Preparation of novel solid lipid microparticles loaded with gentamicin and its evaluation in vitro and in vivo

Objective: To formulate and evaluate solid-reversed-micellar-solution (SRMS)-based solid lipid microparticles (SLMs) for intramuscular administration of gentamicin.

Methods: SRMS formulated with Phospholipon® 90G and Softisan® 154 were used to prepare gentamicin-loaded SLMs. Characterizations based on size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release of gentamicin from the SLMs was performed in phosphate buffer while in vivo release studies were conducted in rats.

Results: Maximum EE% of 90.0, 91.6 and 83.0% were obtained for SLMs formed with SRMS 1:1, 1:2 and 2:1, respectively. Stable, spherical and smooth SLMs of size range 9.80?±?1.46?µm to 33.30?±?6.42?µm were produced. The release of gentamicin in phosphate buffer varied widely with the lipid contents. Moreover, significant (p?<?0.05) amount of gentamicin was released in vivo from the SLMs.

Conclusion: SRMS-based SLMs would likely offer a reliable means of delivering gentamicin intramuscularly.     

Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride

Abstract

The low encapsulation efficiency of conventional solid lipid microparticles (SLMs) especially for hydrophilic drugs has remained a challenge to drug formulation experts. This work seeks to address the issue of inefficient delivery of metformin hydrochloride (MTH), a potent hydrophilic oral antihyperglycemic agent, using novel SLMs based on solidified reverse micellar solutions (SRMS) prepared by melt-emulsification using a lipid derived from Capra hircus and Phospholipon® 90H. Characterization based on size, morphology, zeta potential, polydispersity index, encapsulation efficiency (EE%), loading capacity (LC) and time-resolved stability were carried out on the SLMs. The in vitro release of MTH from the SLMs was performed in phosphate buffer (pH 7.4) while the in vivo antidiabetic properties were investigated in alloxan-induced diabetic rats. Stable, spherical and smooth SLMs were obtained. Loading of MTH into the SLMs had no effect on the surface charge of the particles. The SLMs with 1.0%w/w PEG 4000 resulted in significantly (p?<?0.05) higher EE% while those with 2.0%w/w gave the least. The LC values ranged from 20.3 to 29.1 and 14.6 to 24.1 for SLMs containing 500?mg and 250?mg of MTH, respectively. The in vitro release studies revealed significant release of MTH from the SLMs whereas the in vivo antidiabetic studies indicated that novel SLMs containing 500?mg of MTH gave significantly (p?<?0.05) higher glucose reduction than glucophage®. This research has shown that SLMs based on SRMS offer a new and better approach of delivering MTH, thus encouraging further development of this formulation.     

Sustained release indomethacin-loaded solid lipid microparticles based on solidified reverse micellar solution (SRMS): in vitro and in vivo evaluation

Solidified reverse micellar solutions (SRMS) were formulated using phospholipid (Phospholipon 90H) and triglyceride (Softisan 154) in the ratios of 1:1, 2:1 and 1:2, respectively. SLMs were prepared by melt homogenization technique. Characterization based on yield, mean particle diameter and morphology, pH, thermal analysis and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release was carried out in simulated intestinal fluid (SIF, pH 7.5), while the anti-inflammatory and ulcerogenic properties were studied using rats. From the results, the mean particle diameter of SLMs ranged from 2.19 ± 0.05 μm to 20.77 ± 0.03 μm. Maximum EE% of 96, 93 and 94 % were obtained and showed significant variation within the batches (p < 0.05). The release profile of indomethacin-loaded SLMs showed about 82-99 % drug release at 13 h. Indomethacin-loaded SLMs showed good anti-inflammatory and gastro-protective effects, and could be formulated for once-daily administration, either orally or parenterally, under controlled conditions.     

Solid lipid micro-dispersions (SLMs) based on PEGylated solidified reverse micellar solutions (SRMS): a novel carrier system for gentamicin

Abstract

The purpose of this study was to formulate and evaluate novel PEGylated solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) for improved delivery of gentamicin. Lipid matrix (SRMS) [consisting of 15% w/w Phospholipon® 90G (P90G) in 35% w/w dika wax (Irvingia gabonensis) was formulated and characterized by differential scanning calorimetry (DSC). SLMs were formulated by melt-emulsification using the SRMS, PEG 4000 and gentamicin (1.0, 2.0, 3.0% w/w), and their physicochemical as well as pharmacokinetic parameters determined. In vitro permeation of gentamicin from the SLMs through artificial membrane (0.22?μm pore size) was carried out using Franz’s cell and phosphate-buffered saline (PBS, pH 7.4) as acceptor medium, while bioevaluation was performed using clinical isolates of Pseudomonas aeruginosa and Staphylococcus aureus. Stable and irregularly-shaped gentamicin-loaded SLMs of size range 34.49?±?2.56 to 53.52?±?3.09?µm were obtained. The SLMs showed sustained drug permeation and exhibited time-dependent and capacity-limited bioactivity. Overall, SLMs containing 2% w/w SRMS, 3% w/w gentamicin and PEG 4000 entrapped the highest amount of drug, gave highest IZD against the test organisms and highest permeation flux (5.239?μg/cm².min) and permeation coefficient (1.781?×?10^?6?cm/min) within 420?min, while pure gentamicin gave the least. Preliminary in vivo pharmacokinetic studies also showed an AUC-₂₄ of 1507?µg/h/ml for the optimized formulation, while that of oral drug solution was 678?µg/h/ml. This showed a 2.2-fold increase in the systemic bioavailability of gentamicin from the optimized formulation. PEGylated SRMS-based SLMs prepared with heterolipid from Irvingia gabonensis would likely offer a reliable delivery system for gentamicin.     

Analgesic and Micromeritic evaluations of SRMS-based oral Lipospheres of Diclofenac Potassium

The objective of our work was to study the micromeritic properties of lyophilized diclofenac potassium-loaded lipospheres and to evaluate in vivo, the analgesic properties of diclofenac potassium in the lipospheres in addition to other in vitro properties. Solidified reverse micellar solutions were prepared by fusion using 1:1, 2:1, and 1:2% w/w of Phospholipon^® 90H and Softisan^® 154. Diclofenac potassium (1, 3, and 5% w/w) was incorporated into the solidified reverse micellar solutions. Solidified reverse micellar solutions-based lipospheres were formulated by melt homogenization techniques using Ultra-Turrax homogenizer, and thereafter lyophilized to obtain water-free lipospheres. The lipospheres were characterized in terms of particle size and morphology, stability, thermal analysis, drug content, encapsulation efficiency, and loading capacity. The flow properties of the lipospheres were studied using both direct and indirect methods of assessing flow. The analgesic properties of the lipospheres were studied using the hot plate method. Results obtained showed that the yield of diclofenac potassium-loaded lipospheres was high and the particle size ranged from 0.61±0.07 to 2.55±0.04 μm. The lipospheres had high encapsulation efficiency of 95%, which was affected by the amount of drug loaded, while the loading capacity increased with the increase in drug loading. Diclofenac potassium-loaded lipospheres exhibited poor flow. The formulations exhibited good analgesic effect compared with the reference and had 84 to 86% drug release at 13 h. The lipospheres based on solidified reverse micellar solutions could be used for oral delivery of diclofenac potassium.     

Formulation of novel sustained release rifampicin-loaded solid lipid microparticles based on structured lipid matrices from Moringa oleifera

Abstract

Objectives: To formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G).

Methods: Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized in terms of particle morphology and size, percentage drug content (PDC), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats.

Results: Rifampicin-loaded SLMs had particle size range of 32.50?±?2.10 to 34.0?±?8.40?μm, highest PDC of 87.6% and showed stable pH. SLMs had good sustained release properties with about 77.1% release at 12?h in phosphate buffer (pH 6.8) and 80.3% drug release at 12?h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51% degradation of rifampicin in SGF at 3?h, while rifampicin pure sample had 95.5% degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5?μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p?<?0.05).

Conclusion: Rifampicin-loaded SLMs could be used once daily for the treatment tuberculosis.     

Formulation,in vitro and in vivo evaluation of halofantrine-loaded solid lipid microparticles

Abstract

Context: Formulation, characterization, in vitro and in vivo evaluation of halofantrine-loaded solid lipid microparticles (SLMs).

Objective: The objective of the study was to formulate and evaluate halofantrine-loaded SLMs.

Materials and methods: Formulations of halofantrine-loaded SLMs were prepared by hot homogenization and thereafter lyophilized and characterized using particle size, pH stability, loading capacity (LC) and encapsulation efficiency (EE). In vitro release of halofantrine (Hf) from the optimized SLMs was performed in SIF and SGF. In vivo study using Peter’s Four day suppressive protocol in mice and the mice thereafter subjected to histological studies in kidney and liver.

Results: Results obtained indicated that EE of 76.32% and 61.43% were obtained for the SLMs containing 7% and 3% of Hf respectively. The SLMs loaded with 3% of Hf had the highest yield of 73.33%. Time-dependent pH stability analysis showed little variations in pH ranging from 3.49?±?0.04 to 4.03?±?0.05.

Discussion: The SLMs showed pH-dependent release profile; in SIF (43.5% of the drug for each of H₂ and H₃) compared with SGF (13 and 18% for H₂ and H₃ respectively) after 8?h. The optimized SLMs formulation and Halfan® produced a percentage reduction in parasitemia of 72.96% and 85.71% respectively. The histological studies revealed that the SLMs formulations have no harmful effects on the kidney and liver.

Conclusion: SLMs formulations might be an alternative for patients with parasitemia as there were no harmful effects on vital organs of the mice.     

Formulation in vitro and in vivo evaluation of SRMS-based heterolipid-templated homolipid delivery system for diclofenac sodium

The sole objective of this work was to design successful dosage oral forms of diclofenac sodium (DiNa)-loaded solid lipid microparticles (SLM) based on solidified reverse micellar solution (SRMS). Hot homogenization technique was employed to prepare DicNa SLM using a mixture goat fat and Phospholipon® 90?G as lipid matrix and Tween®-80 as mobile surfactant. Characterization based on percentage yield, morphology, particle size, zeta potential, percentage encapsulation, pH and stability of SLMs were investigated. Anti-inflammatory, gastrointestinal tract (GIT) sparing effect and pharmacokinetics were carried out in rat model after oral administration. Results showed that the SLMs were spherical and smooth. The optimized formulation (SLM-4) had particle size of 79.40?±?0.31?µm, polydispersity index of 0.633?±?0.190, zeta potential of ?63.20?±?0.12?mV and encapsulation efficiency of 91.2?±?0.1% with good stability after 8?months of storage. The DicNa SLM had sustained release effect with good anti-inflammatory activity. Higher and prolonged plasma DicNa concentration was shown by the SLM-4 compared to pure drug and a conventional sample. These studies demonstrate that DicNa-loaded SLM based on SRMS could be a promising oral formulation for enhanced bioavailability, pharmacologic activity and gastrointestinal sparing effect of the NSAID, DicNa.     

Novel solidified reverse micellar solution-based mucoadhesive nano lipid gels encapsulating miconazole nitrate-loaded nanoparticles for improved treatment of oropharyngeal candidiasis

Objective: To develop and evaluate solidified-reverse-micellar-solution (SRMS)-based oromucosal nano lipid gels for improved localised delivery of miconazole nitrate (MN).

Methods: Phospholipon^® 90G and Softisan^® 154 (3:7) were used to prepare SRMS by fusion. Solid lipid nanoparticles (SLNs, 0.25–1.0% w/w MN) formulated with the SRMS by high shear homogenisation were employed to prepare mucoadhesive nano lipid gels. Physicochemical characterisation, drug release in simulated salivary fluid (SSF) (pH 6.8) and anti-candidal activity were carried out.

Results: The SLNs were spherical nanoparticles, had mean size of 133.8?±?6.4 to 393.2?±?14.5?nm, low polydispersity indices, good encapsulation efficiency (EE) (51.96?±?2.33–67.12?±?1.65%) and drug loading (DL) (19.05?±?2.44–24.93?±?1.98%). The nano lipid gels were stable, spreadable, pseudoplastic viscoelastic mucoadhesive systems that exhibited better prolonged release and anti-candidal properties than marketed formulation (Daktarin^® oral gel) (p?Conclusion: This study has shown that SRMS-based nano lipid gels could be employed to prolong localised oromucosal delivery of MN.     

Solid lipid microparticles: An approach for improving oral bioavailability of aspirin

The objectives of the work were to develop a lipid based delivery system for aspirin and to evaluate its physicochemical and pharmacodynamic properties. Aspirin-loaded solid lipid microparticles (SLMs) were formulated by hot homogenization and analysed for their encapsulation efficiency (EE%), in vitro release, particle size, anti-inflammatory and ulcer inhibition properties. Particle size ranged from 33.10 ± 5.85 to 43.50 ± 7.27 µm for batches A1 to A3 SLMs loaded with 1, 3 and 5% aspirin and containing Poloxamer 407, while batches B1, B2 and B3 formulated with Soluplus as surfactant had particle size range of 31.10 ± 1.46 to 45.60 ± 2.92 µm. Batches A1 and B1 containing 1% of aspirin had the highest EE of 70 and 72% respectively. Maximum in vitro release of 95.1 and 93.2% were obtained at 8 h from batches A1 and B1 respectively. SLMs exhibited about 77.8% oedema inhibition, while the reference had 66.7% and ulcer inhibition range of 25–75%. Aspirin-loaded SLMs exhibited good properties and could be used orally twice daily for the treatment of inflammation.     

Sustained ocular delivery of Dorzolamide-HCl via proniosomal gel formulation: in-vitro characterization,statistical optimization,and in-vivo pharmacodynamic evaluation in rabbits

Glaucoma is the second cause of blindness worldwide. Frequent administration of traditional topical dosage forms may lead to patient incompliance and failure of treatment. Our study aims to formulate proniosomal gel formulations that sustain the release of the water-soluble anti-glaucoma drug Dorzolamide-HCl (Dorz). Proniosomal gel formulations were prepared using coacervation phase separation method according to a 5² full factorial design. The effects of Cholesterol and surfactant (Span 40) amounts (independent variables) on the percentage entrapment efficiency (EE%), particle size (PS), and the percent of drug released after 8?h (Q8h) (dependent variables (DVs)) were investigated. An optimized formulation (OF) was chosen based on maximizing EE% and Q8h and minimizing PS. An intraocular pressure (IOP) pharmacodynamic study was performed in rabbits to evaluate the in-vivo performance of the OF-gel compared to the marketed Trusopt^® eye drops. The results showed that the independent variables studied significantly affected EE%, PS, and Q8h. OF was the one containing 60?mg Cholesterol and 540?mg Span 40. It had desirability of 0.885 and its actually measured DVs deviated from the predicted ones by a maximum of 4.8%. The in-vivo pharmacodynamic study showed that OF could result in higher reduction in IOP, significantly sustain that reduction in IOP and increase Dorz bioavailability compared to Trusopt^® eye drops. Thus the OF-gel is very promising for being used in glaucoma treatment.     

Effects of diclofenac on the pharmacokinetics of celastrol in rats and its transport

Context: Diclofenac and celastrol are always used together for the treatment of rheumatoid arthritis; the herb–drug interaction potential between diclofenac and celastrol is still unknown.

Objective: This study investigates the effects of diclofenac on the pharmacokinetics of celastrol in rats.

Materials and methods: Twelve male Sprague-Dawley rats were divided into two groups and received celastrol (1?mg/kg) or both celastrol (1?mg/kg) and diclofenac (10?mg/kg) by oral gavage, and blood samples were collected via the oculi chorioideae vein and determined using the LC-MS method developed in this study. Additionally, the effects of diclofenac on the transport of celastrol were investigated using a Caco-2 cell transwell model.

Results: Diclofenac could significantly (p?C_max (from 66.93?±?10.28 to 41.25?±?8.06?ng/mL) and AUC_0-t (from 765.84?±?163.61 to 451.33?±?110.88?μg?×?h/L) of celastrol in rats. The efflux ratio of celastrol increased significantly (p?Discussion and conclusion: These results indicated that diclofenac could decrease the system exposure of celastrol in rats when they are co-administered, and these effects might be exerted via decreasing its absorption in intestine.     

Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

Purpose: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.

Methods: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5?mg TS?g^?1. Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24?h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.

Results: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7–95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM?<?5% GD?<?5% SA?<?5% GB?<?2.5% GM?<?2.5% SA?<?10% GD?<?10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB–2.5?mg TS?g^?1 SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB–2.5?mg TS?g^?1 stored at 5°C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.

Conclusions: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

Suitability of liposomal carriers for systemic delivery of risedronate using the pulmonary route

Abstract

Objective: This study aims at testing the hypothesis that reversed phase evaporation liposomes (REVs) are suitable for systemic delivery of an anti-osteporotic drug (risedronate sodium (RS)) via pulmonary nebulization.

Materials and methods: RS REVs were prepared using phospholipids and cholesterol with or without stearylamine, and were characterized for morphology, entrapment efficiency (EE%), in vitro release, particle size and aerosolization behavior from an actively vibrating mesh nebulizer. RS accumulation in rat bones following intra-tracheal administration of the selected formulation was assessed using a radiolabelling-based technique, and histological examination of rat lung tissue was performed to assess its safety.

Results: The EE% of RS REVs ranged from 8.8% to 58.96% depending on cholesterol molar ratio, phospholipid type and presence of stearylamine. RS REVs’ particle size ranged from 2.15 to 3.61?µm and were spherical and moderately polydisperse. Nebulization of the selected formulation showed an aerosol output of 85%, a fine particle fraction of 70.75% and a predicted alveolar deposition of 30.39%. The amount of radiolabelled RS deposited in rat bones after pulmonary administration was 20%, while being considerably safe on lung tissues.

Conclusion: Cationic REVs is a promising carrier for systemic delivery of RS for treatment of bone resorptive diseases.     

Effects of degree of quaternization on the preparation and characterization of insulin-loaded trimethyl chitosan polyelectrolyte complexes optimized by central composite design

The aim of the present study was to investigate the effects of varying degrees of quaternization (DQ: 22, 35 and 41%) on the preparation and characterization of insulin (INS)-loaded polyelectrolyte complexes (PECs) prepared by N-trimethyl chitosan chloride (TMC). A two factor-five level central composite design was used for the optimization. The concentrations of INS and TMC were defined as independent variables, while the entrapment efficiency (EE%) and loading efficiency (LE%) as dependent variables. The three optimized INS-TMC PECs were characterized for their size, zeta potential, EE% and LE%. The morphology and electrostatic interaction of PECs were evaluated. Then, the stability in the enzyme solution and in vitro release as well as mucoadhesive properties of the three PECs were all investigated. The results showed that the size and EE% of the optimum formulations were significantly decreased using TMC of higher DQ, while the zeta potential and LE% were slightly influenced by DQ. The stability assay exhibited partial protection of TMC PECs, and the better protective effect was observed for PECs of higher DQ. The in vitro release study presented different initial and sustained release behaviors of INS-TMC PECs and the mucin adsorption study confirmed a positive correlation between the DQ and the mucoadhesive property of PECs.     

Colon-targeted celecoxib-loaded Eudragit® S100-coated poly-ϵ-caprolactone microparticles: Preparation,characterization and in vivo evaluation in rats

Context: Celecoxib suffers from low and variable bioavailability following oral administration of solutions or capsules. Recent studies proved that chemoprevention of colorectal cancer is possible with celecoxib.

Objective: This work aimed to tailor colon-targeted celecoxib-loaded microparticles using time-dependant and pH-dependant coats. Estimation of drug pharmacokinetics following oral administration to fasted rats was another goal.

Methods: A 2³ factorial design was adopted to develop poly-?-caprolactone (PCL) celecoxib-loaded microparticles (F1–F8). To minimize drug-percentages released before colon, another coat of Eudragit^® S100 was applied. In vitro characterization of microparticles involved topography, determination of particle size and entrapment efficiency (EE %). Time for 50% drug release (t_50%) and drug-percentages released after 2 hours (Q_2h) and 4 hours (Q_4h) were statistically compared. Estimation of drug pharmacokinetics following oral administration of double-coat microparticles (F10) was studied in rats.

Results: PCL-single-coat microparticles were spherical, discrete with a size range of 60.66?±?4.21–277.20?±?6.10 μm. Direct correlations were observed between surfactant concentration and EE%, Q_2h and Q_4h. The PCL M.wt. and drug: PCL ratio had positive influences on EE% and negative impacts on Q_2h and Q_4h. When compared to the best achieved PCL-single-coat microparticles (F2), the double-coat microparticles (F10) showed satisfactory drug protection; Q_2h and Q_4h were significantly (P?<?0.01) decreased from 31.84?±?1.98% and 54.72?±?2.10% to 15.92?±?1.78% and 26.93?±?2.76%, respectively. When compared to celecoxib powder, F10 microparticles enhanced the bioavailability and extended the duration of drug-plasma concentration in rats.

Conclusion: The developed double-coat microparticles could be considered as a promising celecoxib extended-release colon-targeting system.     

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery,characterization and in vitro deposition study

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20?μm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40?μM of resveratrol.     

Formulation of ciprofloxacin hydrochloride loaded biodegradable nanoparticles: optimization of technique and process variables

Abstract

Poly lactic-co-glycolic acid (PLGA 502 H) nanoparticles incorporating ciprofloxacin HCl (CP) were prepared by double emulsion solvent diffusion technique.

Methods: The influence of the application of probe sonication besides the high pressure homogenization in the preparation of the secondary emulsion and its application during the solidification step were studied. Their effect on the particle size, Zeta potential and the percent encapsulation efficiency of the drug (EE %) were investigated. The effect of the addition of polyvinyl alcohol (PVA) during the preparation of the primary emulsion was studied. Moreover, the effect of the addition of 0.1?M sodium chloride and/or adjusting the external and extracting phases to pH 7.4 were investigated. The selected formula was examined using IR, X-ray, DSC and SEM and in vitro drug release.

Results: These formulations showed an appropriate particle size ranges between 135.7–187.85?nm, a mean zeta potential ranging from ?0.839 to ?6.81?mV and a mean EE% which ranged from 35% to 69%.

Conclusion: The presented data revealed the superiority of using probe sonication besides high pressure homogenization during the formation of secondary emulsion. Moreover, the results indicated that the tested factors had a pronounced significant effect on the EE%.     

Drug interactions of diclofenac and its oxidative metabolite with human liver microsomal cytochrome P450 1A2-dependent drug oxidation

Abstract

1.?The purpose of this study was to investigate the inhibitory effects of diclofenac on human cytochrome P450 1A2-, 2C19- and 3A4-mediated drug oxidations and to evaluate the drug interaction potential of diclofenac and 4′-hydroxydiclofenac.

2.?Diclofenac was converted to 4′-hydroxydiclofenac by recombinantly expressed human P450 1A2 with K_m and V_max values of 33?µM and 0.20?min^?1, respectively. Diclofenac and 4′-hydroxydiclofenac suppressed flurbiprofen 4′-hydroxylation by P450 2C9 strongly and moderately, respectively; however, they did not affect P450 2C19-dependent S-mephenytoin hydroxylation or P450 3A4-dependent midazolam hydroxylation.

3.?Although the caffeine 3-N-demethylation activity of liver microsomal P450 1A2 was inhibited by simultaneous incubation with diclofenac, the riluzole N-hydroxylation activities of recombinant P450 1A2 and human liver microsomes were inhibited after preincubation with diclofenac or 4′-hydroxydiclofenac for 20?min in the presence of NADPH. Using the inhibition constant (37?µM) of diclofenac on caffeine 3-N-demethylation and the reported 95th percentiles of maximum plasma concentration (10.5?µM) after an oral dose of diclofenac, the in vivo estimated increase in area under the plasma concentration–time curve was 29%.

4.?These results suggest that diclofenac could inhibit drug clearance to a clinically important degree that depends on P450 1A2. Clinically relevant drug interactions in vivo with diclofenac are likely to be invoked via human P450 1A2 function in addition to those caused by the effect of diclofenac on P450 2C9.     

Fabrication and Evaluation of Bi-layer Tablet Containing Conventional Paracetamol and Modified Release Diclofenac Sodium

The objectives of present investigation were to achieve immediate release of paracetamol and tailored release of diclofenac sodium from bi-layer tablets. A 2³ full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bi-layer tablets. The bi-layer tablets showed immediate release of paracetamol and modified release of diclofenac.