Factorial design-optimized and gamma irradiation-assisted fabrication of selenium nanoparticles by chitosan and Pleurotus ostreatus fermented fenugreek for a vigorous in vitro effect against carcinoma cells.

The novelty of the present work looks in the synthesis of aqueous dispersed selenium nanoparticles (Se NPs) using gamma rays with the aid of various natural macromolecules such as citrus pectin (CP), sodium alginate (Alg), chitosan (CS) and aqueous extract of fermented fenugreek powder (AEFFP) using Pleurotus ostreatus for investigating their impact in vitro toward carcinoma cell. The synthesized Se NPs were characterized by XRD, UV-Vis., DLS, HRTEM, SEM, EDX and FTIR. Nucleation and growth mechanisms were also discussed. The factorial design was applied to examine the importance of multiple parameters on Se NPs production with a special focus on temperature and gamma rays influences. FTIR spectrum exhibited the existence of several functional groups in Se NPs-capping macromolecules. Results revealed that Se NPs' size was dramatically-influenced by the type of stabilizer, precursors concentration, pH and the absorbed gamma rays dose. The current research reported the promising antitumor application of Se NPs against Ehrlich Ascites Carcinoma (EAC) and human Colon Adenocarcinoma (CACO) in vitro. The proliferation of EAC was significantly-hindered by Se NPs-CS (38.0 µg/ml) at 60 kGy (IC50 = 23.12%) and Se NPs-AEFFP (19.00 µg/ml) at 15 kGy (IC50 = 7.21%). Also, Se NPs control the generation of CACO cells, IC50 was recorded as 25.32% for Se NPs-CS (38.0 µg/ml) and 8.57% for Se NPs-AEFFP (19.00 µg/ml).

Antimicrobial, antioxidant and anticancer activities of zinc nanoparticles prepared by natural polysaccharides and gamma radiation.

Aqueous dispersed zinc nanoparticles (ZnNPs) were synthesized using natural polysaccherides (chitosan (CS), citrus pectin (CP) and alginate (Alg)) using aqueous fermented fenugreek powder (FFP) by Pleurotus ostreatus as reducing and stabilizing agent or using gamma irradiation. The synthesized ZnNPs are characterized by ultra violect spectroscopy (UV), Transmission electronmicroscopy (TEM), Dynamic light scattering (DLS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). XRD analysis of the ZnNPS confirmed the formation of metallic nanoparticles. The nucleation and growth mechanism of ZnNPs is also discussed. TEM showed that the average diameter of ZnNPs was in the range of 46nm. The size of nanoparticles is influenced by certain parameters such as the choice of stabilizer, pH during synthesis and absorbed dose. Evaluating the antioxidant and anticancer activities of ZnNPs was performed. The results indicating the ZnNPs synthesized by aqueous fermented fenugreek extract have high activity and the average size is 46nm. The results explored that ZnNPs show anticancer activity against Ehrlich Ascites Carcinoma (EAC) and human colon adenocarcinoma (CACO) and the IC50% was 47.5µg/ml and 65µg/ml respectively. Also, ZnNPs had excellent bactericidal activity against gram positive and negative bacteria and yeast.

Antiproliferative activity of novel thiophene and thienopyrimidine derivatives.

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 µM) for compound 3 and (34.04, 45.62 µM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Anticancer activity of novel thiophenes containing a biological active diphenylsulfone, diazepin, piperidine, oxazepine, acryladehyde and sulfonamide moieties.

A variety of thiophene derivatives bearing diphenylsulfone 3,4, diazepines 5b, 6b, phenylamino 7, piperidine 8, benzylpiperidine 9, oxazepines 10b, 11b, acrylaldehydes 12-14 and benzeonesulfanamide 15 were synthesized. some newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human tumor breast cancer cell lines. The tested compounds showed moderate to good cytotoxic activity and indeed, some of them were more potent than doxorubicin as a reference drug.

Rapid pain relief using transdermal film forming polymeric solution of ketorolac.

CONTEXT: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management. OBJECTIVE: Development and evaluation of transdermal ketorolac film forming polymeric solution. MATERIALS AND METHODS: Eudragits(®) RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin. RESULTS: The use of 10% oleic acid, Lauroglycol(®) 90 or Azone(®) with 5% Eudragit(®) RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit(®) RSPO and 10% Lauroglycol(®) 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn't run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation. CONCLUSION: Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.

Dapson in heterocyclic chemistry part VI: synthesis and molecular docking of some novel sulfonebiscompounds of expected anticancer activity.

To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

Synthesis, in-vitro anticancer screening and radiosensitizing evaluation of some new N-(quinoxalin-2-yl)benzenesulfonamide derivatives.

The objective of this work is to synthesize and investigate the anticancer activity of a new series of sulfaquinoxaline derivatives by incorporating biologically active moieties (thiourethane, thiazole, imidazole, imidazopyrimidine, imidazopyrimido-pyrimidine, thienopyrimidine, benzopyrimidinone, benzothiazole, thiazole and pyridine moieties). All the newly synthesized compounds were evaluated for their in-vitro anticancer activity against human liver cell line (HEPG2). All the tested compounds showed comparable activity to that of the reference drug 5-fluorouracil (IC50=40 µM), and the most potent compounds were found to be compounds 4 and 17 (IC50=4.29 and 11.27 µM, respectively). On the other hand, the most potent compounds 4 and 17 were evaluated as radiosensitizing agents.

Synthesis, anticancer activity and radiosensitizing evaluation of some new 2-pyridone derivatives.

Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH4OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3-8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC50 values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC50 value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC50 values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.

Comparative studies of semi-artificial diets on the biology and the bionomics of the European corn borer, Ostrinia nubilalis Hübner (Or.: Lepidoptera, Fam. : Pyralidae).

Comparative studies of two semi-artificial diets (S.A.1 and S.A.2) as well as a natural corn diet were studied on the biology and bionomics of the European corn borer, Ostrinia nubilalis under laboratory conditions. The insect was successfully mass reared for ten successive generations at the conditions of 27 +/- 2 degrees C, 60-80% R.H. in addition of photoperiod of 6:18 (L: D) for larvae and 12:12 (L: D) for the other stages, respectively. Along ten successive generations, there were no significant differences between the larval periods for both artificial diets. The S.A.1 induced the shortest larval period (22.5 days) compared to the artificial diet S.A.2 (24 days) and the natural diet (25 days). Meanwhile, the rearing larvae on the natural diet revealed means of pre-pupal and pupal periods of 2 and 8 days which decreased to 2 and 6.5 days in both artificial diets (S.A.1 and S.A.2), respectively. However, the pupal weight and length were insignificantly increased in S.A.1 (121.7 g and 1.7 cm) than that in the natural diet (115.5 g and 1.8 cm) and were in the artificial diet S.A.2 (101.2 g and 1.7 cm), respectively. Moth longevity (pre-oviposition, oviposition and post-oviposition periods), was affected to a certain extent by the larval diets. The maximal moth longevity was recorded (15 days) for larva reared on the natural diets. On the other hand, the shortest period was observed (10.5 days) for the moth longevity in S.A.1. The artificial diet S.A.2 showed the moth longevity (13 days). The longest oviposition period was recorded (10 days) in the natural diet, while it was only (6.5 days) in the artificial diet S.A.1 compared with (8 days) in the artificial diet S.A.2. The number of the deposited eggs/female throughout the 10 successive generations was (400) in the natural diet, while the artificial diet S.A.1 revealed the least number (304.4) versus (358.2) in the artificial diet S.A.2. On the other hand, the number of hatched eggs/female were (320) in the natural diet, versus (310.9 and 256.5) in the artificial diet S.A.2 and S.A.1, consequently. The highest mean of hatchability percent was 86.93% resulted in the artificial diet S.A.2 compared to. 83.92% in the artificial diet S.A.1 and 80% in the natural diet. It was observed that the shortest total generation period found (41.5) days in the artificial diet S.A.1 while it was (50 and 45.5)days in the natural diet and the artificial diet S.A.2, consequently. The results declared that the artificial diet S.A.1 is a suitable artificial diet as it is considered mass rearing of the European corn borer, Ostrinia nubilalis Hub.

Proniosomes as a carrier system for transdermal delivery of tenoxicam.

Tenoxicam is a non steroidal anti-inflammatory drug (NSAID) widely used in the treatment of rheumatic diseases and characterized by its good efficacy and less side effects compared to other NSAIDs. Its oral administration is associated with severe side effects in the gastrointestinal tract. Transdermal drug delivery has been recognized as an alternative route to oral delivery. Proniosomes offer a versatile vesicle delivery concept with the potential for drug delivery via the transdermal route. In this study, different proniosomal gel bases were prepared, characterized by light microscopy, revealing vesicular structures, and assessed for their drug entrapment efficiency, stability, their effect on in vitro drug release and ex vivo drug permeation. The lecithin-free proniosomes prepared from Tween 20:cholesterol (9:1) proved to be stable with high entrapment and release efficiencies. The in vivo behaviour of this formula was studied on male rats and compared to that of the oral market product. The investigated tenoxicam loaded proniosomal formula proved to be non-irritant, with significantly higher anti-inflammatory and analgesic effects compared to that of the oral market tenoxicam tablets.

Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery.

BACKGROUND: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. OBJECTIVE: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. METHODS: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. RESULTS: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. CONCLUSION: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.

Biopharmaceutical evaluation of formulated metformin/rosiglitazone tablets.

The study aimed to combine two antidiabetic agents with different mechanisms of action, namely, metformin HCl and rosiglitazone maleate, in a tablet to improve glycemic control in patients with type II diabetes. The preformulation study started with development and validation of an HPLC method for the determination of both drugs in the mixture. The results of visual inspection, TLC, DSC, and FT-IR verified the absence of any physical or chemical interaction between both compounds. Four compatible excipients were selected for the formulation of the tablets by wet granulation according to a 2(2) factorial design. The prepared tablet blends were acceptable in terms of the modal size of particle distribution, bulk density, Hausner's ratio, Carr's index, and flowability. All formulations fulfilled the pharmacopoeial specifications for weight variation, content uniformity, friability, and hardness. They released 100% of the drug during the first 45 min, displaying higher dissolution efficiency than commercially available Rosiplus tablets. The tablet formulation that passed the physical and chemical stability study for 24 months at ambient conditions was tested in vivo on healthy volunteers in a cross-over design. Statistical analysis proved that the prepared tablets were bioequivalent to the commercial ones in terms of both the rate and the extent of absorption.

Optimization and characterization of diclofenac sodium microspheres prepared by a modified coacervation method.

A modified coacervation method for preparing diclofenac sodium loaded chitosan (DFS-C) microspheres, using sodium citrate as cross-linking agent was optimized. A full 2(3) factorial design was used to evaluate the effect of chitosan (CS) concentration, cross-linking agent concentration, and cross-linking time on the properties of the prepared microspheres. The modified coacervation method resulted in higher yield of spherical microspheres even with a lower concentration of CS (0.3%, w/v). The morphology of the microspheres was found to be dependent on the formulation and process parameters. The cross-linking agent concentration had the largest impact on swelling, mucoadhesion, and drug release. Kinetic analysis of the release data revealed a quasi-Fickian diffusion mechanism.

Mass rearing of the pink corn borer, Sesamia cretica Led. (Lepidoptera: Noctuidae) larvae, on semi artificial diets.

The effect of two different semi-artificial diets (S.A.D1 and S.A.D2) as well as a natural corn diet on the biology and bionomics of the pink stem borer, Sesamia cretica was studied under laboratory conditions. The insect was successfully mass reared for ten successive generations at the conditions of 27 +/- 2 C degrees and 60-80% R.H. In addition, a photoperiod of 0:24 (L:D) for larvae and 12:12 (L:D) in concern to the other stages, respectively. ALong the ten successive generations, there were no significant differences between the larval periods for both the artificial diets. The S.A.D2 induced the shortest (24.0 days) larval period compared with the natural diet (27.5 days) and S.A.D1 (31.5 days). Rearing larvae on the natural diets revealed a pupal period of 11.0 days, while it was 10.0 days and 8.5 days for the artificial diets (S.A.D1) and in (S.A.D2), in respect. Moth longevity (pre-oviposition, oviposition and post-oviposition periods), to a certain extent, was affected by the larval diets. The maximal moth longevity (13.0 days) was observed for larva reared on corn plants (4, 8 and 1 days). On the other hand, the shortest period (10.5 days) of moth longevity was noticed in SAD2 (1, 9 and 0.5 days). S.A.D1 showed 11.0 days moth longevity (3,7 and 1 days). The longest oviposition period (9.0 days) was recorded in the artificial diet S.A.D2, while it was only 7.0 days in the artificial diet S.A.D1 compared with 8.0 days in case of the natural diet. The number of deposited eggs increased with the progress of the 10 successive generations (G1:G10) from 150 to 265 and from 384 eggs to 564 eggs / female for the S.A.D1 and S.A.D2, in sequence. The highest mean number of deposited eggs per female (564) was for the derived females from larvae fed on the artificial diet in G10 of S.A.D2. The rate of the deposited eggs in S.A.D2 was gradually increased (from 9.70 to 61.14% increase) more than those reared on the natural diet throughout the ten generations. The highest significant percent hatchability (92.69%) has been resulted from the artificial diet SAD2. But, it has been decreased to 85.59% in the artificial diet S.A.D1 in comparison to 65.71% in the natural diet. In addition, the significant shortest total generation period was 44.0 days resulted from the artificial diet S.A.D2, while it was 53.5 and 54.0 days for corn plants and the artificial diet S.A.D1, consequently. In short, results indicated that the S.A.D2 could be considered as a suitable artificial diet for a feasible mass rearing of the pink corn borer, Sesamia cretica led. The S.A.D2 showed the shortest larval, pupal and life span for the generation periods. Moreover, it induced the longest oviposition period and the highest mean number of deposited eggs per female and the highest significant percent of eggs hatchability/fertility. The utilization of this artificial diet (S.A.D2) would supply the researchers with high-quality insects in adequate numbers, at specified times and specific stages of development for the bioassay, toxicological and biological studies.

Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride.

Dilutable nanoemulsions are potent drug delivery vehicles for ophthalmic use due to their numerous advantages as sustained effect and high ability of drug penetration into the deeper layers of the ocular structure and the aqueous humor. The aim of this article was to formulate the antiglaucoma drug dorzolamide hydrochloride as ocular nanoemulsion of high therapeutic efficacy and prolonged effect. Thirty-six systems consisting of different oils, surfactants, and cosurfactants were prepared and their pseudoternary-phase diagrams were constructed by water titration method. Seventeen dorzolamide hydrochloride nanoemulsions were prepared and evaluated for their physicochemical and drug release properties. These nanoemulsions showed acceptable physicochemical properties and exhibited slow drug release. Draize rabbit eye irritation test and histological examination were carried out for those preparations exhibiting superior properties and revealed that they were nonirritant. Biological evaluation of dorzolamide hydrochloride nanoemulsions on normotensive albino rabbits indicated that these products had higher therapeutic efficacy, faster onset of action, and prolonged effect relative to either drug solution or the market product. Formulation of dorzolamide hydrochloride in a nanoemulsion form offers, thus, a more intensive treatment of glaucoma, a decrease in the number of applications per day, and a better patient compliance compared to conventional eye drops.

Polymeric matrix system for prolonged delivery of tramadol hydrochloride, part I: physicochemical evaluation.

Management of moderate or severe chronic pain conditions is the burden of clinicians dealing with patients trying to improve their quality of life and diminish their suffering. Although not a new opioid, tramadol has been recently rediscovered and widely used; this may be due to its favorable chronic safety and dependence profiles together with its high potency. Tramadol is a centrally acting analgesic with half-life of approximately 6 h; therefore, it requires frequent dosing. It is freely soluble in water; hence, judicious selection of retarding formulations is necessary. The current study is focused on the innovation of a novel, simple, monolayer, easy-to-use, cost-effective, and aesthetically acceptable bioadhesive transdermal delivery system overcoming the defects of the conventional "patch" as carrier system for tramadol, ensuring its adequate delivery, along with the physicochemical evaluation of the designed formulations. Monolithic tramadol matrix films of chitosan, different types of Eudragit, and binary mixtures of both were prepared. As a single-polymer film, chitosan film showed best properties except for somewhat high moisture uptake capacity, insufficient strength and rapid release, and permeation. Polymer blends were monitored in order to optimize both properties and performance. Promising results were obtained, with chitosan-Eudragit NE30D (1:1) film showing the most desirable combined, sufficiently rapid as well as prolonged release and permeation profiles along with satisfactory organoleptic and physicochemical properties.

Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs.

Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques. The use of nanotechnology to formulate poorly-water-soluble drugs as nanosuspensions offers the opportunity to address many of the deficiencies associated with this class of molecules. In the present study, the high pressure homogenization method used to prepare nanosuspensions of three practically insoluble glucocorticoid drugs; hydrocortisone, prednisolone and dexamethasone. The effect of particle size in the micron and nano-size ranges as well as the effect of viscosity of the nanosuspension on the ocular bioavailability was studied by measuring the intraocular pressure of normotensive Albino rabbits using shiØetz tonometer. The results show that compared to solution and micro-crystalline suspensions it is a common feature of the three drugs that the nanosuspensions always enhance the rate and extent of ophthalmic drug absorption as well as the intensity of drug action. In the majority of cases nanosuspensions extend the duration of drug effect to a significant extent. The data presented confirms that nanosuspensions differ from micro-crystalline suspensions and solution as ophthalmic drug delivery systems and that the differences are statistically, highly to very highly significant. The results confirm also the importance of viscosity of nanosuspension especially in increasing the duration of drug action.

Design of a transdermal delivery system for aspirin as an antithrombotic drug.

Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.

A transdermal delivery system for glipizide.

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glipizide. For this purpose, inclusion complexes of the drug in beta-cyclodextrin (beta-CyD), dimethyl-beta-cyclodextrin (DM-beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) were prepared. Several percutaneous formulations of the drug and the prepared complexes in different bases (o/w emulsion, polyethylene glycol, carboxymethyl cellulose and Carbopol) were developed. Release studies revealed an improved release of the drug from formulations containing glipizide-CyD complexes. Ex vivo permeation studies through full thickness rat abdominal skin were conducted, whereby the effect of several conventional penetration enhancers (propylene glycol [PG], oleic acid, urea, dimethyl sulfoxide, menthol, limonene and cineole) was monitored. Highest flux was obtained from ointments prepared with Carbopol gel base containing a combination of PG and oleic acid as well as ointments prepared in the same base utilizing glipizide-DM-beta-CyD complex and urea. In vivo studies on diabetic male Wistar rats revealed a marked therapeutic efficacy sustained for about 48 hours. In this respect, two formulations showed best biological performance. In the first formulation, the drug was incorporated in Carbopol gel base in the presence of 20% PG together with 15% oleic acid. The second was prepared by incorporating glipizide-DM-beta-CyD complex in Carbopol gel base in presence of 15% urea. The glucose tolerance test showed suppression of hyperglycaemia induced in glucose-loaded rats. The above-mentioned results might shed a strong beam of light on the feasibility of using glipizide in a transdermal delivery system for treatment of type 2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease.

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy.

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with beta-cyclodextrin and its derivatives (HP-beta-CyD and SBE-beta-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride-HP-beta-CyD-5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 degrees C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.