Collagen-Based Hydrogels for the Eye: A Comprehensive Review.

Collagen-based hydrogels have emerged as a highly promising platform for diverse applications in ophthalmology, spanning from drug delivery systems to biomedical interventions. This review explores the diverse sources of collagen, which give rise to different types of collagen protein. The critical isolation and purification steps are discussed, emphasizing their pivotal role in preparing collagen for biomedical use. To ensure collagen quality and purity, and the suitability of collagen for targeted applications, a comprehensive characterization and quality control are essential, encompassing assessments of its physical, chemical, and biological properties. Also, various cross-linking collagen methods have been examined for providing insight into this crucial process. This comprehensive review delves into every facet of collagen and explores the wide-ranging applications of collagen-based hydrogels, with a particular emphasis on their use in drug delivery systems and their potential in diverse biomedical interventions. By consolidating current knowledge and advancements in the field, this review aims to provide a detailed overview of the utilization of engineered collagen-based hydrogels in ocular therapeutics.

Design of chondroitin sulphate coated proglycosomes for localized delivery of tofacitinib for the treatment of rheumatoid arthritis.

Long-term oral tofacitinib (TOF) administration has been linked to serious side effects majorly immunological suppression. The aim of this work was to enhance the therapeutic efficacy of TOF by chondroitin sulphate (CS) coated proglycosomes through the anchoring of high-affinity CS to CD44 receptors on immune cells in the inflammatory region. The CS was coated onto the TOF-loaded proglycosomes (CS-TOF-PG) formulations and they were evaluated for in vitro drug release, ex vivo (permeation, dermatokinetics) studies. In vivo efficacy studies were carried out in Freund's complete adjuvant (CFA) induced arthritis model. The optimized CS-TOF-PG showed particle sizes of 181.13 ± 7.21 nm with an entrapment efficiency of 78.85 ± 3.65 %. Ex-vivo studies of CS-TOF-PG gel exhibited 1.5-fold high flux and 1.4-fold dermal retention compared to FD-gel. The efficacy study revealed that CS-TOF-PG showed a significant (P < 0.001) reduction in inflammation in arthritic rat paws compared to the TOF oral and FD gel. The current study ensured that the CS-TOF-PG topical gel system would provide a safe and effective formulation for localization and site-specific delivery of TOF at the RA site and overcome the adverse effects associated with the TOF.

Hyaluronic acid-coated proglycosomes for topical delivery of tofacitinib in rheumatoid arthritis condition: Formulation design, in vitro, ex vivo characterization, and in vivo efficacy studies.

Tofacitinib (TF) is a selective oral jakanib approved by the USFDA for the treatment of rheumatoid arthritis (RA). To overcome the adverse effects of orally administered TF, topical delivery can be a suitable choice. The therapeutic efficacy of TF can be improved through the high affinity of natural ligands (hyaluronic acid and chondroitin sulphate) to CD44 receptors on the macrophages or other immune cells in the dermal region. Thus, the present research work was inspired by the possibility to develop and evaluate the potential of hyaluronic acid-coated proglycosomes (HA-TF-PG) as the carrier for site-specific dermal delivery. The normal-PG (N-TF-PG) and HA-TF-PG showed particle sizes of <250 nm. The HA-TF-PG demonstrated 3.15-fold higher retention of TF in the viable dermis layers than the conventional formulation. The in vivo pharmacodynamic study, cytokines, and radiographic study on Complete Freud's Adjuvant-induced arthritic rat model revealed that HA-TF-PG exhibited a significant (P < 0.001) reduction in inflammation in arthritic rat's paw compared to the conventional TF. The developed HA-TF-PG treated groups showed significantly lowered CD44 levels compared to FD-gel and N-TF-PG i.e. 2.28 and 1.32-fold respectively (p < 0.001). In conclusion, The HA-TF-PG can be developed as an effective carrier for the site-specific dermal drug delivery system of TF to treat RA.

Insight into the pivotal role of signaling pathways in psoriasis pathogenesis, potential therapeutic molecules and drug delivery approaches.

Psoriasis is a multifactorial chronic autoimmune skin disorder, the exact cause of which is still under investigation. It is classified into different types displaying various histopathological features such as hyperproliferation, irregular parakeratosis and vascular infiltration of various immune cells with neutrophils in the epidermis. Over the past few decades, psoriasis pathogenesis has been thoroughly researched, leading to several advances in the treatment using small molecules and biologics. This review focuses on describing the role of various signaling pathways, including PDE-4, JAK-STAT, S1P, A3AR and NF-κB, in psoriasis pathogenesis and associated new molecules that are either recently approved or under clinical trials. This study has also addressed the relevance of employing nanotherapeutics to boost the efficacy of psoriasis treatment.

Insight on updates in polysaccharides for ocular drug delivery.

Ocular drug delivery is a significantly challenging task due to the presence of various anatomical and physiological barriers in the eye. Naturally available polysaccharides, when used as drug vehicles provide increased retention time, bioavailability, and penetration due to their unique mucoadhesive and charge-possessing nature. This review discusses the polysaccharide-based drug delivery system for the eye. Polysaccharides like alginic acid, cellulose derivatives, chitosan, pectin, xanthan gum, gellan gum, and hyaluronic acid are reviewed in this report. Additionally, emphasis is given to some of the recently investigated polymers such as sugarcane bagasse cellulose, a polysaccharide extracted from the seeds of Manilkara zapota, and Tremella fuciformis polysaccharide as drug vehicles for effective ocular drug delivery. This review also provides insight on clinical status and FDA-approved polysaccharides for ophthalmic delivery of therapeutics.

Emerging trends in microneedle-based drug delivery strategies for the treatment of rheumatoid arthritis.

INTRODUCTION: The current drug therapies for treating rheumatoid arthritis (RA) include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, or biological products designed to mitigate the symptoms of the disease. These therapies with conventional delivery systems possess limitations such as lack of selectivity and adverse effects in the extra-articular tissues. Microneedles-based transdermal drug delivery gained huge attention that can overcome the limitations associated with conventional preparations. AREAS COVERED: This review aims to provide detailed information on types of microneedles (MNs) and their usage in drug delivery for the management of RA. In addition, it also provides evidence for the effective use of MNs in RA treatment. Various types of MNs, their regulatory status, clinical trials, and patents are also compiled in this review. EXPERT OPINION: Microneedles are small patch-like structures consisting of needles in micron range arranged in array-like structure used to manage drugs designed to be given via transdermal route. Microneedles provide painless delivery, fast onset of action, bypass the first-pass metabolism, and be easily self-administered. In the case of RA treatment, which requires a long-term application of drugs, MN is a new and emerging way to ease the symptoms of RA.

Dermatokinetic assessment of luliconazole-loaded nanostructured lipid carriers (NLCs) for topical delivery: QbD-driven design, optimization, and in vitro and ex vivo evaluations.

The present study is concerned with the QbD-based design and development of luliconazole-loaded nanostructured lipid carriers (NLCs) hydrogel for enhanced skin retention and permeation. The NLCs formulation was optimized employing a 3-factor, 3-level Box-Behnken design. The effect of formulation variable lipid content, surfactant concentration, and sonication time was studied on particle size and % EE. The optimized formulation exhibited particle size of 86.480 ± 0.799 nm; 0.213 ± 0.004 PDI, ≥ - 10 mV zeta potential and 85.770 ± 0.503% EE. The in vitro release studies revealed sustained release of NLCs up to 42 h. The designed formulation showed desirable occlusivity, spreadability (0.748 ± 0.160), extrudability (3.130 ± 1.570), and the assay was found to be 99.520 ± 0.890%. The dermatokinetics assessment revealed the Cmax Skin to be ~ 2-fold higher and AUC0-24 to be ~ 3-fold higher in the epidermis and dermis of NLCs loaded gel in contrast with the marketed cream. The Tmax of both the formulations was found to be 6 h in the epidermis and dermis. The obtained results suggested that luliconazole NLCs can serve as a promising formulation to enhance luliconazole's antifungal activity and also in increasing patient compliance by reducing the frequency of application.

Recent advances in nanocarriers for nutrient delivery.

For the past few years, there has been a surge in the use of nutraceuticals. The global nutraceuticals market in 2020 was USD 417.66 billion, and the market value is expected to increase by 8.9% compound annual growth rate from 2020 to 2028. This is because nutraceuticals are used to treat and prevent various diseases such as cancer, skin disorders, gastrointestinal, ophthalmic, diabetes, obesity, and central nervous system-related diseases. Nutritious food provides the required amount of nutrition to the human body through diet, whereas most of the bioactive agents present in the nutrients are highly lipophilic, with low aqueous solubility leading to poor dissolution and oral bioavailability. Also, the nutraceuticals like curcumin, carotenoids, anthocyanins, omega-3 fatty acids, vitamins C, vitamin B12, and quercetin have limitations such as poor solubility, chemical instability, bitter taste, and an unpleasant odor. Additionally, the presence of gastrointestinal (GIT) membrane barriers, varied pH, and reaction with GIT enzymes cause the degradation of some of the nutraceuticals. Nanotechnology-based nutrient delivery systems can be used to improve oral bioavailability by increasing nutraceutical stability in foods and GIT, increasing nutraceutical solubility in intestinal fluids, and decreasing first-pass metabolism in the gut and liver. This article has compiled the properties and applications of various nanocarriers such as polymeric nanoparticles, micelles, liposomes, niosomes, solid lipid nanocarriers, nanostructured lipid carrier, microemulsion, nanoemulsion, dendrimers in organic nanoparticles, and nanocomposites for effective delivery of bioactive molecules.

Revolutionizing Therapeutic Delivery with Microneedle Technology for Tumor Treatment.

The tumor is an uncontrolled growth of tissue that can be localized (benign) or possesses the capability of metastasis (malignant). The conventional methods of tumor diagnosis, such as acupuncture, endoscopy, and histopathology, and treatment methods, such as injections, chemotherapy, surgery, and radiotherapy, are invasive, expensive, and pose severe safety and management issues for the patients. Microneedle technology is a recently developed approach for active transdermal drug delivery. It is minimally invasive, self-administrable, bypasses the first-pass effect, and effectively delivers chemotherapeutics and drugs at low doses, thus, overcoming the drawbacks of conventional delivery systems. This review provides an idea of the types, materials utilized in the fabrication, and techniques used for the preparation of microneedles (MNs), as well as their application in tumor diagnosis and treatment. Additionally, emphasis is given to the case studies related to MNs-assisted tumor therapy, such as photothermal therapy, gene therapy, photodynamic therapy, chemotherapy, immunotherapy, and various combination therapies. MNs also serve as a tool for diagnosis by the bio-sampling of blood and interstitial skin fluid, as well as biosensing various cancer biomarkers. The combined therapy and diagnostics provide theranostic MNs for enhanced and personalized tumor therapy. The limitations and prospects of MNs development are also discussed.

Revisiting techniques to evaluate drug permeation through skin.

INTRODUCTION: Investigating the transportation of a drug molecule through various layers of skin and determining the amount of drug retention in skin layers is of prime importance in transdermal and topical drug delivery. The information regarding drug permeation and retention in skin layers aids in optimizing a formulation and provides insight into the therapeutic efficacy of a formulation. AREAS COVERED: This perspective covers various methods that have been explored to estimate drug/therapeutics in skin layers using in vitro, ex vivo, and in vivo conditions. In vitro methods such as diffusion techniques, ex vivo methods such as isolated perfused skin models and in vivo techniques including dermato-pharmacokinetics employing tape stripping, and microdialysis are discussed. Application of all techniques at various stages of formulation development where various local and systemic effects need to be considered. EXPERT OPINION: The void in the existing methodologies necessitates improvement in the field of dermatologic research. Standardization of protocols, experimental setups, regulatory guidelines, and further research provides information to select an alternative for human skin to perform skin permeation experiments to increase the reliability of data generated through the available techniques. There is a need to utilize multiple techniques for appropriate dermato-pharmacokinetics evaluation and formulation's efficacy.

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations.

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.

Quality by design (QbD) in the formulation and optimization of liquid crystalline nanoparticles (LCNPs): A risk based industrial approach.

The intersection of lipid-based nanoparticles and lyotropic liquid crystals has provided a novel type of nanocarrier system known as 'lipid-based lyotropic liquid crystals' or 'liquid crystalline nanoparticles' (LCNPs). The unique advantages and immense popularity of LCNPs can be exploited in a better way if the formulation of LCNPs is done using the approach of quality by design (QbD). QbD is a systematic method that can be utilized in formulation development. When QbD is applied to LCNPs formulation, it will proffer many unique advantages, such as better product and process understanding, the flexibility of process within the design space, implementation of more effective and efficient control strategies, easy transfer from bench to bedside, and more robust product. In this work, the application of QbD in the formulation of LCNPs has been explored. The elements of QbD, viz. quality target product profile, critical quality attributes, critical material attributes, critical process parameters, quality risk management, design of experiments, and control strategy for the development of LCNPs have been explained in-depth with case studies. The present work will help the reader to understand the nitty-gritties in the application of QbD in the formulation of LCNPs, and provide a base for QbD-driven formulation of LCNPs with a regulatory perspective.

Chitosan-based microneedles as a potential platform for drug delivery through the skin: Trends and regulatory aspects.

Microneedles (MNs) fabrication using chitosan has gained significant interest due to its ability of film-forming, biodegradability, and biocompatibility, making it suitable for topical and transdermal drug delivery. The presence of amine and hydroxyl functional groups on chitosan permits the modification with tunable properties and functionalities. In this regard, chitosan is the preferred material for fabrication of MNs because it does not produce an immune response in the body and can be tailored as per required strength and functionalities. Therefore, many researchers have attempted to use chitosan as a drug delivery vehicle for hydrophilic drugs, peptides, and hormones. In 2020, the FDA has issued "Regulatory Considerations for Microneedling Products". This official guidance is a sign for future opportunities in the development of MNs. The present review focuses on properties, and modifications of chitosan used in the fabrication of MNs. The therapeutic and diagnostic applications of different types of chitosan-based MNs have been discussed. Further, the regulatory aspects of MN-based devices, and patents related to chitosan-based MNs are discussed.

Spectrophotometric method to quantify tofacitinib in lyotropic liquid crystalline nanoparticles and skin layers: Application in ex vivo dermal distribution studies.

Tofacitinib is an oral Janus kinase inhibitor used in the treatment of Rheumatoid arthritis. The topical delivery of novel Tofacitinib loaded liquid crystal nanoparticles (LCNPs) can provide a controlled release, and also targeted drug delivery to inflamed synovium. There is need of UV spectroscopic method which can determine Tofacitinib in designed nanocarriers like LCNPs, that can be applied to evaluate entrapment efficiency, in vitro drug release, and ex vivo skin studies. In the present study, we have developed and validated a simple and sensitive spectrophotometric method for the quantitative determination of Tofacitinib in methanol and phosphate buffer saline. The linearity range in both the media was 5-30 µg/mL (methanol) and 5-40 µg/ mL (phosphate buffer saline) with high correlation coefficient value (>0.9998). This indicates the clear correlation between Tofacitinib concentrations and their absorbance within the test ranges. The repeatability and intermediate precision articulated by the relative standard deviation were less than 2% in the developed method. The method specificity and applicability were also ascertained by performing recovery studies by spiking method, which was 95.85 ± 1.98% with % RSD 1.24 ± 0.045. The method developed in methanol was successfully applied to determine the entrapment efficiency of Tofacitinib in developed LCNPs formulation and skin retention (dermatokinetics). The method developed in pH 7.4 phosphate buffer saline was applied to quantify Tofacitinib from LCNPs in in vitro and ex vivo drug release samples. In conclusion, a simple, sensitive, accurate, and precise UV spectrophotometric method was established to determine Tofacitinib in in vitro and ex vivo skin studies.

Biodegradable microneedles fabricated with carbohydrates and proteins: Revolutionary approach for transdermal drug delivery.

There has been a surge in the use of transdermal drug delivery systems (TDDS) for the past few years. The market of TDDS is expected to reach USD 7.1 billion by 2023, from USD 5.7 billion in 2018, at a CAGR of 4.5%. Microneedles (MNs) are a novel class of TDDS with advantages of reduced pain, low infection risk, ease of application, controlled release of therapeutic agents, and enhanced bioavailability. Biodegradable MNs fabricated from natural polymers have become the center of attention among formulation scientists because of their recognized biodegradability, biocompatibility, ease of fabrication, and sustainable character. In this review, we summarize the various polysaccharides and polypeptide based biomaterials that are used to fabricate biodegradable MNs. Particular emphasis is given to cellulose and its derivatives, starch, and complex carbohydrate polymers such as alginates, chitosan, chondroitin sulfate, xanthan gum, pullulan, and hyaluronic acid. Additionally, novel protein-based polymers such as zein, collagen, gelatin, fish scale and silk fibroin (polyamino acid) biopolymers application in transdermal drug delivery have also been discussed. The current review will provide a unique perspective to the readers on the developments of biodegradable MNs composed of carbohydrates and protein polymers with their clinical applications and patent status.

Design of temozolomide-loaded proliposomes and lipid crystal nanoparticles with industrial feasible approaches: comparative assessment of drug loading, entrapment efficiency, and stability at plasma pH.

Temozolomide is a drug approved for treating glioblastomas, which has 100% oral bioavailability but gets degraded at physiological pH thus having very short half-life and only 20-30% brain bioavailability. Due to its amphiphilic nature, reported nanoformulations exhibits poor drug loading. The objective of this work was to formulate lipid-based drug delivery systems to enhance the brain bioavailability by prolonging the drug release and circulation time of the drug to overcome the limitations of the existing therapies and possible reduction of side effects. The size of the nanocarriers obtained was less than 300 nm and the PDI obtained was less than 0.3. The designed formulation showed higher entrapment efficiency as compared to the other reported nanocarriers of temozolomide. The designed formulations showed prolonged drug release from 12 to 20 h compared to 6 h for the pure drug. About 95% of the pure drug was degraded at plasma pH at the end of 12 h, whereas only 68% and 77% was degraded when entrapped inside the lipid crystal nanoparticles and proliposomes respectively. Further, pharmacokinetic and animal studies can confirm the potential of these for improvement of brain bioavailability.

Luliconazole loaded lyotropic liquid crystalline nanoparticles for topical delivery: QbD driven optimization, in-vitro characterization and dermatokinetic assessment.

Fungal infections are an important cause of morbidity and pose a serious health concern especially in immunocompromised patients. Luliconazole (LUL) is a topical imidazole antifungal drug with a broad spectrum of activity. To overcome the limitations of conventional dosage forms, LUL loaded lyotropic liquid crystalline nanoparticles (LCNP) were formulated and characterized using a three-factor, five-level Central Composite Design of Response Surface Methodology. LUL loaded LCNP showed particle size of 181 ± 12.3 nm with an entrapment efficiency of 91.49 ± 1.61 %. The LUL-LCNP dispersion in-vitro drug release showed extended release up to 54 h. Ex-vivo skin permeation studies revealed transdermal flux value (J) of LUL-LCNP gel (7.582 µg/h/cm2) 2 folds higher compared to marketed cream (3.3706 µg/h/cm2). The retention of LUL in the stratum corneum was ∼1.5 folds higher and ∼2 folds higher in the epidermis and other deeper layers in comparison to the marketed cream. The total amount of drug penetrated (AUC0-∞) with LCNP formulation was 4.7 folds higher in epidermis and 6.5 folds higher in dermis than marketed cream. The study's findings vouch that LCNP can be a promising and effective carrier system for the delivery of antifungal drugs with enhanced skin permeation.

Psoriasis: pathological mechanisms, current pharmacological therapies, and emerging drug delivery systems.

Psoriasis is a chronic autoimmune skin disorder triggered by either genetic factors, environmental factors, life style, or a combination thereof. Clinical investigations have identified pathogenesis, such as T cell and cytokine-mediated, genetic disposition, antimicrobial peptides, lipocalin-2, galectin-3, vaspin, fractalkine, and human neutrophil peptides in the progression of psoriasis. In addition to traditional therapies, newer therapeutics, including phosphodiesterase type 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, monoclonal antibodies (mAbs), gene therapy, anti-T cell therapy, and phytoconstituents have been explored. In this review, we highlight nanotechnology-related developments for psoriasis treatment, including patented delivery systems and therapeutics currently in clinical trials.

Emerging Trends in Topical Delivery of Curcumin Through Lipid Nanocarriers: Effectiveness in Skin Disorders.

Curcumin is a unique molecule naturally obtained from rhizomes of Curcuma longa. Curcumin has been reported to act on diverse molecular targets like receptors, enzymes, and co-factors; regulate different cellular signaling pathways; and modulate gene expression. It suppresses expression of main inflammatory mediators like interleukins, tumor necrosis factor, and nuclear factor κB which are involved in the regulation of genes causing inflammation in most skin disorders. The topical delivery of curcumin seems to be more advantageous in providing a localized effect in skin diseases. However, its low aqueous solubility, poor skin permeation, and degradation hinder its application for commercial use despite its enormous potential. Lipid-based nanocarrier systems including liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, lyotropic liquid crystal nanoparticles, lipospheres, and lipid nanocapsules have found potential as carriers to overcome the issues associated with conventional topical dosage forms. Nano-size, lipophilic nature, viscoelastic properties, and occlusive effect of lipid nanocarriers provide high drug loading, hydration of skin, stability, enhanced permeation through the stratum corneum, and slow release of curcumin in the targeted skin layers. This review particularly focuses on the application of lipid nanocarriers for the topical delivery of curcumin in the treatment of various skin diseases. Furthermore, preclinical studies and patents have also indicated the emerging commercialization potential of curcumin-loaded lipid nanocarriers for effective drug delivery in skin disorders. Graphical Abstract.