Biowaiver Eligibility of a Lower Strength Ramipril/Hydrochlorothiazide Immediate Release Tablets Using a New Validated HPLC Analytical Method.

Bioequivalence studies are expensive, time consuming and invasive to humans. Accordingly, an alternative in vitro study (biowaivers) has been introduced for drugs which belong to BCS class I and III and for other strengths of already approved higher drug strength. The main objective of this study was to prove the biowaiver eligibility of a lower strength Ramipril/Hydrochlorothiazide (2.5/12.5 mg) tablets. Visual and pharmacopoeial quality tests were performed on the higher and lower generic and on the reference listed drug to determine whether they are pharmaceutically equivalent. All products were investigated using the biowaiver criteria. Dissolution profiles were conducted at pH values 1.2, 4.5 and 6.8. Difference factor (f1) and similarity factor (f2) were calculated. The tested products were successfully complied with pharmacopeial requirements. f1 was below 15 and f2 was above 50 in all dissolution conditions. Precisely, Ramipril showed release higher than 85% within 15 min. f1 and f2 for Hydrochlorothiazide were 8 and 61 respectively at the recommended discriminative pH media.These results suggest that the current biowaiver criteria could be a sufficient guarantee of bioequivalence of the lower strength of Ramizide assuming that the product is manufactured at the same site and contains same quality and grade of excipients and in a proportional amounts.

A validated and stability indicating HPLC method for analysis of diminazene aceturate and antipyrine combination in a ready injectable solution.

Diminazene aceturate and Antipyrine combination therapy is widely used in veterinary medicine. A simple reverse HPLC method for the analysis of samples of a ready injectable formulation containing a mixture of active ingredients and inactive excipients has been developed. The HPLC analysis was carried out using a reversed phase (RP)-C18 (250 mm×4.0 mm, 5 µm) column. The isocratic mobile phase consisted of a mixture of acetonitrile, methanol, phosphate buffer and hexane sulfonate; the flow rate was 0.6 mL/min and ultraviolet detection was at 291 nm. This method was validated in accordance with FDA and ICH guidelines and showed good linearity, accuracy, precision, selectivity and the system suitability results were within the acceptance criteria. A stability-indicating study was also carried out and indicated that this method could be used for purity and degradation evaluation of these formulations.

Formulation and comparative bioavailability of 2 ciprofloxacin sustained release tablets.

BACKGROUND AND THE PURPOSE OF THE STUDY: The aim of this study is to formulate and evaluate the quality of ciprofloxacin (CAS number: 85721-33-1) sustained release tablet (Ciprocare®XR) 1 000 mg ciprofloxacin (test formulation) by comparing its pharmacokinetic parameters with Cipro®XR sustained release tablet (reference formulation). For this purpose ciprofloxacin SR tablets were developed using the 2-layer method. To assess the quality of the produced sustained release tablets a randomized, 2-way, crossover, bioequivalence study was performed in 24 healthy, male volunteers. The selected Middle Eastern volunteers were divided into 2 groups of 12 subjects. One group was treated with the reference formulation and the other one with the test formulation, with a cross-over after a drug washout period of 7 days. Blood samples were collected at fixed time intervals and Ciprofloxacin concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC0-48, AUC0-∞, Cmax, Tmax, Ke and T1/2 were determined for both sustained release tablets and were compared statistically to evaluate the bioequivalence between the 2 formulations of ciprofloxacin, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the 2 formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. According to the obtained results it was concluded that the test and reference formulations are bioequivalent, since they exhibit comparable pharmacokinetic parameters.

Ethosomes for the delivery of anti-HSV-1 molecules: preparation, characterization and in vitro activity.

This paper describes the production, characterization and in vitro activity of ethosomes containing two molecules with antiviral activity, such as acyclovir (ACY) and N1-beta-D-ribofuranosyl-pyrazole [3,4d]pyridazin-7(6p-chlorine-phenyl)-one nucleoside (N1CP). Ethosomes were prepared and morphologically characterized by Cryo-TEM. The encapsulation efficiency was 92.3 +/- 2.5% for ACY and 94.2 +/- 2.8% for N1CP. The release of the drug from vesicles, determined by a Franz cell method, indicated that both drugs were released in a controlled manner. In order to possibly guarantee the stability during long-term storage ethosome suspensions was freeze-dried. It was found that the freeze-dried ethosomes' cakes were compact, glassy characterized by low density and quick re-hydration. However, the storage time slightly influences the percentage of drug encapsulation within ethosomes showing a drug leakage after re-hydration around 10%. The antiviral activity against HSV-1 of both drugs was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that ethosomes allowed a reduction of the ED50 of N1CP evidencing an increase of its antiviral activity. However, ACY remains more active than N1CP. No differences are appreciable between drug-containing ethosomes before and after freeze-drying. Taken together these results, ethosomal formulation could be possibly proposed as mean for topical administration of anti-herpetic molecules.

Appropriate use of oral drops: perception of health professionals and assessment of package insert information.

OBJECTIVES: To evaluate the perception of health professionals and industry personnel towards the appropriate use of oral drops and to assess their package inserts with regard to presence of proper instructions for use and storage. METHODS: The first part was a cross-sectional self-administered questionnaire. The questionnaires were distributed randomly to physicians, pharmacists and decision makers in local pharmaceutical companies. In the second part, the package inserts of medications with oral drops were reviewed to check for presence of proper instructions for storage and proper use. RESULTS: The majority of physicians and pharmacists (73.3% and 71.2%) thought that oral drops can be delivered from the dropper directly into the patient's mouth. 60.8% of physicians and 54.3% of pharmacists thought that the dropper should be clamped vertically when oral drop are dispensed. 72.7% of industry personnel agreed that the angle of inclination affects the drop size. Many of these personnel said their companies did not perform the recommended tests for dose uniformity and calibration. Instructions for storage and proper use were not available in package inserts of many oral drop products in Palestine. CONCLUSIONS: Health professionals should have complete and correct information regarding all factors that affect the proper delivery of oral drops and should counsel patients on the proper method of delivery. Pharmaceutical companies should take into consideration the formulation issues that may affect drop size and provide leaflets and labels with complete and correct instructions on the proper use and storage of oral drops. Package insert information in oral drops needs to be more comprehensive with regard to instructions for use and storage.

Interchangeability of two 500 mg amoxicillin capsules with one 1000 mg amoxicillin tablet after a single oral administration.

The aim of the study was to evaluate if two capsules (Amoxil(®) capsules, 500 mg/capsule) and one tablet (Amoxicare(®) tablets, 1000 mg/tablet) of amoxicillin have similar bioequivalence parameters. For this purpose a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy, male volunteers, divided into two groups of 12 subjects each. One group was treated with the reference standard (Amoxil(®)) and the other one with the generic tablet Amoxicare(®), with a crossover after a wash-out period of 7 days. Blood samples were collected at fixed time intervals and amoxicillin was determined by a validated HPLC method. The pharmacokinetic parameters AUC(0-8), AUC(0-∞), C(max), T(max), K(e) and T(1/2) were determined for both formulations and statistically compared to evaluate the bioequivalence between the two brands of amoxicillin, using the statistical model recommended by the FDA. C(max) and AUC(0-∞) were statistically analyzed using analysis of variance (ANOVA); no statistically significant difference was observed between the two formulations. The 90% confidence intervals between the mean values of C(max) and AUC(0-∞) fall within the FDA specified bioequivalent limits (80-125%) suggesting that the two products are bioequivalent and the two formulations are interchangeable. Based on these findings it was concluded that the practice of interchangeability between the above formulations to achieve better patient compliance could be followed without compromising the extent of amoxicillin absorption.

Weight uniformity of scored tablet halves manufactured by palestinian pharmaceutical companies.

The purpose of this study was to evaluate the weight uniformity of some commonly divided tablets produced by Palestinian Pharmaceutical companies. Volunteers were asked to divide scored tablets. The split units were individually weighed and the relative standard deviation for each product was calculated. Five scored tablet products failed the United States Pharmacopeia test of mass uniformity; this indicates that the splitting of these tablet products is not reliable for the provision of accurate doses. The practice of dividing tablets to achieve therapeutic and economic benefits for the patient may cause significant problems, especially in drugs with low therapeutic indices. Pharmacists may resolve this inconvenience by reformulating the tablet into a new dosage form, such as capsules, which should contain the exact amount of the medication.

Liposomes and micellar dispersions for delivery of benzoheterocyclic derivatives of distamycin A.

In this article we describe the production and characterization of specialized delivery systems for some distamycin derivatives (DD), namely liposomes and micellar dispersions. All the formulations were designed to increase the solubility of DD in an aqueous environment and to reduce the possible toxicity problems related to the administration of these drugs. For instance, liposomes were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters, then characterized in terms of dimensions, morphology, and encapsulation efficacy. The analysis of their in vitro antiproliferative activity on cultured human and mouse leukemic cells demonstrated that liposomes and micellar dispersions containing DD exert quite different effects. These effects were compared with those shown by the free drug depending on type of drug and also cell line used.

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers.

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.

Synthesis and biological effects of a new series of 2-amino-3-benzoylthiophenes as allosteric enhancers of A1-adenosine receptor.

New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-adenosine receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 microM caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g, 3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 microM.

DNA minor-groove binders: results and design of new antitumor agents.

DNA minor-groove binding drugs have been extensively studied in the last years in order to influence the regulation of gene expression in neoplastic disorders by means of specific interactions with DNA bases. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor-groove alkylating agents which showed interesting cytotoxicity profiles, but they cannot be used in humans for various toxicity problems. For this reason many groups applied heterocyclic substitutions extensively, in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence.

Heterocyclic analogs of DNA minor groove alkylating agents.

It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA bases moieties. Pyrrolo[2,1-c],[1,4].benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor groove binders which showed interesting cytotoxicity profiles, refined through already reviewed processes of SAR studies. Among the modifications to the three families of antitumor compounds, heterocyclic substitutions have been extensively applied by many groups in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence. The updated material related to these modifications has been rationalised and ordered to offer an overview of the argument.

Synthesis, solvolytic stability and cytotoxicity of a modified derivative of CPzI, a pyrazole analog of the alkylation subunit of the antitumor agent CC-1065: effect of the nitrogen substitution on the functional reactivity.

The synthesis and the comparative preliminary biological evaluation of a new pyrazole analog (16) of the CC-1065 alkylating unit (CPI) are described. This new derivative showed low cytotoxicity against L1210 murine leukemia (IC50 3064 nM) with respect to reference compound, but contrarily to literature data, was found to be more stable to solvolysis than the natural derivative (+/-)-N-Boc-CPI (pH 3, t1/2 = 212 h vs. 37 h). The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells. This experimental observation allowed us to confirm the importance of free N-H for the anticellular activity.

Synthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activity.

Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.