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Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.
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The concept of multiparticulate dosage forms was introduced in the 1950s. With the increasing use of multiparticulate controlled release (CR) oral dosage forms, in recent times there has been a rise in interest in the methods of preparing these dosage forms. A method that has gained increased usage over the past few years is that of extrusion and spheronization. It has been extensively explored as a potential technique and also as a future method of choice for preparation of multiparticulate CR dosage forms. In this review an attempt is made to outline the general process of extrusion and spheronization and to assess its importance in the development of multiparticulate CR oral dosage forms.
Advanced controlled release (CR) dosage forms are relative newcomers to pharmaceutical markets, and few studies relate their efficacy, safety or compliance benefits to economic value. This literature review was undertaken to assess the cost effectiveness of CR dosage forms using such measures as purchase costs, total treatment costs, and economic value of improved therapeutic outcomes compared with those with non-CR dosage forms. Three therapeutic areas were examined: cardiovascular therapy, pain management and estrogen replacement therapy. In cardiovascular therapy, prescription costs of sustained release (SR) verapamil were significantly higher than for conventional release verapamil. However, these were more than offset by lower physician, hospital and laboratory expenditures for the SR group, in whom compliance was superior. Similarly, patients receiving SR diltiazem had better prescription refill compliance than those using a conventional formulation of the drug, as well as significantly lower aggregate healthcare costs during a 1-year study period. These lower costs with both SR verapamil and diltiazem may relate to better compliance. CR nifedipine has lower daily acquisition costs than the conventional form, simplifies the dosage regimen to once daily, extends the indications of the drug to hypertension as well as angina, and reduces vasodilatory adverse effects by reducing peak plasma drug concentrations and the postdose rate of increase in concentration. Compared with oral clonidine given twice daily, transdermal clonidine, given once weekly, had higher purchase costs, but was associated with improved compliance, reduced adverse effects (due to control of plasma concentrations), and lower nondrug health costs, such as physician, hospital and laboratory costs. Lower costs were also found for once daily oral formulations of various antihypertensives, suggesting that the economics of both types of CR dosage forms related to compliance. CR metoprolol 50 or 100mg and conventional release atenolol 50mg, each given once daily, provided effective beta1-adrenoceptor blockade. The conventional formulation caused deterioration in the sense of well-being that was temporally associated with sharp peaking of its plasma concentrations. Such peaking did not occur with either dose of CR metoprolol, nor did any deterioration in the sense of well-being. Transdermal nitroglycerin (glyceryl trinitrate), compared with long-acting oral nitrates, improved quality of life (QOL) {despite a higher incidence of some adverse effects, such as headache, dizziness and skin irritation}. Furthermore, in some studies, this formulation reduced angina attacks, sublingual nitroglycerin use, and hospitalisation or emergency room use. Cost comparisons between transdermal products favoured those that have superior adhesion.(ABSTRACT TRUNCATED AT 400 WORDS)
Pharmaceutical oral dosage forms are used in this paper to test the sensitivity and spatial resolution of hyperspectral imaging instruments. The first experiment tested the hypothesis that a near-infrared (IR) tunable diode-based remote sensing system is capable of monitoring degradation of hard gelatin capsules at a relatively long distance (0.5 km). Spectra from the capsules were used to differentiate among capsules exposed to an atmosphere containing 150 ppb formaldehyde for 0, 2, 4, and 8 h. Robust median-based principal component regression with Bayesian inference was employed for outlier detection. The second experiment tested the hypothesis that near-IR imaging spectrometry of tablets permits the identification and composition of multiple individual tablets to be determined simultaneously. A near-IR camera was used to collect thousands of spectra simultaneously from a field of blister-packaged tablets. The number of tablets that a typical near-IR camera can currently analyze simultaneously was estimated to be approximately 1300. The bootstrap error-adjusted single-sample technique chemometric-imaging algorithm was used to draw probability-density contour plots that revealed tablet composition. The single-capsule analysis provides an indication of how far apart the sample and instrumentation can be and still maintain adequate signal-to-noise ratio (S/N), while the multiple-tablet imaging experiment gives an indication of how many samples can be analyzed simultaneously while maintaining an adequate S/N and pixel coverage on each sample.
In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.
A specially designed tablet dosage form of the benzodiazepine clorazepate dipotassium (Tranxene) was developed for once-a-day administration. The drug was administered at a dose of 22.5 mg as (1) the tablet, (2) three 7.5 mg capsules, or (3) one 7.5-mg capsule given every 6 hours. Peak serum levels from the tablet were intermediate between those of the single- and divided-dose capsule regimens. The desired decrease in magnitude of peak levels was obtained without affecting the extent of absorption. Pharmacokinetic analysis of the data according to a two-compartment open model with first-order absorption indicated that the serum half-life (t0.5beta) of nordiazepam, the major biotransformation product present in serum, was about 48 hours and served as a basis for the design of a multiple-dose steady-state study. Multiple-dose administration of the tablet and divided-capsule regimen to two groups of subjects for ten days indicated each dosage form yielded similar minimum steady-state serum levels of about 0.6 micrograms/ml which plateaued following seven days of drug administration. The dosage forms were crossed over between the groups on day 11 and administered for an additional four days. The minimum serum levels obtained with the tablet and capsule were not statistically different. Additionally, the peak serum level and area under the curve (pi=24 hours) at steady state were equivalent between the dosage forms. Good agreement was obtained between model-predicted and observed serum levels during multiple-dose administration for both the tablet and capsule regimens. The serum half-life of nordiazepam following 14 days of clorazepate dipotassium administration was similar to that found after a single dose. These results indicate that a single daily dose of drug as the tablet produced serum levels equivalent to a divided-capsule regimen.
An extended-release osmotic dosage form was designed for gastrointestinal delivery of the water-soluble tromethamine salt of the beta-hydroxyacid form of simvastatin, a potent HMG-CoA reductase inhibitor and cholesterol lowering agent. The cholesterol lowering efficacy and systemic plasma drug levels resulting from peroral administration of this dosage form, relative to a powder-filled capsule oral bolus, were evaluated in dogs. A twofold improvement in cholesterol lowering efficacy was realized with the controlled-release dosage form that was accompanied by a drug AUC and Cmax that were 67 and 16%, respectively, of those achieved with the bolus dosage form. These results suggest that extended-release dosage forms have the potential for a dose-sparing advantage in the administration of HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia.
A 200 mg controlled-release unit dosage form which was designed and developed showed desired in vitro release characteristics. This dosage form was subjected to in vivo studies (single and multiple p.o. dosing) in Beagle dogs with the aim of insuring the desired controlled-release performance in a biologic system. Using a parallel study design (intravenous, p.o. solution, p.o. controlled-release standard and p.o. controlled-release test dosage form), the dosage form index (DI), the fraction of drug absorbed (absolute bioavailability) (f) and the extent of (relative) bioavailability (EBA) of the experimental dosage form were determined.
Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. This manuscript discusses the complexity of the PK and PD factors that influence the treatment benefits of CR-GRDF and summarizes the results of our recent in vivo investigations in animal models (rats and dogs) and in human subjects. We found that a CR-GRDF formulation was superior to the other modes of administration for levodopa and riboflavin, but not for metformin. The PK and PD rationales of GRDFs for the studied drugs are presented and discussed. We conclude that due to the complexity of the PK and PD factors for a certain drug, the rationale for continuous administration obtained by CR-GRDF should be assessed and established in vivo.
Oral solid rapidly-disintegrating dosage form has aroused general concern increasingly because of its characteristics about convenient taking, rapid absorption, high bioavailability and not serious adverse drug reaction. This article introduced its mechanism, which was rapid disintegration, fast dissolution or the promoting dissolving action of supplementary material. This dosage form included dispersible tablets, fast dissolving tablets, fast releasing tablets, droppills, granules and tablets by solid dispersible technology, quick-liquefying chewable tablets and dry elixir. It will become a new way for promoting bioavailability in traditional Chinese medicine difficultly-dissolving composition, create up a new dosage form for treating emergency case by traditional Chinese medicine and give a new thinking for studying new supplementary materials. In brief, oral solid rapidly-disintegrating dosage form will have good prospect in the field of traditional Chinese medicine.
Two studies were performed to evaluate two nitroglycerin dosage forms. The dosage forms of main interest were a metered 0.4 mg nitroglycerin spray and a soft gelatin capsule containing 0.8 mg nitroglycerin solution. Each of these two dosage forms was evaluated in a separate study, versus both a placebo and an equivalent sublingual nitroglycerin tablet dose. The studies employed the digital plethysmographic methodology for evaluation of organic nitrate antianginal dosage forms. The results indicated that all the nitroglycerin dose treatments generated significantly greater digital plethysmographic activity versus the placebo. Also, the metered spray and soft gelatin capsule treatments were as effective, or more effective, than the respective sublingual tablet treatment in generating a digital plethysmographic response. Several implications and applications of these results are discussed.
Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.
A collection of dosage forms is presented, which are currently used in the treatment of cardiovascular and circulatory diseases including rarely used dosage forms. For each form important details to be considered during application are listed which are based on individual properties of the specific dosage form. Furthermore, general recommendations on the application of cardiovascular drugs are presented as well as information on dividing and crushing of dosage forms for dose reduction or application via tube, which is permitted for instant release dosage forms whereas modified release systems restrict the ability to divide or crush. Another chapter summarizes the prerequisites for a safe substitution of drugs which requires consideration of the particular dosage form.
Patient acceptance of medications often depends upon individual and cultural preferences for particular dosage forms. A variety of dosage forms also provides the patient and the physician with greater convenience and flexibility. Thus, multiple formulations increase the clinical utility of a drug. In addition to the capsule, dosage forms of piroxicam now available or in an advanced stage of clinical development include a suppository, dispersible tablet, topical gel, and parenteral formulation. (Ed.: The parenteral and topical formulations were launched after the symposium was held, and are now available). The piroxicam suppository offers an alternative to the oral route of administration. Pharmacokinetic studies demonstrate that the 20-mg suppository is bioequivalent to the 20-mg capsule, and clinical studies have shown that it is equal to the capsule in efficacy and toleration. Piroxicam is the only non-steroidal anti-inflammatory drug (NSAID) that is available as a dispersible tablet. This dosage form is also well tolerated by patients and equally effective as the capsule. Intramuscular administration of piroxicam is in development. All these dosage forms offer the convenience of once-a day administration. Piroxicam topical gel (0.5%) has been demonstrated to have anti-inflammatory activity in several animal models. In double-blind clinical trials involving patients with osteoarthritis of the knee, the topical gel was found to be significantly more effective than placebo and well tolerated.