Chronomodulated rupturable pulsatile drug delivery of theophylline: preparation and in vitro characterization

The aim of the present study was to develop and evaluate chronomodulated rupturable pulsatile drug delivery of theophylline for the treatment of nocturnal asthma. Core tablets containing theophylline were coated with two consecutive layers, an inner swelling layer and an outer rupturable coating layer. The effect of formulation variables such as molecular weight of outer rupturable coating layer, type and amount of swelling layer, weight gain of coating film and influence of paddle speed on drug release were investigated. The drug release from the pulsatile tablets exhibited an initial lag period, followed by a stage of rapid drug release. The optimal level of swelling layer (crospovidone) to achieve a fast and complete release was 20 % w/w. The results indicated that lag time was prolonged with the increased weight gain of coating film. Also no significant difference in the drug release was observed for different rotational speeds. In accordance with the chronomodulated therapy of asthma, the lag time criterion of 5 hours was satisfied by formulation having 11 % weight gain of outer rupturable layer.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Jednostavna RP-HPLC metoda za određivanje kombinacije triju lijekova, valsartana, amlodipina i hidroklorotiazida, u humanoj plazmi

A simple RP-HPLC method for the quantification of valsartan (VAL), amlodipine (AML) and hydrochlorothiazide (HCT) in human plasma was developed and validated. VAL, AML and HCT were resolved using a Gemini C18 column and mobile phase gradient starting from 20 % acetonitrile and 80 % 10 mmol L1 ammonium formate (V/V, pH 3.5 ± 0.2, by formic acid) to 70 % acetonitrile and 30 % 10 mmol L1 ammonium formate, over 20 minutes with a flow rate of 1 mL min1. The samples were purified by protein precipitation and extraction. Telmisartan was used as internal standard. The method was validated according to USFDA and EMEA guidelines with good reproducibility and linear responses R = 0.9985 (VAL), 0.9964 (AML), and 0.9971 (HCT). RSDs of intra- and inter-day precision ranged between 2.28.1 and 4.611.7 %, respectively, for all three drugs. Mean extraction recoveries of three QCs for the triple drug combination were 76.5 (VAL), 72.0 (AML) and 73.0 (HCT) % for human plasma. Although the LC-MS/MS method is more sensitive than HPLC, HPLC is still suitable for preliminary pharmacokinetic study. The experiments performed demonstrated that simultaneous determination of all components of the triple drug combination in human plasma can be done by this method. Proposed method can be also used for guidance to the LC-MS/MS method.U radu je opisana i validirana jednostavna RP-HPLC metoda za određivanje valsartana (VAL), amlodipina (AML) i hidroklorotiazida (HCT) u humanoj plazmi. VAL, AML i HCT razlučeni su na koloni Gemini C18. Početni sastav mobilne faze bio je acetonitril (20 %) i 10 mmol L1 otopina amonijevog formijata (80 %, V/V, pH podešen na 3,5 ± 0,2 pomoću mravlje kiseline), a nakon 20 minuta 70 % acetonitrila i 30 % 10 mmol L1 amonijevog formijata, uz protok od 1 mL min1. Uzorci su pročišćeni taloženjem proteina i ekstrakcijom. Telmisartan je upotrijebljen kao unutarnji standard. Metoda je validirana prema uputama USFDA i EMEA uz dobru ponovljivost i linearnost: R = 0.9985 (VAL), 0.9964 (AML), and 0.9971 (HCT). Ponovljivost i intermedijarna preciznost bile su u rasponu 2,28,1, odnosno 4,611,7 % za sve tri ljekovite tvari. Srednji povrat ekstrakcije iz humane plazme za ovu kombinaciju lijekova iznosio je 76,5 (VAL), 72,0 (AML) i 73,0 (HCT) %. Iako je LC-MS/MS metoda osjetljivija od HPLC metode, HPLC je prihvatljiva za preliminarna farmakokinetička ispitivanja. Provedeni pokusi pokazuju da se predloženom metodom mogu istodobno odrediti sastavnice trostruke kombinacije lijekova u humanoj plazmi. Predložena metoda može biti korisna smjernica za LC-MS/MS metodu

Pulsatile drug delivery for the treatment of nocturnal asthma: a chronopharmaceutical approach

The objective of the present study was to develop and evaluate a pulsatile system of theophylline based on chronopharmaceutical considerations. The basic design consists of an impermeable capsule body, which contains the drug and is closed by an erodible tablet plug. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat treatment. The formulation variables such as type of plug material, capsule content, different plug composition, plug weight and plug hardness was investigated to characterize the lag time (t10).The results indicated that drug release from the pulsatile capsule exhibited an initial lag period, followed by a stage of rapid drug release. For the complete and rapid drug release from the capsule body, 15% of effervescent agent had to be included in the capsule content. The lag time criterion of 5 hrs was satisfied by the tablet plug containing 16%HPMC K100LV. A good correlation was observed between erodible tablet weight and lag time.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Chronomodulated rupturable pulsatile drug delivery of theophylline: preparation and in vitro characterization

The aim of the present study was to develop and evaluate chronomodulated rupturable pulsatile drug delivery of theophylline for the treatment of nocturnal asthma. Core tablets containing theophylline were coated with two consecutive layers, an inner swelling layer and an outer rupturable coating layer. The effect of formulation variables such as molecular weight of outer rupturable coating layer, type and amount of swelling layer, weight gain of coating film and influence of paddle speed on drug release were investigated. The drug release from the pulsatile tablets exhibited an initial lag period, followed by a stage of rapid drug release. The optimal level of swelling layer (crospovidone) to achieve a fast and complete release was 20 % w/w. The results indicated that lag time was prolonged with the increased weight gain of coating film. Also no significant difference in the drug release was observed for different rotational speeds. In accordance with the chronomodulated therapy of asthma, the lag time criterion of 5 hours was satisfied by formulation having 11 % weight gain of outer rupturable layer.Colegio de Farmacéuticos de la Provincia de Buenos Aire

RP-HPLC-DAD metoda za određivanje olmesartan medoksomila kao čiste supstancije i u tabletama izloženih razgradnji

A simple, sensitive and precise RP-HPLC-DAD method was developed and validated for the determination of olmesartan medoxomil (AT-II receptor blocker) in the presence of its degradation products. Olmesartan medoxomil and all the degradation products were resolved on a C18 column with the mobile phase composed of methanol, acetonitrile and water (60:15:25, V/V/V, pH 3.5 by orthophosphoric acid) at 260 nm using a photodiode array detector. The method was linear over the concentration range of 1–18 µg mL 1 and precise with RSD 2.0 for each peak and sensitive with LOD 0.03 µg mL−1 and LOQ 0.1 µg mL−1. The method was used to study the drug degradation behavior under forced conditions. Four degradation products (DP-I, II, III, IV) were formed during the degradation study in 0.1 mol L−1 HCl whereas only DP-I, II and III were formed in water, 0.01 mol L−1 NaOH and 3 % H2O2. No significant thermal or photolytic degradation was observed in solid drug. The method was applied successfully for the assay of olmesartan medoxomil in the tablet dosage form.U ovom radu razvijena je i validirana jednostavna, osjetljiva i precizna RP-HPLC-DAD metoda za određivanje olmesartan medoksomila (inhibitor AT-II receptora) u prisutnosti njegovih razgradnih produkata. Olmesartan medoksomil i razgradni produkti kromatografirani su na C18 koloni uz mobilnu fazu metanol/ acetonitril/vo da (60:15:25 V/V/V; pH 3,5 podešen ortofosfornom kiselinom) pri 260 nm uz detektor s fotodiodnim nizom. Metoda je linearna u koncentracijskom rasponu 1–18 µg mL 1 i precizna s RSD < 1 % tijekom ispitivanja repetabilnosti i intermedijarne ponovljivosti. Povrat od 99,3 ± 0,9 do 100,8 ± 1,2 % dokazuje točnost metode. Razvijena metoda je specifična na što ukazuje kromatografsku rezoluciju veću od 2,0 i osjetljiva (LOD = 0,03 µg mL−1 i LOQ = 0,1 µg mL−1). Metoda je upotrebljena za praćenje razgradnje olmesartan medoksomila u uvjetima potencirane razgradnje. U 0,1 mol L−1 HCl detektirana su četiri razgradna produkta (DP-I, II, III, IV), a u vodi, 0,01 mol L−1 NaOH i 3 % H2O2 samo DP-I, II i III. U čvrstom agregatnom stanju nije primjećena značajna termička ni fotolitička razgradnja ljekovite tvari. Metoda je uspješno primijenjena za određivanje olmesartan medoksomila u tabletama

HPLC-DAD Method for the Pharmacokinetic Interaction Study of Atorvastatin with Pioglitazone and Cholestyramine in Wistar Rats

Carotid intima-media thickness is used as a surrogate marker for cardiovascular complications in diabetes mellitus. The combination of atorvastatin and pioglitazone was found to be effective in reducing the thickness of the carotid intima-media layer. The method of RP-HPLC coupled with a diode array detector (DAD) was developed for the pharmacokinetic interaction study of atorvastatin with pioglitazone and cholestyramine, respectively, in Wistar rats. Atorvastatin (ATR) and pioglitazone (PIO) were resolved on a C18 column with a mobile phase composed of 48% methanol, 19% acetonitrile, and 33% 10 mM ammonium formate (v/v/v; pH 3.5±0.3, by formic acid) and a 260 nm detection wavelength on the diode array detector. The method was validated according to international standards with good reproducibility and linear response; mean (r) 0.9987 and 0.9972 to ATR and PIO, respectively. The coefficients of variation of intra- and interassay precision ranged between 4.95–8.12 and 7.29–9.67, respectively. Pharmacokinetic parameters were determined in rats following an oral administration of atorvastatin in the presence and absence of pioglitazone and also with cholestyramine. Compared with the control given atorvastatin alone, the Cmax and AUC of atorvastatin were merely unchanged in rats with the co-administration of pioglitazone, while they decreased by nearly 21 and 15%, respectively, with the concurrent use of cholestyramine. There were no significant changes in Tmax and the plasma half-life (T1/2) of atorvastatin in both cases. The performed experiment demonstrated that the presented method was suitable for the estimation and pharmacokinetic interaction study of atorvastatin with pioglitazone and cholestyramine in Wistar rat plasma

Synergistic antioxidant activity of green tea with some herbs

Cardiovascular diseases, cancer, arthritis, etc. are caused by free radicals that are byproducts of metabolic pathways. Selected plants namely Vitis vinifera, Phyllanthus emblica L., Punica granatum, Cinnamomum cassia, Ginkgo biloba L., and Camellia sinensis Linn. are reported to produce antioxidant property. This study is undertaken to support the hypothesis that formulation of a polyherbal combination of these plants shows a synergistic effect with green tea. The extracts of each drug were characterized by phytochemical studies and tests for phenolics and flavonoids. In vitro antioxidant activity for individual drug and its combination was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide, and nitric oxide free radical scavenging methods. Our results suggest that a combination of all these herbs with green tea can synergistically enhance antioxidant activity and thus lower doses of each herb with green tea may be used. Antioxidant potential of polyherbal combination was also comparable to that of standard ascorbic acid. Studies showed that selected individual plants contained abundant quantity of phenolics and flavonoids and their polyherbal combination with green tea was found to produce best antioxidant activity among all individual extracts. This will help in avoiding undesirable side effects due to higher doses of single herb

Eudragit-coated pectin microspheres of 5-fluorouracil for colon targeting

An objective of the present investigation was to prepare and evaluate Eudragit-coated pectin microspheres for colon targeting of 5-fluorouracil (FU). Pectin microspheres were prepared by emulsion dehydration method using different ratios of FU and pectin (1:3 to 1:6), stirring speeds (500–2000 rpm) and emulsifier concentrations (0.75%–1.5% wt/vol). The yield of preparation and the encapsulation efficiencies were high for all pectin microspheres. Microspheres prepared by using drug:polymer ratio 1:4, stirring speed 1000 rpm, and 1.25% wt/vol concentration of emulsifying agent were selected as an optimized formulation. Eudragit-coating of pectin microspheres was performed by oil-in-oil solvent evaporation method using coat: core ratio (5:1). Pectin microspheres and Eudragit-coated pectin microspheres were evaluated for surface morphology, particle size and size distribution, swellability, percentage drug entrapment, and in vitro drug release in simulated gastrointestinal fluids (SGF). The in vitro drug release study of optimized formulation was also performed in simulated colonic fluid in the presence of 2% rat cecal content. Organ distribution study in albino rats was performed to establish the targeting potential of optimized formulation in the colon. The release profile of FU from Eudragit-coated pectin microspheres was pH dependent. In acidic medium, the release rate was much slower; however, the drug was released quickly at pH 7.4. It is concluded from the present investigation that Eudragit-coated pectin microspheres are promising controlled release carriers for colon-targeted delivery of FU