Fabrication of extended-dissolution divalproex tablets: a green solvent-free granulation technique.

Objective: Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short in vivo half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process.Methods: A lab scale high shear mixer granulator employing six meltable lipid binders (compritol®888 ATO, beeswax, gelucire®50/13, precirol® ATO5, stearyl alcohol, and geleol®) was used for the preparation of tablets. Quality control tests were performed on granules and tablets, and Box-Behnken's design was adopted to investigate the effect of binder concentration, impeller speed, and granulation time on the drug dissolution. Shelf and accelerated stability evaluation, taste assessment, and in vivo pharmacokinetic study were conducted on the selected batches.Results: Results revealed that DVS tablets were successfully prepared, and that the in vitro dissolution of the drug was inversely proportional to the binder concentration. Beeswax and compritol® tablets showed similar dissolution profiles to the marketed product Depakote® 500 ER tablets (F1 < 15 and F2 > 50). The selected batches showed lower moisture content (<2%) and successfully masked the bitter taste compared to uncoated tablets based on a hydrophilic matrix. The in vivo pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol® tablets of 95.6% and 118%, respectively, compared to the marketed product.Conclusion: The solvent free HMG process can be employed to formulate 24 h extended dissolution DVS tablets with masked bitter taste and high stability, and comparable or higher bioavailability than the marketed product.

Optimisation of the microencapsulation of lavender oil by spray drying.

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions. Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated. Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography-mass spectrometry. Results: Lavender microparticles of size 12.42 ± 1.79 µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12 mg w/w%), and encapsulation efficiency (77.89 w/w%). Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.

Optimizing the dermal accumulation of a tazarotene microemulsion using skin deposition modeling.

CONTEXT: It is well known that microemulsions are mainly utilized for their transdermal rather than their dermal drug delivery potential due to their low viscosity, and the presence of penetration enhancing surfactants and co-surfactants. OBJECTIVE: Applying quality by design (QbD) principles, a tazarotene microemulsion formulation for local skin delivery was optimized by creating a control space. MATERIALS AND METHODS: Critical formulation factors (CFF) were oil, surfactant/co-surfactant (SAA/CoS), and water percentages. Critical quality attributes (CQA) were globular size, microemulsion viscosity, tazarotene skin deposition, permeation, and local accumulation efficiency index. RESULTS AND DISCUSSION: Increasing oil percentage increased globular size, while the opposite occurred regarding SAA/CoS, (p = 0.001). Microemulsion viscosity was reduced by increasing oil and water percentages (p < 0.05), due to the inherent high viscosity of the utilized SAA/CoS. Drug deposition in the skin was reduced by increasing SAA/CoS due to the increased hydrophilicity and viscosity of the system, but increased by increasing water due to hydration effect (p = 0.009). Models with very good fit were generated, predicting the effect of CFF on globular size, microemulsion viscosity, and drug deposition. A combination of 40% oil and 45% SAA/CoS showed the maximum drug deposition of 75.1%. Clinical skin irritation study showed that the aforementioned formula was safe for topical use. CONCLUSION: This article suggests that applying QbD tools such as experimental design is an efficient tool for drug product design.

Investigating the effect of punch geometry on high speed tableting through radial die-wall pressure monitoring.

Dwell time mainly depends on punch geometry, so some tableting problems such as capping and lamination could occur at high speed compaction. Robust tools are required to monitor the interaction of punch tip and powder bed at these high speeds. Our aim was to investigate the effect of punch geometry (flat and standard concave) on powder compaction at high speed using radial die-wall pressure (RDWP) as a monitoring tool. Instrumented die guided by compaction simulation was applied for five materials with different compaction behaviors. Flat-faced punch showed higher residual, maximum die-wall pressures, and axial stress transmission than concave punches, p < 0.003. Moreover, flat-faced punches showed less friction upon ejection, p < 0.003. Flat compacts showed higher elastic recovery, tensile strength, and required less work of compaction than convex compacts, p < 0.05. RDWP monitoring was a useful tool to prove that flat-faced punch induced higher radial stresses and particle/particle interactions in comparison to concave punch.

Study of radial die-wall pressure during high speed tableting: effect of formulation variables.

With high-speed compaction cycles as applied in pharmaceutical industrial presses, robust tools like radial die-wall pressure (RDWP) are required to monitor the deformation behavior of formulations under pressure and to avoid common problems such as capping. In this study, the effects of common formulation factors such as lubricant, binder, and drug loading on RDW were investigated. Compaction simulation using Presster™ was applied for five pharmaceutical fillers with different compaction behaviors. Two lubricants, two binders and paracetamol as a model drug were used. Residual die-wall (RDP) and other compaction parameters were measured. Lubricant reduced RDP for fillers with plastic/brittle behavior(s), (p < 0.05), while increased RDP for fillers with plastic/elastic behavior, (p < 0.05), leading to higher tendency for capping in the later fillers. Binder reduced RDP for the fillers, (p < 0.05), hence, decreased capping probability. By increasing drug loading for fillers with plastic/elastic behavior(s), RDP was increased, (p = 0.00001), leading to capping, especially at high compaction pressure and speed. Die-wall instrumentation was useful in investigating formulation variables and detecting capping during high speed tableting.

A novel tool for the prediction of tablet sticking during high speed compaction.

During tableting, capping is a problem of cohesion while sticking is a problem of adhesion. Sticking is a multi-composite problem; causes are either material or machine related. Nowadays, detecting such a problem is a pre-requisite in the early stages of development. The aim of our study was to investigate sticking by radial die-wall pressure monitoring guided by compaction simulation. This was done by using the highly sticking drug; Mefenamic acid (MA) at different drug loadings with different fillers compacted at different pressures and speeds. By increasing MA loading, we found that viscoelastic fillers showed high residual radial pressure after compaction while plastic/brittle fillers showed high radial pressure during compaction, p < 0.05. Visually, plastic/brittle fillers showed greater tendencies for adhesion to punches than viscoelastic fillers while the later showed higher tendencies for adhesion to the die-wall. This was confirmed by higher values of axial stress transmission for plastic/brittle than viscoelastic fillers (higher punch surface/powder interaction), and higher residual die-wall and ejection forces for viscoelastic than plastic/brittle fillers, p < 0.05. Take-off force was not a useful tool to estimate sticking due to cohesive failure of the compacts. Radial die-wall pressure monitoring is suggested as a robust tool to predict sticking.

Study of radial die-wall pressure changes during pharmaceutical powder compaction.

CONTEXT: In tablet manufacturing, less attention is paid to the measurement of die-wall pressure than to force-displacement diagrams. OBJECTIVE: Therefore, the aim of this study was to investigate radial stress change during pharmaceutical compaction. MATERIALS AND METHODS: The Presster(TM), a tablet-press replicator, was used to characterize compaction behavior of microcrystalline cellulose (viscoelastic), calcium hydrogen phosphate dihydrate (brittle), direct compressible mannitol (plastic), pre-gelatinized starch (plastic/elastic), and spray dried lactose monohydrate (plastic/brittle) by measuring radial die-wall pressure; therefore powders were compacted at different (pre) compaction pressures as well as different speeds. Residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) were measured. Various tablet physical properties were correlated to radial die-wall pressure. RESULTS AND DISCUSSION: With increasing compaction pressure, RDP and MDP (P < 0.0001) increased for all materials, with increasing precompaction RDP decreased for plastic materials (P < 0.05), whereas with increasing speed MDP decreased for all materials (P < 0.05). During decompression, microcrystalline cellulose and pre-gelatinized starch showed higher axial relaxation, whereas mannitol and lactose showed higher radial relaxation, calcium hydrogen phosphate showed high axial and radial relaxations. Plastic and brittle materials showed increased tendencies for friction because of high radial relaxation. CONCLUSION: Die-wall monitoring is suggested as a valuable tool for characterizing compaction behavior of materials and detecting friction phenomena in the early stage of development.

Geriatric-Oriented High Dose Nutraceutical ODTs: Formulation and Physicomechanical Characterization.

CONTEXT: Oral disintegrating tablets (ODTs) represent a better option than conventional tablets for geriatric population, owing to their fast onset of action and their better patient compliance. OBJECTIVE: Two principal therapeutic high-dose nutraceuticals; chondroitin sulphate and glucosamine were formulated into an oral disintegration tablet (ODT) intended for sublingual administration, and optimized to improve compliance and achieve rapid onset of action in osteoarthritis treatment. MATERIALS AND METHODS: Different formulations were prepared either by melt granulation or direct compression techniques. Excipients at different ratios such as superdisintegrants, pharmaburst™ C1, spray-dried mannitol, and polyethylene glycols were used to enhance the disintegration time for the ODT systems. RESULTS: Although the ODT systems weighed around 1.3 gm with 60% drug load, some systems disintegrated within 2-3 min with 100% drug release. Pharmaburst™ C1 turned out to be the key excipient responsible for the superdisintegration properties of the ODTs. Dissolution enhancement of the two nutraceuticals could be achieved compared to the marketed conventional tablets. CONCLUSION: The improved disintegration and dissolution properties of our prepared ODTs are expected to enhance the bioavailability of the high dose glucosamine and chondroitin sulphate in comparison with conventional tablets, which delineates them as a promising dosage form for the aforementioned nutraceuticals.

Enhancing the Intestinal Permeation of the Chondroprotective Nutraceuticals Glucosamine Sulphate and Chondroitin Sulphate Using Conventional and Modified Liposomes.

BACKGROUND: Liposomes are promising systems for the delivery of macromolecules and poorly absorbed drugs, owing to their ability to compartmentalize drugs, their biodegradability and biocompatibility. OBJECTIVE: The aim of the present study was to formulate and evaluate conventional and modified glucosamine sulphate (GluS) and chondroitin sulphate (CS) liposomal formulations, to enhance their oral permeation for the treatment of osteoarthritis (OA). METHOD: Liposomal formulations were prepared by the thin-film hydration method using two types of phospholipids; Epikuron 200© and Epikuron 200© SH, and three permeation enhancers; poloxamer 407, cetylpyridinium chloride, and sodium deoxycholate. In-vitro characterization of liposomal formulations was conducted in terms of entrapment efficiency, particle size, zeta potential, viscosity, physical stability and mucoadhesive strength. Surface morphology and vesicle shape, ex-vivo intestinal permeation, and histopathological studies were further carried out on the selected formulation. RESULTS: Results showed that the liposomal formulation containing sodium deoxycholate was the most optimum formula, showing high entrapment efficiency (60.11% for GluS and 64.10% for CS) with a particle size of 4.40 µm, zeta potential of -17.2 mV and viscosity of 2.50 cP. CONCLUSION: The aforementioned formula displayed the highest cumulative % permeated of GluS and CS through rabbit intestinal mucosa compared to the solution of drugs and other liposomal formulations (64.20% for GluS and 78.21% for CS) after 2 hours. There were no histopathological alterations in the intestinal tissue, suggesting the safety of the utilized liposomal formulation. In light of the above, liposomes can be considered promising oral permeation-enhancer system for GluS and CS, which is worthy of future bioavailability experimentation.

Jojoba Oil Soft Colloidal Nanocarrier of a Synthetic Retinoid: Preparation, Characterization and Clinical Efficacy in Psoriatic Patients.

BACKGROUND: Nanotechnology has provided substantial benefits in drug delivery, especially in the treatment of dermatological diseases. Psoriasis is a chronic inflammatory skin disease in which topical delivery of antipsoriatic agents is considered the first line treatment. OBJECTIVE: To investigate whether the encapsulation of the synthetic retinoid tazarotene in a nanocarrier based on jojoba oil would decrease its irritation potential and clinically improve its therapeutic outcome in psoriatic patients. METHOD: A microemulsion system based on jojoba wax and labrasol/plurol isostearique was prepared and characterized. RESULTS: The selected formula displayed spherical morphology, particle size of 15.49±2.41 nm, polydispersity index of 0.20 ±0.08, negative charge and low viscosity. The microemulsion provided two folds increase in skin deposition of tazarotene, correlating with higher reduction in psoriatic patients PASI scores after treatment (68% reduction in PASI scores versus 8.96% reduction with the marketed gel). No irritation was encountered in patients using microemulsion, with redness and inflammation reported with the marketed gel-treated patients. CONCLUSION: Jojoba oil microemulsion proved to be advantageous in reducing the irritancy of tazarotene, enhancing its skin deposition and achieving better therapeutic outcome in psoriatic patients.

Formulation of an antispasmodic drug as a topical local anesthetic.

Mebeverine hydrochloride, a spasmolytic agent on GIT smooth muscles, was reported to have a local anesthetic effect. Thus, it was desired in this study to formulate mebeverine HCl into a gel that could be used locally in the treatment of different oral painful conditions. Poloxamer 407 (P-407) was used as the base for this gel. Different additives were used to enhance drug release from the preparation while others were used to enhance the residence time for the preparation. Different formulae were characterized in terms of drug release and mucoadhesion. The formula which has shown the best compromise between the aforementioned parameters was selected for clinical evaluation in comparison to Lidocaine HCl gel and rheologically examined. The best drug release enhancer was cetrimide (0.005%, w/w), while hydroxypropylcellulose (0.5%, w/w) as a mucoadhesive additive has shown the best compromise between fast drug release and mucoadhesion. The gel formula (G) has shown a better pain reduction efficiency (p=0.0078) and longer duration (p=0.0313) than Lidocaine HCl gel. Histopathological examination has shown no change in the inflammatory cells count of rat oral mucosa. Therefore, it could be concluded that (G) is very promising as a local anesthetic preparation for the treatment of different oral painful conditions.

Lipid based nanocapsules: a multitude of biomedical applications.

Lipid nanocapsules with their unique composition represent a promising biocompatible drug delivery platform in nanometer range with narrow size distribution. They are highly stable in comparison to other nano-vectors and were found to impart very desirable characteristics to the therapeutic molecule being delivered within. The current review sheds the light on the methods of preparation of lipid nanocapsules, which are simple and easily scalable, in addition to providing examples of post insertion of some compounds for prolonging vascular circulation, protection, and targeting several diseases. In addition, the review discusses the vast in vitro and in vivo applications of lipid nanocapsules when administered via different routes such as oral, parenteral and transdermal routes. Promising use of nanocapsules in treatment of cancer, Alzheimer's disease, dermatological conditions and other miscellaneous applications are highlighted.

A highlight on lipid based nanocarriers for transcutaneous immunization.

Transcutaneous vaccination has become a widely used technique for providing immunity against several types of pathogens, taking advantage of the immune components found in the skin. The success in the field of vaccination has not only relied on the type of antigen and adjuvant delivered, but also on how they are delivered. In this regard, particulate carriers, especially nanoparticles have evoked considerable interest, owing to the desirable properties that they impart to the substance being delivered. The presentation of antigens by the nanoparticles mimics the presentation of the immunogen by the pathogen; hence, it creates a similar immune response. Furthermore, nanoparticles protect the antigen from degradation and allow its prolonged release, which maximizes its exposure to the immune cells. The most commonly used materials for the formulation of nanoparticles are either polymer-based or lipid based. This review will focus on the lipid based nanocarriers, either vesicular such as liposomes, transfersomes, and ethosomes, or non-vesicular such as cubosomes, solid lipid nanoparticles, nano-structured lipid carriers, solid in oil nanodispersions, lipoplexes, and hybrid polymeric-lipidic systems. The applications of these carriers in the field of transcutaneous immunization will be discussed in this review as well.

Radial die-wall pressure as a reliable tool for studying the effect of powder water activity on high speed tableting.

The effect of moisture as a function of water activity (Aw) on the compaction process is important to understand particle/water interaction and deformation. Studying powder/moisture interaction under pressure with radial die-wall pressure (RDWP) tool was never done. The aim of our study was to use this tool to study this interaction at high compression pressure and speed. Moreover, the effect of changing ejection cam angle (EA) of the machine on ejection force (EF) was investigated. Also, a new tool for prediction of tablet sticking was proposed. Materials with different deformation behaviors stored at low and high moisture conditions were used. Compaction simulation guided by modeling was applied. High Aw resulted in a low residual die-wall pressure (RDP) for all materials, and a high maximum die-wall pressure (MDP) for plastic materials, p < 0.05. This was due to the lubricating and plasticizing effects of water, respectively. However, microcrystalline cellulose showed capping at high Aw and compaction pressure. By increasing compression pressure at high Aw for all materials, effective fall time (EFT) was increased, p < 0.05, showing tendency for sticking. Increasing EA caused an increase of friction and EF for powders, p < 0.05. RDWP was a useful tool to understand particle/moisture interaction under pressure.

Investigating the effect of particle size and shape on high speed tableting through radial die-wall pressure monitoring.

Investigating particle properties such as shape and size is important in understanding the deformation behavior of powder under compression during tableting. Particle shape and size control the pattern of powder rearrangement and interaction in the die and so the final properties of the compact. The aim of this study was to examine the effect of particle size and shape on compactability. Particle friction and adhesion were investigated through radial die-wall (RDW) pressure monitoring. To fulfill this aim, powders and granules of different sizes and shapes of materials with different compaction behaviors were used. Compaction simulation using the Presster with an instrumented die was applied. Small particle size increased residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) (p<0.05) for plastic and viscoelastic materials, respectively, while big particle size had an opposite effect. No effect was found on brittle material, however big particle size showed higher friction for such materials. Regarding morphology, fibrous elongated particles of microcrystalline cellulose had less friction tendency to the die-wall in comparison to rugged surface mannitol particles. RDW pressure monitoring is a useful tool to understand the compactability of particles in respect to size and shape.

A novel formulation for mebeverine hydrochloride.

The antispasmodic drug mebeverine hydrochloride was formulated into a film-forming gel to be used as a topical local anesthetic. A mixture of cellulose derivatives was used as a base. Additives were used to enhance the release as well as the residence time. Formulations were characterized in terms of drug release, mucoadhesion and rheology. Clinically, the selected formula has shown faster onset (p = 0.0156), longer duration (p = 0.0313), better film residence (p = 0.0313), and no foreign body sensation (p = 0.0313) in comparison to Solcoseryl dental paste. Histopathological examination showed no change in inflammatory cells count, concluding that this topical anesthetic is efficacious and safe orally.