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Objective To investigate the effect of formulation parameters on the preparation of transfersomes as sustained-release delivery systems for lidocaine and to develop and validate a new high-performance liquid chromatography (HPLC) method for analysis. Method Taguchi design of experiment (DOE) was used to optimise lidocaine-loaded transfersomes in terms of phospholipid, edge activator (EA) and phospholipid : EA ratio. Transfersomes were characterised for size, polydispersity index (PDI), charge and entrapment efficiency (%EE). A HPLC method for lidocaine quantification was optimised and validated using a mobile phase of 30%v/v PBS (0.01 m) : 70%v/v Acetonitrile at a flow rate of 1 ml/min, detected at 255 nm with retention time of 2.84 min. The release of lidocaine from selected samples was assessed in vitro. Key findings Transfersomes were 200 nm in size, with PDI ~ 0.3. HPLC method was valid for linearity (0.1–2 mg/ml, R2 0.9999), accuracy, intermediate precision and repeatability according to ICH guidelines. The %EE was between 44% and 56% and dependent on the formulation parameters. Taguchi DOE showed the effect of factors was in the rank order : lipid : EA ratio ˃ EA type ˃ lipid type. Optimised transfersomes sustained the release of lidocaine over 24 h. Conclusion Sustained-release, lidocaine-loaded transfersomes were successfully formulated and optimised using a DOE approach, and a new HPLC method for lidocaine analysis was developed and validated.

Purpose The aim of this study was to develop novel paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery. Method Proliposome powder formulations (i.e. F1 – F27) were prepared employing Lactose monohydrate (LMH), Microcrystalline cellulose (MCC) or Starch as a carbohydrate carriers and Soya phosphatidylcholine (SPC), Hydrogenated soya phosphatidylcholine (HSPC) or Dimyristoly phosphatidylcholine (DMPC) as a phospholipid. Proliposome powder formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid phase to carrier ratio (lipid phase; comprising of phospholipid and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used as model anticancer drug. Results Based on flowability studies, out of 27 formulations; F3, F6, and F9 formulations were selected as they exhibited an excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good compressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr’s index. The selected formulations were reduced into Nano (N) vesicles via probe sonication, followed by spray drying (SD) to get a dry powder of these formulations as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) and exhibited poor to very poor compressibility index values via Carr’s Index. Post tablet manufacturing, F3 tablets formulation showed uniform weight uniformity (129.40 ± 3.85 mg), good crushing strength (14.08 ± 1.95 N), precise tablet thickness (2.33 ± 0.51 mm) and a short disintegration time of 14.35 ± 0.56 min, passing all quality control tests in accordance with British Pharmacopeia (BP). Upon nebulization of F3 tablets formulation, Ultrasonic nebulizer showed better nebulization time (8.75 ± 0.86 min) and high output rate (421.06 ± 7.19 mg/min) when compared to Vibrating mesh nebulizer. PTX-loaded F3 tablet formulations were identified as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines while safe to normal MRC-5 cell lines. Conclusion Overall, in this study LMH was identified as a superior carbohydrate carrier for proliposome tablet manufacturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebulization via Ultrasonic nebulizer.

In an attempt to decrease the dose, anticipated side effects, and the cost of production of glibenclamide, GLC, a potent oral hypoglycemic drug, the enhancement of the dissolution and hence the oral bioavailability were investigated. Adsorption and co-adsorption techniques using carriers having a very large surface area and surface active agents were utilized to enhance the drug dissolution. Moreover, the Langmuir adsorption isotherms were constructed to identify the type and mechanism of adsorption. The optimized formulation showing the highest in vitro release was compressed into mini-tablet to facilitate drug administration to elderly patients and those having swallowing difficulties. The produced mini-tablets were tested for their mechanical strength and in vitro release pattern. In addition, the pharmacodynamic and pharmacokinetic studies in New Zealand rabbits were performed using the optimized mini-tablet formulation. Mini-tablets containing GLC co-adsorbate with Pluronic F-68 and Laponite RD showed 100 ± 1.88% of GLC released after 20 min. Pharmacodynamic studies in rabbits revealed significantly higher (p ≤ 0.05) hypoglycemic effect with the optimized mini-tablets at a lower GLC dose compared to mini-tablets containing the commercial GLC dose. Moreover, pharmacokinetic analysis showed significantly higher (p ≤ 0.05) AUC, Cmax, and shorter Tmax. The optimized mini-tablet formulation showed 1.5-fold enhancement of the oral bioavailability compared to mini-tablets containing untreated GLC. It could be concluded that the co-adsorption technique successfully enhanced the oral bioavailability of GLC. Furthermore, the produced mini-tablets have a higher oral bioavailability with a lower GLC dose, which could offer economic benefit for industry as well as acceptability for patients.

Fast-dissolving oral films (FDFs) provide an alternative approach to increase consumer acceptance by advantage of rapid dissolution and administration without water. Usually, FDFs require taste-masking agents. However, inclusion of these excipients could make developing the formulation a challenging task. Hence, this work employed fused-deposition modeling three-dimensional printing to produce single-layered FDFs (SLFDFs), or multilayered FDFs (MLFDFs) films, with taste-masking layers being separated from drug layer. Filaments were prepared containing polyethylene oxide (PEO) with ibuprofen or paracetamol as model drugs at 60°C. Also, filaments were produced containing polyvinyl alcohol and paracetamol at 130°C. Furthermore, a filament was prepared containing PEO and strawberry powder for taste-masking layer. FDFs were printed at temperatures of 165°C (PEO) or 190°C (polyvinyl alcohol) with plain or mesh designs. High-performance liquid chromatography and mass spectroscopy analysis indicated active ingredient stability during film preparation process. SLFDFs had thicknesses as small as 197 ± 21 μm, and MLFDFs had thicknesses starting from 298 ± 15 μm. Depending on the formulation and design, mesh SLFDFs presented disintegration time as short as 42 ± 7 s, and this was 48 ± 5 s for mesh MLFDFs. SLFDFs showed drug content uniformity in the range of 106.0%-112.4%. In conclusion, this study provides proof-of-concept for the manufacturing of FDFs by using 3D printing.

Understanding the effect of surfactant properties is critical when designing vesicular delivery systems. This review evaluates previous studies to explain the influence of surfactant properties on the behavior of lipid vesicular systems, specifically their size, charge, stability, entrapment efficiency, pharmacokinetics, and pharmacodynamics. Generally, the size of vesicles decreases by increasing the surfactant concentration, carbon chain length, the hydrophilicity of the surfactant head group, and the hydrophilic-lipophilic balance. Increasing surfactant concentration can also lead to an increase in charge, which in turn reduces vesicle aggregation and enhances the stability of the system. The vesicles' entrapment efficiency not only depends on the surfactant properties but also on the encapsulated drug. For example, the encapsulation of a lipophilic drug could be enhanced by using a surfactant with a low hydrophilic-lipophilic balance value. Moreover, the membrane permeability of vesicles depends on the surfactant's carbon chain length and transition temperature. In addition, surfactants have a clear influence on pharmacokinetics and pharmacodynamics such as sustaining drug release, enhancing the circulation time of vesicles, improving targeting and cellular uptake.

Sustained-release mini-tablets are a potentially suitable for paediatric drug delivery or as multi-particulate dosage forms.To evaluate the potential for developing lipophilic matrix mini-tablets and to assess the effects of Compritol® 888 ATO concentration on drug release from differently sized mini-tablets prepared by direct compression.A formulation comprising theophylline as a model soluble drug, 15% w/w Compritol® 888 ATO as the inert matrix-forming agent, with dibasic dicalcium phosphate anhydrous and lactose as diluents was evaluated by producing 12 mm tablets at a range of compression speeds and forces. The same formulation and further formulations with 25, 35 or 45% w/w Compritol® 888 ATO were evaluated by producing 2, 3 and 4 mm mini-tablets.Drug release from matrix tablets was sustained over a period of 12 hours and release rate varied according to the compression force and speed employed. The rate of drug release from matrix mini-tablets was more rapid and increasing Compritol® 888 ATO concentration resulted in slower release rates. The rate of drug release from matrix mini-tablets was inversely proportional to mini-tablet size (2 mm3 mm4 mm). Drug release from the matrix tablets and mini-tablets followed square-root of time kinetics.Tailored drug release from matrix mini-tablets may achieved by altering the size of mini-tablet or level of Compritol® 888 ATO in the formulation and this may have potential in the development of paediatric formulations or multi-particulate dosage forms.

Hypromellose, formerly known as hydroxypropylmethylcellulose (HPMC), is by far the most commonly employed cellulose ether used in the fabrication of hydrophilic matrices. Hypromellose provides the release of a drug in a controlled manner, effectively increasing the duration of release of a drug to prolong its therapeutic effect. This review provides a current insight into hypromellose and its applicability to hydrophilic matrices in order to highlight the basic parameters that affect its performance. Topics covered include the chemical, thermal and mechanical properties of hypromellose, hydration of the polymer matrices, the mechanism of drug release and the influence of tablet geometry on drug-release rate. The inclusion of drug-release modifiers within hypromellose matrices, the effects of dissolution media and the influence of both the external environment and microenvironment pH within the gel matrix on the properties of the polymer are also discussed.

The aim was to enhance the dissolution of lornoxicam (LOR) and to produce mini-tablets with an optimised system to provide a rapid-release multi-particulate formulation. LOR systems were prepared through co-evaporation with either polyethylene glycol 6000 or Pluronic(®) F-68 (PLU) and adsorption onto Neusilin(®) US2 alone or co-adsorption in the presence of different amounts of polysorbate 80. All systems were characterised by FT-IR, differential scanning calorimetry, X-ray diffraction, flowability and dissolution techniques. Mini-tablets were prepared using the system with the optimum dissolution profile and flowability. Tensile strengths, content uniformity and dissolution profiles of the mini-tablets were evaluated. The effects of different excipients and storage conditions on mini-tablet properties were also studied. The optimised rapid-release LOR mini-tablets were further evaluated for their in vivo pharmacokinetic profile. The co-evaporate of LOR with PLU showed significantly faster dissolution and superior flowability and was evaluated together with three directly compressible excipients (Cellactose(®) 80, StarLac(®) (STA) and Emcompress(®)) for mini-tablet formulation. The formulation with STA provided the optimum results in terms of tensile strength, content uniformity and rapid drug release following a 3-month stability study and was selected for further in vivo evaluation. The pharmacokinetic profile indicated the potential of the mini-tablets achieving rapid release and increased absorption of LOR.

The consumption of fibers is associated with many health benefits, such as a reduction of cardiovascular and gastrointestinal diseases, control of body weight, and prevention of diabetes. Despite the widespread use of fiber supplements such as capsules or tablets, there is an almost complete lack of information concerning the technological properties of functional fibers used in nutraceutical formulations. The aim of this work was to characterize the technological properties of citrus fibers necessary for their use as a processing aid in tableting. The results obtained showed that citrus fibers share many properties of other polysaccharides used as tableting excipients, such as thermal behavior and compaction mechanism, together with an appreciable tabletability. However, the most interesting properties resulted from their disintegration power. Citrus fibers behaved in a similar manner to the well-known super disintegrant croscarmellose sodium and resulted to be little susceptible to their concentration, to lubricant type, and lubricant concentration. Thus, this work supports the idea of a potential use of citrus fibers as “active” substances and processing aid in the tableting of nutraceutical products and also as functional excipient in pharmaceutical tablets formulation.

The preparation of lipophilic matrix tablets for the sustained release of water soluble drugs via direct compression is not always feasible due to poor flow and rapid drug release. The aim was to evaluate the potential for developing sustained-release diclofenac sodium tablets, using Compritol® 888 ATO as a lipid matrix, by a wet granulation technique. The effects of wet granulation method (planetary mixer and fluid-bed) and liquid binder type (HPMC Metolose® 603, 606 or 615) on weight uniformity, tensile strength and release rates were investigated. The influence of compression force and speed during tablet manufacture under simulated rotary press production conditions were also evaluated. Rapid release of diclofenac sodium from directly compressed matrices was observed. A wet granulation technique using different HPMC binders produced free-flowing granules and matrices which released diclofenac sodium in a sustained manner over several hours. When the formulation comprising the lowest viscosity grade HPMC (Metolose® 603) was further evaluated using a laboratory scale fluid-bed system, consistently sized granules with good flowability and matrices with good weight uniformity and tensile strengths were produced. Release rates were consistent over a range of compression speeds and forces indicating the suitability of the formulation for production on a rotary tablet press.

Hypromellose (HPMC) has been previously used to control drug release from mini-tablets. However, owing to poor flow, production of mini-tablets containing high HPMC levels is challenging. Directly compressible (DC) HPMC grades have been developed by Dow Chemical Company.To compare the properties of HPMC DC (METHOCEL™ K4M and K100M) with regular (REG) HPMC grades.Particle size distribution and flowability of HPMC REG and DC were evaluated. 3 mm mini-tablets, containing hydrocortisone or theophylline as model drugs and 40% w/w HPMC DC or REG were produced. Mini-tablets containing HPMC DC grades were manufactured using a rotary press simulator at forces between 2-4 kN and speeds of 5, 10, 15 or 20 rpm. Mini-tablets containing HPMC REG were produced manually.The improved flowability of HPMC DC grades, which have a narrower particle size distribution and larger particle sizes, meant that simulated large scale production of mini-tablets with good weight uniformity (CV 1.79-4.65%) was feasible. It was not possible to automatically manufacture mini-tablets containing HPMC REG due to the poor flowability of the formulations. Drug release from mini-tablets comprising HPMC DC and REG were comparable. Mini-tablets containing HPMC DC illustrated a higher tensile strength compared to mini-tablets made with HPMC REG. Mini-tablets produced with HPMC DC at different compression speeds had similar drug release profiles.Production of extended release mini-tablets was successfully achieved when HPMC DC was used. Drug release rate was not influenced by the different HPMC DC grades (K4M or K100M) or production speed.

Mini-tablets are compact dosage forms, typically 2-3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices.To develop ER mini-tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate.The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCEL™ K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied.Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements.This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength.

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied.

The aim of this study was to evaluate the compaction behavior of a model two-component amorphous spray-dried dispersion system compared with the unprocessed excipients, using simulated rotary tablet press production conditions.In this study, the stabilizing polymer, hypromellose acetate succinate (HPMCAS), was solubilized and spray dried with and without sodium lauryl sulfate (SLS). The impact of compression force and speed on the tabletting process was quantified by means of tablet tensile strength, compaction energy, and Heckel analysis.Addition of the surfactant SLS, spray dried or as a physical mix, reduced the tablet strength. However, a lesser impact on the unprocessed excipients was observed in comparison with the spray-dried excipients. In the presence of 1% (w/w) SLS, tablets displayed a tendency to cap when compressed at higher speeds, supported by high elastic energy values indicating high uniaxial stress upon decompression. In the presence of 3% (w/w) SLS, tablets could not be produced at high speeds. Heckel analysis revealed a greater strain rate sensitivity of HPMCAS when spray dried in the presence of surfactant. Exposure of samples to a range of relative humidities before compaction had no effect on tablet strength.This study has shown that spray drying of HPMCAS in the presence of a surfactant affects the compressibility of the material, resulting in decreased tablet strength, increased elastic deformation, and capping.

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.

Release profiles of aspirin from hypromellose matrices in hydro-ethanolic media were studied. Percent aspirin released increased with increasing levels of ethanol in the dissolution media, correlating with the drug's solubility, however, dose dumping of aspirin did not occur. An initial rapid release was observed in media comprising 40% ethanol. Release in these conditions was considered to be both erosion and diffusion-mediated, in contrast to the release in 0, 10, 20 and 30% ethanol media, where erosion-controlled release dominated. Image analysis of matrix swelling indicated a slower initial interaction between ethanol and hypromellose accounting for the initial rapid release. Cloud point studies suggested that ethanol retarded hydration of the polymer.

The sticking of a model ibuprofen-lactose formulation with respect to compaction force, punch tip geometry and punch tip embossment was assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Three sets of ‘normal’ concave punches were used to evaluate the influence of punch curvature and diameter. The punches were 10, 11 and 12 mm in diameter, respectively. The 10-mm punch was embossed with a letter ‘A’ logo to assess the influence of an embossment on sticking. Flat-faced punches (12.5 mm) were used for comparison with the concave tooling. Surface profiles (Taylor Hobson Talysurf 120) of the upper punch faces were obtained to evaluate the surface quality of the tooling used. Following compaction, ibuprofen attached to the upper punch face was quantified by spectroscopy. Increasing punch curvature from flat-faced punches to concave decreased sticking. Altering punch diameter of the concave punches had no effect on sticking when expressed as μg mm−2. The embossed letter ‘A’ logo increased sticking considerably owing to the probable concentration of shear stresses at the lateral faces of the embossed logo.

A model formulation, comprising ibuprofen and direct compression lactose (Tablettose 80) was used to assess the influence of two lubricants, magnesium stearate and stearic acid, on punch tip adherence. Lubricant concentrations were varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w colloidal silica (Aerosil 200) were examined, to assess the influence of the glidant on the anti-adherent effects of the lubricants. Differential scanning calorimetry (DSC) was used to examine the effect of the lubricants on the melting temperature of ibuprofen. Tablets were compacted using a single punch tablet press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel punches, tooling was 12.5-mm diameter in each case. The upper punch faces were characterized by obtaining Taylor Hobson Talysurf surface profiles. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. At low concentrations of each lubricant, the levels of sticking observed were similar. Whilst sticking increased at magnesium stearate concentrations above 1%, sticking with stearic acid remained relatively constant at all concentrations. DSC revealed that the melting temperature of ibuprofen was lowered by the formation of eutectic mixtures with both lubricants. However, the onset temperature of melting and melting point were lowered to a greater extent with magnesium stearate compared with stearic acid. When using uncoated tooling at 40 kN, the deleterious effects of magnesium stearate on the tensile strength of the tablets also contributed to sticking. When using chrome-plated punches at 10 kN, the tensile strength reduction by the presence of magnesium stearate was less pronounced, as was the level of sticking.

The sticking of three model ibuprofen–lactose formulations with respect to compaction force and the surface quality of the upper punch were assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Two sets of 12.5-mm flat-faced punches were used to evaluate the influence of surface quality. A third set of chrome-plated tooling was also used. Surface profiles (Taylor Hobson Talysurf 120) of the normal tooling upper punches indicated a large difference in quality. The punches were subsequently classified as old (Ra = 0.33 μm) or new (Ra = 0.04 μm) where Ra is the mean of all positive deviations from zero. Surface profiles of sample tablets were also obtained. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. Punch surface roughness, compaction force and the blend composition were all significant factors contributing to sticking. Chrome plating of punch faces increased sticking at a low compaction force but decreased sticking at higher forces. Surface roughness of the tablets did not correlate with the corresponding data for sticking, indicating that this is not a suitable method of quantifying sticking.