Carrier incorporating an ocular drug, polymerisation mould and method for obtaining said carrier incorporating an ocular drug

Abstract

The present invention relates to a carrier incorporating an ocular drug, a polymerisation mould and a method for obtaining said carrier incorporating the drug. The carrier incorporating the ocular drug comprises a cured PDMS / ocular drug body with the pharmaceutically acceptable amount of ocular drug dissolved in acetone and incorporated into the PDMS base polymer prior to curing.

Description

[0001] DESCRIPTION

[0002] Ocular drug delivery vehicle, polymerization mold and method for obtaining said ocular drug delivery vehicle

[0003] Technical field of the invention

[0004] The present invention falls within the field of medicine, and more specifically within the medical specialty of ophthalmology. Specifically, it relates to an ocular drug delivery vehicle, such as an intraocular lens (IOL) or a capsular tension ring (CTR), that releases a drug, for example, dexamethasone (DX), in a sustained manner. This ocular drug delivery vehicle requires the use of a specific procedure and mold for its manufacture.

[0005] Background of the invention

[0006] An intraocular lens (IOL) is an artificial lens implanted inside the eye to replace or enhance the function of the natural lens, which is to focus images onto the retina so they are seen clearly. Other devices may be required. One example is capsular tension rings (CTRs). CTRs are a group of ocular prostheses used to improve the outcomes of lens surgery in various situations. For example, they allow for postoperative anatomical stabilization of eyes with zonular pathology (a ligamentous structure that holds the lens in place within the eyeball).

[0007] Eye diseases are generally treated topically in the form of eye drops. The bioavailability of the drug is very low, and only 1 to 5% of the administered amount actually reaches the internal eye tissues. Most of the drug is lost through tear drainage and blinking, among other factors. In clinical practice, solutions much more concentrated than the amount needed for treatment are used, due to this poor penetration through the cornea. Furthermore, prolonged, regular administration (even lifelong, as in the case of glaucoma—the second leading cause of irreversible blindness in people over 60—uveitis, and corneal transplant patients) is necessary, and it must be done correctly. Therefore, the effectiveness of the treatment depends on the patient's skill and adherence to the prescribed regimen.Furthermore, the continuous application of 0.1% dexamethasone (DX) eye drops for extended periods (between 3 weeks and 1 year) can cause irreversible optic nerve damage, visual acuity and field defects, and the formation of posterior subcapsular cataracts and thinning of the cornea or sclera. Therefore, it is necessary to find a method that allows for more controlled drug delivery or release into the eyes. Other methods used to treat eye diseases that attempt to administer the drug more effectively include intravitreal microinjections, implants, or iontophoresis. However, these methods can alter the structure of the eyes and produce side effects such as increased intraocular pressure, retinal detachment, intraocular bleeding, and burns or infections.Intravitreal injections of anti-angiogenic drugs are administered chronically, monthly, for the treatment of several highly relevant eye diseases, such as age-related macular degeneration (AMD - the leading cause of irreversible blindness in people over 60).

[0008] The use of drug-eluting contact lenses (IOLs) allows the active ingredient to be released in a controlled manner and directly onto the cornea. The advantages of using IOLs over topical eye drops are that they promote penetration of the active ingredient and therefore its therapeutic efficacy, while also avoiding potential side effects from overexposure to the drug (allowing for adjustment of the effective dose according to the patient and improving tolerance, while also preventing allergic ocular reactions). Another practical advantage is that it does not depend on the patient's or third party's willingness or ability to administer the treatment, since the IOL itself releases the drug in the indicated amounts and for the necessary time.

[0009] A drug delivery vehicle is an artificial medium containing a drug that is released into the human body once implanted. Thus, the use of intraocular lenses (IOLs) as a delivery vehicle for an ocular drug is of interest, for example, in the postoperative period following cataract surgery (clouding of the lens and the most frequent cause of reversible blindness worldwide), glaucoma, or uveitis. The major advantage of doped IOLs (IOLs plus), acting as a drug delivery vehicle, is that they allow for adequate and continuous drug administration, regardless of patient compliance and without requiring any additional action (such as instilling eye drops postoperatively to prevent infection) after IOL implantation. Numerous polymers have been proposed for the development of drug-eluting ocular lenses.They are mainly based on poly(2-hydroxyethyl methacrylate) (pHEMA), and polylactic-co-glycolic acid (PLGA), but the use of polymethyl methacrylate (PMMA) has also been described, and in some cases also silicone hydrogels, such as polydimethylsiloxane (PDMS).

[0010] In the state of the art, different methods are known for incorporating an ocular drug into lenses:

[0011] • Soaking method: This method involves immersing the lens in a solution of the active ingredient. It is an easy, fast, and low-cost process. However, it results in rapid drug release, low drug diffusion, large quantities of solvent, and sometimes the doped lens cannot be stored and must be used immediately. Examples include PolyHEMA gels immersed in DX solutions, commercial lenses immersed in DX and vitamin E solutions, IOLs (HEMA-silicone hydrogel), and CeeOn (AMO) silicone lenses.

[0012] • Solvent casting. This method incorporates the polymer and the active ingredient, and polymerization occurs at high temperatures. It offers prolonged release and direct use. However, the high temperatures can lead to degradation of the active ingredient. PLGA films with DX embedded in commercial lenses have been described, yielding 1500 pg in 7 days. It requires heat or UV light for polymerization and pre-made lenses.

[0013] • Incorporation of nanoparticles, implants, or reservoirs containing the active ingredient. This results in longer-lasting releases. The active ingredient can be encapsulated, preventing enzymatic reactions. However, these nanoparticles can aggregate and affect the optics and transparency, and the stability of the nanomaterial can vary over time, potentially releasing the active ingredient. Chitosan nanoparticles with DX have been described as releasing 43 pg in 10 days, and PMMA IOLs at 730.63–1074.02 ng / mL.

[0014] • Molecular imprinting: Cavities with affinity for the active ingredient are created. This method allows for prolonged release and the incorporation of large quantities. It is applicable to some active ingredients that need to be stable during polymerization. In other words, it involves a complex design.

[0015] • Technologies using supercritical fluids. These methods allow for prolonged and high-volume releases. Furthermore, the polymer structure is preserved. However, they can affect the optical properties of the lenses and require high equipment and operational costs. Several IOLs have been described: FLEX (Tecsoft foldable acrylic IOLs), 150–300 pg / IOL in vitro; rigid pMMA (Fred Hollows IOLs): hydrophobic; HEMA / pMMA (Shenyang Bio Medical Device Co. Ltd), 5–25 pg / IOL.

[0016] • Surface modification. This method facilitates lens release but can affect the lens's optical properties, such as transparency. IOLs coated with polymer fibers and DX surfaces obtained by spin coating have been described.

[0017] Therefore, one of the greatest challenges in research on ocular drug delivery vehicles, such as IOLs, is designing a vehicle that achieves sustained and prolonged drug release over at least a month. This means preventing the entire drug from being released immediately upon contact with the eye or within a few hours. Furthermore, fundamental principles must be guaranteed, such as continued lens clarity and transparency, as well as user safety. For this reason, the choice of material and the lens synthesis or preparation method are crucial to ensuring appropriate characteristics.

[0018] The paper by Clasky Danielle P. et al., titled “Modeling the Effects of Disease, Drug Properties, and Material on Drug Transport From Intraocular Lenses,” published in the journal Translational Vision Science & Technology in May 2022, aims to develop computational fluid dynamics models to investigate the ability of intraocular lenses (IOLs) to release drugs at therapeutic concentrations. The authors study the release of the compounds dexamethasone (DX), ganciclovir, and dextran from intraocular lenses made of two materials: polydimethylsiloxane (PDMS) and poly(2-hydroxyethyl methacrylate) p(PHEMA). They demonstrate that PDMS lenses allow for sustained release of DX. This information is presented in the accompanying document, titled Supplementary Material, in Section D.2-PDMS refers to polydimethylsiloxane (PDMS) intraocular lenses that incorporate DX by immersion; it is also indicated that only the release of DX from PDMS intraocular lenses was simulated, and they select the initial concentration of DX in the PDMS of the IOL that fixes it at 0.20 mol / m. 3 Section F.2 analyzes the diffusion coefficient of DX in PDMS.

[0019] In the document by Diana Morarescu et al., entitled “Effect of delivery of MMP inhibitors from PDMS as a model IOL material on PCO markers,” published in the journal Biomaterials in March 2010, the release of three matrix metalloproteinase (MMP) inhibitors from intraocular lenses made of polydimethylsiloxane (PDMS) is examined as a treatment for posterior capsule opacification (PCO) or secondary cataract formation after IOL implantation. Two loading methods are described that allowed for the continuous release of the inhibitors for periods exceeding five months in some cases. On page 2404, in section “2. Materials and methods: 2.1. Sample preparation,” a PDMS preparation procedure is described, following the manufacturer's instructions, using a 10:1 ratio of elastomer base to curing agent. The MMPI inhibitors used: GM6001, MMP 2 / 9 inhibitor I, and MMP 2 / 9 inhibitor II.The inhibitors have a similar molecular weight but differ in their functional groups. These inhibitors were dissolved in dimethylformamide (DMF) or ethanol. The appropriate inhibitor solution was mixed with the PDMS elastomer base before the addition of the curing agent. After the addition of the curing agent, the drug-loaded films or discs were cured for approximately 48 h. eC. An alternative method for preparing infraocular lenses is also described, involving immersing PDMS lenses in inhibitor solutions in ethanol. The authors of this document themselves indicate that this is one of several promising hypotheses in the field, as they suggest that the drugs used to dope the material, in combination with the type of solvent used, affect the structure, refractive index, and transparency of the PDMS matrix (Section 4), resulting in a negative system response that renders it unusable for the desired application.

[0020] It is therefore desirable to develop a vehicle for the sustained incorporation of drugs, for more than a month, so that said vehicle avoids the drawbacks existing in the devices of the state of the art, by being a safer and more effective vehicle in the therapeutic treatment and eye health.

[0021] Explanation of the invention

[0022] The object of the present invention is the development of a drug delivery vehicle solution. According to the present invention, the drug to be released in the delivery vehicle is an ocular drug, for example, an anti-inflammatory drug such as dexamethasone (DX). In this way, the present invention provides a solution for the treatment of inflammatory eye diseases that is more effective and practical than current treatments. The release of an anti-inflammatory drug, such as DX, must be sustained over time and in adequate amounts to achieve the desired therapeutic effect. Therefore, the drug delivery vehicle according to the present invention must meet characteristics of biocompatibility, flexibility, oxygen permeability, water content, thermal and oxidative stability, among others, such as, for example, high optical transparency.

[0023] According to the present invention, the drug delivery vehicle is made from a PDMS-based polymer. This material exhibits good biocompatibility, flexibility, thermal and oxidative stability, and particularly high oxygen permeability, although it is also hydrophobic and has a low water content. Additionally, it has high optical transparency, enabling it to function as an intraocular lens (IOL). Furthermore, it is low-cost and easy to manufacture, which directly impacts the cost of the resulting IOL. However, during the development of a PDMS-based drug delivery vehicle according to the present invention, difficulties or challenges for its use have been encountered that were not initially considered in previous solutions.In an additional aspect, the solution also refers to a procedure for obtaining a drug delivery vehicle, preferably doped with an anti-inflammatory drug, such as DX.

[0024] Unlike previous solutions, the incorporation of the drug, for example, DX, is carried out during the polymerization and solidification process of the polymer used to obtain the drug delivery vehicle, that is, prior to the curing of the base polymer. In this way, not only is the preparation of the device and its doping carried out in a single synthetic step, but the behavior of a drug delivery vehicle resulting from the procedure according to the present invention differs substantially from other vehicles where the incorporation of the drugs into the vehicle is carried out, once synthesized according to processes known in the prior art, such as, for example, by immersing the vehicle in a solution of a high concentration of the drug to be incorporated.The choice of solvent and the volume added is key to the final result, avoiding subsequent problems in the vehicle, such as the transmittance of the material that affects transparency in the case of an IOL.

[0025] Additionally, the curing stage of the resulting mixture by adding a curing agent is not trivial. According to the present invention, in contrast to what is known in the field of art, curing is carried out in an open mold at a temperature between 15 and 25°C. eC, preventing the formation of small bubbles in the vehicle, as occurs at higher temperatures such as those used in the prior art or with the use of a closed mold. In other words, this curing takes place at a controlled temperature and in an open mold, thus preventing the degradation of the active ingredient and the formation of bubbles in the drug delivery vehicle, improving the applicability of the vehicle obtained during this procedure. For this purpose, the open mold is a polymerization mold comprising a slit with an open contact surface at the top that receives a PDMS-ocular drug solution dissolved in acetone to be cured.

[0026] Therefore, the process for obtaining an ocular drug delivery vehicle according to the present invention comprises the following steps: dissolving an ocular drug in acetone, incorporating a pharmaceutically acceptable amount of said ocular drug dissolved in acetone into a PDMS base polymer, incorporating a curing agent, resulting in a homogeneous curable solution, and curing the mixture in an open polymerization mold at a temperature between 15-25 eC, resulting in a drug delivery vehicle. The result of this procedure is a drug delivery vehicle that can be used after sterilization. In this regard, it is important to note that the procedure according to the present invention prevents any modification of the vehicle's characteristics during the subsequent sterilization process required for its implantation in a user. Thus, it was confirmed that, according to the present procedure, there is no release of the drug, in particular DX, nor inactivation of the molecule, using a common sterilization method, similar to that used to sterilize surgical materials, with steam at 134 e C.

[0027] Unlike previous solutions, this vehicle, such as an IOL or an ATC, comprises a PDMS base polymer and a drug, for example, DX, dissolved in acetone and incorporated into the PDMS base polymer prior to room temperature curing. The result is a safer and more effective drug delivery vehicle for ocular health and treatment, enabling sustained release of the ocular drug for at least one month, unaffected by the sterilization step required prior to implantation, and maintaining the vehicle's optical properties.

[0028] Therefore, according to the present invention, it has been validated and demonstrated that the use of acetone, unlike other solvents suggested in the prior art, as a solvent for an ocular drug, for its incorporation into a PDMS base polymer prior to curing at room temperature in an open polymerization mold, yields a vehicle for incorporating said ocular drug suitable for in vivo use. The development of an equivalent solution, suitable for human use, can be achieved according to a common and usual development process for this type of solution, following the indications and characteristics described in the present invention.

[0029] In the figures of the present invention, reference is made to the following set of elements:

[0030] 100 Drug delivery vehicle

[0031] 200 Polymerization mold

[0032] 201 Central curved zone

[0033] 202 Peripheral Zone

[0034] 203 Contact surface

[0035] 204 Mold groove

[0036] Brief description of the figures

[0037] Figure 1 shows a schematic of an embodiment of an ocular drug delivery vehicle: a) of the intraocular lens (IOL) type and b) of the capsular tension ring (CTR) type.

[0038] Figure 2 shows a schematic of an embodiment of a mold used to obtain an ocular drug incorporation vehicle: a) of the intraocular lens (IOL) type and b) of the capsular tension ring (CTR) type.

[0039] Figure 3a shows a newly synthesized dexamethasone-doped intraocular lens (LlOdop) (a) and an untreated or control intraocular lens (LlOnt) (b). Figure 3b shows a dexamethasone-doped intraocular lens (LlOdop) (a) and an untreated or control intraocular lens (LlOnt) (b) after being sterilized, implanted in rabbits for 4 weeks, and removed.

[0040] Figure 4 shows a comparative graph of the Modulation Transfer Function (MTF) versus the spatial frequency (Spa.Freq. - c / mm) of the mean of three lenses for a 3 mm pupil: dexamethasone-doped intraocular lens (LlOdop), dexamethasone-doped intraocular lens after dexamethasone release (LlOlib), and untreated or control intraocular lens (LlOnt). Figure 5 shows a comparative graph of the percentage of spectral transmission (TR) versus the wavelength (Å - nm) of the mean of three lenses: dexamethasone-doped intraocular lens (LlOdop), dexamethasone-doped intraocular lens after dexamethasone release (LlOlib), and untreated or control intraocular lens (LlOnt).

[0041] Figure 6 shows a chromatogram of the intensity (I - mUA) detected of dexamethasone in vitreous aqueous humor with time (t - min) in in vitro studies after t1, t2, 2 hours, t3, 1 day, t5, 7 days, t7, 12 days, 13 days and 16 days.

[0042] Figure 7 shows a representation of the cumulative amount of dexamethasone over time (t - hours) for two doped lenses (LiOdopI and LIOdop2) in vitro.

[0043] Figure 8 shows a representation of a liquid chromatography with Q-TOF mass spectrometry detector (EIC for m / z 393.2066 ± 20 ppm) of the detection of dexamethasone in samples extracted from aqueous humor of a rabbit after implantation of a doped intraocular lens (IlOdop - D3) on days 1 (a), 7 (b), 15 (c) and 28 (d) after the operation.

[0044] Figure 9 shows a representation of the change in prostaglandin concentration in aqueous humor at different times after implantation of a doped intraocular lens (LlOdop) and an untreated or control intraocular lens (LlOnt).

[0045] Detailed description of the invention

[0046] The object of the present invention is the development of a delivery vehicle for an ocular drug, for example, an anti-inflammatory drug such as dexamethasone (DX). In this way, the present invention provides a more effective and practical solution for the treatment of inflammatory eye diseases than current treatments. The release of the anti-inflammatory drug, such as DX, must be sustained over time and in adequate amounts to achieve the desired therapeutic effect.

[0047] Figure 1 shows examples of embodiments of an ocular drug delivery vehicle (100) (a) of the intraocular lens (IOL) type and (b) of the capsular tension ring (CTR) type. Thus, an IOL-type drug delivery vehicle (100) must meet characteristics of biocompatibility, flexibility, oxygen permeability, water content, thermal and oxidative stability, among others common to all delivery vehicles (100), as well as high optical transparency. In one particular embodiment, the IOL has a lens optic diameter of approximately 6 mm and an external diameter of approximately 14 mm. The CTR, for its part, may have an internal diameter of 10 mm and an external diameter of 12 mm. Therefore, the drug delivery vehicle can be an intraocular lens (IOL), a capsular tension ring (CTR), or a combination of these vehicles.

[0048] In a first aspect, the invention relates to a process for obtaining an ocular drug delivery vehicle (100). In particular, the ocular drug delivery vehicle (100) is doped with an anti-inflammatory ocular drug, such as DX. The process according to the present invention comprises the following steps: dissolving an ocular drug in acetone, incorporating a pharmaceutically acceptable amount of said drug dissolved in acetone into a PDMS base polymer, incorporating a curing agent, resulting in a curable homogeneous mixture, and curing the mixture in an open mold at a temperature between 15-25°C. e C, resulting in an ocular drug incorporation vehicle (100).

[0049] As indicated in the article by Clasky Danielle P; et al. entitled “Modeling the Effects of Disease, Drug Properties, and Material on Drug Transport From Intraocular Lenses”, polydimethylsiloxane (PDMS) is a polymeric material that presents promising conditions in the development of intraocular lenses (IOLs), compared to pHEMA-based IOLs, which are more hydrophobic and oxygen permeable.

[0050] Other alternatives considered in the prior art are also unacceptable as a base polymer for the ocular drug delivery vehicle (100) according to the present invention. PMMA polymer is a rigid and durable polymer, but it does not meet other requirements necessary for the present invention. For example, its low oxygen permeability prevents sufficient oxygen from reaching the eye, specifically the cornea. This results in gradual damage, and one of the most serious consequences can be corneal edema, but it can also lead to the growth of striae, cysts, and visible signs of corneal hypoxia or neovascularization. Therefore, PMMA polymer was ruled out as a material for an ocular drug delivery vehicle according to the present invention.On the other hand, other polymers such as PLGA require the use of ultraviolet light during polymerization, which can affect the drug's stability, chemically altering and deactivating it so that it no longer produces the desired therapeutic effect. Therefore, these polymers have also been discarded. Consequently, the base polymer used for the ocular drug delivery vehicle is PDMS. This material exhibits good biocompatibility, flexibility, thermal and oxidative stability, high optical transparency, and especially high oxygen permeability, although it is also hydrophobic and has a low water content. Furthermore, it is a low-cost and easy-to-manufacture polymer, which directly impacts the cost of the ocular drug delivery vehicle.However, during the development of intraocular lenses (IOLs) according to the present invention, based on PDMS, difficulties or challenges for their use have been identified that were not initially considered in previous solutions.

[0051] As stated in the article by Clasky Danielle P. et al. entitled “Modeling the Effects of Disease, Drug Properties, and Material on Drug Transport From Intraocular Lenses,” the method of drug delivery determines the subsequent release of the drug after implantation. In other words, an ocular drug delivery vehicle (100) obtained by a different method produces a substantially different effect, even with a similar drug load. Therefore, comparing a vehicle (100) such as the one described in the present invention with other solutions obtained by a different method presents a significant limitation, leading to surprising results.

[0052] However, in this procedure, the incorporation of the ocular drug occurs during the polymerization and solidification process of the polymer used to obtain the IOL, in contrast to many previous solutions. That is, it occurs prior to the polymer curing. Thus, the behavior of an ocular drug delivery vehicle (100), for example, of the IOL type, resulting from the procedure according to the present invention differs substantially and is not comparable to the IOL suggested, for example, by the model considered by Clasky et al., where the incorporation of the drugs into the IOL is carried out, once the IOL has been synthesized, by immersing the IOL in a solution with a high concentration of the drug to be incorporated.

[0053] On the other hand, the document by Morarescu Diana et al., entitled “Effect of delivery of MMP inhibitors from PDMS as a model IOL material on PCO markers,” is well known. In this document, in addition to evaluating the process of preparing infraocular lenses by immersing PDMS lenses in inhibitor solutions in ethanol, a PDMS preparation procedure is described. In this procedure, the MMPI inhibitors used were dissolved in dimethylformamide (DMF) or ethanol and mixed with the PDMS polymer base before the addition of a curing agent. Consequently, after the addition of the curing agent, the drug-doped films were cured at 37 e C.

[0054] As initially indicated, the material, in combination with the type of solvent used, can affect the PDMS matrix. In this case, unlike the previous solutions, the drug is incorporated using acetone as the solvent. Acetone has a low boiling point and high volatility, allowing for complete evaporation and achieving good transparency of the PDMS matrix. This avoids the drawbacks that were not identified or suggested in previous solutions, such as those proposed by Clasky et al. or Morarescu et al. In other words, thanks to the use of acetone, the polymer curing process occurs homogeneously, preserving the material's transparency.

[0055] The use of acetone not only prevents alteration of the PDMS matrix characteristics, such as its transparency, but also makes it possible to perform the curing stage at room temperature, within the range of 15–25°C. eC, preferably between 18 - 22 e C. Curing at room temperature is carried out for at least two days, so that the resulting vehicle is solidified. Generally, after 24 hours, the mixture placed in a polymerization mold is still in a gel state. Using room temperature curing avoids the increased cost of using an oven to control curing conditions at a higher temperature. These results are not achievable using other solvents, such as ethanol or methanol, suggested in the prior art. In one particular case, the ocular drug is an anti-inflammatory drug. Alternatively, other drugs acceptable for use with acetone would be: antibiotics, quinolone derivatives (ofloxacin, ciprofloxacin), aminoglycosides such as tobramycin, as well as other antiglaucoma or anti-inflammatory drugs such as corticosteroids.

[0056] In a more specific embodiment, the ocular drug is dexamethasone (DX) or a drug with a similar chemical structure and / or nature (e.g., prednisone or prednisolone, all belonging to the corticosteroid group). DX is practically insoluble in water, sparingly soluble in dichloromethane, and exhibits moderate solubility in solvents such as ethanol, methanol, or acetone, making it impossible for an expert to determine an ideal solvent for this type of drug a priori. In another specific embodiment, stirring via a powerful magnet was used to achieve a homogeneous PMDS-DX mixture, after which the curing agent could be added. The homogeneous mixture was then cured by depositing it into a polymerization mold (200).

[0057] In a further aspect, the invention relates to a polymerization mold (200) for obtaining an ocular drug delivery vehicle (100). This mold (200) comprises a slit (204) with a contact surface (203), defining a space to contain a PDMS-ocular drug solution to be cured. The contact surface (203) of this slit (204) is open at the top. The characteristic of a contact surface (203) being open at the top is fundamental for obtaining an ocular drug delivery vehicle (100), especially in the case of an IOL, since the presence of a top closure (closed mold) generates bubbles during the curing of the vehicle (100), which results in a loss of the optical characteristics of the resulting vehicle (100). This limitation is particularly relevant in the case of an IOL, whose main function is to allow the user to have clear vision.

[0058] The polymerization mold (200) is made of a non-reactive material during the polymerization process. An example of such a material is an aluminum mold. Alternatively, the mold (200) can be made of glass or polystyrene. The use of an aluminum mold allows for obtaining a plano-convex mold, specifically designed to produce a plano-convex lens, due to the need for a central area comprising a curve so that the IOL includes a curvature of the convex surface to achieve the desired power. As shown in Figure 2, the mold (200) can have several embodiments, depending on whether it is intended for obtaining an IOL vehicle (100) or an ATO vehicle (100).Thus, a polymerization mold (200) for obtaining an IOL-type drug delivery vehicle of length L3 comprises a curved central zone (201) of diameter L1, configured to obtain a convex lens, and a peripheral zone (202) of diameter L2, surrounding the curved central zone (201), configured to obtain a sheet around the convex lens obtained in the curved central zone (201). In a particular embodiment, the diameter L1 is 6 mm, appropriate for the rabbit's eye, while the diameter L2 is 14 mm, which will serve to cut out haptics to hold the IOL in the rabbit's lens sac. For its part, a polymerization mold (200) of an ATC-type vehicle (100) comprises a groove (204) where the contact surface (203) has a circular arrangement, so that the resulting capsular tension ring comprises a cavity configured to receive an IOL, doped or undoped.In a particular embodiment, the polymerization mold (200) of capsular tension rings (ATC) has a slit (204) in the shape of a circular semi-ring, with an internal diameter of 12 mm and a cross-section of 1 mm.

[0059] Therefore, contrary to what has been mentioned or suggested in the state of the art, the use of oven curing, using temperatures higher than ambient temperature (25 e C) Bubble formation is observed in the IOL due to the rapid drying generated by the oven. Therefore, in the present invention, curing is carried out in an open mold at room temperature, below 25 e C, and preferably between 15-25 e C, and preferably between 18-22 eC. This prevents the formation of small bubbles on the lens, as occurs at higher temperatures such as those used in the prior art. Additionally, the curing process takes place at a controlled temperature for at least two days, thus preventing the degradation of the active ingredient. This procedure prevents any alteration of the IOL's characteristics during the subsequent sterilization process required for implantation in a patient. In this regard, it is clear that, according to this procedure, there is no drug release or inactivation of the molecule when using standard sterilization, similar to that used for surgical instruments, with steam at 134°C. eC. A novel ocular drug delivery vehicle (IOL) has been developed, comprising a PDMS-DX cured body. Unlike previous solutions, this IOL comprises a PDMS-DX cured body where the pharmaceutically acceptable amount of DX is dissolved in acetone and incorporated into the PDMS base polymer prior to curing, substantially modifying its subsequent applicability. In particular, the IOL according to this solution can comprise 0.1–1 mg of ocular drug per g of PDMS. The ATC code, on the other hand, can comprise 10–1000 mg of ocular drug per g of PDMS.

[0060] Thus, as described in the following examples, the development of an ocular drug delivery vehicle (100) is validated and demonstrated, such that said vehicle (100) allows for a sustained and maintained release of an ocular drug, DX, in a safer and more effective manner for therapeutic treatment and ocular health. Example 1 - Amount of dexamethasone (DX)

[0061] To dope the IOL with adequate therapeutic amounts, the effective dextrose (DX) absorbed into the eyes via eye drops was first calculated. In this case, 1 mg / mL DX solutions are used, and 1–2 drops are administered (corresponding to a volume of 0.1–0.05 mL). Furthermore, the effective / therapeutic amount is between 1% and 5% of the administered amount. Therefore, the calculation shows that between 0.5 and 5 pg of DX is used per dose. The proposed IOLs were doped with higher amounts, specifically between 5 and 40 pg of DX, considering the need for prolonged release. For this purpose, 10–20 mg / mL solutions were prepared in different solvents, and small volumes of 10–100 pL per gram of PDMS were added. It was observed that the volume of addition modified the transmittance of the material. The greater the volume of solvent, the lower the transmittance, so smaller volumes were used (1 OpL).No variations in transmittance were observed for the studied concentration range (10–20 mg / mL), but variations were observed for higher concentrations. It was decided to use 20 mg / mL for doping with a higher concentration.

[0062] Example 2 - Solvent Selection

[0063] For the assessment of the incorporation of an ocular drug, the behavior of an anti-inflammatory drug such as dexamethasone (DX) was assessed in multiple solvents described in the state of the art. The following table shows the results of several DX solutions with 20 mg DX / mL of solvent according to various solvents. The transmittance of an undoped IOL is 95% in the visible region, meaning the IOL material only absorbs 5% and therefore has good optical transparency. Preparations of DX-doped IOLs using acetone and methanol in quantities of 10 µL of a 20 mg / mL solution show similar transmittances. However, despite achieving good transparency, a film using methanol as a solvent is not recommended for IOL production due to the toxicity of this compound. When using ethanol, which is non-toxic, the transmittance was found to be lower than that obtained using acetone. In conclusion, acetone is the only acceptable solvent for incorporating DX prior to curing to obtain a drug delivery vehicle.

[0064] As a follow-up to the test to determine the solvent to be used, a test was performed to determine the amount of solvent. For this purpose, 20 mg of DX were mixed with 0.5, 1, and 2 mL of acetone. Perfect dissolution was observed in 2 mL, but dissolution in 1 mL using a stirrer is also acceptable. Thus, the drug-to-solvent ratio is in the range of 10–20 mg / mL

[0065] Unfortunately, the use of solvents other than acetone increases the opacity of the material, thus substantially limiting its use, given that one of the characteristics of an ocular drug delivery vehicle (100) according to the present invention is high optical transparency. The biocompatibility of the solvents used was also considered; toxic solvents such as methanol and dimethylformamide were ruled out.

[0066] Therefore, the ability to use acetone as a solvent was validated and demonstrated, in contrast to other solvents suggested in the state of the art.

[0067] Example 3 - Preparation of an Ocular Drug Incorporation Vehicle In one particular embodiment, the PDMS-DX doped intraocular lens (IOLdop) was prepared by weighing 1 g of the PDMS base polymer into a vial and adding 10 pL of a 20 mg / mL DX solution in acetone. The DX content is 0.2 mg DX per g of PDMS. Considering that, in an embodiment intended for the rabbit eye, an IOL weighs between 37 and 39 mg, the amount of DX per rabbit IOL is 6–8 pg. Per lens, the DX content is an adequate amount compared to the effective amount used in eye drops. If one drop corresponds to 30 pL, and its effectiveness ranges from 1% to 5%, this means that approximately 3–15 pg of DX are actually therapeutically active in ocular treatment.Once the gel was homogeneous, using, for example, a spatula or a magnetic stirrer, 0.1 g of the curing agent (hydrogen methyl dimethyl siloxane) was added and mixed again until homogeneous. The resulting gel was placed in a polymerization mold (200) specifically designed for IOLs. This polymerization mold was open to prevent bubble formation during curing. Once contained in the mold (200), it was left to polymerize for 72 hours at room temperature to obtain the IOL. The untreated or control intraocular lens (IOLt) made of PDMS was prepared following the same procedure, but in this case, 10 µL of acetone (without dexamethasone - DX) was added. Figure 3a shows a PDMS IOLt with DX (a) prepared according to this procedure, and a freshly synthesized IOLt (b). These can be compared with the IOLs after they have been implanted.Figure 3b shows a LlOdop with DX (a) and a LlOnt (b) after being sterilized, incorporated into rabbits for 4 weeks and removed.

[0068] In parallel, the ATO comprising a PDMS-DX body was prepared by weighing 1 g of the PDMS base polymer into a vial and adding 0.01 mL of a 700 mg / mL DX solution in acetone. The DX content in this case is 7 mg DX per g of PDMS. Considering that the ring weighs 5–40 mg, the amount of DX per ring is 35–280 pg. Once the gel was homogeneous, using, for example, a spatula or a magnetic stirrer, 0.1 g of the curing agent (hydrogen methyl dimethyl siloxane) was added and mixed again until homogeneous. The resulting gel was deposited into an ATC polymerization mold (200). The ATC polymerization mold (200) used was a circular semi-ring with an internal diameter of 12 mm and a cross-section of 1 mm. The mold was left open to prevent bubble formation during drying. It was left to polymerize for 72 hours at room temperature. eC, for obtaining the ring-type vehicle (100). Example 4 - Viability of the doped intraocular lens (DOL)

[0069] An intraocular lens (IOL) drug delivery vehicle requires high optical capacity. This means that the entire manufacturing process, as well as its subsequent sterilization, must preserve the optical characteristics of the lens, since the primary function of the implanted IOL—to form sharp images on the retina while maintaining maximum transparency in the visible region—cannot be compromised at any point. To determine the viability of the IOL, a series of studies were conducted on its characteristics.

[0070] First, the Modulation Transfer Function (MTF) was determined, providing a measure of the optical quality of the image formed by the lens, for both a DX-doped and an undoped IOL. Figure 4 shows a comparative graph of the Modulation Transfer Function (MTF) versus the spatial frequency (Spa.Freq. - c / mm) of the mean of three IOLs for a 3 mm pupil: a DX-doped intraocular lens (DlOdop), a DX-doped intraocular lens (LlOlib), and an untreated or control intraocular lens (LlOnt). The results show a decrease in the MTF for the LlOdop compared to the LlOnt. However, once the drug is released, the values ​​become similar again, with the MTF of an LlOdop and an LlOnt being equal.

[0071] Regarding transparency, Figure 5 shows a comparative graph of the percentage of spectral transmission (TR) versus the wavelength (A - nm) of the mean of three IOLs: DX-doped intraocular lens (DlOdop), DX-doped intraocular lens after release (LlOlib), and untreated intraocular lens (LlOnt).

[0072] Therefore, a slight decrease in the spectral transmission curve in the visible region is observed for the LlOdop compared to the LlOnt. However, both curves recover to levels similar to those of the LlOnt after drug release. Therefore, it can be concluded that the incorporation of DX does not affect the optical quality of the IOL resulting from the present invention.

[0073] Example 5 - Amount of dexamethasone (DX) released in vitro

[0074] Additionally, the amount of DX released from the prepared IOLs was studied. For this purpose, the lenses were immersed in water and in simulated aqueous humor, resulting in a reduced release into the aqueous humor. Furthermore, among the studies in simulated aqueous humor prepared in the laboratory, two types of studies were conducted: one in which the IOL was left in the same medium throughout the experiment and small aliquots of the solution were taken for analysis at different times (reconstituting the medium so that the final volume was the same); and another in which the entire volume was extracted and fresh aqueous humor solution was introduced at each measurement, thus simulating the regeneration / renewal of the aqueous humor, analogous to the process that takes place in the eyes. Artificial aqueous humor was prepared by dissolving between 0.0138 - 0.0275 g of glucose, 0.0038 g of albumin, 0.2586 g of NaCl, 0.0084 g of KCl and 0.0.320 g of CaCl₂·4H₂O were dissolved in 25 mL of water. This solution was transferred to an amber vial with a cap and shaken with a vortex mixer (Labnet International, USA) until completely dissolved. IOLs weighing 38 ± 0.5 mg were immersed in 0.5 mL of vitreous aqueous humor. Volumes of 0.1 mL were taken with a plastic syringe and filtered using syringe filters.

[0075] To detect and quantify DX, a chromatographic system was used. High-performance liquid chromatography (HPLC) studies were performed using a capillary pump liquid chromatography system (Agilent Technologies 1200 series, Waldbronn, Germany) equipped with a diode array detector with an 80 nL cell. Chromatographic separation was carried out on a ZORBAX SB-C18 analytical column (35 x 0.5 mm, 5 pm, Agilent). Chromatographic conditions were modified to detect and quantify DX with high sensitivity (cumulative concentrations in ppb or ng). Variables such as mobile phase, flow rate, injection volume, and capillary column were analyzed for this purpose. Thus, the following chromatographic system was used: TEOS-MTEOS S¡O2NP as the extraction phase, acetonitrile and ultrapure water (40:60 v / v) as the mobile phase and an injection volume of 50 pL.Additionally, the flow rate used was 7 and 12 pL / min, and 100, 500, and 1000 pL Hamilton syringes were used for the injection. A calibration curve for DX in water was established, ranging from 10 to 750 ppb of DX, with a detection limit of 2.5 ppb. Under these conditions, a peak was obtained at 4.5 min corresponding to DX, with similar results for 100 ppb DX standards in aqueous humor.

[0076] Figure 6 shows a chromatogram of the intensity (I - mAU) of DX detected in the vitreous aqueous humor over time (t - min) in in vitro studies. A peak corresponding to DX is observed at a retention time of 4.8–5 minutes. Substituting the peak area into the calibration curve obtained with DX standards allows for the calculation of the amounts of drug released. The results are shown in Figure 7, which represents the cumulative amount of DX released over time. The study was conducted for two doped IOLs, showing comparable results (IOLdop1 and IOLdop2). The cumulative release amounts are between 200–300 ng in 8–12 days (200–300 h) and 700–800 ng in 16 days (400 h).

[0077] Example 6 - Amount of dexamethasone (DX) released in vivo

[0078] A pilot study was conducted on seven eyes of New Zealand White rabbits (Oryctolagus cuniculus) in which DX-doped intraocular lenses (D1-D7) were implanted. The animals used in this study were clinically healthy female rabbits without ocular pathology. A bilateral lens extraction procedure (cataract surgery) was performed, followed by implantation of an intraocular lens (IOL) in the capsular bag, obtained according to the procedure of the present invention. The IOLs were then cut, surgically sterilized, and inserted into the rabbits' eyes for 27 days. After IOL implantation, postoperative checks were performed at 24 hours, 48 ​​hours, 5 days, and then weekly until the end of the study month. Postoperative treatment consisted of administering ofloxacin antibiotic eye drops every 12 hours to all rabbits for two weeks to prevent intraocular infection.

[0079] To conduct the study, a DX-doped intraocular lens (D1-D7) was implanted in the right eye (OD) of the same rabbit, and a C1-C7-doped intraocular lens (LlOnt) was implanted in the left eye (OI) as a control. The control eye received only antibiotic treatment. To evaluate DX release and monitor inflammatory biomarkers (prostaglandins), aqueous humor analysis was performed on the day of the procedure and 1, 7, 15, and 28 days after lens implantation. A 30G needle paracentesis was performed to extract a 50 ml sample of aqueous humor. An example of this type of doped intraocular lens is shown in Figure 3B. For the determination of the amount of DX, each of the LlOdop, D1 - D7, was immersed in a solution of 0.5 mL of methanol and 50% ethanol for 1 h with stirring, and samples were taken.

[0080] The samples were analyzed by liquid chromatography with Q-TOF mass spectrometry detection. For this purpose, 20 pL of sample were injected into a Posohell 120 EC-C18 column (2.1 x 50 mm, 1.9 urn Agilent 699675-902) at 35 e C with thermostat. The mobile phases used were 0.1% formic acid (A) in acetonitrile (B) with a gradient starting at 5% B, increasing to 10% in the first minute, and then to 90% by minute 10, where it was maintained for 2 minutes. A column conditioning step was performed between injections. The mass spectrometer was used in full sen mode from m / z 100-1000 and electrospray positive ionization (ESI+) under the following conditions: drying gas temperature and flow rate 300 e C and 10 L / min, nebulizer pressure 45 psi, heat gas temperature and flow 350 eC and 1 L / min, capillary voltage of 3500 V. Data were collected by profiling in scan rate mode at 1.5 spectra per second. Mass measurements were obtained by calibrating the release solutions using an ESI dual nebulizer. A calibration solution or standard (G1969-85000) containing the mass references am / z 121.0509 (protonated purine) and m / z 922.0098 (protonated (1H,1H,3H-tetrafluoroproxy) phosphazine or HP-921) was used in positive ion mode, and the solutions were introduced continuously using an isocratic pump (Agilent, Santa Clara, California, USA). Thus, a capillary pre-concentration stage is carried out in a tube (with columns synthesized in the MINTOTA group) coupled to the system that allows the samples to be analyzed directly, without prior treatment.

[0081] The weights of the lenses used (D1 to D7) and the amount of DX in each lens, calculated based on weight and DX content per gram, are shown below. The amount of DX extracted from the lens after implantation in the rabbits was determined by liquid chromatography with Q-TOF mass spectrometry detection (EIC for m / z 393.2066 ± 20 ppm). Very low or negligible amounts of DX were observed. Figure 8 shows a liquid chromatography representation of DX detection in aqueous humor samples taken from a rabbit after IOL implantation (D3) on days 1 (a), 7 (b), 15 (c), and 28 (d) post-surgery. It can be observed that DX is indeed released from the IOL and passes into the rabbit's aqueous humor. The presence of DX was detected in all periodic extractions (days 1, 7, 15, and 28 post-surgery) and in all rabbits.

[0082] A fraction of the extracted aqueous humor (25 pm) was analyzed to determine the concentration of prostaglandin (8-OH-dG), an indicator of inflammatory processes. Figure 9 shows a representation of the change in prostaglandin concentration in the aqueous humor at different times after the implantation of a D1 (D) and C1 (C) lens. The red line represents the median of the sample, and the rectangle is the interquartile range. The whiskers show the range of sample values ​​that are not considered extreme measurements (red crosses). Finally, the medians of the results for each lens have been joined with a line to show the trend of change over time.

[0083] Changes in prostaglandin concentration in the aqueous humor over time after surgery exhibit an inverted U-shaped pattern, peaking between the first 24 hours and the first week post-surgery, followed by a decline that tends to return to baseline values ​​by the end of the study period (4 weeks). Although this pattern is common to both control eyes and eyes treated with IlOdop, the data show a trend toward lower values ​​in the IlOdop eyes, which approach the initial median value of the sample by day 28, while the control eyes remain far from this value. The magnitude of the differences between the samples, on average, decreases from 249 pg / ml at 24 hours post-surgery to 183 pg / ml at the end of the study period. There are three extreme measurements, corresponding to the eye treated with IlOdop D2 on day 28, IlOnt C7 at 24 hours, and IlOnt C6 on day 7.By removing these three values, the two-way MANOVA test shows a significant effect of the time elapsed since the operation (F=4, 131 , p=0.005) and of the use of the doped lens (F=5.9851 , p=0.017), with significantly higher concentrations for the control population, and significant differences between day 0 and the first day after the operation (mean difference and confidence interval -451 .26, [-901 .03 -1 .4978] with p=0.049) and between day 1 and 28 (mean difference and confidence interval 545.45 and [87.124, 1003.8], with p= 0.012).Although these are initial results, the proportion of normal eyes among those implanted with the doped lens suggests that the procedure is effective and, therefore, it is possible to validate and demonstrate that the use of acetone, contrary to other solvents suggested in the state of the art, as a solvent for an ocular drug, for its incorporation into a PDMS base polymer prior to curing at room temperature in an open mold, resulting in a vehicle for incorporating said ocular drug, is suitable for in vivo use.

Claims

CLAIMS 1.- An ocular drug incorporation vehicle comprising a PDMS-ocular drug cured body characterized in that the PDMS-ocular drug cured body comprises the pharmaceutically acceptable amount of ocular drug dissolved in acetone and incorporated into the PDMS base polymer prior to curing.

2. The drug delivery vehicle according to claim 1, wherein the vehicle is an intraocular lens (IOL), a capsular tension ring (CTR), or a combination of these vehicles.

3. The drug delivery vehicle according to claim 2, wherein the IOL comprises 0.1-1 mg of ocular drug per g of PDMS.

4. The drug delivery vehicle according to claim 2, wherein the ATC comprises 10-1000 mg of ocular drug per g of PDMS.

5. A polymerization mold for an ocular drug incorporation vehicle characterized in that it comprises a slit (204) comprising a top-open contact surface (203) receiving a PDMS-ocular drug solution dissolved in acetone to be cured.

6. The polymerization mold according to claim 5, wherein the slit comprises: a central curved zone (201) of diameter L1, configured to obtain a convex lens, and a peripheral zone (202) of diameter L2, in contact with the central curved zone (201), configured to obtain a sheet around the convex lens obtained in the central curved zone (201). 7.- The polymerization mold according to claim 5, wherein the slit (204) is a semi-circular ring-shaped slit.

8. The polymerization mold according to any one of claims 5 to 7, wherein the mold is a non-reactive mold.

9. The polymerization mold according to claim 8, wherein the mold is made of aluminum.

10. A process for obtaining an ocular drug delivery vehicle according to any one of claims 1 to 4, characterized in that it comprises the following steps: a) Dissolving an ocular drug in acetone, b) Incorporating a pharmaceutically acceptable amount of said drug dissolved in acetone into a PDMS base polymer, c) Incorporating a curing agent, and d) Curing the mixture in a polymerization mold according to any one of claims 5 to 9, at a temperature between 15 and 25 °C. e C resulting in an ocular drug delivery vehicle. 11.- The procedure for obtaining an ocular drug incorporation vehicle according to claim 10, wherein the ocular drug is an anti-inflammatory drug. 12.- A method for obtaining an ocular drug delivery vehicle according to any one of claims 10 to 11, wherein the method further comprises a step of sterilizing the drug delivery vehicle resulting from step d).

13. The process for obtaining an ocular drug incorporation vehicle according to claim 12, wherein the sterilization step is a surgical steam sterilization at 134 e C.

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