.e. a release which
will increase as the pH rises, such as, for example,
a controlled release of active substance in the
intestinal tract. One possible application ls
a delayed-release tablet which is resistant to
gastric iuices.
Low molecular weight poly-D,L-lactide has particularly
'~ high rates of active substance release. The release
rate may be slowed down to any desired extent by
the addition of higher molecular weight polymers
and also copolymers, lactides and glycolides.
I On the other hand, by the addition of other polymers,
.g. polyacrylates (for example EudragitR NE 30 D)
the release rate may be increased to a desired
extent. It is therefore possible to adapt the
pharmaceutical composition of the invention to
the individual active substance and the particular
j requirements of therapy.
,.,
The pharmaceutical composition of the invention
!I can alternatively be prepared in the form of a
~ matrix-type tablet.
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1 329767
- i0
Thus in a further aspect the invention provides
a process for the preparation of an oral pharmaceutical
composition according to the invention, which process
comprises compressing into tablet form a mixture
of a said carrier or coating material and a said
active substance, optionally after the granulation
of said mixture or of one or more of the components
thereof, said mixture optionally further containing
one or more pharmaceutical carriers or excipients.
To prepare a matrix tablet, the active substance
is conveniently mixed with a polymer or copolymer
~ or mixture thereof as hereinbefore described, optionally
; including small amounts of excipients conventional
in pharmaceutical preparations, such as magnesium
stearate, Aerosil and the like, the mixture conveniently
being prepared and compressed by known methods,
e.g. using granules formed by moist granulation,
; or by direct compression of polymer material and
~, active substance.
' 20
The following are some examples of polymers and
copolymsrs which are particularly suitable for
the manufacture of matrix-type tablets:
25 poly (L-lactide~, molecular weight of between
1000 and 5000 (determined
j~ by terminal group titration)
;~ poly (L-lactide), inherent viscosity between
0.5 and 1.5
, 1
poly (D,L--lactide) inherent viscosity between
1.5 and 2.5
poly (D,L-lactide-co-glycolide) 50~50, inherent
viscosity hetween 0.2 and 1.0
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- 1] ~ 32976 7
poly tD,L~lactide-co-glycolide) 75:25, inherent
viscosity between 0.2 and l.0
The following polymers and copolymers are particularly
preferred:
poly~ lactic acid tmolecular weight of 2000)
poly-L-lactide (MVis = 43,000)
poly-D,L-lactide ( viS = 363,000)
copolymer [pol~(D,L-lactide-co-glycolide)~ 50:50
copolymer ipoly(D~L-lactide-co-glycolide)] 75:25
The selection of preferred polymers listed above
i5 also useful in the preparation of the other
pharmaceutical forms described herein. This list
is given by way of example, ~ithout restricting
the invention to the use of the polymers or molecular
weights or inherent viscosities specified.
The matrix tablet of the invention conveniently
has a very high content of active substance, which
may be up to 90% by weight relative to the total weight
of the composition, depending on the active substance.
A content of 40% by weight of active substance is generally
regaraed as the lower limit
In the case of highly active pharmaceutical active sub-
stances it is sometimes necessary to incorporate into a
matrix tablet smaller quantities of active substance
than those referred to above; in such a case it is highly
advantageous to add a readily soluble excipient, e.g.
I lactose, or even some excipients which are less soluble
or insoluble in water, to ensure a release of active
suhstance within 24 hours.
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1 329767
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In contrast to the rapidly decomposing delayedrelease tablets described previously, the matrix
tablet of the invention allows release of active
substance into the stomach. The release characteristics
are determined not only by the polymer composition
but also by the form of the matrix tablet. An
increase in molecular weight of the polymer slows
down the rate of release.
A further embodiment of the pharmaceutical composition
of the invention consists of forms for oral administration
having a retardant coating of a carrier or coating
material as hereinbefore described, e.g. of a homopolymer
or copol~mer of the compounds of formulae I, II,
III and IV hereinbefore described, preferably of
a lactide/glycolide homopolymer or copolymer, optionally
combined with other polymers such as water soluble
polymers, e.g. polyethylene glycol, or water-swellable
polymers such as EudragitR NE 30 D.
Thus in a still further aspect the invention provides
a process for the preparation of an oral pharmaceutical
composition according to the invention, which process
comprises applying to granules or pellets comprising
a said active substance a retardant coating comprising
a said carrier or coating material whereby to yield
coated granules or pellets of which the retardant
coating constitutes from 3 to 30~ of the total
` weight.
i 30
The method used to produce retardant coatings is
well known to those skilled in the art and requires
no special explanation. ~hus, for example, the
active substance in the form of pellets (e.g. about
1.0 to 1.6 mm pellets) may be coated in a fluidised
bed granulator with a polymer dissolved in a suitable
solvent. Coatings may also be applied using the

1 32q767
- 13 -
coating pan method. In general, the quantity of
retardant coating amounts to 3 to 30% by weight,
preferably 5 to 20, more particularly 5 to 10%
by weight, relative to the total weight of the composition.
Spray solutions used in this process will generally
have a polymer content of 5 to 10~ by weight.
As previously described in connection with the
matrix tablet, the release of th~ active substance
starts in the stomach and may be varied over a
lengthy period of time by changing the molecular
weight of the coating material. The rates of release
may additionally be varied by combining the coating
material with other water-soluble polymers, e.g.
polyethylene glycols (for example polyethylene
glycol 6000~.
In a yet further aspect the invention provides
a process for the preparation of an oral pharmaceutical
composition according to the invention, which process
comprises admixing a said active substance and
I a said carrier or coating material, optionally
''! together with one or more pharmaceutical carriers
or excipients, and extruding the mixture obtained.
j In this process, the carrier or coating material
is preferably a finely divided polymer material.
~, This is mixed with the active substance and optional
excipients such as lactose and is then extruded.
The extruded shapes, e.g. small rods containing
i the active substance may then be further processed
~` to form suitable galenic preparations. The pharmaceuticals
produced by the so-called extrusion method have
the advantage that there is no need for any solvent
in their manufacture.
, ' ' . ' .
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1 3297G7
- ]4 -
The pharmaceutical preparations according to the
invention are also suitable for stabilising certain
active substances in pharmaceuticals.
Some pharmaceutically active substances from the
group comprising the sympathicomimetics of the
phenylethylamine type have a tendency to undergo
oxidative changes on storage: in particular, on
exposure to moisture slightly or more seriously
discoloured products may form. Experience has
shown that such changes take place more readily
in a neutral or alkaline pH, than in an acidic
medium.
The addition of acid to pharmaceuticals of this
kind is not the ideal remedy in every case. However,
` polymers of lactic acid, which are hydrolytically
broken down to the monomer in the presence of water,
may act as a latent acid reservoir releasing acid
as required.
A granulated tablet material containing 7.5~ of
m-proterenol sulphate ~trade mark: Alupent) discolours
;~ within 48 hours, if kept at about 60C sealed up
~ in the presence of the moisture of the granules.
i 25 Similar granules to which 5~ of poly (L-lactic
acid) having a molecular weight of 2000 has been
~ added show no discolouration under identical conditions.
!~, The Examples which follow are intended to illustrate
the invention without restricting its scope in
anyway.
Unless otherwise stated, all ratios and percentages
with the exception of comonomer contents of copolymers
~ 35 herein are bY weight and molecular weights gi-ven
- herein are number average molecular weights. Comonomer
contents of copolymers are, unless otherwise stated,
expressed as mole ratios or mole %.
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1 329767
- 15 -
Example 1
Poly-D,L-lactide (degree of polymerisation 4 to
6) is taken up in methylene chloride and mixed
with 1~ by weight of clonidine base. The solvent
is then removed and the film produced is ground
up cold. The ground material obtained is adjusted
by screening to a log-normal distribution, e.g.
with the parameters (dz = 80 micrometers,C~ = 0.23)
(dz is the average diameter of the particles, ~
is standard deviation) and the release of the clonidine
is measured by HPLC in a USP tester XVII. When
the rate of release of the clonidine from this
oligomeric poly-lactide is determined, it can be
; seen that virtually no drug is released in the
gastric juice phase ~pH 1.2; retention time lh);
the drug is only released as it passes into the
intestinal juice. Table 1 shows the percentage
release data for clonidine vver an observation
! period of 6 hoursO
Table 1: Release data for the batch We T 66 in
a modified USP tester XVII
,
j 0.25 h 0.6 ~ of active substance
1 h 0.8 released
25 2 h 29.8
4 h 55.6
6 h 70.8
Example 2: Matrix tablets
Theophylline-polymer granules were obtained by
moist granulation with an organic solvent. From
the granulate matrix tablets were prepared using
an eccentric press EKO with a 12 mm ~ flat facetted
; 35 convex punch.
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-16- 27400-87
1 32~767
The rate of active substance release was measured using a
USP 21 tester, paddle model, lO0 and lS0 rpm, buffer pH 2
(artificial gastic juice, 0.06 N hydrochloic acid), pH 6.5
(artificial intestinal juice, 0.06 N hydrochloic acid, pH
adjusted to pH 6.5 with tri-sodium phosphate).
Table 2 shows the percentage release data for theophylline
over an observation period of 7 hour~.
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Tahle 2 : Release data for theophylline
a) Composition A Release
Theophylline 80% lh 18.5~
Poly(~,L-lactide) 20~ 3h 31.3%
5h 40.1
Mg stearate 0.3~ 7h 47.1
Aerosil 0.3~
Dichloromethane AOml
Remarks: Tablets look the same after release, very
` hard. Measurements were carried out at lOO rpm
b~ ~ (Theophylline granulate) Release
TheophYlline 80% lh 21.l~
Poly(D,L-lactide-co- 3h 36.0~
glycolide) 50:50 20~ 5h 46.6%
7h 55.4%
external phase:
Mg stearate 0.3%
Aerosil 0.3~
; Dichl~romethane 20ml
j Remarks: After the release, the tablets look the
same, very hard. Measurements carried out at 100 rpm
c) Composition tTheophylline granulate Release
(0.8-l.Omm)
Theophylline 80% lh 24.3
Poly(D,L-lactide-co- 3h 42.8~
glycolide) 75:25 20~ 5h 54.9%
~, 7h 64.3%
external phase:
Mg stearate 1.0
Aerosil 0.3~
Dichloromethane 50ml
Measurements were carried out at 150 rpm.
d) Composition (Theophylline granulate) Release
less than 0.3mm)
Theophylline 80% lh 23.8%
Poly(D,L-lactide) 20% 3h 40.7%
5h 52.3%
; Dichloromethane 40ml 7h 61.2
Ethanol lOml
Remarks: The tablets were still stable after the
release. Measurements were carried out at 150 rpm.
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e) Composition (Theophylline granulate Release
lOO~ (less than 0.3))
A B
Theophylline 80% lh 25.3~ 21.l~
Poly-L-lactide, 3h 63.0% 44.3%
: Molecular weight 5h 86.2% 61.5
about 2000 20% 7h 95.6% 74.8
Dichloromethane 20ml
.~ Remarks: The tablets are unaltered after the release.
Measurements were carried out at 150 rpm.
A = Bardness 140 KN B = ~ardnesr lSO KN
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Example 3 : Coated compositions
Coated compositions for oral administration wereprepared using theophylline as the active substance
and using various polymeric coating materials which
comprised polylactides alone or in combination with
other polymers such as Polyethylene glycol 6000, and
EudragitR NE 30 D. The coated compositions were
prepared in the form of rounded pellets of about
1.0-16 mm size and containing about 80% active substance.
The coating process was performed under the following
parameters:
spraying/apparatus: WST 1
solvent: methylene chloride
15 batch si~e: about 1.2 kg
spray solution: 5~ polymer in each case
, ~unless otherwise stated)
`~ The rate of release of the active substance was measured
in vitro using a USP21 tester (paddle) 150 rpm, buffer
pH 1O2/pH 6.5
~'
~ Table 3 shows the percentage release data for theophylline
- over an observation period of 7 hours. (% contents
referred to in this Example are on a dry weight basis
and MW stands for molecular weight~.

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Table 3
Polymer coating composition Release for
5%10% Coatinqs
l.O.Poly-L-lactide, (MW
about 2000) 100~ lh 43.8%
3h 91.7%
5h 97.5~
` 7h 98.5%
,~ .
l.l.Poly-L-lactide,
~MW about 2000) 75% lh 12.5% 22.8
Eudragit NE30D 25~ 3h 33.5% 44.2%
5h 52.5~ 56.6%
7h 68.4% 65.7%
1.2.Poly-L-lactide
(MW about 2000) 50% lh 10.3% 16.5%
Eudragit NE30D 50% 3h 30.1% 37.9%
5h 51.2% 51.9%
7h 66.3% 61.8%
1.3.Poly-L-lactide
(MW about 2000) 75~ lh 100.0
Polyethylene glycol 3h
6000 25% 5h
7h
1 1.4.Poly-L-lactide 50% lh ~ 100.0
Polyethylene glycol 3h
' 6000 50% 5h
7h
~' 2ØPoly-L-lactide
~ (inherent viscosity lh 55.6
'; 0.9 dl/g) 100% 3h 87.6
' 5h 94.5
7h 96.8
2.1.Poly-L-lactide
: (inherent viscosity lh1.1%0.9
o.9 dl/g) 94% 3h 2.9% 2.3
Eudragit NE30D 6% 5h4.8% 1.9
7h 6.5% 3.7
~' 2.2.Poly-L-lactide
(inherent viscosity lh3.7%0.7
0.9 dl/g) 88% 3h 7.9% 1.9
Eudragit NE30D 12% 5h11.9%3.2
`~ 7h15.5% 4.6
2.3.Poly-L-lactide
(inherent viscosity lh1.3%1.3
0.9 gl/g) 75~ 3h 3.0% 2.3
; Eudragit NE30D 25~ 5h4.7~ 3.2
7h 6.3% 4.0
Remarks: a 4~ lacquer sol~tion was used for coating
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2.4.Poly-L-lactide
(inherent viscosity lh 1.5~ 1.1%
0.9 dl/g) 50% 3h 3.5% 2.4%
Eudragit NE30D 50% 5h 5.5% 3.6%
7h 7.7% 5.0~
Remarks: 3% lacquer solutions were used for coating
2.5.Poly-L-lactide
(inherent viscosity lh 78.1% 20.9%
0.9 dl/g) 75~ 3h 94.3% 48.4%
Polyethylene glycol 5h 97.5~ 64O9~
6000 25% 7h 98.5% 75.6%
2.6.Poly-L-lactide
~inherent viscosity lh 100.0%
0.9 dl/g) 100% 3h
5h
7h
i All the percentages given refer to the total content
actually found. Example 3 illustrates the release
' rates for 5 and 10% coatings. The polymer contents
listed total 1007.
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