Profiling gene expression dynamics underpinning conventional testing approaches to better inform pre-clinical evaluation of an age appropriate spironolactone formulation.

There is a need to accelerate paediatric formulation evaluation and enhance quality of early stage data in drug development to alleviate the information pinch point present between formulation development and clinical evaluation. This present work reports application of DNA microarrays as a high throughput screening tool identifying markers for prediction of bioavailability and formulation driven physiological responses. With a focus on enhancing paediatric medicine provision, an oral liquid spironolactone suspension was formulated addressing a paediatric target product profile. Caco-2 cells cultured on transwell inserts were implemented in transport assays in vitro and DNA microarrays were used to examine gene expression modulation. Wistar rats were used to derive in vivo bioavailability data. In vitro, genomic, and in vivo data sets were concurrently evaluated linking drug transport and the genomic fingerprint generated by spironolactone formulation exposure. Significant changes in gene expression are reported as a result of formulation exposure. These include genes coding for ATP-binding cassette (ABC) transporters, solute carrier (SLC) transporters, cytochrome P450 (CYP) enzymes, and carboxylesterase enzymes. Genomic findings better inform pre-clinical understanding of pharmacokinetic and pharmacodynamic responses to spironolactone and its active metabolites than current in vitro drug transport assays alone.

Understanding the compaction behaviour of low-substituted HPC: macro, micro, and nano-metric evaluations.

The fast development in materials science has resulted in the emergence of new pharmaceutical materials with superior physical and mechanical properties. Low-substituted hydroxypropyl cellulose is an ether derivative of cellulose and is praised for its multi-functionality as a binder, disintegrant, film coating agent and as a suitable material for medical dressings. Nevertheless, very little is known about the compaction behaviour of this polymer. The aim of the current study was to evaluate the compaction and disintegration behaviour of four grades of L-HPC namely; LH32, LH21, LH11, and LHB1. The macrometric properties of the four powders were studied and the compaction behaviour was evaluated using the out-of-die method. LH11 and LH22 showed poor flow properties as the powders were dominated by fibrous particles with high aspect ratios, which reduced the powder flow. LH32 showed a weak compressibility profile and demonstrated a large elastic region, making it harder for this polymer to deform plastically. These findings are supported by AFM which revealed the high roughness of LH32 powder (100.09 ± 18.84 nm), resulting in small area of contact, but promoting mechanical interlocking. On the contrary, LH21 and LH11 powders had smooth surfaces which enabled larger contact area and higher adhesion forces of 21.01 ± 11.35 nN and 9.50 ± 5.78 nN, respectively. This promoted bond formation during compression as LH21 and LH11 powders had low strength yield.

Evaluating the role of amino acids and isothermal dry particle coating in modulating buccal permeation of large molecule drug vancomycin.

The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin's permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.

Dissolution rate enhancement, in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions.

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.

Trigger release liposome systems: local and remote controlled delivery?

Target-specific delivery has become an integral area of research in order to increase bioavailability and reduce the toxic effects of drugs. As a drug-delivery option, trigger-release liposomes offer sophisticated targeting and greater control-release capabilities. These are broadly divided into two categories; those that utilise the local environment of the target site where there may be an upregulation in certain enzymes or a change in pH and those liposomes that are triggered by an external physical stimulus such as heat, ultrasound or light. These release mechanisms offer a greater degree of control over when and where the drug is released; furthermore, targeting of diseased tissue is enhanced by incorporation of target-specific components such as antibodies. This review aims to show the development of such trigger release liposome systems and the current research in this field.

Novel, Fully Characterised Bovine Taste Bud Cells of Fungiform Papillae.

Current understanding of functional characteristics and biochemical pathways in taste bud cells have been hindered due the lack of long-term cultured cells. To address this, we developed a holistic approach to fully characterise long term cultured bovine taste bud cells (BTBCs). Initially, cultured BTBCs were characterised using RT-PCR gene expression profiling, immunocytochemistry, flowcytometry and calcium imaging, that confirmed the cells were mature TBCs that express taste receptor genes, taste specific protein markers and capable of responding to taste stimuli, i.e., denatonium (2 mM) and quinine (462.30 µM). Gene expression analysis of forty-two genes implicated in taste transduction pathway (map04742) using custom-made RT-qPCR array revealed high and low expressed genes in BTBCs. Preliminary datamining and bioinformatics demonstrated that the bovine α-gustducin, gustatory G-protein, have higher sequence similarity to the human orthologue compared to rodents. Therefore, results from this work will replace animal experimentation and provide surrogate cell-based throughput system to study human taste transduction.

Formulation and Bioequivalence Testing of Fixed-Dose Combination Orally Disintegrating Tablets for the Treatment of Tuberculosis in the Paediatric Population.

Tuberculosis (TB) is believed to affect around 10 million people worldwide. Treatment for TB includes isoniazid and rifampicin, with fixed-dose combination (FDC) recommended for improved patient compliance. Similarly, orally disintegrating tablets (ODTs) are an increasingly popular dosage form that aid compliance since they do not require swallowing. In this study ODTs of isoniazid and rifampicin, either as discrete or FDC doses, were formulated and bioequivalence between single and combination doses compared using in vitro and in silico approaches. Dissolution profiles were compared using FDA advised difference (f1) and similarity (f2) testing in biorelevant media. Rifampicin release from FDCs decreased by approximately 15% in fed-state media (failed f1 and f2), which was attributed to enhanced rifampicin degradation in the presence of isoniazid at lower pH. Apparent permeability (Papp) values derived from Caco-2 transport studies were included alongside dissolution results into a physiologically based pharmacokinetic (PBPK) model, to simulate in vivo bioavailability in healthy subjects. Models showed no difference in bioavailability between formulations or dosing (fasted or fed) state, despite the failures in dissolution-based bioequivalence testing, highlighting shortcomings in f1 and f2 assessment and the strength of PBPK models.

Evaluation of anti-biofilm activity of acidic amino acids and synergy with ciprofloxacin on Staphylococcus aureus biofilms.

Acidic amino acids, aspartic acid (Asp) and glutamic acid (Glu) can enhance the solubility of many poorly soluble drugs including ciprofloxacin (Cip). One of the mechanisms of resistance within a biofilm is retardation of drug diffusion due to poor penetration across the matrix. To overcome this challenge, this work set to investigate novel counter ion approach with acidic amino acids, which we hypothesised will disrupt the biofilm matrix as well as simultaneously improve drug effectiveness. The anti-biofilm activity of D-Asp and D-Glu was studied on Staphylococcus aureus biofilms. Synergistic effect of combining D-amino acids with Cip was also investigated as a strategy to overcome anti-microbial resistance in these biofilms. Interestingly at equimolar combinations, D-Asp and D-Glu were able to significantly disperse (at 20 mM and 40 mM) established biofilms and inhibit (at 10 mM, 20 mM and 40 mM) new biofilm formation in the absence of an antibiotic. Moreover, our study confirmed L-amino acids also exhibit anti-biofilm activity. The synergistic effect of acidic amino acids with Cip was observed at lower concentration ranges (<40 mM amino acids and <90.54 µM, respectively), which resulted in 96.89% (inhibition) and 97.60% (dispersal) reduction in CFU with exposure to 40 mM amino acids. Confocal imaging indicated that the amino acids disrupt the honeycomb-like extracellular DNA (eDNA) meshwork whilst also preventing its formation.

High-throughput screening of excipients with a biological effect: a kinetic study on the effects of surfactants on efflux-mediated transport.

OBJECTIVE: In this study, we develop and apply a high-throughput screening protocol to investigate the activity of non-ionic surfactants, with a broad range of hydrophilic-lipophilic balance values, against ABCB1-mediated efflux transport and ABCC2-mediated efflux transport. METHODS: Caco-2 cells were grown for 7 days in 96-well plates, then washed and incubated with the test materials for 2 h in the presence of 2.5 µm of either rhodamine 123 (R-123) or 5(6)-Carboxy-2',7' dichlorofluorescein diacetate as probes of ABCB1 and ABCC2, respectively. KEY FINDINGS: Of the surfactants tested, no activity against ABCC2 was detected and all surfactants showing efficacy against ABCB1 had a HLB value of 22 or below. Inhibition of ABCB1 was seen in the order of efficacy to be poloxamer 335 > poloxamer 40 > Crovol A-70 > Myrj S-40 > poloxamer 184 > poloxamer 182 > Etocas 40 > Tween 20 > Etocas 29 > Tween 80 > Acconon C-44 > Span 20. With regard to this inhibition, the distribution of hydrophilic regions is more important than the HLB value. CONCLUSION: This work demonstrates a high-throughput protocol for detecting materials that can modulate ABCB1-mediated efflux. These surfactants could be exploited to improve oral delivery of drugs prone to efflux.

Delivery of Poorly Soluble Drugs via Mesoporous Silica: Impact of Drug Overloading on Release and Thermal Profiles.

Among the many methods available for solubility enhancement, mesoporous carriers are generating significant industrial interest. Owing to the spatial confinement of drug molecules within the mesopore network, low solubility crystalline drugs can be converted into their amorphous counterparts, which exhibit higher solubility. This work aims to understand the impact of drug overloading, i.e., above theoretical monolayer surface coverage, within mesoporous silica on the release behaviour and the thermal properties of loaded drugs. The study also looks at the inclusion of hypromellose acetate succinate (HPMCAS) to improve amorphisation. Various techniques including DSC, TGA, SEM, assay and dissolution were employed to investigate critical formulation factors of drug-loaded mesoporous silica prepared at drug loads of 100-300% of monolayer surface coverage, i.e., monolayer, double layer and triple layer coverage. A significant improvement in the dissolution of both Felodipine and Furosemide was obtained (96.4% and 96.2%, respectively). However, incomplete drug release was also observed at low drug load in both drugs, possibly due to a reversible adsorption to mesoporous silica. The addition of a polymeric precipitation inhibitor HPMCAS to mesoporous silica did not promote amorphisation. In fact, a partial coating of HPMCAS was observed on the exterior surface of mesoporous silica particles, which resulted in slower release for both drugs.

Conceptualisation, Development, Fabrication and In Vivo Validation of a Novel Disintegration Tester for Orally Disintegrating Tablets.

Disintegration time is the key critical quality attribute for a tablet classed as an Orally Disintegrating Tablet (ODT). The currently accepted in vitro testing regimen for ODTs is the standard United States Pharmacopeia (USP) test for disintegration of immediate release tablets, which requires a large volume along with repeated submergence of the dosage form within the disintegration medium. The aim of this study was to develop an in vivo relevant ODT disintegration test that mimicked the environment of the oral cavity, including lower volume of disintegration medium, with relevant temperature and humidity that represent the conditions of the mouth. The results showed that the newly developed Aston test was able to differentiate between different ODTs with small disintegration time windows, as well as between immediate release tablets and ODTs. The Aston test provided higher correlations between ODT properties and disintegration time compared to the USP test method and most significantly, resulted in a linear in vitro/in vivo correlation (IVIVC) (R2 value of 0.98) compared with a "hockey stick" profile of the USP test. This study therefore concluded that the newly developed Aston test is an accurate, repeatable, relevant and robust test method for assessing ODT disintegration time which will provide the pharmaceutical industry and regulatory authorities across the world with a pragmatic ODT testing regime.

Vaccine adjuvant systems: enhancing the efficacy of sub-unit protein antigens.

Vaccination remains a key tool in the protection and eradication of diseases. However, the development of new safe and effective vaccines is not easy. Various live organism based vaccines currently licensed, exhibit high efficacy; however, this benefit is associated with risk, due to the adverse reactions found with these vaccines. Therefore, in the development of vaccines, the associated risk-benefit issues need to be addressed. Sub-unit proteins offer a much safer alternative; however, their efficacy is low. The use of adjuvanted systems have proven to enhance the immunogenicity of these sub-unit vaccines through protection (i.e. preventing degradation of the antigen in vivo) and enhanced targeting of these antigens to professional antigen-presenting cells. Understanding of the immunological implications of the related disease will enable validation for the design and development of potential adjuvant systems. Novel adjuvant research involves the combination of both pharmaceutical analysis accompanied by detailed immunological investigations, whereby, pharmaceutically designed adjuvants are driven by an increased understanding of mechanisms of adjuvant activity, largely facilitated by description of highly specific innate immune recognition of components usually associated with the presence of invading bacteria or virus. The majority of pharmaceutical based adjuvants currently being investigated are particulate based delivery systems, such as liposome formulations. As an adjuvant, liposomes have been shown to enhance immunity against the associated disease particularly when a cationic lipid is used within the formulation. In addition, the inclusion of components such as immunomodulators, further enhance immunity. Within this review, the use and application of effective adjuvants is investigated, with particular emphasis on liposomal-based systems. The mechanisms of adjuvant activity, analysis of complex immunological characteristics and formulation and delivery of these vaccines are considered.

Current opinions and recommendations of paediatric healthcare professionals - The importance of tablets: Emerging orally disintegrating versus traditional tablets.

The appropriate prescribing of paediatric dosage forms is paramount in providing the desired therapeutic effect alongside successful medication adherence with the paediatric population. Often it is the opinion of the healthcare practitioner that dictates which type of dosage form would be most appropriate for the paediatric patient, with liquids being both the most commonly available and most commonly used. Orally disintegrating tablets (ODTs) are an emerging dosage form which provide many benefits over traditional dosage forms for paediatric patients, such as rapid disintegration within the oral cavity, and the reduction in the risk of choking. However the opinion and professional use of healthcare practitioners regarding ODT's is not known. This study was designed to assess the opinions of several types of healthcare professionals (n = 41) regarding ODTs, using a survey across two hospital sites. Results reaffirmed the popularity of liquids for prescribing in paediatrics, with 58.0% of participants preferring this dosage form. ODTs emerged as the second most popular dosage form (30.0%), with healthcare practitioners indicating an increasing popularity amongst patients in the hospital setting, belief with 63.0% of practitioners agreeing that many liquid formulations could be substituted with a suitable ODT. The desired properties of an ideal ODT were also identified by healthcare practitioners preferring a small, fast disintegrating tablet (90.2% and 95.1% respectively), with the taste, disintegration time and flavour being the three most important attributes identified (29.5%, 28.7% and 21.7% respectively). This study provided a pragmatic approach in assessing healthcare professional's opinions on ODTs, highlighting the ideas and thoughts of practitioners who are on the frontline of paediatric prescribing and treatment and gave an indication to their preference for ODT properties.

Quality by Design (QbD) based process optimisation to develop functionalised particles with modified release properties using novel dry particle coating technique.

Quality by Design (QbD), a current trend employed to develop and optimise various critical pharmaceutical processes, is a systematic approach based on the ethos that quality should be designed into the product itself, not just end tested after manufacture. The present work details a step-wise application of QbD principles to optimise process parameters for production of particles with modified functionalities, using dry particle coating technology. Initial risk assessment identified speed, air pressure, processing time and batch size (independent factors) as having high-to-medium impact on the dry coating process. A design of experiments (DOE) using MODDE software employed a D-optimal design to determine the effect of variations in these factors on identified responses (content uniformity, dissolution rate, particle size and intensity of Fourier transform infrared (FTIR) C = O spectrum). Results showed that batch size had the most significant effect on dissolution rate, particle size and FTIR; with an increase in batch size enhancing dissolution rate, decreasing particle size (depicting absence of coated particles) and increasing the FTIR intensity. While content uniformity was affected by various interaction terms, with speed and batch size having the highest negative effect. Optimal design space for producing functionalised particles with optimal properties required maximum air pressure (40psi), low batch size (6g), speed between 850 to 1500 rpm and processing times between 15 to 60 minutes. The validity and predictive ability of the revised model demonstrated reliability for all experiments. Overall, QbD was demonstrated to provide an expedient and cost effective tool for developing and optimising processes in the pharmaceutical industry.

Amino acids as cryoprotectants for liposomal delivery systems.

Liposomes provide an efficient delivery system for solubilisation and delivery of both small and macro molecules. However, they suffer from the disadvantage of instability when stored as aqueous dispersions. Cryoprotection of the liposomal systems provides an effective approach to overcome poor stability whilst maintaining formulation characteristics, although, the formulation of a freeze-dried product requires the consideration of not only the selection of an appropriate cryoprotectant, but also needs careful consideration of the processing parameters including pre-freezing conditions, primary and secondary drying protocols along with optimisation of cryoprotectant concentration. This current work investigates the application of amino acids as potential cryoprotectants for the stabilisation of liposomes, and results indicate that amino acids show biphasic nature of stabilisation with 4 mol of cryoprotectant per mole of the lipid exhibiting optimum cryoprotection. The investigations of process parameters showed that the pre-freezing temperatures below the glass transition of the amino acids followed by drying for over 6h resulted in stable formulations. Studies investigating the efficiency of drug retention showed that the cryoprotection offered by lysine was similar to that shown by trehalose, suggesting that amino acids act as effective stabilizers. ESEM analysis was carried out to monitor morphology of the rehydrated liposomes.

An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug.

Powder blend homogeneity is a critical attribute in formulation development of low dose and potent active pharmaceutical ingredients (API) yet a complex process with multiple contributing factors. Excipient characteristics play key role in efficient blending process and final product quality. In this work the effect of excipient type and properties, blending technique and processing time on content uniformity was investigated. Powder characteristics for three commonly used excipients (starch, pregelatinised starch and microcrystalline cellulose) were initially explored using laser diffraction particle size analyser, angle of repose for flowability, followed by thorough evaluations of surface topography employing scanning electron microscopy and interferometry. Blend homogeneity was evaluated based on content uniformity analysis of the model API, ergocalciferol, using a validated analytical technique. Flowability of powders were directly related to particle size and shape, while surface topography results revealed the relationship between surface roughness and ability of excipient with high surface roughness to lodge fine API particles within surface groves resulting in superior uniformity of content. Of the two blending techniques, geometric blending confirmed the ability to produce homogeneous blends at low dilution when processed for longer durations, whereas manual ordered blending failed to achieve compendial requirement for content uniformity despite mixing for 32 minutes. Employing the novel dry powder hybrid mixer device, developed at Aston University laboratory, results revealed the superiority of the device and enabled the production of homogenous blend irrespective of excipient type and particle size. Lower dilutions of the API (1% and 0.5% w/w) were examined using non-sieved excipients and the dry powder hybrid mixing device enabled the development of successful blends within compendial requirements and low relative standard deviation.

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.

Dosage form preference consultation study in children and young adults: paving the way for patient-centred and patient-informed dosage form development.

OBJECTIVES: The current study aims to evaluate dosage form preferences in children and young adults together with identifying the key pragmatic dosage form characteristics that would enable appropriate formulation of orally disintegrating tablets (ODTs). METHODS: International, multisite, cross-sectional questionnaire of children and young adults aged from 6 to 18 years. Eligibility was based on age, ability to communicate and previous experience in taking medications. The study was carried out at three locations: the UK, Saudi Arabia and Jordan. The questionnaire instrument was designed for participant self-completion under supervision of the study team. RESULTS: 104 questionnaires were completed by the study cohort (n=120, response rate 87%). Results showed that ODTs were the most preferred oral dosage forms (58%) followed by liquids (20%), tablets (12%) and capsules (11%). The preferred colours were pink or white while the preferred size was small (<8 mm) with a round shape. With regard to flavour, strawberry was the most preferred (30.8%), while orange was the least preferred (5.8%). The results also showed that the most important physical characteristics of ODTs were disintegration time followed by taste, size and flavour, respectively. CONCLUSIONS: The results of our study support the WHO's claim for a shift of paradigm from liquid towards ODTs dosage forms for drug administration to young children older than 6 years. Data from this study will also equip formulators to prioritise development of key physical/performance attributes within the delivery system.

Microparticle surface layering through dry coating: impact of moisture content and process parameters on the properties of orally disintegrating tablets.

OBJECTIVES: The aim of this study was to investigate the influence of process parameters during dry coating on particle and dosage form properties upon varying the surface adsorbed moisture of microcrystalline cellulose (MCC), a model filler/binder for orally disintegrating tablets (ODTs). METHODS: The moisture content of MCC was optimised using the spray water method and analysed using thermogravimetric analysis. Microproperty/macroproperty assessment was investigated using atomic force microscopy, nano-indentation, scanning electron microscopy, tablet hardness and disintegration testing. KEY FINDINGS: The results showed that MCC demonstrated its best flowability at a moisture content of 11.2% w/w when compared to control, comprising of 3.9% w/w moisture. The use of the composite powder coating process (without air) resulted in up to 80% increase in tablet hardness, when compared to the control. The study also demonstrated that surface adsorbed moisture can be displaced upon addition of excipients during dry processing circumventing the need for particle drying before tabletting. CONCLUSIONS: It was concluded that MCC with a moisture content of 11% w/w provides a good balance between powder flowability and favourable ODT characteristics.

Colonic delivery of indometacin loaded PGA-co-PDL microparticles coated with Eudragit L100-55 from fast disintegrating tablets.

The aim of this work was to investigate the efficient targeting and delivery of indometacin (IND), as a model anti-inflammatory drug to the colon for treatment of inflammatory bowel disease. We prepared fast disintegrating tablets (FDT) containing IND encapsulated within poly(glycerol-adipate-co-É·-pentadecalactone), PGA-co-PDL, microparticles and coated with Eudragit L100-55 at different ratios (1:1.5, 1:1, 1:0.5). Microparticles encapsulated with IND were prepared using an o/w single emulsion solvent evaporation technique and coated with Eudragit L-100-55 via spray drying. The produced coated microparticles (PGA-co-PDL-IND/Eudragit) were formulated into optimised FTD using a single station press. The loading, in vitro release, permeability and transport of IND from PGA-co-PDL-IND/Eudragit microparticles was studied in Caco-2 cell lines. IND was efficiently encapsulated (570.15±4.2µg/mg) within the PGA-co-PDL microparticles. In vitro release of PGA-co-PDL-IND/Eudragit microparticles (1:1.5) showed significantly (p<0.05, ANOVA/Tukey) lower release of IND 13.70±1.6 and 56.46±3.8% compared with 1:1 (89.61±2.5, 80.13±2.6%) and 1:0.5 (39.46±0.9 & 43.38±3.12) after 3 and 43h at pH 5.5 and 6.8, respectively. The permeability and transport studies indicated IND released from PGA-co-PDL-IND/Eudragit microparticles had a lower permeability coefficient of 13.95±0.68×10-6cm/s compared to free IND 23.06±3.56×10-6cm/s. These results indicate the possibility of targeting anti-inflammatory drugs to the colon using FDTs containing microparticles coated with Eudragit.