Buccoadhesive tablets for insulin delivery: in-vitro and in-vivo studies.

In the present work, insulin (6 U/kg) was formulated into bioadhesive buccal tablets using Carbopol 934, Hydroxypropyl cellulose (HPC) or Hydroxypopylmethyl cellulose (HPMC) and different absorption promoters. The effect of different ratios of HPC or HPMC to Carbopol on the rate of water uptake was studied. The axial and radial detachment force as well as the duration of adhesion of tablets to a porcine buccal tissues were also investigated. Furthermore the hypoglycemic effect of some formulations containing HPMC and Carbopol in different ratios with different additives and enhancers was studied using diabetic male beagle dogs. The rate of water uptake of tablets prepared with 3:1, 1:1 or 1:3 of HPC or HPMC: Carbopol was directly proportion to the Carbopol content of the tablet. The incorporation of enhancers (10%) to tablets prepared with HPMC: Carbopol of 1:1 ratio did not affect to a great extent the rate of tablets hydration. On the other hand, coating one side of the tablet with 50 mg of the impermeable cutina led to a significant reduction in the rate of tablets' water uptake reaching 50% to 75% in comparison with the uncoated tablets. Carbopol had the most influential effect on both mucoadhesion force and duration followed by HPMC. Tablets prepared with 100% HPC completely eroded within 6 hours during the measurement of the duration of adhesion. The incorporation of Carbopol with this polymer significantly improved its mucoadhesion duration reaching more than 24 hours with the 1:3 HPC: Carbopol. Ten percent of either sodium salicylate (NaSal) or sodium deoxycholate (NaDC) did not affect the duration of mucoadhesion of tablets prepared with 1:1 HPMC: Carbopol while 10% of Witepsol or Cacao butter and 1% of polyoxyethylene-9-lauryl ether (POELE) significantly reduced it. Tablets made using a polymer mixture of HPMC: Carbopol 934, 1:3 resulted in improved pharmacodynamic parameters producing a relative hypoglycemia (RH) of 6.72%. Furthermore, tablets made using polymer mixture of HPMC: Carbopol 934 in a ratio of 1:1 and containing 1% POELE resulted in 26% reduction in plasma glucose levels and producing 9.42% RH. Inclusion of other promoters such as 10% sodium deoxycholate or 10% sodium salicylate gave rise to RH values of 7.93 and 8.65% respectively.

Taste masking of diclofenac sodium using microencapsulation.

This study addresses how to mask the undesirable taste of diclofenac sodium (DS) without interfering with an adequate rate of drug release. DS microcapsules were successfully prepared using a system of ethylcellulose (EC)-toluene-petroleum ether. The system was optimized by the construction of the phase diagram and determination of the amount of EC precipitated under different solvent:non-solvent ratios to determine the most appropriate conditions for preparing good microcapsules. Microcrystalline cellulose (Avicel) and lactose were mixed with DS powder and converted into spherical cores by the wet agglomeration technique which facilitated coacervation and formation of thin and uniform microcapsule walls. Diethylphthalate (DEP) and Polyethyleneglycol 600 (PEG) in different concentrations (20 or 40% w/w) were used as plasticizers to impart better elasticity to the microcapsules. The microcapsules were evaluated for DS released against crushed commercial DS enteric coated tablet (Voltaren). The prepared microcapsules were taste evaluated by a taste panel of 10 volunteers. The results revealed that the optimum solvent:non-solvent ratio required for microcapsule formation was 1:2. Microcapsules containing PEG 20% or DEP 40% showed a faster rate of DS release compared to that obtained from other microcapsules and crushed commercial enteric coated tablets (Voltaren). The palatability and the taste of DS were significantly improved by microencapsulation. The extent of taste masking was influenced by the microcapsule core:wall ratio, the presence of additives within the core, the type and concentration of plasticizer and initial core size.

Nutritional status of institutionalized and free-living elderly in Alexandria.

Because of an increase in the number of elderly and the problems of nutrition associated with them, it is of interest to study the nutritional status of elderly persons in Alexandria City. The purpose of this study was to assess the nutritional status of elderly population and to compare between the nutritional status of those institutionalized and those living free. The study was conducted on 240 elderly persons (120 institutionalized and 120 free living) selected randomly from institutions and from different sites. The basic data, weight, height, body mass index (BMI) of each were recorded. Dietary intake study was done by using 24 hours recall for 3 consecutive days and food frequency were used to obtain the best estimate of food intake. Energy and nutrient intakes were obtained and compared with the recommended dietary allowance (RDAs). The main findings of the study revealed that the mean age of the institutionalized elderly was greater than those living free. Percent of obesity among females was 71.7% among free living and 45% among institutionalized. Under-nutrition was present in 11.7% and 8.3% of institutionalized males and females respectively. Food habits showed that institutionalized subjects consume more amounts of many food items than free-living. Total daily energy intake was found to be below the recommendation for all subjects, with higher intake among institutionalized than free living. Nutrient intakes among institutionalized and free living elderly were inadequate except thiamin, riboflavin, vitamin C and iron. The nutrients least adequately supplied in the diets of elderly are vitamin A and calcium along with energy deficits. In conclusion both institutionalized and free living are at risk for developing nutrient deficiencies. Deficient energy, calcium and vitamin A are common problems among most subjects. The composition of the diet among free living subjects seem to be also poor in some micronutrients. We recommended a nutrition intervention program and nutrition education to improve nutritional status of elderly people.

Gonadotrophin and testosterone suppression by 7alpha-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men.

The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) is a potent suppressor of gonadotrophin that has several advantages for long term administration to normal or hypoandrogenic men. The aim of this study was to examine MENT serum concentrations following subdermal insertion of MENT acetate (MENT Ac) implants and their effects on gonadotrophins, testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin, prostate specific antigen and insulin-like growth factor-1 serum concentrations in normal men. A total of 45 healthy men were recruited at three clinics. Each subject received one, two or four implants for 28 days. Serum samples were obtained before insertion and on days 8, 15, 22, 29, 36 and 43 after implant insertion. The average daily dose delivered in vivo by one implant was approximately 500 microg. One, two or four MENT Ac implants produced dose dependent and sustained serum MENT concentrations for the entire duration of treatment of 0.7 +/- 0.1, 1.2 +/- 0.1 and 2.0 +/- 0.1 nmol/l respectively. This treatment induced a dose dependent decrease in gonadotrophin and androgen serum levels. Two and four implants induced maximal suppression that was maintained throughout treatment and was completely reversed after removal of the implants. The mean decreases were 93 +/- 1% for testosterone, 80 +/- 3% for DHT, 97 +/- 1% for luteinizing hormone and 95 +/- 1% for follicle stimulating hormone. No serious adverse reactions were reported by the volunteers and no consistent changes in clinical chemistry and haematology were found. These results indicate that MENT Ac implants are an efficient way of MENT administration and confirm the potent gonadotrophin and androgen suppressive effect of this drug.

Pharmacokinetics of 7 alpha-methyl-19-nortestosterone (MENT) delivery using subdermal implants in healthy men.

We studied the pharmacokinetics of 7 alpha-methyl-19-nortestosterone (MENT), a potent synthetic androgen, administered by subdermal implants. The implants contained 112 +/- 4 mg of MENT acetate in a polyethylene vinyl acetate copolymer. MENT acetate released from the implants is rapidly hydrolyzed to MENT in vivo. Fifteen healthy Finnish men were randomized to have either one, two, or four implants inserted in the medial aspect of the upper arm. The implants remained in place for 4 weeks. Blood samples were obtained before implant insertion, 1, 2, 3, and 4 weeks after insertion, and 1 and 2 weeks after removal. Serum MENT concentrations were determined by gas chromatography with mass selective detection. The MENT levels attained in each implant group remained at a steady level during the 4 weeks of implant use. The mean steady state MENT concentrations in the one, two, and four implant groups were 0.6, 1.4, and 2.3 nmol/L, respectively. Serum MENT concentrations during implant use were clearly dose dependent; the between-subject effect of implants as well as the differences between each pair of groups were all statistically significant. The release rate of MENT from one, two, and four implants was calculated to be approximately 0.3, 0.8, and 1.3 mg/day, respectively. This study suggests that MENT acetate implants are a promising method for long-term androgen administration in hypogonadism and male contraception.

PIP: The authors studied the pharmacokinetics of 112 +or- 4 mg of MENT acetate in a polyethylene vinyl acetate copolymer. MENT acetate released from the implants is rapidly hydrolyzed to MENT in vivo. 15 healthy Finnish men were randomized to have either 1, 2, or 4 implants inserted in the medial aspect of the upper arm. The implants remained in place for 4 weeks. Blood samples were obtained before implant insertion, 1, 2, 3, and 4 weeks after insertion, and 1 and 2 weeks after removal. Serum MENT concentrations were determined by gas chromatography with mass selective detection. The MENT levels attained in each implant group remained at a steady level during the 4 weeks of implant use. The mean steady state MENT concentrations in the 1, 2, and 4 implant groups were 0.6, 1.4, and 2.3 nmol/l, respectively. Serum MENT concentrations during implant use were clearly dose dependent; the between-subject effect of implants as well as the differences between each pair of groups were all statistically significant. The release rate of MENT from 1, 2, and 4 implants was calculated to be approximately 0.3, 0.8, and 1.3 mg/day, respectively. The study suggests that MENT acetate implants are a promising method for long-term androgen administration in hypogonadism and male contraception.

Beta-cyclodextrin as a direct compression excipient compared to conventional ones.

Beta-Cyclodextrin was evaluated as a direct compression excipient and compared to conventional excipients. The measured physical properties included particle size and particle size distribution, flowability, bulk density, and hygroscopicity. Compression characteristics were evaluated by measuring compactibility, compression force-hardness profiles and compression force requirements. The materials studied were directly compressed into tablets and the produced tablets were evaluated with regard to uniformity of weight, disintegration time, crushing strength and friability. The results suggest that beta-cyclodextrin is a good candidate as a direct compression excipient.

Effect of dimethyl-beta-cyclodextrin on nitrazepam stability.

Nitrazepam was found to form an inclusion complex with heptakis; 2,6 di-O-methyl-beta-cyclodextrin (DM-beta-CD) in solution. The phase solubility diagram was found to be AL type with no precipitation of the inclusion complex formed. The kinetic studies of nitrazepam hydrolysis in DM-beta-CD solution at 30, 40 and 50 degrees C was followed spectrophotometrically, as the degradation products of the drug did not interfere with such assay. It was found that the degradation of nitrazepam in acidic media followed the first order reaction kinetics at the temperatures studied. Inclusion complexation of nitrazepam in DM-beta-CD resulted in a relatively improved stability of the drug in solution at 30 degrees C. On the other hand, no appreciable stabilization was achieved at higher temperatures (40 and 50 degrees C).

Study of the interaction of clobazam with cyclodextrins in solution and in the solid state.

Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.