Formulation and In Vitro-Ex vivo Evaluation of Cannabidiol and Cannabidiol-Valine-Hemisuccinate Loaded Lipid-Based Nanoformulations for Ocular Applications.

The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.3 ± 0.1 mg/mL) and CBD-VHS (11.2 ± 0.2 mg/mL). The globule size for the lead CBD formulations (NE and NMC) ranged between 205 and 270 nm while CBD-VHS-NMC formulation had a particle size of about 78 nm. The sterilized formulations, except for CBD-VHS-NMC at 40 °C, were stable for three months of storage (last time point tested). Release, in terms of CBD, in the in-vitro release/diffusion studies over 18 h, were faster from the CBD-VHS nanomicelles (38 %) compared to that from the CBD nanoemulsion (16 %) and nanomicelles (33 %). Transcorneal permeation studies revealed improvement in CBD permeability and flux with both formulations; however, a greater improvement was observed with the NMC formulation compared to the NE formulation. In conclusion, the nanoformulations prepared could serve as efficient topical ocular drug delivery platforms for CBD and its analog.

Improved Topical Ophthalmic Natamycin Suspension for the Treatment of Fungal Keratitis.

Purpose: Natamycin (NT) is used as a first-line antifungal prescription in the treatment of fungal keratitis (FK) and is commercially available as a 5% w/v ophthalmic suspension. NT shows poor water solubility and light sensitivity. Thus, the present investigation is aimed to enhance the fraction of NT in solution in the commercial formulation by adding cyclodextrins (CDs), thereby improving the delivery of the drug into deeper ocular tissues. Methods: The solubility of NT in different CDs, the impact of ultraviolet (UV) light exposure, stability at 4°C and 25°C, in vitro release, and ex vivo transcorneal permeation studies were performed. Results: NT exhibited the highest solubility (66-fold) in randomly methylated-ß-cyclodextrin (RM-ßCD) with hydroxypropyl-ßCD (HP-ßCD) showing the next highest solubility (54-fold) increase in comparison to market formulation Natacyn® as control. The stability of NT-CD solutions was monitored for 2 months (last-time point) at both storage conditions. The degradation profile of NT in NT-RM-ßCD and NT-HP-ßCD solutions under UV-light exposure followed first-order kinetics exhibiting half-lives of 1.2 h and 1.4 h, respectively, an almost 3-fold increase over the control solutions. In vitro release/diffusion studies revealed that suspensions containing RM-ßCD and HP-ßCD increased transmembrane flux significantly (3.1-fold) compared to the control group. The transcorneal permeability of NT from NT-RM-ßCD suspension exhibited an 8.5-fold (P < 0.05) improvement compared to Natacyn eyedrops. Furthermore, the addition of RM-ßCD to NT suspension increases the solubilized fraction of NT and enhances transcorneal permeability. Conclusion: Therefore, NT-RM-ßCD formulations could potentially lead to a decreased frequency of administration and significantly improved therapeutic outcomes in FK treatment.

Gatifloxacin Loaded Nano Lipid Carriers for the Management of Bacterial Conjunctivitis.

Bacterial conjunctivitis (BC) entails inflammation of the ocular mucous membrane. Early effective treatment of BC can prevent the spread of the infection to the intraocular tissues, which could lead to bacterial endophthalmitis or serious visual disability. In 2003, gatifloxacin (GTX) eyedrops were introduced as a new broad-spectrum fluoroquinolone to treat BC. Subsequently, GTX use was extended to other ocular bacterial infections. However, due to precorneal loss and poor ocular bioavailability, frequent administration of the commercial eyedrops is necessary, leading to poor patient compliance. Thus, the goal of the current investigation was to formulate GTX in a lipid-based drug delivery system to overcome the challenges with the existing marketed eyedrops and, thus, improve the management of bacterial conjunctivitis. GTX-NLCs and SLNs were formulated with a hot homogenization-probe sonication method. The lead GTX-NLC formulation was characterized and assessed for in vitro drug release, antimicrobial efficacy (against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa), and ex vivo permeation. The lead formulation exhibited desired physicochemical characteristics, an extended release of GTX over a 12 h period, and was stable over three months at the three storage conditions (refrigerated, room temperature, and accelerated). The transcorneal flux and permeability of GTX from the GTX-NLC formulation were 5.5- and 6.0-fold higher in comparison to the commercial eyedrops and exhibited a similar in vitro antibacterial activity. Therefore, GTX-NLCs could serve as an alternative drug delivery platform to improve treatment outcomes in BC.

Formulation and processing of solid self-emulsifying drug delivery systems (HME S-SEDDS): A single-step manufacturing process via hot-melt extrusion technology through response surface methodology.

The objective of the current study is the formulation development and manufacturing of solid self-emulsifying drug delivery systems (HME S-SEDDS) via a single-step continuous hot-melt extrusion (HME) process. For this study, poorly soluble fenofibrate was selected as a model drug. From the results of pre-formulation studies, Compritol® HD5 ATO, Gelucire® 48/16, and Capmul® GMO-50 were selected as oil, surfactant and co-surfactant respectively for manufacturing of HME S-SEDDS. Neusilin® US2 was selected as a solid carrier. The design of experiments (response surface methodology) was employed to prepare formulations via a continuous HME process. The formulations were evaluated for emulsifying properties, crystallinity, stability, flow properties and drug release characteristics. The prepared HME S-SEDDS showed excellent flow properties, and the resultant emulsions were stable. The globule size of the optimized formulation was 269.6 nm. The DSC and XRD studies revealed the amorphous nature of the formulation and FTIR studies showed no significant interaction between fenofibrate and excipients. The drug release studies showed significant (p < 0.05) improvement in solubility compared to the pure drug (DE15 = 45.04 for the optimized formulation), as >90% of drug release was observed within 15 min. The stability studies for the optimized formulation were conducted for 3 months at 40 °C/75% RH.

Development and In vivo Pharmacokinetic and Pharmacodynamic Evaluation of an Oral Innovative Cyclodextrin Complexed Lipid Nanoparticles of Irbesartan Formulation for Enhanced Bioavailability.

Background: Irbesartan (IR) is used in the treatment of hypertension, heart failure, and nephropathy in Type II diabetes. IR bioavailability is limited by poor solubility and presystemic metabolism. In our previous investigations, cyclodextrin (HPßCD) complexed solid lipid nanoparticles (SLNs) of IR were prepared, optimized, and characterized. The current study aimed to confirm the reproducibility of the previous methodology and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) performance of the selected lead formulations in an experimental animal model. Methods: SLNs were prepared by hot homogenization followed by probe sonication with IR/HPßCD inclusion complex loaded into a solid lipid (Dynasan 112). SLNs were evaluated for physical characteristics, drug content, entrapment efficiency, in vitro release profile, and surface morphology. The pharmacokinetic and pharmacodynamic behavior of the SLNs were evaluated in Wistar rats. Results: Photon correlation spectroscopy, drug content, entrapment efficiency, and dissolution studies results were reproducible and consistent with our earlier investigation. PK studies showed 2.1-, 6.6-, and 9.9-fold improvement in the relative oral bioavailability of the drug from IR-HPßCD, IR-SLN, and IR-HPßCD-SLN formulations, respectively compared to IR suspension. However, IR-HPßCD-SLNs showed 1.5- and 4.7-fold improvement in the relative oral bioavailability of the drug compared to IR-SLN and IR-HPßCD formulations, respectively. PD studies in hypertensive Wistar rats showed a good control over systolic blood pressure for 48 h for SLN formulations compared to 2 h for IR suspension. However, the IR-HPßCD inclusion complex exhibited immediate antihypertensive activity (0.5 h) with a period of systolic blood pressure control similar to IR suspension. Conclusions: The current approach exhibited improved oral bioavailability along with improved and prolonged pharmacodynamic effect.

A systemic review on development of mesoporous nanoparticles as a vehicle for transdermal drug delivery.

Recent advances in drug delivery technologies utilizing a variety of carriers have resulted in a paradigm shift in the current approach to diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) were developed in response to the need for materials with high thermal, chemical, and mechanical properties. The synthesis, ease of surface functionalization, tunable pore size, large surface area, and biocompatibility of MSNs make them useful in a variety of biomedical applications such as drug delivery, theranostics, and stem cell research. In addition, MSNs have a high capability of delivering actives ranging from small molecules such as drugs and amino acids to larger peptides, vaccines, and antibodies in general. Moreover, MSN-based transdermal delivery has sparked a lot of interest because of the increase in drug stability, permeation, and ease of functionalization. The functionalization of MSNs plays an important role in the efficient delivery of therapeutic agents in a highly controlled manner. This review introduced dermal and transdermal drug delivery systems, explained the anatomy of the skin, and summarized different barriers that affect the transdermal delivery of many therapeutic agents. In addition, the fundamentals of MSNs together with their physicochemical properties, synthesis approaches, raw materials used in their fabrication, and factors affecting their physicochemical properties will be covered. Moreover, the applications of MSNs in dermal and transdermal delivery, the biocompatibility of MSNs in terms of toxicity and safety, and biodistribution will be explained with the help of a detailed literature review. The review is covering the current and future perspectives of MSNs in the pharmaceutical field with therapeutic applications.

Cationic Solid SMEDDS of Efavirenz for Improved Oral Delivery: Development by Central Composite Design, In Vitro and In Vivo Evaluation.

Efavirenz (EFV) is an anti-HIV drug with high dose and 40% oral bioavailability (BA). The aim was to improve the bioavailability by designing cationic solid SMEDDS. Solubility data, ternary phase diagrams, and central composite design were employed in design. Globule size, TEM, DSC, and SEM studies were used for characterization. Optimized L-SMEDDS contained 20 mg of EFV, 10 mg of Peceol, 43.5 mg of Tween 80, and 40 mg of Labrafac Lipophile WL-1349 and the characters included mean globule size-94 nm, PDI-0.255, and ZP-28 mV. Later, octadecylamine was added to get L-SMEDDS with + 38 mV charge. L-SMEDDS was converted into solid S-SMEDDS by adsorbing onto silica carriers. Syloid XDP was preferred based on flow and oil adsorption capacity. The % drug (EFV) release from powder, L-SMEDDS, and solid SMEDDS were 14.04, 94.47, and 85 respectively in first 30 min. TEM picture showed dispersed globules. DSC and SEM studies indicated the loss of drug crystallinity in S-SMEDDS. Pharmacokinetic (PK) studies in Wistar rats revealed 4.12 fold hike in BA for optimized cationic S-SMEDDS when compared to EFV suspension. Increased absorption could be due to the positive charge on globules. Thus, cationic S-SMEDDS emerged as a potential novel delivery system for improvement in BA and has scope for reducing the high dose for AIDS patients by future clinical studies.

Cannabidiol Loaded Topical Ophthalmic Nanoemulsion Lowers Intraocular Pressure in Normotensive Dutch-Belted Rabbits.

Cannabidiol (CBD) is the major non-psychoactive and most widely studied of the cannabinoid constituents and has great therapeutic potential in a variety of diseases. However, contradictory reports in the literature with respect to CBD's effect on intraocular pressure (IOP) have raised concerns and halted research exploring its use in ocular therapeutics. Therefore, the current investigation aimed to further evaluate CBD's impact on the IOP in the rabbit model. CBD nanoemulsions, containing Carbopol® 940 NF as a mucoadhesive agent (CBD-NEC), were prepared using hot-homogenization followed by probe sonication. The stability of the formulations post-moist-heat sterilization, in terms of physical and chemical characteristics, was studied for three different storage conditions. The effect of the formulation on the intraocular pressure (IOP) profile in normotensive Dutch Belted male rabbits was then examined. The lead CBD-NEC formulation (1% w/v CBD) exhibited a globule size of 259 ± 2.0 nm, 0.27 ± 0.01 PDI, and 23.2 ± 0.4 cP viscosity, and was physically and chemically stable for one month (last time point tested) at 4 °C, 25 °C, and 40 °C. CBD-NEC significantly lowered the IOP in the treated eyes for up to 360 min, with a peak drop in IOP of 4.5 mmHg observed at the 150 min time point, post-topical application. The IOP of the contralateral eye (untreated) was also observed to be lowered significantly, but the effect lasted up to the 180 min time point only. Overall, topically administered CBD, formulated in a mucoadhesive nanoemulsion formulation, reduced the IOP in the animal model studied. The results support further exploration of CBD as a therapeutic option for various inflammation-based ocular diseases.

Innovative Treatment Strategies to Accelerate Wound Healing: Trajectory and Recent Advancements.

Wound healing is highly specialized dynamic multiple phase process for the repair of damaged/injured tissues through an intricate mechanism. Any failure in the normal wound healing process results in abnormal scar formation, and chronic state which is more susceptible to infections. Chronic wounds affect patients' quality of life along with increased morbidity and mortality and are huge financial burden to healthcare systems worldwide, and thus requires specialized biomedical intensive treatment for its management. The clinical assessment and management of chronic wounds remains challenging despite the development of various therapeutic regimens owing to its painstakingly long-term treatment requirement and complex wound healing mechanism. Various conventional approaches such as cell therapy, gene therapy, growth factor delivery, wound dressings, and skin grafts etc., are being utilized for promoting wound healing in different types of wounds. However, all these abovementioned therapies are not satisfactory for all wound types, therefore, there is an urgent demand for the development of competitive therapies. Therefore, there is a pertinent requirement to develop newer and innovative treatment modalities for multipart therapeutic regimens for chronic wounds. Recent developments in advanced wound care technology includes nanotherapeutics, stem cells therapy, bioengineered skin grafts, and 3D bioprinting-based strategies for improving therapeutic outcomes with a focus on skin regeneration with minimal side effects. The main objective of this review is to provide an updated overview of progress in therapeutic options in chronic wounds healing and management over the years using next generation innovative approaches. Herein, we have discussed the skin function and anatomy, wounds and wound healing processes, followed by conventional treatment modalities for wound healing and skin regeneration. Furthermore, various emerging and innovative strategies for promoting quality wound healing such as nanotherapeutics, stem cells therapy, 3D bioprinted skin, extracellular matrix-based approaches, platelet-rich plasma-based approaches, and cold plasma treatment therapy have been discussed with their benefits and shortcomings. Finally, challenges of these innovative strategies are reviewed with a note on future prospects.

Design of Topical Moxifloxacin Mucoadhesive Nanoemulsion for the Management of Ocular Bacterial Infections.

Ocular bacterial infections can lead to serious visual disability without proper treatment. Moxifloxacin (MOX) has been approved by the US Food and Drug Administration as a monotherapy for ocular bacterial infections and is available commercially as an ophthalmic solution (0.5% w/v). However, precorneal retention, drainage, and low bioavailability remain the foremost challenges associated with current commercial eyedrops. With this study, we aimed to design a MOX-loaded nanoemulsion (NE; MOX-NE) with mucoadhesive agents (MOX-NEM) to sustain MOX release, as well as to overcome the potential drawbacks of the current commercial ophthalmic formulation. MOX-NE and MOX-NEM formulations were prepared by hot homogenization coupled with probe sonication technique and subsequently characterized. The lead formulations were further evaluated for in vitro release, ex vivo transcorneal permeation, sterilization, and antimicrobial efficacy studies. Commercial MOX ophthalmic solution was used as a control. The lead formulations showed the desired physicochemical properties and viscosity. All lead formulations showed sustained release profiles a period of more than 12 h. Filtered and autoclaved lead formulations were stable for one month (the last time point tested) under refrigeration and at room temperature. Ex vivo transcorneal permeation studies revealed a 2.1-fold improvement in MOX permeation of the lead MOX-NE formulation compared with Vigamox® eyedrops. However, MOX-NEM formulations showed similar flux and permeability coefficients to those of Vigamox® eyedrops. The lead formulations showed similar in vitro antibacterial activity as the commercial eyedrops and crude drug solution. Therefore, MOX-NE and MOX-NEM formulations could serve as effective delivery vehicles for MOX and could improve treatment outcomes in different ocular bacterial infections.

Development of α-Tocopherol Succinate-Based Nanostructured Lipid Carriers for Delivery of Paclitaxel.

The management of retinoblastoma (RB) involves the use of invasive treatment regimens. Paclitaxel (PTX), an effective antineoplastic compound used in the treatment of a wide range of malignant tumors, poses treatment challenges due to systemic toxicity, rapid elimination, and development of resistance. The goal of this work was to develop PTX-loaded, α-tocopherol succinate (αTS)-based, nanostructured lipid carrier (NLCs; αTS-PTX-NLC) and PEGylated αTS-PTX-NLC (αTS-PTX-PEG-NLC) to improve ocular bioavailability. The hot homogenization method was used to prepare the NLCs, and repeated measures ANOVA analysis was used for formulation optimization. αTS-PTX-NLC and αTS-PTX-PEG-NLC had a mean particle size, polydispersity index and zeta potential of 186.2 ± 3.9 nm, 0.17 ± 0.03, −33.2 ± 1.3 mV and 96.2 ± 3.9 nm, 0.27 ± 0.03, −39.15 ± 3.2 mV, respectively. The assay and entrapment efficiency of both formulations was >95.0%. The NLC exhibited a spherical shape, as seen from TEM images. Sterilized (autoclaved) formulations were stable for up to 60 days (last time point checked) under refrigerated conditions. PTX-NLC formulations exhibited an initial burst release and 40% drug release, overall, in 48 h. The formulations exhibited desirable physicochemical properties and could lead to an effective therapeutic option in the management of RB.

Dual Drug Loaded Lipid Nanocarrier Formulations for Topical Ocular Applications.

Introduction: Untreated ocular infections can damage the unique fine structures of the eye with possible visual impairments and blindness. Ciprofloxacin (CIP) ophthalmic solution is prescribed as first-line therapy in ocular bacterial infections. Natamycin (NT) ophthalmic suspension is one of the progenitors in ocular antifungal therapy. Nanostructured lipid carriers (NLCs) have been widely examined for ocular penetration enhancement and distribution to deeper ocular tissues. The objective of the current study was to prepare NLCs loaded with a combination of CIP and NT (CIP-NT-NLCs) and embed them in an in-situ gelling system (CIP-NT-NLCs-IG). This novel formulation will target the co-delivery of CIP and NT for the treatment of mixed ocular infections or as empirical treatment in case of limited access to healthcare diagnostic services. Methods: CIP-NT-NLC and CIP-NT-NLC-IG formulations were evaluated based on physicochemical characteristics, in vitro release, and ex vivo transcorneal permeation studies and compared against commercial CIP and NT ophthalmic eye drops. Results and Discussion: NLCs formulation (0.1% CIP and 0.3% NT) showed particle size, polydispersity index, and zeta potential of 196.2 ± 1.2 nm, 0.43 ± 0.06, and -28.1 ± 1.4 mV, respectively. Moreover, CIP-NT-NLCs showed entrapment efficiency of 80.9 ± 2.9 and 98.7 ± 1.9% for CIP and NT, respectively. CIP-NT-NLCs-IGformulation with 0.2% w/v gellan gum demonstrated the most favorable viscoelastic characteristics for ocular application. CIP-NT-NLCs and CIP-NT-NLCs-IG formulations exhibited a sustained release pattern for both drugs over 24 h. Moreover, CIP-NT-NLCs and CIP-NT-NLC-IG formulations showed 4.0- and 2.2-folds, and 5.0- and 2.5-folds enhancement in ex vivo transcorneal permeability of CIP and NT, respectively, compared to the control formulations. Conclusion: The results suggest that this dual nanoparticulate-based in-situ gelling drug delivery system can serve as a promising topical delivery platform for the treatment of ocular infections.

Impact of mucoadhesive agent inclusion on the intraocular pressure lowering profile of Δ9-tetrahydrocannabinol-valine-hemisuccinate loaded nanoemulsions in New Zealand white rabbits.

The current study aimed to determine the effect of inclusion of a mucoadhesive agent on the intensity and duration of intraocular pressure (IOP) lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS) loaded in a nanoemulsion (THC-VHS-NE) formulation. THC-VHS-NE formulation with Carbopol®940NF added as a mucoadhesive agent (THC-VHS-NEC) was prepared using hot-homogenization followed by probe sonication and characterized. A comparative evaluation of the IOP lowering activity of THC-VHS-NEC, THC-VHS-NE, THC-NEC, and commercial latanoprost ophthalmic solution, was undertaken in normotensive New Zealand white rabbits. The effect of pH, surfactant concentration, and autoclave process on the IOP lowering activity of THC-VHS-NEC was also studied. The formulation demonstrated desired viscosity, physicochemical properties, and autoclave process stability. The THC-VHS-NEC formulation showed a significant (p < 0.05) improvement in the duration of IOP lowering activity, compared to THC-NEC and THC-VHS-NE. Moreover, in this model, THC-VHS-NEC was more effective than commercially available latanoprost ophthalmic formulation, in terms of both duration and intensity of IOP lowering. A change in formulation pH, surfactant concentration, or sterilization process did not impact the IOP lowering activity of THC-VHS-NEC. Overall, inclusion of a mucoadhesive agent in THC-VHS-NE formulation, significantly increased the duration of activity, and could lead to a once- or twice- a day dosing regimen.

6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects.

Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Cyclodextrin Complexed Lipid Nanoparticles of Irbesartan for Oral Applications: Design, Development, and In Vitro Characterization.

Irbesartan (IR) is an angiotensin II receptor antagonist drug with antihypertensive activity. IR bioavailability is limited due to poor solubility and first-pass metabolism. The current investigation aimed to design, develop, and characterize the cyclodextrin(s) (CD) complexed IR (IR-CD) loaded solid lipid nanoparticles (IR-CD-SLNs) for enhanced solubility, sustained release behavior, and subsequently improved bioavailability through oral administration. Based on phase solubility studies, solid complexes were prepared by the coacervation followed by lyophilization method and characterized for drug content, inclusion efficiency, solubility, and in vitro dissolution. IR-CD inclusion complexes demonstrated enhancement of solubility and dissolution rate of IR. However, the dissolution efficiency was significantly increased with hydroxypropyl-ßCD (HP-ßCD) inclusion complex than beta-CD (ßCD). SLNs were obtained by hot homogenization coupled with the ultrasonication method with IR/HP-ßCD inclusion complex loaded into Dynasan 112 and glycerol monostearate (GMS). SLNs were evaluated for physicochemical characteristics, in vitro release, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and physical stability at room temperature for two months. The optimized SLNs formulation showed particle size, polydispersity index, zeta potential, assay, and entrapment efficiency of 257.6 ± 5.1 nm, 0.21 ± 0.03, -30.5 ± 4.1 mV, 99.8 ± 2.5, and 93.7 ± 2.5%, respectively. IR-CD-SLN and IR-SLN dispersions showed sustained release of IR compared to the IR-CD inclusion complexes. DSC results complimented PXRD results by the absence of IR endothermic peak. Optimized IR-CD complex, IR-SLN, and IR-CD-SLN formulations were stable for two months at room temperature. Thus, the current IR oral formulation may exhibit improved oral bioavailability and prolonged antihypertensive activity, which may improve therapeutic outcomes in the treatment of hypertension and heart failure.

Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, in vitro Release, and ex vivo Hemolysis.

Primaquine (PQ), an 8-aminoquinoline antimalarial drug, has been widely used for the eradication of hypnozoites from the liver and, therefore, recognized as the radical cure of malaria. However, the clinical applications of PQ are restricted to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to severe dose-related hemolytic side effects. Nanoparticle carriers have shown great potential in achieving higher PQ concentrations in the target site, thereby reducing dose-related systemic toxicity caused by non-specific exposure. This work aims to develop, compare, and evaluate three PQ-loaded lipid-based drug carriers including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nano-emulsions (NE). The optimized PQ-SLN, PQ-NLC, and PQ-NE had a particle size of 250 nm, a PDI range of 0.1 to 0.3, a zeta potential of - 30 mV, and entrapment efficiency of ~ 90%. All lipid formulations showed sustained release in both simulated gastric and intestinal fluids over 6 h. Four empirical models - including zero-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models - were tested to understand the drug release mechanisms of PQ-SLN, PQ-NLC, and PQ-NE. The model fitness was found to be the highest in the Korsmeyer-Peppas model for all the PQ-loaded lipid formulations (R2: 0.88-0.94). No significant changes were observed in the entrapment efficiency, particle size, and PDI of lipid formulations throughout 1 month of storage at 4 °C and 25 °C. PQ-SLN and PQ-NLC can be further lyophilized with cryoprotectants to improve long-term stability. Finally, the treatment of erythrocytes with PQ-SLN, PQ-NLC, and PQ-NE reduced erythrocyte hemolysis by approximately 4.5-fold compared to the free drug solution.

Chrono modulated multiple unit particulate systems (MUPS) via a continuous hot melt double extrusion technique: Investigation of the formulation and process suitability.

The current study is aimed at the development of chrono modulated multiple unit particulate systems (MUPS) of nifedipine (ND) by a continuous double extrusion process. ND, a poorly soluble drug was formulated into an amorphous solid dispersion (ASD) to improve its solubility. Further, the ASD was converted into MUPS to control the drug release through a combination of pulsatile and sustained release portions. In the preparation of the ASD, the polymer HPMCAS LG was employed at different concentrations. MUPS were formulated by using Eudragit® FS100, Eudragit® RSPO, Klucel™ HF and lipids Precirol® ATO 5, Geleol™, Compritol® ATO5. The differential scanning calorimetry and powder X-ray diffraction studies of MUPS revealed the amorphous nature of ND. Scanning electron microscopy (SEM) studies depicted the surface morphology of the ASD and the gradual change in the surface of the coated MUPS during in-vitro release studies. The in-vitro drug release profiles of ASD indicated significant improvement (p < 0.05) of solubility of ND and MUPS demonstrated a combination of pulsatile and zero-order controlled release up to 12 h. Accelerated stability studies for MUPS at 40 °C/75% RH revealed the formulations were stable. These findings suggest hot melt double extrusion as a potential alternative for conventional techniques to produce MUPS.

PLGA/PLA-Based Long-Acting Injectable Depot Microspheres in Clinical Use: Production and Characterization Overview for Protein/Peptide Delivery.

Over the past few decades, long acting injectable (LAI) depots of polylactide-co-glycolide (PLGA) or polylactic acid (PLA) based microspheres have been developed for controlled drug delivery to reduce dosing frequency and to improve the therapeutic effects. Biopharmaceuticals such as proteins and peptides are encapsulated in the microspheres to increase their bioavailability and provide a long release period (days or months) with constant drug plasma concentration. The biodegradable and biocompatible properties of PLGA/PLA polymers, including but not limited to molecular weight, end group, lactide to glycolide ratio, and minor manufacturing changes, could greatly affect the quality attributes of microsphere formulations such as release profile, size, encapsulation efficiency, and bioactivity of biopharmaceuticals. Besides, the encapsulated proteins/peptides are susceptible to harsh processing conditions associated with microsphere fabrication methods, including exposure to organic solvent, shear stress, and temperature fluctuations. The protein/peptide containing LAI microspheres in clinical use is typically prepared by double emulsion, coacervation, and spray drying techniques. The purpose of this review is to provide an overview of the formulation attributes and conventional manufacturing techniques of LAI microspheres that are currently in clinical use for protein/peptides. Furthermore, the physicochemical characteristics of the microsphere formulations are deliberated.

Exosomes as Naturally Occurring Vehicles for Delivery of Biopharmaceuticals: Insights from Drug Delivery to Clinical Perspectives.

Exosomes as nanosized vesicles are emerging as drug delivery systems for therapeutics owing to their natural origin, their ability to mediate intercellular communication, and their potential to encapsulate various biological molecules such as proteins and nucleic acids within the lipid bilayer membrane or in the lumen. Exosomes contain endogenous components (proteins, lipids, RNA) that could be used to deliver cargoes to target cells, offering an opportunity to diagnose and treat various diseases. Owing to their ability to travel safely in extracellular fluid and to transport cargoes to target cells with high efficacy, exosomes offer enhanced delivery of cargoes in vivo. However, several challenges related to the stabilization of the exosomes, the production of sufficient amounts of exosomes with safety and efficacy, the efficient loading of drugs into exosomes, the clearance of exosomes from circulation, and the transition from the bench scale to clinical production may limit their development and clinical use. For the clinical use of exosomes, it is important to understand the molecular mechanisms behind the transport and function of exosome vesicles. This review exploits techniques related to the isolation and characterization of exosomes and their drug delivery potential to enhance the therapeutic outcome and stabilization methods. Further, routes of administration, clinical trials, and regulatory aspects of exosomes will be discussed in this review.