Muhammad Usman Minhas

Synthesis of chemically cross-linked polyvinyl alcohol-co-poly (methacrylic acid) hydrogels by copolymerization; a potential graft-polymeric carrier for oral delivery of 5-fluorouracil

Background of the StudyThe propose of the present work was to develop chemically cross-linked polyvinyl alcohol-co-poly(methacrylic acid) hydrogel (PVA-MAA hydrogel) for pH responsive delivery of 5-Fluorouracil (5-FU).MethodsPVA based hydrogels were prepared by free radical copolymerization. PVA has been cross-linked chemically with monomer (methacrylic acid) in aqueous medium, cross-linking agent was ethylene glycol di-methacrylate (EGDMA) and benzoyl peroxide was added as reaction initiator. 5-FU was loaded as model drug. FTIR, XRD, TGA and DSC were performed for characterization of copolymer. Surface morphology was studied by SEM. pH sensitive properties were evaluated by swelling dynamics and equilibrium swelling ratio at low and higher pH.ResultsFTIR, XRD, TGA and DSC studies confirmed the formation of new copolymer. Formulations with higher MAA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release has been observed at pH 7.4.ConclusionsThe current study concludes that a stable copolymeric network of PVA was developed with MAA. The prepared hydrogels were highly pH responsive. This polymeric network could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.

Cross-linked β-cyclodextrin and carboxymethyl cellulose hydrogels for controlled drug delivery of acyclovir

To explore the potential role of polymers in the development of drug-delivery systems, this study investigated the use of β-cyclodextrin (β-CD), carboxymethyl cellulose (CMC), acrylic acid (AA) and N’ N’-methylenebis-acrylamide (MBA) in the synthesis of hydrogels for controlled drug delivery of acyclovir (ACV). Different proportions of β-CD, CMC, AA and MBA were blended with each other to fabricate hydrogels via free radical polymerization technique. Fourier transform infrared spectroscopy (FTIR) revealed successful grafting of components into the polymeric network. Thermal and morphological characterization confirmed the formation of thermodynamically stable hydrogels having porous structure. The pH-responsive behaviour of hydrogels has been documented by swelling dynamics and drug release behaviour in simulated gastrointestinal fluids. Drug release kinetics revealed controlled release behaviour of the antiviral drug acyclovir in developed polymeric network. Cross-linked β-cyclodextrin and carboxymethyl cellulose hydrogels can be used as promising candidates for the design and development of controlled drug-delivery systems.

Alginate-polyvinyl alcohol based interpenetrating polymer network for prolonged drug therapy, Optimization and in-vitro characterization

A new natural and synthetic polymeric blend to form interpenetrating polymer network (IPN) hydrogels was synthesized utilizing sodium alginate and PVA as polymers by free radical polymerization employing 2-Acylamido-2-methylpropane-sulfonic acid as monomer (AMPS) and tramadol HCl as model drug through 32 level full factorial design to evaluate the impact of selected independent factors i.e. polymer (sodium alginate) and monomer (AMPS) contents on swelling index at 18th hour, percent drug release at 18th hour, time required for 80% drug release and drug entrapment efficiency as dependent variables. FTIR, SEM, sol-gel analysis, equilibrium swelling studies and in-vitro release kinetics were performedfor in-vitro characterization of formulated IPN hydrogels. In-vitro studies carried out at pH 1.2 and pH 7.4 revealed pH independent swelling and drug release from polymeric IPN, providing controlled drug release for an extended period of time with improved entrapment efficiency, thereby concluding that this polymeric blend may be a promising system for the prolonged drug delivery.

Synthesis and evaluation of chondroitin sulfate based hydrogels of loxoprofen with adjustable properties as controlled release carriers

Mixtures of polymer (chondroitin sulfate) and monomer (AMPS) in the presence of co-monomer (MBA) were employed for the production of hydrogels, with adjustable properties, following free radical copolymerization. The hydrogels structural properties were assessed by FTIR, DSC, TGA, SEM and XRD which confirmed the development and stability of synthesized structure. The results from FTIR analysis showed that CS react with the AMPS monomer during the polymerization process and confirmed the grafting of AMPS chains onto CS backbone. The surface morphology of CS-co-poly(AMPS) hydrogels, as evident by SEM, corresponds to their improved swelling ability due to high porosity. Thermal analysis showed that crosslinking formed a stable hydrogel network which is thermally more stable than its basic ingredients. The effects of pH revealed an increasing trend in swelling with increasing concentration of either CS or AMPS. In addition, different modalities for drug loading were studied with respect to drug homogeneous distribution; loxoprofen sodium was employed as model drug and was loaded by swelling-diffusion method. In vitro drug release profiles and kinetics were assessed to confirm their reproducibility and reliability. Higuchi model is the best fit model to explain drug release from formed gels indicating diffusion-controlled release. Similarly, Korsmeyer-Peppas model yields remarkably good adjustments where release kinetics involves a combination of diffusion in hydrated matrix and polymer relaxation. Conclusively, CS-co-poly(AMPS) hydrogels could be a potential alternate to conventional dosage forms for controlled delivery of loxoprofen sodium for extended period of time.

Preparation and characterization of alginate-PVA-based semi-IPN: controlled release pH-responsive composites

The objective was to develop naturally derived polymer-based hydrogels with high mechanical strength and a controlled delivery of drug for extended period of time. Here, we report the fabrication of chemically cross-linked polyvinyl alcohol-graft-poly(acrylic acid)/sodium alginate hydrogel as a semi-interpenetrating polymer network (SIPN). For the preparation of SIPN hydrogels, SA and PVA were cross-linked with AA monomer in the presence of co-monomer EGDMA through free-radical polymerization reaction, using APS as an initiator. Loxoprofen sodium was loaded as a model drug. FTIR, XRD, TGA, and DSC were performed for the characterization of copolymer. Surface morphology was studied by SEM. Swelling studies were carried out at low and higher pH to evaluate pH-dependent swelling of formed SIPN hydrogels. FTIR, XRD, TGA, and DSC studies confirmed the formation of a new copolymer. Developed SIPN hydrogels showed maximum swelling, drug loading, and drug release at pH 7.4 while low at pH 1.2. Moreover, formulations with higher AA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release have been observed at pH 7.4. In vitro release profile of loxoprofen sodium was found dependent on pH, concentration of monomers, and cross-linking agent. Gel% and yield% for the prepared SIPN hydrogels were determined and found that gel% or yield% is directly proportional to the concentration of polymers, i.e., SA and PVA, due to their behavior as macromolecule radicals for monomer. The results from FTIR analysis showed that both SA and PVA react with the acrylic acid monomer during the polymerization process and result into the formation of SIPN. The formation of semi-IPN structure significantly improved the surface morphology of SIPN hydrogels as evident by SEM, which corresponds to their improved swelling ability and mechanical strength. Drug release mechanism from the formed SIPN was explained by kinetic modeling and found that first-order, Higuchi model, and Korsmeyer–Peppas model are the best fit models to explain drug release from hydrogels. Conclusively, prepared hydrogels were highly pH-responsive and showed good mechanical strength and time-dependent drug release. SIPN hydrogels could be a potential carrier network for controlled delivery of loxoprofen sodium for extended period of time.

Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

OBJECTIVE The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of 800 mg piracetam. METHODS A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. RESULTS The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). CONCLUSIONS A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study. It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice.

Formulation and in vitro evaluation of mucoadhesive controlled release matrix tablets of flurbiprofen using response surface methodology

The objective of the current study was to formulate mucoadhesive controlled release matrix tablets of flurbiprofen and to optimize its drug release profile and bioadhesion using response surface methodology. Tablets were prepared via a direct compression technique and evaluated for in vitro dissolution parameters and bioadhesive strength. A central composite design for two factors at five levels each was employed for the study. Carbopol 934 and sodium carboxymethylcellulose were taken as independent variables. Fourier transform infrared (FTIR) spectroscopy studies were performed to observe the stability of the drug during direct compression and to check for a drug-polymer interaction. Various kinetic models were applied to evaluate drug release from the polymers. Contour and response surface plots were also drawn to portray the relationship between the independent and response variables. Mucoadhesive tablets of flurbiprofen exhibited non-Fickian drug release kinetics extending towards zero-order, with some formulations (F3, F8, and F9) reaching super case II transport, as the value of the release rate exponent (n) varied between 0.584 and 1.104. Polynomial mathematical models, generated for various response variables, were found to be statistically significant (P<0.05). The study also helped to find the drugs optimum formulation with excellent bioadhesive strength. Suitable combinations of two polymers provided adequate release profile, while carbopol 934 produced more bioadhesion.

Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.

Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects

Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti-inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target-specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC.

Novel polymeric composites based on carboxymethyl chitosan and poly(acrylic acid): in vitro and in vivo evaluation

The purpose of the study was to develop a novel, efficient, stable, chemically crosslinked polymeric system that have pH responsive behaviour and can effectively release 5-FU in a controlled manner. Furthermore it can target colonic cancer minimizing the side effects of in vivo chemotherapy via 5-FU. Swelling and drug release studies were performed to evaluate its in vitro release behaviour. Hydrogels were also characterized by FTIR, SEM and DSC. In vitro cytocompatibility and cytotoxicity of the hydrogels were determined by MTT assay using HeLa cells. Developed hydrogels were then administered to rabbits orally to evaluate its pharmacokinetic behaviour in vivo. Maximum swelling, drug loading and release were observed at pH 7.4. Similarly maximum absorption was achieved at pH 7.4 in rabbits. It is concluded that CMC-co-poly(AA) have a great potential to be used for controlled drug delivery and colonic targeting for the delivery for various anticancer drugs.Graphical Abstract