Application of Quality by Design in the Development of Hydrogen Sulfide Donor Loaded Polymeric Microparticles.

Hydrogen sulfide (H2S) is a multifaceted gasotransmitter molecule which has potential applications in many pathological conditions including in lowering intraocular pressure and providing retinal neuroprotection. However, its unique physicochemical properties pose several challenges for developing its efficient and safe delivery method system. This study aims to overcome challenges related to H2S toxicity, gaseous nature, and narrow therapeutic concentrations range by developing polymeric microparticles to sustain the release of H2S for an extended period. Various formulation parameters and their interactions are quantitatively identified using Quality-by-Design (QbD) approach to optimize the microparticle-based H2S donor (HSD) delivery system. Microparticles were prepared using a solvent-evaporation coacervation process by using polycaprolactone (PCL), soy lecithin, dichloromethane, Na2S.9H2O, and silicone oil as polymer, surfactant, solvent, HSD, and dispersion medium, respectively. The microparticles were characterized for size, size distribution, entrapment efficiency, and H2S release profile. A Main Effects Screening (MES) and a Response Surface Design (RSD) model-based Box-Behnken Design (BBD) was developed to establish the relationship between critical process parameters (CPPs) and critical quality attributes (CQAs) qualitatively and quantitatively. The MES model identified polymer to drug ratio and dispersion medium quantity as significant CPPs among others, while the RSD model established their quantitative relationship. Finally, the target product performance was validated by comparing predicted and experimental outcomes. The QbD approach helped in achieving overall desired microparticle characteristics with fewer trials and provided a mathematical relationship between the CPPs and the CQAs useful for further manipulation and optimization of release profile up to at least 30 days.

Comparison of colorimetric, spectroscopic and electrochemical techniques for quantification of hydrogen sulfide.

Background: Hydrogen sulfide (H2S), an endogenous gasotransmitter, has potential applications in several conditions. However, its quantification in simulated physiological solutions is a major challenge due to its gaseous nature and other physicochemical properties. Aim: This study was designed to compare four commonly used H2S detection and quantification methods in aqueous solutions. Methods: The four techniques compared were one colorimetric, one chromatographic and two electrochemical methods. Results: Colorimetric and chromatographic methods quantified H2S in millimolar and micromole ranges, respectively. The electrochemical methods quantified H2S in the nanomole and picomole ranges and were less time-consuming. Conclusion: The H2S quantification method should be selected based on the specific requirements of a research project in terms of sensitivity, response time and cost-effectiveness.

Development of ELISA-Based Assay for Detection of SARS-CoV-2 Neutralizing Antibody.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulates the plasma B cells to secrete specific antibodies against the viral antigen. However, not all antibodies can prevent the virus from entering the cells. The subpopulation of antibodies which blocks the entry of the virus into host cells is termed neutralizing antibodies (NAbs). The gold standard test for the detection of NAbs is the viral plaque reduction and neutralization test; however, various other methods can also be utilized to detect NAbs. In this study, we have developed an Enzyme Linked Immunosobent Assay (ELISA)-based protocol for rapid detection of SARS CoV-2 NAb by inhibiting the binding of the spike protein receptor-binding domain to angiotensin converting enzyme 2 and compared it with cPASS neutralizing antibody kit, which was approved by the Food and Drug Administration (FDA). The results obtained suggest that the in-house ELISA developed for the detection of NAbs against SARS-CoV-2 is rapid and reliable. Compared to FDA-approved GenScript's cPass assay, the specificity and the sensitivity of the in-house-developed ELISA kit were 100% (95% confidence intervals of 69.15-100.00) and 96% (95% confidence intervals of 86.29-99.51), respectively. Thus, the ELISA protocol developed to test the neutralizing activities of antibodies is rapid, which requires a BSL-2 infrastructure facility and can be easily performed. It has very high potential applications in the rapid screening of NAb against SARS-CoV-2.

A Comparative Analysis of Effectiveness of Recombinant Interleukin-11 Versus Papaya Leaf Extract for Treatment of Thrombocytopenia: A Review.

Platelets or thrombocytes play an important role in thrombosis and maintaining hemostasis. Thrombocytes help in forming blood clots at the site of the wound. When the level of platelets decreases, uncontrolled bleeding occurs which can result in mortality. A decrease in the blood platelet level is known as thrombocytopenia which can be caused due to various reasons. A variety of treatment options are available for thrombocytopenia like platelet transfusion, splenectomy, platelet management with various types of corticosteroids, and recombinant interleukin-11 (rhIL-11). The use of rhIL-11 is approved by FDA for the treatment of thrombocytopenia. rhIL-11 is a recombinant cytokine that is administered to patients suffering from chemotherapy-induced thrombocytopenia as it enhances megakaryocytic proliferation which aids in platelet production. But this treatment has various side effects and is costly. Hence, there is a crucial need to identify cost-effective alternative strategies that present no side effects. The majority of the population in low-income countries requires a functional and cost-effective treatment for low thrombocyte count. Carica papaya is a tropical herbaceous plant that has been reported in recovering low platelet count during dengue virus infection. Even though multiple benefits of the Carica papaya leaf extract (CPLE) are popular, the active compound present in it, which mediates these benefits, remains to be identified. This review aims to highlight the different aspects of rhIL-11 and CPLE-induced platelet counts and their limitations and benefits in the treatment of thrombocytopenia. The literature related to the treatment of thrombocytopenia using rhIL-11 and CPLE from 1970 to 2022 was searched using PubMed and Google Scholar databases with the keywords Recombinant Interleukin-11, Papaya Leaf Extract, Thrombocytopenia, and Platelets.

Antiobesity, Antihyperglycemic, and Antidepressive Potentiality of Rice Fermented Food Through Modulation of Intestinal Microbiota.

The present study has been aimed at evaluating the antiobesity, antihyperglycemic, and antidepressive potentials of Asparagus racemosus starter-based rice fermented foods. High-throughput NGS technology has revealed a number of bacterial genera in the prepared fermented rice, such as Lactobacillus (29.44%), Brevundimonas (16.21%), Stenotrophomonas (6.18%), Pseudomonas (3.11%), Bacillus (2.88%), and others (<2%). Eight-week administration of rice fermented food has increased food intake, whole-body weight, organ weight, different fat masses, serum lipid profiles, and histology of liver and adipose tissues in HFD-induced obese mice. In addition, upregulation of fatty acid oxidation and downregulation of adipocytogenesis- and lypogenesis-related genes along with the expression of their regulatory nuclear factors such as PPARα, PPARγ, PPARδ, and SREBP-1c have also been noted. Moreover, fermented food decreases fasting blood glucose level and improves glucose and insulin tolerance as well as the expression of GLUT4 receptor. Antiobesity and antihyperglycemic effects are also supported by the changes in insulin, leptin, and adiponectin hormone levels. The real-time polymerase chain reaction (RT-PCR) and denaturing gradient gel electrophoresis (DGGE) analyses have clearly demonstrated the intense colonization of Bacteroides, Lactobacillus, and Bifidobacterium, as well as the suppressed growth rate of γ- and δ-Proteobacteria and Firmicutes in the gut after fermented food intake. In the intestine, the latter group of microorganisms possibly modulate short-chain fatty acid (SCFA) levels such as acetate, butyrate, and propionate more than twofold. The impairment of memory-learning and anxiety-like obesity-associated cognitive phenotypes is mitigated significantly (p < 0.01) by fermented food as well. Thus, the formulated fermented food could be used as a natural therapeutic to alleviate obesity and its associated psychological and pathophysiological ailments.

Unmet needs in glaucoma therapy: The potential role of hydrogen sulfide and its delivery strategies.

Glaucoma is an optic neuropathy disorder marked by progressive degeneration of the retinal ganglion cells (RGC). It is a leading cause of blindness worldwide, prevailing in around 2.2% of the global population. The hallmark of glaucoma, intraocular pressure (IOP), is governed by the aqueous humor dynamics which plays a crucial role in the pathophysiology of the diesease. Glaucomatous eye has an IOP of more than 22 mmHg as compared to normotensive pressure of 10-21 mmHg. Currently used treatments focus on reducing the elevated IOP through use of classes of drugs that either increase aqueous humor outflow and/or decrease its production. However, effective treatments should not only reduce IOP, but also offer neuroprotection and regeneration of RGCs. Hydrogen Sulfide (H2S), a gasotransmitter with several endogenous functions in mammalian tissues, is being investigated for its potential application in glaucoma. In addition to decreasing IOP by increasing aqueous humor outflow, it scavenges reactive oxygen species, upregulates the cellular antioxidant glutathione and protects RGCs from excitotoxicity. Despite the potential of H2S in glaucoma, its delivery to anterior and posterior regions of the eye is a challenge due to its unique physicochemical properties. Firstly, development of any delivery system should not require an aqueous environment since many H2S donors are susceptible to burst release of the gas in contact with water, causing potential toxicity and adverse effects owing to its inherent toxicity at higher concentrations. Secondly, the release of the gas from the donor needs to be sustained for a prolonged period of time to reduce dosing frequency as per the requirements of regulatory bodies. Lastly, the delivery system should provide adequate bioavailability throughout its period of application. Hence, an ideal delivery system should aim to tackle all the above challenges related to barriers of ocular delivery and physicochemical properties of H2S itself. This review discusses the therapeutic potential of H2S, its delivery challenges and strategies to overcome the associated chalenges.

Polymeric Nanoparticles for Transdermal Delivery of Polyphenols.

Polyphenols comprise a large group of naturally occurring plant secondary metabolites with various nutritional and health benefits. They are safe and are found abundantly in the diet. Current research on polyphenols focuses on their mechanism and their benefits on human health. However, due to their low solubility and bioavailability, delivery from the conventional route has been a challenge and their translation into clinical applications has been limited. Topical and transdermal delivery of polymeric nanoparticles will act as a novel therapeutic approach for promising delivery of polyphenols. In this review, we have evaluated the existing scientific literature and summarized the potential use of polymeric nanoparticles as a carrier for polyphenolic compounds for delivery via topical and transdermal routes for the treatment of skin cancers such as melanoma.

Injectable in situ gelling delivery system for the treatment of jawbone infections.

Aim: A polymeric in situ gelling delivery system for localized and sustained delivery to jawbone infections was developed. Materials & methods:In situ gelling delivery systems were prepared using either Poly(dl-lactic acid) or chitosan and Pluronic F127/Pluronic F68. Metronidazole nanoparticles were prepared using poly(dl-lactide-co-glycolide) or chitosan. Poly(dl-lactide-co-glycolide) was used for microparticles. Particles were characterized for size, charge and morphology. Results: Viscosity and yield stress of the gels were 0.4 Pa.s and 2 Pa, respectively, with 70% cell viability over 72 h. Around 90% of loaded metronidazole was released at a sustained rate over 1 week. Conclusion: Use of appropriate amount of nano/microparticles in the gel resulted in a sustained release over a period of 1 week - needed for jawbone infection.

Novel Curcumin-Resveratrol Solid Nanoparticles Synergistically Inhibit Proliferation of Melanoma Cells.

Polyphenols such as curcumin (Cur) and resveratrol (Res) have been recently shown to have potential to inhibit proliferation of highly aggressive melanoma cells. This study was designed to investigate the feasibility of a topical delivery system, using a solid lipid nanoparticles (SLNs) loaded delivery systems, that can enhance the skin penetration and anti-cancer efficacy of combination of these polyphenols. Negatively charged Cur-Res SLNs with a mean diameter of 180.2 ± 7.7 nm were prepared using high shear homogenization method. Cur-Res SLNs were found to be stable up to 2 weeks under 4°C. The in vitro release study showed that Res was released five time more than curcumin. The permeability of resveratrol was about 1.67 times that of curcumin from the SLN-gel formulation which was significantly (p < 0.05) lower than from SLN suspension. More than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study suggesting potentially utility of Cur-Res SLNs in the treatment of localized melanoma. In fact, the electrical cell-substrate impedance sensing (ECIS) measurements suggested that Cur-Res combination has potential to stop cell migration of B16F10 melanoma cells. Furthermore, both, Cur-Res SLNs and Cur-Res solution at the ratio of 3:1 demonstrated a strong synergistic inhibition of SK-MEL-28 melanoma cell proliferation. Further evaluation of Cur-Res SLNs in vivo melanoma models are warranted to establish the clinical utility of Cur-Res formulations in melanoma therapy.

Obesity: A Risk Factor for COVID-19.

INTRODUCTION: Emerging data have demonstrated increased mortality of COVID-19 patients suffering from comorbid conditions such as Type II diabetes, hypertension, and cardiovascular diseases. Underlying risk in all these patients is an increase in bodyweight or obesity. The adverse health effects of obesity and how these factors enhance the risk of mortality in COVID-19 patients is still unexplored. OBJECTIVE: The enhanced fat deposition might be a risk factor for increased mortality in COVID-19 patients. METHOD: We have reviewed and collected the information from online databases: Pubmed, Google scholar, Researchgate, to highlight the systematic link between obesity with associated risks in COVID-19. RESULT: We have reported the first study during the pandemic from France and New York, to a currently reported study in Mexico and found individuals with BMI ≥35 kg/m2 or >40 kg/m2 have greater risk of developing critical illness due to COVID-19, thereby increasing mortality. CONCLUSION: Our study suggests obesity in childhood, adolescence, and adulthood can be considered a profound risk factor for greater susceptibility and severity of COVID-19 and is associated with nutritional, lifestyle, cardiac, respiratory, renal, and immunological alterations, which may potentiate the complications of SARS-CoV-2 infection. Further suggesting to check on BMI during this pandemic situation.

Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma.

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.

Some Functional Properties of khambir, an Ethnic Fermented Cereal-Based Food of Western Himalayas.

Traditional leavened wheat-based flat bread khambir is a staple food for the high-altitude people of the Western Himalayan region. The health promoting abilities of two types of khambir, yeast added khambir (YAK) and buttermilk added khambir (BAK), were evaluated. A group of microbes like yeast, mold, lactic acid bacteria (LAB), and Bifidobacterium sp. were abundant in both khambir but in varied proportions. Both are enriched with phenolics and flavonoids. The aqueous extracts of both breads strongly inhibited the growth of enteropathogens. Molecular docking experiments showed that phenolic acid, particularly p-coumaric acid, blocked the active sites of ß-glucosidase and acetylcholine esterase (AChE), thereby inhibiting their activities. YAK and BAK showed antiradical and antioxidant activity ranging from 46 to 67% evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing/antioxidant power (FRAP) assays. The aqueous extract of both khambir samples protected the arsenic toxicity when examined under an in situ rat intestinal loop model study. The arsenic induced elevated levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione, lipid peroxidation (LPO) and DNA fragmentation, and transmembrane mitochondrial potential was alleviated by khambir extract. These results scientifically supported its age-old health benefit claims by the consumer at high altitude and there are enough potentialities to explore khambir as a medicinal food for human welfare.

MicroRNA-145 Impedes Thrombus Formation via Targeting Tissue Factor in Venous Thrombosis.

Venous thromboembolism (VTE), the third leading cardiovascular complication, requires more understanding at molecular levels. Here, we have identified miR-145 as a key molecule for regulating thrombus formation in venous thrombosis (VT) employing network based bioinformatics approach and in vivo experiments. Levels of miR-145 showed an inverse correlation with thrombus load determined by coagulation variables. MiRNA target prediction tools and in vitro study identified tissue factor (TF) as a target gene for miR-145. The restoration of miR-145 levels in thrombotic animals via in vivo miR-145 mimic delivery resulted in decreased TF level and activity, accompanied by reduced thrombogenesis. MiR-145 levels were also reduced in VT patients and correlated with increased TF levels in patients, thereby, confirming our preclinical findings. Our study identifies a previously undescribed role of miRNA in VT by regulating TF expression. Therefore, restoration of miR-145 levels may serve as a promising therapeutic strategy for management of VT.

A Review of Patents on Therapeutic Potential and Delivery of Hydroge n Sulfide.

BACKGROUND: Hydrogen sulfide (H2S) is a colorless gas with a characteristic smell of rotten eggs. Once only thought of as a toxic gas, evidence now shows that H2S plays major roles in pathological and physiological activities. These roles are being utilized to treat diseases and disorders ranging from hypertension, inflammation, edema, cardiovascular issues, chronic pain, cancer, and many more. Challenges facing the use of H2S currently involve achieving the optimum therapeutic concentrations, synthesizing chemically and physiologically stable donors, and developing clinically appropriate delivery systems. METHODS: We did an extensive literature search on therapeutic potentials and related issues of H2S which were presented in a systematic flow pattern in introduction. Patents accepted/filed on various aspects of hydrogen sulfide were searched using the United States Patent and Trademark Office database at http://patft.uspto.gov/ and google patents at https://patents.google.com/. The important search terms combined with H2S were therapeutic effect, pharmacological action, biochemistry, measurement, and delivery. We also incorporated our own experiences and publications while discussing the delivery approaches and associated challenges. RESULTS: In the process, researchers have discovered novel techniques in preparing the noxious gas by discovering and synthesizing H2S donors and developing controlled and predictable delivery systems. Donors utilized thus far include derivatives of anti-inflammatory drugs like H2S -aspirin, Allium sativum extracts, inorganic salts, phosphorodithioate derivatives, and thioaminoacid derivatives. Use of controlled delivery systems for H2S is critical to maintain its physiological stability, optimum therapeutic window, increase patient compliance, and make it easier to manufacture and administer. Numerous patents overcoming the challenges of using H2S therapeutically with various donors and delivery mechanisms have been reviewed. CONCLUSION: The scientific knowledge gained from the last decade researches has moved H2S from a foul smelling pungent gas to the status of a gasotransmitter with many potential therapeutic applications. However, developing a suitable donor and a delivery system using that donor for providing precise and sustained release of H2S for an extended period, is critically needed for any further development towards its translation into clinical practices.

In vitro-controlled release delivery system for hydrogen sulfide donor.

Hydrogen sulfide (H2S) is having many potential pharmacological and physiological actions which reported that therapeutically useful concentration is low (100-160 µM) and a higher concentration could be toxic. Most of its donors produce it on coming into contact with water. All of these problems could be solved by a controlled-release delivery system which does not utilize water in any of its development steps. Therefore, 12 sustained release formulations were prepared by dissolving sodium hydrogen sulfide (NaHS)-a model H2S donor-in polymer solutions, prepared by dissolving polymers (consisted of either polylactide (PLA) or polylactide co-glycolide (PLGA), containing free carboxylic acid or capped allyl ester end group) in a mixture of benzyl benzoate (BB) and benzyl alcohol (BA). The formulation was injected in simulated tear fluid (STF) from which samples were withdrawn at specified times and assayed for NaHS content. We found decrease in burst and overall release with increase in polymer concentration from 10 to 20% w/v. The formulations containing free end group showed significant (p < 0.05) reduction of burst release (11% vs 21%). However, the overall release or the average amount released per hour was found to be significantly (p < 0.05) increased for formulations containing polymers with free end group than those with capped end group. A sustained level of H2S was found to be maintained for 72 h which should be further increased to a month to make it a viable H2S donor delivery system in addition to investigating toxicity profile specifically for the purpose of subconjunctival ocular delivery.

Investigation of effects of terpene skin penetration enhancers on stability and biological activity of lysozyme.

The transport of proteins through skin can be facilitated potentially by using terpenes as chemical enhancers. However, we do not know about the effects of these enhancers on the stability and biological activity of proteins which is crucial for the development of safe and efficient formulations. Therefore, this project investigated the effects of terpene-based skin penetration enhancers which are reported as nontoxic to the skin (e.g., limonene, p-cymene, geraniol, farnesol, eugenol, menthol, terpineol, carveol, carvone, fenchone, and verbenone), on the conformational stability and biological activity of a model protein lysozyme. Terpene (5% v/v) was added to lysozyme solution and kept for 24 h (the time normally a transdermal patch remains) for investigating conformational stability profiles and biological activity. Fourier transform infrared spectrophotometer was used to analyze different secondary structures, e.g., α-helix, ß-sheet, ß-turn, and random coil. Conformational changes were also monitored by differential scanning calorimeter by determining midpoint transition temperature (Tm) and calorimetric enthalpy (ΔH). Biological activity of lysozyme was determined by measuring decrease in A (450) when it was added to a suspension of Micrococcus lysodeikticus. The results of this study indicate that terpenes 9, 10, and 11 (carvone, L-fenchone, and L-verbenone) decreased conformational stability and biological activity of lysozyme significantly (p < 0.05) less than other terpenes used in this study. It is concluded that smaller terpenes containing ketones with low lipophilicity (log K (ow) ∼2.00) would be optimal for preserving conformational stability and biological activity of lysozyme in a transdermal formulation containing terpene as permeation enhancer.

Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges.

Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery problem that is caused by its unfavorable pharmacokinetic and physical properties. Paclitaxel is currently formulated in a mixture of Cremophor EL and ethanol, which is diluted 5-20 times with normal saline or 5% dextrose prior to administration via slow infusion to avoid precipitation in plasma. Many adverse reactions to the PTX formulation have been reported because of the presence of Cremophor EL, including hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets. Significant research efforts have been conducted to develop an alternative formulation approach to increase the aqueous solubility of PTX without using Cremophor, thereby decreasing its toxicity. This article reviews the various investigated formulation approaches including pastes; liposomes; conjugates with antibodies, peptides, and fatty acids; nanospheres and microspheres; cyclodextrin complexes; emulsions; mucoadhesive gel; prodrugs; and nanoparticulate systems. The pros and cons of each approach are also discussed. Finally, this review concludes with a discussion of nanoparticulate delivery, which is the most promising PTX delivery system of the future because it incorporates the benefits of other approaches such as conjugation, complexation, and prodrugs.

Smart polymers for controlled delivery of proteins and peptides: a review of patents.

Protein and peptide-based therapeutic agents have unique physiochemical properties such as high molecular weight, short half life, requirement of a sustained plasma level for the desired therapeutic effect, liable to physical and chemical instability by gastric enzymes and harsh acidic environment as well as first pass metabolism, which makes their delivery a challenge. The delivery of proteins and peptides using various routes of administration like oral, nasal, rectal, pulmonary, buccal, vaginal and transdermal route is found to exhibit limitations, poor permeability and degradation being major limitations. Use of parenteral route is found to overcome these problems but patient compliance is poor due to the need for frequent administration. Use of control delivery for these drugs using smart polymers seems promising as they overcome the limitations posed by other routes of delivery. Smart polymers increase patient compliance, maintain stability of the drug, and maintain drug level in therapeutic window and are easy to manufacture. Different types of smart polymer-based delivery systems, such as sensitive to temperature, phase, pH, electric charge, light, and biochemicals, and their application in controlling the release of the incorporated drug to obtain a sustained plasma level has been discussed. Smart polymers, however, face challenges with regard to high burst release, unpredictable behavior in later part of biphasic release profile, overall drug release kinetics, conformational stability during processing, and preserving biological activity after getting released. Several patents overcoming these inherent problems associated with smart polymers have been reviewed. At the end, the future direction and potential of smart polymer-based delivery system for drug delivery has been presented in brief.