Oral Sustained Release Formulation Research Articles

Oral sustained delivery of theophylline using in-situ gelation of sodium alginate

Gels formed in situ following oral administration of aqueous solutions of sodium alginate (1.0–2.0%w/v) to rats were evaluated as sustained release vehicles for the delivery of theophylline. The liquid formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the alginate. Bioavailability of theophylline from alginate gels formed by in situ gelation in the rat stomach was increased by 1.3–2-fold in rats for alginate concentrations of 2.0 to 1.0%w/v respectively compared with that from a proprietary oral sustained release formulation containing an identical drug concentration. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.

Pharmacodynamic and pharmacokinetic rationales for the development of an oral controlled-release amoxicillin dosage form

The goal of this investigation was to develop an oral sustained-release formulation for amoxicillin that would maximize the duration of active drug concentration in the extracellular fluid, thus increasing the dosing interval while assuring antimicrobial activity. This rationale is based on the pharmacodynamic properties of the drug which is non- concentration dependent on the one hand, while requiring long exposure of the pathogen to the drug with minimal post-antibiotic effect on the other. Due to pharmacokinetic constraints, including short biological half-life and limited `absorption window' (confined to the small intestine) with poor colonic absorption, the new matrix tablet formulation, composed of hydrophilic (hydroxypropyl methyl-cellulose) polymer, was designed to release 50% of its contents within the first 3 h and to complete the drug release process over 8 h (under in vitro conditions). The pharmacokinetics of the new formulation was evaluated in 12 healthy volunteers and compared to a conventional gelatin capsule with both formulations containing 500 mg amoxicillin. The plasma concentrations of active amoxicillin and penicilloic acid were determined by an HPLC method with a fluorometric detector. It was found that the area under the concentration–time curve and maximal serum amoxicillin concentrations following the sustained release preparation were lower than the immediate release formulation. However, the time over the required threshold concentrations, i.e. the minimal inhibitory concentration (MIC) as well as the more clinically relevant parameter — four times MIC of the drug against susceptible pathogens, was found to be maintained for significantly longer periods. The results suggest that in order to achieve a twice daily dosing regimen that will provide therapeutic concentrations for the whole 12 h dosing intervals, a larger dose of the new formulation should be given (e.g. 750 mg or even 1g twice daily). This recommendation is based on the large interindividual differences of the extent of amoxicillin absorption found in this investigation, and is intended to assure that the `poor' absorbers will also benefit from full antibiotic efficacy. This dosing regimen will lead to increased patient compliance and improved therapeutic outcome.

Time-dependent effect of isradipine on the nocturnal hypertension in chronic renal failure

Nocturnal hypertension is frequently observed in chronic renal failure and contributes to the risk of target organ damages. We assessed whether antihypertensive therapy may restore a nocturnal blood pressure (BP) fall in this condition. A sustained-release oral formulation (SRO) of isradipine was used, and the possible differences in the response to morning nu evening dosing were also investigated. Sixteen hypertensive patients with chronic renal failure due to parenchymal kidney disease were studied after 2 weeks of single-blind placebo runin. According to the double-blind, randomized, cross-over design, they received 5 mg isradipine SRO at 08:00, or at 20:00 for 4 weeks, separated by a single-blind placebo period of 2 weeks. A 24-h BP monitoring at 10-min intervals was carried out at the end of each treatment using a SpaceLabs 90207 instrument. Under placebo, blunt BP profiles were observed, whereas HR showed a mean nocturnal fall of 17.4%, which remained unaltered after isradipine. Both isradipine treatments were equally effective in reducing the mean 24-h BP levels. However, the evening regimen showed a more pronounced effect during the night. The mean nocturnal fall in systolic/diastolic BP represented 4.8/8.7% and 7.5/10.9% of the corresponding daytime mean after morning and evening dosing, respectively. Only the evening administration reset the normal synchronization of the 24-h BP and HR profiles. Our findings demonstrate that antihypertensive treatment may restore a nocturnal BP fall in renal patients. An evening regimen of isradipine SRO seems more apt than a morning regimen to obtain this therapeutic goal.

Localization of Drug Release Sites from an Oral Sustained‐Release Formulation of 5‐ASA (Pentasa®) in the Gastrointestinal Tract Using Gamma Scintigraphy

Release of 5-ASA from a sustained release formulation (Pentasa, Ferring A/S, Copenhagen, Denmark) was monitored with plasma sampling for up to 24 hours in nine volunteers under both fasted and fed conditions. Drug absorption was correlated with location of the sustained-release microgranules in the gastrointestinal tract by gamma scintigraphy. Disintegration of the labeled tablet preparation occurred in the stomach within 20 minutes and acetylated 5-ASA was detectable in the plasma less than 60 minutes after ingestion. No significant differences were detected in either transit times through the small intestine, peak plasma acetylated 5-ASA concentration or lag time to absorption between fasted and fed individuals. Peak plasma concentration of acetylated 5-ASA usually occurred when the microgranules were present in the small intestine or ascending colon. The pharmacoscintigraphic study confirmed that 5-ASA release from the formulation occurred throughout the gastrointestinal tract, and that food effects on the in vivo behavior of the preparation were minimal.

Issues in contemporary drug delivery. Part VI: Advanced cardiac drug formulations.

To identify and discuss the clinical utility of new delivery systems and formulations of cardiac drugs. Studies describing or evaluating new drug delivery systems for cardiac drugs were identified through a MEDLINE literature search. All studies describing or evaluating new delivery systems for cardiac drugs were reviewed. Data were abstracted and evaluated by each author independently. The most common oral sustained-release formulations include the wax-matrix system, the gastrointestinal therapeutic system (GITS), and the spheroidal oral drug absorption system (SODAS). The wax-matrix delivery system is limited by the occurrence of "dose-dumping." In a low-pH setting, the wax-matrix formulation may dissolve too rapidly, liberating the entire dose in a short period of time. The clinical relevance of this phenomenon is unknown. The GITS and SODAS formulations are less likely to be affected by pH and food. Nitroglycerin is available by many routes of administration. The topical patch forms are convenient to use, but are associated with the development of tolerance. A buccal formulation incorporates a relatively short onset of effect with a three- or four-times-daily dosing regimen. Although tolerance is less of a problem with buccal nitroglycerin than with topical nitrates, this formulation is less convenient to use because of buccal irritation and interference with eating and talking. A new spray formulation of nitroglycerin offers longer shelf-life storage stability and an easier mode of administration. The spray canister is stable for three years compared with 12 weeks for an opened bottle of sublingual nitroglycerin tablets. Sublingual administration of oral cardiac drugs offers the potential for a more rapid onset of effects. Although nifedipine is often given sublingually, objective data indicate that it is not absorbed buccally but rather in the stomach. It appears that the chew-and-swallow route is most appropriate for nifedipine. Captopril is absorbed sublingually but its efficacy has not been demonstrated. Transdermal clonidine improves compliance and is associated with fewer adverse effects than oral clonidine. Transdermal formulations of beta-blockers are currently being evaluated. Further advancements in the development of novel delivery systems for cardiac drugs are expected in the future.

Influence of technological variables on release of drugs from hydrophilic matrices

Hydrophilic matrices are an interesting option when developing an oral sustained-release formulation. Entering the field of pharmaceutical technology almost 40 years ago, they have been steadily growing as regards applications, largely as a result of the increasing need for suitable polymers. Recently, the physico-chemical mechanisms implied in controlling release from such systems have been subjected to new studies, providing the basis for en interpretation of the many deta concerning the dependence of the behaviour of these systems with respect to the technological variables involved in the processes used in their fabrication. It is from this viewpoint that this article analyzes bibilographic information and considers the possibilites for modulating release of drugs of high end low solubility through control of their physical properties, the correct choise of gelling agent and correctly setting up the conditions for fabrication.

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.

Pharmacokinetics of Acrivastine After Oral and Colonic Administration

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Pharmacodynamics and tolerance of oral sustained release ritodrine

A new oral sustained release formulation of ritodrine was tested for patient tolerance in this open study. The doses tested were 120 mg/day, 240 mg/day, and 360 mg/day. No objective toxicity was seen at any level. Doses of 120 mg/day and 240 mg/day were well-tolerated. Of the subjects who received the 360 mg/day dose, most tolerated it well.

Pharmacokinetics of organic nitrates in man: an overview.

The pharmacokinetics of glyceryl trinitrate are still not completely understood. The substance disappears rapidly from plasma largely by extrahepatic mechanisms. It is converted in glyceryl dinitrates and glyceryl mononitrates. After transdermal application of a controlled delivery system, plasma concentrations of glyceryl trinitrate can be maintained over the time period of application but, as for other routes, there are important intra- and inter-individual variations and fluctuations. Isosorbide dinitrate disappears less rapidly from the body; it is converted to the isosorbide mononitrates. Plasma concentrations of isosorbide dinitrate and mononitrates are quite predictable in different circumstances, e.g. on application of oral sustained release formulations. Measurement of the plasma concentrations of nitrates has been used to characterize different preparations and routes of administration. However, these plasma concentrations cannot be used to predict the effect, probably because of the important counter-regulation and tolerance which develop rapidly after administration of the drugs.

Effects of Formulation on the Pharmacokinetics of Orally Administered Pinacidil in Humans

Serum concentrations, relative bioavailability, and urinary excretion of pinacidil [(±)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate] from two sustained-release oral formulations (tablet and capsule) were compared in 12 healthy volunteers. Maximum measured serum concentrations (Cmax) from the sustained-release tablet and capsule did not differ significantly (75 ± 17 versus 70 ± 14 ng/mL, p > 0.05), but the time to achieve maximum concentration (tmax), was longer for the capsule (2.4 ± 1.8 versus 0.98 ± 0.5 h, p < 0.05), There was no significant difference in bioavailability between the formulations, as measured by the area under the concentration—time curve (AUCo—8 h; 279 ± 99 versus 311 ± 85 ng·h/mL, p > 0.05). Twenty-four hour urinary excretion of both pinacidil and its major metabolite, pinacidil pyridine-N-oxide, was similar for both tablet and capsule preparations (3.9 ± 1.2 and 55 ± 19% versus 4.4 ± 1.0 and 55 ± 14%, respectively, of the administered dose, p > 0.05).

Steady-state concentrations of drugs with short half-lives when administered in oral sustained release formulations

Recognizing that the time available for drug absorption after oral administration is limited, and assuming an effective absorption time of 9–12h, we have calculated the ratio of maximum to minimum drug concentrations in plasma at steady-state for drugs with different elimination half-lives given in sustained release products that release the drug in a first-order manner with a half-life of 3 or 4 h. The results suggest that drugs with relatively short elimination half-lives (⩽ 6 h) and low therapeutic indices (⩽3) must be given no less frequently than every 12 h. Drugs with pronounced multicompartment characteristics after oral dosing may need to be given at dosing intervals considerably shorter than their biologic half-lives unless they are administered in a sustained release formulation.

Some Studies of a Sustained Release Principle

Urinary excretion of drug after oral dosage of chlorpheniramine as maleate salt and in an oral sustained release formulation was studied, and the urinary excretion and plasma levels of tritium radioactivity obtained after crossover administration of tritium-tagged phenylephrine as hydrochloride and in sustained release formulation were compared. The urinary excretion of both drugs varied widely among individuals, indicating that this parameter is limited in value as a reflection of oral absorption. No relation between blood level and excretion of tritiated phenylephrine was apparent.