Nevin Çelebi

Controlled Delivery of Peptides and Proteins

The final aim/target of Pharmaceutical Sciences is to design successful dosage forms for effective therapy, considering individual patient needs and compliance. Development of new drug entities, particularly using peptides and proteins, is growing in importance and attracting increased interest, as they are specifically effective at a comparably low dose. These very potent and specific peptides and proteins can now be produced in large quantities due to increased knowledge and advancements in biotechnological and pharmaceutical applications. A number of peptide and protein products are now available on the market, and numerous studies investigating them have been published in the literature. Although many peptide/protein like products are generally designed for parenteral administration, some other noninvasive routes have also been used. For example, desmopressin is delivered nasally and deoxyribonuclease by inhalation. Although peptides and proteins are generally orally inactive, cyclosporine is an exception. In order to design and develop long-acting, more effective peptide/protein drugs, the controlled release mechanisms and effective parameters need to be understood and clarified. Therefore, we review herein various peptide/protein delivery systems, including biodegradable and nondegradable microspheres, microcapsules, nanocapsules, injectable implants, diffusion-controlled hydrogels and other hydrophilic systems, microemulsions and multiple emulsions, and the use of iontophoresis or electroporation, and discuss the results of recent researches.

A study of the inclusion complex of naproxen with β-cyclodextrin

The aim of this study was to increase the solubility and dissolution rate of naproxen (NAP) by inclusion complex formation with β-cyclodextrin (β-CD). The solubility of NAP with β-CD in aqueous solution was determined. The apparent stability constant, Kc, was calculated from the slope and intercept of the AL solubility diagram as 568 M−1. The solid complexes of NAP with β-CD in 1:1 molar ratio were prepared by the freeze-drying and neutralization method. The formation of an inclusion complex with β-CD in solid state was confirmed by X-ray diffractometry, IR spectroscopy and differential scanning calorimetry (DSC). The dissolution rate of NAP from the inclusion complex was much more rapid than of NAP alone. The amount of NAP released from the tablet surfaces was determined for tablets pressed under 3500 kg/cm2. It was seen that the total released amount of NAP from the NAP/β-CD complex was greater than that of intact NAP.

An investigation on skin wound healing in mice with a taurine-chitosan gel formulation.

Summary. The process of wound healing begins immediately following surface lesions or just after exposure to radiation, chemical agents or extreme temperatures.Taurine (2-aminoethane sulfonic acid), an amino acid containing sulfur, is found in almost all tissues in mammals, playing various important physio-logical roles in each organ. Taurine exhibits an antioxidant effect and is also known to have effects on cell proliferation, inflammation and collagenogenesis. Many antioxidants have been used to eliminate the negative effects of oxygen free radicals on wound healing.The objective of the present study was to examine the wound healing effect in mice of taurine-chitosan gel, which releases taurine slowly over a long time period. Fifty mM of taurine in 1.5% chitosan polymer (TAU-GEL) and 1.5% chitosan polymer (CHI-GEL) were applied to full thickness skin wounds of mice once a day for seven days. After seven days of treatment, lipid peroxide formation-malondialdehyde (MDA) and hydroxyproline (HPX) levels and the tensile strength of wound tissues were measured. All results were compared with those of the untreated control group (CONT). The structural alterations in the skin layers were also histologically investigated.It was found that locally administered TAU-GEL form significantly increased wound tensile strength by decreasing the MDA and increasing HPX levels. These results were supported by histological findings. All observations suggest that taurine gel may be effective in wound healing.

Lecithin-based microemulsion of a peptide for oral administration: preparation, characterization, and physical stability of the formulation.

The objective of our study was to prepare and characterize a stable microemulsion formulation for oral administration of a peptide, e.g., rh-insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90G (lecithin), absolute alcohol, and bidistilled water. Commercially available soybean lecithins (namely, Phospholipon 80, phosphatidylcholine purity 76 ± 3%, and Phospholipon 90G, phosphatidylcholine purity 93 ± 3%) were used in the study. The results showed that the phase diagram obtained using a low purity lecithin was not similar to that obtained with a high purity lecithin. We observed that the microemulsion area was wider at the phase diagram obtained with the higher purity lecithin. We found that the extent of the microemulsion region depended upon both the purity of the lecithin and the surfactant/co-surfactant (s/co-s) mixing ratios (Km). The rheological studies showed that microemulsions followed a Newtonian behavior. Such physical characteristics as viscosity, turbidity, density, conductivity, refractive index, droplet size, physical appearance, and phase separation of the microemulsion were measured at different temperatures (4°C, 25°C, and 40°C) during 6 months. The results indicated that the physical characteristics of the developed microemulsions did not change under different storage temperatures (p > 0.05).

Effects of epidermal growth factor dosage forms on dermal wound strength in mice

Abstract— The effect of topically administered epidermal growth factor (EGF) dosage forms was investigated on skin wound healing in mice. Two EGF dosage forms were prepared containing 100 ng mL−1 EGF. The solution dosage form was prepared in 0·9% w/v NaCl. A bioadhesive gel form was prepared in 0·2% Carbopol 940 polymer. The two dosage forms were applied on the skin incision wounds of mice at the rate of 5 μL twice a day for 7 and 15 days. The wound tear strength was tested for skin wound healing at the 7th and 15th days of treatment and compared with controls. The results indicate that the wound tear strength of mice were significantly higher at the 15th day of treatment in the gel‐treated group compared with the solution‐treated mice and controls (P < 0·001).

Effects of epidermal growth factor microemulsion formulation on the healing of stress-induced gastric ulcers in rats.

The effects of intragastric (i.g.) administration of microemulsion formulation of epidermal growth factor (EGF) on the healing of acute gastric ulcers induced by cold-restraint stress in rats was studied and compared with intraperitoneal (i.p.) administration of solutions. In the microemulsion formulation (W/O), labrafil M 1944 CS was the oil phase. Arlacel 186 and Brij 35 were used as the surfactants. Absolute alcohol and distilled water were used as the co-surfactant and the aqueous phase, respectively. Acute gastric lesions were induced by cold-restraint stress for 4 h in the refrigerator (4.0+/-0.5 degrees C). EGF was administered at a dose of 6 microg/kg per day intraperitoneally and intraperitoneally for 7 days. Basal gastric acid secretion (microequiv. H+/30 min), ulcer score (mm(2)) and tissue mucus levels (microg/g tissue) were measured. Basal gastric secretion was significantly reduced after the administration of EGF microemulsion (ME+EGF) (P<0.05). There was no significant decrease in basal gastric acid secretion following i.p (IPEGF) and i.g (IG-EGF) of EGF administrations of solutions compared to their control groups (P>0.05). The results indicate that the highest reduction in the basal acid secretion was seen after the administration of a microemulsion of EGF formulation. The mean ulcer score was reduced by i.g treatment with the microemulsion dosage form of EGF in 7 days from 15.9+/-1.4 to 1.16+/-0.45 mm(2) and was almost completely healed in four of the animals. The results demonstrate that the ulcer score was significantly reduced in i.p. (IPEGF) solution (P<0.005), i.g (IG-EGF) solution (P<0.01) and i.g. microemulsion (ME+EGF) (P<0.01) treated groups compared to untreated group. In IG-EGF, ME+EGF treated groups, mucus levels increased significantly compared to their control groups(P<0.05 and P<0.01). In contrast, there was no significant change in the mucus levels following i.p. EGF administration (P>0.05).

Evaluation of chitosan gel containing liposome-loaded epidermal growth factor on burn wound healing.

The objective of this study is to develop a chitosan gel formulation containing liposomes loaded with epidermal growth factor (EGF) and to evaluate their effects on the healing of second‐degree burn wounds in rats by immunohistochemical, histochemical and histological methods. EGF‐containing multilamellar liposomes which were carried in chitosan gel, EGF gel and EGF‐loaded liposome formulations were prepared. The in vivo experiments were performed on female Sprague Dawley rats. Second‐degree standard burn wounds were formed on rats and liposomes containing 10 µg/ml EGF in 2% chitosan gel, EGF‐chitosan gel and EGF‐loaded liposome formulations were applied daily to the burn wounds and biopsies were taken at the 3rd, 7th and 14th day of the treatment. When the results were evaluated immunohistochemically, there were significant increases in cell proliferation observed in the EGF‐containing liposome in chitosan gel (ELJ) formulation applied group (P < 0·001). The histochemical results showed that the epithelisation rate in the ELJ group was the highest compared with the other group results (P < 0·001). The histological results indicated and supported these findings and faster epithelisation was observed in the ELJ group compared with the other groups.

Factors influencing release of salbutamol sulphate from poly(lactide-co-glycolide) microspheres prepared by water-in-oil-in-water emulsion technique

Abstract Biodegradable microspheres containing salbutamol sulphate were prepared using water-in-oil-in-water (w/o/w) emulsion technique. Biodegradable polymers of two different molecular weights were used: PLGA 50/50 and PLGA 75/25. In the preparation of the formulations, we used 2 3 factorial design based on three independent variables which are drug loading, amount of gelatin and concentration of PVA. The dependent variables are particle size of the microspheres and entrapment ratio %. The in-vitro release of PLGA microspheres was studied in buffer solution of pH 7.4 at 37°C. A biphasic release behavior of salbutamol sulphate from microspheres was observed. Initially, a burst effect and then slow release was observed. It was found that the biodegradable microspheres of salbutamol sulphate were prepared with PLGA 75/25 by w/o/w emulsion technique obtained extended release obtained for 8 h. PVA concentration was effective on the particle size of microspheres prepared with PLGA 75/25 ( p

Effect of EGF dosage forms on alkali burned corneal wound healing of mice

The local treatment effects of EGF forms on alkali burned mice corneal wounds were identified. The corneal wounds were induced by 0.5 M NaOH solution on the corneal surfaces of the mice. The local epidermal growth factor solutions (100 ng/ml) and gel form in 0.2 per cent w/w carbopol 940 (100 ng/ml) were dropped in 5 microliters aliquots into the eye twice a day. The corneal wounds were measured for 15 days at 7-day intervals and examined histologically at the end of 15th day of the experimental period. The results indicated that topical epidermal growth factor treatment in solution improved the healing of alkali burned corneal wounds when compared with epidermal growth factor delivered in a polymer system.

The effect of some natural polymers on the solubility and dissolution characteristics of nifedipine

Abstract The effect of natural polymers, such as water-soluble gelatin and egg albumin, on the solubility and dissolution characteristics of nifedipine has been studied. Comparison of such polymers was carried out by complexation with β-cyclodextrin. The interaction of nifedipine with these polymers both in aqueous solution and in the solid state was examined by performing solubility analysis, powder X-ray diffractometry and differential scanning calorimetry measurements. In addition, the surface tension of the samples was evaluated. Solid mixtures of nifedipine and polymer in various ratios were prepared by the kneading technique and their dissolution was carried out according to the dispersed amount method. It was found that water-soluble gelatin and β-cyclodextrin resulted in a significant increase in the rate of dissolution of nifedipine as compared to drug alone. Further, water-soluble gelatin may be particularly useful for the enhancement of dissolution of nifedipine.