Bioadhesive opthalmic insert.

Bioadhesive Ophthalmic Insert

The subject of the invention is a bioadhesive ophthalmic insert, more particularly a bioadhesive ophthalmic insert intended for the sustained and controlled release of one or more medicinal substances.

In human medicine as in veterinary medicine, many pharmaceutical compositions are known to date which are used in the treatment of the most varied eye disorders, whether they are inflammations such as conjunctivitis, infections of viral origin or bacterial, glaucoma or dry eye syndrome for example. These compositions are most often in the form of eye drops, gels, ointments, films or even inserts which are deposited, in the latter case, either in the conjunctival cul-de-sac or under the upper eyelid. .

The use of ophthalmic inserts is in particular sought when the prescribed treatment must be of long duration or requires a prolonged contact time of the active principle, or even when applications must be repeated frequently. In such cases, the aim is both the comfort of the subject treated, by reducing the number of operations required for example, and the controlled release of the active substance over a sufficiently long period. Essentially, such inserts are obtained from a water-soluble polymer or copolymer, in particular from a water-soluble cellulose derivative incorporating the active substance in variable proportions (see for example US-A-4,179,497, 4,343,787, 3,870,791 or EP-A-0.108.661). A single polymer material is then used, which efforts are made to adapt to the intended purpose according to its specific characteristics, by acting on parameters such as viscosity, molecular weight, crystallinity for example. The means of action available are, however, very limited.

- 2 At the present time, the ophthalmic inserts available do not make it possible to obtain prolonged residence times, while guaranteeing an appropriate release of the active substance. In addition, a fortuitous displacement of the insert is often observed, either as it passes behind the eye or as it leaves the orbit. The invention has the merit of proposing a new type of ophthalmic insert making it possible to advantageously overcome such drawbacks, ensuring in particular the permanence of its positioning and the lasting release of the medicinal active principle.

The subject of the invention is a bioadhesive ophthalmic insert, in particular a bioadhesive ophthalmic insert intended for the sustained and controlled release of at least one medicinal substance consisting of a matrix of composite polymer material in which the medicinal substance is incorporated, the said matrix of polymer composite material comprising:

- a water-soluble biocompatible polymer and

- a bioadhesive biocompatible polymer.

A subject of the invention is also an ophthalmic insert as defined above characterized by a matrix of composite polymer material comprising:

- a non-water-soluble biocompatible polymer,

- a water-soluble biocompatible polymer and

- a bioadhesive biocompatible polymer.

Advantageously, the matrix of composite polymer material 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, the remainder optional 100% by weight consisting of the non-water-soluble biocompatible polymer.

According to the invention, it is advantageously possible to use, as water-soluble biocompatible polymer, a hydroxyalkylcellulose, a maltodextrin, a chitosan, a modified starch such as for example a pregelatinized starch, a destructured starch (see for example US-A-4,900,361). or a partially hydrolyzed starch, or else a polyvinyl alcohol, this enumeration being however not exhaustive. Preferably a

- 3 hydroxyalkylcellulose such as a hydroxyethylcellulose or a hydroxypropylcellulose with a molecular weight of between 10,000 and 1,000,000 or more, preferably between 80,000 and 125,000. Such products are found in the specialist trade.

According to the invention, as water-insoluble biocompatible polymer, it is advantageously possible to use a water-insoluble alkylcellulose, preferably an ethylcellulose such as for example EC-N 50 NE © (Hercules) or else Ethocel® (Premium Dow). Added in adequate proportions to the mass of water-soluble polymer, ethylcellulose has the effect of significantly lengthening the period of dissolution of the ophthalmic insert and, consequently, the period of release of the drug substance. Surprisingly, the incorporation of¹ethylcellulose in the polymer material chosen in accordance with the invention, nevertheless leads to the complete dissolution of the insert.

According to the invention, the matrix of polymer material comprises a bioadhesive polymer, that is to say a natural or synthetic polymer capable of stable interaction with a biological substrate, such as the mucosa of the conjunctival cul-de-sac for example. As a bioadhesive biocompatible polymer, one can advantageously use a polymer of the polyvinyl carboxylic acid type (carboxy vinylpolymer) or even certain polysaccharides or derivatives of bioadhesive polysaccharides such as, for example, cellulose ethers, methylhydroxyethylcellulose (Benecel® ME Aquaion, Tylose® MH Hoechst) or methylhydroxypropyl-cellulose (Benecel® MP Aqualon) for example. It is also possible to use sodium carboxymethylcelluloses such as Blanose® Type 7 or 9 (Aqualon) or Tylose® C (Hoechst) for example.

- 4 An unneutralized polyvinyl carboxylic acid is preferably used, with a molecular weight of between 450,000 and 4Ό00Ό00, such as Carbopol® 934 P, 980, 984, 954, (Goodrich) or Noveon® AAI (Goodrich). This use of non-neutralized material in an ophthalmic insert is at first sight surprising since it is recognized as an irritant: in fact, it is normally used in the form of the sodium salt. Dispersed in adequate proportions within the mass of polymeric material, this type of bioadhesive polymer loses its irritant character and guarantees a prolonged residence time of the insert. In addition, this type of polymer ensures the positioning of the insert in its initial location, thus offering all the desired security.

According to the invention, the polymers listed above are also chosen according to their extrudable or thermoformable nature, guaranteeing an optimal preparation method, in particular as regards the intimate mixing of the constituents and the incorporation of the substance. medicated. The mixing of the selected ingredients and their subsequent extrusion or thermoforming can be carried out by means of the usual techniques.

In a preferred embodiment of the invention, the constituents of the matrix of composite polymer material are distributed as follows:

- hydroxypropylcellulose from 50 to 99.5% by weight

- non-neutralized polyvinylic carboxylic acid of 0.5 to 5.0% by weight, the possible remainder to 100% by weight being constituted by ethylcellulose.

According to the invention, most generally 0.5 to 50% by weight, for example approx. 25% by weight of drug substance in the insert depending on the nature of the

- 5 drug substance, the type of condition to be treated and the desired effect. L¹insert according to the invention will most generally be in the form of a stick, disc, pellet or film, depending on requirements.

As a medicinal substance, the most diverse appropriate agents can be used, such as antibacterial, antiviral, antimycotics, antiglaucoma, antiphlogistic, anti-inflammatory, antiallergic, vasoconstrictor, vasodilator, miotics, mydriatics, anesthetics or even lubricating preparations. (artificial tears). This enumeration is not, however, exhaustive. The invention will be illustrated with the aid of the examples below, which are in no way limiting.

Example 1

An insert is prepared containing gentamycin sulfate as a medicinal substance, incorporated in an amount of 25% by weight in a matrix of binary polymer material obtained from the following components:

- hydroxypropylcellulose (Klucel® HXF - Aqualon)

- unneutralized polyvinyl carboxylic acid (Carbopol® 934 P - Goodrich), to which a further approx. 0.5% (relative to the total weight) of sodium fluorescein as UV tracer.

The samples are prepared after thorough mixing of the above ingredients in the pulverulent state, then extrusion using a piston extruder, under the following conditions: extrusion temperature approx. 160 ° C, duration 2 min, extrusion pressure 200 kPa, die diameter 1.5 mm. In order to obtain perfect homogenization of the various constituents, two successive extrusions are carried out. The inserts selected for experimentation are in the form of rods 5 mm long and 1.35 to 1.45 mm in diameter.

- 6 For the in vivo experiment, the samples were deposited in the posterior part of the conjunctival cul-de-sac of rabbits (1 to 5 subjects per experiment). The presence or absence of the insert is then determined by means of a UV lamp, visual checks being carried out at regular intervals. The results obtained have been collated in the table below.

<td>Sample.</td><td>HPC *</td><td>Carbopol®</td><td>Duration</td><td>Failure rate</td>

<td>no</td><td> %</td><td> %</td><td>h</td><td> **</td>

<td> 011</td><td> 100</td><td> 0</td><td> 7</td><td> 40</td>

<td> 013</td><td> 99,5</td><td> 0,5</td><td> 8</td><td> 0</td>

<td> 018</td><td> 99,0</td><td>1, o</td><td> 16</td><td> 0</td>

* Hydroxypropylcellulose ** number of inserts expelled expressed in%

Example 2

An insert is prepared containing gentamycin sulfate as a drug substance, incorporated in an amount of 25% by weight in a matrix of ternary polymer material obtained from the following components:

- ethylcellulose EC N-50 NF® (Hercules)

- hydroxypropylcellulose (Klucel® HXF - Aqualon)

- unneutralized polyvinyl carboxylic acid (Carbopol® 934 P - Goodrich), to which a further approx. 0.5% (relative or total weight) of sodium fluorescein as UV tracer.

The samples are then subjected to the extrusion process described above, in order to then be tested in vivo under identical conditions, on the rabbit. The results observed are collated in the table below.

<td>Sample.</td><td>HPC *</td><td>EC **</td><td>Carbopol®</td><td>Duration</td><td>Failure rate</td>

<td>no</td><td> %</td><td> %</td><td> %</td><td>h</td><td> ***</td>

<td> 017</td><td> 89,5</td><td> 10,0</td><td> 0,5</td><td> 9</td><td> 15</td>

<td> 020</td><td> 89,0</td><td> 10,0</td><td> 1, 0</td><td> 21</td><td> 0</td>

<td> 022</td><td> 79,0</td><td> 20,0</td><td> 1,0</td><td> 19</td><td> 0</td>

<td> 026</td><td> 78,0</td><td> 20,0</td><td> 2, 0</td><td> 19</td><td> 0</td>

<td> 028</td><td> 77,0</td><td> 20,0</td><td> 3,0</td><td> 20</td><td> 0</td>

<td> 030</td><td> 7 6,0</td><td> 20,0</td><td> 4,0</td><td> 20</td><td> 0</td>

<td> 031</td><td> 75,5</td><td> 20,0</td><td> 4,5</td><td> 19</td><td> 0</td>

* Hydroxypropylcellulose ** Ethylcellulose *** number of inserts expelled expressed in%