One Factor at a Time and factorial experimental design for formulation of l-carnitine microcapsules to improve its manufacturability.

l-carnitine is an essential dietary supplement of physiological importance. Handling and manufacture of l-carnitine is difficult due to its hygroscopic nature, resulting in impairing its flow properties, as well as solid dosage form stability. The study aimed at reducing l-carnitine hygroscopicity through its encapsulation within a hydrophobic, pH-insensitive polymer. A solid in oil in oil (s/o/o) emulsion solvent evaporation technique for microencapsulation was adopted to exclude the possibility of water uptake. The polymers used were two ethyl cellulose (EC) grades with different viscosities. The chosen solvent for the polymer was acetone, and liquid paraffin was the dispersion medium in which both the drug and polymer were insoluble. Sixteen formulations were developed, and evaluated to study the formulation parameters as anti-coalescent type, mixing speed, surfactant type and polymer ratio, and viscosity grade. A "One Factor at A Time" (OFAT) design of experiment, and a factorial design were utilized. Study results revealed that successful microencapsulation occurred by using Aerosil 200 (0.1 %) as anti-coalescent, a mixing speed of 1000 rpm, and Ethocel Std 20 at a 3:1 drug-to-polymer ratio. Microcapsule formulation containing l-carnitine base, successfully compressed into tablets, showed acceptable water content, disintegration time, hardness, and dissolution. Moreover, it showed acceptable stability upon storage at 40 °C at 75 % RH for six months compared to l-carnitine tablets prepared by wet granulation.

A Comparative Study on Cyclodextrin Derivatives in Improving Oral Bioavailability of Etoricoxib as a Model Drug: Formulation and Evaluation of Solid Dispersion-Based Fast-Dissolving Tablets.

Etoricoxib, as a model drug, has a poor solubility and dissolution rate. Cyclodextrin derivatives can be used to solve such a problem. A comparative study was run on three cyclodextrin derivatives, namely ß-CD, HP ß-CD, and SBE ß-CD, to solve the drug problem through the formulation of solid dispersions and their preparation into fast-dissolving tablets. Preparations utilized different (1:1, 1:2, and 1:4) drug:carrier ratios. Nine fast-dissolving tablets (containing 1:4 drug: carrier) were formulated using Prosolv ODT® and/or F-melt® type C as super-disintegrants. Optimized formulation was chosen based on a 32 factorial design. The responses chosen were the outcomes of the in vitro evaluation tests. The optimized formulation that had the highest desirability (0.86) was found to be SD-HP3, which was prepared from etoricoxib: HP ß-CD at a 1:4 ratio using equal amounts of Prosolv ODT® and F-melt® type C. An in vivo evaluation of SD-HP3 on a rabbit model revealed its superiority over the marketed product Arcoxia®. SD-HP3 showed a significantly lower Tmax (13.3 min) and a significantly higher Cmax (9122.156 µg/mL), as well as a significantly higher AUC, than Arcoxia®. Thus, the solubility, dissolution, and bioavailability of etoricoxib were significantly enhanced.

An overview on liquisolid technique: its development and applications.

With its simplicity and cost-effectiveness, the liquisolid technique offers solutions for numerous formulation problems. Among these are dissolution enhancement and sustaining drug release, and the liquisolid technique dealt with both approaches. This review focuses on the latest advances in the technique. It discusses modified additives for use as carrier materials, which secure the required large surface area for enclosing liquids. The review also covers the modern liquipellet technique derived from the extrusion/palletization technique. Also, the liquiground term is introduced, combining the advantages of co-grinding with the liquisolid concept. Furthermore, several grades of Eudragits, and hydrophilic retarding polymers are mentioned to explain modes of sustaining drug release. This review sums up the liquisolid technique development and its applications recently achieved.

What is this review about? This review is about a formulation technique known as 'liquisolid'. The article discusses the application of this technique in enhancing dissolution of water insoluble drugs and sustaining release of other drugs. It also complies the advances in this technique. How is the review structured? This review gives a highlight on the preparation of liquisolid compacts, the additives used formulation for both enhancing drug dissolution and drug release retardation. The review also includes sections for drug-release enhancement and the advances in this method as liquipellets and liquiground. There is also a section for utilizing this technique to sustain and control drug release. What can we conclude? In its simplicity of formulation, liquisolid techniques fits preparing solid dosage forms for a variety of release patterns.

Curcumin-loaded nanostructured lipid carriers prepared using Peceol™ and olive oil in photodynamic therapy: development and application in breast cancer cell line.

PURPOSE: To potentiate the anticancer activity of curcumin (CUR) by improving its cell penetration potentials through formulating it into nanostructured lipid carriers (NLCs) and using the prepared NLCs in photodynamic therapy. METHODS: A 3×4 factorial design was used to obtain 12 CUR-NLCs using two factors on different levels: (1) the solid lipid type at four levels and (2) the solid to liquid lipid ratio at three levels. Olive oil, Tween 80 and lecithin were chosen as liquid lipid, surfactant and co-surfactant, respectively. CUR-NLCs prepared by high shear hot homogenization method were evaluated by determination of particle size (PS), polydispersity index, zeta potential (ZP), entrapment efficiency percent, drug loading percent and in vitro drug release. Optimization was based on the evaluation results using response surface modeling (RSM). Optimized formulae were tested for their in vitro release pattern and for dark and photo-cytotoxic anticancer activity on breast cancer cell line in comparison to free CUR. RESULTS: Evaluation tests showed the appropriateness of NLCs prepared from glyceryl monooleate and Geleol™ helped choosing two optimized formulae, PE3 and GE3. PE3 (prepared using glyceryl monooleate) showed enhanced release rates compared to GE3 (prepared from Geleol) and superior cytotoxic anticancer activity compared to both GE3 and free CUR under both light and dark conditions. The small mean PS, spherical shape as well as the negative ZP enhanced the internalization of the NLCs within cells. Modulation and inhibition of P-glycoprotein expression by glyceryl monooleate synergized the cytotoxic activity of CUR. CONCLUSION: CUR loading in NLCs enhanced its cell penetration and cytotoxic anticancer properties both in dark and in light conditions.

Solving manufacturing problems for L-carnitine-L-tartrate to improve the likelihood of successful product scale-up.

L-carnitine-L-tartrate, a non-essential amino acid, is hygroscopic. This causes a problem in tablet production due to pronounced adhesion of tablets to punches. A 33 full factorial design was adopted to suggest a tablet formulation. Three adsorbents were suggested (Aerosil 200, Aerosil R972, talc) to reduce stickiness at three concentrations (1, 3 and 5 %), and three fillers (mannitol, Avicel PH 101, Dibasic calcium phosphate) were chosen to prepare 27 formulations. Micromeritic properties of formulations were studied, and tablets were prepared by wet granulation. Absence of picking, sticking or capping, recording of sufficient hardness, acceptable friability and tablet ejection force indicated formulation success. The resulting formulation prepared using Avicel PH 101 and 1 % Aerosil 200 was submitted to further investigation in order to choose the most suitable compression conditions using a 33 full factorial design. Variables included compression force, tableting rate and magnesium stearate (lubricant) concentration. The formulation prepared at compression force of 25 kN, using 2 % magnesium stearate, at a production rate of 30 tablets/ minute, was found to be the most appropriate scale up candidate.

Formulation and Evaluation of Nanocrystals of a Lipid Lowering Agent.

Atorvastatin calcium, the lipid lowering agent, is taken as a model drug characterized by poor water solubility and bioavailability. In this study an attempt was made for preparation of nanocrystals using high pressure homogenization. A number of stabilizers were included as well as polymers at different concentrations, and the formulations were homogenized for ten cycles at a pressure of 1000 bars. The obtained nano crystals were evaluated by determining their size, zeta potential, saturated solubility and dissolution rate. Results revealed that Formulation 3, containing (10: 1) drug to sodium lauryl sulphate ratio, possessed the highest saturated solubility and dissolution rate, and hence was analyzed by X-ray diffraction analysis, differential scanning calorimetry, Fourrier transform infrared spectroscopy and scanning electron microscopy. An in-vivo study was carried out on the successful formulation in comparison to drug powder using rats as experimental animals. A significant increase in the area under the concentration-time curve Cpmax and MRT for nanocrystals was observed in comparison to the untreated atorvastatin calcium.

Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies.

Leflunomide, the disease-modifying anti-rheumatic drug was formulated as microspheres for prolonged drug release in the form of intraarticular injection. Eight formulations were developed using three biodegradable PDLG polymers (lactide/glycolide copolymer) and polycaprolactone (PLC) at two drug:polymer ratios (1:2 and 1:4). Solvent evaporation method was employed using polyvinyl alcohol or hydropxypropyl methylcellulose as stabilizers. Formulations were assessed for encapsulation efficiency, yield, particle size, release pattern and SEM. F6 (PDLG 5010), with appropriate particle size and prolonged drug release, was chosen for in-vivo studies using arthritis induced rats, which were intrarticularly injected with F6 or took oral Avara(®). Nuclear factor-kappa B measurements and histopathologic studies were conducted. There was significant reduction of inflammation caused by both F6 and oral Avara(®). Histopathologic studies showed minimal infiltration by chronic inflammatory cells and no angiogenesis in F6 compared to Avara(®). Results also revealed biocompatibility of the polymer used.

Formulation of ketotifen fumarate fast-melt granulation sublingual tablet.

The purpose of this study was to prepare sublingual tablets, containing the antiasthmatic drug ketotifen fumarate which suffers an extensive first-pass effect, using the fast-melt granulation technique. The powder mixtures containing the drug were agglomerated using a blend of polyethylene glycol 400 and 6000 as meltable hydrophilic binders. Granular mannitol or granular mannitol/sucrose mixture were used as fillers. A mechanical mixer was used to prepare the granules at 40 degrees C. The method involved no water or organic solvents, which are used in conventional granulation, and hence no drying step was included, which saved time. Twelve formulations were prepared and characterized using official and non official tests. Three formulations showed the best results and were subjected to an ex vivo permeation study using excised chicken cheek pouches. The formulation F4I possessed the highest permeation coefficient due to the presence of the permeation enhancer (polyethylene glycol) in an amount which allowed maximum drug permeation, and was subjected to a pharmacokinetic study using rabbits as an animal model. The bioavailability of F4I was significantly higher than that of a commercially available dosage form (Zaditen solution-Novartis Pharma-Egypt) (p > 0.05). Thus, fast-melt granulation allowed for rapid tablet disintegration and an enhanced permeation of the drug through the sublingual mucosa, resulting in increased bioavailabililty.

Improvement of dissolution properties of Carbamazepine through application of the liquisolid tablet technique.

The aim of the work was to improve the dissolution properties of the practically insoluble antiepileptic drug, Carbamazepine (CBZ) by adopting the liquisolid compaction technique. Reported liquid load factors, and excipient ratios were used to calculate the required amounts of excipients necessary to prepare the compacts or tablets according to a mathematical model. Avicel PH 102, and Aerosil 200 were used as the carrier and the coating materials, respectively, and explotab was used as disintegrant to prepare four tablet formulae, out of which formula 1 was successfully compressed into tablets. The dissolution patterns of liquisolid CBZ tablets, carried out according to the USP, were comparable to those of Tegretol. The protection of male albino mice against the convulsion, induced by electroshock, was lower in case of liquisolid tablets compared to Tegretol suspension and tablets probably due to the precipitation of CBZ in the silica pores resulting from its high dose.