Development of a Biodegradable Polymer-based Implant to Release Dual Drugs for Post-operative Management of Cataract Surgery

Development of a Biodegradable Polymer-based Implant to Release Dual Drugs for Post-operative Management of Cataract Surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development of a Biodegradable Polymer-based Implant to Release Dual Drugs for Post-operative Management of Cataract Surgery Nayana E Subhash, Soumya Nair, Srilatha Parampalli Srinivas, Nagarajan Theruveethi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3987612/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 May, 2024 Read the published version in Drug Delivery and Translational Research → Version 1 posted 5 You are reading this latest preprint version Abstract Cataract surgery is followed by post-operative eye drops for a duration of 4-6 weeks. The multitude of ocular barriers, coupled with the discomfort experienced by both the patient and their relatives in frequently administering eye drops, significantly undermines patient compliance, ultimately impeding the recovery of the patient. This study aimed to design and develop an ocular drug delivery system as an effort to achieve a drop-free post-operative care after cataract surgery. An implant was prepared containing a biodegradable polymer Poly-lactic-co-glycolic acid (PLGA), Dexamethasone (DEX) as an anti-inflammatory agent, and Moxifloxacin(MOX) as an antibiotic. Implant characterization and drug loading analysis were conducted. In vitro drug release profile showed that the release of the two drugs are correlated with the clinical prescription for post operative eye drops. In vivo study was conducted on New Zealand albino rabbits where one eye underwent cataract surgery, and the drug delivery implant was inserted into the capsular bag after placement of the synthetic intraocular lens (IOL). Borderline increase in the intraocular pressure (IOP) was noted in the test sample group. Slit-lamp observations revealed no significant anterior chamber reaction in all study groups. Histopathology study of the operated eye revealed no significant pathology in the test samples. This work aims at developing the intra ocular drug delivery implant which will replace the post-operative eye drops and help the patient with the post-operative hassle of eye drops. PLGA implant post cataract management ocular drug delivery dual drug release Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 1. Introduction The controlled release of ophthalmic drugs has been widely studied over the years. The aim is to provide a platform for drug delivery with reduced frequency and toxicity with limited use of invasive techniques. A cataract is an ocular condition caused because of the clouding of the ocular lens and leads to vision impairment. It is often seen in the elderly population also known as senile cataract. There are various other causes for cataract like diabetes and prolonged steroid application[ 1 ]. It is accounts for over 15.2 million cases representing almost 45% of the population affected by ocular conditions globally and responsible for about 71.2% of cases of vision impairment in India's population over 50 years of age [ 2 , 3 ]. The clouding is mostly due to the modifications in the lens proteins which may be due to changes in morphology, biochemistry, or physical changes of the lens[ 4 ]. It is easily corrected by cataract surgery which involves the replacement of the natural but opaque lens with an artificial clear one. Because of the possible risk of post-surgery complications, the procedure is followed up with post-operative care where the patient is prescribed to use topical anti-inflammatory and antibiotics for a period of 4–6 weeks in a tapering pattern [ 5 ]. A fundamental challenge in ocular drug delivery is the sustained distribution of drugs to the anterior and posterior segments of the eye with low systemic exposure. Patient compliance is often a difficulty in the process of recovery as a majority of the population affected is the elderly [ 6 , 7 ]. A drawback of topical instillation of drugs is that there is only 1–5% of the applied drug can reach the aqueous humor which is attributed to the various ocular barriers present in the eye[ 8 – 10 ]. Another important drawback is the need for a bystander to help instill the eye drops especially in the elderly pateints. The various physiological barriers prevent and hamper the entry of drugs into the eye leading to low bioavailability of drugs in the ocular tissues. The tear turnover rate is about 16% per minute during the time a person is awake[ 11 ], while the aqueous humor turnover is 1-1.5% of its volume per minute[ 12 ]. To improve the bioavailability of drugs in ocular tissues there is a need for frequent administration of eye drops. Many carrier based drug delivery systems like contact lenses, nanoparticles, IOLs, implants, and hydrogels have been developed to deliver a drug or a combination of drugs to the eye[ 7 , 13 – 15 ]. The use of drug delivery devices can potentially reduce the need for frequent administration of medication and prolong the bioavailability of drugs to treat ocular conditions[ 16 ].One of the objectives of this is to replace the post-operative eye drops and make the process “Drop Free” and improve patient compliance. In the treatment of conditions like inflammation and infection, sustained drug release from a biocompatible and biodegradable polymer matrix would be a huge advancement[ 17 ]. The drugs are entrapped within the polymer matrix and they are released in slow and sustained manner as the matrix degrades[ 18 ]. Poly-lactic-co-glycolic acid (PLGA) is a biodegradable and biocompatible polymer and it is FDA approved for clinical applications[ 19 ]. It is a frequently used polymer matrix for drug delivery[ 20 ]. Biodegradable and controlled release implants hold significant promise in enhancing the therapeutic effectiveness while minimizing the unwanted side effects across various drug treatments[ 21 ]. A variety of procedures are available for the manufacturing of these implants like hot-melt extrusion, compression, melting and molding[ 22 , 23 ]. Over 20 marketed medications based on PLGA have been approved by the FDA till date[ 24 ]. Ozurdex is one of the first intraocular biodegradable implants to be marketed. It is an intravitreal implant contains 0.7mg of DEX and the effect is exhibited for a period of 6 months[ 25 ]. There have been reports on implant migration and increase in intraocular pressure where Ozurdex was used. In some cases, it can also cause corneal edema leading to the need for surgical removal of the implant[ 26 ]. Surodex is a biodegradable PLGA implant containing 60µg of DEX inserted into the anterior chamber to manage post-cataract surgery inflammation. It has a release profile for about 7 days [ 27 ]. DEX loaded PLGA implant when inserted into the capsular bag was shown to be efficient in the delivery of drugs to both anterior and posterior segments of the eye for the management of post-surgery inflammation and for uveitis [ 17 ]. In the current market, there is a noticeable absence of products offering drop-free post-operative care. Even Surodex, previously considered for this purpose, had the clinical study discontinued. Our study aims to pioneer an ocular drug delivery system tailored for post-operative care following cataract surgery, enabling patients to forgo the use of eye drops[ 28 ]. This innovative implant, is the first of its kind which incorporates the two drugs commonly used in post-operative care which is prepared using hot-melt extrusion and positioned within the capsular bag during surgery. This effectively addresses the potential complications such as infection and inflammation after cataract surgery. By integrating the implant insertion into the surgical procedure itself, we aim to seamlessly merge surgery with treatment. The extruder used in this study was custom made at a local workshop in a frugal way such that it costs less than one twentieth of the commercially available extruders. It was prepared such that it can work with a minimum load of 3g of material thereby cutting down on material needed per extrusion. We used the polymer PLGA along with the anti-inflammatory drug DEX and the anti-biotic MOX to develop a biodegradable implant by single screw hot-melt extrusion and implant was sterilised using ethylene oxide gas. 2. Materials and methods 2.1 Materials PLGA (50: 50 ester terminated 65-95KDa) was purchased from Nomisma Healthcare Pvt.Ltd (Vadodara, Gujarat, India), DEX was a gift sample from Symbiotec Pharmalab Pvt.Ltd ( Indore, Madhya Pradesh, India), MOX was a gift sample from Shankus Pharmaceuticals (Santej, Gujarat, India), Acetonitrile and Methanol were purchased from Merck (India), sodium dihydrogen phosphate and disodium hydrogen phosphate were purchased from Himedia (India), Tono-Pen AVIA was purchased from Reichert Technologies. 2.2 Methods 2.2.1 HPLC method development Methods were developed for the simultaneous analysis of DEX and MOX using RP-HPLC (SHIMADZU LC-20AD). The column used was Phenomenex Gemini C18 250mm and a flow rate of 1.0mL/minute was maintained. DEX was analyzed using a 60:40 ratio of acetonitrile and water as the mobile phase. The analysis of MOX was done using a 35:65 ratio of acetonitrile and 0.05M phosphate buffer (pH 7.4). For the combination drug analysis, the mobile phase used was acetonitrile and 0.05M phosphate buffer (pH 7.4) in a 50:50 ratio. DEX was detected at 239nm while MOX was detected at 295nm. Stock solutions of the drugs were prepared in acetonitrile for DEX and phosphate buffer for MOX. For combination the stock solutions were prepared in 1:1 ratio of acetonitrile and phosphate buffer to obtain a concentration of 1mg/ml. Various dilutions of known concentrations were prepared from the stock solutions and calibration curve was prepared to find out unknown concentration using RP-HPLC from above-mentioned methods. . 2.2.2 Stability of drug The stability of the drugs DEX and MOX, individually and in combination was analyzed. 1mg of each of the drug sets were weighed and dissolved in phosphate buffer of pH 7.4 and kept in a rocker shaker at 37℃ for a period of 30 days. Aliquots were taken at regular time intervals and analyzed using the RP-HPLC method previously described. 2.2.3 Implant preparation The drug loaded polymer implant was prepared using a single screw hot melt extruder. Table 1 shows the dimensions and geometrical design parameters of the extruder. Two stainless steel barrels with adjustable temperature control were used. The first and second barrel were set to 78℃ and 68℃ respectively. The setup was allowed to pre-heat for one hour before the extrusion was conducted. PLGA 50:50 (65-95KDa), DEX, and MOX were taken in the ratio of 10:2:1 and mixed thoroughly before being fed into the extruder. The sample extruded was collected and chopped to obtain implants of approximately 1mm in length. Implants containing individual drugs and polymer were also prepared. The length, diameter, and weight of each implant were measured and were then stored in a -20℃ freezer till further use. 2.2.4 X-ray diffraction analysis (XRD) XRD studies were done using Rigaku Miniflex 600 (5th Gen) system. A known dimension of the implant was placed on a sample holder in the chamber for powder X-ray diffraction analysis. XRD patterns were generated for DEX, MOX, PLGA, and dual drug-loaded PLGA implant to understand the uniformity of drug loading in the implant. 2.2.5 Scanning Electron Microscopy (SEM) SEM analysis was done using EVO MA18 with Oxford EDS(X-act) Model instrument to study the size and surface morphology of the implant. The samples were fixed on aluminum stubs and were gold sputter coated, observed at 100x and 2000x magnification. Analysis was also done on implant samples that were collected at different time intervals after being kept in phosphate buffer at 37 o C in rocker shaker kept at 100 rpm to observe the change in surface morphology of the implant with time. 2.2.6 Drug loading Implants in triplicates were placed in vials containing 1ml of methanol and kept in a rocker shaker for 2 days, after which the samples were centrifuged at 10000 rpm for 30min. The supernatant was collected and kept for drying. The dried samples were later resuspended in 1ml of solvent (1:1 acetonitrile and buffer mixture) and the concentration of the drug was analyzed using RP-HPLC. To access the batch to batch variation three different sets of the implants were prepared by hotmelt extrusion and analysed for their drug loading. 2.2.7 In vitro drug release Implant samples were taken in triplicates, and each one was kept in 1ml of 0.1M phosphate buffer (pH 7.4) in a rocker shaker at 37℃. The samples were collected at defined time intervals and replenished with 1ml buffer. Samples were collected for a period of six weeks and were analyzed using RP-HPLC. The cumulative drug release concentration was plotted with respect to time (in days). 3. In vivo study 3.1 Animals Institutional Animal Ethics Committee (IAEC/KMC/36/2018) approval was obtained before starting the study. New Zealand albino rabbits of average age 2 years were used, and each animal was placed in an individual cage and supplied with adequate food and water. 3.2 Study design The rabbits were divided into four groups: Group 1 – Normal control; n = 4 – No Surgery Group 2 – Positive control; N = 4 – Phacoemulsification & IOL implantation, topical application of DEX- MOX eye drops, without implant Group 3 – Sham control; N = 4 – Phacoemulsification, IOL implantation, plain PLGA implant (without drugs) inserted, topical drops of DEX and MOX were administered regularly as per the guidelines. Group 4 – Test control; N = 4 – Phacoemulsification, IOL implantation, combination drug implant, no topical drops administered The positive control group, sham control group, and test group underwent phacoemulsification surgery on the right eye. The implants were used after ethylene oxide gas sterilization. The implant was placed in the inferior fornix of the capsular bag during surgery after implantation of the IOL. Post-operative eye drops (Miflodex- contains DEX and MOX ) were applied in a tapering pattern for 6 weeks in the positive control and sham control groups on the operated eye. Nepalact (nepafenac: non-steroidal anti-inflammatory agent) was administered thrice a day on the operated eye of the three groups. Nepafenac eye drops are recommended to reduce post operative cystoid macular edema after cataract surgery in humans and is a standard of care. Weekly observations were made using handheld slit-lamp to observe the anterior segment and tonopen to check the intra ocular pressure. 3.3 Histopathology At the end of the observation period, the animals were sacrificed, and the enucleated eyes were examined for gross morphology and were then preserved in 10% neutral buffered formalin for further processing. Following this the tissues were dehydrated by immersion through different grades of alcohol. Subsequently, the tissues were embedded in paraffin, forming sturdy blocks that were stored at 4°C until further processing. Utilizing a rotary microtome, sections of uniform thickness were cut, forming ribbons that were then mounted on gelatin-coated slides. The staining process involved deparaffinization using xylene, followed by hydration using descending alcohol grades and subsequent staining with hematoxylin and eosin. After dehydrating with ascending alcohol grades and clearing with xylene, the sections were cover-slipped with DPX (Distyrene Plasticizer Xylene). To maintain objectivity, the slides underwent coding and blinding before histopathological assessment by a pathologist to reveal insights into tissue composition and characteristics. 4. Results and Discussion 4.1 HPLC method development and stability of drugs The drugs were analyzed using RP-HPLC. The retention time was found to be 3.3min and 5.1min for DEX and MOX respectively in the combination setup (Fig1). For the individual drugs, the retention time was 4.2min for both (Supplementary Fig S2 and S3). The drug concentration in the dilutions prepared from the stock was quantified using the developed method. The standard graph plotted was later used to analyze the drug loading and in vitro release profile ( Supplementary data Fig S4). During the stability analysis, it was noticed that MOX was relatively stable with less than 10% degradation was observed in 30 days. Gradual degradation was observed in the DEX sample (Fig 2a). while the degradation was comparatively more pronounced when DEX was placed in combination with MOX with 35 % degraded by day 30 (Fig 2b). This is probably due to interaction between the drugs in liquid phase. The PLGA matrix has a protective effect on the drugs from preventing degradation inside the implant. The degradation is initated only on exposure to the buffer[29]. The release from the implant is in controlled and sustained manner and once it releases from the implant it will be cleared in a day inside the eye, it may not affect the actual outcome of the drugs. 4.2 Implant preparation and characterization The implants were prepared using a single screw hot melt extruder by setting the heating to a temperature above the glass transition temperature of PLGA (Fig 3 a&b)[30]. Hot-melt extrusion emerges as a viable approach in crafting biodegradable implants, proving its effectiveness through its continuous and industrial-friendly process. Its distinct advantage lies in eliminating the requirement for solvents or water, setting it apart from methods reliant on solvents[31]. One of the limitations faced while using the extruder was the inconstistency in the size of the filament obtained. In order to achieve consistent drug loading with minimal variation, we maintained a constant weight, enabling us to attain the desired level of drug loading (Table 2). The filament was chopped to obtain implants weighing 1.6 mg each (Fig 4). The combination implant had 270.3±23µg of DEX and 153.4±12µg of MOX per implant. DEX individual implant contained 268.8±9µg of the drug per implant and MOX individual implant contained 143.3±2µg of the drug per implant. The variation in drug loading among the three batches of prepared implant was found to be 3.1% for dexamethasone and 8.4% for moxifloxacin. The amount of drug to be used for the preparation of implant was calculated based on the total drug utilised during the post-operative care while using eye drops, drug loading in established ocular implants and works by Yan et al., and Chennamaneni et al. While calculating the amount of drug utilized with eye drops, one drop was considered as 50µl, and the values of 1% and 5% of the total drug used were taken, as these are considered indicative of the bioavailability of the drug upon application of eye drops. Yan et al. [14] developed a hydrogel system incorporated with DEX, MOX and Genistein and Chennamaneni et al. [17]developed an implant by compression of DEX loaded PLGA microparticles. Both studies have highlighted the use of approximately 100 or 300µg of DEX and 200µg of MOX in developing drug delivery systems intended for insertion into the capsular bag to manage post-cataract surgery complications though in vivo studies were not conducted in the work by Yan et al . Despite the lower quantity of drugs loaded into the implant in our study compared to the quantities reported in previous research, our findings indicate a notable therapeutic effect. Notably, the amount of DEX integrated into PLGA implant Surodex is significantly less than what was utilized in our study, but it is essential to acknowledge that the drug release profile of Surodex lasts only for 7 days[32]. XRD patterns were generated for DEX (Fig 5), MOX (Fig 6), PLGA (Fig 7), and a combination of drug-loaded PLGA implants (Fig 8) to understand the crystallinity of the developed product. The sharp peaks observed in the XRD patterns of DEX and MOX shows the crystalline nature of the two while the lack of the same in the XRD pattern of PLGA tells its amorphous nature. Characteristic broad peaks of amorphous nature were obtained on analysis of the drug loaded implant. This infers that the drugs are homogenously dispersed within the polymeric matrix Figure 9 shows the SEM image of the dual drug loaded implant. In figure 10 it can be observed that the surface turns more uneven over the course of the study. PLGA is a bulk eroding polymer [33], and the eroded areas seen on the surface show the degradation of the polymer. The primary mechanism behind drug release in PLGA polymer stems from a dual process involving the infiltration of water into its matrix and the gradual erosion of the bulk due to the hydrolysis of co-polymer chains[19]. On exposure to the aqueous medium, the water enters the system and initiates the degradation. The breakdown of PLGA into lactic and glycolic acid which resultes in the creation of an acidic environment, intensifying the autocatalyzing nature of the PLGA polymer[34]. When the drug is exposed to the penetrating water it either dissolves/diffuses out of the polymer matrix[35]. As the duration of exposure to the aqueous medium increases, the degradation is higher, as evidenced by the increased porosity observed on the implant. 4.3 In vitro drug release The in vitro release profile is as shown in Figure 11. It was observed that MOX was released at a faster pace than DEX in the combination implant. There was a release of about 22% of MOX in 24hrs while for DEX it was 2%. A similar trend was observed for the individual drug implants ( Supplementary data Fig S5 and S6). There was not much variation in the release profile of the drugs from the implant when loaded individually and in combination. According to the AIOS guidelines, for the first fifteen days antibiotic should be administered with an anti-inflammatory drug, and next fifteen days only an anti-inflammatory drug should be administered through eye drops[6, 31]. We obtained a similar release trend of the drugs from the developed implant. The PLGA polymer is used as the matrix. It is a biocompatible, biodegradable, and provides a method for controlled drug release for various time intervals [23]. Variations in the lactic acid: glycolic acid ratio, the molecular weight of the polymer, and the type of end group can help manipulate the drug release kinetics[20, 21]. DEX follows a triphasic release from PLGA implant which involves small burst release in the first 24 hours which was about 2% in this study, then a lag phase for about 15 days which later increases in the 3 rd week onwards. The initial burst release can be attributed to the loosely adhrerd DEX which on the surface of the implant which is uncoated by the polymer matrix that can easily be dissolved on exposure to water [36]. After the initial burst release in the first 24hrs, the lag phase is noticed in the release of DEX which is approximately 12% of the total. This could be due to the hydrophobic nature of both the polymer and the drug which limits the exposure of drug to the buffer [22]. After the lag phase a substantial increase in the release of DEX is noticed upto the completion of the drug release. This is because by this time there is sufficient degradation of the polymer and improved uptake of buffer into the matrix allowing the dissolution of the drug. This triphasic release of DEX from PLGA implant has been reported for the intravitreal imlant Ozurdex[25, 36]. The difference in the release profile of DEX between the developed implant and Ozurdex can be attributed to its composition. The composition ratio of drug to polymer in Ozurdex consists of 60% DEX, 30% acid-terminated and 10% ester-terminated 50:50 PLGA (7-17KDa)[37]. However, in the fabricated implant, the ratio is approximately 17% DEX, 9% moxifloxacin (MOX) and 74% ester-terminated 50:50 PLGA (65-95KDa). The polymer drug ratio can also affects the release profile and the use of lower molecular weight and acid terminated PLGA increases the rate degradation of polymer. Thereby, there is a shorter lag time and the release is completed faster in Ozurdex with the release being completed in about 30 days. The fabricated implant used a higher molecular weight PLGA and a much lesser amount of drug leading to an increased lag time and longer release period of drug. The release of DEX from the prepared implant is independent of the presence of MOX as a similar trend is observed in the release profile of the DEX only implant. The similar type of release was observed with thin film strip of PLGA encapsulated with DEX wound around the optic of IOL [16]. The faster release of MOX as noticed in the in vitro release profile may be because of the pronounced osmotic effect due to its hydrophilic nature[18]. 4.4 In vivo study A total of 12 rabbit eyes underwent cataract surgery and out of this four of them received the dual drug loaded implant. The implant was inserted into the capsular bag after the placement of the IOL (Fig 12). The slit-lamp observations revealed that there was no significant anterior chamber reaction in all groups. No displacement of the IOL was observed. It was difficult to spot the implant during the weekly observations, probably due to the reduction in size due to degradation of polymer and increased transparency due to release of drugs. The implant was in the capsular bag inferiorly in most cases (Fig 13 and 14). In one case in the test group, the implant had stuck to the center of the bag while in another case it had migrated to the anterior chamber. IOP measurement were taken every week post surgery (Table 3). An increased IOP was observed in the test group during the period of study which may be due to high DEX concentration in the eye as observed in the in vitro release profile. Ocular hypertension or evelation of IOP due to application of steroids have been reported to be dosage and time dependent[38, 39]. Concerning the elevated IOP, glaucoma due to the long-term use of steroids is a known complication[40]. This can be managed by making adjustments to the steroid load during implant preparation. Insertion of the implant in the capsular bag will allow the bidirectional flow of drugs, increase the drug availability to the local tissues and the sustained drug release will turn improve the clinical outcome[41]. As the implant is biodegradable, the insertion of the implant during surgery helps to combine surgery and treatment without the need for surgical removal of the implant once the drug reservoir is exhausted[16]. 4.5 Histopathology After the observation period, the eyes of the rabbits from all groups were enucleated and taken for histopathology studies. On gross examination of the operated eye, it was observed that the cornea was clear, the iris was normal and IOL was in the capsular bag. The histopathology results are based on the report given by the pathologist. There was no gross histopathological variation observed in the samples of unoperated eyes. No significant pathology was observed in samples of the normal control group. Focal edema and a few chronic inflammatory cells were observed in the cornea of samples from the sham control group. Edema and mild chronic inflammation of the cornea were observed in samples of the positive control group. In the test group, the cornea was normal. Edema and mild chronic inflammation in the iris and the ciliary body were observed. One sample of the test group showed congested blood vessels in the choroid. The retina appeared normal with no significant pathology. Any other differences seen in the images are artifactual, and occurred during the preparation process of the specimens.The results revealed the biocompatibility of the implant at the site of insertion (Fig 15). Images for cornea, ciliary body and retina of all samples are given in the supplementary data (Supplimentary data Fig S7 a, b and c). 5. Conclusions and future work The delivery of drugs via eye drops encounters challenges because of numerous ocular barriers. This study focuses on the creation of a dual drug-loaded biodegradable implant to manage post-cataract surgery inflammation and infection. We have demonstrated that the developed implant, when positioned in the capsular bag, effectively addresses the limitations of topical drug administration. The drugs DEX and MOX were concurrently released from the implant for a period extending beyonf 30days, achieving therapeutic efficacy. The release pattern of drugs from the implant aligns with the prescribed dosage regimen. During the initial week, there is a delay in DEX release, and a marginal increase in IOP was observed in the test groups. Hence, future work will involve optimizing the drug-loading and the release profile of the implant by exploring different polymer variations. Additionally, efforts will be directed towards ensuring the consistency in the size of filament to meet the requirements of bulk production. Declarations Ethics Approval and consent to participate All institutional and national guidelines for the care and use of laboratory animals were followed. The approval was granted by the Institutional Animal Ethics Committee (AIEC) of Kasturba Medical College, Manipal (IAEC/KMC/36/2018). Consent for publication All the authors have approved the final manuscript and agreed for its publication. Availability of data and materials The authors confirm that the data supporting the findings of this study are available. Competing interest The authors declare no competing interests. Funding This project was funded by the BIRAC-BIG Grant and Intramural Grant by Manipal Academy of Higher Education. Author Contributions Nayana Elizabeth Subhash: Data collection, analysis, writing – original draft and editing. Soumya S: In vivo study- surgery, observation and writing-review and editing. Srilatha P S: Histopathology analysis and writing- review and editing. Nagarajan T: In vivo - sample collection and images for histopathology. Sulatha V Bhandary: Conceptualization, supervision,analysis, writing-review and editing. Bharath Raja Guru: Original idea, conceptualization, analysis, supervision, writing – review and editing. Acknowledgements This project was financially supported by BIRAC-BIG scheme by Department of Biotechnology (DBT), India and Intramural Fund by Manipal Academy of Higher Education. The authors extend our appreciation to Symbiotec Pharmalab Pvt. Ltd (Indore, Madhya Pradesh, India) and Shankus Pharmaceuticals (Santej, Gujarat, India) for generously providing the DEX and MOX respectiverly which were utilized in this study. Special acknowledgment goes to Shastry’s Multi Solutions for their assistance in the fabrication and development of the extruder. We express our gratitude to Mr. Sridar Prabhu, Mr. Nithyananda Kamath, and Mrs. Benedicta A Soans for their valuable aid and support during the in vivo study. Additionally, we would like to thank the Central Instrumentation Facility at Manipal Academy of Higher Education for their support in utilizing facilities such as SEM and XRD. 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Development of a novel bioerodible dexamethasone implant for uveitis and postoperative cataract inflammation. J Controlled Release. 2013;167:53–9. https://doi.org/10.1016/j.jconrel.2013.01.007 . Bode C, Kranz H, Fivez A, et al. Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants. J Controlled Release. 2019;306:97–107. https://doi.org/10.1016/j.jconrel.2019.05.039 . Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier. Polym (Basel). 2011;3:1377–97. https://doi.org/10.3390/polym3031377 . Bassand C, Benabed L, Charlon S, et al. 3D printed PLGA implants: APF DDM vs. FDM. J Controlled Release. 2023;353:864–74. https://doi.org/10.1016/j.jconrel.2022.11.052 . Park H, Otte A, Park K. Evolution of drug delivery systems: From 1950 to 2020 and beyond. J Controlled Release. 2022;342:53–65. https://doi.org/10.1016/j.jconrel.2021.12.030 . Wachowiak S, Danede F, Willart JF, et al. PLGA implants for controlled dexamethasone delivery: Impact of the polymer chemistry. J Drug Deliv Sci Technol. 2023;86:104648. https://doi.org/10.1016/j.jddst.2023.104648 . Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharm. 2008;364:298–327. https://doi.org/10.1016/j.jddst.2023.104648 . Wang Y, Qin B, Xia G, Choi SH. FDA’s Poly (Lactic-Co-Glycolic Acid) Research Program and Regulatory Outcomes. AAPS J. 2021;23. https://doi.org/10.1016/j.ijpharm.2008.04.042 . Costello MA, Liu J, Wang Y, et al. Reverse engineering the Ozurdex dexamethasone intravitreal implant. Int J Pharm. 2023;634. https://doi.org/10.1016/j.ijpharm.2023.122625 . Pardo-López D, Francés-Muñoz E, Gallego-Pinazo R, Díaz-Llopis M. Anterior chamber migration of dexametasone intravitreal implant (Ozurdex®). Graefe’s Archive Clin Experimental Ophthalmol. 2012;250:1703–4. https://doi.org/10.1007/s00417-011-1802-x . Tan DTH, Chee S, Lim L, et al. Randomized Clinical Trial of Surodex Steroid Anterior versus Posterior Placement of Two Surodex in. Ophthalmology. 2001;108:2172–81. https://doi.org/10.1016/S0161-6420(01)00839-9 . Wong CW, Metselaar JM, Storm G, Wong TT. A review of the clinical applications of drug delivery systems for the treatment of ocular anterior segment inflammation. Br J Ophthalmol. 2021;105:1617–22. https://doi.org/10.1136/bjophthalmol-2020-315911 . Matter B, Ghaffari A, Bourne D et al. (2019) Dexamethasone Degradation in Aqueous Medium and Implications for Correction of In Vitro Release from Sustained Release Delivery Systems. AAPS PharmSciTech 20:. https://doi.org/10.1208/s12249-019-1508-7 . Veeran MG, Thomas RR, Ramakrishnan R, et al. Quality-by-Design Approach for Optimization and Processing of PLGA Polymer Film by Hot Melt Extrusion. J Pharm Innov. 2022;17:1282–94. https://doi.org/10.1007/s12247-021-09600-2 . Kamel R, Abbas H. PLGA-based monolithic filaments prepared by hot-melt extrusion: In-vitro comparative study. Ann Pharm Fr. 2018;76:97–106. https://doi.org/10.1016/j.pharma.2017.09.002 . Wadood AC, Armbrecht AM, Aspinall PA, Dhillon B. Safety and efficacy of a dexamethasone anterior segment drug delivery system in patients after phacoemulsification. J Cataract Refract Surg. 2004;30:761–8. https://doi.org/10.1016/j.jcrs.2003.08.028 . Körber M. PLGA erosion: Solubility- or diffusion-controlled? Pharm Res. 2010;27:2414–20. https://doi.org/10.1007/s11095-010-0232-5 . Saraf I, Kushwah V, Alva C, et al. Influence of PLGA End Groups on the Release Profile of Dexamethasone from Ocular Implants. Mol Pharm. 2023;20:1307–22. https://doi.org/10.1021/acs.molpharmaceut.2c00945 . Von Burkersroda F, Schedl L, Opferich AG. (2002) Why degradable polymers undergo surface erosion or bulk erosion. https://doi.org/10.1016/S0142-9612(02)00170-9 . Costello MA, Liu J, Chen B, et al. Drug release mechanisms of high-drug-load, melt-extruded dexamethasone intravitreal implants. Eur J Pharm Biopharm. 2023;187:46–56. https://doi.org/10.1016/j.ejpb.2023.04.003 . Shiah J-G, Bhagat R, Blanda WM, et al. Ocular implant made by a double extrusion process. US Patent. 2012;8(318):070B2. Armaly MF. Effect of Corticosteroids on Intraocular Pressure and Fluid Dynamics: I.The Effect of Dexamethasone* in the eye. Arch Ophthalmol. 1963;70:88–97. https://doi.org/10.1001/archopht.1963.00960050484010 . Andrew Whitlock N, Mcknight B, Corcoran KN, et al. Increased intraocular pressure in mice treated with dexamethasone. Invest Ophthalmol Vis Sci. 2010;51:6496–503. https://doi.org/10.1167/iovs.10-5430 . Wykrota AA, Abdin AD, Munteanu C et al. (2023) Incidence and treatment approach of intraocular pressure elevation after various types of local steroids for retinal diseases. Graefe’s Archive for Clinical and Experimental Ophthalmology. https://doi.org/10.1007/s00417-023-06163-5 . Chennamaneni SR, Bohner A, Bernhisel A, Ambati BK. Pharmacokinetics and efficacy of bioerodible Dexamethasone implant in Concanavalin a-induced uveitic cataract rabbit model. Pharm Res. 2014;31:3179–90. https://doi.org/10.1007/s11095-014-1410-7 . Tables Table 1: Dimensions and geometrical design parameters of the extruder Symbol Description Value dbarrel the inner diameter of the barrel 12mm hchannel mean distance from the screw root to the barrel wall 1.2mm in the beginning and 1 mm at the end hclearance clearance between barrel and extruder screw 0.05 mm wchannel channel width 4.00 mm wpitch the pitch of the extruder screw 6mm in the beginning and 5.6 mm at the end. Table 2: Dimensions and weight of implant Sl.No Sample type Diameter (mm) Length (mm) Weight (mg) 1 Combination 1.13 1.04 1.6 2 Combination 1.16 1.09 1.6 3 Combination 1.19 1.1 1.6 4 DEX 1.05 1.03 1.6 5 DEX 1.04 1.07 1.6 6 DEX 1.11 1.08 1.6 7 MOX 1.09 1.01 1.6 8 MOX 1 1.05 1.6 9 MOX 1.07 1 1.6 10 PLGA 1.14 1 1.6 11 PLGA 1.09 1.02 1.6 12 PLGA 1.10 1.01 1.6 Table 3 : IOP measurements in rabbit Time Intraocular Pressure (mm Hg) Normal control Positive control Sham control Test Week1 25.5±3.5 27.5±5.5 28.5±4.5 31.5±3.5 Week2 22±4 26.5±7.5 25±2 38±2 Week3 30 31.5±1.5 26±1 43.5±0.5 Week 4 23.5±6.5 31±1 28.5±1.5 33±3 Supplementary Files supplimentary26thfeb.docx Cite Share Download PDF Status: Published Journal Publication published 02 May, 2024 Read the published version in Drug Delivery and Translational Research → Version 1 posted Editorial decision: Major Revisions Needed 15 Mar, 2024 Reviewers agreed at journal 04 Mar, 2024 Reviewers invited by journal 03 Mar, 2024 Editor assigned by journal 27 Feb, 2024 First submitted to journal 26 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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10:09:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3987612/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3987612/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s13346-024-01604-y","type":"published","date":"2024-05-02T19:58:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52102746,"identity":"eb212d10-73fb-4a97-abf6-38e1b7a5f314","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40266,"visible":true,"origin":"","legend":"\u003cp\u003eHPLC chromatogram for MOX (3.3min) and DEX (5.1min) at 239nm wavelength, run in 50:50 acetonitrile: buffer\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/c72b17d2e3532fa3828880c1.png"},{"id":52102748,"identity":"2209d331-4e8f-4e1a-ba4c-32e83b85aeaf","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":417744,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e: Stability profile of DEX individually and in combination at pH 7.4\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb\u003c/strong\u003e: Stability profile of MOX individually and in combination at pH 7.4\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/0643d68b1a768cd849c079e4.png"},{"id":52102753,"identity":"817af5fe-a0dd-411b-a0d9-4759186b7c1c","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1314701,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea:\u003c/strong\u003e Single screw hot melt extruder\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb\u003c/strong\u003e: Single screw hot melt extruder\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/eb0b4ebc329b95f312fcc01e.png"},{"id":52104554,"identity":"3728567d-865e-45ca-b786-82f5024f82fa","added_by":"auto","created_at":"2024-03-06 19:25:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":274445,"visible":true,"origin":"","legend":"\u003cp\u003eImplants- Plain PLGA( left) and DEX-MOX PLGA (right)\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/bb02a2a72d99c549564055e3.png"},{"id":52102750,"identity":"80036f3f-2e75-4fef-9763-ae973ce48a37","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":72642,"visible":true,"origin":"","legend":"\u003cp\u003eXRD of DEX\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/c78086b3fada3b04c4d009a3.png"},{"id":52102752,"identity":"8a0c9a32-665a-40fc-bbdb-dd07a50c4002","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":43338,"visible":true,"origin":"","legend":"\u003cp\u003eXRD of MOX\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/19d35967ce578f34cb7811a6.png"},{"id":52102749,"identity":"be37cd98-9d68-4b60-a266-da94b7581fe7","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":97545,"visible":true,"origin":"","legend":"\u003cp\u003eXRD of PLGA\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/86e1514f72f7a5230f38ca96.png"},{"id":52102757,"identity":"00ab942c-f85b-46e0-833b-9f4b29c261a3","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":64151,"visible":true,"origin":"","legend":"\u003cp\u003eXRD of combination implant\u003c/p\u003e","description":"","filename":"Fig8.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/142493274a7d04a2cd65eefc.png"},{"id":52102754,"identity":"5a1a2f86-71b3-44fb-a579-ebb0199631f3","added_by":"auto","created_at":"2024-03-06 19:17:18","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":1109712,"visible":true,"origin":"","legend":"\u003cp\u003eSEM image of the implant\u003c/p\u003e","description":"","filename":"Fig9.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/dea82dbcbf01803dee8e2e54.png"},{"id":52102759,"identity":"550640ea-28f7-482b-89aa-b8d2d304dd80","added_by":"auto","created_at":"2024-03-06 19:17:19","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":888041,"visible":true,"origin":"","legend":"\u003cp\u003eSEM image of the implant in phosphate buffer (pH 7.4) Row 1 left to right day -0,7,21. Row 2 left to right- day28, 35,42\u003c/p\u003e","description":"","filename":"Fig10.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/670981f8d15ccfbe476dc250.png"},{"id":52102761,"identity":"75b57fc3-ffcd-4c3a-bc5b-15eaf10d9f9a","added_by":"auto","created_at":"2024-03-06 19:17:19","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":221523,"visible":true,"origin":"","legend":"\u003cp\u003eRelease profile of DEX and MOX in combination implant\u003c/p\u003e","description":"","filename":"Fig11.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/f172031af2bc7d6ba428d3ca.png"},{"id":52104558,"identity":"2d7e5618-2804-4eac-8590-d0df69c57bbc","added_by":"auto","created_at":"2024-03-06 19:25:20","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":802785,"visible":true,"origin":"","legend":"\u003cp\u003eImplant in the eye during surgery – left to right- Insertion, Position adjustment, Post adjustment\u003c/p\u003e","description":"","filename":"Fig12.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/97abc2e13f4697b98e900839.png"},{"id":52104555,"identity":"237b1aac-dce6-401e-8d5c-2c60fe38815a","added_by":"auto","created_at":"2024-03-06 19:25:18","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":382027,"visible":true,"origin":"","legend":"\u003cp\u003eImplant in the eye after surgery on day 1\u003c/p\u003e","description":"","filename":"Fig13.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/4cd05b434c53bd1d754823c7.png"},{"id":52102758,"identity":"efec1fec-0d97-4b58-a8c9-c133f4c5f977","added_by":"auto","created_at":"2024-03-06 19:17:19","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":615045,"visible":true,"origin":"","legend":"\u003cp\u003eOperated eye at 6 weeks – from left to right- Normal control, Positive control, Sham control, Test\u003c/p\u003e","description":"","filename":"Fig14.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/d7242bbfd68860337f86e795.png"},{"id":52104557,"identity":"47bfb4cd-23f4-410e-ada3-9e2df02f4a20","added_by":"auto","created_at":"2024-03-06 19:25:20","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":690441,"visible":true,"origin":"","legend":"\u003cp\u003eHistology of ocular tissues of right eye at 6 weeks (A) Cornea, (B) Iris and ciliary body, (C) Retina\u003c/p\u003e","description":"","filename":"Fig15.png","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/6b1ba8a79629a2d4ae5cbfb2.png"},{"id":56042894,"identity":"c2e288be-78ab-4d4e-9864-c13ee410ca06","added_by":"auto","created_at":"2024-05-07 20:08:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7818309,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/04546a83-408c-4f51-832b-9e4dd4ac4264.pdf"},{"id":52102760,"identity":"79f535f6-693f-4b8f-91f5-3e2e224d6ecd","added_by":"auto","created_at":"2024-03-06 19:17:19","extension":"docx","order_by":22,"title":"","display":"","copyAsset":false,"role":"supplement","size":637919,"visible":true,"origin":"","legend":"","description":"","filename":"supplimentary26thfeb.docx","url":"https://assets-eu.researchsquare.com/files/rs-3987612/v1/dbaefd4e668644ebf9fa46b6.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eDevelopment of a Biodegradable Polymer-based Implant to Release Dual Drugs for Post-operative Management of Cataract Surgery\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe controlled release of ophthalmic drugs has been widely studied over the years. The aim is to provide a platform for drug delivery with reduced frequency and toxicity with limited use of invasive techniques. A cataract is an ocular condition caused because of the clouding of the ocular lens and leads to vision impairment. It is often seen in the elderly population also known as senile cataract. There are various other causes for cataract like diabetes and prolonged steroid application[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is accounts for over 15.2\u0026nbsp;million cases representing almost 45% of the population affected by ocular conditions globally and responsible for about 71.2% of cases of vision impairment in India's population over 50 years of age [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The clouding is mostly due to the modifications in the lens proteins which may be due to changes in morphology, biochemistry, or physical changes of the lens[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It is easily corrected by cataract surgery which involves the replacement of the natural but opaque lens with an artificial clear one. Because of the possible risk of post-surgery complications, the procedure is followed up with post-operative care where the patient is prescribed to use topical anti-inflammatory and antibiotics for a period of 4\u0026ndash;6 weeks in a tapering pattern [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A fundamental challenge in ocular drug delivery is the sustained distribution of drugs to the anterior and posterior segments of the eye with low systemic exposure. Patient compliance is often a difficulty in the process of recovery as a majority of the population affected is the elderly [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A drawback of topical instillation of drugs is that there is only 1\u0026ndash;5% of the applied drug can reach the aqueous humor which is attributed to the various ocular barriers present in the eye[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another important drawback is the need for a bystander to help instill the eye drops especially in the elderly pateints.\u003c/p\u003e \u003cp\u003eThe various physiological barriers prevent and hamper the entry of drugs into the eye leading to low bioavailability of drugs in the ocular tissues. The tear turnover rate is about 16% per minute during the time a person is awake[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], while the aqueous humor turnover is 1-1.5% of its volume per minute[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. To improve the bioavailability of drugs in ocular tissues there is a need for frequent administration of eye drops. Many carrier based drug delivery systems like contact lenses, nanoparticles, IOLs, implants, and hydrogels have been developed to deliver a drug or a combination of drugs to the eye[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The use of drug delivery devices can potentially reduce the need for frequent administration of medication and prolong the bioavailability of drugs to treat ocular conditions[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].One of the objectives of this is to replace the post-operative eye drops and make the process \u0026ldquo;Drop Free\u0026rdquo; and improve patient compliance. In the treatment of conditions like inflammation and infection, sustained drug release from a biocompatible and biodegradable polymer matrix would be a huge advancement[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The drugs are entrapped within the polymer matrix and they are released in slow and sustained manner as the matrix degrades[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Poly-lactic-co-glycolic acid (PLGA) is a biodegradable and biocompatible polymer and it is FDA approved for clinical applications[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It is a frequently used polymer matrix for drug delivery[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Biodegradable and controlled release implants hold significant promise in enhancing the therapeutic effectiveness while minimizing the unwanted side effects across various drug treatments[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A variety of procedures are available for the manufacturing of these implants like hot-melt extrusion, compression, melting and molding[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOver 20 marketed medications based on PLGA have been approved by the FDA till date[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Ozurdex is one of the first intraocular biodegradable implants to be marketed. It is an intravitreal implant contains 0.7mg of DEX and the effect is exhibited for a period of 6 months[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. There have been reports on implant migration and increase in intraocular pressure where Ozurdex was used. In some cases, it can also cause corneal edema leading to the need for surgical removal of the implant[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Surodex is a biodegradable PLGA implant containing 60\u0026micro;g of DEX inserted into the anterior chamber to manage post-cataract surgery inflammation. It has a release profile for about 7 days [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. DEX loaded PLGA implant when inserted into the capsular bag was shown to be efficient in the delivery of drugs to both anterior and posterior segments of the eye for the management of post-surgery inflammation and for uveitis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the current market, there is a noticeable absence of products offering drop-free post-operative care. Even Surodex, previously considered for this purpose, had the clinical study discontinued. Our study aims to pioneer an ocular drug delivery system tailored for post-operative care following cataract surgery, enabling patients to forgo the use of eye drops[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This innovative implant, is the first of its kind which incorporates the two drugs commonly used in post-operative care which is prepared using hot-melt extrusion and positioned within the capsular bag during surgery. This effectively addresses the potential complications such as infection and inflammation after cataract surgery. By integrating the implant insertion into the surgical procedure itself, we aim to seamlessly merge surgery with treatment. The extruder used in this study was custom made at a local workshop in a frugal way such that it costs less than one twentieth of the commercially available extruders. It was prepared such that it can work with a minimum load of 3g of material thereby cutting down on material needed per extrusion. We used the polymer PLGA along with the anti-inflammatory drug DEX and the anti-biotic MOX to develop a biodegradable implant by single screw hot-melt extrusion and implant was sterilised using ethylene oxide gas.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Materials\u003c/h2\u003e\n \u003cp\u003ePLGA (50: 50 ester terminated 65-95KDa) was purchased from Nomisma Healthcare Pvt.Ltd (Vadodara, Gujarat, India), DEX was a gift sample from Symbiotec Pharmalab Pvt.Ltd ( Indore, Madhya Pradesh, India), MOX was a gift sample from Shankus Pharmaceuticals (Santej, Gujarat, India), Acetonitrile and Methanol were purchased from Merck (India), sodium dihydrogen phosphate and disodium hydrogen phosphate were purchased from Himedia (India), Tono-Pen AVIA was purchased from Reichert Technologies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Methods\u003c/h2\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.1 HPLC method development\u003c/h2\u003e\n \u003cp\u003eMethods were developed for the simultaneous analysis of DEX and MOX using RP-HPLC (SHIMADZU LC-20AD). The column used was Phenomenex Gemini C18 250mm and a flow rate of 1.0mL/minute was maintained. DEX was analyzed using a 60:40 ratio of acetonitrile and water as the mobile phase. The analysis of MOX was done using a 35:65 ratio of acetonitrile and 0.05M phosphate buffer (pH 7.4). For the combination drug analysis, the mobile phase used was acetonitrile and 0.05M phosphate buffer (pH 7.4) in a 50:50 ratio. DEX was detected at 239nm while MOX was detected at 295nm.\u003c/p\u003e\n \u003cp\u003eStock solutions of the drugs were prepared in acetonitrile for DEX and phosphate buffer for MOX. For combination the stock solutions were prepared in 1:1 ratio of acetonitrile and phosphate buffer to obtain a concentration of 1mg/ml. Various dilutions of known concentrations were prepared from the stock solutions and calibration curve was prepared to find out unknown concentration using RP-HPLC from above-mentioned methods. .\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.2 Stability of drug\u003c/h2\u003e\n \u003cp\u003eThe stability of the drugs DEX and MOX, individually and in combination was analyzed. 1mg of each of the drug sets were weighed and dissolved in phosphate buffer of pH 7.4 and kept in a rocker shaker at 37℃ for a period of 30 days. Aliquots were taken at regular time intervals and analyzed using the RP-HPLC method previously described.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.3 Implant preparation\u003c/h2\u003e\n \u003cp\u003eThe drug loaded polymer implant was prepared using a single screw hot melt extruder. Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the dimensions and geometrical design parameters of the extruder. Two stainless steel barrels with adjustable temperature control were used. The first and second barrel were set to 78℃ and 68℃ respectively. The setup was allowed to pre-heat for one hour before the extrusion was conducted. PLGA 50:50 (65-95KDa), DEX, and MOX were taken in the ratio of 10:2:1 and mixed thoroughly before being fed into the extruder. The sample extruded was collected and chopped to obtain implants of approximately 1mm in length. Implants containing individual drugs and polymer were also prepared. The length, diameter, and weight of each implant were measured and were then stored in a -20℃ freezer till further use.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.4 X-ray diffraction analysis (XRD)\u003c/h2\u003e\n \u003cp\u003eXRD studies were done using Rigaku Miniflex 600 (5th Gen) system. A known dimension of the implant was placed on a sample holder in the chamber for powder X-ray diffraction analysis. XRD patterns were generated for DEX, MOX, PLGA, and dual drug-loaded PLGA implant to understand the uniformity of drug loading in the implant.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.5 Scanning Electron Microscopy (SEM)\u003c/h2\u003e\n \u003cp\u003eSEM analysis was done using EVO MA18 with Oxford EDS(X-act) Model instrument to study the size and surface morphology of the implant. The samples were fixed on aluminum stubs and were gold sputter coated, observed at 100x and 2000x magnification. Analysis was also done on implant samples that were collected at different time intervals after being kept in phosphate buffer at 37\u003csup\u003eo\u003c/sup\u003e C in rocker shaker kept at 100 rpm to observe the change in surface morphology of the implant with time.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.6 Drug loading\u003c/h2\u003e\n \u003cp\u003eImplants in triplicates were placed in vials containing 1ml of methanol and kept in a rocker shaker for 2 days, after which the samples were centrifuged at 10000 rpm for 30min. The supernatant was collected and kept for drying. The dried samples were later resuspended in 1ml of solvent (1:1 acetonitrile and buffer mixture) and the concentration of the drug was analyzed using RP-HPLC. To access the batch to batch variation three different sets of the implants were prepared by hotmelt extrusion and analysed for their drug loading.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.7 \u003cem\u003eIn vitro\u003c/em\u003e drug release\u003c/h2\u003e\n \u003cp\u003eImplant samples were taken in triplicates, and each one was kept in 1ml of 0.1M phosphate buffer (pH 7.4) in a rocker shaker at 37℃. The samples were collected at defined time intervals and replenished with 1ml buffer. Samples were collected for a period of six weeks and were analyzed using RP-HPLC. The cumulative drug release concentration was plotted with respect to time (in days).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"3. In vivo study ","content":"\u003cp\u003e3.1 Animals\u003c/p\u003e\n\u003cp\u003eInstitutional Animal Ethics Committee (IAEC/KMC/36/2018) approval was obtained before starting the study. New Zealand albino rabbits of average age 2 years were used, and each animal was placed in an individual cage and supplied with adequate food and water.\u003c/p\u003e\n\u003cp\u003e3.2 Study design\u003c/p\u003e\n\u003cp\u003eThe rabbits were divided into four groups:\u003c/p\u003e\n\u003col style=\"list-style-type: lower-roman;\"\u003e\n \u003cli\u003eGroup 1 \u0026ndash; Normal control; n = 4 \u0026ndash; No Surgery\u003c/li\u003e\n \u003cli\u003eGroup\u0026nbsp;2\u0026nbsp;\u0026ndash;\u0026nbsp;Positive\u0026nbsp;control;\u0026nbsp;N\u0026nbsp;=\u0026nbsp;4\u0026nbsp;\u0026ndash;\u0026nbsp;Phacoemulsification\u0026nbsp;\u0026amp;\u0026nbsp;IOL\u0026nbsp;implantation, topical application of DEX- MOX eye drops, without \u0026nbsp;implant\u003c/li\u003e\n \u003cli\u003eGroup\u0026nbsp;3\u0026nbsp;\u0026ndash;\u0026nbsp;Sham\u0026nbsp;control;\u0026nbsp;N\u0026nbsp;=\u0026nbsp;4\u0026nbsp;\u0026ndash;\u0026nbsp;Phacoemulsification, IOL\u0026nbsp;implantation,\u0026nbsp;plain\u0026nbsp;PLGA\u0026nbsp;implant (without drugs) inserted, topical drops of \u0026nbsp;DEX and MOX were administered regularly as per the guidelines.\u003c/li\u003e\n \u003cli\u003eGroup 4 \u0026ndash; Test control; N = 4 \u0026ndash; Phacoemulsification, IOL implantation, combination drug implant, no topical drops administered \u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe positive control group, sham control group, and test group underwent phacoemulsification surgery on the right eye. The implants were used after ethylene oxide gas sterilization. The implant was placed in the inferior fornix of the capsular bag during surgery after implantation of the IOL. Post-operative eye drops (Miflodex- contains DEX and MOX ) were applied in a tapering pattern for 6 weeks in the positive control and sham control groups on the operated eye. Nepalact (nepafenac: non-steroidal anti-inflammatory agent) was administered thrice a day on the operated eye of the three groups. \u0026nbsp;Nepafenac eye drops are recommended to reduce post operative cystoid macular edema after cataract surgery in humans and is a standard of care.\u0026nbsp;Weekly observations were made using handheld slit-lamp to observe the anterior segment and tonopen to check the intra ocular pressure.\u003c/p\u003e\n\u003cp\u003e3.3 Histopathology\u003c/p\u003e\n\u003cp\u003eAt the end of the observation period, the animals were sacrificed, and the enucleated eyes \u0026nbsp;were \u0026nbsp;examined for gross morphology and were then preserved in 10% neutral buffered formalin for further processing. Following this the tissues were dehydrated by immersion through different grades of alcohol. Subsequently, the tissues were embedded in paraffin, forming sturdy blocks that were stored at 4\u0026deg;C until further processing. Utilizing a rotary microtome, sections of uniform thickness were cut, forming ribbons that were then mounted on gelatin-coated slides. The staining process involved deparaffinization using xylene, followed by hydration using descending alcohol grades and subsequent staining with hematoxylin and eosin. After dehydrating with ascending alcohol grades and clearing with xylene, the sections were cover-slipped with DPX (Distyrene Plasticizer Xylene).\u003c/p\u003e\n\u003cp\u003eTo maintain objectivity, the slides underwent coding and blinding before histopathological assessment by a pathologist to reveal insights into tissue composition and characteristics.\u003c/p\u003e"},{"header":"4. Results and Discussion","content":"\u003cp\u003e4.1 HPLC method development and stability of drugs\u003c/p\u003e\n\u003cp\u003eThe drugs were analyzed using RP-HPLC. The retention time was found to be 3.3min and 5.1min for DEX and MOX respectively in the combination setup (Fig1). For the individual drugs, the retention time was 4.2min for both (Supplementary Fig S2 and S3). The drug concentration in the dilutions prepared from the stock was quantified using the developed method. The standard graph plotted was later used to analyze the drug loading and \u003cem\u003ein vitro\u003c/em\u003e release profile ( Supplementary data Fig S4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the stability analysis, it was noticed that MOX was relatively stable with less than 10% degradation \u0026nbsp;was observed \u0026nbsp;in \u0026nbsp;30 days. Gradual degradation was observed in the \u0026nbsp; DEX sample (Fig 2a). \u0026nbsp;while the degradation was comparatively more pronounced when DEX was placed in combination with MOX with 35 % degraded by day 30 (Fig 2b). This is probably due to interaction between the drugs in liquid phase. The PLGA matrix has a protective effect on the drugs from preventing degradation inside the implant. The degradation is initated only on exposure to the buffer[29]. The release from the implant is in controlled and sustained manner and once it releases from the implant it will be cleared in a day inside the eye, it may not affect the actual outcome of the drugs.\u003c/p\u003e\n\u003cp\u003e4.2 Implant preparation and characterization\u003c/p\u003e\n\u003cp\u003eThe implants were prepared using a single screw hot melt extruder by setting the heating to a temperature above the glass transition temperature of PLGA \u0026nbsp;(Fig 3 a\u0026amp;b)[30]. \u0026nbsp;Hot-melt extrusion emerges as a viable approach in crafting biodegradable implants, proving its effectiveness through its continuous and industrial-friendly process. Its distinct advantage lies in eliminating the requirement for solvents or water, setting it apart from methods reliant on solvents[31]. \u0026nbsp;One of the limitations faced while using the extruder was the inconstistency in the size of the filament obtained. In order to achieve consistent drug loading with minimal variation, we maintained a constant weight, enabling us to attain the desired level of drug loading (Table 2).\u003c/p\u003e\n\u003cp\u003eThe filament was chopped to obtain implants weighing 1.6 mg each (Fig 4). The combination implant had 270.3\u0026plusmn;23\u0026micro;g of DEX and 153.4\u0026plusmn;12\u0026micro;g of MOX \u0026nbsp;per implant. DEX individual implant contained 268.8\u0026plusmn;9\u0026micro;g of the drug per implant and MOX individual implant contained 143.3\u0026plusmn;2\u0026micro;g of the drug per implant. The variation in drug loading among the three batches of prepared implant was found to be 3.1% for dexamethasone and 8.4% for moxifloxacin.\u003c/p\u003e\n\u003cp\u003eThe amount of drug to be used for the preparation of implant was calculated based on the total drug utilised during the post-operative care while using eye drops, drug loading in established ocular implants and works by Yan \u003cem\u003eet al.,\u0026nbsp;\u003c/em\u003eand Chennamaneni \u003cem\u003eet al. \u0026nbsp;\u0026nbsp;\u003c/em\u003eWhile calculating the amount of drug utilized with eye drops, one drop was considered as 50\u0026micro;l, and the values of 1% and 5% of the total drug used were taken, as these are considered indicative of the bioavailability of the drug upon application of eye drops. Yan \u003cem\u003eet al.\u003c/em\u003e[14]\u0026nbsp;developed a hydrogel system incorporated with DEX, MOX and Genistein and Chennamaneni \u003cem\u003eet al.\u003c/em\u003e[17]developed an implant by compression of DEX loaded PLGA microparticles. Both studies have highlighted the use of approximately 100 or 300\u0026micro;g of DEX and 200\u0026micro;g of MOX in developing drug delivery systems intended for insertion into the capsular bag to manage post-cataract surgery complications though \u003cem\u003ein vivo\u0026nbsp;\u003c/em\u003estudies were not conducted in the work by Yan \u003cem\u003eet al\u003c/em\u003e . Despite the lower quantity of drugs loaded into the implant in our study compared to the quantities reported in previous research, our findings indicate a notable therapeutic effect. Notably, the amount of DEX integrated into PLGA implant Surodex is significantly less than what was utilized in our study, but it is essential to acknowledge that the drug release profile of Surodex lasts only for 7 days[32].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXRD patterns were generated for DEX (Fig 5), MOX (Fig 6), PLGA (Fig 7), and a combination of drug-loaded PLGA implants (Fig 8) to understand the crystallinity of the developed product. The sharp peaks observed in the XRD patterns of DEX and MOX shows the crystalline nature of the two while the lack of the same in the XRD pattern of PLGA tells its amorphous nature. Characteristic broad peaks of amorphous nature were obtained on analysis of the drug loaded implant. This infers that the drugs are homogenously dispersed within the polymeric matrix\u003c/p\u003e\n\u003cp\u003eFigure 9 shows the SEM image of the dual drug loaded implant. In figure 10 it can be observed that the surface turns more uneven over the course of the study. PLGA is a bulk eroding polymer [33], and the eroded areas seen on the surface show the degradation of the polymer. The primary mechanism behind drug release in PLGA polymer stems from a dual process involving the infiltration of water into its matrix and the gradual erosion of the bulk due to the hydrolysis of co-polymer chains[19]. On exposure to the aqueous medium, the water enters the system and initiates the degradation. The breakdown of PLGA into lactic and glycolic acid which \u0026nbsp;resultes in the creation of an acidic environment, intensifying the autocatalyzing nature of the PLGA polymer[34]. \u0026nbsp;When the drug is exposed to the penetrating water it either dissolves/diffuses out of the polymer matrix[35]. As the duration of exposure to the aqueous medium increases, the degradation is higher, as evidenced by the increased porosity observed on the implant.\u003c/p\u003e\n\u003cp\u003e4.3 \u003cem\u003eIn vitro\u003c/em\u003e drug release\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003ein vitro\u0026nbsp;\u003c/em\u003erelease profile is as shown in Figure 11. \u0026nbsp;It was observed that MOX was released at a faster pace than DEX in the combination implant. There was a release of about 22% of MOX in 24hrs while for DEX it was 2%. A similar trend was observed for the individual drug implants ( Supplementary data Fig S5 and S6). There was not much variation in the release profile of the drugs from the implant when loaded individually and in combination. According to the AIOS guidelines, for the first fifteen days antibiotic should be administered with an anti-inflammatory drug, and next fifteen days only an anti-inflammatory drug should be administered through eye drops[6, 31]. \u0026nbsp;We obtained a similar release trend of the drugs from the developed implant.\u003c/p\u003e\n\u003cp\u003eThe PLGA polymer is used as the matrix. It is a biocompatible, biodegradable, and provides a method for controlled drug release for various time intervals [23]. Variations in the lactic acid: glycolic acid ratio, the molecular weight of the polymer, and the type of end group can help manipulate the drug release kinetics[20, 21]. \u0026nbsp;DEX follows a triphasic release from PLGA implant which involves small burst release in the first 24 hours which was about 2% in this study, then a lag phase for about 15 days which later increases in the 3\u003csup\u003erd\u003c/sup\u003e week onwards. The initial burst release can be attributed to the loosely adhrerd \u0026nbsp; DEX \u0026nbsp;which on the surface of the implant which is uncoated by the polymer matrix that can easily be dissolved on exposure to water [36]. After the initial burst release in the first 24hrs, the lag phase is noticed in the release of DEX which is approximately 12% of the total. This \u0026nbsp;could be due to the hydrophobic nature of both the polymer and the drug which limits the exposure of drug to the buffer [22]. After the lag phase a substantial increase in the release of DEX is noticed upto the completion of the drug release. This is because by this time there is sufficient degradation of the polymer and improved uptake of buffer into the matrix allowing the dissolution of the drug. This triphasic release of DEX from PLGA implant has been reported for the intravitreal imlant Ozurdex[25, 36]. The difference in the release profile of DEX between the developed implant and Ozurdex can be attributed to its composition. The composition ratio of drug to polymer in Ozurdex consists of 60% DEX, 30% acid-terminated and 10% ester-terminated 50:50 PLGA (7-17KDa)[37]. However, in the fabricated implant, the ratio is approximately 17% DEX, 9% moxifloxacin (MOX) and 74% ester-terminated 50:50 PLGA (65-95KDa). The polymer drug ratio can also affects the release profile and the use of lower molecular weight and acid terminated PLGA increases the rate degradation of polymer. Thereby, there is a shorter lag time and the release is completed faster in Ozurdex with the release being completed in about 30 days. The fabricated implant used a higher molecular weight PLGA and a much lesser amount of drug leading to an increased lag time and longer release period of drug. The release of DEX from the prepared implant is independent of the presence of MOX as a similar trend is observed in the release profile of the DEX only implant. The similar type of release was observed with thin film strip of PLGA encapsulated with DEX wound around the optic of IOL [16]. The faster release of MOX as noticed in the \u003cem\u003ein vitro\u0026nbsp;\u003c/em\u003erelease profile may be because of the pronounced osmotic effect due to its hydrophilic nature[18].\u003c/p\u003e\n\u003cp\u003e4.4 \u003cem\u003eIn vivo\u003c/em\u003e study \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 12 rabbit eyes underwent cataract surgery and out of this four of them received the dual drug loaded implant. The implant was inserted into the capsular bag after the placement of the IOL (Fig 12). The slit-lamp observations revealed that there was no significant anterior chamber reaction in all groups. No displacement of the IOL was observed. It was difficult to spot the implant during the weekly observations, probably due to the reduction in size due to degradation of polymer and increased transparency due to release of drugs. The implant was in the capsular bag inferiorly in most cases (Fig 13 and 14). In one case in the test group, the implant had stuck to the center of the bag while in another case it had migrated to the anterior chamber. IOP measurement were taken every week post surgery (Table 3). An increased IOP was observed in the test group during the period of study which may be due to high DEX concentration in the eye as observed in the \u003cem\u003ein vitro\u0026nbsp;\u003c/em\u003erelease profile. Ocular hypertension or evelation of IOP due to application of steroids have been reported to be dosage and time dependent[38, 39]. Concerning the elevated IOP, glaucoma due to the long-term use of steroids is a known complication[40]. This can be managed by making adjustments to the steroid load during implant preparation. Insertion of the implant in the capsular bag will allow the bidirectional flow of drugs, increase the drug availability to the local tissues and the sustained drug release will turn improve the clinical outcome[41]. As the implant is biodegradable, the insertion of the implant during surgery helps to combine surgery and treatment without the need for surgical removal of the implant once the drug reservoir is exhausted[16].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.5 Histopathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter the observation period, the eyes of the rabbits from all groups were enucleated and taken for histopathology studies. On gross examination of the operated eye, it was observed that the cornea was clear, the iris was normal and IOL was in the capsular bag. The histopathology results are based on the report given by the pathologist. There was no gross histopathological variation observed in the samples of unoperated eyes. No significant pathology was observed in samples of the normal control group. Focal edema and a few chronic inflammatory cells were observed in the cornea of samples from the sham control group. Edema and mild chronic inflammation of the cornea were observed in samples of the positive control group. In the test group, the cornea was normal. Edema and mild chronic inflammation in the iris and the ciliary body were observed. One sample of the test group showed congested blood vessels in the choroid. The retina appeared normal with no significant pathology. Any other differences seen in the images are artifactual, and occurred during the preparation process of the specimens.The results revealed the biocompatibility of the implant at the site of insertion (Fig 15). Images for cornea, ciliary body and retina of all samples are given in the supplementary data (Supplimentary data \u0026nbsp;Fig S7 a, b and c).\u0026nbsp;\u003c/p\u003e"},{"header":"5. Conclusions and future work","content":"\u003cp\u003eThe delivery of drugs via eye drops encounters challenges because of numerous ocular barriers. This study focuses on the creation of a dual drug-loaded biodegradable implant to manage post-cataract surgery inflammation and infection. We have demonstrated that the developed implant, when positioned in the capsular bag, effectively addresses the limitations of topical drug administration. The drugs DEX and MOX were concurrently released from the implant for a period extending beyonf 30days, achieving therapeutic efficacy. The release pattern of drugs from the implant aligns with the prescribed dosage regimen. During the initial week, there is a delay in DEX release, and a marginal increase in IOP was observed in the test groups. Hence, future work will involve optimizing the drug-loading and the release profile of the implant by exploring different polymer variations. Additionally, efforts will be directed towards ensuring the consistency in the size of filament to meet the requirements of bulk production.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll institutional and national guidelines for the care and use of laboratory animals were followed. The approval was granted by the Institutional Animal Ethics Committee (AIEC) of Kasturba Medical College, Manipal (IAEC/KMC/36/2018).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have approved the final manuscript and agreed for its publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis project was funded by the BIRAC-BIG Grant and Intramural Grant by Manipal Academy of Higher Education.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNayana Elizabeth Subhash: Data collection, analysis, writing \u0026ndash; original draft and editing. Soumya S: \u003cem\u003eIn vivo\u0026nbsp;\u003c/em\u003estudy- surgery, observation and writing-review and editing. Srilatha P S: Histopathology analysis and writing- review and editing. Nagarajan T: \u003cem\u003eIn vivo\u003c/em\u003e- sample collection and images for histopathology. Sulatha V Bhandary: Conceptualization, supervision,analysis, writing-review and editing. Bharath Raja Guru: Original idea, conceptualization, analysis, supervision, writing \u0026ndash; review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was financially supported by BIRAC-BIG scheme by Department of Biotechnology (DBT), India and Intramural Fund by Manipal Academy of Higher Education.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors extend our appreciation to Symbiotec Pharmalab Pvt. Ltd (Indore, Madhya Pradesh, India) and Shankus Pharmaceuticals (Santej, Gujarat, India) for generously providing the DEX and MOX respectiverly which were utilized in this study. Special acknowledgment goes to Shastry\u0026rsquo;s Multi Solutions for their assistance in the fabrication and development of the extruder. We express our gratitude to Mr. Sridar Prabhu, Mr. Nithyananda Kamath, and Mrs. Benedicta A Soans for their valuable aid and support during the \u003cem\u003ein vivo\u003c/em\u003e study. Additionally, we would like to thank the Central Instrumentation Facility at Manipal Academy of Higher Education for their support in utilizing facilities such as SEM and XRD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data generated and analysed during the course of the study are available from the corresponding author on request.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKhan J, Shaw S. Risk of cataract and glaucoma among older persons with diabetes in India: a cross-sectional study based on LASI, Wave-1. 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(2023) Incidence and treatment approach of intraocular pressure elevation after various types of local steroids for retinal diseases. Graefe\u0026rsquo;s Archive for Clinical and Experimental Ophthalmology. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00417-023-06163-5\u003c/span\u003e\u003cspan address=\"10.1007/s00417-023-06163-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChennamaneni SR, Bohner A, Bernhisel A, Ambati BK. Pharmacokinetics and efficacy of bioerodible Dexamethasone implant in Concanavalin a-induced uveitic cataract rabbit model. Pharm Res. 2014;31:3179\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11095-014-1410-7\u003c/span\u003e\u003cspan address=\"10.1007/s11095-014-1410-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Dimensions and geometrical design parameters of the extruder\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymbol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDescription\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eValue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003edbarrel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003ethe inner diameter of the barrel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e12mm\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003ehchannel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003emean distance from the screw root to the barrel wall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e1.2mm in the beginning and 1 mm at the end\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003ehclearance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003eclearance between barrel and extruder screw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e0.05 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003ewchannel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003echannel width\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e4.00 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2014652014652%\" valign=\"top\"\u003e\n \u003cp\u003ewpitch\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"53.663003663003664%\" valign=\"top\"\u003e\n \u003cp\u003ethe pitch of the extruder screw\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.135531135531135%\" valign=\"top\"\u003e\n \u003cp\u003e6mm in the beginning and 5.6 mm at the end.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eDimensions and weight of implant\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"507\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003eSl.No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eSample type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eDiameter (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003eLength (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003eWeight (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eCombination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eCombination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eCombination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eDEX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eDEX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eDEX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eMOX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eMOX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003eMOX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003ePLGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003ePLGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.079051383399209%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003ePLGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.110671936758894%\" valign=\"top\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33201581027668%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e: IOP measurements in rabbit\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.13144758735441%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"78.86855241264558%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Intraocular Pressure (mm Hg)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.061310782241016%\" valign=\"top\"\u003e\n \u003cp\u003eNormal control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\" valign=\"top\"\u003e\n \u003cp\u003ePositive control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.832980972515855%\" valign=\"top\"\u003e\n \u003cp\u003eSham control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.832980972515855%\" valign=\"top\"\u003e\n \u003cp\u003eTest\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.166666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eWeek1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.333333333333332%\" valign=\"top\"\u003e\n \u003cp\u003e25.5\u0026plusmn;3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.5%\" valign=\"top\"\u003e\n \u003cp\u003e27.5\u0026plusmn;5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e28.5\u0026plusmn;4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e31.5\u0026plusmn;3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.166666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eWeek2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.333333333333332%\" valign=\"top\"\u003e\n \u003cp\u003e22\u0026plusmn;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.5%\" valign=\"top\"\u003e\n \u003cp\u003e26.5\u0026plusmn;7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e25\u0026plusmn;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e38\u0026plusmn;2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.166666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eWeek3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.333333333333332%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.5%\" valign=\"top\"\u003e\n \u003cp\u003e31.5\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e26\u0026plusmn;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e43.5\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.166666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eWeek 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.333333333333332%\" valign=\"top\"\u003e\n \u003cp\u003e23.5\u0026plusmn;6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.5%\" valign=\"top\"\u003e\n \u003cp\u003e31\u0026plusmn;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e28.5\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18%\" valign=\"top\"\u003e\n \u003cp\u003e33\u0026plusmn;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"drug-delivery-and-translational-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddtr","sideBox":"Learn more about [Drug Delivery and Translational Research](https://www.springer.com/journal/13346)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ddtr/default.aspx","title":"Drug Delivery and Translational Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"PLGA implant, post cataract management, ocular drug delivery, dual drug release","lastPublishedDoi":"10.21203/rs.3.rs-3987612/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3987612/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCataract surgery is followed by post-operative eye drops for a duration of 4-6 weeks. The multitude of ocular barriers, coupled with the discomfort experienced by both the patient and their relatives in frequently administering eye drops, significantly undermines patient compliance, ultimately impeding the recovery of the patient. This study aimed to design and develop an ocular drug delivery system as an effort to achieve a drop-free post-operative care after cataract surgery. An implant was prepared containing a biodegradable polymer Poly-lactic-co-glycolic acid (PLGA), Dexamethasone (DEX) as an anti-inflammatory agent, and Moxifloxacin(MOX) as an antibiotic. Implant characterization and drug loading analysis were conducted. \u003cem\u003eIn vitro \u003c/em\u003edrug release profile showed that the release of the two drugs are correlated with the clinical prescription for post operative eye drops. \u003cem\u003eIn vivo \u003c/em\u003estudy was conducted on New Zealand albino rabbits where one eye underwent cataract surgery, and the drug delivery implant was inserted into the capsular bag after placement of the synthetic intraocular lens (IOL). Borderline increase in the intraocular pressure (IOP) was noted in the test sample group. Slit-lamp observations revealed no significant anterior chamber reaction in all study groups. Histopathology study of the operated eye revealed no significant pathology in the test samples. This work aims at developing the intra ocular drug delivery implant which will replace the post-operative eye drops and help the patient with the post-operative hassle of eye drops.\u003c/p\u003e","manuscriptTitle":"Development of a Biodegradable Polymer-based Implant to Release Dual Drugs for Post-operative Management of Cataract Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 19:17:13","doi":"10.21203/rs.3.rs-3987612/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-03-15T04:58:59+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-03-04T08:05:14+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-03T07:02:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-27T05:15:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Drug Delivery and Translational Research","date":"2024-02-26T08:43:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"drug-delivery-and-translational-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddtr","sideBox":"Learn more about [Drug Delivery and Translational Research](https://www.springer.com/journal/13346)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ddtr/default.aspx","title":"Drug Delivery and Translational Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"32da99d0-1c26-48ab-a51d-b801b0257532","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-07T20:03:59+00:00","versionOfRecord":{"articleIdentity":"rs-3987612","link":"https://doi.org/10.1007/s13346-024-01604-y","journal":{"identity":"drug-delivery-and-translational-research","isVorOnly":false,"title":"Drug Delivery and Translational Research"},"publishedOn":"2024-05-02 19:58:20","publishedOnDateReadable":"May 2nd, 2024"},"versionCreatedAt":"2024-03-06 19:17:13","video":"","vorDoi":"10.1007/s13346-024-01604-y","vorDoiUrl":"https://doi.org/10.1007/s13346-024-01604-y","workflowStages":[]},"version":"v1","identity":"rs-3987612","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3987612","identity":"rs-3987612","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}