Microneedles (MNs) are micron-sized needles, typically <2 mm in length, arranged either as an array or as single needle. These MNs offer a minimally invasive approach to ocular drug delivery due to their micron size (reducing tissue damage compared to that of hypodermic needles) and overcoming significant barriers in drug administration. While various types of MNs have been extensively researched, significant progress has been made in the use of hollow MNs (HMNs) for ocular drug delivery, specifically through suprachoroidal injections. The suprachoroidal space, situated between the sclera and choroid, has been targeted using optical coherence tomography-guided injections of HMNs for the treatment of uveitis. Unlike other MNs, HMNs can deliver larger volumes of formulations to the eye. This review primarily focuses on the use of HMNs in ocular drug delivery and explores their ocular anatomy and the distribution of formulations following potential HMN administration routes. Additionally, this review focuses on the influence of formulation characteristics (e.g., solution viscosity, particle size), HMN properties (e.g., bore or lumen diameter, MN length), and routes of administration (e.g., periocular transscleral, suprachoroidal, intravitreal) on the ocular distribution of drugs. Overall, this paper highlights the distinctive properties of HMNs, which make them a promising technology for improving drug delivery efficiency, precision, and patient outcomes in the treatment of ocular diseases.
The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch.
Drug Delivery Systems , Skin , Humans , Polymers/pharmacology , Needles , Administration, Cutaneous
Artificial intelligence (AI) has emerged as a powerful tool that harnesses anthropomorphic knowledge and provides expedited solutions to complex challenges. Remarkable advancements in AI technology and machine learning present a transformative opportunity in the drug discovery, formulation, and testing of pharmaceutical dosage forms. By utilizing AI algorithms that analyze extensive biological data, including genomics and proteomics, researchers can identify disease-associated targets and predict their interactions with potential drug candidates. This enables a more efficient and targeted approach to drug discovery, thereby increasing the likelihood of successful drug approvals. Furthermore, AI can contribute to reducing development costs by optimizing research and development processes. Machine learning algorithms assist in experimental design and can predict the pharmacokinetics and toxicity of drug candidates. This capability enables the prioritization and optimization of lead compounds, reducing the need for extensive and costly animal testing. Personalized medicine approaches can be facilitated through AI algorithms that analyze real-world patient data, leading to more effective treatment outcomes and improved patient adherence. This comprehensive review explores the wide-ranging applications of AI in drug discovery, drug delivery dosage form designs, process optimization, testing, and pharmacokinetics/pharmacodynamics (PK/PD) studies. This review provides an overview of various AI-based approaches utilized in pharmaceutical technology, highlighting their benefits and drawbacks. Nevertheless, the continued investment in and exploration of AI in the pharmaceutical industry offer exciting prospects for enhancing drug development processes and patient care.
Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application.
Drug Delivery Systems , Infusion Pumps, Implantable , Humans
Triamcinolone acetonide (TA) is a corticosteroid that has been used to treat posterior segment eye diseases. TA is injected intravitreally in the management of neovascular disorders; however, frequent intravitreal injections result in many potential side effects and poor patient compliance. In this work, a 3D bioprinter was used to prepare polycaprolactone (PCL) implants loaded with TA. Implants were manufactured with different shapes (filament-, rectangular-, and circle-shaped) and drug loadings (5, 10, and 20%). The characterisation results showed that TA was successfully mixed and incorporated within the PCL matrix without using solvents, and drug content reached almost 100% for all formulations. The drug release data demonstrate that the filament-shaped implants (SA/V ratio~7.3) showed the highest cumulative drug release amongst all implant shapes over 180 days, followed by rectangular- (SA/V ratio~3.7) and circle-shaped implants (SA/V ratio~2.80). Most implant drug release data best fit the Korsmeyer−Peppas model, indicating that diffusion was the prominent release mechanism. Additionally, a biocompatibility study was performed; the results showed >90% cell viability, thus proving that the TA-loaded PCL implants were safe for ocular application.
Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral routes of delivery. Deferasirox (DFS) is an iron chelator employed in several ailments where iron overload plays an important role in disease manifestation. In this study, DFS was formulated into a nanosuspension (NSs) through wet media milling employing PVA as a stabilizer and successfully loaded in polymeric dissolving microneedles (DMNs). The release studies for DFS-NS clearly showed a threefold increased dissolution rate compared to pure DFS. The mechanical characterization of DFS-NS-DMNs revealed that the system was sufficiently strong for efficacious skin penetration. Optical coherence tomography images confirmed an insertion of up to 378 µm into full-thickness porcine skin layers. The skin deposition studies showed 60% drug deposition from NS-DMN, which was much higher than from the DFS-NS transdermal patch (DFS-NS-TP) (without needles) or pure DFS-DMNs. Moreover, DFS-NS without DMNs did not deposit well inside the skin, indicating that DMNs played an important role in effectively delivering drugs inside the skin. Therefore, it is evident from the findings that loading DFS-NS into novel DMN devices can effectively deliver DFS transdermally.
Purpose: Age-related macular degeneration is a vision-threatening disorder affecting the posterior segment of the eye. Drug delivery to the posterior segment is challenging owing to the complex anatomical and physiological structure, necessitating monthly injections of antivascular endothelial growth factors. Thermoresponsive hydrogels provide sustained drug delivery and ease of injection, due to their sol-gel transition. Poly (N-isopropyl acrylamide) (PNIPAAm) is a widely researched thermoresponsive hydrogel; however, insufficient wet strength and a wide mesh network make it inept for the entrapment of small molecules. Methods: A novel approach of grafting PNIPAAm with chitosan is exploited. A chitosan concentration altered in 10%, 30%, and 50% compared to PNIPAAm is investigated for entrapment of a small-molecular weight, hydrophilic drug, sunitinib (SUN), a multiple tyrosine kinase receptor inhibitor. Furthermore, these hydrogels were characterized using 1H-NMR, FTIR, differential scanning calorimetry (DSC), and thermogravimetric analysis for chemical characterization and viscosity, swellability, syringeability, degradation, and In-vitro permeation using Franz-diffusion cell. Results: In-vitro drug release kinetics suggested that the release of SUN could be controlled with the percentage of chitosan grafting; however, gel strength (3%-5% w/v) of 30% Cs-g-PNIPAAm did not significantly affect percentage drug release. Sustained release of SUN was observed for 1 month. In-vitro permeation studies on porcine sclera suggested that a thermoresponsive gel of chitosan grafted PNIPAAm (Cs-g-PNIPAAm) was able to sustain the drug release by 40%, compared to SUN solution. Conclusions: The study indicates that the synthesized Cs-g-NIPAAm hydrogel has the potential to serve as a tailorable injectable platform for intrascleral drug delivery applications.
Chitosan , Hydrogels , Animals , Chitosan/chemistry , Drug Delivery Systems , Hydrogels/chemistry , Sunitinib , Swine , Temperature
In current study, novel in situ formed injectable self-assembled thermoreversible depot gels based on N-(Vinylcaprolactam) were synthesized with a carbohydrate polymer i.e. sodium alginate in aqueous solution using cold method. The prepared gels preparations were intended to be utilized as 5-FU delivery depot after injectable administration through subcutaneous route. The structural characterization of self-assembled gels samples were studied through FTIR. The thermal properties of newly formed gels complexes were investigated by DSC and TGA. While the morphology of gels were assessed through SEM. The tunable gelation temperatures and phase transition of optimized formulations were confirmed by tube inverting, rheology determination and optical transmittance test. Thermo and pH response was evaluated at different temperatures and in various acidic and basic buffer solutions. In vitro release experiments were conducted using Franz diffusion system to monitor the controlled delivery fashion of gels matrices. Results concluded that depot gels exhibit controlled delivery fashion with maximum release at pH 7.4 and 37 ± 2 °C. The biocompatible nature of blank gels samples was assessed by MTT assay against Vero cell lines and was found safe. While killing ability of 5-FU encapsulated gels was evaluated against HeLa (19 ± 0.22 µg/ml; 23 ± 0.55 µg/ml) and MCF-7 (21 ± 0.06 µg/ml and 22 ± 0.34 µg/ml) cancer cell lines and were found effective to kill cancer cells. Histopathological study showed that gels depot is safe with no harmful effects on major organs. The in vivo bioavailability in rabbits showed controlled release (Cmax, 4465.78 ± 1.99 ng/ml) in comparison to free drug (Cmax, 4883.73 ± 3.32 ng/ml) administration after subcutaneous injection.
Alginates , Fluorouracil , Alginates/chemistry , Animals , Biological Availability , Delayed-Action Preparations/pharmacology , Fluorouracil/chemistry , Fluorouracil/pharmacology , Gels/chemistry , Humans , Hydrogels/chemistry , Rabbits , Rheology
Chronic fungal infection of the cornea could lead to blindness if not treated properly. Topical amphotericin B (AMP-B) is considered the first treatment of choice for ocular fungal infection. However, factors related to its poor solubility and penetration through intact cornea lead to poor bioavailability. Microneedles (MNs) are emerging as a minimally invasive method to enhance ocular drug delivery. This study aims to investigate the potential use of biodegradable poly(vinylpyrrolidone) (PVP) and hyaluronic acid (HA)-based rapidly dissolving MNs for delivery of AMP-B to treat fungal infection. The data obtained illustrates PVP/HA MN arrays' reproducibility, good mechanical strength, and faster dissolution with 100% drug recovery. Multiphoton microscopic results revealed that MNs successfully penetrate the corneal tissue and enhance AMP-B permeation through corneal layers. Furthermore, PVP/HA MN arrays showed high solubility. Both PVP and HA successfully decreased AMP-B cytotoxicity when compared to free drug. More interestingly, the biocompatible MN formulations preserved the antifungal activity of AMP-B, as demonstrated by significant inhibition of fungal growth. Therefore, this study shows the feasibility of ocular delivery of the poorly soluble AMP-B using a fast-dissolving MN patch.
Amphotericin B , Eye Infections, Fungal , Humans , Administration, Cutaneous , Drug Delivery Systems/methods , Eye Infections, Fungal/drug therapy , Hyaluronic Acid/therapeutic use , Needles , Reproducibility of Results
The delivery of drugs to the posterior segment of the eye remains a tremendously difficult task. Prolonged treatment in conventional intravitreal therapy requires injections that are administered frequently due to the rapid clearance of the drug molecules. As an alternative, intraocular implants can offer drug release for long-term therapy. However, one of the several challenges in developing intraocular implants is selecting an appropriate in vitro dissolution testing model. In order to determine the efficacy of ocular implants in drug release, multiple in vitro test models were emerging. While these in vitro models may be used to analyse drug release profiles, the findings may not predict in vivo retinal drug exposure as this is influenced by metabolic and physiological factors. This review considers various types of in vitro test methods used to test drug release of ocular implants. Importantly, it discusses the challenges and factors that must be considered in the development and testing of the implants in an in vitro setup.
Drug Delivery Systems , In Vitro Techniques , Intravitreal Injections , Pharmaceutical Preparations , Solubility
Treatment of neovascular ocular diseases involves intravitreal injections of therapeutic proteins using conventional hypodermic needles every 4-6 weeks. Due to the chronic nature of these diseases, these injections will be administrated to patients for the rest of their lives and their frequent nature can potentially pose a risk of sight-threatening complications and poor patient compliance. Therefore, we propose to develop nanoparticle (NP)-loaded bilayer dissolving microneedle (MN) arrays, to sustain delivery of protein drugs in a minimally invasive manner. In this research, a model protein, ovalbumin (OVA)-encapsulated PLGA NPs were prepared and optimised using a water-in-oil-in-water (W/O/W) double emulsion method. The impact of stabilisers and primary sonication time on the stability of encapsulated OVA was evaluated using an enzyme-linked immunosorbent assay (ELISA). Results showed that the lower primary sonication time was capable of sustaining release (77 days at 28.5% OVA loading) and improving the OVA bioactivity. The optimised NPs were then incorporated into a polymeric matrix to fabricate bilayer MNs and specifically concentrated into MN tips by high-speed centrifugation. Optimised bilayer MNs exhibited good mechanical and insertion properties and rapid dissolution kinetics (less than 3 min) in excised porcine sclera. Importantly, ex vivo transscleral distribution studies conducted using a multiphoton microscope confirmed the important function of MN arrays in the localisation of proteins and NPs in the scleral tissue. Furthermore, the polymers selected to prepare bilayer MNs and OVA NPs were determined to be biocompatible with retinal cells (ARPE-19). This delivery approach could potentially sustain the release of encapsulated proteins for more than two months and effectively bypass the scleral barrier, leading to a promising therapy for treating neovascular ocular diseases.
Angiogenesis Inhibitors/administration & dosage , Drug Delivery Systems/methods , Nanoparticles/chemistry , Administration, Ophthalmic , Angiogenesis Inhibitors/pharmacokinetics , Animals , Cell Line , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/pathology , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Compounding/methods , Drug Liberation , Humans , Ovalbumin/administration & dosage , Ovalbumin/pharmacokinetics , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Posterior Eye Segment/blood supply , Posterior Eye Segment/pathology , Ranibizumab/administration & dosage , Ranibizumab/pharmacokinetics , Retinal Neovascularization/drug therapy , Retinal Neovascularization/pathology , Sclera/metabolism , Swine
Scleral and corneal membranes represent substantial barriers against drug delivery to the eye. Conventional hypodermic needles-based intraocular injections are clinically employed to overcome these barriers. This study, for the first time, investigated a non-invasive alternative to intraocular injections by laser irradiation of ocular tissues. The P.L.E.A.S.E.® laser device was applied on excised porcine scleral and corneal tissues, which showed linear relationships between depths of laser-created micropores and laser fluences at range 8.9-444.4 J/cm2. Deeper and wider micropores were observed in scleral relative to corneal tissues. The permeation of rhodamine B and fluorescein isothiocyanate (FITC)-dextran were investigated through ocular tissues at different laser parameters (laser fluences 0-44.4 J/cm2 and micropore densities 7.5 and 15%). Both molecules showed enhanced permeation through ocular tissues on laser irradiation. Maximum transscleral permeation of the molecules was attained at laser fluence 8.9 J/cm2 and micropore density 15%. Transcorneal permeation of rhodamine B increased with increasing either laser fluence or micropore density, while that of FITC-dextran was not affected by either parameter. The transscleral water loss increased significantly after laser irradiation then returned to the baseline values within 24 h, indicating healing of the laser-created micropores. Laser irradiation is a promising technique to enhance intraocular delivery of both small and large molecule drugs.
Drug Delivery Systems , Pharmaceutical Preparations , Animals , Lasers , Needles , Sclera , Swine
Curcumin has been reported to be used widely against many types of pathological conditions in clinics. However, due to its limitations such as poor solubility, poor oral absorption and low stability have limited its applications. In the current study, a series of novel chemically cross-linkable depot gel formulations were developed based on thermoresponsive micellar polymer (Pluronic®127) with polyelectrolyte hydrophilic monomer, that is, 2-acrylamido-2-methylpropane sulfonic acid by cold and in situ grafting polymerization method. The formulations were aimed to deliver curcumin at controlled rate from in situ formed depot after administration through subcutaneous route in vivo. The sol-gel phase transitions of formulations were observed by rheological analysis, tube titling and optical transmittance measurements. Maximum swelling of gel formulations was observed at pH 7.4 and below CGT, that is, 25 °C. The in vitro release profile exhibits maximum drug release at pH 7.4 and 25 °C owing to relaxed gel state. In vitro degradation profile of gel formulations showed controlled degradation rate. Cell growth inhibition study confirmed the biocompatibility and safe nature of bare gel formulations against L929 cell lines. In vitro cytotoxic study showed that curcumin loaded in gel formulation has controlled pharmacological activity against HeLa and MCF-7 cancer cells as compared to free drug solution. The IC50 values calculated for pure curcumin solution (30 ± 0.77 µg/ml for HeLa and 27 ± 0.39 µg/ml for MCF-7) were found higher in comparison to curcumin-loaded thermogels against HeLa (19 ± 0.28 µg/ml and 23 ± 0.81 µg/ml) and MCF-7 (22 ± 0.54 µg/ml and 21 ± 0.49 µg/ml). Histopathological and hematological analysis showed the biocompatible nature of hydrogels. Structural confirmation was done by Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectroscopy (1H NMR). Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) confirmed the thermal stability of the gel formulation. The porous structure of gel formulations was assessed by scanning electron microscopic (SEM) analysis. Results concluded that newly developed gel formulations have thermoresponsive behavior with phase transition at body temperature and can be used as in situ controlled drug depot.
Curcumin , Poloxamer , Curcumin/pharmacology , Drug Liberation , Humans , Hydrogels , Phase Transition , Spectroscopy, Fourier Transform Infrared
Methotrexate (MTX) is one of the mainstays of treatment for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) and it is mainly administered either orally or by subcutaneous (SC) injection, which are not so satisfactory. While orally administered MTX is associated with variable bioavailability and causes gastrointestinal side effects, including nausea and vomiting, SC injection is painful and produces high peak blood levels of MTX. Transdermal delivery presents an attractive alternative administration route. However, MTX passive permeation through the skin is hindered by the skin barrier and MTX physicochemical properties. To address these issues, hydrogel-forming microneedle arrays (HFMN) and a patch-like reservoir loaded with MTX (MTX-RV) were developed and combined to form a minimally invasive patch to deliver MTX transdermally in a sustained manner. HFMN were prepared from an aqueous blend of poly (vinyl alcohol) (PVA) and poly (vinyl pyrrolidone) (PVP) which was crosslinked chemically with citric acid (CA) at 130ËC. MTX-RV was prepared from hydroxypropyl methylcellulose (HPMC) and glycerol. Both the HFMN and MTX-RV were fully characterised and then combined to form an integrated patch, which was evaluated ex vivo and in preclinical studies. The HFMN demonstrated a satisfactory mechanical strength and insertion capability into excised neonatal porcine skin, as well as moderate swelling properties. The MTX-RV incorporated a high dose of MTX (150.3 ± 5.3 µg/mg) without precipitation. The integrated patch delivered MTX at a steady-state flux of 506.8 ± 136.9 µg.cm2/h in an ex vivo setup. Furthermore, in preclinical studies performed in Sprague Dawley rats, MTX appeared in blood after 1 h from patch application at a concentration of 7.6 ± 2.0 nM. MTX blood level increased gradually to reach its peak, Cmax = 35.1 ± 5.1 nM, at 24 h. Importantly, the HFMN were removed intact from the skin with only mild erythema, despite the cytotoxic nature of MTX. Accordingly, the integrated patch produced in this work represents a promising minimally invasive transdermal drug delivery system that can overcome the skin barrier and deliver MTX in a sustained manner. This may help in minimising or even avoiding the nausea and vomiting, associated with the conventional administration routes.
Antirheumatic Agents/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems , Methotrexate/administration & dosage , Administration, Cutaneous , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/toxicity , Chemistry, Pharmaceutical , Delayed-Action Preparations , Female , Hydrogels , Methotrexate/pharmacokinetics , Methotrexate/toxicity , Needles , Polyvinyl Alcohol/chemistry , Povidone/chemistry , Rats , Rats, Sprague-Dawley , Skin Absorption , Swine , Transdermal Patch
Bevacizumab is a full-length human monoclonal antibody used to treat various neovascular diseases such as wet age-related macular degeneration (AMD), diabetic eye disease and other problems of the retina. Monthly intravitreal injections of bevacizumab (Avastin®) are effective in the treatment of wet AMD. However, there is a growing demand in the development of sustained release ophthalmic formulations. Therefore, this study aims, for the first time, to develop a rapid, simple, and sensitive method using size exclusion chromatography coupled with fluorescence detection for routine quantification of bevacizumab in ophthalmic formulations and during in vitro release studies. The selected chromatographic conditions included an aqueous mobile phase composed of 35â¯mM sodium phosphate buffer and 300â¯mM sodium chloride (pH 6.8), a flow rate of 0.5â¯mL/min, and the fluorescence detector was operated at excitation and emission wavelengths of 280 and 340â¯nm, respectively. The peak area-concentration relationship maintained its linearity over concentration range of 0.1-20⯵g/mL (R2 = 0.9993), and the quantitation limit was 100â¯ng/mL. The method was validated for specificity, accuracy, precision, and robustness. The developed method had a run time of 6â¯min at temperature 25⯰C, making it a unique validated method for rapid and cost-effective quantification of bevacizumab.
Angiogenesis Inhibitors/analysis , Bevacizumab/analysis , Ophthalmic Solutions/analysis , Chromatography, Gel , Chromatography, High Pressure Liquid , Fluorescence , Intravitreal Injections , Linear Models , Reproducibility of Results , Sensitivity and Specificity , Vascular Endothelial Growth Factor A/antagonists & inhibitors
In this study, for the first time, we have reported a sustained transdermal drug delivery from thermoresponsive poloxamer depots formed within the skin micropores following microneedle (MN) application. Firstly, we have investigated the sol-gel phase transition characteristics of poloxamers (PF®127, P108, and P87) at physiological conditions. Rheological measurements were evaluated to confirm the critical gelation temperature (CGT) of the poloxamer formulations with or without fluorescein sodium (FS), as a model drug, at various concentrations. Optimized poloxamer formulations were subjected to in vitro release studies using a vial method. Secondly, polymeric MNs were fabricated using laser-engineered silicone micromolds from various biocompatible polymeric blends of Gantrez S-97, PEG 10000, PEG200, PVP K32, and PVP K90. The MN arrays were characterized for mechanical strength, insertion force determination, in situ dissolution kinetics, moisture content, and penetration depth. The optimized MN arrays with good mechanical strength and non-soluble nature were used to create micropores in the neonatal porcine skin. Microporation in neonatal porcine skin was confirmed by dye-binding study, skin integrity assessment, and histology study. Finally, the in vitro delivery of FS from optimized poloxamer formulations was conducted across non-porated vs microporated skin samples using vertical Franz diffusion cells. Results concluded that permeation of FS was sustained for 96 h across the MN-treated skin samples containing in situ forming depot poloxamer formulations compared to non-microporated skin which sustained the FS delivery for 72 h. Confocal microscopic images confirmed the distribution of higher florescence intensity of FS in skin tissues after permeation study in case of MN-treated skin samples vs intact skin samples.
Needles , Poloxamer/administration & dosage , Skin/metabolism , Administration, Cutaneous , Animals , Animals, Newborn , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Drug Liberation , Gels , Microinjections , Poloxamer/chemistry , Skin Absorption , Swine , Temperature
The objectives of this study were to develop biodegradable poly-lactic-co-glycolic acid (PLGA) based injectable phase inversion in situ forming system for sustained delivery of triamcinolone acetonide (TA) and to conduct physicochemical characterisation including in vitro drug release of the prepared formulations. TA (at 0.5%, 1% and 2.5% w/w loading) was dissolved in N-methyl-2-pyrrolidone (NMP) solvent and then incorporated 30% w/w PLGA (50/50 and 75/25) polymer to prepare homogenous injectable solution. The formulations were evaluated for rheological behaviour using rheometer, syringeability by texture analyser, water uptake and rate of implant formation by optical coherence tomography (OCT) microscope. Phase inversion in situ forming formulations were injected into PBS pH 7.3 to form an implant and release samples were collected and analysed for drug content using a HPLC method. All formulations exhibited good syringeability and rheological properties (viscosity: 0.19-3.06 Pa.s) by showing shear thinning behaviour which enable them to remain as free-flowing solution for ease administration. The results from OCT microscope demonstrated that thickness of the implants were increased with the increase in time and the rate of implant formation indicated the fast phase inversion. The drug release from implants was sustained over a period of 42 days. The research findings demonstrated that PLGA/NMP-based phase inversion in situ forming implants can improve compliance in patient's suffering from ocular diseases by sustaining the drug release for a prolonged period of time and thereby reducing the frequency of ocular injections.
Glucocorticoids/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Pyrrolidinones/chemistry , Triamcinolone Acetonide/chemistry , Administration, Ophthalmic , Drug Implants , Drug Liberation , Elasticity , Viscosity
PURPOSE: To investigate the sustained ocular delivery of small and large drug molecules from photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) implants with varying pore forming agents. METHODS: Triamcinolone acetonide and ovalbumin loaded photocrosslinked PEGDA implants, with or without pore-forming agents, were fabricated and characterised for chemical, mechanical, swelling, network parameters, as well as drug release and biocompatibility. HPLC-based analytical methods were employed for analysis of two molecules; ELISA was used to demonstrate bioactivity of ovalbumin. RESULTS: Regardless of PEGDA molecular weight or pore former composition all implants loaded with triamcinolone acetonide released significantly faster than those loaded with ovalbumin. Higher molecular weight PEGDA systems (700 Da) resulted in faster drug release of triamcinolone acetonide than their 250 Da counterpart. All ovalbumin released over the 56-day time period was found to be bioactive. Increasing PEGDA molecular weight resulted in increased system swelling, decreased crosslink density (Ve), increased polymer-water interaction parameter (χ), increased average molecular weight between crosslinks (Mc) and increased mesh size (ε). SEM studies showed the porosity of implants increased with increasing PEGDA molecular weight. Biocompatibility showed both PEGDA molecular weight implants were non-toxic when exposed to retinal epithelial cells over a 7-day period. CONCLUSION: Photocrosslinked PEGDA implant based systems are capable of controlled drug release of both small and large drug molecules through adaptations in the polymer system network. We are currently continuing evaluation of these systems as potential sustained drug delivery devices.
Biological Products/pharmacokinetics , Drug Delivery Systems/methods , Drug Liberation , Glucocorticoids/pharmacokinetics , Polyethylene Glycols/chemical synthesis , Administration, Ophthalmic , Biological Products/administration & dosage , Cell Line , Diabetic Retinopathy/drug therapy , Drug Compounding/methods , Drug Implants , Glucocorticoids/administration & dosage , Humans , Macular Degeneration/drug therapy , Materials Testing , Molecular Weight , Ovalbumin/administration & dosage , Ovalbumin/pharmacokinetics , Porosity , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/drug effects , Triamcinolone Acetonide/administration & dosage , Triamcinolone Acetonide/pharmacokinetics
The threat of antimicrobial resistance to society is compounded by a relative lack of new clinically effective licensed therapies reaching patients over the past three decades. This has been particularly problematic within antifungal drug development, leading to a rise in fungal infection rates and associated mortality. This paper highlights the potential of an ultrashort peptide, (naphthalene-2-ly)-acetyl-diphenylalanine-dilysine-OH (NapFFKK-OH), encompassing hydrogel-forming and antifungal properties within a single peptide motif, thus overcoming formulation (e.g., solubility, drug loading) issues associated with many currently employed highly hydrophobic antifungals. A range of fungal susceptibility (colony counts) and cell cytotoxicity (MTS cell viability, LIVE/DEAD staining® with fluorescent microscopy, haemolysis) assays were employed. Scanning electron microscopy confirmed the nanofibrous architecture of our self-assembling peptide, existing as a hydrogel at concentrations of 1% w/v and above. Broad-spectrum activity was demonstrated against a range of fungi clinically relevant to infection (Aspergillus niger, Candida glabrata, Candida albicans, Candida parapsilosis and Candida dubliniensis) with greater than 4 log10 CFU/mL reduction at concentrations of 0.5% w/v and above. We hypothesise antifungal activity is due to targeting of anionic components present within fungal cell membranes resulting in membrane disruption and cell lysis. NapFFKK-OH demonstrated reduced toxicity against mammalian cells (NCTC 929, ARPE-19) suggesting increased selectivity for fungal cells. However, further studies relating to safety for systemic administration is required, given the challenges toxicity has presented in the wider context of antimicrobial peptide drug development. Overall this study highlights the promise of NapFFKK-OH hydrogels, particularly as a topical formulation for the treatment of fungal infections relating to the skin and eyes, or as a hydrogel coating for the prevention of biomaterial related infection.
