Iranian Journal of Pharmaceutical Research
Volume:3 Issue: 2, Spring 2004

Chitosan with excellent biodegradable and biocompatible characteristics has received attention as an oral drug delivery vehicle for controlled-release formulations. In this study an enteric-coated capsule containing theophylline-chitosan beads based on 23 factorial designs was prepared as a colon drug delivery system. The theophylline-chitosan gel beads were formulated by adding the drug-containing solution of chitosan into tripolyphosphate solutions, dropwise. The obtained beads were washed with water and freeze-dried before filling into the capsules. Eudragit® S100 was then used to enteric-coat the prepared capsules. Drug entrapment efficiency and the effects of different variables including: bead morphology, swelling behavior of the beads and the release behavior of the system on these parameters were investigated. Results showed that the highest and lowest swelling ratio is obtained at pH 4.5 and 7.2, respectively. These studies have shown that chitosan concentration and drug polymer weight ratio significantly affect the drug entrapment. Decreasing the drug solubility in external phase caused a significant increase in drug loading. External phase saturation with theophylline and tripolyphosphate, as well as decreasing temperature, have increased drug loading. Furthermore, the lowering of temperature had a significant effect on bead''s hardness. The release of theophylline from freeze-dried beads filled in enteric-coated capsules was also investigated. Release of theophylline was prolonged with saturation of both drug and tripolyphosphate in the external phase. Results showed that the release of theophylline from chitosan beads is possibly due to more than one mechanism, possibly dissolution, diffusion and relaxation of the polymer chains.

In the long-term management of ulcerative colitis patients, repeat dosing maybe required. Since 5-ASA is largely absorbed from the upper intestine, selective delivery of drugs into the colon may be regarded as a better method of drug delivery with fewer side effects and a higher efficacy. The aim of this study was to prepare and evaluate a double coated multiparticulate system for 5-ASA delivery using gelatin and ethylcellulose as the primary and secondary polymer respectively. Gelatin microspheres containing 5-aminosalicylic acid was produced using the solvent evaporation method. Prepared gelatin microspheres were spherical, free flowing, non-aggregated and showed no degradation in the acidic medium. Entrapment efficacy of microspheres was about 50%. Results showed that drug release was fast and complete and is affected by the amount of core material entrapped. Gelatin microspheres were then coated by ethylcellulose using a coacervation phase separation technique. The idea for this approach was to prepare a delayed drug delivery system, in which, ethylcellulose protects particles for the first 6 h transit through the gastrointestinal tract. However, it was shown that this system could provide a suitable drug release pattern for colonic delivery of active agents, as 30% of the drug was released from the ethylcellulose-coated microcapsules within 6 h, while this amount was 90% of the loaded drug for gelatin microspheres under the same condition.

There have been numerous efforts to formulate insulin into an oral dosage form. The major problems involved with the oral administration of insulin are acidic and enzymatic decomposition by the gastric medium, and poor absorption in the small intestine due to its macromolecular structure. This study attempted to test the enhancing ability of two absorption enhancers, sodium glycocholate (Na-GC) and sodium salicylate (Na-Sal), in different parts of rat''s gastro-intestinal tract. The amount of insulin in each formulation was 0.6 iu/kg body weight. The concentration of enhancers (Na-Sal or Na-GC) in each formulation was 10 mg/ml. Formulations made of insulin and enhancers were prepared and injected directly to stomach, duodenum, jejunum and ileum of anesthetized rats through an abdominal incision. Blood samples were taken at 45 and 60 min intervals. The glucose concentration was determined by the o-toluidine method. Injections (IP) of insulin and normal saline were positive and negative controls, respectively. The blood glucose concentrations showed a significant decrease (p<0.05) due to the injection of insulin into duodenum, while the effect noted in jejunum was insignificant (p>0.05). Also, there was no anti-hyperglycemic effect accompanied by formulations administered into the stomach and ileum. It could be concluded that insulin, if formulated in a protected form to prevent acidic and enzymatic decomposition, in combination with such enhancers may overcome hyperglycemia due to insulin deficiency.

Using ion-exchange resins, a multiple-unit type of oral floating dosage system has been prepared to prolong gastric emptying time of dosage form. The system is composed of beads of drug-resin complex, which are loaded with bicarbonate ions and coated with a hydrophobic polymer. The system is so designed that when the beads reach the stomach, chloride ions are exchanged with bicarbonate and drug ions. The generated CO2 is entrapped in the polymeric coated resins and causes the beads to float. In this study, Amberlite-IRA 900 was loaded with diclofenac and bicarbonate ions, using a batch method. The beads were encapsulated with a hydrophobic polymer (ethyl cellulose or Eudragit RS-100). To find an appropriate formulation, the factors affecting the drug loading, floating ability and drug release were investigated. Based on the result obtained, maximum loading efficiency was attained at 3 h, using an aqueous diclofenac solution and resin beads measuring 430 µm in diameter. Drug release from both uncoated complexes of diclofenac-resin, and diclofenac-bicarbonate-resin occurred via particle-diffusion. The ethyl cellulose-coated beads have a desirable floating capability in comparison with the Eudragit RS-100 coated beads on HCl 0.1M solution containing 0.02% polysorbate 80.

A rapid, simple and sensitive high-performance liquid chromatography method was developed for determination of ciprofloxacin in plasma by means of ultraviolet detection. Ofloxacin was used as an internal standard and separation carried on a Novapak C18 column using a mobile phase of 0.01 M phosphate buffer (pH =2.6): methanol (82: 18 v/v). Extraction of drug was performed from plasma by liquid-liquid extraction and the average recovery was 78.2% The assay is precise, with inter-assay coefficient of variation of 6.70 % at 0.25-8 mg/ml (n=3). Using UV detection at 277 nm the detection limit for ciprofloxacin was 20 ng/ml of plasma and the mean extraction recovery was 78.2 %. Short elution time, using UV detector and usage of ofloxacin as internal standard are advantages of this method

Breast cancer is one of the most common malignancies among women. Although chemotherapy remains a major therapeutic approach to treat cancers, drug therapy often fails for several reasons, particularly the drug resistance. Resistance to multiple chemotherapeutic agents is one of the most important problems in the treatment of different types of cancers. Therefore, in this study a resistant sub line of the human breast cancer T47D cells was isolated in vitro by stepwise exposure to increasing concentrations of Adriamycin (ADR) to compare the characteristics of parent and resistant cells. We also evaluated the phenomenon of cross-resistance to some other chemotherapeutic drugs. A significant increase in doubling time of resistant cells, named T47D/ADR, (94 h) was observed when compared to the parental T47D cells (50 h) that indicates a relatively slow growth rate pattern of these cells. T47D/ADR cells were 4 fold resistant to adriamycin and also showed cross-resistance to vincristin (VCR, 3.5 fold) and to etoposide (VP-16, 5.5 fold) when compared to parent cells. Therefore, our results indicate that T47D/ADR cells are also cross-resistant to structurally and functionally different chemotherapeutic agents and can be used as a model for studying molecular changes of drug resistance.

There is growing evidence indicating that neuronal calcium channels play an important role in the mechanism of morphine dependence. In this study, the effects of acute and chronic administration of nitrendipine on naloxone precipitated morphine withdrawal signs were investigated. Mice were rendered dependent to morphine by subcutaneous injection of morphine over a period of 5 days. In chronic studies, nitrendipine (25 and 50 mg/kg, i.p.), or vehicle injections were given once a day during the morphine treatment, and the last injection of nitrendipine was given 24 h before the morphine withdrawal. For acute studies, nitrendipine (25 and 50 mg/kg, i.p.) was given 1 h after the last dose of morphine (1 h before naloxone). A single injection of nitrendipine at 25 mg/kg was ineffective in blocking most signs of morphine withdrawal, however, at 50 mg/kg nitrendipine blocked signs such as hair raising, sniffing, diarrhea and number of jumping. The concurrent injections of nitrendipine with morphine prevented most signs of morphine withdrawal. In agreement with previous findings, these results suggest that alterations in voltage-sensitive calcium channels play a role in the adaptations that occur on chronic treatment with morphine.

Antimicrobial activity of different culture extract of Oudemansiella sp grown on liquid medium (MYGP) were tested. Different fungi (C. albicans, C. lipolytica, Saccharomyces cervisiea, Cladosporium herbarum, and Aspergillus niger) and bacteria (Microccocus luteus, E. coli, Staphylococcus aureus, and Staphylococcus epidermidis) were used as test organisms. Various antimicrobial assay methods including paper disc agar diffusion and microdilution method, were employed to determine possible activity of the extracts. Relative MIC values showed strong activity of the ethyl acetate extract of the fungus against tested bacteria and fungi, especially filamentous fungi.

The present study was carried out to evaluate the antioxidant and free radical scavenging activity of methanolic extract of Ervatamia coronaria leaves (Apocynaceae) in various systems. DPPH radical, superoxide anion radical, nitric oxide radical and hydroxyl radical scavenging assays were carried out to evaluate the antioxidant potential of the extract. The antioxidant activity of methanolic extract increased in a dose dependent manner. About 50, 100, 250 and 500 µg of methanol extract of Ervatamia coronaria (MEEC) showed 61.33, 66.21, 72.04 and 76.83% inhibition respectively on peroxidation of linoleic acid emulsion. Like antioxidant activity, the effect of MEEC on reducing power increases in a dose dependent manner. In DPPH radical scavenging assay the IC50 value of the extract was found to be 167.09 µg/ml. MEEC was found to inhibit the nitric oxide radicals generated from sodium nitroprusside. The IC50 value was found to be 83.375 µg/ml, whereas the IC50 value of curcumin was 20.4 µg/ml. Moreover, the MEEC was found to scavenge the superoxide generated by PMS/NADH-NBT system. MEEC was also found to inhibit the hydroxyl radical generated by Fenton''s reaction, where the IC50 value of MEEC was found to be more than 1000 µg/ml and for catechin the IC50 value was found to be 5 µg/ml, which indicates the prooxidant activity of MEEC. The amounts of total phenolic compounds were also determined in this study. The results obtained in the present study indicate that the MEEC can be a potential source of natural antioxidant.

Many aldehydes are important components of natural flavours. They are used in food, cosmetic, and biomedical industries in large amounts. Plant cells or microorganisms carry out their production by biotransformation, which is one of the biotechnological methods that allow them to be defined as ''natural''. Cell cultures of Silybum marianum and Peganum harmala have been studied with a view to investigat their abilities to produce flavonolignans and b-carboline alkaloids respectively. However, we have isolated S. marianum and P. harmala culture strain, which are able to metabolise several aromatic aldehydes. Ten culture strains derived from S. marianum and P. harmala were examined for their ability to biotransform exogenous aromatic aldehyde compounds, including benzaldehyde, 2-methoxybenzaldehyde, 4-methoxybenzaldehyde, cinnamaldehyde and 3-methoxy, 4-hydroxy benzaldehyde. Callus cultures of Silybum marianum and Peganum harmala were established from seedlings, and healthy suspensions were grown using the Murashige and Skoog medium. Exogenous aromatic aldehydes were fed to S. marianum and P. harmala cell suspension cultures. Biotransformation reactions were detected over 24 h of incubation. The cultures then extracted with dichloromethane and extracts subjected to GC and GC-MS analysis. The S. marianum cultured cells in this study exhibit greater selectivity in the reduction of aromatic aldehydes than P. harmala cultured cells. The ability of cultured plant cells to biotransform substrate appears to be dependent on the culture strains as well as the nature and position of the substituent on the aromatic ring.