Preparation of stabilized submicron fenofibrate crystals on niacin as a hydrophilic hydrotropic carrier.

Fenofibrate is antihyperlipidemic which has low and variable oral bioavailability due to erratic dissolution characteristics. Niacin showed a potential atheroprotective effects suggesting possible co-administration with fenofibrate with a potential for development of fixed dose combination. The chemical structure of both drugs highlights the opportunity for interaction upon co-processing due to the existence of complementary hydrogen bonding sites. Accordingly, fenofibrate and niacin were co-processed by wet co-grinding and the resulting product was assessed using scanning electron microscopy, FTIR, thermal analysis and X-ray diffraction in addition to dissolution studies. The instrumental analysis indicated the development of submicron fenofibrate crystals stabilized over the surface of niacin crystals. The developed submicron crystals showed fast dissolution of fenofibrate depending on the relative proportions of fenofibrate to niacin. Co-processing of both drugs at dose ratio which contained higher proportion of niacin resulted in further enhancement in the dissolution rate. This further enhancement was attributed to the hydrotropic effect of niacin which was proved by solubility study in addition to size reduction. This supposition was confirmed from the inferior dissolution of fenofibrate from the physical mixture. The study introduces fenofibrate/niacin as potential fixed dose combination for augmented dissolution rate and pharmacological effects.

Eutexia for enhanced dissolution rate and anti-inflammatory activity of nonsteroidal anti-inflammatory agents: Caffeine as a melting point modulator.

Fast dissolution of nonsteroidal anti-inflammatory drugs (NSAIDs) is a prerequisite from patient perspective. However, most NSAIDs are slowly dissolving acidic compounds. Caffeine, a commonly used analgesic adjuvant with NSAIDs showed high potential as eutectic co-former for acidic compounds. The study investigated eutectic forming potential of caffeine with meloxicam, aceclofenac and flurbiprofen. Each drug was co-ground with caffeine in various ratios and the products were characterized by thermal analysis to determine the optimum eutectic composition from phase diagram and Tamman's triangle. The optimum systems were subjected to X-ray powder diffraction (XRPD), Fourier-transform infrared (FTIR) and dissolution studies. Co-ground systems at dose ratio were also assessed for drug dissolution and anti-inflammatory effect using carrageenan induced rat paw edema method. Eutexia was confirmed by thermal analysis with the optimum composition being 1:1, 1:1 and 1:2 (NSAID: caffeine) for aceclofenac, flurbiprofen and meloxicam, respectively. Eutexia did not alter FTIR spectra with minor changes being recorded in XRPD patterns. The eutectic systems underwent fast liberation of drugs with fast dissolution being retained even at dose ratios. Dissolution enhancement was associated with enhanced anti-inflammatory response. The study introduced caffeine as eutectic forming analgesic for fixed dose combination with NSAIDs to enhance drug dissolution and anti-inflammatory effect.

Self dispersing mixed micelles forming systems for enhanced dissolution and intestinal permeability of hydrochlorothiazide.

Mixed micelles provide promising strategy for enhancing dissolution and permeability of drugs. However, their fluid nature limited the stability of the loaded drug and hindered the development of stable oral dosage form. Accordingly, the objective was to develop solid self dispersing mixed micelle forming systems (MMFS) for enhanced dissolution and intestinal permeability of hydrochlorothiazide. Pseudoternary phase diagrams were constructed using sodium cholate, lecithin with either poloxamer 407 or PEG 4000 to determine the composition of MMFS. Both polymer free and poloxamer or PEG containing MMFS were prepared as homogenous matrices or as solid self dispersing powder. The later was developed by adsorption of MMFS on avicel-aerosil mixture. Differential scanning calorimetry provided an evidence for existence of hydrochlorothiazide as molecular dispersion in the MMFS. Dispersing polymer free, PEG 4000 or poloxamer based MMFS in aqueous medium produced micelles having size values of 119, 52.6 and 28nm, respectively. The zeta potential values were -61.8, -59.5 and -19.5mV for the same systems, respectively. Preparation of solid self dispersing MMFS enhanced the dissolution rate of hydrochlorothiazide. The intestinal absorption of hydrochlorothiazide from its aqueous solution and polymer incorporating mixed micellar systems was monitored using in situ rabbit intestinal perfusion technique. The permeability results showed a clear trend for enhanced membrane transport of the drug after being incorporated into poloxamer containing mixed micellar system. The study thus introduced a versatile easily formulated solid self dispersing system with high potential for solving the dissolution and permeability problems of class IV drugs.

Effects of Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on sildenafil disposition in beagle dogs.

The present study was conducted to investigate the effects of some commonly used herbs namely Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetics of sildenafil in beagle dogs. The study design involved four treatments in a non-balanced crossover design. Sildenafil was given one tablet 100 mg orally to each dog and blood samples were obtained. After a suitable washout period, animals were commenced on a specific herb treatment for 1 week. Blood samples were withdrawn at different time intervals and sildenafil was analyzed by HPLC method. Oral administration of Nigella sativa resulted in reduction of AUC0-∞, C max and t 1/2 as compared to the control. Treatment of Lepidium sativum resulted in a significant reduction in the C max and AUC. There were no significant differences between the rests of the pharmacokinetic parameters relative to those of the control. For Trigonella foenum-graecum, the effects were similar to those obtained in case of Lepidium sativum. It was concluded that concurrent use of investigated herbs alters the pharmacokinetics of sildenafil. Co-administration of investigated herbs should be cautious since their concomitant use might result in decrease in sildenafil bioavailability.

Microemulsion for simultaneous transdermal delivery of benzocaine and indomethacin: in vitro and in vivo evaluation.

This study investigated simultaneous transdermal delivery of indomethacin and benzocaine from microemulsion. Eucalyptus oil based microemulsion was used with Tween 80 and ethanol being employed as surfactant and cosurfactant, respectively. A microemulsion formulation comprising eucalyptus oil, polyoxyethylene sorbitan momooleate (Tween 80), ethanol and water (20:30:30:20) was selected. Indomethacin (1% w/w) and benzocaine (20% w/w) were incorporated separately or combined into this formulation before in vitro and in vivo evaluation. Application of indomethacin microemulsion enhanced the transdermal flux and reduced the lag time compared to saturated aqueous control. The same trend was evident for benzocaine microemulsion. Simultaneous application of the two drugs in microemulsion provided similar enhancement pattern. The in vivo evaluation employed the pinprick method and revealed rapid anesthesia after application of benzocaine microemulsion with the onset being 10 min and the action lasting for 50 min. For indomethacin microemulsion, the analgesic effect was recorded after 34.5 min and lasted for 70.5 min. Simultaneous application of benzocaine and indomethacin provided synergistic effect. The onset of action was achieved after 10 min and lasted for 95 min. The study highlighted the potential of microemulsion formulation in simultaneous transdermal delivery of two drugs.

Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: effects of cosurfactants.

This study investigated the effects of cosurfactants on the transdermal delivery of hydrocortisone (model drug) from eucalyptus oil microemulsion. Eucalyptus oil which was successfully employed for steroidal drugs was used as the oil. Tween 80 which was readily miscible with eucalyptus oil was used as surfactant. Ethanol, isopropanol and propylene glycol which are relatively tolerable by the skin were employed as cosurfactants. Pseudo-ternary phase diagrams were constructed in the presence and absence of cosurfactants. Microemulsion formulations containing 20% oil, 20% water and 60% of either Tween 80 or 1:1 surfactant/cosurfactant mixture were compared. Incorporation of cosurfactants expanded the microemulsion zone. The cosurfactant free microemulsion was viscous showing pseudo-plastic flow. The cosurfactant containing preparations were less viscous with Newtonian flow. The drug loading and release rate were increased in the presence of cosurfactants with the release depending on the viscosity. Incorporation of hydrocortisone in microemulsion increased the transdermal flux compared to saturated aqueous solution. The presence of cosurfactants increased the transdermal drug flux compared to the cosurfactant free formulation. Ethanol produced the greatest effect followed by propylene glycol and isopropanol. The presence of cosurfactant and its type can thus affect both the phase behavior and the transdermal delivery potential of microemulsion.