Afzal R. Mohammed

Formulation and characterisation of lyophilised rapid disintegrating tablets using amino acids as matrix forming agents.

Despite recent advances in the formulation of lyophilised rapid disintegrating tablets (RDTs), the inclusion of matrix supporting/disintegration enhancing agents has been limited to the use of saccharides and polyols. In this study, the feasibility of using amino acids as matrix forming agents in lyophilised RDTs was investigated. Twelve amino acids were chosen (alanine, arginine, threonine, glycine, cysteine, serine, histidine, lysine, valine, asparagine, glutamine and proline), and the suitability for freeze drying, mechanical properties and disintegration time after inclusion of the amino acids at varied concentration were studied. In addition, the porosity of the RDTs and wettability profile of the amino acids were investigated to understand the mechanisms of disintegration. The results suggest the suitability of these amino acids for the lyophilisation regime, as they displayed satisfactory safety margin between the glass transition and shelf temperature (-40 degrees C), except proline-based formulations. Moreover, the crystallisation behavior of alanine, glycine, cysteine and serine at high concentration increased the stability of the formulation. The characterisation of the RDTs suggests that high concentration of the amino acids is required to enhance the mechanical properties, whereas only optimum concentrations promote the disintegration. Moreover, wetting time of the amino acid and porosity of the tablet are the two factors that control the disintegration of RDTs.

Formulation of multiparticulate systems as lyophilised orally disintegrating tablets

The current study aimed to exploit the electrostatic associative interaction between carrageenan and gelatin to optimise a formulation of lyophilised orally disintegrating tablets (ODTs) suitable for multiparticulate delivery. A central composite face centred (CCF) design was applied to study the influence of formulation variables (gelatin, carrageenan and alanine concentrations) on the crucial responses of the formulation (disintegration time, hardness, viscosity and pH). The disintegration time and viscosity were controlled by the associative interaction between gelatin and carrageenan upon hydration which forms a strong complex that increases the viscosity of the stock solution and forms tablet with higher resistant to disintegration in aqueous medium. Therefore, the levels of carrageenan, gelatin and their interaction in the formulation were the significant factors. In terms of hardness, increasing gelatin and alanine concentration was the most effective way to improve tablet hardness. Accordingly, optimum concentrations of these excipients were needed to find the best balance that fulfilled all formulation requirements. The revised model showed high degree of predictability and optimisation reliability and therefore was successful in developing an ODT formulation with optimised properties that were able deliver enteric coated multiparticulates of omeprazole without compromising their functionality.

Environmental Scanning Electron Microscopy Offers Real-Time Morphological Analysis of Liposomes and Niosomes

Liposomes have been imaged using a plethora of techniques. However, few of these methods offer the ability to study these systems in their natural hydrated state without the requirement of drying, staining, and fixation of the vesicles. However, the ability to image a liposome in its hydrated state is the ideal scenario for visualization of these dynamic lipid structures and environmental scanning electron microscopy (ESEM), with its ability to image wet systems without prior sample preparation, offers potential advantages to the above methods. In our studies, we have used ESEM to not only investigate the morphology of liposomes and niosomes but also to dynamically follow the changes in structure of lipid films and liposome suspensions as water condenses on to or evaporates from the sample. In particular, changes in liposome morphology were studied using ESEM in real time to investigate the resistance of liposomes to coalescence during dehydration thereby providing an alternative assay of liposome formulation and stability. Based on this protocol, we have also studied niosome-based systems and cationic liposome/DNA complexes.

Preparation and Evaluation of Amino Acid Based Salt Forms of Model Zwitterionic Drug Ciprofloxacin

Preparation and Evaluation of Amino Acid Based Salt Forms of Model Zwitterionic Drug Ciprofloxacin Ciprofloxacin (CIP) is a quinolone derivative which is widely used for the treatment of a number of urinary tract infections. It exhibits its antimicrobial activity by inhibiting bacterial DNA gyrase enzyme. BCS classification of CIP is challenging due to the absence of any linear dose proportionality of AUC in humans. Yet, most of the studies classify CIP as a BCS IV (low solubility & low permeability drug) candidate. This study aims at exploiting the zwitterionic nature of CIP and investigates the ability of acidic and basic amino acids to form new salts with the primary aim of improving its solubility. Two salts were prepared using L-glutamic acid and L-aspartic acid as counter ions which resulted in increasing CIP solubility by 2.9x103 and 2.5x103 folds respectively. On the other hand, cationic amino acids namely (L-arginine, L-lysine & L-histidine) failed to form any salts. To investigate the absence of salt formation with the cationic amino acids, the role of inter- and intra molecular interactions between CIP and amino acids on the salt formation was studied using molecular dynamic simulation. Both the experimental and theoretical results revealed that ionic and hydrophobic interactions are essential for salt formation and that the ionic interaction and/or hydrophilic interactions between CIP and amino acids molecules should be greater than hydrophobic interactions between CIP molecules. Future work will study the effect of the salts on the permeability behaviour of CIP across Caco-2 monolayers.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability.

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption.

Designing nonionic surfactant vesicles for the delivery of antigens for systemic and alternative delivery routes

Bilayer vesicles can be prepared from a range of molecules including nonionic surfactants. Vesicles built from nonionic surfactants are known as nonionic surfactant vesicles or niosomes. Whilst structurally similar to liposomes, the use of nonionic surfactants in a formulation may offer advantages in terms of chemical stability and reduced cost in some cases. In general, the ability of surfactant blends to form vesicles is dependent on their combined critical packing parameter, with cholesterol often being used to support the formation of vesicle constructs. To enhance the potency and delivery of antigens, niosomes can be designed to protect antigens against degradation in harsh in vivo environments, including the oral route, and enhance delivery of antigens to appropriate target sites. Key considerations in the design of niosomal adjuvants include the choice of surfactants, the surface properties of the vesicles, the method of preparation, the cholesterol content and the inclusion of immunostimulatory agents. Manipulation of these attributes allows vesicle constructs to be designed and built that can be used to deliver antigens via a range of delivery routes.

Multiparticulate Systems for Paediatric Drug Delivery

This chapter explores the feasibility of formulating drugs as multiparticulates for children. The paediatric population is diverse and ranges from preterm infants to teenagers between 16 and 18 years of age. Salient physiological differences exist within this population as compared with adults which translate to significant changes in pharmacokinetic characteristics of administered drugs. Thus paediatrics should not be treated as ‘miniature’ adults requiring simple dose reduction during drug therapy administration. Factors such as physiology/drug pharmacokinetics, child capability, duration and frequency of therapy, convenience and acceptability as well as impact on caregivers must be considered during choice and design of paediatric dosage forms. Multiparticulates are solid dosage forms containing small discrete spherical subunits <2.5 mm in size, with each unit displaying characteristic functionalities that are independent of other subunits. Multiparticulates present a versatile and convenient dosage form with multiple applications such that they can be sprinkled on semisolid meals for younger children, or compressed into fast disintegrating tablets for older children. Major considerations during paediatric multiparticulate drug development include palatability and taste masking since these are oral dosage forms that release the drug in close proximity of the taste buds, robustness of coatings that give each subunit its individualised functionality, safe use of excipients as well as the ease of extemporaneous preparations where individual dose titration may be required. The World Health Organization (WHO) has proposed a paradigm shift from the use of liquids to age-appropriate solid dosage forms for paediatrics, and this may result in an increased number of approved multiparticulate paediatric formulations in the market.