Long-acting injectable biodegradable cylindrical implant of anti-VEGF agent

Abstract

The invention relates to a long-acting injectable biodegradable cylindrical implant (1) for delivering anti-VEGF agents intraocularly. The implant (1) comprises a nanoporous, sintered polycaprolactone (PCL) hollow cylinder (2) filled with a highly concentrated anti-VEGF agent (3), such as Bevacizumab, Ranibizumab, or similar, in liquid, semisolid, or solid form, and sealed at both ends (4). The implant, measuring 8-10 mm in length and 0.4-0.6 mm in diameter, provides sustained release of the therapeutic agent over a period of one year or more, and can be administered via intravitreal, subconjunctival, peribulbar, subtenon, or retrobulbar injection. The method for fabricating the implant includes electrospinning, sintering, salt leaching to create nanopores, and sealing the loaded implant. The device is stable and biocompatible, offering a controlled, long-term therapeutic option for intraocular treatment applications. FIG. 1

Specification

Description:FIELD OF THE INVENTION
Present invention relates to a drug delivery system and formulation that releases drugs inside the eye for an extended period of time to minimize administration frequency. More specifically, present invention relates to an implant that injects an anti- vascular endothelial growth factor (anti-VEGF) biopharmaceutical agent for treatment of ocular conditions mainly age-related macular degeneration. The implant is designed to be fully biodegradable, and it releases the therapeutic agent gradually over time.
BACKGROUND OF THE INVENTION
The human eye is divided into the anterior and posterior segments. The posterior segment is delicate, vascularized, and not readily available for non-invasive therapy. The conditions that affect the posterior segment are diabetic macular edema (DME), age-related macular degradation (AMD), diabetic retinopathy (DR), and proliferative vitreoretinopathy (PVR). The growing population of aged patients poses a risk for these diseases. These conditions require consistent treatment to prevent vision loss [Journal of Controlled Release. 350 (2022) 538-568. https://doi.org/10.1016/j.jconrel.2022.08.040].
AMD is a chronic and progressive disease, can lead to irreversible blindness [Ophthalmol Retina. 4 (2020) 662-672. https://doi.org/10.1016/J.ORET.2020.01.012]. It results from a complex interplay of factors, including lipid dysregulation, angiogenesis, inflammation, and disturbances in complement and matrix pathways, causing gradual vision loss. Early stages are marked by drusen and retinal pigment epithelium (RPE) abnormalities, while late stages can be neovascular (Wet) or non-neovascular (Dry) AMD [The Lancet. 392 (2018) 1147-1159. https://doi.org/10.1016/S0140-6736(18)31550-2]. Late diagnosis may lead to permanent blindness and impaired vision [Ophthalmology. 120 (2013) 844-851. https://doi.org/10.1016/J.OPHTHA.2012.10.036]. Irregularities in metabolic pathways and growth factors, such as vascular endothelial growth factor (VEGF), Epidermal growth factor (EGF), and Fibroblast growth factors (FGF), contribute to angiogenesis [Int J Biol Macromol. 110 (2018) 7-16. https://doi.org/10.1016/j.ijbiomac.2018.01.120; Ophthalmology. (2019). https://doi.org/10.1016/j.ophtha.2019.09.024; Prog Retin Eye Res. 54 (2016) 64-102. https://doi.org/10.1016/j.preteyeres.2016.04.003; Ophthalmology. 119 (2012) 2290-2297. https://doi.org/10.1016/j.ophtha.2012.06.014; Optometry - Journal of the American Optometric Association. 75 (2004) 216-229. https://doi.org/10.1016/S1529-1839(04)70049-4; New England Journal of Medicine. 355 (2006) 1474-1485. https://doi.org/10.1056/NEJMra062326]. Numerous drug delivery routes for ocular diseases, like systemic, topical, periocular, and intravitreal methods, are explored by researchers. Topical routes have limited availability due to rapid precorneal loss and short contact time. Systemic routes are efficient but restricted by the blood-retinal barrier, requiring high doses and potential side effects. Intravitreal routes are safe but have difficulties like retinal detachment, hemorrhage, and endophthalmitis. It also requires frequent injections to maintain optimal drug concentration [Adv Drug Deliv Rev. 58 (2006) 1131-1135. https://doi.org/10.1016/J.ADDR.2006.07.027].
Implant formulation is a widely investigated approach for sustained delivery of therapeutics, especially for the intravitreal route. Ocular implants can be biodegradable and non-biodegradable. Non-biodegradable implants can release drugs for long-term, but they are generally larger and need surgical interventions.
The current treatment for AMD involves the use of anti-VEGF intravitreal injections, which exhibit limitations like short half-life and rapid elimination. The treatment of AMD is challenging due to the lack of ocular formulations that contain VEGF inhibitors which can offer sustained release for one year or more. This unavailability has created a significant demand for developing long-acting implants in view to meet these requirements. To address these issues, the study aimed to design a biodegradable sustained drug delivery implant that utilized nanofiber technology to achieve prolonged and effective drug release for AMD management. Electrospun nanofibers are being studied as a potential solution for delivering the necessary drugs to the eye. Nanofiber technology allows the production of nanoporous biodegradable cylindrical implants with tunable properties. Polymeric materials are used to fabricate these implants that have tunable features and are biodegradable, making them an attractive option for sustained drug delivery systems. The sustain delivery implants would enable the controlled delivery of biological drugs and would allow precise regulation of the release rate. Techniques such as the mandrel electrospinning technique, thin film electrospinning technique, and silicone tube molding technique are being explored for preparing long-acting cylindrical implants.
Lance et al. extensively developed thin, porous PCL films, as rate-controlling membranes for sustained-release devices [Drug Deliv Transl Res. 6 (2016) 771-780. https://doi.org/10.1007/s13346-016-0298-7; Bioeng Transl Med. 4 (2019) 152-163. https://doi.org/10.1002/btm2.10121]. They studied flat devices for sustained release of various therapeutic proteins such as ranibizumab and aflibercept for up to 10 weeks [Bioeng Transl Med. 4 (2019) 152-163. https://doi.org/10.1002/btm2.10121]. However, these devices had flat seals, making it difficult to insert them seamlessly with a needle. Additionally, their relatively large diameter (1 mm) required significant miniaturization to fit within the widely accepted upper limit (500 μm) established by Ozurdex® [Journal of Ocular Pharmacology and Therapeutics. 30 (2014) 387-391. https://doi.org/10.1089/JOP.2013.0231/ASSET/IMAGES/LARGE/FIGURE2.JPEG]. Jiang et al. have made significant progress in this field by developing a tubular device architecture for delivering protein therapeutics that can fit within the bore of a 21 G needle [J Control Release. 320 (2020) 442-456. https://doi.org/10.1016/j.jconrel.2020.01.036]. Their devices are based on an electrospun tubular construct of chitosan and polycaprolactone, with a wall thickness of approximately 90 μm. These devices can be filled with liquid or slurry formulations; however, their small size and wall thickness may limit broader translation and present challenges with storage. Waterkotte et al. have demonstrated a methodology to fabricate tubular devices from a flat film of PCL, which can be heated, and superglue sealed to fabricate liquid-loaded devices [ACS Biomater Sci Eng. 8 (2022) 4428-4438. https://doi.org/10.1021/ACSBIOMATERIALS.2C00808/SUPPL_FILE/AB2C00808_SI_001.PDF]. These devices have been observed to release over 1 mg of bevacizumab over 90 days. However, the greater payload correlated with a larger 946 μm diameter of the device, which may require an 18 G or larger needle for delivery by injection. Furthermore, the superglue used to prevent leakage should be carefully assessed due to potential cytotoxicity concerns associated with cyanoacrylates. Bernards et al. fabricated tubular devices that could effectively deliver protein therapeutics through injection. The emphasis is on producing uniformly cylindrical devices supporting drug loading and ensuring reliable wall thickness. Dip-cast tubes effectively achieved a wall thickness of 30 μm, allowing increased reservoir volume for drug loading. The devices could be loaded with solid or liquid formulations, and highly compacted pellets of protein with a diameter of 300 μm are used to maximize the loading capacity. The devices could be capped using self-sealing techniques or a plug of solid polymer, which may help in generating a fully cylindrical form factor and avoid any distortion that could inhibit insertion and deployment by the needle. The study demonstrated the devices' safe and repeated intraocular injection using a 22 G needle, both in vitro and in vivo. The use of placebo devices established a favourable safety profile for multiple devices present within the eye. Moreover, the devices fabricated using this method achieved sustained release of BSA for over 400 days, owing to the potentially long lifespan of PCL-based materials [ACS Materials Au. (2023). https://doi.org/10.1021/acsmaterialsau.3c00004]. In a related study by Angkawinitwong et al., electrospinning is used to fabricate a solid form of bevacizumab designed to offer prolonged release while maintaining antibody stability. The fibers are generated using aqueous bevacizumab solutions buffered with poly-ε-caprolactone sheath and had smooth and cylindrical morphologies with diameters of approximately 500 nm. Both sets of bevacizumab-loaded fibers exhibited sustained release profiles in an aqueous outflow model of the eye. The developed formulation displayed a zero-order reservoir-type release system with a t1/2 of 52.9 ± 14.8 days. The study demonstrated that the bevacizumab in the formulation did not undergo degradation during fiber fabrication or release, thereby ensuring the release of the antibody for two months [Acta Biomater. 64 (2017) 126-136. https://doi.org/10.1016/j.actbio.2017.10.015].
Currently, monthly intravitreal injections of anti-VEGF agents are used for the treatment of AMD but it is hampered by several noteworthy drawbacks. These encompass the several challenges posed to patients, especially the elderly or those with mobility issues, due to frequent healthcare visits. Additionally, there is an inherent risk of infection associated with the invasive nature of the administration. Complications like intraocular bleeding, increased pressure, and inflammation are associated with frequent injections. Furthermore, the recurrent nature of monthly injections may contribute to retinal detachment, diabetic retinopathy, retinal vascular occlusions and other retinal complications. These challenges underscore the need for innovative approaches to enhance the efficacy and patient experience in AMD management.
Genentech, Inc. has recently developed a PDS, Susvimo™ a non-biodegradable implant for the controlled delivery of ranibizumab in the treatment of AMD which represents a significant advancement in ocular drug delivery. The Susvimo™ requires refilling every six months. This medical device is strategically designed to alleviate the burden of frequent injections by providing a controlled and sustained release of the therapeutic agent. Key components of a typical PDS include an implantable device surgically placed in the eye, housing a reservoir for the storage and controlled release of ranibizumab. Additionally, some PDS designs permit the refill or replacement of the reservoir without additional surgical procedures, extending the duration of treatment. Notwithstanding the benefits, PDS has many drawbacks such as infection and tissue damage post-implantation, compatibility issues with specific drugs, potential device-related complications, patient-specific variability in responses, limited adjustability post-implantation, high costs, accessibility challenges, and potential difficulties in removal. Due to these concerns, the PDS is recalled from the market, leaving no long-acting drug delivery system available for the treatment of AMD [Int J Retina Vitreous. 9 (2023) 6. https://doi.org/10.1186/s40942-023-00446-z].
OBJECT OF THE INVENTION
Principal object of present invention is to provide an injectable polymeric implant for sustained release of anti-VEGF agent over an extended period addressing the challenge of maintaining high drug concentrations for AMD treatment.
Another object of present invention is to provide an injectable polymeric implant for sustained release of anti-VEGF agent for a period of one year or longer, overcoming the limitations of existing treatment durations.
Another object of present invention is to provide a platform allowing higher drug loading within and injectable polymeric implant for ensuring a consistent and effective dosage of anti-VEGF agent for AMD patients.
Another object of present invention is to provide an injectable polymeric implant for sustained release of anti-VEGF agent that minimize potential interactions between the anti-VEGF agent and the implant material to optimize anti-VEGF agent release and efficacy while reducing adverse effects.
Another object of present invention is to provide an injectable polymeric implant for sustained release of anti-VEGF agent offering a promising solution addressing current treatment limitations, potentially becoming a long-term therapeutic option for individuals suffering from AMD.
Another object of present invention is to enhance the overall efficacy and convenience of AMD treatment by providing an injectable polymeric implant for sustained release of anti-VEGF agent effectively managing the disease over an extended period, potentially improving patient quality of life.
SUMMARY OF THE INVENTION
A long-acting injectable biodegradable cylindrical implant of anti-VEGF agent is disclosed. Anti-VEGF agent bevacizumab is selected as a model drug for implementation of present invention. Cylindrical, biodegradable injectable implant, its development and characterization is described. The lyophilization technique is used to generate highly concentrated solutions of specific anti-VEGF agents. The meticulous incorporation of these concentrated agents into the designed biodegradable implants, followed by a thorough examination of physicochemical attributes and stability is presented. The assessment of feasibility included the implantation of this biodegradable cylindrical implant into a goat eye model, marking a crucial step in achieving the outlined objectives. The distinctive advantage of present invention approach lies in its capacity to circumvent the degradation of bevacizumab during the fabrication of the implant. Looking at the inherent susceptibility and instability of monoclonal antibodies (mAbs) to various environmental factors encountered during processing and storage, this methodology offers a significant advancement. Features of the present invention, including extended drug release, patient-friendly administration, enhanced biocompatibility, real-time monitoring, and adaptive adjustment, along with other ground breaking elements, collectively surpass the capabilities of existing prior art solution.
The fabrication of the injectable biodegradable cylindrical implant of anti-VEGF agent involves mainly five steps; (a) development of a hollow cylinder, (b) sintering under vacuum, (c) salt leaching to generate porous structure, (d) lyophilization and loading of liquid therapeutic antibody in implant and (e) sealing of implant.
The fabrication and optimization for the developed implant is done to obtain properties like a nanoporous surface, high drug loading capacity, biodegradability, ability to be injected by a 21 G needle, and protection of the structural and functional activity of the anti-VEGF drug for one year. The implant is capable of releasing anti-VEGF drug through pores controlled by a polymeric porous membrane. The implant is found to be with more ocular acceptance compared to non-biodegradable implants. Unlike other implants requiring surgery for administration and removal, the implant as per present invention is biodegradable and do not require any surgery for administration or removal. The proposed porous biodegradable injectable implant sustain anti-VEGF drug release for 12 months and reduce the administration frequency compared to current marketed intravitreal injections, which require monthly injections. The present multifaceted, non-invasive approaches not only address current drawbacks associated with AMD treatment but also set new standards for efficacy, patient acceptance, and the practicality of long-term therapeutic interventions. The developed implant demonstrates not only industry scalability but also possesses substantial commercialization capability, affirming its potential for widespread market adoption.
BRIEF DESCRIPTION OF THE DRAWINGS
The features of the invention as per the present patent application are described with reference to the following drawings in which like elements are labeled similarly. The present invention will be more clearly understood from the detailed description and the accompanying drawings, wherein:
FIG. 1 is a schematic diagram showing long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent as per present invention.
FIG. 2 is a schematic diagram showing a method for fabrication of long-acting injectable biodegradable cylindrical implant of anti-VEGF agent by mandrel electrospinning technique where: (A). Electrospinning: fabrication of PCL hollow cylinder using mandrel collector, (B). Sintering: polymer coated rod sintering to generate microcylinder, (C). Mandrel rod removal: create central hollow cylinder and, (D). Salt leaching to generate uniform nanopores.
FIG. 3 is a diagram showing mandrel electrospinning for implant development. A. Schematic diagram of the developed mandrel, B. Image of motor with mandrel collector, C. 22 G spinal needle as mandrel collector, D. Working assembly of mandrel electrospinning.
FIG. 4 shows FE-SEM images of nanofibers of mandrel implant at 5.00KX magnification.
FIG. 5 is a schematic diagram showing methodology for lyophilization of bevacizumab and reconstitution in buffer at high concentration followed by loading of it in implant and end sealing where; (A). Bevacizumab sample frozen at -80 °C for 12 h, (B). Lyophilization at <50 mtoor pressure for 6 h, (C). Reconstitution of lyophilized powder in PBS pH 7.4 to obtain 500 mg/mL concentration, (D). loading of concentrated (500 mg/mL) solution using 1 mL insulin syringe in implant and (E). sealing of implant.
List of designations/ reference numbers in figure
1. a long-acting injectable biodegradable cylindrical implant of anti-VEGF agent
2. a nanoporous hollow cylinder
3. an anti- Vascular Endothelial Growth Factor (VEGF) agent
4. sealing applied at both ends of the nanoporous hollow cylinder (2)
DETAILED DESCRIPTION OF THE INVENTION
The description of illustrative embodiments according to principles of the present invention is intended to be read in connection with the accompanying drawings, which are to be considered as a part of the entire written description.
A long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent is shown in FIG. 1. The long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent is madeup of a nanoporous hollow cylinder (2) sealed at both the ends after filling an anti- Vascular Endothelial Growth Factor (VEGF) agent (3) into it. The nanoporous hollow cylinder (2) is a sintered porous microcylinder made up of Polycapralactone (PCL) or Polycapralactone (PCL) with Sodium salt. The anti-VEGF agent used is macromolecule of Bevacizumab or Ranibizumab or Aflibercept or Brolucizumab or Faricimab or any combination of it in highly concentrated liquid or semisolid or solid formulation. The injectable biodegradable cylindrical implant (1) is in the form of a rod or a cylinder or a nanofiber or a microtube having a length of 8-10 mm, an outer diameter of 0.4-0.6 mm and a wall thickness of 0.06-0.125 mm. The injectable biodegradable cylindrical implant (1) is configured for intraocular administration. The said implant (1) is designed to be administered via intravitreal, subconjunctival, peribulbar, subtenon, or retrobulbar injection. The injectable biodegradable cylindrical implant (1) provides controlled release of anti-VEGF agent (3) for intraocular treatment applications. The injectable biodegradable cylindrical implant (1) and the injectable biodegradable cylindrical implant (1) containing anti-VEGF agent (3) shows stability at 6M real-time study. The injectable biodegradable cylindrical implant (1) containing anti-VEGF agent (3) sustained release of the therapeutic agent of greater than about 1 year. The anti-VEGF agent used is a peptide or protein.
A method for fabrication of long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent is discussed in detail along with example. The said method includes; (a) preparing a sintered porous polycaprolactone (PCL) microcylinder, (b) lyophilization and loading of liquid therapeutic antibody in the sintered porous polycaprolactone (PCL) microcylinder and (c) sealing of the loaded sintered porous polycaprolactone (PCL) microcylinder with porous structure.
The sintered porous polycaprolactone (PCL) microcylinder is prepared by mandrel electrospinning technique. Electrospinning creates nanofibers by applying a high voltage between a syringe containing a polymer solution and a metal collector (Rod or plate). During this process, a high electrostatic field deforms the polymer solution into a Taylor Cone that ejects liquid streams, producing submicron-diameter polymer fibers. A nanoporous hollow cylinder is created using the mandrel electrospinning technique, as demonstrated in FIG. 2, and the polymer solution as per composition shown in Table 1. To prepare the polymer solution, 50 mg of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and 450 mg of polycaprolactone (PCL) with an average molecular weight Mn 80,000 g/mol are dissolved in 10 g of hexafluoroisopropanol (HFIP) and stirred at 60 ºC for one hour. After the polymer is completely dissolved, the clear solution is filled into a 10 mL syringe. The mandrel rod is fixed in an electrospinning mandrel holder and rotated at 1000-1500 rpm. The PCL and HEPES solution is electrospun at a flow rate of 1 mL/h, while the voltage difference between the positive and negative terminals is kept at 20-24 kV. The distance between the rotating mandrel rod and polymer solution discharging 22 G needle is maintained as 10-15 cm. The oscillation of the mandrel rod is kept as 7 cm. The chamber temperature is maintained as 24-33 ºC, and the relative humidity is maintained as 20-40%.
Table 1
Sr. no. Sample name Quantity (mg/g) Vendor/ Supplier Catalogue no. Lot no.
1 Polycaprolactone (Mn 80,000) 450 mg Sigma-Aldrich 440744 MKCD7192
2 HEPES Sodium Salt 50 mg Sigma-Aldrich H3784 SLCC3250
3 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) 10 g Sisco Research Laboratories Pvt Ltd 98573 7591493

The nanofibers are collected on the mandrel rod during the electrospinning process. They are then removed and sintered in a vacuum oven at a temperature of 58-60 ºC and a vacuum of -760 mmHg for four hours to generate a microcylinder. After sintering, the mandrel rod is removed from the implant to create a hollow cylinder. This hollow cylinder is then subjected to salt leaching in water for 12 h to generate uniform nanopores. After salt leaching, the implant is vacuum-dried at 50 ºC and subjected to further characterization.
The development process of the injectable implant using mandrel involved the creation of a specialized mandrel collection rod, as depicted in FIG. 3. The mandrel collection rod is meticulously crafted using a check drill, which served as a rotating mandrel rod holder that could be interchanged based on preference. Using an electrospinning instrument motor, the rod attached to the check drill could rotate. The assembly is removable and could be adjusted to manufacture polycaprolactone (PCL) microcylinder. A series of preliminary experiments are conducted to determine the optimal size of mandrel rods. Following the optimization of electrospinning parameters and polymer concentration, a small stainless steel mandrel rod is selected to produce the final cylindrical injectable implant. An inner rod of the spinal needle is employed as a mandrel collecting rod. The polymer nanofibers are collected on the mandrel and then characterized for nanofiber geometry using FE-SEM, as shown in FIG. 3. The average diameter of fibres is found to be 224.555 ± 85.97 nm. The fibers formed on the rod are intricately interconnected and exhibited remarkable mechanical flexibility in a cylindrical structure.
Furthermore, the fibers demonstrated adequate strength and strong adhesion between layers, indicating their suitability as the building blocks for an implant. After the electrospinning process, the polycaprolactone (PCL) microcylinder is subjected to sintering in a vacuum oven, which reduced its size and increased its strength. Furthermore, the stainless steel rod is eliminated, and the sintered polycaprolactone (PCL) microcylinder underwent salt leaching, which generated a uniform porous structure. Ultimately, the sintered porous polycaprolactone (PCL) microcylinder is dried in a vacuum oven and subjected to rigorous characterization studies. Finally, the optimized batches of the sintered porous polycaprolactone (PCL) microcylinder are loaded with drugs.

The methodology for preparing concentrated bevacizumab and loading it into the developed sintered porous polycaprolactone (PCL) microcylinder is depicted in FIG. 5. The commercial drug product, bevacizumab (Bevatas 100 mg/4 mL), is transferred into a tube of 10 mL. The sample is frozen at -80 °C for 12 h followed by lyophilization using an ilshinbiobase (ilshinbiobase, Korea) at less than 50 mTorr pressure for 6 h. The temperature of the condenser surface is kept at -84 ± 5 °C. The lyophilized concentrated sample is stored in a bottle at 2-8 °C for further use. The lyophilized powder samples are dissolved in phosphate-buffered saline (PBS) pH 7.4 at the 500 mg/mL concentration to obtain concentrated protein. The sample is gently shaken on a vortex mixture (Remi CM- 101 vortex mixer) for 5 min to obtain a homogeneous mixture. The concentrated bevacizumab solution is filled in a 1 mL insulin syringe (Needle outer diameter is 261 m). The sample is filled in sintered porous polycaprolactone (PCL) microcylinder followed by sealing of both ends by pressing ends with hot forceps, as shown in FIG. 5.
The developed porous biodegradable injectable implant sustains the release of anti-VEGF drugs for a year time period and reduces the administration frequency of current marketed intravitreal injections i.e. monthly injections. Present inventions provide cost-effective and patient friendly therapy to society.
The developed porous biodegradable injectable implant and the biodegradable injectable implant containing therapeutic molecules show stability at 6M real-time study.
The dimensions and design of the porous biodegradable injectable implant is unique and it can be easily administered with a 20 G needle via an intravitreal route. While other implants need surgery for administration and removal, the developed implant is biodegradable and it does not require any surgery for administration as well as removal.
The porous biodegradable injectable implant is useful for patients suffering from AMD and Diabetic retinopathy disease and they helps to reduce blindness. The implant therapy reduces overall treatment costs. , Claims:We Claim:
1. A long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent comprising of:
• a nanoporous hollow cylinder (2);
• an anti- Vascular Endothelial Growth Factor (VEGF) agent (3) filled in the nanoporous hollow cylinder (2); and
• sealing (4) applied at both ends of the nanoporous hollow cylinder (2);
characterized in that
• the nanoporous hollow cylinder is a sintered porous microcylinder made up of Polycapralactone (PCL) or Polycapralactone (PCL) with Sodium salt,
• the anti-VEGF agent is macromolecule of Bevacizumab or Ranibizumab or Aflibercept or Brolucizumab or Faricimab or any combination of it in highly concentrated liquid or semisolid or solid formulation,
• the injectable biodegradable cylindrical implant (1) is in the form of a rod or a cylinder or a nanofiber or a microtube,
• the injectable biodegradable cylindrical implant (1) is having length of 8-10 mm and outer diameter of 0.4-0.6 mm,
• the injectable biodegradable cylindrical implant (1) is having wall thickness of 0.06-0.125 mm,
• the injectable biodegradable cylindrical implant (1) is configured to be injected intraocular,
• the injectable biodegradable cylindrical implant (1) is configured to be administered via intravitreal or subconjunctival or peribulbar or subtenon or retrobulbar injection,
• the injectable biodegradable cylindrical implant (1) provides controlled release of anti-VEGF agent (3) for intraocular treatment applications,
• the injectable biodegradable cylindrical implant (1) and the injectable biodegradable cylindrical implant (1) containing anti-VEGF agent (3) show stability at 6M real-time study,
• the injectable biodegradable cylindrical implant (1) containing anti-VEGF agent (3) sustained release of the anti-VEGF agent of greater than about 1 year, and
2. The long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent as claimed in claim 1, wherein said anti-VEGF agent is a peptide or protein.
3. A method for fabrication of long-acting injectable biodegradable cylindrical implant of anti-VEGF agent comprising steps of:
(a) preparing a sintered porous polycaprolactone (PCL) microcylinder
(b) lyophilization and loading of liquid therapeutic antibody in the sintered porous polycaprolactone (PCL) microcylinder; and
(c) sealing of the loaded sintered porous polycaprolactone (PCL) microcylinder with porous structure;
Characterized in that
a method for preparing the sintered porous polycaprolactone (PCL) microcylinder, comprising:
• dissolving 50 mg of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and 450 mg of polycaprolactone (PCL) with an average molecular weight of approximately 80,000 g/mol in 10 g of hexafluoroisopropanol (HFIP) at 60 ºC, followed by stirring until a clear solution is obtained,
• transferring the clear solution into a 10 mL syringe for electrospinning,
• electrospinning the solution onto a rotating mandrel rod at a flow rate of 1 mL/h, under an applied voltage difference between 20-24 kV, wherein:
o the mandrel rotates at 1000-1500 rpm,
o the distance between the solution-dispensing needle (22G) and the mandrel rod is 10-15 cm,
o the mandrel oscillates along a 7 cm path,
o the chamber temperature is maintained between 24-33 ºC, and
o the relative humidity is kept between 20-40 % RH,
• collecting the electrospun nanofibers on the mandrel rod to form a fibrous layer,
• sintering the collected nanofiber layer in a vacuum oven at 58-60 ºC under a vacuum of -760 mmHg for four hours to form a microcylinder,
• removing the mandrel rod from the microcylinder to create a hollow structure,
• subjecting the hollow microcylinder to a salt leaching process in water for 12 hours to create uniform nanopores within the structure of the hollow microcylinder, and
• vacuum drying the nanoporous microcylinder implant at 50 ºC following salt leaching to complete the preparation,
a method for preparing a concentrated bevacizumab solution, loading it the into sintered porous polycaprolactone (PCL) microcylinder and sealing of the loaded sintered porous polycaprolactone (PCL) microcylinder, comprising:
• transferring a commercial Bevacizumab solution Bevatas 100 mg/4 mL into a 10 mL tube,
• freezing the bevacizumab solution at -80 °C for 12 hours,
• lyophilizing the frozen solution under a pressure of less than 50 mTorr for 6 hours, with the condenser surface maintained at -84 ± 5 °C,
• storing the resulting lyophilized bevacizumab powder at a temperature of 2-8 °C,
• dissolving the lyophilized powder in phosphate-buffered saline (PBS) at pH 7.4 to achieve a final concentration of 500 mg/mL, followed by gentle mixing for 5 minutes on a vortex mixer to ensure homogeneity,
• loading the concentrated bevacizumab solution into a 1 mL insulin syringe with a needle outer diameter of 261 µm, and
• introducing the loaded bevacizumab solution into the sintered porous polycaprolactone (PCL) microcylinder and followed by sealing both ends of the implant using heated forceps to encapsulate the solution,
the long-acting injectable biodegradable cylindrical implant (1) of anti-VEGF agent is designed to allow for controlled release of bevacizumab for therapeutic applications.
4. The method for fabrication of long-acting injectable biodegradable cylindrical implant of anti-VEGF agent as claimed in claim 3, wherein the obtained sintered porous polycaprolactone (PCL) microcylinder implant has uniform nanopores and is biocompatible for potential biomedical applications.
5. The method for fabrication of long-acting injectable biodegradable cylindrical implant of anti-VEGF agent as claimed in claim 3, wherein average diameter of the electrospun nanofibers is 224.555 ± 85.97 nm.
6. The method for fabrication of long-acting injectable biodegradable cylindrical implant of anti-VEGF agent as claimed in claim 3, wherein the polycaprolactone (PCL) microcylinder is manufactured by electrospinning nanofiber, developed mandrel collector, and silicone tube (i.e. solvent casting) methods.

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