RU2843006C1 - Novel drug delivery system for ophthalmic use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to ophthalmic formulations. Disclosed is a drug delivery system comprising a decellularized corneal stroma frame having microparticles dispersed within the surface and/or bound to the surface, comprising at least one pharmaceutically active molecule, dispersed in a matrix containing a composition comprising from 85 wt./wt.% up to 95 wt./wt.% lactic-glycolic acid (PLGA) copolymer, polyethylene glycol and albumin, where the particles are characterized by a particle size distribution according to measurement using laser diffraction technology in range between 1.9 mcm and 7 mcm, and the pharmaceutically active molecule is a protein or peptide. There are also disclosed a method for preparing the drug delivery system and using it for treating ophthalmic diseases.

EFFECT: group of inventions provides the active molecule release at a constant rate, and the delivery system is highly biocompatible and non-immunogenic.

18 cl, 3 dwg, 1 tbl, 6 ex

Description

Field of technology to which the invention relates

The present invention relates to the field of ophthalmic slow-release formulations for delivering active substances to the surface of the eye, in particular for the treatment of corneal pathologies.

State of the art

Local instillation of drugs in the form of eye drops is the preferred and generally accepted route of treatment for most anterior segment diseases of the eye.

However, this route of administration is extremely ineffective and has extremely poor bioavailability. After instillation, the lacrimal flow moves the drug from the ocular surface to the nasolacrimal ducts within minutes, and thus most of it is lost through nasolacrimal drainage. Only 5% of the total amount of drug administered is available for a sufficient period of time in contact with the ocular surface to exert its therapeutic effect.

This requires frequent administration of large amounts of the drug with very poor patient compliance and makes the effective dose inaccurate.

In order to achieve effective drug concentration and retention time on the anterior surface of the eye, punctal obturators have been used, thereby reducing the dose and frequency of administration. They are small medical devices that are inserted into the tear duct of the eye to block the duct and thus prevent drainage of fluid from the eye. However, they may be poorly tolerated by patients and cause complications such as increased lacrimation, foreign body sensation, infection, pyogenic granuloma, erosion of the lacrimal canaliculi, dacryocystitis and increased allergy symptoms.

One alternative approach has been to develop sustained-release delivery systems that extend the corneal residence time of drugs in the anterior segment of the eye, such as viscous solutions, mucoadhesive materials, or drug-eluting contact lenses.

For example, US 20040241207 discloses a contact lens with embedded drug nanoparticles that diffuse through the contact lens into the sub-lens tear film when the lens is applied to the eye.

However, contact lenses or other artificial polymers have the disadvantage of possibly triggering immune reactions in patients.

In addition to the above, the bioavailability of the drug is further reduced by the physiological barriers of the eye, which significantly limits the concentration of the drug in the inner layers of the cornea. In particular, the corneal epithelium is lipophilic and exhibits tight junctions between cells, which leads to its limited permeability to drug molecules, in particular, hydrophilic drug molecules.

Therefore, there is a need to develop a biocompatible, non-immunogenic delivery system that addresses the above-mentioned issues and makes it possible to obtain sufficient concentrations of drug molecules over a sufficient period of time in the anterior eye.

The essence of the invention

The inventors of the present invention have surprisingly discovered the possibility of functionalizing corneal stroma with lactic acid-glycolic acid copolymer (PLGA) microparticles containing pharmaceutically active molecules and using it for controlled release delivery of these molecules to the anterior region of the eye.

Accordingly, a first object of the invention is a drug delivery system suitable for ophthalmological use and comprising a decellularized corneal stromal scaffold having microparticles dispersed within the surface and/or associated with the surface, comprising at least one pharmaceutically active molecule dispersed in a matrix comprising a composition consisting of at least 70% lactic acid-glycolic acid copolymer (PLGA).

The second objective of the invention is a technological process for manufacturing a drug delivery system corresponding to the first objective of the invention.

A third object of the invention is a pharmaceutically active molecule for use in the treatment of pathologies of the anterior region of the eye, wherein said pharmaceutically active molecule is administered using a drug delivery system corresponding to the first object of the invention.

A fourth objective of the invention is a method of treating pathologies of the anterior region of the eye, comprising administering a pharmaceutically active molecule using a drug delivery system corresponding to the first objective of the invention.

Description of figures

Fig. 1 shows transmission electron microscopy (TEM) images showing the lenticule without treatment (panel A) and the lenticule after decellularization with 0.1% SDS (panel B) in accordance with the description of the invention in Example 2.

Fig. 2 shows images of lenticules obtained using confocal microscopy in accordance with the description of the invention in Example 4. In detail, panel A shows a three-dimensional reconstruction revealing the superficial localization of Fluo-MPs microparticles (light gray dots) in the lenticule; panel B shows a two-dimensional image revealing the distribution of Fluo-MPs microparticles (light gray dots) between collagen fibers (dark gray area).

Fig. 3 shows the kinetics of rhNGF release in vitro from the lenticule as measured in Example 6. The diagram shows the cumulative release of rhNGF from PLGA-MPs containing it previously incorporated into the lenticule.

Detailed description of the invention

The first object of the present invention is a drug delivery system comprising a decellularized corneal stromal scaffold having microparticles dispersed within the surface and/or associated with the surface, comprising at least one pharmaceutically active molecule dispersed in a matrix comprising a composition consisting of at least 70% (w/w) of a copolymer of lactic acid and glycolic acids (PLGA).

According to one preferred embodiment of the invention, the corneal stromal scaffold according to the first object of the invention is a graft obtained from the cornea of the patient being treated or from a donor.

For example, said corneal stroma may be obtained from a donor undergoing refractive eye surgery, preferably refractive lenticule extraction (ReLex) or femtosecond lenticule extraction (FLEx). Alternatively, said corneal stroma may be derived from a cadaveric tissue donor.

According to another preferred embodiment of the invention, said corneal stromal scaffold is an engineered corneal stromal scaffold obtained in vitro.

Preferably, said corneal stromal framework is a corneal stromal lenticule.

Preferably, said corneal stromal lenticule has a thickness in the range between 80 and 300 μm, preferably between 100 and 150 μm, and/or a diameter between 4 and 9 mm, preferably between 5 and 8 mm, more preferably between 6 and 7 mm.

Preferably, said corneal stromal scaffold is acellular.

The absence of cells in the stroma makes it immunogenically compatible and creates pores in the framework that include microparticles.

According to one preferred embodiment, said microparticles are dispersed within a decellularized corneal stromal scaffold.

According to one preferred embodiment, said microparticles are both dispersed within the surface of the decellularized corneal stromal scaffold and associated with that surface.

Preferably, said matrix of the drug delivery system according to the first object of the invention comprises at least 75% (w/w), preferably 80% (w/w), more preferably 85% (w/w), of a lactic acid-glycolic acid copolymer (PLGA).

Preferably, said matrix comprises from 85% (w/w) to 95% (w/w), more preferably 89% (w/w), of lactic acid-glycolic acid copolymer (PLGA).

According to one particularly preferred embodiment, said PLGA copolymer is characterized by a copolymer composition consisting of from 50% (w/w) to 75% (w/w), preferably 75% (w/w), lactic acid and from 50% (w/w) to 25% (w/w), preferably 25% (w/w), glycolic acid.

According to another preferred embodiment, also in combination with the previous embodiments, said PLGA copolymer is amorphous.

According to another preferred embodiment, also in combination with the previous embodiments, said PLGA copolymer has a molecular weight in the range between 4000-15000 g/mol.

A PLGA copolymer particularly suitable for use in the drug delivery system of the invention is, for example, the product marketed under the trade name Resomer® RG752H and is a copoly(D,L-lactide-glycolide).

Preferably, said matrix further comprises, in addition to PLGA, one or more additional components selected from polyethylene glycol, preferably low molecular weight polyethylene glycol, more preferably PEG400, albumin, preferably human serum albumin (HSA), and/or trehalose. Preferably, said matrix comprises a composition consisting of PLGA, PEG400, HAS and trehalose, wherein PLGA is present in an amount of at least 70% (w/w) of the total composition.

According to one preferred embodiment of the invention, said microparticles consist of said matrix together with at least one pharmaceutically active molecule dispersed therein.

Preferably, in order to obtain both an effective incorporation into or binding to the corneal stromal framework and a suitable release rate of the pharmaceutically active molecule, the microparticles are characterized by a particle size distribution as measured using laser diffraction technology in the range between 1 and 15 μm, preferably between 1.5 and 10 μm, more preferably between 1.9 and 7 μm. Preferably, said particle size is measured using a Mastersizer2000 particle size analyzer with a Hydro 2000μP wet sample dispersion unit (Malvern Panalytical).

The drug delivery system according to the invention is capable of releasing a pharmaceutically active molecule at a controlled rate, preferably over a period of at least one month.

Preferably, said pharmaceutically active molecule is a protein or peptide.

The protein in question may be of natural origin or synthetically produced, preferably it is a recombinant protein.

According to one preferred embodiment, said pharmaceutically active molecule is a growth factor or a peptide or protein mimicking a growth factor. More preferably, said pharmaceutically active molecule is a neurotrophin or a peptide or protein mimicking a neurotrophin.

According to the present invention, the term "neurotrophin" refers to proteins, including recombinant proteins, which act as growth promoters for neurons. These include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4); the term "peptide or protein that mimics neurotrophin" refers to any peptide or protein of natural or synthetic origin that is capable of acting as an agonist for one or more neurotrophin receptors. For example, a protein that mimics neurotrophin may be a protein that has mutations or truncations relative to a natural wild-type neurotrophin, but is capable of activating one or more neurotrophin receptors. Peptidomimetics may be either linear or cyclic peptides.

Particularly preferred pharmaceutically active molecules according to the invention are nerve growth factor or peptides or proteins mimicking nerve growth factor. Said nerve growth factor is preferably human nerve growth factor, more preferably recombinant human nerve growth factor.

The amount of pharmaceutically active molecule dispersed in the microparticle matrix will vary depending on the desired dose administered to the anterior part of the eye. Preferably, when said pharmaceutically active molecule is a nerve growth factor, it is contained in said microparticle matrix in an amount in the range between 30 and 100 ng, preferably between 50 and 90 ng, more preferably between 60 and 80 ng, calculated for each mg. According to the present invention, the expression "decellularized corneal stromal scaffold having microparticles bound to the surface" means that the microparticles are retained and retained on the surface of the decellularized corneal stromal scaffold by an attractive force, which can be of various types.

A second object of the present invention is a method for producing a drug delivery system according to the above description of the invention, comprising the following steps:

a. obtaining a corneal stromal framework in accordance with the above description of the invention, preferably a corneal stromal lenticule, from a donor cornea in accordance with the above description of the invention;

b. removing cellular material from said scaffold, if any, thereby obtaining a decellularized corneal stromal scaffold;

c. incubating said decellularized corneal stromal scaffold in a suspension of microparticles containing at least one pharmaceutically active molecule dispersed in a matrix containing a composition consisting of at least 70% (w/w) of a lactic-glycolic acid copolymer (PLGA) in accordance with the above description of the invention.

Preferably, in step a., said corneal stromal framework is a corneal stromal lenticule with a thickness in the range between 80 and 300 μm, preferably between 100 and 150 μm, and/or a diameter between 4 and 9 mm, preferably between 5 and 8 mm, more preferably between 6 and 7 mm.

Preferably, in step b. of the above-mentioned method according to the invention, said cellular material is removed in such a way as to obtain an amount of residual cells in said corneal stromal framework that is less than 0.5% (w/w), more preferably to obtain an acellular lenticule.

Preferably, said cellular material is removed by incubating the lenticule in a surfactant solution. According to one preferred embodiment, said surfactant is sodium dodecyl sulfate (SDS), preferably at a concentration in the range between 0.05 and 0.2%, more preferably 0.1%.

In order to achieve effective removal of the cellular component from the lenticule, incubation with the surfactant solution must be carried out for at least 20 hours, preferably for at least 24 hours.

When the corneal stromal scaffold is a corneal stromal lenticule, the decellularized lenticules obtained in step b. can be co-incubated with microparticles immediately after extraction from the donor.

More preferably, the decellularized lenticules obtained in step b. are dehydrated and stored at room temperature until use. According to this embodiment, the above-mentioned method further comprises, after step b. and before step c., a step b', where the decellularized lenticules are dehydrated, preferably by treatment at a temperature in the range between 50° and 70°C, preferably between 55° and 65°C, more preferably 60°C, for 1 to 3 hours, preferably 2 hours.

Dehydration of decellularized lenticules is particularly advantageous because it significantly increases the potential for microparticle incorporation into the stroma.

Incubation of the corneal stromal scaffold with the microparticle suspension at stage c is preferably carried out at room temperature.

Preferably, said incubation is carried out for a period of time ranging between 1 and 5 hours, preferably 3 hours.

The microparticles of step c. of the method according to the present invention are obtained using the following steps:

a. obtaining a water/oil emulsion containing a pharmaceutically active substance and a lactic-glycolic acid copolymer.

b. obtaining an aqueous solution containing polyvinyl alcohol mixed with the same organic solvent as used in the oil phase of step a.

c. mixing the emulsion and solution obtained in steps a. and b., and homogenizing to thereby obtain a water/oil/water emulsion.

d. evaporation of the organic solvent, thereby obtaining a precipitation of microparticles.

i.e. extraction and washing of precipitated microparticles.

f. freeze drying of microparticles.

Preferably, in step a. the lactic-glycolic acid copolymer is present at a concentration in the range between 10 and 30% (w/v), preferably between 15 and 25% (w/v), more preferably between 18 and 22% (w/v).

Preferably, said oil phase in step a. is ethyl acetate.

Preferably, in step b., the concentration of polyvinyl alcohol in the aqueous solution is in the range between 0.5 and 2% (w/v), preferably 1% (w/v).

A drug delivery system obtained using a process technology corresponding to the second objective of the invention has all the features corresponding to the first objective of the invention.

As will be demonstrated in Example 6, the drug delivery device of the invention is capable of releasing a pharmaceutically active molecule from microparticles incorporated into a corneal stromal scaffold at a controlled rate over a period of at least one month.

The delivery system according to the invention can be advantageously used to deliver pharmaceutically active molecules to the anterior segment of the eye.

Administration to the patient can be carried out in different ways depending on the specific pathology being treated.

For example, in a case where it is necessary for a pharmaceutically active molecule to exhibit its activity on the inner layers of the cornea, the delivery system can be implanted into a surgically created intrastromal pocket in the patient's eye, for example, formed using a femtosecond laser. Alternatively, the delivery system can be applied to the surface of the cornea.

The active molecule in the delivery system will be released at a constant rate, thus maintaining an effective concentration at the site of action throughout the treatment.

The delivery system according to the invention is highly biocompatible and non-immunogenic and is therefore well tolerated by patients.

Accordingly, a third object of the invention is a pharmaceutically active molecule according to the above description of the invention for use in the treatment of ocular pathologies, preferably pathologies of the anterior region of the eye, wherein said pharmaceutically active molecule is administered in a drug delivery system corresponding to the first object of the invention.

The fourth objective of the invention is a method for treating ocular pathologies, preferably pathologies of the anterior region of the eye, comprising administering a pharmaceutically active molecule in a drug delivery system corresponding to the first objective of the invention.

EXPERIMENTAL SECTION

Example 1

Production of microparticles containing rhNGF (recombinant human nerve growth factor)

Microparticles formed from a lactic acid-glycolic acid copolymer (PLGA) matrix containing rhNGF were prepared according to the procedure described below.

A solution was prepared at 0.85 mg/mL rhNGF in formulation buffer (50 mmol/L sodium phosphate monohydrate, 100 mmol/L sodium chloride, pH 7.2).

An aqueous solution W1 was prepared containing 150 μl of the rhNGF solution obtained above, 6.01 mg of human serum albumin (HSA), and 150 μl of polyethylene glycol 400 (PEG400) (v/w/v ratio 1:40:1).

Thereafter, 150 μl of solution W1 was added to 7.5 ml of solution O containing 20% (w/v) PLGA (Resomer® RG752H) in ethyl acetate and homogenized at 17,400 rpm for 3 min in an Ultraturrax t25 basic homogenizer (IKA) using an 8G probe.

The resulting W1/O emulsion was quickly added to 30 mL of an aqueous solution of W2 containing 1% (w/v) polyvinyl alcohol (PVA) (Mowiol® 40-88) mixed with 900 μL of ethyl acetate and homogenized again at 1200 rpm for 30 min. The resulting double emulsion (W1/O/W2), tube wash and material recovery water were stirred for 3 h at 500 rpm at room temperature using an RW20D overhead stirrer (IKA) with a 2-blade PTFE-coated propeller stirrer to ensure evaporation of the organic solvent and precipitation of the microparticles. The suspension was collected in two 50 ml polypropylene tubes (Eppendorf Lobind protein) and centrifuged at 7400 rpm for 15 min at 4°C. Microparticles were isolated and washed 6 times with 50 ml Milli-Q grade water by centrifugation at 7400 rpm for 15 min at 4°C. Microparticles were then resuspended in aqueous trehalose at 2% (w/v). The resulting suspension was transferred to Class 1 siliconized ISO glass ampoules and frozen at - 80°C for subsequent lyophilization. The microparticles produced using this technique exhibited an incorporation efficiency of greater than 73% (55.5 ng rhNGF/mg microparticles versus the theoretical value of 76 ng rhNGF/mg microparticles) with a particle size distribution ranging between 1.9 and 6.9 μm as measured using the Hydro 2000μP wet sample dispersion method using a Mastersizer2000 analyzer (Malvern). The final microparticle composition was 89% (w/w) PLGA.

Example 2

Obtaining dehydrated decellularized lenticules

Human corneal lenticules, ranging in thickness between 100 and 150 μm, were obtained using the SMALL (small incision lenticule extraction) procedure according to the technique described in Sekundo W, Kunert KS, Blum M. Br J Ophthalmol. 2011; 95:335–339 and cryopreserved until further processing.

Later, lenticules were obtained for use in functionalization according to the following procedure.

The lenticules were thawed and the cellular component of the lenticules was eliminated by incubation in 0.1% SDS for 24 h at room temperature followed by 3 washes in PBS (phosphate buffered saline) (24 h in each case).

As demonstrated in Fig. 1, which shows the transmission electron microscopy (TEM) analysis of the lenticule before (panel A) and after (panel B) treatment with SDS solution, complete removal of the cellular component was achieved.

The decellularized corneal lenticules were then dehydrated by treatment at 60°C for 2 hours and stored at room temperature until use.

Example 3

Functionalization of lenticules

The rhNGF-containing microparticles obtained in Example 1 were used to functionalize the dehydrated decellularized lenticules obtained in Example 2.

In detail, 20 mg of the microparticles obtained in Example 1 were suspended in 0.175 ml of 0.9% NaCl solution, and one lenticule was added to the resulting suspension and incubated for 3 hours at room temperature using an orbital shaker at 200 rpm.

After this, the lenticule was removed from the suspension and washed 10 times in 0.4 ml of 0.9% NaCl solution (thoroughly).

Example 4

Analysis of functionalized lenticules

The functionalized lenticule obtained according to the invention description in Example 3 was lysed by incubation with 0.2 ml of a solution at 5 mg/ml collagenase IA in PBS buffer containing 100 mg/l Ca ²⁺ /Mg ²⁺ at 37°C for 30 minutes, this step was carried out for the specific lysis of the lenticule while preserving the already released rhNGF factor (supernatant) and whole rhNGF-MPs microparticles (granules). The lysed samples were centrifuged for 10 minutes at 8000 rpm and 4°C.

The supernatant phase obtained from centrifugation contains rhNGF already released by the microparticles, whereas the granule phase contains intact MPs.

The supernatant phase was collected and immediately stored at -20°C until analysis.

The residual beads corresponding to intact microparticles released by the lenticule upon lysis were treated with 0.05 ml ethyl acetate to lyse the PLGA shell of MPs and 0.100 ml PBS buffer containing 100 mg/L Ca ²⁺ /Mg ²⁺ was added to safely extract rhNGF. The samples were centrifuged for 5 min at 8000 rpm and the aqueous phase (bead phase) was collected.

Each medium collected from the supernatant and pellet phase was diluted 1:3 in PBS buffer containing 100 mg/L Ca ²⁺ /Mg ²⁺ and analyzed using an ELISA assay to detect the concentration of rhNGF.

The supernatant phase contains rhNGF already released by the MPs, while the granule phase contains intact MPs.

The results obtained from the analysis of the three lenticules are shown in Table 1 below.

Table 1

Sample Concentration of rhNGF in each phase (pg/ml) Cumulative rhNGF concentration (pg/mL) Free and released rhNGF/rhNGF in MP Lenticula 1 Supernatant (free and released rhNGF) 6387 7617 84% Granules (whole microparticles MPs) 1230 16% Lenticula 2 Supernatant (free and released rhNGF) 3455 4384 79% Granules (whole microparticles MPs) 929 21% Lenticula 3 Supernatant (free and released rhNGF) 3904 4639 84% Granules (whole microparticles MPs) 735 16%

The results obtained demonstrate high reproducibility in different lenticules of the ratio between the released rhNGF factor and the rhNGF factor contained in the microparticles.

Example 5

Distribution of rhNGF-MPs microparticles in lenticules

Fluorescent PLGA microparticles (Fluo-MPs) (supplied by S.I.C., #LGFG5000) were used to test the interaction of microparticles with lenticule.

5 mg Fluo-MPs were suspended in 0.175 ml of 0.9% solution and one lenticule was added to the resulting suspension and incubated for 3 hours at room temperature using an orbital shaker at 200 rpm.

After this, the lenticule was removed from the suspension and washed 10 times in 0.4 ml of 0.9% NaCl solution (thoroughly).

To assess the binding or incorporation of Fluo-MPs microparticles into the lenticule and their location, collagen within the lenticule was stained using immunofluorescence using the protocol described below.

The lenticule was fixed in 4% paraformaldehyde for 10 min, washed 3 times in PBS 1X for 5 min and then incubated for 1 hour with Anti-Collagen I primary antibody (Abcam, Cat# ab34710) in 1% BSA (bovine serum albumin) solution prepared in PBS 1X. After that, it was washed again 3 times in PBS 1X for 5 min and incubated for 1 hour with Anti-rabbit Cy3 secondary antibody (Jackson ImmunoResearch Laboratories, Cat# 111-165-144) in 1% BSA solution prepared in PBS 1X and washed 3 times in PBS 1X for 5 min.

Finally, the immunostained lenticule was placed on a coverslip and analyzed using a Zeiss LMS-800 confocal microscope.

As demonstrated by the obtained data shown in Fig. 2, the microparticles were mainly bound on the surface of the lenticule.

Example 6

In vitro kinetics of rhNGF release from lenticule-embedded MPs

The kinetics of rhNGF release from functionalized lenticules in vitro were assessed using the following method.

The functionalized lenticule obtained according to the invention description in Example 3 was incubated in a tube containing 0.150 ml PBS at 37°C using an orbital shaker at 80 rpm (LoBind tubes were used to preserve rhNGF).

Time points were set at t=0, 2, 4 or 24 hours and t=2, 5, 7, 9, 12, 14, 16, 19, 21, 23 or 25 days.

At each time point, the lenticule was removed from the original tube and transferred to a new tube containing 0.150 ml PBS and incubated again at 37°C using an orbital shaker at 80 rpm.

Each sample was immediately stored at -20°C.

After 1 month, samples were analyzed without dilution using ELISA to assess rhNGF titer.

As shown in Fig. 3, the release of rhNGF from the MPs microparticles incorporated into the lenticule was sustained for approximately one month. In particular, neurotrophin was released rapidly in the first 24 hours, and the release was maintained constant until the end of the experiment.

Claims (28)

1. A drug delivery system comprising a decellularized corneal stromal scaffold having microparticles dispersed within the surface and/or associated with the surface, containing at least one pharmaceutically active molecule dispersed in a matrix comprising a composition comprising from 85% w/w to 95% w/w of a lactic acid-glycolic acid copolymer (PLGA), polyethylene glycol and albumin, wherein the particles are characterized by a particle size distribution as measured using laser diffraction technology in the range between 1.9 and 7 μm, and the pharmaceutically active molecule is a protein or peptide. 2. The drug delivery system of claim 1, wherein the matrix comprises 89% w/w of a lactic acid-glycolic acid copolymer (PLGA). 3. The drug delivery system of claim 1 or 2, wherein the polyethylene glycol is a low molecular weight polyethylene glycol, more preferably PEG400, and the albumin is human serum albumin (HSA). 4. The drug delivery system according to paragraphs 1-3, wherein said corneal stromal framework is a transplant obtained from a donor cornea. 5. The drug delivery system of claims 1-4, wherein said corneal stromal framework is a corneal stromal lenticule. 6. The drug delivery system of claim 5, wherein said corneal stromal lenticule is obtained from a donor cornea using refractive eye surgery, preferably refractive lenticule extraction (ReLex) or femtosecond lenticule extraction (FLEx). 7. The drug delivery system according to claim 5 or 6, wherein said corneal lenticule has a thickness in the range between 80 and 300 μm, preferably between 100 and 150 μm, and/or a diameter between 4 and 9 mm, preferably between 5 and 8 mm, more preferably between 6 and 7 mm. 8. The drug delivery system of claim 1, wherein said pharmaceutically active molecule is a growth factor or a peptide or protein that mimics a growth factor. 9. The drug delivery system of claim 1 or 8, wherein said pharmaceutically active molecule is a neurotrophin or a peptide or protein that mimics a neurotrophin. 10. The drug delivery system of claims 1-9, wherein said pharmaceutically active molecule is a nerve growth factor or a peptide or protein that mimics a nerve growth factor. 11. The drug delivery system of claim 10, wherein the amount of said nerve growth factor in said microparticles is in the range between 30 and 100 ng, preferably between 50 and 90 ng, more preferably between 60 and 80 ng, calculated per mg of microparticles. 12. A method for producing a drug delivery system according to paragraphs 1-11, comprising the following steps: a. obtaining a corneal stromal scaffold from a donor cornea; b. removing cellular material from said scaffold, if any, thereby obtaining a decellularized corneal stromal scaffold; c. incubating said decellularized corneal stromal scaffold in a suspension of microparticles comprising at least one pharmaceutically active molecule dispersed in a matrix comprising a composition comprising from 85% w/w to 95% w/w of a copolymer of lactic acid and glycolic acid (PLGA), polyethylene glycol and albumin, wherein the particles are characterized by a particle size distribution as measured using laser diffraction technology in the range between 1.9 and 7 μm, and the pharmaceutically active molecule is a protein or peptide. 13. The production method according to item 12, wherein at stage a a corneal stromal framework is obtained, which is a corneal stromal lenticule. 14. The method according to claim 12 or 13, wherein in step b said cellular material is removed by incubating the corneal stromal scaffold in a surfactant solution. 15. The method according to claim 14, wherein said surfactant is sodium dodecyl sulfate, preferably at a concentration in the range between 0.05 and 0.2%, preferably 0.1%. 16. The method according to paragraphs 12-15, wherein the said microparticles of step c are obtained using the following steps: a. obtaining a water/oil emulsion containing a pharmaceutically active substance and a matrix comprising a copolymer of lactic-glycolic acids, polyethylene glycol and albumin; b. obtaining an aqueous solution containing polyvinyl alcohol mixed with the same organic solvent as used in the oil phase of step a; c. mixing the emulsion and solution obtained in steps a and b and homogenizing to thereby obtain a water/oil/water emulsion; d. evaporation of the organic solvent, thereby obtaining a precipitate of microparticles; e. extraction and washing of precipitated microparticles; f. freeze drying of microparticles. 17. Use of a drug delivery system according to paragraphs 1-11 for the treatment of eye pathologies. 18. The use according to claim 17, which is preferred for the treatment of pathologies of the anterior region of the eye.