Ehab A. Hosny

Oral delivery of insulin from enteric-coated capsules containing sodium salicylate: effect on relative hypoglycemia of diabetic beagle dogs.

The hypoglycemic effect of Eudragit S100 enteric-coated capsules containing sodium salicylate as an absorption promoter formulated with insulin in various ways: as physical mixture, by wet granulation or in suppository bases (polyethylene glycol 4000 or Witepsol W35) was studied in hyperglycemic beagle dogs. The capsules containing insulin formulated with sodium salicylate (50 mg) and prepared by either physical mixing or wet granulation using 10% polyvinyl pyrollidone gave almost the same results producing a maximum reduction in plasma glucose level (C(max)) of 81.53+/-8.21 and 79.59+/-5.75%, T(max) of 6 and 5 h, area under the curve (AUC) of 69.37+/-48.64 and 57.98+/-23.15% reduction hour (% red. h) and resulting in relative hypoglycemia (RH) of 8.73+/-6.12 and 7.29+/-2.91%, respectively. Formulation of insulin with sodium salicylate in PEG 4000 produced a lower AUC of 37.30+/-10.36% red. h and RH of 4.69+/-1.3%. While, formulation in Witepsol W35 (0.5, 1.0 and 2.0 g) that was sieved to produce particle size of 180-315 microm and filled in enteric-coated capsules showed that formulating insulin and sodium salicylate in 1 g base is the best formulation. It produced 25% reduction in plasma glucose levels of the hyperglycemic beagle dogs at T(max) of 4 h and the largest AUC of 100.10+/-25.72% red. h, resulting in the highest RH of 12.59+/-3.23%. In conclusion, 25-30% reduction in plasma glucose levels and RH of about 12.5% relative to subcutaneous injection of regular soluble insulin can be achieved by formulating insulin in Witepsol W35 (1 g) with sodium salicylate (50 mg) as an absorption promoter, reducing the resulting mass into particle size 180-315 microm, packing into hard gelatin capsules and coating with Eudragit S100.

Effect of coating of aluminum carboxymethylcellulose beads on the release and bioavailability of diclofenac sodium.

The production of spheres loaded with diclofenac sodium by the cross linking technique was achieved. The hydrophilic polymer sodium carboxymethylcellulose (Na-CMC) which gels in the presence of a cross linking agent, aluminum chloride (AlCl3), was used as a matrix forming agent for the bead production. To obtain a regular and uniform rate of drug release, the produced beads were coated with sodium alginate to increase the pathway of the diffused medium. Two processing variables were studied, the flocculating agent concentration (20, 40 and 60% w/v) and different coating times (15, 30 and 60 min). The results show that the higher concentrations of aluminum chloride (40 and 60% w/v) produced more uniform and rounded beads than that prepared using 20% w/v salt. The particle size of the core beads decreased insignificantly (P > 0.05) as the flocculating agent concentration increased. The coating time did not affect the particle size of the coated beads within the same concentration of aluminum chloride. The dissolution studies showed that the release rate of diclofenac sodium from the core beads increased with the increase of AlCl3 concentration and that the rate of drug release was markedly reduced after the coating of the core beads with Na-alginate. The results also show a linear relationship for drug release over a 4-5 h period from the core beads where it showed a longer straight line relationship (7 h) for the coated beads. The coating of the Al-CMC beads, prepared using 60% w/v AlCl3.6H2O, with 2% w/v aqueous solution of Na-alginate resulted in a significant (P < 0.05) sustaining action of the Al-CMC beads as indicated by the shift in Tmax from 1.7 +/- 0.84 to 3 +/- 0.71 h and the prolongation of the MRT from 7.86 +/- 0.54 to 10.82 +/- 1.33 h. The Cmax increased significantly from 5.43 +/- 2.91 to 11.66 +/- 6.18 micrograms/ml while the AUC0-->24 increased insignificantly (P > 0.05) from 39.82 +/- 26.61 to 57.92 +/- 25.58 micrograms h/ml resulting in a relative bioavailability of 145.45% relative to Al-CMC beads.

Comparative study of in-vitro release and bioavailability of sustained release diclofenac sodium from certain hydrophilic polymers and commercial tablets in beagle dogs

Hydrophilic colloids interact with metallic ions to yield crosslinked insoluble salts. Such principle was utilized in the preparation of diclofenac sodium beads from sodium alginate and sodium carboxymethylcellulose. Hard spherical beads of aluminum alginate and aluminum carboxymethylcellulose with a narrow particle size distribution (1.60 +/- 0.12 and 3.10 +/- 0.20 mm) and low friability (0.5 and 1.4%) respectively were obtained with high yield (80-90%) and a drug content approaching 70-80%. The type and concentration of the polymers as well as the pH of the dissolution medium were found to affect the rate of drug release. Beads prepared from Na-alginate showed a non-significantly (p > 0.05) faster rate of drug release than that prepared from NaCMC. The higher the polymer concentration, the slower was the rate of drug release. Diclofenac sodium did not release in 0.1 N HCl (pH 1.2) for 2 h and released in phosphate buffer solution (pH 6.8) from the two formulations studied and from the commercial Voltaren Retard tablet. The two formulations of the beads resulted in a sustained release action of diclofenac sodium for 24 h. They showed Kel values of 0.02 +/- 0.01 and 0.3 +/- 0.01 h-1 and these correspond to t1/2 of 34.65 and 27.70 for the Na-alginate and NaCMC beads, respectively. They also showed mean residence time (MRT) values of 9.56 +/- 2.5 and 7.86 +/- 0.54 h, respectively. They also showed non-significant (p > 0.05) differences with respect to their plasma levels, Cmax, Tmax and AUC0-->24 h. The relative bioavailability of the two formulations were 59.01 and 47.96%, respectively, relative to that of the commercial Voltaren Retard tablets of Ciba-Geigy which showed a Kel of 0.044 h-1 corresponding to a t1/2 of 15.75 h and MRT of 7.45 +/- 1.10 h.

Promotion of oral insulin absorption in diabetic rabbits using pH-dependent coated capsules containing sodium cholate

The hypoglycemic effect of oral insulin (40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing various doses of sodium cholate (20, 50, 100 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). Sodium cholate (20 and 50 mg/capsule) produced a dose-related enhancement of an insulin-induced decrease in the blood glucose level. Insulin capsules containing sodium cholate (50 mg/capsule) produced a steady reduction of the blood glucose level reaching 69% of the initial values (P < 0.01) by 3 h and 48% (P < 0.001) by 5 h after administration. This capsule produced an AUC0-5 h of 125 +/- 14.8 mg.h/dl with relative hypoglycemia (R.H.) of 25.8% compared with insulin s.c. The capsules containing sodium cholate (100 mg), however, did not significantly (P > 0.05) improve the hypoglycemic effect of insulin more than the smaller dose (50 mg/capsule) producing an AUC and R.H. of 135 +/- 12.3 mg.h/dl and 27.9%, respectively. The capsule coated with Eudragit S100 and containing insulin mixed with sodium cholate seems to be a promising formulation to overcome the unavailability of oral insulin.

Hypoglycemic Effect of Oral Insulin in Diabetic Rabbits Using pH-Dependent Coated Capsules Containing Sodium Salicylate Without and with Sodium Cholate

The hypoglycemic effect of oral insulin (20 U and 40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing sodium salicylate (50 mg) without and with sodium cholate (50 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). The capsules containing 20 U insulin + sodium salicylate (50 mg) produced a significant reduction in plasma glucose level to 82 and 73% of initial values at 2 and 3 hr after administration, respectively. The blood glucose level slowly returned to normal values at 5 hr. The AUC0-5 hr was 73.7 +/- 43.5 mg.hr/dl compared to 242 +/- 70.5 mg.hr/dl for insulin (20 U, s.c.) with a relative hypoglycemia of 30.4%. A higher dose of oral insulin (40 U) + sodium salicylate (50 mg) was more effective in reducing plasma glucose level which steadily decreased and reached 56% of the initial value by 5 hr (AUC0-5 hr = 132 +/- 41.5 mg.hr/dl and relative hypoglycemia = 27.3%). Sodium cholate (50 mg), however, slightly improved sodium salicylate effect producing an AUC0-5 hr of 139 +/- 37.3 mg.hr/dl with relative hypoglycemia of 28.7%. The relative hypoglycemia of pH-dependent coated capsules reached in the present experiment is the highest found so far.

Effect of Different Bile Salts on the Relative Hypoglycemia of Witepsol W35 Suppositories Containing Insulin in Diabetic Beagle Dogs

Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 ± 83 mg%h and 28% ± 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50–200 mg/suppository were used, and we found that 150 mg NaDC produced 35% ± 13% RH. We also studied the influence of different doses of insulin (5–20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level Cmax. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 ± 13 mg% h and an RH of 49% ± 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previously with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hypoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100 mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as Cmax, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.

Bioavailability of sustained release indomethacin suppositories containing polycarbophil

The bioavailability of indomethacin from polyethylene glycol base, commercial suppositories Indocid∗, MSD and from polyethylene glycol base containing 5, 6 and 8% of polycarbophil, with the purpose of obtaining a controlled release suppositories, was determined in dogs. The results show that polycarbophil as a bioadhesive increased absorption and improved the bioavailability of indomethacin where the areas under the curves for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil were 19.5, 14.9, 31.2, 21.4 and 21.2 μ h ml−1, respectively. The maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) were 4.76, 2.98, 4.50, 2.36 and 1.29 μg/ml and 1, 1, 1, 1 and 12 h for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil, respectively. The data indicate that as the polycarbophil concentration increased from 0 to 5% in the polyethylene glycol suppositories, the plasma levels and bioavailability improved significantly (p < 0.1, Students t-test), whereas on increasing from 5 to 6 and 8% the plasma levels and bioavailability decreased significantly (p < 0.05). At 8% polycarbophil concentration, sustained release suppositories were produced but a decrease in plasma levels was observed.

Formulation, in-vitro release and ex-vivo spasmolytic effects of mebeverine hydrochloride suppositories containing polycarbophil or polysorbate 80

The release of mebeverine hydrochloride, in two different strengths 100 and 200 mg, from different suppository bases was studied in-vitro to choose the best base to be used in-vivo. The results showed that the fastest release of the drug was from polyethylene glycol 4000 suppository base. On studying the effects of the suppositories on some spasmogens on the isolated guinea-pig ileum the polyethylene glycol suppository containing 100 mg drug gave zero antagonism to acetyl choline (ACh), histamine and barium chloride (BaC12). Addition of 1% Tween 80 or 5% polycarbophil to the suppository formulation resulted in 33.3, 29.5, 12.1 and 25.3, 32.7 and 25.7% antagonism to ACh, histamine and BaC12, respectively. The suppository formulation containing 200 mg drug produced 60, 33.3 and 60% antagonism to the three agonists arranged in the same order previously mentioned. The addition of 1% Tween 80 or 5% polycarbophil to the formulation resulted in a significant increase in the drug antagonism to the three agonists producing 86, 65, 62 and 90, 66 and 90% antagonism, respectively. Weighing the suppository remaining after 2 h of administration revealed that addition of 1% Tween 80 to the formulation increased significantly (P < 0.05) the dissolution of the suppository by 52–58% indicating the wetting effect of that additive. While, addition of 5% polycarbophil although improved the availability of the drug it did not affect the dissolution of the suppository indicating the adhesive effect that the polycarbophil exerts between the particles.

Polycarbophil as a controlled release matrix

Abstract The hydrophilic polymer, polycarbophil, was used as a sustained release delivery system for propranolol hydrochloride and indomethacin as water soluble and water insoluble drugs, respectively. The rate of release of either drug was found to be dependent on the polymer content of the tablet formulations. As the polycarbophil content increased, the amount released of either drug decreased. The mechanism of release of either drug was found to be dependent on the drug as well as on the polycarbophil content in the tablets.

Formulation and comparative evaluation of bioadhesive containing diclofenac sodium and commercial enteric coated tablets in-vitro and in dogs

Polycarbophil containing diclofenac sodium tablets were formulated using two different size of granules. The granules were obtained by evaporation under reduced pressure of polycarbophil particles loaded with alcoholic solution of the drug. The in-vitro release of these bioadhesive containing tablets was evaluated together with that of Ciba-Geigy commercially available enteric coated tablets ‘Voltaren’ in simulated gastric fluid for 2 h followed by another 2 h in simulated intestinal fluid. The Voltaren tablets released no drug in simulated gastric fluid but released all their drug contents within 1 h in simulated intestinal fluid. The tablets formulated using polycarbophil granules of smaller size (0.18-0.313 mm) released about 13% of their drug contents in simulated gastric fluid and released the remaining drug in simulated intestinal fluid within 0.5 h of dissolution, while tablets formulated with larger granules size (0.5-0.8 mm) released 10% of their drug contents in the first medium and released the remaining drug within 2 h in the second. The in-vivo evaluation in dogs of these two tablet formulations of polycarbophil and that of entericcoated Voltaren tablets each containing 50 mg drug revealed that the bioadhesive tablets formulated with smaller granules size were bioequivalent to Voltaren tablets producing a non-significantly different (P > 0.05) Cmax, Tmax and AUC. The results also indicated the effect of bioadhesive granules size on rate and extent of absorption where tablets formulated with smaller granules size showed higher Cmax, shorter Tmax, larger AUC and higher relative bioavailability compared with those tablets formulated with larger granules size.