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PubMed2003

Stability of tiagabine in two oral liquid vehicles.

The stability of tiagabine hydrochloride in two extemporaneously prepared oral suspensions stored at 4 and 25 degrees C for three months was studied. Tiagabine is used for adjunctive therapy for the treatment of refractory partial seizures. It is currently available in a tablet dosage form, which cannot be used in young children who are unable to swallow and given doses in milligrams per kilogram of body weight. No stability data are available for tiagabine in any liquid dosage form. Five bottles contained tiagabine 1 mg/mL in 1% methylcellulose:Simple Syrup, NF (1:6), and another five bottles had tiagabine 1 mg/mL in Ora-Plus:Ora-Sweet (1:1). Three samples were collected from each bottle at 0, 7, 14, 28, 42, 56, 70, and 91 days and analyzed by a stability-indicating high-performance liquid chromatographic method (n = 15). At 4 degrees C, the mean concentration of tiagabine exceeded 95% of the original concentration for 91 days in both formulations. At 25 degrees C, the mean concentration of tiagabine exceeded 90% of the original concentration for 70 days in Ora-Plus:Ora-Sweet formulation and for 42 days in 1% methylcellulose:syrup formulation. No changes in pH or physical appearance were seen during this period. The stability data for two formulations would provide flexibility for compounding tiagabine. Tiagabine hydrochloride 1 mg/,mL in extemporaneously prepared liquid dosage forms and stored in plastic bottles remained stable for up to three months at 4 degrees C and six weeks at 25 degrees C.

Administration, Oral↗

PubMed1994

Preference for high- versus low-potency marijuana.

With many drugs of abuse, humans and other species display a preference for higher doses (or more potent dosage forms) over lower doses (or less potent dosage forms). The present study was designed to determine whether this generalization would hold for marijuana smoking by humans. Twelve regular marijuana smokers participated in two independent and identical choice trials in which, on separate sessions, they first sampled marijuana of two different potencies (0.63% and 1.95% delta-9-tetrahydrocannabinol; THC) and then, on the next session, chose which of the two, as well as how much, to smoke. During sampling sessions, the high-potency marijuana produced a greater heart rate increase and greater subjective effects than the low-potency marijuana. Subjects chose the high-potency marijuana significantly more often than the low-potency marijuana (21 out of 24 choice occasions). These results support the hypothesis that the reinforcing effects of marijuana, and possibly its abuse liability, are positively related to THC content.

Adult↗

PubMed1997

Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin.

The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called "square-wave" profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.

Administration, Buccal↗

PubMed1989

Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size.

The intestinal absorption of cyclosporine was measured in situ in rats using an olive oil emulsion prepared by either stirring or homogenization. The surface area of the homogenized dosage form was twice that of the stirred dosage form. The apparent permeability of cyclosporine from the homogenized emulsion was about twice that of the emulsion prepared by stirring. The examination of absorption in different intestinal segment lengths suggested the presence of an "absorption window." The absorption of cyclosporine appeared to be concentration independent and, therefore, non-carrier mediated. The dependence of absorption upon the intestinal perfusion rate suggested that the stagnant aqueous layer is the rate-limiting barrier in cyclosporine absorption. These results indicate that the bioavailability of cyclosporine administered in an emulsion can possibly be increased by enhancing its rate of absorption through the reduction of droplet size.

Animals↗

PubMed1998

Comparison of bone regeneration in a rabbit skull defect by recombinant human BMP-2 incorporated in biodegradable hydrogel and in solution.

The objective of this study is to compare bone regeneration induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) incorporated into a biodegradable gelatin hydrogel with that by rhBMP-2 in aqueous solution. After treating rabbit skull defects of 6 mm diameter with the two rhBMP-2 dosage forms, both of them increased the bone mineral density (BMD) at the skull defects with implantation time to a significantly higher extent than a rhBMP-2-free aqueous solution and a rhBMP-2-free empty gelatin hydrogel (p < 0.05). There was no quantifiable difference in BMD between the two dosage forms of rhBMP-2. Histological examination revealed that the integrity of newly generated bone increased with the rhBMP-2 dose, irrespective of the dosage form. The bone defect was filled with regenerated bone 21 days after treatment.

Absorptiometry, Photon↗

PubMed1977

Antipyretic therapy. Comparison of rectal and oral paracetamol.

The absorption of paracetamol from syrup, tablet and two different suppository bases was compared in six adult volunteers using urinary excretion measurements. The total amount of paracetamol and its metabolites excreted and the peak excretion rates were lower from the suppository bases than from the oral dosage forms. Absorption was a little better from a polyethylene glycol suppository base than from a triglyceride base. The antipyretic efficacy of a paracetamol syrup and suppository at a dose of 10 mg/kg was compared in 30 children between the age of 4 months and 12 years, who had infections and a rectal temperature above 38.5 degrees C. Both dosage forms produced a significant decrease in temperature, the greatest fall being about 2 hours earlier with the oral dosage form. The syrup also seemed to be significantly (p less than 0.05) more effective (maximum fall of temperature 1.58 degrees C) in reducing fever than the suppository, which produced its greatest fall of temperature (1.24 degrees C) six hours after insertion of the suppository. From the practical point of view both forms can be regarded as safe and effective antipyretics.

Acetaminophen↗

PubMed1984

Comparative aspirin absorption kinetics after administration of sodium- and potassium-containing buffered solutions.

Twelve fasting normal volunteers received three aspirin dosage forms in a single 325-mg dose in a complete crossover study; the plasma aspirin and salicylic acid levels and the urine salicylic acid and salicyluric acid levels were measured over 10 h. The three dosage forms included an unbuffered tablet and two effervescent solutions, one with sodium bicarbonate-citrate buffer and the other with potassium bicarbonate-citrate buffer. A significantly faster absorption rate was observed with the sodium bicarbonate-citrate buffer, when compared with the potassium bicarbonate-citrate buffer and the unbuffered tablets, which were equivalent. These differences were attributed primarily to gastric emptying rate differences. Urine pH and salicylate renal clearance were significantly affected by the single dose of antacid buffer. The area under the curve and urine accumulation comparisons suggested that approximately 25% more aspirin reaches the general circulation intact after administration of the unbuffered tablet than the two solutions, but that the total salicylate absorbed is equivalent for all three dosage forms. This difference in aspirin bioavailability is probably due to the fact that the two buffered solutions are predominantly absorbed through the intestine, in which presystemic hydrolysis occurs, whereas a significant portion of the tablet dose is absorbed through the gastric mucosa.

Adult↗

PubMedDate not supplied

[First experience in the use of a new Russian narcotic analgesic prosidol in oncology].

Prosidol, a new Russian narcotic analgesic, was used in various dosage forms (buccal and oral tablets, injection solution) in 113 cancer patients for the treatment of chronic pain, as a component of total anesthesia, and for postoperative analgesia. The best results were attained with the universal noninvasive dosage form, buccal tablets, used for the treatment of chronic pain in incurable patients. Analgesic properties of buccal prosidol are close to those of tramadol, the drug is well tolerated by the patients and causes no grave side effects. As a drug for postoperative analgesia prosidol was highly effective in patients after extracavitary oncologic surgery and less effective after thoracal and abdominal interventions. As a component of total anesthesia prosidol is inferior to fentanyl and approximately similar to promedol. An advantage of prosidol is its highly effective universal noninvasive dosage form, buccal tablets, which may be used for rapid analgesia in any situation.

Administration, Buccal↗

PubMed2004

Pharmacodynamics of beta-blockers in heart failure: lessons from the carvedilol or metoprolol European trial.

Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of beta-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the beta1-/beta2-/alpha1-adrenergic receptors with carvedilol versus selective beta1-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between beta-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all beta-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and dosage forms) that have been proven to reduce mortality in this patient population.

Adrenergic beta-Antagonists↗

PubMed2006

Drug excipients.

The therapeutical use of drugs involves the application of dosage forms, serving as carrier systems together with several excipients to deliver the active ingredient to the site of action. Drug delivery technology combines an understanding of medicinal chemistry and pharmacology with the skill of formulation, aiming the preparation of improved pharmaceuticals. The recently introduced Biopharmaceutical Classification System provides guidance for dosage form design, taking the molecular and physico-chemical properties of drugs into consideration through their solubility and permeability characteristics. Pharmaceutical excipients used for oral dosage form have been traditionally assumed as being inert. However, recent experience and new results have shown that they can interact with the active drug ingredient, affecting its dissolution, absorption and bioavailability. Classification of the excipients is based on their role in the pharmaceutical formulation and on their interactions influencing drug delivery, based on their chemical and physico-chemical properties. The main classes are the antioxidants, coating materials, emulgents, taste- and smell-improvers, ointment bases, conserving agents, consistency-improvers and disintegrating materials. Some of the excipients may serve multiple purposes; for example, methylcellulose is a coating material, is applied in the preparation of suspensions, to increase viscosity, as a disintegrating agent or binder in tablets. The aim of this paper is to review the drug-excipients with respect to their chemistry, importance and interactions altering the pharmacokinetics of the drug substances. Emphasis will be given to two major classes of excipients: the antioxidants and disintegrants (substances facilitating disintegration of the drug tablets in the gastro-intestinal tract). Details will be given on the mechanisms through which they can alter drug effectiveness and tolerance, and control their application. Examples and references will be given for their analysis.

Excipients↗

PubMed2003

The importance of characterizing the crystal form of the drug substance during drug development.

The existence of a new physical form of a drug substance with a bioavailability significantly different from that of the original form can have serious effects on the therapeutic levels of the dosage form. The goal of any dosage form is to ensure reproducible safe exposure during preclinical and clinical studies, and ultimately for the marketed product. This review discusses the different physical forms of a drug substance, including amorphous forms, polymorphs, hydrates and salts, and the importance of characterizing the form of the drug substance during development. A definition of the different forms is provided, and enantiotropism, monotropism and polyamorphicity are discussed. This article provides examples of cases in which changes in the physical form resulted in changes in stability and/or bioavailability of the product. The review also discusses some of the methods used to quantify the physical form of a drug substance in a product.

Animals↗

PubMedDate not supplied

In vitro effects of clarithromycin on human polymorphonuclear leukocyte functions.

BACKGROUND: It has been shown that antibacterial agents affect polymorphonuclear leukocytes (PMNs), which are active in the body's first line of defense, in different ways. However, few studies have investigated the effects of tablet dosage forms as opposed to pure powder forms. There is a need to demonstrate the clinical relevance of previous results with commercially available products. METHODS: We examined the effects of clarithromycin solutions, prepared separately from either pure powder or commercially available tablets (250 mg), on human PMNs. The in vitro effects of each solution, adjusted to therapeutic concentration (1 mg/l), on PMN adherence, chemotaxis, phagocytosis, candidacidal capacity and superoxide production were studied. RESULTS: Solutions prepared from pure clarithromycin powder did not affect the adherence, phagocytosis or superoxide production of PMNs, but did inhibit (p<0.05) chemotaxis and candidacidal capacity. By contrast, a decrease (p<0.05) in all functions except phagocytosis was observed with solutions prepared from the tablet dosage form of clarithromycin. CONCLUSION: The results of this study suggest that the tablet dosage form of clarithromycin may have a more pronounced inhibitory effect on human PMN functions than solutions prepared from the pure powder form.

Anti-Bacterial Agents↗

PubMed1982

Moment analysis for the separation of mean in vivo disintegration, dissolution, absorption, and disposition time of ampicillin products.

The in vivo disintegration, dissolution, absorption, and disposition processes of ampicillin products are separated by means of moment analysis. This method is model-independent, that is, any specific model is not assumed. The mean residence time (MRT), mean absorption time (MAT), mean dissolution time (MDT), and mean disintegration time (MDIT) are calculated for several dosage forms of ampicillin. The fraction of dose absorbed (F) is also separated into several fractions corresponding to these in vivo processes. Bioavailability and bioequivalence are discussed in terms of the zero and first moments. The flip-flop behavior of ampicillin is proved by the fact that the MRT following intravenous injection is less than the MAT of any oral dosage form. Absorption of released ampicillin is proved by the fact that the MRT following intravenous injection is less than the MAT of any oral dosage form. Absorption of released ampicillin is proved to be a rate-determining step, since the MRT of released ampicillin in the GI tract is the greatest of all MRT corresponding to the in vivo processes. Moment analysis is compared with classical compartment theory, and a new component concept is introduced.

Adult↗

PubMed2006

WHO expert committee on specifications for pharmaceutical preparations. Fortieth report.

This report presents the recommendations of an international group of experts convened by the World Health Organization to consider matters concerning the quality assurance of pharmaceuticals and specifications for drug substances and dosage forms. The report is complemented by a number of annexes. These include: a list of available International Chemical Reference Substances and International Infrared Spectra; supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms; updated supplementary guidelines on good manufacturing practices for the manufacture of herbal medicines; supplementary guidelines on good manufacturing practices for validation; good distribution practices for pharmaceutical products; a model quality assurance system for procurement agencies (recommendations for quality assurance systems focusing on prequalification of products and manufacturers, purchasing, storage and distribution of pharmaceutical products); multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability; a proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms; and additional guidance for organizations performing in vivo bioequivalence studies.

Drug Industry↗

PubMed1978

Bioavailability of three commercial sustained-release tablets of quinidine in maintenance therapy.

The bioavailability of three quinidine formulations was estimated during a dosing interval at steady state following their administration in 12 selected patients in accordance with a Latin-square 3 x 3. Each subject received the three dosage forms as two tablets every 12 hr for 6 days. Blood and urine samples were taken on the 7th day during the regular 12-hr dosing interval. Unchanged quinidine was determined by a reported spectrofluorometric procedure. The total fluorescence of plasma quinidine and metabolites also was monitored. The data obtained indicate that one dosage form gave a high peak level followed by a fall in the concentration. The two other forms presented a relatively lower peak followed by a plateau and then a decline. The differences between the dose-corrected values of Cp,max were statistically significant. Secondary effects were observed particularly with one dosage form and could be related to the high Cp,max value and/or the high percentage of quinidine liberated rapidly in the GI tract. Blood and urinary data indicated an equivalent degree of absorption. The dissolution behavior of the formulations and their absorption data suggest that there is a correlation between the quantity dissolved at 30 min and Cp,max.

Adult↗

PubMed2003

[Importance of interfacial characteristics in pharmaceutical technology].

Since drug release from the dosage forms has priority to absorption from the gastrointestinal system, physico-chemical characterisation of pharmaceutical systems is essential during the development of an optimal formulation with high efficacy and quality. Interfacial parameters of several pharmaceutical excipients were studied regarding their possible modifying effect on drug release from the dosage form. These inactive ingredients may influence the interfacial phenomena of the drug carrier system, which behaviour determines both the efficacy and the quality of the pharmaceutical preparation In this work authors deal mainly with the two introducing steps of the LADME model influenced by interfacial parameters on them, namely with the liberation of drug from the dosage form and with the characteristics influencing the absorption through biological membranes, respectively. The objective of the present work was to study modifying effects of excipients on drug liberation in connection with their physical and chemical characteristics such as interfacial tension of solid and liquid phases, wetting contact angle of solid phase and--a calculated quantity,--adhesion tension of the solid particles.

Binding Sites↗

PubMed1984

An in vivo single- and multiple-dose study of several marketed brands of conventional and controlled-release theophylline.

In a single-dose study, 18 healthy adult males consumed each of six dosage forms of theophylline. A conventional-release tablet, a syrup, and four competing brands of controlled-release theophylline were studied. Serial serum samples were obtained and analyzed via high pressure liquid chromatography (HPLC). After achieving steady state, 15 healthy adult males consumed each of five dosage forms of theophylline in a multiple-dose study. Serial blood samples were obtained between 0 and 72 hours and subjected to analysis with HPLC. The results indicated that the controlled-release products were not bioequivalent, although they achieved longer time-to-peak values than did the immediate-release syrup and the conventional-release tablet. A single sustained-release product was uniquely different on most pharmacokinetic parameters when compared with the remaining three controlled-release products. In general, the dosage form variation exceeded the individual subject variation on the single-dose study, but the opposite was true for the multiple-dose study.

Adult↗

PubMed1984

Nitroglycerin concentration in plasma: comparison between transdermal therapeutic system and ointment.

This double-blind cross-over study evaluates in 12 male volunteers the time course of nitroglycerin concentration in plasma with use of the TTS-nitroglycerin, a controlled-release transdermal dosage form for nitroglycerin, and compares the bioavailability of nitroglycerin delivered from the transdermal system with that from three successive applications of 0.5 inch of 2% nitroglycerin ointment placed at 8 hr intervals over 10 cm2 of skin. The mean amounts of nitroglycerin available when subjects wore the TTS-nitroglycerin or received successive applications of ointment were 15.8 mg +/- 1.8 (SE) and 9.8 mg +/- 0.8, respectively. Mean plasma concentrations for both treatments ranged from 10-18 pg/ml-cm2. The normalized areas under the curves--353 and 410 pg/hr/ml-cm2, respectively--did not differ significantly. The ratio of clearance from the two dosage forms was 0.98 +/- 0.12. All subjects experienced mild-to-moderate side effects of nitrate therapy with both dosage forms and also decrease in blood pressure and increase in heart rate.

Administration, Topical↗

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