Note: Descriptions are shown in the official language in which they were submitted.
Bioadhesive ophthalmic insert
The invention relates to a bioadhesive ophthalmic insert, more particularly a
bioadhesive ophthalmic insert intended for the prolonged and controlled
release of
one or more medicinal substances.
Numerous pharmaceutical compositions have hitherto been known in both human
and
veterinary medicine for use in the treatment of the most widely varying eye
disorders, e.g., inflammation, such as conjunctivitis, viral or bacterial
infections,
glaucoma or dry eye syndrome. These compositions are most usually in the form
of
eye lotions, gels, ointments, films, or inserts which, in the latter case, are
placed
either in the conjunctival sac or beneath the top eyelid.
Ophthalmic inserts are used more particularly when the prescribed treatment is
to be
of a long duration or requires an extended contact time of the active
principle or
alternatively when the applications have to be repeated frequently. In such
cases, the
comfort of the patient is also a requisite, and is allowed for by reducing the
number
of operations required, for example, and the same applies to controlled
release of the
active substance over a sufficiently long period. Inserts of this kind have
mainly
been produced from a water-soluble polymer or copolymer, inter alia from a
water-soluble cellulose derivative incorporating the active substance in
varying
proportions (for example see US-A-4 179 497, 4 343 787, 3 870 791 or
EP-A-0 108 661). A single polymeric material is then used, and the attempt is
made to adapt it to the required objective depending on its actual
characteristics, by
varying parameters such as viscosity, molecular weight, and crystallinity, for
example. However, the available room for manoeuvre is very much limited.
At the present time, the ophthalmic inserts available do not provide prolonged
residence times with a guarantee of suitable release of the active substance.
Also,
accidental movement of the insert is frequently observed, the insert passing
either
behind the eye or leaving the socket. The invention has the advantage of
proposing
CA 02119109 2002-03-20
.)
a new type of ophthalmic insert which advantageously enables such
disadvantages to be
obviated, while inter alia ensuring permanent positioning and lasting release
of the active
medicinal principle.
The invention relates to a bioadhesive ophtalmic insert, more particularly a
bioadhesive
ophtalmic insert intended for the prolonged and controlled release of at least
one
medicinal substance, comprising a matrix of composite polymeric material in
which the
medicinal substance is incorporated, the said polymeric composite material
matrix
comprising:
- a water-soluble biocompatible polymer and
- a bioadhesive biocompatible polymer..
More particularly, the present invention relates to a solid ophthalmic insert
intended for
the prolonged and controlled release of at least one medicinal substance,
which comprises
a matrix of composite polymeric material in which the medicinal substance is
incorporated, characterized in that said composite polymeric material matrix
comprises
a mixture of:
- a water-soluble bioc:ompatible polymer and
- a bioadhesive biocompatible polymer,
said mixture being extrudalole or therrrroformable.
The invention also relates to an ophtavlmic insert as defined above
characterized by a
matrix of composite polymeric. material comprising:
- a water-insoluble biocompatible polymer,
- a water-soluble bior~ompatible polymer and
- a bioadhesive biocompatible polymer.
More particularly, the invention also relates to a solid ophthalmic insert
intended for the
prolonged and controlled release of at least one medicinal substance, which
comprises a
matrix of composite polymeric; material. in which the medicinal substance is
incorporated,
characterized in that said composite polymeric material matrix comprises a
mixture of
CA 02119109 2002-03-20
3
- a water-insoluble biocompatible polymer,
- a water-soluble bioc:ompatible polymer and
- a bioadhesive biocompatible polymer,
said mixture being extrudable or thermoformable.
Advantageously, the comps>site polymeric material matrix of the insert
according to the
invention comprises from 50 to 99.5°% by weight of the water-soluble
biocompatible
polymer and from 0.5 to 5.0% by weight of the bioadhesive biocompatible
polymer, any
remainder up to 100% by weight being provided by the water-insoluble
biocompatible
polymer.
For example, the present invention more particularly provide a solid
ophthalmic insert
intended for the prolonged and controlled release of at least one medicinal
substance,
which comprises a matrix of composite polymeric material in which the
medicinal
substance is incorporated, characterized in that said composite polymeric
material matrix
comprises a mixture of
- from 50 to 99.5 % by weight of a water-soluble biocompatible polymer,
- from 0.5 to 5 % by 4veight of a bioadhesive biocompatible polymer, and
- from 0 to 49.5 % by weight of a water-insoluble biocompatible polymer,
said mixture being extrudable or thermoformable.
According to the. invention, the vvater-soluble biocompatible polymer used is
advantageously a hydroxyalk;yl cellulose, a maltodexlrin, a chitosan, a
modified
starch, such as, for example, a pregelatinised starch., a destructured starch
(see for example
US-A-4 900 361 ) or a partial 1y hydrolysed starch, or alternatively a
polyvinyl alcohol, this
list being in no way exhausti~re. Preferably, a hydroxyalkyl cellulose is
used, such as a
hydroxyethyl cellulose or a hyciroxy-propyl cellulose of a molecular weight
between 10
000 and I 000 000 or more, preferably between 80 000 and I 25 000. Products of
this kind
are available in the specialised trade.
According to the invention, the water-insoluble biocompatible polymer used is
CA 02119109 2002-03-20
4
advantageously a water-insoluble alkyl cellulose, preferably an ethyl
cellulose, for
example EC-N 50 NFC~ (Hercules) or' Ethocel0 (Premium Dow). Added in adequate
proportions to the mass of water-soluble polymer, the effect of the ethyl
cellulose is to
prolong substantially the dissolution time of the ophthalmic insert and hence
the period
or release of the medicinal substance. Surprisingly, the incorporation of
ethyl cellulose in
the polymeric material selected according to the invention results in complete
dissolution
of the insert nevertheless.
According to the invention, tile polymeric material matrix comprises a
bioadhesive
polymer, i.e. a natural or synthetic polymer capable of stable interaction
with a biological
substrate, such as the mucosa of the conjunctival sac, for example. The
bioadhesive
biocompatible polymer used is advanta~;eously apolymer ofthe polyvinyl
carboxylic acid
type (carboxy vinylpolymerl or alternatively certain bioadhesive
polysaccharides or
polysaccharide derivatives. such as for example, cellulose ethers,
methylhydroxyethyl
cellulose (BenecelC~% ME Adualon, Tylosco? MN Hoechst) or methylhydroxypropyl
cellulose (BenecelCRC MP Aqualon), for c~xarnple. It is also possible sodium
carboxymethyl
celluloses, such as BlanoseC~'hype 7 or 9 (Adualon ) or TyloserJ C (Hoechst)
for example.
Preferably, a non-neutralised polyvin~rl carboxylic acid is used of a
molecular weight
between 450 000 and 4 000 000, such as a Carbopol~~ 934 P, 980, 984, 954,
(Goodrich)
or Noveon~ AAI (Goodrich). This use of non-neutralised material in an
ophthalmic
insert is at first sight surprising since it is recognised as an irritant. In
actual fact, it is
normally used in the form ol'a sodium salt. Dispersed in adequate proportions
within the
mass ofpolyrneric material this type ofbioadhesive polymer loses its irritant
character and
guarantees a prolonged residence time for the insert. Also, this type
ofpolymer ensures
positioning of the insert in its initial position, thus offering all the
required security.
According to the invention, the polymers listed above are also selected in
dependence on
their extrudable or thermofornrable character, the guarantee of an optimal
preparation
process, more particularly insofar as concerns intimate mixing of the
constituents and
incorporation of the medicinal substance. Mixing of the selected ingredients
and their
CA 02119109 2002-03-20
subsequent extrusion or thermoforming may be effected by means of the
conventional
techniques.
In one preferred embodiment ofthe invention, the constituents of the composite
polymeric
material matrix are divided up as follows:
- hydroxypropyl cellulose 5(? to'~9.5°,% by weight
- non-neutralised pol~,winyl carboxylic acid 0.5 to 5.0% by weight,
any remainder up to 100% by weight being ethyl cellulose.
For example, the present invention more particularly provide a solid
ophthalmic insert
intended for the prolonged and controlled release of at least one medicinal
substance,
which comprises a matrix ovF composite polymeric material in which the
medicinal
substance is incorporated, cha~~acterized in that said composite polymeric
material matrix
comprises a mixture of
from 50 to 99.5 % by weight of hydroxypropylcellulose,
- from ().5 to 5 % by weight of a non-neutralized polyvinylcarboxylic acid,
and
- from 0 to 49.5 % by weight of ethylcellulose,
said mixture being extrudal7le or therrr~oformable.
According to the invention, 0.5 to 50°~o by weight, of medicinal
substance is generally
incorporated in the insert depending on the nature of the medicinal substance,
the type of
disorder to be treated and the required effect. The inset according to the
invention will
more generally be in the loan of a small uod, disc, pastille or film,
depending on
requirements.
As an example of medicinal substance. the most diverse appropriate agents can
be used,
such as antibacterial, antiviral, anlimycotic, anti-glaucoma, antiphlogistic,
anti-
CA 02119109 2002-03-20
5a
inflammatory, anti-allergy, vasoconstrictive, vasodilatory, myotic, mydriatie,
or
anaesthetic agents or altecwnatively lubricating action preparations
(artificial tears).
However, this list is not exUar~:ctive.
The medicinal substance wil l be advantageously submitted before its
incorporation in the
composite polymeric material matrix, to a physical pretreatment for decreasing
its release
rate.
This physical pretreatment may for example consist in changing the medical
substance
into an inclusion product in a support (form such as liposomes, coacervates,
nanospheres
or nanoparticles for example), into an adsorption product on a support or into
a co-
precitation product with a support, said support being a pharmaceutically
acceptable
product which is water-soluL~le and/or biodegradable and/or able to lose its
physical
cohesion when brought inter contact with a biological fluid.
However, according to a preferred embodiment, said physical pretreatment
comprises
forming a solid solution between said medicinal substance and a
pharmaceutically
acceptable product which is water-soluble and/or biodegradable and/or able to
lose its
physical cohesion when brcauf;ht into contact with a biological fluid; the
weight ratio of
said medicinal substance to~ said product may vary in a broad range, a
preferred range
being 10/2 to 10/10.
The above mentioned support and product may for example be chosen among the
acrylic
acid polymers (PAA); methacrylic acid copolymers (such as EUDRAGIT~ L or S);
carboxylic acid esters of celkulose or cellulose derivatives such as cellulose
acetate (CA),
cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT),
cellulose acetate
butyrate (CAI3), cellulose acetate propionate (CAPr), hydroxypropylmethyl
cellulose
phthalate (HPMCP), hydrcrxypropylmethyl cellulose acetate succinate (HPMCAS),
methylcellulose acid phthalate and ethyl (hydroxyethyl) cellulose acid
phthalate;
polymers of vinyl esters of carboxylic acids such as polyvinyl
acetate phthalate (PVAP ); carboxylic acid esters of starch such as starch
_.
6
acetate phthalate ; and their mixtures.
The formation of said solid solution may be carried out by dissolving said
pharmaceutically acceptable product which is water-soluble and/or
biodegradable
and/or able to lose its physical cohesion, in an appropriate solvent, adding
under
stirring the medicinal substance to the thus obtained solution, removing said
solvent
preferably by vacuum evaporation and crushing the solid residue.
The invention will be illustrated by reference to the following examples,
which have
no limiting force.
Example 1
An insert was prepared which contained gentamycin sulphate as medicinal
substance,
incorporated in a proportion of 25% by weight in a binary polymeric material
matrix
produced from the following components:
- hydroxypropyl cellulose (Klucel~ HXF - Aqualon)
- non-neutralised polyvinyl carboxylic acid (Carbopol~ 934 P - Goodrich),
to which was also added about 0.5% (with respect to the total weight) of
sodium
fluorescein as UV tracer.
The samples were prepared after intimate mixture of the above ingredients in
powder
form, followed by extrusion by means of a piston extruder, under the following
conditions: extrusion temperature about 160°C, duration 2 minutes,
extrusion pressure
200 kPa, die diameter 1.5 mm. To obtain perfect homogenisation of the various
constituents, two successive extrusions were carried out. The inserts kept for
experimentation were in the form of small rods 5 mm long and 1.35 to 1.45 mm
in
7
diameter.
For in vivo experimentation, the samples were deposited in the rear part of
the
conjunctiva) sac of rabbits (1 to 5 subjects per experiment). The presence or
absence
of the insert was then determined by means of an ultraviolet lamp, visual
checks
being made at regular intervals. The results obtained were combined in the
following
table:
Sample HPC* Carbopol~ Duration Rejection rate
No % % h
O11 100 0 7 40
013 99.5 0.5 8 0
018 99.0 1.0 16 0
* hydroxypropyl cellulose
** number of inserts rejected expressed as a percentage
Example 2
An insert was prepared which contained gentamycin sulphate as medicinal
substance,
incorporated in a proportion of 25% by weight in a ternary polymeric material
matrix
produced from the following components:
- ethyl cellulose EC N-50 NF's
- hydroxypropyl cellulose (Klucel~ HXF - Aqualon)
- non-neutralised polyvinyl carboxylic acid (Carbopol~ 934 P - Goodrich),
- ~~~.~:~(D9
8
to which there was. also added about 0.5% (with respect to the total weight)
of
sodium fluorescein as ultraviolet tracer.
The samples were then subjected to the extrusion process described
hereinbefore, and
were then tested in vivo under identical conditions on rabbits. The results
were
collected in the following table:
Sample HPC* EC* * Carbopol~ Duration Rejection rate
No. % % % h
017 89.5 10.0 0.5 9 15
020 89.0 10.0 1.0 21 0
022 79.0 20.0 1.0 19 0
026 78.0 20.0 2.0 19 0
028 77.0 20.0 3.0 20 0
030 76.0 20.0 4.0 20 0
031 75.5 20.0 4.5 19 0
* Hydroxypropyl cellulose
* * Ethyl cellulose
* * * number of inserts rejected expressed as a percentage
Example 3
Preparation of inserts containing_a solid solution of gentamicine-CAP and
evaluation
in do s
This preparation is carried out in three steps, i.e. preparation of the solid
solution (I),
preparation of the product to be extruded (II) and extrusion (III).
9
(I) $gparation of the solid solution Gentamicine-CAP
~ Dissolution, at reflux, of 90 g of CAP in 500 ml of acetone,
~ Addition, under stirring, of 150 g of Gentamicine sulphate,
~ Removing of the acetone by vacuum evaporation and then in a vacuum
drying oven,
~ Crushing of the solid residue,
~ Sieving of the crushed residue for recovering particles having 500 ~.m
(II) Preparation of the product to be extruded
~ Mixing in a mixer HPC, EC and Carbopol ~ 934 P in the following
proportions : HPC : 67 % ; EC : 30 % ; Carbopol~ 934 P : 3 %,
~ Incorporation of 20 g of the solid solution prepared in step (I), to 30 g of
the above-obtained mixture,
~ Homogenization.
(III) Extrusion
~ Use is made of a BETOL~ 1820) type laboratory screw extrusion device
working under the following conditions : temperature of zone 1 : 140° C
;
temperature of zones 2 and 3 : 150° C, ; die diameter : 2 mm ;
extrusion
temperature : 160° C.
~ This device is supplied with the preparation obtained in step (II),
~ Extrusion with a screw rotation speed of 20 to 40 rpm,
~ Evaluation of the Gentamicine concentration in dogs (Beagle).
The release of Gentamicine from the above-prepared inserts has been
evaluated as follows:
_ 2~1~~.~9
The insert is deposited in the conjunctiva) sac, 4 ~,1 of tears are taken as a
sample at regular intervals and the Gentamicine concentration is determined
by immunofluorescence polarization.
The results obtained are given in the following table (6 or 12 test animals
per
group).
~~ Time (h) 6 12 18 24 30 36
Average (~,,g/ml] 3767 3707 3519 3433 3357 3341
Standard-Deviation 395 245 101 59 126 300
(pg/ml]
Time (h) 42 48 54 60 66 72
Average [~ug/ml] 3320 3339 2671 1809 1108 462
Standard-Deviation 142 194 85 111 39 10 ~!~
(M,g/ml]
The above results show that Gentamicine is present in an effective
concentration,
higher than the minimum inhibitive concentration during 72 hours.
Example 4
Preparation of inserts by heat compression
Ophthalmic inserts of square section are prepared as follows
After mixing of HPC (KLUCEL~ HXF NF, Aqualon~), EC (EC N-50 NFL Hercules)
and a derivative of polyacrylic acid (Carbopol~ 934 P, Goodrich) in the
following
proportions : HPC : 80 % ; EC : 18 % and Carbopol~ : 2 %), the obtained powder
11
mixture is placed on the lower die of a heat compression concentration device.
The
heat compression is carried out with the following conditions : compression at
40.105 Pa during one minute ; temperature-rising : up to 150° C and
stalilization at
this temperature during 1 mn ; cooling by a pneumatic system up to room
temperature ; decreasing of the pressure and removal from the mold. The thus
obtained product is cut to obtain extruded pieces having a length of 5 mm long
and
a square section of 1,5 mm width.
