Formulation and Development of Oral Sustained Release Systems for Selected Drug Candidates

This thesis deals with the investigations carried out by the writer with the objective of developing oral sustained release formulations for widely used antiviral drug acyclovir and anti emetic drug prochlorperazine maleate for the evaluation of their sustained release potential with the commercially available immediate release tablets. The first chapter of the thesis deals with a brief introduction to the conventional drug therapy, concept of sustained release drug delivery system, its relevance with respect to oral drug delivery, the anatomy and physiological considerations of the GIT, oral controlled release drug delivery system, significance and reasons for developing oral controlled release drug delivery system (CRDDS), ideal drug candidates for CRDDS, types of sustained/controlled release products, monolithic matrix system as oral CRDDS, mechanism of drug release from HPMC matrix system and estimation of drugs in biological medium. Literature survey on the investigations that have been carried out so far on the development of sustained release drug delivery systems and current developments for the selected drug candidates is being mentioned. The aim and objectives along with the place of work is presented in the second chapter of the thesis. In particular, it explains the need for designing a suitable drug delivery system for the drug candidates selected in the present investigation. The third chapter of the thesis explains in detail the experimental procedures that were adopted, namely preformulation studies, formulation and evaluation of sustained release sustained release tablets, stability studies of the developed formulations, bioanalytical method development with its validation and bioavailability studies. The fourth chapter describes in detail the experimental results obtained in the present study along with detailed discussion of the results supported by photographic plates, tables and figures. The pharmacokinetic parameters of the two different formulations of acyclovir and prochlorperazine maleate were compared statistically by one way ANOVA (analysis of variance) by using SPSS version 13.0. The pharmacokinetic parameters like Cmax, Tmax, AUC0-t, t½, Kel and AUC0-∞ of the immediate release and sustained release formulations of acyclovir and prochlorperazine maleate were found to be significantly different (p <0.05) by one way ANOVA. Based on these observations, it is concluded that the formulated matrix tablets containing acyclovir and prochlorperazine are capable of exhibiting sustained release properties, stable and feasible for industrial scale production. Thus they are capable of reducing the dose intake, minimize the blood level oscillations, dose related adverse effects, cost and ultimately improve the patient compliance in the therapeutic management of herpes simplex, herpes zoster for acyclovir and nausea associated with vomiting in the radiation induced cancer therapy for prochlorperazine maleate. Further studies involving their suitability for long time application, shelf life determination, bioavailability and clinical investigations in large populations may, however, be necessary to further establish its potential and therapeutic efficacy

SUSTAINED RELEASE MICROBEADS OF RITONAVIR: IN VITRO AND IN VIVO EVALUATION

Objective: The main aim of the present investigation was to develop sustained release microbeads of ritonavir that has a shorter half-life (3-5 h) and requires twice a day administration. These formulations exhibit a sustained release of ritonavir that would expect to improve the therapy, better drug utilization, and patient compliance. Methods: Gellan-chitosan and calcium chloride reinforced beads of ritonavir were prepared by ionotropic gelation method employing different concentrations of gellan, chitosan, calcium chloride and drug. The prepared beads were evaluated for various physicochemical parameters such as particle size determination, drug entrapment efficiency, swelling studies, infrared spectroscopy study, differential scanning calorimetry, x-ray diffraction analysis, scanning electron microscopy, in vitro drug release study and in vivo bioavailability studies. Results: From the results, formulation GC-II exhibited higher drug entrapment efficiency (79.65±0.012), higher swelling index, sustained drug release over a period of 24 h, increased oral bioavailability (2.07 times higher than that of pure drug) and decreased elimination rate (2.15 times lesser for ritonavir microbeads) with prolonged elimination half-life (2.15 times more than pure drug) as compared to pure drug. Conclusion: Ritonavir microbeads have demonstrated as a better delivery system for the sustained release of the drug; which may in turn circumvent the drawbacks associated with the conventional therapy

NANOSPONGES: A REVIEW

The recent advance in nanotechnology has lead to the development of targeted drug delivery system. However, targeting a molecule to a particular site using a drug delivery system effectively requires a specialized drug delivery system. The discovery of nanosponge has become a significant step in overcoming certain problems such as drug toxicity, poor bioavailability and release of drug in a predictable fashion as they can accommodate both hydrophilic and hydrophobic drug. Nanosponges exhibit a porous structure in nature which has the unique ability to entrap the drug moieties and offers a merit of desire release. Nanosponges are tiny sponges that can circulate in the body to reach the specific site and binds on the surface to release the drug in a controlled and predictable manner. Nanosponges can be formulated by crosslinking of cyclodextrine with carbonyl or di-carboxylate (Crosslinkers). Nano sponge's technology has been explored widely for the delivery of drugs for oral administration, topical administration, and parental administration. Nanosponges can also serve as an effective carrier for enzyme, proteins, vaccine and antibodies. The present review highlights the method of preparation, characterization and their potential application in drug delivery system

DISSOLUTION ENHANCEMENT OF DIACEREIN USING WATER SOLUBLE CARRIER BY SOLID DISPERSION TECHNOLOGY

Diacerein is generally used in the treatment of Osteoarthritis , this drug comes under the class anthraquinone. The drug is practically insoluble in water and exhibits exceptionally slow and intrinsic dissolution rate with poor bioavailability. In the present study, diacerein and β-cyclodextrin (β-CD) solid dispersions were prepared with a view to study the effect and influence of β-CD on the solubility and dissolution rate of this poorly aqueous soluble drug. Phase solubility profile revealed that the solubility of diacerein was significantly increased in the presence of β-CD and indicating the possible 1:1 stoichiometric inclusion complex with a stability constant of 339.66 M-1. Effect of variable such as drug: Carrier ratios were studied. Physical characterization of the solid dispersion was characterized by Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction studies (XRD). These studies revealed that a distinct loss of drug crystallinity in the solid dispersion is ostensibly accounting for enhancement of dissolution rate in distilled water containing 0.1% Tween 80. The scanning electron microscopy (SEM) study revealed that all the binary systems appeared as agglomerates and exhibiting the presence of a homogenous solid phase which could also be responsible for the enhanced dissolution rate in comparison with the pure drug. The drug release from the prepared solid dispersion exhibited a first order kinetics. Solid dispersion of diacerein showed a 7.66 times fold increase in dissolution rate over the pure drug

Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology

Polymeric nanoparticles (NPs) are particles within the size range from 1 to 1000 nm and can be loaded with active compounds entrapped within or surface-adsorbed onto the polymeric core. The term “nanoparticle” stands for both nanocapsules and nanospheres, which are distinguished by the morphological structure. Polymeric NPs have shown great potential for targeted delivery of drugs for the treatment of several diseases. In this review, we discuss the most commonly used methods for the production and characterization of polymeric NPs, the association efficiency of the active compound to the polymeric core, and the in vitro release mechanisms. As the safety of nanoparticles is a high priority, we also discuss the toxicology and ecotoxicology of nanoparticles to humans and to the environment.This research was supported by the Portuguese Science and Technology Foundation (FCT/MCT) and from European Funds (PRODER/COMPETE) through the projects M-ERA-NET/0004/2015-PAIRED, UIDB/04469/2020 (strategic fund) and UIDB/04033/2020 (to CITAB), co-financed by FEDER, under the Partnership Agreement PT2020info:eu-repo/semantics/publishedVersio

Recent Amendments in Handling Clinical Trials in India (Schedule Y)

India has been considered as a hub for conducting various multi centre trials, the Central Drugs Standard Control Organization (CDSCO), headed by the Drug Controller General of India (DCGI), lays down the regulations for the conduct of clinical trials in India. This trend has but changed from 2011 when most of the trials are being outsourced to other countries like China and Philippines. The conduct of trials, regulations in India and quality of data generated may be the cause for this development. Updating our knowledge about these is of utmost importance in today turbulent scenario that prevails in the pharmaceutical industry. The path was smooth until 2011, when a dramatic drop in conducting and delivering the international Randomized controlled trials (RCT) outsourced to India was noticed. According to certain calculations, this drop is up to 50%. At the same time international outsourcing of RCTs to China, Russia and Philippines has increased. In a pursuit to find an answer to this drastic decline, the conduct of trials, ethics, regulatory environment and the quality of data, all are challenged. This review focuses on the changes in regulatory aspects introduced subsequently and their impact on clinical trials in India. Some proposals of amendment in D and C rules have been approved by Drug Technical Advisory Board (DTAB)

Nanomaterials in the Wound Healing Process: New Insights and Advancements

Wounds, which are becoming more common as a result of traumas, surgery, burns, and chronic illnesses like diabetes, remain a critical medical problem. Infectious bacteria impact the healing process, particularly if its biofilm (biological films) leads to a prolonged effect. Nanomaterials have emerged as promising candidates in the field of wound healing due to their unique properties and versatile applications. New insights into the interactions between nanomaterials and wound microenvironments have shed light on the mechanisms underlying their therapeutic effects. However, a significantly minimal amount of research has been carried out to see if these nanomaterials significantly promote the wound healing process. In this review, we provided an outline of the various types of nanomaterials that have been studied for healing wounds and infection prevention. Overall, the utilization of nanomaterials in wound healing holds great promise and continues to evolve, providing new opportunities for the development of effective and efficient wound care therapies

Effect of Hydrophilic Polymers on the Release Rate and Pharmacokinetics of Acyclovir Tablets Obtained by Wet Granulation: In Vitro and In Vivo Assays

This study aims to evaluate the feasibility of producing acyclovir-containing modified release matrix tablets by a wet granulation method based on the type and concentration of two pharmaceutical-grade hydrophilic matrix polymers (i.e., hydroxypropyl methylcellulose (HPMC), carbomers, and their combinations) commonly used in biomedical applications. The mechanical properties of the tablets and in vitro and in vivo performance were studied. The physicochemical properties of the raw materials and corresponding physical mixtures were characterized by differential scanning calorimetry, showing that the hydrophilic polymers did not influence the physicochemical properties of the drug. The wet granulation process improved the flow and compression properties of the obtained granules. This method enabled the preparation of the matrix tablets of acyclovir with appropriate mechanical properties concerning hardness and friability. The drug release kinetics was governed by the type and concentration of the hydrophilic polymers composing the matrices. The study has proven that HPMC-composed tablets were superior in modified drug release properties compared to carbomer- and HPMC/carbomer-based tablets. Mathematical analysis of the release profiles, determined in a medium adjusted to pH 1.2 followed by pH 7.4, revealed that the drug released from the hydrophilic tablets followed non-Fickian first-order kinetics. An optimal HPMC-based formulation submitted to accelerated stability studies (40 &deg;C, 75% RH) was stable for three months. A complete cross-over bioavailability study of the selected acyclovir-loaded sustained release tablets and marketed immediate-release tablets were compared in six healthy male volunteers. The extent of drug absorption from the sustained release tablets was significantly greater than that from immediate-release pills, which may improve the drug&rsquo;s antiviral properties attributed to the lower elimination rate and enhanced acyclovir half-life

Physicochemical, pharmacokinetic and pharmacodynamic characterization of isradipine tablets for controlled release

Isradipine is a dihydropyridine calcium channel blocker (CCB) commonly used as vasodilator with antihypertensive properties. A remote-controlled release formulation for isradipine would substantially improve the clinical outcomes of the patients requiring chronic long-term treatment. In this work, sustained release tablets of isradipine, composed of hydroxypropylmethyl cellulose (HPMC), have been produced by wet granulation and their in vitro and in vivo characterization was compared to a conventional tablet dosage form of immediate release as preliminary assessment. Tablets composed of 15.0% (wt/wt) HPMC exhibited a sustained release profile over a period of 24 hours. The release of isradipine followed a Fickian diffusion pattern obeying to the first order kinetics and the extent of absorption was even higher in comparison to the developed conventional tablets, which showed immediate drug release. In vivo studies were carried out in rabbits, showing that the extent of isradipine absorption from the developed tablets was higher in comparison to immediate release tablets due to the modified release profile obtained for the former (p < 0.05). Our results suggest that sustained release tablets of isradipine are an efficient solid dosage form to overcome the limitations encountered in conventional immediate release tablets.EBS acknowledges the financial support received from the Portuguese Science and Technology Foundation (FCT/MCT) and European Funds (PRODER/COMPETE) for the projects M-ERA-NET/0004/2015-PAIRED and UIDB/04469/2020, co-financed by FEDER, under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio