Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System.

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

Evaluation of the versatile character of a nanoemulsion formulation.

The formulate-ability of six model active pharmaceutical ingredients (API), with different physico-chemical profiles, in a nanoemulsion designed to be intraveinously administrable was explored. Nanoemulsions were spontaneously generated at room temperature by pouring a phosphate buffer in an anhydrous mixture containing pharmaceutically acceptable triglycerides and non-ionic surfactants. After determination of the apparent solubility of each API in excipients and characterization of mixtures by DSC, API-loaded nanoemulsions were formulated and characterized in terms of granulometric properties, surface potential, drug recovery efficiency, pH, osmolarity, in vitro drug release, and stability. Except ciprofloxacin, a BCS class IV drug, all studied APIs were soluble in at least one excipient used, i.e. Labrasol. At 2 wt% API, all drug-loaded nanoemulsions present properties compatible with i.v. administration. The formulation should permit to increase apparent solubility of poorly water-soluble APIs, and also to prolong delivery of hydrophobic as well of more hydrophilic compounds. Herein, the relative affinity of the API for nanodroplets and the release medium would directly influence drug release profiles. Nanoemulsions were stable for 7 days. They could also been extemporaneously reconstituted before use. Such a versatile nanoemulsion would provide a valuable option as formulation strategy for improvement of drug properties.

Use of re-esterified palm oils, differing in their acylglycerol structure, in fattening pig diets.

Re-esterified oils are new fat sources obtained from the chemical esterification of acid oils with glycerol (both economically interesting by-products from oil refining and biodiesel industries, respectively). The different fatty acid (FA) positional distribution and acylglycerol composition of re-esterified oils may enhance the apparent absorption of saturated fatty acids (SFA) and, therefore, their overall nutritive value, which might lead to an increased deposition of SFA. The aim of the present study was to investigate the potential use of re-esterified palm oils, in comparison with their corresponding acid and native oils in fattening pig diets, studying their effects on fatty acid apparent absorption, acylglycerol and free fatty acid (FFA) composition of feces, growth performance, carcass-fat depots and fatty acid composition of backfat. Seventy-two crossbred boars and gilts (average weight of 24.7 ± 2.55 kg) were blocked by initial BW (nine blocks of BW for each gender), housed in adjacent individual boxes, and fed one of the four dietary treatments, which were the result of a basal diet supplemented with 4% (as-fed basis) of native palm oil (PN), acid palm oil (PA), re-esterified palm oil low in mono- and diacylglycerols (PEL), or re-esterified palm oil high in mono- and diacylglycerols (PEH). Regarding results from the digestibility balance, PA and PN showed similar apparent absorption coefficients (P>0.05), despite the high, FFA content of the former. However, re-esterified palm oils (both PEL and PEH) showed a higher apparent absorption of total FA than did their corresponding native and acid oils (P0.05). We conclude that re-esterified oils are interesting fat sources to be considered in fattening pigs.

Toxicological evaluation of neem (Azadirachta indica) oil: acute and subacute toxicity.

Neem (Azadirachta indica), popularly known as traditional medicine is a native plant in India. Neem oil is a vegetable oil derived from seeds or fruits of the neem tree through pressing or solvent extraction, and largely used in popular medicine to have antifungal, antibacterial, antimalarial, antiparasitic, anti-inflammatory, as well as immunemodulatory properties in different animal species. In the present study, acute and 28-day subacute toxicity tests were carried out. In the acute toxicity test, the LD50 values of neem oil were found to be 31.95g/kg. The subacute treatment with neem oil failed to change body weight gain, food and water consumption. Serum biochemistry analysis showed no significant differences in any of the parameters examined under the dose of 1600mg/kg/day. Histopathological exams showed that the target organs of neem oil were testicle, liver and kidneys up to the dose of 1600mg/kg/day.

Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate.

PURPOSE: To prepare a self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate, with enhanced dissolution and better chance of oral absorption. METHOD: All-trans-retinol acetate SNEDDS was prepared using different concentrations of soybean oil (solvent) Cremophor EL (surfactant) and Capmul MCM-C8 (co-surfactant). Particle size and turbidity of the SNEDDS were determined after adding water to the oily solution. Dissolution profile of SNEDDS filled in hydroxyl propyl methyl cellulose (HPMC) capsules was determined by using water in USP apparatus 2. Ternary phase diagrams were constructed to identify the self-nanoemulsified region. The SNEDDS were evaluated by the visual observation, turbidity in nephrometric turbidity units (NTU), mean particle size (microm) and Fourier transformed-infrared spectroscopy (FT-IR). SNEDDS were thermally characterized using differential scanning calorimetry (DSC) to ensure the compatibility of the SNEDDS ingredient. RESULTS: From the data obtained in this work, it was clear that surfactant to co-surfactant ratio has the main impact on the physical characteristics of the emulsion formed. The optimum surfactant to co-surfactant ratio was found to be 2:1 (37.5-50% for Cremophor EL, and 18.75-25% for Capmul MCM-C8). With this ratio, the resultant nanoemulsions obtained have a particle size range of 0.103-0.051 microm, turbidity range of 18.12-2.18 NTU and t30 values (cumulative% all-trans-retinol acetate dissolved in 30 min) of 90.42-99.5. Also the thermograms obtained from DSC experiments showed that there is no incompatibility or interaction between the SNEDDS ingredients (soybean oil, Cremophor EL, and Capmul MCM-C8) and all-trans-retinol acetate. CONCLUSION: The present study revealed that the self-nanoemulsified drug delivery system of all-trans-retinol acetate increased its dissolution rate and has the potential to enhance its bioavailability without interaction or incompatibility between the ingredients.

A novel cubic phase of medium chain lipid origin for the delivery of poorly water soluble drugs.

The existence of a novel cubic liquid crystalline phase is described within the pseudo-ternary system comprising lauric acid, monolaurin, and simulated endogenous intestinal fluid (SEIF). This phase behaviour has been characterized using cross-polarizing light microscopy (CPLM), and the structure of the cubic phase identified by small angle X-ray scattering (SAXS). The presence of the cubic phase was found to be temperature sensitive within the 20-37 degrees C range making it putative material for in situ gelation purposes. The cubic phase was shown to have a high capacity to solubilise a model poorly water-soluble drug, cinnarizine, and initial in vitro release data highlight the potential of this phase to provide sustained release. Absorption of cinnarizine from the cubic phase was studied in an unconscious rat model via duodenal administration and blood sampling via the carotid artery. The rate of absorption was significantly reduced when compared to a simple suspension formulation, a likely combination of retarded erosion of the cubic phase together with hindered drug release from the cubic matrix. The results of this study suggest that this cubic phase may potentially be of benefit in the delivery of poorly water-soluble compounds due to its high loading capacity and potential for sustained release. The ability to manipulate this system using temperature may warrant further interest in delivery applications via other routes of administration.

Elimination of Elyzol 25% Dentalgel matrix from periodontal pockets.

Elyzo 25% Dentalgel (EDG) which is developed for use in the treatment of periodontitis is a suspension of metronidazole benzoate (40%) in a mixture of glyceryl mono-oleate (GMO) and triglyceride (sesame oil). Metronidazole can be detected in the periodontal pockets 24-36 h after application. The aim of the present study was to estimate the period of time that the gel matrix persists on periodontal pockets after 1 application of EDG. 12 patients were included in the study. From each patient, 1 sample was taken before and immediately after, and 1, 2, 3, 4, 5, 6, 8, 12 and 24 h after application. Subgingival scaling followed by absorption of gingival crevicular fluid with filter paper was used for sampling. The sampling unit was 1 tooth. Each sample was assayed for the amount of GMO and oleic acid (a degradation product of GMO) by means of high-performance liquid chromatography (HPLC) with UV detection. To allow determination of the GMO dose applied into the pockets and to estimate the recovery rate of the sampling method, 1 tooth in each patient was selected for sampling as soon as the gel had set, i.e., about 10 min after application. Only in 1 patient was a detectable amount of GMO within the pocket revealed 24 h after application. This amount was approximately 0.5% of the mean GMO dose applied around 1 tooth. GMO was found no longer than 12 h in the remaining patients.

Lymphatic absorption of hypolipidemic compound, 1-O-[p-(myristyloxy)-alpha-methylcinnamoyl] glycerol (LK-903).

The intestinal absorption process of 1-O-[p-(myristyloxy)-alpha-methylcinnamoyl] glycerol (LK-903), a new hypolipidemic compound, was studied in rats. When 3H-LK-903 or 3H-LKA [3H-p- (myristyloxy)-alpha-methyl cinnamic acid], labeled at the cinnamic acid moiety, or 14C-LK-903, labeled at the glycerol moiety, were administered orally to thoracic duct-cannulated rats at a dose of 0.233 mmol/kg, 31.1, 6.7 and 18.1% of the dose, respectively, appeared in the lymph within 24 h. In this case, radioactive compounds in the lymph lipids consisted of LKA (radioactivity was not detected in the fraction of LKA with 14C-LK-903), LK-903, diglyceride analogues and triglyceride analogues. The percentages of the triglyceride analogues were the highest, followed by the diglyceride analogues. On the other hand, when doubly labeled LK-903 (3H/14C = 1, corrected ratio) was administered orally, the values of 3H/14C for the monoglyceride, diglyceride and triglyceride analogues in the lymph were 1.2-1.5, 1.7-1.9 and 1.9-2.7, respectively. The lymphatic absorption of LK-903 was stimulated by the presence of lecithin but inhibited by a high dose of triolein. The results indicated that (1) LK-903 formed micelles in the intestine, (2) a large part of LK-903 was absorbed as such, (3) a part of LK-903 was hydrolyzed in the intestinal mucosa, and (4) a part of LKA formed by hydrolysis was again utilized to synthesize the higher glycerides and absorbed via the lymphatic absorption route for lipids.