WO2012114138A1

WO2012114138A1 - Biodegradable implants for the controlled subconjunctival release of an active molecule

Info

Publication number: WO2012114138A1
Application number: PCT/IB2011/000324
Authority: WO
Inventors: Alberto Della Martina; Raymond Andrieu; Denis GRUBER; Philippe Le Goff
Original assignee: Cerebel-Invest Sa
Priority date: 2011-02-21
Filing date: 2011-02-21
Publication date: 2012-08-30
Also published as: WO2012114186A1

Abstract

The invention relates to a biodegradable device in the form of a small patch, which can be implanted surgically under the conjunctiva, enabling the controlled and sustained release of one or more active molecules. The patch in question is provided in the form of a small piece of non-woven fabric consisting of one or more layers, the characteristics of which can vary in terms of the included active molecule(s) and/or the controlled release properties.

Description

BIODEGRADABLE IMPLANTS FOR CONTROLLED RELEASE

SUB-CONJUNCTIVAL OF AN ACTIVE MOLECULE

The present invention relates to the field of devices or implants intended to be implanted in the eye. It relates to a biodegradable device intended to be inserted under the conjunctiva, under a surgically established flap, in order to release an active molecule in situ.

In almost all cases of eye surgery, it is necessary to prescribe postoperative treatments, whether for preventive purposes to avoid, for example, infections of the operated site, for the purpose of reducing the effects of surgery.

secondary and postoperative risks of surgery (antibiotics, anti-inflammatories, painkillers, moisturizers, etc.) or for the improvement of the effect of treatment.

Due to the anatomy and physiology of the eye, it is often difficult to obtain effective doses of active molecule by systemic routes in this organ without reaching doses inducing serious side effects. Therefore, in most postoperative treatments, as well as for the treatment of chronic diseases of the eye, eye drops are used which must be administered to patients once or several times a day. This type of treatment has several limitations. Indeed, it is dependent on the diligence of the patient which can be very variable since the pathologies of the eye are often painless and the relief felt with the administration of the drug is thus very weak. Then, the liquid formulations are quickly removed by the tears and the dilution in the eye depends on the dryness of the eye of each patient. Thus, a very small portion of the administered dose reaches the intraocular tissues and the effective dose is very variable from one individual to another. This is why eye drops are highly dosed, their administration must be repeated, and the effective dose is poorly controlled. This problem has led to the development of controlled release systems for active molecules allowing the localized administration of precise doses. These systems often also have the advantage of allowing a prolonged release of active molecule and thus avoiding repeated administration of the drug.

In the case of ocular applications, there are several types of systems for such purpose. It is possible to classify in a first type the permanent devices using either physico-chemical methods or mechanical methods to release the drug. The microparticles or microcapsules may constitute a second type. Finally, there are implants of the type "plate (s)" or "sheet (s)" that can be grouped into a third type.

The first type has significant disadvantages among which it is possible to mention the need to implant a device constituting a foreign body in the eye and / or its proximity (with the inconvenience to the patient that it may constitute), the risks of rejection and / or infection related to such implantation and the need to possibly have to perform a second intervention to extract the implant when the treatment is completed.

The second type involves for its use microparticle deposition techniques or microcapsules, either liquid when the capsules are in suspension, or solid when they are in the form of powder, difficult to control in the context of an operation of ophthalmic surgery. In the first case, the practitioner will be confronted with the same problems as the patient who self-instills eye drops, that is to say that the total amount of microcapsules actually deposited (and therefore active molecule administered) is difficult. to control. In the second case, the handling of a powder is difficult in the operating room and its deposition in a particular place of the eye, natural and / or obtained by surgery, is delicate. The third type is probably the most suitable for anatomy and ocular function as well as for implantation in ophthalmic surgery. However, the devices known to date for ophthalmic applications are of monolithic type. In addition, the polymers used to make these implants, mainly polylactides, polyglycolides and combinations of these two types of polymers, have mechanical characteristics that make these implants rigid and brittle if they are designed too thick.

The present invention overcomes the disadvantages of the prior art and is distinguished by the features set forth in the claim. The invention will now be described in detail in the description which follows.

Briefly, the invention is a biodegradable device in the form of a small dressing, implantable surgically under the conjunctiva.

Unlike devices of this type described to date in the literature, the invention is in the form of a piece of cloth, of size to be implanted in the eye, made of non-woven biodegradable polymer fibers at the same time. inside which the active molecule is dispersed. This morphology of material makes it possible to overcome the problems of rigidity of the polymers constituting the implant, the fabric thus produced being naturally flexible.

The invention is a medical device intended to be implanted under the conjunctiva in the context of ophthalmic surgery. It is more specifically a patch cut in a nonwoven fabric.

The patch has dimensions adapted to its implantation surgically under the conjunctiva, typically a few millimeters long and wide and a few tenths of a millimeter thick.

The fabric in which the patch according to the invention is cut may consist of one or more "layers" of fibers, integral with each other, each layers which may be identical or different from others in terms of dimensions, characteristic and / or constituents.

Moreover, each of these layers can be homogeneous or see one or more of its characteristics vary through the layer. For the purpose of explaining the possible variations of the characteristics within the same layer, it is possible to give a non-limiting example: a layer consisting of a constant or variable gradient of thickness of the fibers constituting the layer or a gradient of porosity between the fibers.

The possible different layers of the patch according to the invention may be integral with each other by their implementation, that is to say that the method for making the different layers is able in itself to ensure that any successive layers remain interdependent without the use of other means. Alternatively, it is possible to use welding techniques, especially autogenous welding, or bonding, especially with a biological adhesive, biocompatible and preferably biodegradable.

In the patch is incorporated, dissolved in the mass of fibers comprising the structure of one or more layers of the fabric, one or more active molecules, which may be different from one layer to another.

One or more organic polymers, in the latter case in the form of copolymers or mixtures, all biocompatible and bioabsorbable, preferably the least inflammatory possible, preferably chemically close, but may have different degradation rates, can be used to achieve any or part of the possible different layers of the patch.

To form the fibers of each layer of the nonwoven according to the invention, the chosen organic polymer (s), or their (their) copolymer (s) or mixture (s), are preferably hydrophobic so that the resorption of the fibers, Physiological medium in the tissues, preferentially proceeds by erosion, the penetration of water into the fibers being limited.

This mode of degradation makes it possible to obtain longer resorption times, which are essential for the presence of the implant to be sufficiently long to reach release times of interest for ophthalmic applications.

In addition, the swelling of the polymer being reduced, the diffusion of the active molecule out of the mass of fibers where it is incorporated, is not accelerated. This advantageously allows better control and prolongation of the release of the active molecule out of the fibers.

It is appropriate at this point to define the polymers that fall within the scope of the present invention. It may be, for each possible layer of the fabric, a single polymer or a copolymer or a mixture of different polymers as described below.

The adjective "organic", used here to describe the polymer, is used in the chemical sense of the term. That is, it consists of one or more chemical compounds essentially based on carbon (C), hydrogen (H), oxygen (O) and / or nitrogen (N). ) with optionally one or more heteroatoms such as sulfur (S), chlorine (Cl), phosphorus (P) and / or trace elements, in extremely minor proportions.

By bioabsorbable is meant here a chemical body capable of biodegrading and resorbing in the organic body medium, that is to say, to disappear, fully or almost, in the presence of tissues and organic body fluids that eliminate the products. degradation, and this at the temperature

body. It is provided according to the invention that the device is resorbed while releasing the active molecule or molecules, during the time of presence in situ, corresponding to a sufficient time so that the desired therapeutic effect is achieved. Such a duration can be of the order of a few days to a few months.

Biocompatible and biodegradable polymer materials are, like biological molecules, organic compounds. Preferentially but not necessarily, the biodegradable polymers envisaged for the invention are chosen from those that degrade without being directly involved in the

metabolic processes and in particular not being sensitive to activity

enzyme. These polymers only bioabsorb under the effect of physicochemical processes, especially hydrolysis, independently of the activity

metabolic or enzymatic. However, the products of this resorption, they can be involved in the activity of cells and enzymes to be themselves possibly degraded, excreted and / or eliminated.

The chemical natures of the main polymers known to be

bioresorbables include polyesters, polyorthoesters, polyanhydrides, poly (ether) esters, polyamino acids and polydepsipeptides (eg Buchholz B "Analysis and characterization of resorbable dl-lactide-trimethylene carbonate copolyesters" Journal of Materials Science: Materials in Medicine, 1993; 4 (4): 381-388.)

In a schematic, but not exhaustive manner, the bioresorbable organic polymers can be described by a basic unit corresponding to the following semi-developed general formula:

~ [-X ₁ -C (O) -R ₁ -Y ₁ -S ₁ -] ~ [-X ₂ -C (O) -R ₂ -Y ₂ -S ₂ -] ~ eq. 1 in which:

C (O) denotes a group> C = O, ie a ketone group or a part of a carboxylic acid Xi and X ₂ are an oxygen atom (-0-) or a

secondary amine group (-NH-), which can become an amide bond

Yi (respectively Y ₂ ) denotes an oxygen atom (-O-), a group

(-NH-), or a single or double chemical bond directly connecting Ri to Si (or R ₂ to S ₂ )

Ri; R2; and S ₂ denote linear carbon chains or

branched from 0 to 10 carbon atoms, saturated or partially unsaturated, with or without heteroatoms.

In a particular case, if X ₁ and X ₂ , R 1 and R ₂ , Y ₁ and Y _{2 as} well as Si and S ₂ are identical in pairs, then the first monomer (the one whose indices are 1) is identical to the second (that whose indices are 2) and it is then a homopolymer. In the opposite cases, they are copolymers.

In particular, in order to avoid being exposed to the mechanisms of protein degradation by the enzymes that attack the proteins and lyse the amide or peptide bonds (proteases, peptidases), it is preferable to choose polymeric materials that have no amide function or same amino function. The bioabsorbable polymer materials are therefore preferably polymerized from monomers having no amine function (-NH ₂ , - NH- or = N-) and therefore no nitrogen (N). Therefore, in the above general synthetic formula, all the cases in which the groups X ₁ , Y ₁ , X ₂ , Y ₂ are amino groups will be excluded. The X ₁ and X _{2 groups} therefore consist of an oxygen atom or ether bond -O- (which becomes an ester bond since it forms -O-

C (O) -R). Thus, among the vast class of the preceding families, appeared an advantageous structure taking the following form:

~ [-OC (O) -R ₁ -Yi-S ₁ -] ~ [-O-C (O) -R ₂ -Y ₂ -S ₂ -] ~ eq.2 in which:

-O-C (O) - denotes a part of the polymer formed by a

group -O-C = 0, that is to say an ester bond

R and R ₂ denote a linear or branched carbon chain containing from 0 to 10 carbon atoms (C) and preferably from 0 to 3 C

Yi (resp.Y2) denotes an oxygen atom (ie an ether bond or alcohol function) or a single or double chemical bond connecting Ri to Si (or R2 to S ₂ )

Si and S ₂ denote a carbon chain, linear or branched, having from 0 to 10 carbon atoms (C) and preferably from 0 to 3 C.

Among these types of polymers, two appear more particularly interesting. The first type is obtained when Y or Y ₂ is an oxygen atom, respectively giving the structures ~ [-O-C (O) -Ri-O-Si-] ~ and ~ [-O-C (O) - R2-O-S ₂ -] ~, that is to say ester-ether. The other, simpler type is obtained when Yi or Y ₂ is a direct chemical bond (single or double), giving

respectively the structures ~ [-O-C (O) -R | -] ~ or ~ [-O-C (O) -Rn-] ~ in which R | or Ru are carbon chains having from 0 to 20 carbon atoms, preferably from 0 to 6 C.

Thus, among these two last types of polymers, corresponding to the two large families of poly (ester-ethers) and polyesters, all or part of the device of the invention should advantageously consist of

homopolymers which are polylactides (where RI = RM and is a group -CH (CH ₃ ) -), polyglycolides (where R 1 = R n and is a group -CH ₂ -) and polydioxanones (where R 1 = R ₂ and is a group -CH ₂ - and where Si = S ₂ is a group -CH ₂ -CH ₂ -), as well as their copolymers or mixtures. However, other homopolymers and copolymers of the series or their mixtures may be used.

Alternatively, another type of bioabsorbable organic polymer of interest for the realization of all or part of the device of the invention is that corresponding to the case where, in the eq.2, and / or R ₂ disappears, replaced by a simple chemical bond or double giving the following semi-developed formula:

- [- O-CiOJ-Y ^ SH-I-O-CiOJ-Ya-SH-eq

In this case, if Y ₁ and Y ₂ respectively designate an oxygen atom and Si and S ₂ linear or branched carbon chains, then the resulting polymer ~ [- 0-C (O) -O-Si-] ~ [ -O-C (O) -O-S ₂ -] - is a poly (alkylenecarbonate) (if Si = S ₂ ) or a poly (co-alkylenecarbonate) (if Si ≠ S ₂ ).

These polymers have the ability to be resorbed in vivo according to established and predictable resorption modes, especially in their duration, independent of the organic activity of the tissue, and whose rate of chemical degradation is mainly related to the temperature, the latter being substantially constant in human tissues.

It thus becomes possible to defer and modulate the resorption of the device according to the invention, in addition to the variation of the microstructure of the possible nonwoven layers, as a function of the polymeric material (s) chosen from such families of organic polymeric materials. bioresorbable. In this way, it is possible to form the possible different layers of the nonwoven from a different polymer or copolymer or polymer blend, so to assign each layer different properties of release of the active molecules or it contains.

Among the polymers considered, polydioxanones are known to cause virtually no inflammatory reaction, making them prime candidates for the contemplated ophthalmic applications. They are also widely approved and used as materials for the manufacture of sutures used in the context of eye surgery.

The active molecules envisaged to be incorporated into the fibers constituting the fabric in which the devices are cut out, are preferentially, but not necessarily, among those commonly used in the treatment of ocular pathologies.

Non-exhaustively include molecules belonging to the following classes: angiotensin-converting enzyme inhibitors, endogenous cytokines, basement membrane-mediating agents, endothelial cell growth-regulating agents, antagonists or blockers adrenoceptors, receptor antagonists or blockers

cholinergic drugs, aldose reductase inhibitors, analgesics,

anesthetics, antiallergics, anti-inflammatories, hypotensives, vasoconstrictors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infectives, antitumorals, antimetabolites, angiogenesis inhibitors, tyrosine kinase inhibitors antibiotics, analgesics, anthelmintics, antiparasitics, anti-blockers, antimicrobials, anti-glaucoma drugs, antineoplastics,

immunosuppressants, anti-prostaglandins, mydriatics, myosics, protease inhibitors, vasodilators, growth factors, etc.

Advantageously, but not necessary, it is intended to make all or some of the possible different layers constituting the fabric, in which the patch is cut, by the method known as electrospinning. This method consists in stretching with a difference in electrical potential a fiber produced by a extrusion system of a melt or a solution of polymer (s). In the latter case, the solvent may be simple or consists of a mixture of solvents. In the following, we will use "solvent" in a broad sense, designating both simple solvents and solvent mixtures.

By varying the various parameters of implementation of the method, it is possible to control the characteristics of the nonwoven fabric produced and thus the release properties of the active molecule (s). Among these parameters, one will quote in a non-exhaustive way: the characteristics (in particular the average molecular weight, the distribution of the molecular weights, the architecture

molecular (linear, branched, etc.) of the polymer (s) used, the characteristics of the melt or of the polymer solution (s) such as the viscosity and its surface tension, the potential difference applied between the nozzle of the system extrusion and the target receiving the projected fiber, the distance between these same nozzle and target, the flow rate produced by the extrusion system. In the case of a solution, these characteristics also depend on the chosen solvent and in particular, but not only, the concentration.

It is thus possible to obtain fabrics consisting of fibers whose diameter may range from a few tens of nanometers to a few tens of micrometers. These fibers can be more or less "fused" together, which can go as far as forming continuous films, at one end of the range, or structures resembling spun sugar or cotton at the other extreme.

Advantageously, the felt-like structures, where the fibers form a carpet and are wholly or partially fused at their points of contact, are

generally preferred.

In the case of electrospinning, the incorporation of the active molecule or molecules can be done in two ways. When the active molecule or molecules are soluble in the same solvent as the polymer (s) and they are not denatured by the solvent and / or the polymer or polymers, it suffices simply to add them to the solution in the desired proportions.

If the active molecule or molecules are not soluble in the solvent used and / or would be denatured by the interaction with the polymer (s) and / or the solvent, it is possible to use the technique of co-axial electrospinning. This technique involves debiting simultaneously, using a double nozzle

concentric, the solution of or polymers that will constitute the envelope of the fibers and the solution of the active molecule or molecules that will constitute the core of the fibers.

This technique simply requires that the two solvents, that of the polymer (s) and that of the active molecule (s), are not miscible, and also a greater control of the different parameters of implementation of the method. It is indeed necessary to adjust these parameters, in particular the ratio of the flows of the two solutions, in order to allow the formation of a continuous core-envelope structure.

It is also possible to incorporate one or more active molecules into the polymer (s) forming the envelope of such a structure and to introduce these same active or other molecules into the hollow core of the fibers when it is desirable to modulate the times. release of (possibly different) active molecules.

Claims

A surgically implantable device in the eye for the sustained and controlled release of one or more active molecules in the form of a piece of soft nonwoven fabric.

2. Device according to the claim, characterized in that the device consists of one or more organic polymeric materials

bioresorbable.

3. Device according to one of the preceding claims, characterized in that the device consists of at least one layer of nonwoven fabric.

4. Device according to one of the preceding claims, characterized in that the device consists of one or more layers whose characteristics can vary through one, several or each of the layers.

5. Device according to one of the preceding claims, characterized in that the possible different layers constituting the device remain integral with each other by implementation of the successive layers.

6. Device according to claims 1 to 4, characterized in that the

possible various layers constituting the device remain integral with each other by welding, especially autogenous welding, or bonding, in particular with a biological adhesive, biocompatible and

preferentially biodegradable.

7. Device according to one of the preceding claims, characterized in that each of the possible different layers constituting the device are made using a bioresorbable organic polymer material, known to be the most biocompatible possible and the least inflammatory possible, such as, but not limited to, a polylactide, a polyglycolide, a polycaprolactam, a polycaprolactone and especially polydioxanone, or a copolymer or mixture of the aforesaid materials.

8. Device according to claims 1 to 6, characterized in that the

Possible different layers constituting the device are made using a bioresorbable organic polymer material, among which polydioxanone is preferred.

9. Device according to one of the preceding claims, characterized in that one or more possible different layers constituting the device contain, incorporated (s) in the fibers forming the nonwoven constituting each possible layer, one or more active molecules.

10. Device according to one of the preceding claims, characterized in that one or more of the active molecules are among, but are not limited to: angiotensin converting enzyme inhibitors, endogenous cytokines, agents influencing the

basement membrane, agents influencing endothelial cell growth, adrenoceptor antagonists or blockers, cholinergic receptor antagonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatories, hypotensives , vasoconstrictors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infectives, antitumorals, antimetabolites, angiogenesis inhibitors, tyrosine kinase inhibitors, antibiotics, analgesics, anthelmintics, antiparasitics , anti-baegic, antimicrobial, antiglaucoma, antineoplastic, immunosuppressant, anti-prostaglandin, mydriatic, myosic, protease inhibitor, vasodilator, growth factor.

11. Device according to one of the preceding claims, characterized in that all or some of the possible layers of the invention are obtained by the method of electrospinning or co-axial electrospinning.