Current Issue : April - June Volume : 2016 Issue Number : 2 Articles : 8 Articles
Formulation of solid dispersions using BCS class II drugs is one of the fruitful technologies to improve the drug solubility and dissolution rate to improve the bioavailability, but suffers from poor flowability and stability. To overcome the above problems, present research was intended to prepare the solid dispersions using combination of melt dispersion and surface adsorption methods. In the present study flurbiprofen melt dispersion granules were prepared by incorporating vitamin E TPGS as the carrier material and lactose as an adsorbent to improve the dissolution rate and flowability. Melt dispersion granules were evaluated for angle of repose, solubility studies, differential scanning calorimetry, in vitro dissolution studies, stability studies and finally subjected to pharmacokinetic studies. From the differential scanning calorimetry studies, change in the drug peak in formulation revealed the change in drug crystallinity. F4 formulation showed not only good flowability but also complete drug release in 15 min when compared to other formulations and pure drug. From the pharmacokinetic evaluation, F4 formulation showed 1.38- fold higher bioavailability and 1.32-fold higher Cmax compared to plain flurbiprofen. Hence, the formulated vitamin E TPGS melt dispersion granules were able to improve the dissolution rate as well as the bioavailability of flurbiprofen....
Introduction: The in vitro-in vivo pharmacokinetic correlation\nmodels (IVIVC) are a fundamental part of the drug discovery and\ndevelopment process. The ability to accurately predict the in vivo\npharmacokinetic profile of a drug based on in vitro observations can\nhave several applications during a successful development process.\nObjective: To develop a comprehensive model to predict the in vivo\nabsorption of antiretroviral drugs based on permeability studies, in\nvitro and in vivo solubility and demonstrate its correlation with the\npharmacokinetic profile in humans.\nMethods: Analytical tools to test the biopharmaceutical properties\nof stavudine, lamivudine y zidovudine were developed. The kinetics\nof dissolution, permeability in caco-2 cells and pharmacokinetics of\nabsorption in rabbits and healthy volunteers were evaluated.\nResults: The cumulative areas under the curve (AUC) obtained in\nthe permeability study with Caco-2 cells, the dissolution study and\nthe pharmacokinetics in rabbits correlated with the cumulative AUC\nvalues in humans. These results demonstrated a direct relation between\nin vitro data and absorption, both in humans and in the in vivo model.\nConclusions: The analytical methods and procedures applied to the\ndevelopment of an IVIVC model showed a strong correlation among\nthemselves. These IVIVC models are proposed as alternative and cost/\neffective methods to evaluate the biopharmaceutical properties that\ndetermine the bioavailability of a drug and their application includes\nthe development process, quality assurance, bioequivalence studies\nand pharmacosurveillance....
Context: The development of an improved, efficacious human GH (hGH) product administered by\na noninjectable route of delivery such as the nasal route is highly desirable. We have developed a\nnovel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however,\nthe translation of these results into the clinical setting is essential because past attempts to\ndevelop such formulations by other groups have been unable to induce IGF-1 in man.\nObjective: The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and\ntolerability of CP024 compared with a sc hGH injection.\nDesign: This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover\nstudy in eight healthy volunteers.\nSetting: The study was carried out at a contract research organization, Quotient Bioresearch.\nVolunteers: Eight healthy male volunteers, given an iv infusion of octreotide to suppress the\nendogenous GH secretion during the study period, participated in the study. No volunteers were\nwithdrawn due to side effects.\nMain Outcome Measures: Measurement of hGH and IGF-1 levels and tolerability of the drug\nproduct was performed.\nResults: No serious adverse events were reported and no subjects withdrawn from study due to the\ntreatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained\nas compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice\ndaily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no\nsignificant difference to those obtained after the sc injection of hGH.\nConclusions: The study indicates that CP024 is a promising candidate for an efficacious nasal\nproduct for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc\ninjection, despite the lower plasma hGH concentration obtained. A dose-response study is needed\nto evaluate the optimal nasal dose. (J Clin Endocrinol Metab 100: 4364ââ?¬â??4371, 2015)...
Background: The complex relationship between drug concentrations and bacterial growth rates require not only\nthe minimum inhibitory concentration but also other parameters to capture the dynamic nature of the relationship.\nTo analyse this relationship between tetracycline concentration and growth of Escherichia coli representative of those\nfound in the Danish pig population, we compared the growth of 50 randomly selected strains. The observed net\ngrowth rates were used to describe the in vitro pharmacodynamic relationship between drug concentration and net\ngrowth rate based on Emax model with three parameters: maximum net growth rate (Ã?±max); concentration for a half maximal\nresponse (Emax); and the Hill coefficient (Ã?³).\nResults: The net growth rate in the absence of antibiotic did not differ between susceptible and resistant isolates\n(P = 0.97). The net growth rate decreased with increasing tetracycline concentrations, and this decline was greater in\nsusceptible strains than resistant strains. The lag phase, defined as the time needed for the strain to reach an OD600\nvalue of 0.01, increased exponentially with increasing tetracycline concentration. The pharmacodynamic parameters\nconfirmed that the Ã?±max between susceptible and resistant strains in the absence of a drug was not different. EC50\nincreased linearly with MIC on a logââ?¬â??log scale, and Ã?³ was different between susceptible and resistant strains.\nConclusions: The in vitro model parameters described the inhibition effect of tetracycline on E. coli when strains\nwere exposed to a wide range of tetracycline concentrations. These parameters, along with in vivo pharmacokinetic\ndata, may be useful in mathematical models to predict in vivo competitive growth of many different strains and for\ndevelopment of optimal dosing regimens for preventing selection of resistance....
Background: Previously, we validated the mouse thigh infection model to test the therapeutic equivalence of\ngeneric antibiotic products. Here, our aim was to compare the in vivo efficacy of amikacin products in clinical use in\nColombia using this animal model.\nResults: All except one generic product had the same in vitro potency, judging by the lack of differences on MIC\nand MBC compared with the innovator. However, eight of nine generic products failed in the neutropenic mouse\nthigh infection model to achieve the innovator�s maximum effect (Emax � 5.65 for the generics vs. 6.58 log10 CFU/g for\nthe innovator) against Escherichia coli SIG-1, after subcutaneous treatment every 6 h with doses ranging from 1.5 to\n3072 mg/kg per day.\nConclusion: As we demonstrated previously with other antibiotics such as vancomycin, gentamicin and oxacillin,\nthe generic products of amikacin failed the in vivo efficacy testing. The therapeutic equivalence should be assessed\nin vivo before clinical approval of generic products....
We investigate the pharmacokinetics of two different cephalexin formulations administered to llamas by the intravenous (IV),\nintramuscular (IM), and subcutaneous (SC) routes, the minimum inhibitory concentration (MIC) of cephalexin against some\nEscherichia coli and staphylococci isolated from llamas, and we apply the PK/PD modelling approach, so that effective dosage\nrecommendations for this species could be made. Six llamas received immediate (10mg/kg, IV, IM, and SC) and sustained (8mg/kg\nIM, SC) release cephalexin. Pharmacokinetic parameters were calculated by noncompartmental approach. Immediate release SC\nadministration produced a significantly longer elimination half-life as compared with the IV and IM administration (1.3 Ã?± 0.2\nversus 0.6 Ã?± 0.1 and 0.6 Ã?± 0.1 h, resp.) and higher mean absorption time as compared with the IM administration (1.7 Ã?± 0.5 versus\n0.6 Ã?± 0.4 h). Absolute bioavailability was in the range of 72ââ?¬â??89% for both formulations and routes of administration. Cephalexin\nMIC90 values against staphylococci and E. coli were 1.0 and 8.0 ...
Background: Abacavir and lamivudine are approved for once-daily use in HIV-infected adults. Limited pharmacokinetic\n(PK) data for abacavir and lamivudine in children are available.\nMethods: A crossover study to compare PK of once- versus twice-daily abacavir and lamivudine was conducted in\nvirologically suppressed HIV-infected Thai children aged <18years, with bodyweight of at least 14 kg, HIV RNA\n<50 copies/mL and HLA-B*5701 negative. Abacavir and lamivudine daily doses by bodyweight were 300 and 150 mg for\n14ââ?¬â??<20 kg, 450 and 300 mg for 20ââ?¬â??<25 kg, and 600 and 300 mg for ââ?°Â¥25 kg, respectively. Originator abacavir and\nlamivudine scored tablets were administered. Intensive PK sampling was performed after 14 days of each dose. PK\nparameters were determined using non-compartmental analysis.\nResults: Thirty children (57% male) were enrolled, 10 per weight band. Median (IQR) age was 8.8 (6.6ââ?¬â??11.3) years and\nbodyweight was 21.9 (19.2ââ?¬â??30.6) kg. The geometric means (GM) AUC0ââ?¬â??24 of once- and twice-daily abacavir were 14.43\nand 10.65 mg.h/L, respectively. The geometric mean ratio (GMR) of AUC0ââ?¬â??24 for once- versus twice-daily abacavir dosing\nwas 1.36 [90% confidence interval (CI) 1.11ââ?¬â??1.66]. The GM AUC0ââ?¬â??24 of once- and twice-daily lamivudine were 17.70 and\n18.11 mg.h/L, respectively. The GMR of AUC0ââ?¬â??24 for once- versus twice-daily lamivudine dosing was 0.98 (90% CI\n0.84ââ?¬â??1.14). At 96 weeks, 90% had HIV RNA <50 copies/mL and there were no serious adverse events.\nConclusion: Abacavir exposure was greater with once-daily dosing, while lamivudine once- and twice-daily exposures were\nbioequivalent. Once-daily abacavir and lamivudine using weight-band dosing is a treatment option for children....
Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of\ntype 1 diabetes. Because little is known about its absorption and effects in humans,\nwe investigated the pharmacokinetics and pharmacodynamics of GABA in healthy\nvolunteers. Twelve subjects were subjected to an open-labeled, three-period trial\ninvolving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three\ntimes/day for 7 days, with a 7-day washout between each period. GABA was rapidly\nabsorbed (Tmax: 0.5 âË?¼ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed\nafter repeated oral GABA administration for 7 days. Remarkably, GABA significantly\nincreased circulating insulin levels in the subjects under either fasting (1.6-fold, single\ndose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose;\n1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under\nfasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01).\nHowever, there were no significant differences in the insulin-to-glucagon ratio and no\nsignificant change in glucose levels in these healthy subjects during the study period.\nImportantly, GABA significantly decreased glycated albumin levels in the repeated dosing\nperiod. Subjects with repeated dosing showed an elevated incidence of minor adverse\nevents in comparison to placebo or the single dosing period, most notably transient\ndiscomforts such as dizziness and sore throat. However, there were no serious adverse\nevents observed throughout the study. Our data show that GABA is rapidly absorbed and\ntolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal\nsecretion, suggest potential therapeutic benefits for diabetes....
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