This document describes research into developing a smart pH-responsive hydrogel for controlled delivery of the anticancer drug capecitabine. The researchers synthesized a hydrogel network using hydroxypropyl-β-cyclodextrin, agarose, and methacrylic acid via free radical polymerization. The capecitabine-loaded hydrogels were characterized and found to efficiently load and release the drug in a pH-responsive manner. Acute oral toxicity tests in animals found the hydrogel to have a good safety profile with no signs of toxicity. The findings indicate the developed hydrogel shows potential as a controlled delivery system for anticancer agents.
This document describes a study that prepared and evaluated carvedilol-loaded solid lipid nanoparticles (SLNs) for oral drug delivery. Compritol 888 ATO (COMP) was selected as the lipid material based on its solubility parameter relative to carvedilol. Design of experiments was used to optimize the concentrations of COMP and Poloxamer 188 surfactant in blank SLNs and carvedilol-loaded SLNs. The optimized formulation containing 7.5% COMP, 5.0% Poloxamer 188, and 1.11% carvedilol had a particle size of 161 nm and 94.8% drug entrapment efficiency. In vitro studies showed the SLNs protected carvedilol from acidic environments and
This document discusses the importance and challenges of measuring 25-hydroxyvitamin D (25OHD) levels to assess vitamin D status. It outlines that 25OHD measurement by immunoassay is commonly used in clinical settings due to convenience, but current assays have limitations, particularly in detecting vitamin D metabolites from vitamin D2 supplements. Reference methods like liquid chromatography-mass spectrometry are more accurate but too complex for routine use. The document calls for improved assays that can reliably detect both D2 and D3 metabolites, as well as continued quality assurance efforts, to enhance the clinical assessment of vitamin D status.
This document describes a method for simultaneously determining the concentrations of levodopa, carbidopa, and their metabolites in human plasma and urine samples using liquid chromatography with electrochemical detection (LC-EC). The method involves online sample clean-up and enrichment using a switching valve and pre-column. Several interfering endogenous compounds are eliminated, allowing for the sensitive and selective quantification of the target analytes. Recovery studies on human plasma samples showed good accuracy and precision. The method is simple, inexpensive, and suitable for routine analysis and kinetic studies of these important drugs and their metabolites.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Lipid profiling and corresponding biodiesel quality of mortierella isabellina...zhenhua82
Four lipid extraction methods (Bligh & Dyer, hexane & isopropanol, dichloromethane & methanol, and hexane) were evaluated to extract lipid from freeze- and oven-dried fungus Mortierella isabellina ATCC42613. The highest lipid yield (41.8%) was obtained from Bligh & Dyer extraction on the oven-dried fungal biomass with a methanol:chloroform:water ratio of 2:1:0.8. Other lipid extraction methods on both freeze- and oven-dried samples had lipid yields ranging from 20.7% to 35.9%. Non-polar lipid was the main lipid class (more than 90% of total lipid) in M. isabellina. Regarding fatty acid profile, there was no significant difference on fatty acid concentration between different drying and extraction methods. Estimation of biodiesel fuel properties using correlative models further demonstrated that the fungal biodiesel is a good alternative to fossil diesel.
This study investigated the effects of the antioxidant baicalein on the pharmacokinetics of the calcium channel blocker nimodipine in rats. Baicalein inhibited the activity of CYP3A4, a key enzyme involved in nimodipine metabolism, in a concentration-dependent manner. It also enhanced the accumulation of a P-glycoprotein substrate, suggesting it inhibits this efflux transporter. When administered with oral nimodipine, baicalein significantly increased nimodipine bioavailability by inhibiting its intestinal and hepatic metabolism and intestinal efflux, without affecting intravenous nimodipine pharmacokinetics. This drug-drug interaction between baicalein and nimodipine could impact their combined
This document summarizes a study that analyzed the phenolic profile and antioxidant activity of extracts from different parts (roots, leaves, fruits) of the Citrullus colocynthis plant. Reverse phase high performance liquid chromatography was used to simultaneously quantify phenolic acids and flavonoids in ethanol and hexane extracts. The major phenolic compounds identified were ferulic acid, vanillic acid, p-coumeric acid, gallic acid, p-hydroxy benzoic acid, chlorogenic acid, quercetin, myricetin and catechin. Total phenolic and flavonoid contents were highest in ethanol extracts of the leaves. Ethanol extracts of the leaves also exhibited the highest antioxidant and DPPH radical sc
This study synthesized eight new fluorinated quinazolinone-sulphonamide hybrid compounds and evaluated their anticancer activity. One compound showed significant anticancer activity with low toxicity compared to the reference drug mitoxantrone. Biological assays also demonstrated moderate anticancer activity for the compounds compared to reference drugs. The compound with the best activity profile was identified for further evaluation as an anticancer agent.
This document describes a study that prepared and evaluated carvedilol-loaded solid lipid nanoparticles (SLNs) for oral drug delivery. Compritol 888 ATO (COMP) was selected as the lipid material based on its solubility parameter relative to carvedilol. Design of experiments was used to optimize the concentrations of COMP and Poloxamer 188 surfactant in blank SLNs and carvedilol-loaded SLNs. The optimized formulation containing 7.5% COMP, 5.0% Poloxamer 188, and 1.11% carvedilol had a particle size of 161 nm and 94.8% drug entrapment efficiency. In vitro studies showed the SLNs protected carvedilol from acidic environments and
This document discusses the importance and challenges of measuring 25-hydroxyvitamin D (25OHD) levels to assess vitamin D status. It outlines that 25OHD measurement by immunoassay is commonly used in clinical settings due to convenience, but current assays have limitations, particularly in detecting vitamin D metabolites from vitamin D2 supplements. Reference methods like liquid chromatography-mass spectrometry are more accurate but too complex for routine use. The document calls for improved assays that can reliably detect both D2 and D3 metabolites, as well as continued quality assurance efforts, to enhance the clinical assessment of vitamin D status.
This document describes a method for simultaneously determining the concentrations of levodopa, carbidopa, and their metabolites in human plasma and urine samples using liquid chromatography with electrochemical detection (LC-EC). The method involves online sample clean-up and enrichment using a switching valve and pre-column. Several interfering endogenous compounds are eliminated, allowing for the sensitive and selective quantification of the target analytes. Recovery studies on human plasma samples showed good accuracy and precision. The method is simple, inexpensive, and suitable for routine analysis and kinetic studies of these important drugs and their metabolites.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Lipid profiling and corresponding biodiesel quality of mortierella isabellina...zhenhua82
Four lipid extraction methods (Bligh & Dyer, hexane & isopropanol, dichloromethane & methanol, and hexane) were evaluated to extract lipid from freeze- and oven-dried fungus Mortierella isabellina ATCC42613. The highest lipid yield (41.8%) was obtained from Bligh & Dyer extraction on the oven-dried fungal biomass with a methanol:chloroform:water ratio of 2:1:0.8. Other lipid extraction methods on both freeze- and oven-dried samples had lipid yields ranging from 20.7% to 35.9%. Non-polar lipid was the main lipid class (more than 90% of total lipid) in M. isabellina. Regarding fatty acid profile, there was no significant difference on fatty acid concentration between different drying and extraction methods. Estimation of biodiesel fuel properties using correlative models further demonstrated that the fungal biodiesel is a good alternative to fossil diesel.
This study investigated the effects of the antioxidant baicalein on the pharmacokinetics of the calcium channel blocker nimodipine in rats. Baicalein inhibited the activity of CYP3A4, a key enzyme involved in nimodipine metabolism, in a concentration-dependent manner. It also enhanced the accumulation of a P-glycoprotein substrate, suggesting it inhibits this efflux transporter. When administered with oral nimodipine, baicalein significantly increased nimodipine bioavailability by inhibiting its intestinal and hepatic metabolism and intestinal efflux, without affecting intravenous nimodipine pharmacokinetics. This drug-drug interaction between baicalein and nimodipine could impact their combined
This document summarizes a study that analyzed the phenolic profile and antioxidant activity of extracts from different parts (roots, leaves, fruits) of the Citrullus colocynthis plant. Reverse phase high performance liquid chromatography was used to simultaneously quantify phenolic acids and flavonoids in ethanol and hexane extracts. The major phenolic compounds identified were ferulic acid, vanillic acid, p-coumeric acid, gallic acid, p-hydroxy benzoic acid, chlorogenic acid, quercetin, myricetin and catechin. Total phenolic and flavonoid contents were highest in ethanol extracts of the leaves. Ethanol extracts of the leaves also exhibited the highest antioxidant and DPPH radical sc
This study synthesized eight new fluorinated quinazolinone-sulphonamide hybrid compounds and evaluated their anticancer activity. One compound showed significant anticancer activity with low toxicity compared to the reference drug mitoxantrone. Biological assays also demonstrated moderate anticancer activity for the compounds compared to reference drugs. The compound with the best activity profile was identified for further evaluation as an anticancer agent.
The document discusses preformulation studies that are conducted prior to developing a dosage form for a new drug. The objectives are to determine the drug's physicochemical properties, solubility, stability, and compatibility with excipients. Key tests include solubility studies under various conditions, stability studies of solid and liquid states under stress conditions like heat, light and pH, and chemical characterization of properties like oxidation and hydrolysis. The outcomes aim to develop a formulation that safely delivers the drug to the site of action as intended.
DM Garby_Unbound 25-Hydroxyvitamin D ExBiology 2015David Garby
1) The study evaluated methods for measuring unbound 25-hydroxyvitamin D (25HD) in plasma, including a HPLC/MS/MS method and sample treatment methods like centrifugal filtration.
2) None of the sample treatment methods were able to extract detectable quantities of unbound 25HD from plasma. Experiments on 25HD partitioning suggested it does not distribute homogeneously in aqueous solutions without a carrier at low concentrations.
3) The results support that 25HD must rapidly bind to a carrier like vitamin D binding protein in physiological systems, as there appears no need for significant unbound 25HD given kidney uptake mechanisms.
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
A Review- Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspen...Dhaval shah
This document reviews pharmaceutical and pharmacokinetic aspects of nanocrystalline suspensions. It discusses how nanocrystals have emerged as a potential formulation strategy to enhance dissolution rate and solubility for poorly soluble drugs. The review provides an in-depth look at processing methods, quantitative assessments of solubility and dissolution rates, and their correlation to pharmacokinetic data. It also discusses the lack of understanding around changes in thermodynamic and kinetic properties like solubility and dissolution rate upon nanosizing, and reviews literature on quantitatively studying the effect of particle size and surface area on initial dissolution rate enhancement.
Segment and Sequential Stratergies for Solution Phase Peptide SynthesisRUTUJAPAWAR32
This document discusses strategies for solution phase peptide synthesis, including linear and convergent approaches. Linear strategies involve stepwise coupling of amino acids from the C to N terminus, while convergent strategies condense pre-made peptide segments. Both approaches can be used, considering factors like the target peptide complexity, protection schemes, and economics. Convergent synthesis has advantages like dividing labor and being closer to starting materials, but linear strategies may be better for smaller peptides due to issues with segment coupling like low concentration and solubility. Common techniques discussed include manual synthesis using syringes or the tea bag method, and automated synthesis systems.
2.Sagar Goda Biological classification system (BCS); its significance on diss...Sagar Goda
This presentation provides a detailed information about Biopharmaceutics classification system(BCS) and its significance on dissolution study as well as its application in dosage form development.
Applications of Poly (lactic acid) in Tissue Engineering and Delivery SystemsAna Rita Ramos
Applications of Poly (lactic acid) in Tissue Engineering and Delivery Systems
Poly (lactic acid) is a thermoplastic derived from renewable resources and is at present, one of the most promising biodegradable and nontoxic biopolymers. In addition to its versatility and consequent large-scale production, PLA can be processed with a large number of techniques.
Due to its excellent mechanical properties and biocompatibility, this polymer is becoming largely applied in the biomedical field such as in tissue engineering for scaffolds and in delivery systems in the form of micro and nanoparticles. Furthermore, because it’s relatively cheap and an eco-friend, it has been considered as one of the solutions to lessen the dependence on petroleum-based plastics and solid waste problems.
In order to maximize the knowledge and development of this polymer, it is necessary to understand the material synthesis, proprieties, manufacturing processes, main applications, commercialization and its market state, which will be presented in this review.
1. A new Schiff base ligand was synthesized by condensing amoxicillin and 4-(dimethylamino)benzaldehyde. Mixed ligand complexes were synthesized from reactions of the Schiff base ligand with metal salts such as Fe(II), Co(II), Ni(II), Cu(II), and Zn(II) along with nicotinamide.
2. The complexes were characterized using various techniques such as elemental analysis, FT-IR, UV-Vis, magnetic susceptibility measurements, and evaluating their conductivities. The data indicated the complexes had octahedral geometries and were non-electrolytes.
3. The antimicrobial activities of the complexes were evaluated against various bacteria and found to have
Experimental and theoretical solubility advantage screening of bi-component s...Maciej Przybyłek
This document describes an experimental and theoretical study to screen potential solubilizers for curcumin. In the experimental phase, the solubility of curcumin was measured in binary mixtures with 24 excipients. The highest solubility enhancement was found with pyrogallol, caffeine, theophylline, and nicotinamide. A theoretical QSPR model was then developed using molecular descriptors to predict solubility. This model was applied to screen over 230,000 compounds and predict solubility for curcumin analogs and naturally occurring turmerones to identify new excipients.
This presentation discusses impurities in residual solvents and provides guidelines for their classification and acceptable limits. It summarizes the ICH Q3C guideline, which classifies residual solvents into four categories based on toxicity. Class 1 solvents are to be avoided, while Class 2 solvents should be limited and Class 3 solvents have low toxic potential but levels should not exceed recommendations. Analytical methods for determining residual solvent levels are also covered. The guideline aims to recommend safe amounts of residual solvents in pharmaceuticals to protect patient safety.
This document discusses the synthesis of poly(lactic acid) (PLA) biomaterials. There are two main synthetic methods - direct polycondensation and ring-opening polymerization of lactide monomers. Direct polycondensation includes solution and melt polycondensation, but yields PLA with low molecular weight. Ring-opening polymerization using metal catalysts is more common and can produce high molecular weight PLA, but the metal catalysts require removal. Recent research focuses on developing non-toxic catalysts and new polymerization conditions.
This document summarizes research on immobilizing the enzyme laccase in an alginate-gelatin mixed gel and using it to decolorize synthetic dyes like crystal violet. Key findings include:
1) Spherical beads were formed using various alginate concentrations, with 5% alginate beads having the highest mechanical stability.
2) Both free and immobilized laccase worked best at pH 8-9 and 50°C for crystal violet decolorization.
3) The immobilized laccase retained 85% activity after 5 reuse cycles and effectively decolorized various dyes like amido black and malachite green.
In vitro and in vivo evaluation of positively charged liposaccharide derivati...Adel Abdelrahim, PhD
This document describes a study evaluating positively charged liposaccharide derivatives as oral absorption enhancers for delivering anionic drugs. Positively charged liposaccharide derivatives were synthesized and combined with the anionic model drug piperacillin through ion pairing. The conjugates were evaluated in vitro and in vivo to assess antimicrobial activity, plasma stability, permeability across Caco-2 cell monolayers, and oral absorption. Results showed that ion pairing the liposaccharide derivatives with piperacillin improved permeability in Caco-2 cells without altering antimicrobial activity, indicating potential as oral absorption enhancers.
Pharmacosomes are lipid-based vesicular drug delivery systems where drugs are covalently bound to lipids. They can incorporate both hydrophilic and lipophilic drugs and deliver them in a targeted manner. Pharmacosomes have advantages like high drug loading, direct delivery to the site of action, and reduced toxicity. They are formulated using techniques like solvent evaporation, ether injection, and lyophilization. Pharmacosomes show potential for improving drug absorption, transport, and therapeutic effects. Evaluation methods include assessing solubility, drug content, surface morphology, thermal behavior, and in vitro drug release.
APPLICATIONS OF PLA - POLY (LACTIC ACID) IN TISSUE ENGINEERING AND DELIVERY S...Ana Rita Ramos
Poly (lactic acid) is a thermoplastic derived from renewable resources and is at present, one of the most promising biodegradable and nontoxic biopolymers. In addition to its versatility and consequent large-scale production, PLA can be processed with a large number of techniques.
Due to its excellent mechanical properties and biocompatibility, this polymer is becoming largely applied in the biomedical field such as in tissue engineering for scaffolds and in delivery systems in the form of micro and nanoparticles. Furthermore, because it’s relatively cheap and an eco-friend, it has been considered as one of the solutions to lessen the dependence on petroleum-based plastics and solid waste problems.
In order to maximize the knowledge and development of this polymer, it is necessary to understand the material synthesis, proprieties, manufacturing processes, main applications, commercialization and its market state, which will be presented in this review.
1. Introduction
2. Poly (lactic acid)
2.1. Precursors
2.2. Synthesis
2.3. Proprieties
2.4. Processing
2.5. Biomedical Applications
2.6. Other Applications
3. Economic Potential of PLA
4. Conclusions
The document discusses the Biopharmaceutics Classification System (BCS), which classifies drugs based on their solubility and permeability properties to determine if in vivo bioequivalence studies are necessary. The BCS considers a drug's dissolution, solubility, and intestinal permeability. Class I drugs that are highly soluble and permeable may qualify for a biowaiver if they demonstrate rapid dissolution. Data on solubility, permeability, and dissolution is required to support a biowaiver request for a Class I drug.
This document discusses in vitro-in vivo correlations (IVIVC), which relate the dissolution of a drug from its dosage form in vitro to its bioavailability or absorption rate in vivo. It defines IVIVC and explains its significance in reducing bioequivalence studies. The key parameters that can be correlated are discussed, including dissolution rate versus absorption rate, percent dissolved versus percent absorbed, and percent dissolved versus pharmacokinetic parameters. The different levels of IVIVC - Level A, B, and C - are outlined. A case study example of developing a Level A IVIVC for leflunomide microspheres is provided. In conclusion, the current focus is on validating Level A correlations and further research is needed
This document discusses key drug-like properties that are important for drug discovery. It covers properties such as solubility, permeability, metabolic stability and how they impact pharmacokinetics and bioavailability. Modifying a molecule's structure can optimize these properties. For example, adding ionizable groups can increase solubility while reducing logP or molecular weight. Understanding how changes impact multiple properties is crucial for medicinal chemists to design drug candidates with balanced absorption and response profiles.
This document provides a synopsis for a Master's thesis project titled "Formulation and Evaluation of Fast Dissolving Films of Lisinopril". The project aims to develop fast dissolving films of the hypertension drug Lisinopril to improve patient compliance. Literature on fast dissolving drug delivery systems and films has been reviewed. The planned work involves preparing Lisinopril films using natural and synthetic polymers through various techniques and evaluating the films for properties like drug content, dissolution, and pharmacodynamics. If successful, the fast dissolving Lisinopril films could provide quick action and ease of administration benefits for hypertension patients.
A Review- Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspen...Dhaval shah
This document reviews pharmaceutical and pharmacokinetic aspects of nanocrystalline suspensions. It discusses how nanocrystals have emerged as a potential formulation strategy to enhance dissolution rate and solubility for poorly soluble drugs. The review provides an in-depth look at processing methods, quantitative assessments of solubility and dissolution rates, and their correlation to pharmacokinetic data. It also discusses the lack of understanding around changes in thermodynamic and kinetic properties like solubility and dissolution rate upon nanosizing, and reviews literature on quantitatively studying the effect of particle size and surface area on initial dissolution rate enhancement.
The document discusses preformulation studies that are conducted prior to developing a dosage form for a new drug. The objectives are to determine the drug's physicochemical properties, solubility, stability, and compatibility with excipients. Key tests include solubility studies under various conditions, stability studies of solid and liquid states under stress conditions like heat, light and pH, and chemical characterization of properties like oxidation and hydrolysis. The outcomes aim to develop a formulation that safely delivers the drug to the site of action as intended.
DM Garby_Unbound 25-Hydroxyvitamin D ExBiology 2015David Garby
1) The study evaluated methods for measuring unbound 25-hydroxyvitamin D (25HD) in plasma, including a HPLC/MS/MS method and sample treatment methods like centrifugal filtration.
2) None of the sample treatment methods were able to extract detectable quantities of unbound 25HD from plasma. Experiments on 25HD partitioning suggested it does not distribute homogeneously in aqueous solutions without a carrier at low concentrations.
3) The results support that 25HD must rapidly bind to a carrier like vitamin D binding protein in physiological systems, as there appears no need for significant unbound 25HD given kidney uptake mechanisms.
The document discusses the pH partition theory of drug absorption from the gastrointestinal tract. The theory states that a drug's absorption is governed by its dissociation constant (pKa), the lipid solubility of its unionized form, and the pH of the absorption site. According to the theory, only the unionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its unionized form depends on the drug's pKa and the pH of the solution based on the Henderson-Hasselbalch equation. While the pH partition theory explains many observations, it has limitations such as not accounting for the presence of an unstirred water layer and virtual membrane pH at the absorption
A Review- Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspen...Dhaval shah
This document reviews pharmaceutical and pharmacokinetic aspects of nanocrystalline suspensions. It discusses how nanocrystals have emerged as a potential formulation strategy to enhance dissolution rate and solubility for poorly soluble drugs. The review provides an in-depth look at processing methods, quantitative assessments of solubility and dissolution rates, and their correlation to pharmacokinetic data. It also discusses the lack of understanding around changes in thermodynamic and kinetic properties like solubility and dissolution rate upon nanosizing, and reviews literature on quantitatively studying the effect of particle size and surface area on initial dissolution rate enhancement.
Segment and Sequential Stratergies for Solution Phase Peptide SynthesisRUTUJAPAWAR32
This document discusses strategies for solution phase peptide synthesis, including linear and convergent approaches. Linear strategies involve stepwise coupling of amino acids from the C to N terminus, while convergent strategies condense pre-made peptide segments. Both approaches can be used, considering factors like the target peptide complexity, protection schemes, and economics. Convergent synthesis has advantages like dividing labor and being closer to starting materials, but linear strategies may be better for smaller peptides due to issues with segment coupling like low concentration and solubility. Common techniques discussed include manual synthesis using syringes or the tea bag method, and automated synthesis systems.
2.Sagar Goda Biological classification system (BCS); its significance on diss...Sagar Goda
This presentation provides a detailed information about Biopharmaceutics classification system(BCS) and its significance on dissolution study as well as its application in dosage form development.
Applications of Poly (lactic acid) in Tissue Engineering and Delivery SystemsAna Rita Ramos
Applications of Poly (lactic acid) in Tissue Engineering and Delivery Systems
Poly (lactic acid) is a thermoplastic derived from renewable resources and is at present, one of the most promising biodegradable and nontoxic biopolymers. In addition to its versatility and consequent large-scale production, PLA can be processed with a large number of techniques.
Due to its excellent mechanical properties and biocompatibility, this polymer is becoming largely applied in the biomedical field such as in tissue engineering for scaffolds and in delivery systems in the form of micro and nanoparticles. Furthermore, because it’s relatively cheap and an eco-friend, it has been considered as one of the solutions to lessen the dependence on petroleum-based plastics and solid waste problems.
In order to maximize the knowledge and development of this polymer, it is necessary to understand the material synthesis, proprieties, manufacturing processes, main applications, commercialization and its market state, which will be presented in this review.
1. A new Schiff base ligand was synthesized by condensing amoxicillin and 4-(dimethylamino)benzaldehyde. Mixed ligand complexes were synthesized from reactions of the Schiff base ligand with metal salts such as Fe(II), Co(II), Ni(II), Cu(II), and Zn(II) along with nicotinamide.
2. The complexes were characterized using various techniques such as elemental analysis, FT-IR, UV-Vis, magnetic susceptibility measurements, and evaluating their conductivities. The data indicated the complexes had octahedral geometries and were non-electrolytes.
3. The antimicrobial activities of the complexes were evaluated against various bacteria and found to have
Experimental and theoretical solubility advantage screening of bi-component s...Maciej Przybyłek
This document describes an experimental and theoretical study to screen potential solubilizers for curcumin. In the experimental phase, the solubility of curcumin was measured in binary mixtures with 24 excipients. The highest solubility enhancement was found with pyrogallol, caffeine, theophylline, and nicotinamide. A theoretical QSPR model was then developed using molecular descriptors to predict solubility. This model was applied to screen over 230,000 compounds and predict solubility for curcumin analogs and naturally occurring turmerones to identify new excipients.
This presentation discusses impurities in residual solvents and provides guidelines for their classification and acceptable limits. It summarizes the ICH Q3C guideline, which classifies residual solvents into four categories based on toxicity. Class 1 solvents are to be avoided, while Class 2 solvents should be limited and Class 3 solvents have low toxic potential but levels should not exceed recommendations. Analytical methods for determining residual solvent levels are also covered. The guideline aims to recommend safe amounts of residual solvents in pharmaceuticals to protect patient safety.
This document discusses the synthesis of poly(lactic acid) (PLA) biomaterials. There are two main synthetic methods - direct polycondensation and ring-opening polymerization of lactide monomers. Direct polycondensation includes solution and melt polycondensation, but yields PLA with low molecular weight. Ring-opening polymerization using metal catalysts is more common and can produce high molecular weight PLA, but the metal catalysts require removal. Recent research focuses on developing non-toxic catalysts and new polymerization conditions.
This document summarizes research on immobilizing the enzyme laccase in an alginate-gelatin mixed gel and using it to decolorize synthetic dyes like crystal violet. Key findings include:
1) Spherical beads were formed using various alginate concentrations, with 5% alginate beads having the highest mechanical stability.
2) Both free and immobilized laccase worked best at pH 8-9 and 50°C for crystal violet decolorization.
3) The immobilized laccase retained 85% activity after 5 reuse cycles and effectively decolorized various dyes like amido black and malachite green.
In vitro and in vivo evaluation of positively charged liposaccharide derivati...Adel Abdelrahim, PhD
This document describes a study evaluating positively charged liposaccharide derivatives as oral absorption enhancers for delivering anionic drugs. Positively charged liposaccharide derivatives were synthesized and combined with the anionic model drug piperacillin through ion pairing. The conjugates were evaluated in vitro and in vivo to assess antimicrobial activity, plasma stability, permeability across Caco-2 cell monolayers, and oral absorption. Results showed that ion pairing the liposaccharide derivatives with piperacillin improved permeability in Caco-2 cells without altering antimicrobial activity, indicating potential as oral absorption enhancers.
Pharmacosomes are lipid-based vesicular drug delivery systems where drugs are covalently bound to lipids. They can incorporate both hydrophilic and lipophilic drugs and deliver them in a targeted manner. Pharmacosomes have advantages like high drug loading, direct delivery to the site of action, and reduced toxicity. They are formulated using techniques like solvent evaporation, ether injection, and lyophilization. Pharmacosomes show potential for improving drug absorption, transport, and therapeutic effects. Evaluation methods include assessing solubility, drug content, surface morphology, thermal behavior, and in vitro drug release.
APPLICATIONS OF PLA - POLY (LACTIC ACID) IN TISSUE ENGINEERING AND DELIVERY S...Ana Rita Ramos
Poly (lactic acid) is a thermoplastic derived from renewable resources and is at present, one of the most promising biodegradable and nontoxic biopolymers. In addition to its versatility and consequent large-scale production, PLA can be processed with a large number of techniques.
Due to its excellent mechanical properties and biocompatibility, this polymer is becoming largely applied in the biomedical field such as in tissue engineering for scaffolds and in delivery systems in the form of micro and nanoparticles. Furthermore, because it’s relatively cheap and an eco-friend, it has been considered as one of the solutions to lessen the dependence on petroleum-based plastics and solid waste problems.
In order to maximize the knowledge and development of this polymer, it is necessary to understand the material synthesis, proprieties, manufacturing processes, main applications, commercialization and its market state, which will be presented in this review.
1. Introduction
2. Poly (lactic acid)
2.1. Precursors
2.2. Synthesis
2.3. Proprieties
2.4. Processing
2.5. Biomedical Applications
2.6. Other Applications
3. Economic Potential of PLA
4. Conclusions
The document discusses the Biopharmaceutics Classification System (BCS), which classifies drugs based on their solubility and permeability properties to determine if in vivo bioequivalence studies are necessary. The BCS considers a drug's dissolution, solubility, and intestinal permeability. Class I drugs that are highly soluble and permeable may qualify for a biowaiver if they demonstrate rapid dissolution. Data on solubility, permeability, and dissolution is required to support a biowaiver request for a Class I drug.
This document discusses in vitro-in vivo correlations (IVIVC), which relate the dissolution of a drug from its dosage form in vitro to its bioavailability or absorption rate in vivo. It defines IVIVC and explains its significance in reducing bioequivalence studies. The key parameters that can be correlated are discussed, including dissolution rate versus absorption rate, percent dissolved versus percent absorbed, and percent dissolved versus pharmacokinetic parameters. The different levels of IVIVC - Level A, B, and C - are outlined. A case study example of developing a Level A IVIVC for leflunomide microspheres is provided. In conclusion, the current focus is on validating Level A correlations and further research is needed
This document discusses key drug-like properties that are important for drug discovery. It covers properties such as solubility, permeability, metabolic stability and how they impact pharmacokinetics and bioavailability. Modifying a molecule's structure can optimize these properties. For example, adding ionizable groups can increase solubility while reducing logP or molecular weight. Understanding how changes impact multiple properties is crucial for medicinal chemists to design drug candidates with balanced absorption and response profiles.
This document provides a synopsis for a Master's thesis project titled "Formulation and Evaluation of Fast Dissolving Films of Lisinopril". The project aims to develop fast dissolving films of the hypertension drug Lisinopril to improve patient compliance. Literature on fast dissolving drug delivery systems and films has been reviewed. The planned work involves preparing Lisinopril films using natural and synthetic polymers through various techniques and evaluating the films for properties like drug content, dissolution, and pharmacodynamics. If successful, the fast dissolving Lisinopril films could provide quick action and ease of administration benefits for hypertension patients.
A Review- Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspen...Dhaval shah
This document reviews pharmaceutical and pharmacokinetic aspects of nanocrystalline suspensions. It discusses how nanocrystals have emerged as a potential formulation strategy to enhance dissolution rate and solubility for poorly soluble drugs. The review provides an in-depth look at processing methods, quantitative assessments of solubility and dissolution rates, and their correlation to pharmacokinetic data. It also discusses the lack of understanding around changes in thermodynamic and kinetic properties like solubility and dissolution rate upon nanosizing, and reviews literature on quantitatively studying the effect of particle size and surface area on initial dissolution rate enhancement.
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticlespeertechzpublication
In recent years, robustness and surface engineering of dosage form made improvement in
pharmacokinetics with decrease in dose of drug. Specifi city with adherence of ligands has now become
the reality as surface modifi cation can easily deceive phagocytic system. Lipid molecules ensures the
release of drug at lymphatic system, entrapment of polymeric nanoparticles in lipoidal core led to the
avoidance of disadvantage of low entrapment effi ciency if use of hydrophobic drug with hydrophobic
polymer becomes essential. Various studies have been published and the best formulations with optimal
In vitro and In vivo results are highlighted in this paper. In this review most advanced researches and
accepted patents were discussed so to act as a medium for getting everything regarding lipid polymer
hybrid particles under one umbrella.
In recent years, robustness and surface engineering of dosage form made improvement in pharmacokinetics with decrease in dose of drug. Specificity with adherence of ligands has now become the reality as surface modifi cation can easily deceive phagocytic system. Lipid molecules ensures the
release of drug at lymphatic system, entrapment of polymeric nanoparticles in lipoidal core led to the
avoidance of disadvantage of low entrapment effi ciency if use of hydrophobic drug with hydrophobic polymer becomes essential. Various studies have been published and the best formulations with optimal In vitro and In vivo results are highlighted in this paper. In this review most advanced researches and accepted patents were discussed so to act as a medium for getting everything regarding lipid polymer hybrid particles under one umbrella.
This document describes the synthesis and characterization of a series of anionic liposaccharide derivatives intended to act as absorption enhancers and improve oral bioavailability of drugs. The liposaccharides were designed with a lipophilic lipid side chain and a hydrophilic head containing glucose and glutamic acid. Isothermal titration calorimetry was used to determine the critical aggregation concentrations and thermodynamic profiles of the liposaccharides. Two liposaccharides formed nanoparticles below 100 nm and had critical aggregation concentrations below 0.325 mM, indicating favorable aggregation in aqueous solution driven by entropy.
Investigating the Effect of Molecular Weight of Polyvinylpyrrolidone and Hydr...Smruti Chaudhari, Ph.D.
This document summarizes a study investigating the effect of molecular weight of polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) polymers on maintaining supersaturation of the weakly acidic drug indomethacin. Non-formulated methods like solvent shift and solvent casting were used to screen the ability of different PVP and HPMC grades to generate and maintain indomethacin supersaturation. Solid dispersions of indomethacin with PVP and HPMC were also prepared using spray drying. Results showed that higher molecular weight PVP generated greater supersaturation while higher molecular weight HPMC generated lower supersaturation. Solid dispersions with high molecular weight P
The document describes the design, synthesis, and testing of novel lipopeptide conjugates as potential antimicrobial agents. A library of conjugates was designed based on a template consisting of a hydrophobic moiety, dipeptide, and spermidine. Conjugates containing linoleic acid exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships revealed that optimal activity required a hydrophobicity of 50-70% and a minimum charge of +2. Active conjugates were found to have different modes of action, damaging bacterial cell membranes and DNA. Two conjugates showed selective membrane disruption of pathogenic MRSA and were identified as promising leads for further optimization and development as antimicrobial agents.
International Journal of Clinical Pharmacology & Toxicology (IJCPT) ISSN:2167-910X is an Open Access journal, which aims to develop coherent means to modify drug therapy, with respect to the patient's genotype, and to ensure maximum efficiency with minimal contrary effects.
International Journal of Clinical Pharmacology & Toxicology (IJCPT) ISSN:2167-910X is an Open Access journal and a peer-reviewed journal. Clinical Pharmacology & Toxicology is the all-encompassing and becoming an increasingly important discipline for the identification of disease targets and drug designing with their toxicological effects and means to eradicate diseases.
Simultaneous and Rapid Separation and Determination of Vitamins B1, B2, PP, a...BRNSSPublicationHubI
This document describes the development and validation of an ion-pair reverse phase high performance liquid chromatography (RP-HPLC) method for the simultaneous determination of four B vitamins (thiamine hydrochloride, riboflavin, niacinamide, and pyridoxine hydrochloride) in multivitamin tablets. The method utilizes a mobile phase of water, methanol, and glacial acetic acid at a ratio of 72:27:1 to separate the vitamins on a C18 column. An ion pairing reagent, heptanesulfonic acid sodium salt, is added to the mobile phase. The developed method allows for the rapid simultaneous separation and determination of the four vitamins in a single run of under
This document summarizes a seminar presentation on pharmacosomes. Pharmacosomes are colloidal dispersions of drugs that are covalently bound to lipids. They can exist as vesicular, micellar, or hexagonal aggregates depending on the drug-lipid complex. The presentation discusses the advantages of pharmacosomes over other drug delivery systems like liposomes, as well as their importance, formulation, evaluation, applications, and limitations. The key components and preparation methods for pharmacosomes are also outlined.
This document summarizes a study that developed and optimized chitosan-alginate nanoparticles for oral delivery of the drug rosuvastatin calcium. The nanoparticles were prepared using ionotropic gelation and characterized for properties such as size, surface charge, drug loading efficiency, and in vitro drug release. The optimized nanoparticles had an average size of 349.3 nm, a zeta potential of +29.1 mV, high drug loading and entrapment efficiencies, and showed a fast initial release followed by more gradual release over 24 hours. The study demonstrated that the chitosan-alginate nanoparticle system improved rosuvastatin solubility and has potential to enhance its oral bioavailability and therapeutic efficacy.
Formulation and evaluation of Muco adhesive Buccal Tablets of Ramprildoddaapurupa
The buccal mucosa lines the inner cheek and Buccal formulations are placed in the mouth between upper gingiva(gums) and cheek to treat local and systemic conditions.
Drugs which undergoes Extensive first pass metabolism and drug degradation in acidic media, GI tract can be administered through buccal route.
The oral cavity has been used as a site for local and systemic drug delivery.
Method Development and Validation for Estimation of Oral Hypoglycaemic Drug D...ijtsrd
HPLC is a chromatographic technique employed in active compound chemistry and biochemistry to separate a mixture and substances with the goal of identifying, measuring, and purifying the different components of the mixture. Its a much better variety of column and traditional chromatography. The objective of the research work is to develop and validate a simple and accurate reverse phase chromatographic method to estimate amount of drug in dosage form. The developed method successfully can be applied to estimate the amount of Dapagliflozin in tablet dosage form. After oral administration of dapagliflozin, the maximum plasma concentration Concentration max under two hours. High performance liquid chromatographic system was alleviated according to the chromatographic settings. After attaining the steady base line, to verify the system suitability, a single 40 µg ml of standard solution proportional to 100 test concentration of dapagliflozin was injected into the HPLC system. The gradient mobile phase flow rate programming assisted in optimising the lengthy run duration and resolution of sample analysis, making the approach more cost effective and quick. Validation of the developed and optimized HPLC method was carried out according to ICH guidelines with respect to parameters such as linearity, specificity, precision and accuracy. Junaid Ahmed | Himanchal Sharma | Shiva Teotia "Method Development and Validation for Estimation of Oral Hypoglycaemic Drug Dapagliflozinina Tablet Dosage form by the Employment of Rp-HPLC" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46395.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46395/method-development-and-validation-for-estimation-of-oral-hypoglycaemic-drug-dapagliflozinina-tablet-dosage-form-by-the-employment-of-rphplc/junaid-ahmed
This document summarizes research on the development and evaluation of gastric floating tablets for controlled delivery of three antiplatelet drugs: prasugrel hydrochloride, clopidogrel bisulfate, and dipyridamole. The drugs were selected based on their similar physicochemical properties and pH-dependent solubility. Floating drug delivery systems were developed using hydrophilic HPMC K100M and hydrophobic Compritol 888 ATO polymers alone and in combination to study their effects on drug release. Tablets were prepared by effervescent techniques with melt granulation and direct compression. In vitro tests found that formulations with polymer blends provided more sustained drug release over 8 hours compared to formulations with single polymers.
This document describes a study that used response surface methodology to optimize the solvent system for recovering the biopolymer pullulan from fermentation broth. Four solvents (ethanol, acetone, isopropanol, tetrahydrofuran) were selected and their interactions studied using a 20-experiment D-optimal design. The results identified a solvent system with lower ethanol that recovered 1.44 times more pullulan than conventional methods. Statistical analysis generated a model to understand the solvent interactions and identify compositions giving higher pullulan yields, enhancing downstream processing efficiency.
The document describes the synthesis and evaluation of nitromethane substituted chalcone derivatives for their antimicrobial and antitubercular activity. Chalcones were synthesized from substituted acetophenones and aldehydes under basic conditions. Michael adducts were obtained by reacting the chalcones with nitromethane under Michael addition reaction conditions. The structures of the compounds were characterized using NMR and IR spectroscopy. Docking studies were performed to study the binding interactions of the compounds with various Mycobacterium tuberculosis protein targets. The compounds were evaluated for their in vitro antitubercular, anthelmintic and antimicrobial activity. Some compounds showed good activity against Mycobacterium tuberculosis and against various microorgan
This document describes research into synthesizing and evaluating Michael adducts derived from chalcones for biological activity. Michael adducts were synthesized by reacting chalcones with nitromethane under basic conditions. Various chalcones were first synthesized by reacting substituted acetophenones with substituted aldehydes under basic conditions. The resulting Michael adducts underwent molecular docking studies against various Mycobacterium tuberculosis protein targets as well as evaluation for anti-tubercular, anthelmintic, and antimicrobial activity. Several of the synthesized compounds showed promising anti-tubercular activity at 50μg/ml and good anthelmintic activity, suggesting electron donating groups aid activity.
Introduction,Drug- Excipient Compatibility Experimental Design ,Excipient role in drug destabilization,DRUG EXCIPIENT COMPATIBILTY IN PARENTERAL PRODUCTS.This topic are described.
This document describes the development and validation of a QuEChERS-based extraction and HPLC-FLD method for the screening and determination of polycyclic aromatic hydrocarbons (PAHs) in edible seafood. The method uses acetonitrile extraction followed by the addition of salts to induce water partitioning. Extracts are filtered and analyzed by HPLC with fluorescence detection. The method was validated in three laboratories and found to have recoveries ranging from 78-99% for 15 PAHs in seafood including oysters, shrimp, crab, and finfish. The method provides detection limits in the sub to low ppb range and is a more rapid and simplified approach compared to established GC/MS methods.
Transdermal patches are designed to deliver drugs through the skin for systemic absorption. Quality control tests are important to ensure patches perform as intended. Tests include evaluating physicochemical properties like thickness, weight, drug content and release. In vitro tests assess drug release and permeation. In vivo tests in animals and humans provide information on drug pharmacokinetics, efficacy, safety and irritation potential. Stability studies over 6 months under controlled conditions also help ensure patch quality is maintained over shelf life. Together these tests provide a comprehensive evaluation of transdermal patch performance.
Cytokines are small glycoproteins that act as signaling molecules between cells of the immune system. They are produced by a variety of immune cells including macrophages, monocytes, lymphocytes, and others. Cytokines function in both autocrine and paracrine manners through binding to specific cell surface receptors. They have a wide range of effects, including promoting or inhibiting inflammation, activating T cells and B cells, regulating hematopoiesis, and exhibiting anti-infective and anti-proliferative properties through interaction with their receptors on target cells. The functions of cytokines are pleiotropic, meaning they can have multiple effects on different cell types.
This document discusses heating, ventilation, and air conditioning (HVAC) systems and their importance in manufacturing quality pharmaceutical products. It addresses how HVAC systems control factors like temperature, humidity, air particles, and microbes. Contamination can originate from the environment, operators, or equipment and cross-contamination needs to be minimized. Proper HVAC design, maintenance, and procedures are critical to maintaining clean manufacturing conditions. The document also defines humidity measurement and different HVAC system types like central air conditioning. Dehumidification is important for operations in humid climates. In conclusion, air handling systems are critical systems that must be properly designed and treated as such.
This document describes the development and characterization of hydrogel microparticles containing lovastatin for the purpose of enhancing its solubility and bioavailability. Lovastatin is a poorly water soluble drug with low oral bioavailability. β-cyclodextrin and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) were used to synthesize poly(β-CD-g-AMPS) hydrogel microparticles via free radical polymerization. Various formulations with different ratios of β-CD, AMPS, crosslinker and initiator were prepared and tested for drug entrapment efficiency, particle size, swelling, and in vitro drug release. The lovastatin loaded microparticles showed up to 9.37
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise causes chemical changes in the brain that may help protect against mental illness and improve symptoms.
This document discusses pharmaceutical calculations including molarity, molality, and percentage concentration. It then covers topics related to emulsions including HLB value, emulsion types (O/W and W/O), emulsion stability testing, and factors that can cause emulsion instability such as creaming, flocculation, coalescence, and phase inversion. Specific examples are provided to illustrate pharmaceutical calculations for molarity and molality. Testing methods are also described for determining emulsion type using staining, fluorescence, and wetting of filter paper.
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
This presentation was provided by Steph Pollock of The American Psychological Association’s Journals Program, and Damita Snow, of The American Society of Civil Engineers (ASCE), for the initial session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session One: 'Setting Expectations: a DEIA Primer,' was held June 6, 2024.
How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
The simplified electron and muon model, Oscillating Spacetime: The Foundation...RitikBhardwaj56
Discover the Simplified Electron and Muon Model: A New Wave-Based Approach to Understanding Particles delves into a groundbreaking theory that presents electrons and muons as rotating soliton waves within oscillating spacetime. Geared towards students, researchers, and science buffs, this book breaks down complex ideas into simple explanations. It covers topics such as electron waves, temporal dynamics, and the implications of this model on particle physics. With clear illustrations and easy-to-follow explanations, readers will gain a new outlook on the universe's fundamental nature.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
How to Fix the Import Error in the Odoo 17Celine George
An import error occurs when a program fails to import a module or library, disrupting its execution. In languages like Python, this issue arises when the specified module cannot be found or accessed, hindering the program's functionality. Resolving import errors is crucial for maintaining smooth software operation and uninterrupted development processes.
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
The complex relationship between human activities and the environment has been the focus
of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
more evident. A crucial element of this impact is the alteration of vegetation cover, which plays a
significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
2. 2 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
valent interactions [3]. The presence of hydrophilic function-
al groups such as –OH, –COOH, -CONH2, -CONH, and
SO3H in the developed polymeric structure is responsible for
the absorption of a large amount of water by hydrogels and
is also helpful for the encapsulation of hydrophilic drugs.
Hydrogels have numerous applications in medicines and clin-
ical practice like tissue engineering and regenerative
medicine, cellular immobilization, diagnostics, separation of
biomolecules or cells, and barrier materials to regulate bio-
logical adhesions. Presently, hydrogels have been developed
in different forms like discs, microparticles, nanoparticles,
coatings, matrixes, composites, slabs, and films depending
upon the required use [4].
Hydroxypropyl-β-Cyclodextrin (HP-β-CD) is a useful cy-
clodextrin (CD)derivative because of its high solubility in
aqueous solution i.e. greater than 1200mg/ml. It is non-irri-
tant to skin, eyes, and mucosal linings [5]. Similarly,
agarose is a neutral linear polysaccharide consisting of
β-1,3-linked D-galactose and α-1, 4-linked 3,6-anhydro-α-L-
galactose. It dissolves in hot water at 60-70°C and forms a
thermoreversible gel on cooling (35-40°C). Moreover, it pos-
sesses the excellent gel-forming ability, swelling properties
in aqueous media, and mechanical properties. Hydrogels de-
veloped from pure agarose are clear, rigid, brittle, thermorev-
ersible, and offer a diffusion-assisted release of therapeutic
agents [6, 7].
Capecitabine is a prodrug of 5-fluorouracil and a potent
anticancer agent used for the treatment of colorectal cancer
at a dose of 41.66mg/kg two times a day. The anticancer
mechanism of capecitabine is attributed to its conversion to
5-fluorouracil in the tumour microenvironment by the enzy-
matic action, slowing down the tumour growth by inhibiting
the synthesis of DNA. Despite its potency as anticancer
agent, the clinical feasibility of capecitabine is limited due
to its erratic absorption, low bioavailability, fluctuating plas-
ma concentration, and early clearance from the body. More-
over, its therapeutic regimen (41.66mg/kg two times a day)
shows numerous adverse effects which also reduce patient
compliance. Therefore, in order to alleviate the aforemen-
tioned issues with the use of capecitabine, a newer sustained
release delivery system is needed for controlled release of
drugs in the plasma, improved plasma half-life, and im-
proved patient compliance [8].
The present study aimed to synthesize the capecitabine-
loaded HP-β-CD/agarose-co-methacrylic acid (MAA) hydro-
gels for controlled delivery of capecitabine by using a tech-
nique of free radical polymerization in which methylene bis
acrylamide (MBA) and ammonium persulfate (APS) were
used as crosslinker and initiator, respectively. To the best of
our knowledge, this is the pioneer study, which reveals the
use of these polymers for the development of hydrogel to re-
lease capecitabine at a controlled rate. The developed capec-
itabine-loaded hydrogels were characterized for various
physicochemical characterization, swelling ratio, thermal sta-
bility, and release kinetics. To further validate the safety of
the developed hydrogel, it was evaluated for acute oral toxic-
ity using rabbits.
2. MATERIALS AND METHODS
2.1. Materials
Capecitabine was purchased from Wuhanvanz Pharma,
Jingkai Future city Hubli, China. HP- β-CD (99%), agarose,
methacrylic acid (99%), N, N-methylene bisacrylamide
(99%), ammonium persulfate (99%), and methanol (99.7%)
were purchased from Sigma-Aldrich Co., St Louis, MO,
USA. Potassium dihydrogen phosphate, orthophosphoric
acid, and sodium hydroxide were purchased from Dae-Jung,
Korea. Distilled water was freshly prepared in the research
lab of the Faculty of Pharmacy, The University of Lahore.
All the chemicals used were of analytical grade.
2.2. Synthesis of HP-β-CD/agarose-g-poly(MAA) Hydro-
gels
The free radical polymerization technique was used for
the synthesis of HP-β-CD agarose hydrogels by using differ-
ent amounts of polymers, monomers, and crosslinkers.
Twelve formulations were developed (HPAG1 to HPAG12)
as shown in Table (1). For that, an accurate quantity of
agarose was weighed using an electronic weighing balance
(Shimadzu, AUW220D Japan) and poured into a specific
volume of hot distilled water (60-70 °C) with continuous stir-
ring on a hot plate magnetic stirrer until the solution became
clear. On the other hand, the weighed quantity of HP-β-CD
was dissolved in distilled water at room temperature. Similar-
ly, the solution of APS was prepared in a small volume of
distilled water separately, half of it was added to agarose so-
lution, and the remaining half was added into HP-β-CD solu-
tion dropwise to create active sites on polymer backbone
with thorough stirring. Afterward, both the polymer mix-
tures were mixed together thoroughly by the addition of HP-
β-CD solution into the agarose solution dropwise with cont-
inuous stirring. Monomer (MAA) was added in the above
mixture followed by the addition of cross-linker (MBA)
with continuous mixing. The final volume of the mixture
was achieved by adding the deionized distilled water. The
formed mixture was then subjected to thorough stirring until
a homogenous mixture was formed and then was transferred
to glass tubes which were sonicated for 3 to 5 min to remove
any dissolved gas. After the sonication, the glass tubes were
covered with aluminium foil and placed in the water bath
(Memmert) at different temperatures and duration such as
45°C for 1h, 50°C for 2 hours, 55°C for 4 hours, 60°C for 6
hours, and 65°C for 12 hours. After 24 hours, the formed hy-
drogels were removed by breaking the test tubes from the
backside and were cut into discs which were washed with
ethanol and distilled water solution (50:50) and dried in a
lyophilizer (Christ Alpha 1- 4 LD, Japan) at -55°C [9]. The
proposed chemical structure of HP-β-CD/agarose-g-poly
(MAA) hydrogels is presented in (Fig. 1).
2.3. Characterization
2.3.1. Loading of Capecitabine
Capecitabine was then loaded into the weighed dried
discs of different hydrogels. Briefly, 1% w/v solution of
3. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 3
capecitabine was prepared by adding 1g of the drug in a
beaker containing a specified volume of phosphate buffer so-
lution (pH 7.4) and stirred on a hotplate magnetic stirrer at
room temperature for approximately 30 minutes to obtain a
clear solution. The pre-weighed hydrogel discs were soaked
in the prepared capecitabine solution until swelled to equilib-
rium. After removal from the drug solution, the swollen
discs were blotted with filter paper and dried in a hot air
oven (Memmert) at 45°C followed by drying at room tem-
perature.
2.3.2. Quantification of Capecitabine
The percentage of drug-loaded into hydrogels was calcu-
lated using the following equation:
Where, WD = final weight of dried discs of hydrogels af-
ter immersion in the drug solution
Wd = initial weight of dried hydrogel discs before immer-
sion in the drug solution.
2.3.3. In-Vitro Swelling Studies
The pH-responsive behaviour of hydrogels was evaluat-
ed by performing the swelling experiments. For that, the
dried discs were precisely weighed using an electric weigh-
ing balance (Shimadzu, AUW220D) and then placed in phos-
phate buffer solution (pH 7.4) at 37°C. After specified time
intervals (0.5, 1, 1.5, 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42, and
48 hours) swollen discs were removed from the solution,
blotted with absorbent paper, and weighed again. The experi-
ment was continued until all the discs achieved a constant
weight. The following equation was used to calculate the per-
centage swelling of hydrogels [10].
Where, Wo is the initial weight of the dried disc and Wt
is the weight of swollen disc at time t.
Table 1. Composition of HP-β-CD/agarose-g-poly(MAA) hydrogels.
Codes
HP-β-CD
(g/100g)
Agarose
(g/100g)
MAA
(g/100g)
MBA
(g/100g)
APS
(g/100g)
HPAG1 0.5 0.25 10 0.15 0.15
HPAG2 1 0.25 10 0.15 0.15
HPAG3 1.5 0.25 10 0.15 0.15
HPAG4 0.5 0.5 10 0.15 0.15
HPAG5 0.5 1 10 0.15 0.15
HPAG6 0.5 1.5 10 0.15 0.15
HPAG7 0.5 0.25 15 0.15 0.15
HPAG8 0.5 0.25 20 0.15 0.15
HPAG9 0.5 0.25 25 0.15 0.15
HPAG10 0.5 0.25 10 0.17 0.15
HPAG11 0.5 0.25 10 0.20 0.15
HPAG12 0.5 0.25 10 0.23 0.15
Fig. (1). Proposed chemical structure of HP-β-CD/agarose-g-poly(MAA) hydrogel. (A higher resolution / colour version of this figure is avai-
lable in the electronic copy of the article).
4. 4 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
2.3.4. Sol-gel Fraction
A sol-gel fraction was determined to find out the reac-
tants utilized during the synthesis of HP-β-CD/agarose-g-
poly(MAA) hydrogels. For that, dried discs were weighed
on an electronic weighing balance and crushed into small
pieces. Extraction was conducted in Soxhlet apparatus con-
taining boiling distilled water for 4 hours so that the co-poly-
meric network could be freed from unreacted reactants. The
extracted hydrogel pieces were removed using the filter pa-
per and dried at room temperature for 24 hours followed by
drying in a hot air oven at 40-45°C and were finally re-
weighed [11]. A sol-gel fraction was calculated by using the
following equations:
Where, Wo = Initial weight of dried disc before extrac-
tion and Wt = Final weight of dried disc after extraction.
Moreover, the Sol fraction was calculated by the following
expression:
Solfraction = 100 - gelfraction
2.3.5. Fourier-Transforms Infrared (FTIR) Spectroscopy
Pure capecitabine, HP-β-CD, agarose, physical mixture,
drug-loaded and unloaded hydrogels were subjected to FTIR
analysis to check the complex formation and compatibility
between the ingredients. All the samples were grounded and
dried after mixing with KBr, then 65 kN pressure was used
for 1 minute to convert into a disc having 12mm thickness.
Scanning of these samples was done at 4000 to 500cm
-1
us-
ing Thermos Fischer scientific Nicolet6700TM FTIR spec-
trophotometer [12].
2.3.6. Scanning Electron Microscopy (SEM)
The surface morphology and shape of prepared hydro-
gels were examined using the SEM (Vega 3, Tuscan). The
optimum size discs of dried hydrogel were cut and attached
with double adhesive tape on an aluminium stub. A gold
coating having a thickness of 300 Å was done on aluminium
stubs. The current of 10kV was set for scanning of coating
[13].
2.3.7. Differential Scanning Calorimeter (DSC)
Drug, polymers, monomer, and developed hydrogels
were also subjected to DSC studies in order to determine the
phase transition temperatures and heat of fusion under rising
temperature. Properly ground samples were covered in an
aluminium pan. Operation of SDT (Q600 TA USA) was car-
ried out at a rate of 10°C/min under nitrogen stream using a
temperature range of 0-400°C. The analysis was done in tri-
plicate for each sample [14].
2.3.8. Thermogravimetric Analysis (TGA)
The thermal stability of the newly developed polymeric
network compared to its individual formulation ingredients
at elevated temperature was determined using TGA thermal
analysis under the same conditions as in DSC.
2.3.9. Powder X-Ray Diffraction (PXRD) Analysis
PRXD Xpert having pan analytical software was used to
confirm the nature i.e. amorphous or crystalline of pure
capecitabine, polymers, and loaded hydrogels. Scanning was
done at 2θ = 10
o
-70
o
[15].
2.3.10. Elemental Dispersive X-ray Spectroscopy
The elemental composition and atomic weight of compo-
nents were determined using a microanalysis technique
which is energy dispersive spectroscopy. This technique was
utilized by using INCA 200 m oxford, UK, for developed hy-
drogels. The pure drug, unloaded, and loaded hydrogels
were subjected to energy dispersive spectroscopy and their
spectra were recorded [16].
2.4. In-Vitro Drug Release
To confirm the pH-responsive release of capecitabine
from hydrogels, the in-vitro drug release studies were car-
ried out at pH 1.2 and 7.4 using the USP dissolution appara-
tus Type-II containing 900 ml of buffer solution in each bas-
ket at 37 ± 0.5 °C. Paddle speed was kept at 50rpm. Sam-
pling was done at specified intervals i.e. 0.5, 1, 1.5, 2, 3, 4,
6, 8, 10, 12, 14, 16, 18, 20, 22 and 24hrs and UV visible
spectrophotometer was used for quantitative analysis of
capecitabine at λmax=300 nm [17].
2.5. Kinetic Model of Drug Release Data
Drug concentration, swelling, and diffusion rate are the
prime factors that affect drug release from the hydrogel.
Hence, the mechanism of capecitabine release from devel-
oped hydrogels was determined by applying the kinetic mod-
els (Zero order, First order, Higuchi, and Korsmeyer-Pep-
pas) on release data through DD solver adds in the option of
Microsoft Excel. Values of n and R
2
provided the mech-
anism of drug release and best fit model, respectively.
Fickian diffusion was governed by the value of “n” equal to
0.45, anomalous or non-fickian diffusion was shown by val-
ues ranging within 0.45-0.89, and case-II transport or ze-
ro-order was proved by a value equal to 0.89 [17].
Zero-order kinetics
Ft = Fo-Kot
First-order kinetics
In (1 - F) = - K1t
Higuchi model
Ft = KHt
1/2
Where, Ft = Fraction of drug release in time t, Fo= Total
amount of Capecitabine in polymeric networks, Ko K1, and
KH are the rate constants for Zero order, First order, and
Higuchi models, respectively.
Korsmeyer-Peppas model is described as;
5. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 5
Mt/M∞ shows the portion of Capecitabine released at
time t, K3 is rate constant and n describes release exponent.
2.6. Acute Oral Toxicity Studies Using an Animal Model
The acute oral toxicity of HP-β-CD/agarose-co-poly
(MAA) hydrogel on biochemical, lipid and renal profiles, vi-
tal organs, and physical activity of rabbits was carried out us-
ing the twelve healthy albino rabbits according to the OECD
guidelines. All the study protocols were reviewed and ap-
proved by the Institutional Research Ethics Committee of
Faculty of Pharmacy, The University of Lahore notification
no. IREC-2019-137A.The experimental animals were accli-
matized in stainless steel cages for 7 days and were fed with
a proper diet and water. Rabbits were divided into two
groups i.e. group A (control) and group B (test) by keeping
six rabbits in each group. Following the overnight fasting, a
dose of 2 g/kg of finely crushed hydrogel was administered
to each animal of the group B via the feeding tube, and both
the groups were kept under observation for food consump-
tion and water intake, body weight, skin allergies, and any
physical changes for 14 days. On 7
th
day, the blood samples
were collected from each animal. Prior to blood collection,
the ears of animals were cleaned off hairs by applying hair
removal cream and 2-3ml of the blood sample was collected
from the marginal vein of the ear by using 3cc syringes (In-
jekt
®
) and then transferred into EDTA tubes. The collected
blood samples were subjected to centrifugation for 15 min-
utes (Hitachi Zentrifugen EBA 20, Hitachi Ltd., Tokyo, Ja-
pan) at 5000 rpm for haematological analysis, AST, ALT,
lipid, and renal profile. After 14 days, all rabbits were re-
weighed and then anesthetized by injecting them with a com-
bination of ketamine and xylazine (70:30) at a dose of
1ml/kg into their thigh muscles. Blood samples were with-
drawn again by heart puncture, and vital organs (heart, liver,
kidney, lungs, intestine, stomach, spleen, and brain) were re-
moved and washed with PBS. These organs were then
stored in 10% formalin solution for microscopic evaluation
using H&E histological examination [18].
3. RESULTS AND DISCUSSION
3.1. Drug Loading Efficiency into a Hydrogel
Capecitabine was loaded into the hydrogel by diffusion
method. The entrapment of capecitabine into different hydro-
gel formulations was expressed as percent drug loading. The
resulting data presented in Fig. (2) showed that the loading
efficiency of capecitabine was found to be optimum in
HPAG9 hydrogel formulation (approximately 90%), com-
pared to HPAG1-HPAG3 hydrogels (approximately 80% to
87.31%), HPAG4-HPAG6 (70% to 85%). Results have also
revealed that the drug-loading efficiency of capecitabine
was exponentially increased by increasing the concentration
of HP-β-CD, agarose, and MAA contents, while drug load-
ing efficiency was decreased with an increase in MBA con-
tents (Fig. 2).
Fig. (2). Effect of concentration of ingredients on capecitabine loading efficiency, (A) Hydroxypropyl beta cyclodextrin (HP-β-CD) (B)
Agarose (C) Methacrylic acid (MAA) and D) Methylene bis acrylamide (MBA). (A higher resolution / colour version of this figure is avail-
able in the electronic copy of the article).
6. 6 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
3.2. Swelling Behaviour
The effect of different concentrations of HP-β-CD,
agarose, MAA, and MBA on the swelling behaviour of hy-
drogels has also been evaluated at pH 7.4 (Fig. 3). Results
showed that the swelling was found to increase with an in-
crease in HP-β-CD, agarose, and MAA concentration while
swelling decreased by increasing MBA contents. The in-
creasing HP-β-CD contents resulted in a parallel increase in
swelling tendency from 88% to 95% for formulations
HPAG1 to HPAG3, respectively (Fig. 3A). HP-β-CD is a
highly hydrophilic polymer that is enriched in hydroxyl
groups that undergo deprotonation at pH 7.4 along with ion-
ized carboxylate groups (pKa = ͠4.5–5)from MAA induce re-
pulsion, causing considerable expansion of polymeric
chains. The swelling percentage was also increased from
71.33% to 78.99% in HPAG4 to HPAG6 formulations with
an increase in agarose contents (Fig. 3B). This slight rise in
swelling was expected to be due to ionization of hydroxyl
groups attached to the monosaccharide units of agarose
thereby causing the repulsion between polymeric chains, re-
sulting in swelling and uptake of swelling media. However,
this swelling was lower compared with HP-β-CD due to its
less hydrophilic nature at low temperature. Our results were
in agreement with a previous study in which researchers de-
veloped agarose and polyvinyl alcohol-based hydrogels and
observed poor swelling behaviour in agarose-based hydrogel
formulations [19].
Similarly, our results have also revealed a significant in-
crease in swelling from 89.54% to 97% (p<0.05, ANOVA)
in hydrogel formulations (HPAG7 to HPAG9) by increasing
the MAA contents (Fig. 3C). This effect may be attributed
to the availability of more carboxylate ions at pH 7.4 result-
ing in polymeric repulsion and expansion of hydrogel net-
work, leading to greatly improved uptake of swelling media
due to the availability of more free volume within the hydro-
gel network. Our results were also in agreement with the pre-
vious study in which researchers developed dual-responsive
(pH and temperature) hydrogels by free radical polymeriza-
tion technique and found that MAA-concentration depen-
dent on the increase in swelling of developed hydrogel [20].
On the other hand, a significant decrease in the swelling
tendency of hydrogel from 85.45% to 72.45% was observed
by increasing the MBA contents (Fig. 3D). This was expect-
ed to be associated with an increased cross-linking density
which leads to a reduction in network interconnected pores
and ultimately halted the diffusion process. Our results were
in agreement with previous studies in which Tanan and col-
leagues developed natural polymer-based hydrogels involv-
ing MBA as cross-linker [21].
Fig. (3). Effect of concentration of different ingredients on the swelling tendency of a hydrogel, (A) Hydroxypropyl beta cyclodextrin (H-
P-β-CD), (B) Agarose (C) Methacrylic acid (MAA), and (D) Methylene bis acrylamide (MBA). (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
7. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 7
Fig. (4). Gel fraction (%) of hydrogel formulations (HPAG1 –HPAG12). (A higher resolution / colour version of this figure is available in
the electronic copy of the article).
3.3. Analysis of Sol-gel Fraction
A sol-gel fraction was determined to observe the effect
of formulation ingredients on gel fraction. Gel fraction of all
formulations (HPAG1-HPAG12) was ranged from 80.88%
to 94.12%. By increasing the quantities of polymer,
monomer, and cross-linker, a consistent increase in gel frac-
tion was noticed. In HPAG1 to HPAG3hydrogel formula-
tions, gel fraction was increased from 83.28% to 92.85%,
while inHPAG4 to HPAG6 hydrogel formulations, gel frac-
tion was ranged from80.88% to 89.12% that was less as com-
pared to HP-β-CD-based formulations (Fig. 4). This compar-
ative decrease in gel fraction may be due to the availability
of less reactive hydroxyl groups from agarose at the reaction
temperature. A rise in MAA contents has promoted gel frac-
tion from 82.15 to 94.12% due to the existence of more reac-
tive free radicals (deprotonated carboxylate ions) at pH 7.4.
This character also facilitates the rapid propagation of poly-
merization. Formulations containing MBA (HPAG10 to
HPAG12) have exhibited a 82.43 to 91.15% rise in gel frac-
tion due to high crosslinking density and higher polymeriza-
tion. Fekete and co-researchers developed hydrogels contain-
ing MBA as cross-linker. Similar findings in terms of gel
fraction were noted [22].
3.4. FTIR Analysis
FTIR analysis was performed to validate the structural
and compositional features of developed hydrogel formula-
tions as well as successful loading of capecitabine (Fig. 4).
IR spectrum of capecitabine presented evident peaks at
1035.13cm
-1
(C-F stretching vibrations), 1240cm
-1
(tetrahy-
drofuran ring), 1650.15cm
-1
(pyrimidine carbonyl stretching
vibrations), 1697.20cm
-1
and 1720.11cm
-1
(urethane car-
bonyl stretching vibrations), 3100.21cm
-1
(N-H stretching)
and 3300cm
-1
(O-H stretching vibrations) (Fig. 5C). Typical
bands of agarose were present at 1030.16cm
-1
, 1450.09cm
-1
,
1680.23cm
-1,
and 3640.19cm
-1
due to C-O bending, C-C bend-
ing, C=O stretching, and OH stretching, respectively (Fig.
5A). Prominent peaks of HP-β-CD displayed at
1040.1cm
-1
(C=O vibrations), 1651.24cm
-1
(H-O-H bending),
2980.19cm
-1
(C-H stretching) and 3610cm
-1
(O-H stretching)
(Fig. 5B).
FTIR spectrum of MBA showed distinct peaks at
1650.10cm
-1
, 3000.13cm
-1
, 3100cm
-1
and 3300.20cm
-1
corre-
sponding to C=O stretching, symmetric –CH2 stretching,
asymmetric –CH2 stretching, and N-H stretching vibrations,
respectively. No remarkable variations were seen in the IR
spectrum of the physical mixture thereby ensured the ingredi-
ent’s compatibility (Fig. 5D). IR spectra of capec-
itabine-loaded and unloaded hydrogels have presented the
typical peaks of both individual polymers with sound varia-
tions. The peak observed at 3610cm-1
due to O-H groups in
HP-β-CD spectrum was displaced to 3730.11cm
-1
while the
peak at 1450.09cm
-1
(C-C bending) of agarose was shifted to
the 1500.15cm-1
within spectrum of a drug-loaded network.
Furthermore, capecitabine peaks at 1650.15cm
-1
and
1720.11cm
-1
due to carbonyl groups of pyrimidine and ure-
thane groups respectively were shifted to 1625.20cm-1
and
1661.15cm
-1
. Peaks at 3640.19 cm
-1
due to –OH group
stretching in agarose were shifted to 3730.11cm
-1
. Peaks at
2980.19 cm-1
due to C-H stretching in HP-β-CD were shifted
to 2970.0cm
-1
. Moreover, the intensity of peak due to tetrahy-
drofuran ring (1240 cm
-1
) was markedly reduced in capec-
itabine loaded network (Fig. 5F). The switching of peaks
and variation in their intensities confirmed new polymer syn-
thesis.
3.5. Scanning Electron Microscopy (SEM)
The surface morphology of developed pH-sensitive hy-
drogel was investigated using SEM analysis at different mag-
nifications. The resulting photomicrograph revealed that hy-
drogels were having cracks on their surfaces (Fig. 6). The
presence of cracks on the surface of the developed hydrogel
was expected due to excessive drying during lyophilisation
at -55°C. These cracks may facilitate the uptake of dissolu-
tion media into the hydrogel network. Upon complete
swelling, the volume of cracks was reduced due to repulsion
of polymeric chains and resulted in slow release of capec-
itabine. Other researcher works pertaining to hydrogel sur-
face morphology and the presence of cracks [23] have also
obtained similar findings.
8. 8 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
3.6. Thermal Analysis
The thermal behaviour of pure capecitabine, HP-β-CD,
agarose, and capecitabine-loaded hydrogel was analyzed us-
ing DSC and TGA analyses. DSC analysis is performed to
evaluate the structural and functional features of materials as
a function of temperature. DSC analysis of pure capec-
itabine, HP-β-CD, agarose, and capecitabine-loaded hydro-
gel was performed (Fig. 7A). DSC curve of capecitabine has
shown an endothermic peak at 132.31°C (0.02265J/g) corre-
sponding to the melting range of capecitabine, validating its
crystalline nature. Another peak at 159.70°C (0.004427J/g)
was due to partial degradation of capecitabine while the
peak at 456.35°C (0.0007347J/g) was attributed to its com-
plete combustion. HP-β-CD presented an endothermic peak
at 68.5°C (0.02845J/g) due to loss of moisture contents
while peaks at 322.78°C (0.0007733J/g) and 455.36°C
(0.005812J/g) were due to melting and complete combustion
of HP-β-CD, respectively. Agarose displayed slight en-
dothermic peaks at 105.02°C (0.06403J/g) corresponding to
the loss of moisture contents and at 311.45°C (0.04048J/g)
due to phase transition and partial combustion. A sharp
exothermic peak was also observed at 439.46°C
(0.02918J/g) which was due to the complete combustion of
agarose. In the case of a drug-loaded hydrogel, a slight en-
dothermic peak observed near 106.67°C (0.06964J/g) was
due to moisture loss while peak seen at 348.67°C
(0.005809J/g) indicated the change of state from solid into a
liquid. Capecitabine incorporation and conversion into an
amorphous state were evident from the drug-loaded DSC
thermogram as no drug peak was observed. Moreover, the
peak presented above 500°C depicted the complete combus-
tion of a polymeric network (Fig. 7A).
Fig. (5). FTIR spectra of (A) Agarose (B) HP-β-CD (C) Capecitabine (D) Physical mixture (E) Unloaded hydrogel (F) Drug loaded hydro-
gels.
9. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 9
Fig. (6). SEM photomicrograph of capecitabine-loaded hydrogels.
Fig. (7A). DSC analysis of HP-β-CD, agarose, capecitabine, and capecitabine-loaded hydrogel. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
10. 10 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
Fig. (7B). TGA analysis of HP-β-CD, agarose, capecitabine, and capecitabine-loaded hydrogel. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
TGA analysis of pure drug, polymers, and drug-fabricat-
ed hydrogel was performed to evaluate mass loss against in-
creasing temperature. TGA thermogram of capecitabine dis-
played gradual decline in mass with increasing temperature
i.e. 92.24% (134.22°C), 71.62% (179.09°C), 45.73%
(296.39°C) and 23.22% (494.74°C). In the case of HP-β-
CD, initially, 9.68% weight loss was recorded at 82.40°C
that was further increased to 13.24% at temperature
312.03°C (above the melting point of HP-β-CD), 76.59% at
378.86°C, and 91.046% at 517.49°C. Similarly, for agarose,
gradual decrease in intact mass was noted i.e. 85.15%,
81.73%, 40.22%, and 17.26% against temperature
101.60°C, 277.20°C, 336.91°C, and 460.61°C, respectively.
Moreover, capecitabine-loaded network depicted 86.35% in-
tact mass at 99.47°C, 77.16% at 225.30°C, 66.59% at
346.87°C, 45.74% at 373.88°C and 19.50% of remaining
mass at 552.32°C (Fig. 7B). Hence, the developed co-poly-
meric network was more stable as compared to ingredients.
3.7. XRD Analysis
Powder X-ray diffraction studies on pure ingredients and
fabricated networks were conducted to check their physical
nature (amorphous or crystalline). HP-β-CD diffractogram
presented fused peaks thereby reflecting amorphous nature.
Capecitabine showed intense and differentiated peaks at 2Ɵ
= 10.75
o
, 18.95
o
, 19.6
o
, 20.05
o
, 21.45
o
, 22.1
o
, 25.45
o,
and
28.65
o
leading to its crystalline nature (Fig. 8). These charac-
teristic peaks were not seen and transformed into fused
peaks in the case of the capecitabine-loaded network thereby
proving its amorphous nature. The transformation of capec-
itabine from a crystalline into amorphous nature may be due
to its inclusion into cavities of HP-β-CD. Similar findings
were reported by a study involving HP-β-CD conducted by
Wang and co-workers [24].
3.8. Energy-Dispersive X-ray Spectroscopy (EDX)
Elemental analysis and chemical composition of hydro-
gels were confirmed by energy dispersive spectroscopy, a
surface analysis technique that measures the binding energy
of electrons within atoms of 5-10nm depth. EDX spectra of
capecitabine, unloaded hydrogels and capecitabine-loaded
hydrogels are presented in (Fig. 9). In capecitabine, peaks of
carbon, oxygen, fluorine, and nitrogen were displayed in con-
centrations of 56.06%, 29.54%, 3.87%, and 10.52%, respec-
11. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 11
tively. Peaks of fluorine and nitrogen were absent in unload-
ed hydrogel as these atoms are an integral part of capec-
itabine and these peaks were present in capecitabine loaded
hydrogel thus confirming the successful loading of capec-
itabine into the grafted network. Mahmood and co-workers
confirmed elemental composition and loading of acyclovir
into the developed pH-sensitive network [25]. Confirmation
of capecitabine into the developed carrier system was also
confirmed in a quite similar manner.
3.9. Release Studies
The effects of concentration of HP-β-CD, agarose, and
MBA on the release of capecitabine at pH 1.2 and 7.4 were
investigated (Fig. 10). At pH 1.2, all the formulations (H-
PAG1-HPAG12) were resulted in minimal capecitabine re-
lease i.e. 9.965%-13.651%, while at pH 7.4 it was between
71% to 94.25%. Capecitabine release was significantly im-
proved (p<0.05)with the rise of HP-β-CD, agarose, and
MAA contents, and optimum release was observed in
HPAG3 (94.25%), HPAG6 (90.71%), and HPAG9
(88.11%). Availability of free hydroxy groups (-OH) and car-
boxylic groups (-COOH) from both of the polymers and
MAA, respectively in ionic state at pH 7.4 resulted in repul-
sion between polymeric chains and higher swelling,
promoting the uptake of capecitabine solution, higher load-
ing and higher percentage release of capecitabine. Asghar et
al. have utilized MAA as a pH-sensitive monomer for venla-
faxine release in a controlled fashion. Similar impacts of
MAA were seen in the current study [26].
With the rise of MBA contents, capecitabine release was
decreased up to 82.06% (HPAG12). A higher ratio of cross-
linker contributed to the development of a more dense struc-
ture and poor swelling. So, penetration of physiological
fluid into the network was lowered resulting in the decrease
of capecitabine release [27].
Different kinetic models were applied on capecitabine re-
lease data and based upon the coefficient of regression
(R
2
)values, the best-fit model was zero-order kinetics. Thus,
sustained release of capecitabine from the network was no-
ticed. Exponent “n” value determined the mechanism of
capecitabine release from the carrier system. It was greater
than 0.89 for most of the developed formulations thus high-
lighting Super Case II transport except formulations HPAG3
and HPAG6 which followed non-fickian diffusion (Table 2).
Fig. (8). XRD diffractograms of (A) Capecitabine, (B) agarose, (C)
HP-β-CD and (D) Capecitabine loaded hydrogels. (A higher resolu-
tion / colour version of this figure is available in the electronic
copy of the article).
Fig. (9). EDX spectra of (A) Capecitabine (B) unloaded and (C) capecitabine loaded hydrogels. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
12. 12 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
Fig. (10). Capecitabine release from formulations (HPAG1 – HPAG12) at pH1.2 and pH 7.4. (A higher resolution / colour version of this fig-
ure is available in the electronic copy of the article).
Table 2. Results of kinetic modelling on capecitabine release data.
Formulation
Zero-order 1
st
order Higuchi Model Korsmeyer Peppas
R
2
R
2
R
2
R
2
n
HPAG1 0.9925 0.9241 0.8216 0.9961 1.112
HPAG2 0.9871 0.9260 0.8592 0.9875 0.965
HPAG3 0.9694 0.9282 0.8949 0.9812 0.836
HPAG4 0.9906 0.9271 0.8086 0.9972 1.157
HPAG5 0.9877 0.9318 0.8513 0.9877 0.994
HPAG6 0.9678 0.9404 0.8990 0.9819 0.824
HPAG7 0.9882 0.9388 0.8417 0.9885 1.032
HPAG8 0.9882 0.9448 0.8425 0.9885 1.031
HPAG9 0.9830 0.9490 0.8832 0.9878 0.890
HPAG10 0.9865 0.9418 0.8312 0.9879 1.070
HPAG11 0.9816 0.9340 0.8082 0.9879 1.157
HPAG12 0.9856 0.9535 0.8756 0.9883 0.916
3.10. Toxicological Evaluation
To validate the safety of developed hydrogel, different
parameters including body weight, water and food intake,
certain illnesses i.e. fever, diarrhoea, dermal and ocular
toxicity were also monitored for 14 days in the present study
(Table 3). No significant variation in weight, water, and
food intake was noticed in the treated and controlled group
of animals. Ocular and dermal toxicities were absent. Bio-
chemical and haematological analyses of blood samples
were performed on those that have presented acceptable re-
sults (Table 4). Liver, kidney, and lipid profiles were also
within a healthy range (Table 5).
13. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 13
Table 3. Clinical findings during acute oral toxicity studies.
Observations Group I (Control) Group II (Tested)
Signs of illness Not observed Not observed
Bodyweight (Kg)
Pre-treatment 1.98±0.04 2.01±0.04
Day 1 1.98±0.02 2.02±0.03
Day 7 2.03±0.04 2.06±0.04
Day 14 2.06±0.05 2.09±0.04
Water intake (ml)
Pre-treatment 184.16±1.23 189.34±0.12
Day 1 190.45±2.03 193.45±1.71
Day 7 199.17±3.35 200.63±1.25
Day 14 205.13±2.53 204.24±2.25
Food intake(g)
Pretreatment 69.26±1.11 70.31±1.18
Day 1 71.33±1.50 71.20±1.23
Day 7 70.74±1.21 72.39±1.43
Day 14 74.61±1.06 75.471±1.12
Dermal toxicity Not seen Not seen
Ocular toxicity Absent Absent
Mortality Zero Zero
Table 4. Results of biochemical analysis of rabbits’ blood.
Parameters Group I (Control) Group II (Treated with Hydrogels)
Haemoglobin (g/dl) 9.5 11.0
pH 6.99 ± 0.18 7.11 ± 0.30
White blood cells (×10
3
/µl) 2.5 ± 0.41 2.4 ± 0.32
Red blood cells (×10
6
/ µl) 4.72 ± 1.27 4.76 ± 1.41
Platelets (×10
9
L
-1
) 4.46 ± 0.17 4.59 ± 0.17
Monocytes (%) 3.39 ± 0.29 3.48 ± 0.19
Neutrophils (%) 54.47 ± 2.13 54.73 ± 2.16
Lymphocytes (%) 62.65 ± 3.45 62.51 ± 3.24
Mean corpuscular volume (%) 62.5±2.21 63.64 ± 2.33
Mean corpuscular haemoglobin (pg/cell) 20.1±0.71 23.1 ± 0.69
Mean corpuscular haemoglobin conc. (%) 32.2±1.11 32.0 ± 1.09
Table 5. Kidney, liver, and lipid profiles.
Biochemical Analysis Group I (Control) Group II (Treated with Hydrogels)
ALT (IU/L) 159.64 ± 4.21 158.55 ± 5.56
AST (IU/L) 59 ± 3.21 65.57 ± 3.66
Urea (mmol/L) 15.61 ± 0.42 16.62 ± 1.62
Creatinine (mg/dL) 1.91 ± 0.31 1.90 ± 0.11
Uric acid (mg/dL) 4.24 ± 1.14 4.63 ± 1.11
Cholesterol (mg/dL) 62.35 ± 2.42 64.53 ± 2.33
Triglycerides (mg/dL) 60.68 ± 4.45 59.37 ± 4.56
14. 14 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
To detect the toxic effects of developed hydrogels on vi-
tal organs histopathological studies were also conducted.
For this purpose rabbits were sacrificed on the 14th
day of
study, vital organs were removed, stored in 10% formalin so-
lution and tissue slides were prepared. Microscopic evalua-
tion of these H & E stained histopathological slides was
made. Both groups (control and tested) did not show any
pathological change in tissues of vital organs (Fig. 11).
Moreover, no signs of degeneration, lesions, inflammation,
and abnormalities were seen. Cardiac tissues of both control
and tested animals revealed a precise pattern of cardiomyo-
cytes without any evidence of hypertrophic cells. There was
no sign of myocardial infarction.
Fig. (11). Histopathological examination of rabbit’s vital organs.
(A higher resolution / colour version of this figure is available in
the electronic copy of the article).
The liver section of control and tested animals displayed
slight hyperplasia in the portal triad region and accumula-
tion of inflammatory cells. An extracellular matrix was also
observed to be deposited around the portal triad. Microscop-
ic evaluation of lung showed emphysema, pulmonary oede-
ma, and hyperplasia. Moreover, alveolar accumulation was
also noted but there was no sign of lung fibrosis. These ab-
normalities were also seen in liver and lung sections of the
control group so these could not be considered as toxic ef-
fects of administered fabricated carrier systems.
The kidneys of rabbits showed no tubular and ductile da-
mage. Normal kidneys were observed having intact glomeru-
lus and bowman capsules in both control and treated groups.
Moreover, a normal spleen was observed having well-differ-
entiated red and white pulp with occasional hemosiderin
crystals. Uniform distribution of white blood cells was noted
in the white pulp. The intestines of rabbits were observed to
be showing normal columnar epithelium. Intact muscularis
was seen with no sign of inflammation or hyperplasia.
Furthermore, photomicrographs of the brain presented
no sign of cellular degeneration and inflammatory cell infil-
tration. Brain cortical regions were intact. Axons were clear
with nuclei and astrocytes were observed to be normal. No
difference was observed among the control group and group
treated with HP-β-CD/agarose-co-poly (MAA) hydrogels.
CONCLUSION
In the current study, capecitabine loaded pH-sensitive
HP-β-CD/agarose-g-poly(MAA) hydrogels were successful-
ly developed, tuned, and characterized for different charac-
teristic features such as drug loading efficiency, structural
and compositional characteristics, thermal stability, swelling
behaviour, morphology, physical form, elemental analysis,
and release kinetics. By optimising the different ingredients,
hydrogel having controlled release characteristics was fabri-
cated. The pH-responsive behaviour of hydrogel was validat-
ed by evaluating the release behaviour of developed hydro-
gel at different pH, showing significantly higher release at
higher pH compared with lower pH. The controlled release
feature of developed hydrogel will be enabled to maintain
the therapeutic levels of capecitabine, improve bioavailabili-
ty and patient compliance. Excellent swelling, high gel con-
tents and high water holding capacity also make these deliv-
ery systems an ideal choice for the delivery of therapeutic
agents having poor bioavailability. For establishing a safety
profile, the developed hydrogels were also tested for acute
oral toxicity in terms of body weight, water and food intake,
dermal toxicity, ocular toxicity, biochemical analysis, and
histological examination of specimens were collected from
treated and tested group animals. The toxicity analysis evi-
denced an excellent safety profile with no signs of oral, der-
mal, or ocular toxicities, as well as no pathologic variations
in blood chemistry and histology. These results evidenced
that the developed hydrogels exhibit excellent pharmaceuti-
cal and therapeutic potential to be employed as smart pH-re-
sponsive hydrogel systems for the controlled delivery of
drugs.
15. Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 15
ETHICS APPROVAL AND CONSENT TO PARTICI-
PATE
All the study protocols were reviewed and approved by
the Institutional Research Ethics Committee of Faculty of
Pharmacy, The University of Lahore notification no.
IREC-2019-137A.
HUMAN AND ANIMAL RIGHTS
No humans were used in this study. All animals’ proce-
dures performed were in accordance with the Laboratory An-
imal Care Guidelines.
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
The authors confirm that the data supporting the findings
of this research are available within the article.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ACKNOWLEDGMENTS
The authors would like to sincerely acknowledge the
“University of Sargodha and University of Lahore, Lahore,
Pakistan” for providing instrumental support in executing
the present research project.
REFERENCES
Soni, G.; Yadav, K.S. Nanogels as potential nanomedicine carrier
[1]
for treatment of cancer: A mini review of the state of the art. Sau-
di Pharm. J., 2016, 24(2), 133-139.
http://dx.doi.org/10.1016/j.jsps.2014.04.001 PMID: 27013905
Bhattarai, N.; Gunn, J.; Zhang, M. Chitosan-based hydrogels for
[2]
controlled, localized drug delivery. Adv. Drug Deliv. Rev., 2010,
62(1), 83-99.
http://dx.doi.org/10.1016/j.addr.2009.07.019 PMID: 19799949
Mishra, B.; Upadhyay, M.; Reddy, A.S.; Vasant, B.G. Muthu, M.
[3]
Hydrogels: an introduction to a controlled drug delivery device,
synthesis and application in drug delivery and tissue engineering.
Austin J Biomed Eng., 2017, 4, 1037.
Mahmood, A.; Ahmad, M.; Sarfraz, R.M.; Usman, M.U. Develop-
[4]
ment of acyclovir loaded β‐cyclodextrin‐g‐poly methacrylic
acid hydrogel microparticles: an in vitro characterization. Adv. Po-
lym. Technol., 2018, 37, 697-705.
http://dx.doi.org/10.1002/adv.21711
Cal, K.; Centkowska, K. Use of cyclodextrins in topical formula-
[5]
tions: practical aspects. Eur. J. Pharm. Biopharm., 2008, 68(3),
467-478.
http://dx.doi.org/10.1016/j.ejpb.2007.08.002 PMID: 17826046
Maurer, S.; Junghans, A.; Vilgis, T.A. Impact of xanthan gum, su-
[6]
crose and fructose on the viscoelastic properties of agarose hydro-
gels. Food Hydrocoll., 2012, 29, 298-307.
http://dx.doi.org/10.1016/j.foodhyd.2012.03.002
Yuan, Y.; Wang, L.; Mu, R.J.; Gong, J.; Wang, Y.; Li, Y.; Ma, J.;
[7]
Pang, J.; Wu, C. Effects of konjac glucomannan on the structure,
properties, and drug release characteristics of agarose hydrogels.
Carbohydr. Polym., 2018, 190, 196-203.
http://dx.doi.org/10.1016/j.carbpol.2018.02.049 PMID: 29628238
Kelly, C.; Bhuva, N.; Harrison, M.; Buckley, A.; Saunders, M.
[8]
Use of raltitrexed as an alternative to 5-fluorouracil and capec-
itabine in cancer patients with cardiac history. Eur. J. Cancer,
2013, 49(10), 2303-2310.
http://dx.doi.org/10.1016/j.ejca.2013.03.004 PMID: 23583220
Verma, C.; Negi, P.; Pathania, D.; Sethi, V.; Gupta, B. Preparation
[9]
of pH-sensitive hydrogels by graft polymerization of itaconic acid
on tragacanth gum. Polym. Int., 2019, 68, 344-350.
Afinjuomo, F.; Fouladian, P.; Parikh, A.; Barclay, T.G.; Song, Y.;
[10]
Garg, S. Preparation and Characterization of Oxidized Inulin Hy-
drogel for Controlled Drug Delivery. Pharmaceutics, 2019, 11(7),
356.
http://dx.doi.org/10.3390/pharmaceutics11070356 PMID:
31336580
Akalin, G.O.; Pulat, M. Preparation and characterization of κ-car-
[11]
rageenan hydrogel for controlled release of copper and manganese
micronutrients. Polym. Bull., 2020, 77, 1359-1375.
http://dx.doi.org/10.1007/s00289-019-02800-4
Che, Y.; Li, D.; Liu, Y.; Ma, Q.; Tan, Y.; Yue, Q.; Meng, F. Physi-
[12]
cally cross-linked pH-responsive chitosan-based hydrogels with
enhanced mechanical performance for controlled drug delivery.
RSC Advances, 2016, 6, 106035-106045.
http://dx.doi.org/10.1039/C6RA16746B
Kanmaz, N.; Saloglu, D.; Hizal, J. Humic acid embedded chi-
[13]
tosan/poly (vinyl alcohol) pH-sensitive hydrogel: Synthesis, char-
acterization, swelling kinetic and diffusion coefficient. Chem.
Eng. Commun., 2019, 206, 1168-1180.
http://dx.doi.org/10.1080/00986445.2018.1550396
Nesrinne, S.; Djamel, A. Synthesis, characterization and rheologi-
[14]
cal behavior of pH sensitive poly (acrylamide-co-acrylic acid) hy-
drogels. Arab. J. Chem., 2017, 10, 539-547.
http://dx.doi.org/10.1016/j.arabjc.2013.11.027
Farhadnejad, H.; Mortazavi, S.A.; Erfan, M.; Darbasizadeh, B.;
[15]
Motasadizadeh, H.; Fatahi, Y. Facile preparation and characteriza-
tion of pH sensitive Mt/CMC nanocomposite hydrogel beads for
propranolol controlled release. Int. J. Biol. Macromol., 2018, 111,
696-705.
http://dx.doi.org/10.1016/j.ijbiomac.2018.01.061 PMID:
29337099
Zou, C.; Liu, Y.; Yan, X.; Qin, Y.; Wang, M.; Zhou, L. Synthesis
[16]
of bridged β-cyclodextrin–polyethylene glycol and evaluation of
its inhibition performance in oilfield wastewater. Mater. Chem.
Phys., 2014, 147, 521-527.
http://dx.doi.org/10.1016/j.matchemphys.2014.05.025
Nayak, A.K.; Pal, D. Development of pH-sensitive tamarind seed
[17]
polysaccharide-alginate composite beads for controlled diclofenac
sodium delivery using response surface methodology. Int. J. Biol.
Macromol., 2011, 49(4), 784-793.
http://dx.doi.org/10.1016/j.ijbiomac.2011.07.013 PMID:
21816168
Gong, C.Y.; Shi, S.; Dong, P.W.; Yang, B.; Qi, X.R.; Guo, G.;
[18]
Gu, Y.C.; Zhao, X.; Wei, Y.Q.; Qian, Z.Y. Biodegradable in situ
gel-forming controlled drug delivery system based on thermosensi-
tive PCL-PEG-PCL hydrogel: part 1-Synthesis, characterization,
and acute toxicity evaluation. J. Pharm. Sci., 2009, 98(12),
4684-4694.
http://dx.doi.org/10.1002/jps.21780 PMID: 19367619
Qi, X.; Su, T.; Tong, X.; Xiong, W.; Zeng, Q.; Qian, Y.; Zhou, Z.;
[19]
Wu, X.; Li, Z.; Shen, L.; He, X.; Xu, C.; Chen, M.; Li, Y.; Shen,
J. Facile formation of salecan/agarose hydrogels with tunable
structural properties for cell culture. Carbohydr. Polym., 2019,
224, 115208.
http://dx.doi.org/10.1016/j.carbpol.2019.115208 PMID: 31472869
Rasib, S.Z.M.; Muhamad, N.F.; Akil, H.M.; Hamid, Z.A.A.; Te-
[20]
bal, N. Preparation and Characterization of pH-and Tempera-
ture-responsive by Different Composition Chitosan-P (MAA- co-
NIPAM) Hydrogel for Drug Delivery System. Jixie Gongcheng
Xuebao, 2017, 4, 123-133.
Tanan, W.; Panichpakdee, J.; Saengsuwan, S. Novel biodegrad-
[21]
able hydrogel based on natural polymers: Synthesis, characteriza-
tion, swelling/reswelling and biodegradability. Eur. Polym. J.,
2019, 112, 678-687.
16. 16 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
http://dx.doi.org/10.1016/j.eurpolymj.2018.10.033
Fekete, T.; Borsa, J.; Takacs, E.; Wojnarovits, L. Synthesis of cel-
[22]
lulose-based superabsorbent hydrogels by high-energy irradiation
in the presence of crosslinking agent. Radiat. Phys. Chem., 2016,
118, 114-119.
http://dx.doi.org/10.1016/j.radphyschem.2015.02.023
Date, P.; Tanwar, A.; Ladage, P.; Kodam, K.M.; Ottoor, D.
[23]
Biodegradable and biocompatible agarose–poly (vinyl alcohol) hy-
drogel for the in vitro investigation of ibuprofen release. Chem.
Pap., 2020, 1, 1-14.
http://dx.doi.org/10.1007/s11696-019-01046-8
Wang, L.L.; Zheng, W.S.; Chen, S.H.; Han, Y.X.; Jiang, J.D. De-
[24]
velopment of rectal delivered thermo-reversible gelling film encap-
sulating a 5-fluorouracil hydroxypropyl-β-cyclodextrin complex.
Carbohydr. Polym., 2016, 137, 9-18.
http://dx.doi.org/10.1016/j.carbpol.2015.10.042 PMID: 26686100
Mahmood, A.; Ahmad, M.; Sarfraz, R.M.; Minhas, M.U. β-CD
[25]
based hydrogel microparticulate system to improve the solubility
of acyclovir: Optimization through in-vitro, in-vivo and toxicologi-
cal evaluation. J. Drug Deliv. Sci. Technol., 2016, 36, 75-88.
http://dx.doi.org/10.1016/j.jddst.2016.09.005
Asghar, S.; Minhas, M.U.; Ahmad, M.; Khan, K.U.; Sohail, M.;
[26]
Khalid, I. Hydrophobic–hydrophilic cross‐linked matrices for
controlled release formulation of Highly water‐soluble drug ven-
lafaxine: Synthesis and evaluation studies. Adv. Polym. Technol.,
2018, 37, 3146-3158.
http://dx.doi.org/10.1002/adv.22085
Xu, S.; Li, H.; Ding, H.; Fan, Z.; Pi, P.; Cheng, J.; Wen, X. Allylat-
[27]
ed chitosan-poly(N-isopropylacrylamide) hydrogel based on a
functionalized double network for controlled drug release. Carbo-
hydr. Polym., 2019, 214, 8-14.
http://dx.doi.org/10.1016/j.carbpol.2019.03.008 PMID: 30926010