Cansel Kose Ozkan

Formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers: In vitro and in vivo evaluation

First-pass metabolism can be overcome by sublingual drug delivery, and quick drug entry into the systemic circulation can be obtained. In certain diseases such as migraine therapy, taking fast pharmacological response is an important criteria. In this study, zolmitriptan sublingual tablets were prepared by direct compression method using different mucoadhesive polymers such as hydroxypropyl methyl cellulose, chitosan and sodium carboxy methyl cellulose at a concentration range of 0.5-5% to reduce flushing action of saliva and provide enough time for drug to be absorbed. Tablets were evaluated for the physical properties, and optimum formulations were chosen for in vivo studies to carry on sheep model. The tablets disintegrated rapidly, and dissolution tests revealed that zolmitriptan was dissolved from the formulation within the compendial limits. This especially showed us that the concentration range of polymers is in acceptable limit. It was also concluded that microcrystalline cellulose, spray-dried lactose and sodium starch glycolate are the appropriate excipient and formulated in good proportions. In vivo studies indicated that formulation containing 5% chitosan has the maximum C(max) and AUC and minimum t(max) values (p<0.05). As a result, sublingual tablet administration of zolmitriptan formulated with appropriate excipients and especially with chitosan seems promising alternative to traditional routes.

Comparison of the effect of topical and systemic melatonin administration on delayed wound healing in rats that underwent pinealectomy

Abstract Objectives. Melatonin is a hormone which has many systemic effects in addition to its strong antioxidant properties. The aim of the present study was to investigate the difference between sytemic and topical administration of melatonin by forming a chronic wound model in rats whose release of basal melatonin was supressed by pinealectomy. Material and methods. Experimental animals used in the study were divided into four equal groups: (i) a group of normal animals with wound formation (control), (ii) a group of animals who underwent pinelaectomy and wound formation (PINx), (iii) a group that underwent PINx + systemic melatonin administration, and (iv) a group that underwent PINx + topical melatonin administration. Fifteen days after pinealectomy, a bipediculed flap was formed on the back of the rats under anesthesia and then six excisional skin wounds were produced in all groups. Following the treatment that lasted 7 days, on day 8 the wound surface areas were measured and wound tissues were removed under anesthesia. In these tissues the levels of malondialdehit (MDA) and hydroxyproline (OH-proline) and the activities of superoxide dismutase(SOD) and glutathion peroxidase (GSH-Px) were measured. Results. In the PINx group, OH-prolin levels decreased significantly compared to the control group and wound surface areas increased. MDA levels increased compared to the control group, and SOD and GSH-Px decreased accordingly. Conversely, in two melatonin groups in which melatonin was administered systemically or topically MDA decreased while SOD ve GSH-Px enzymes increased. Conclusion. In conclusion, in the present study it was shown that wound healing was prolonged in experimental animals deprived of melatonin through pinealectomy. Melatonin exerts positive effects on wound healing, whether it is administered topically or systemically.

Development and validation of an RP-HPLC method for the determination of valacyclovir in tablets and human serum and its application to drug dissolution studies

Abstract A specific, sensitive, simple, and rapid HPLC method has been developed for the determination of valacyclovir (VACL) in raw material, pharmaceutical dosage forms, and human serum, in order to carry out drug dissolution studies from tablets. The chromatographic separation was achieved with acetonitrile:methanol:0.067 M KH2PO4 (27:20:53, v/v/v) adjusted to pH 6.5 with 3 M NaOH as mobile phase, a Waters Spherisorb C18 column, and UV detection at 244 nm. Etodolac was used as an internal standard. Linearity range was 5–20,000 ng mL−1. Limit of detection obtained was 0.38 and 0.14 ng mL−1 in mobile phase and spiked human serum samples, respectively. The described method can be readily applied, without any interferences from the excipients, for the determination of the drug in tablets, human serum samples, and drug dissolution studies. #Presented at 11th International Pharmaceutical Technology Symposium, September 9–11, 2002, Istanbul, Turkey.

Nasal administration of metoclopramide from different dosage forms: in vitro, ex vivo, and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p < 0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p < 0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.

Effect of different polymers and their combinations on the release of metoclopramide HCl from sustained-release hydrophilic matrix tablets

Metoclopramide HCl (MTC) is commonly used for the management of gastrointestinal disorders. It has a short biological half-life and is usually administered four times daily to maintain effective concentrations throughout the day. The aim of this study is to develop sustained-release hydrophilic matrix tablet formulations of drug to achieve reproducible and predictable release rates, extended duration of activity, decreased toxicity, reduction of required dose, optimized therapy, and improved patient compliance. Hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose sodium (NaCMC), chitosan and Carbopol 981 were incorporated in the matrix system separately or in combinations as release controlling factor by direct compression technique. Compatibility among the formulation components was assessed by DSC and FTIR analysis. MTC release from matrix was evaluated by using the US Pharmacopeia dissolution apparatus II. All formulations met the criteria of pharmacopeial requirements. Dissolution studies show that polymer type and concentration are important parameters on drug release. Chitosan, carbopol and NaCMC formulations exhibited pH-dependent drug release profile whereas HPMC did not. All the formulations containing 1:1 ratio of HPMC and chitosan exhibited desired drug release showing that all active substance releases progressively in a period of whole dissolution time and therefore it can be regarded as worthy of consideration for the manufacture of sustained-release MTC product.

The Effect of α-Tocopherol and Selenium on Human Gingival Fibroblasts and Periodontal Ligament Fibroblasts In Vitro

BACKGROUND The aim of the present study is to evaluate the effect of α-tocopherol and selenium on gingival fibroblasts (GFs) and periodontal ligament fibroblasts (PDLFs) in terms of proliferation, basic fibroblast growth factor (bFGF) release, collagen type I synthesis, and wound healing. METHODS Primary cultures of human GFs and PDLFs were isolated. Four test groups and a control group free of medication was formed. In group E, 60 μM α-tocopherol was used, and in groups ES1, ES2, and ES3, the combination of 60 μM α-tocopherol with 5 × 10(-9) M, 10 × 10(-9) M, and 50 × 10(-9) M selenium was used, respectively. Viability, proliferation, bFGF, and collagen type I synthesis from both cell types were evaluated at 24, 48, and 72 hours, and healing was compared on a new wound-healing model at 12, 24, 36, 48, and 72 hours. RESULTS α-Tocopherol alone significantly increased the healing rate of PDLFs at 12 hours and increased bFGF and collagen type I release from GFs and PDLFs at 24, 48, and 72 hours. The α-tocopherol/selenium combination significantly enhanced the proliferation rate of both cells at 48 hours, decreased the proliferation of PDLFs at 72 hours, and increased the healing rate of GFs at 12 hours and PDLFs at 12 and 48 hours. bFGF and collagen type I synthesis was also increased in both cell types at 24, 48, and 72 hours by α-tocopherol/selenium combination. CONCLUSION α-Tocopherol and α-tocopherol/selenium combination is able to accelerate the proliferation rate and wound-healing process and increase the synthesis of bFGF and collagen type I from both GFs and PDLFs.

RP‐HPLC Assay of Rofecoxib from Pharmaceutical Dosage Forms and Human Plasma and Its Drug Dissolution Studies

ABSTRACT A high performance liquid chromatographic (HPLC) method is described for the determination of rofecoxib (RFC) in bulk drug, tablets, and human plasma samples. The methods are linear over the concentration ranges 0.005–30.0 and 0.010–10 µg mL−1 in mobile phase and human plasma, respectively. Chromatography was carried out on a reversed phase Spherisorb ODSI column using a mixture of acetonitrile:methanol: 0.067 M KH2PO4 (27:20:53, v/v/v) adjusted to pH 6.95 with 3 M NaOH. Detection was realized at 244 nm using a DAD detector. The retention time observed for RFC and etodolac (internal standard) at about 7.5 and 10.7 min, respectively. The proposed RP‐HPLC method was validated for precision, accuracy, ruggedness, and recovery. The limit of detection was found to be 0.00143 and 0.00301 µg mL−1 in mobile phase and human plasma samples, respectively. The proposed method allows a number of cost and time saving benefits. The described method can be readily applied for the analysis of tablets, drug dissolution studies, and human plasma samples. This method could be used without any interference from tablet matrix and endogenous substance from the plasma samples.