Dosage formulations

Dosage formulation. Immediate-release formulations of terazosin and doxazosin are quickly absorbed and produce high peak plasma levels. Modified- or extended-release formulations of doxazosin, alfuzosin, and tamsulosin produce lower peak levels, but more sustained therapeutic plasma levels, than immediate-release formulations and have less potential for producing hypotensive episodes, thereby allowing initiation of treatment with a therapeutic dose and once daily dosing.25-27... 

Several randomized trials have demonstrated that leuprolide and goserelin are effective agents when used alone in patients with advanced prostate cancer.19 Response rates around 80% have been reported, with a lower incidence of adverse effects compared with estrogens.19 There are no direct comparative trials of the currently available LHRH agonists or the dosage formulations, but a recent meta-analysis reported that there is no difference in efficacy or toxicity between leuprolide and goserelin. Therefore, the choice between the two usually is made based on cost and patient and physician preference for a dosing schedule. 

In this table, it can be recognized that there are problems inherent in these types of formulations from both the patient s and the manufacturer s point of view. This is why most pharmaceutical companies make attempts to avoid these types of dosage forms, if at all possible. However, with the advent of biotechnological products, which often do not lend them, selves to conventional dosage formulations, parenteral and invasive measures may be the only answer. 

Oral Dosage Forms. The advantages of oral dosage formulations have already been discussed. It appears that this route of delivery is preferred by physician, patients, and manufacturers alike. The relatively low cost of oral dosage forms makes them a... 

Tiltabs. Tiltab tablets represent one of the few dosage formulations that has been developed expressly to meet the needs of patients with impaired dexterity [185], Marketed by Smith, Kline French Laboratories, Ltd. in several European countries, the novelty of the Tiltab design is its irregular shape that prevents it from lying flat. Apparently, tablets manufactured in this fashion are easier to handle by those with impaired dexterity. Moreover, these tablets are readily identifiable by patients so that differentiation from other medication is facilitated. Other innovations like this are needed for drug-delivery systems with the particular needs of the geriatric patient in mind. 

IV. PHARMACEUTICAL FACTORS IN ORAL DOSAGE FORMULATIONS FOR SELECT POPULATIONS... 

The relevance of particle size to solid dosage formulations has been determined by a number of individuals [54,190-196], As is illustrated in Table 13, particle size affects the solid dosage formulation in numerous ways. For instance, particle size can have a profound effect on the dissolution of a formulation within the GI tract. This is most notably characterized by the Noyes-Whitney equation ... 

Table 13 Processes in Solid Dosage Formulation Affected by Particle Size...

Ungell, A.-L., Abrahamsson, B., Biopharmaceutical support in candidate drug selection, in Pharmaceutical Preformulation and Formulation. A Practical Guide from Candidate Drug Selection to Commercial Dosage Formulation. Gibson, M. (ed.), Interpharm Press, 2001. 

In Phase III, the final dosage formulation has been established and the pivotal clinical trials are being conducted. Degradation products have been identified, so the method selectivity should be reevaluated to ensure that all degradants can be detected and quantitated. The analytical methods are completely validated, and appropriate for routine quality assurance and control purposes. The type and frequency of system suitable testing (SST) should be determined, and an excellent publication on SST for chromatography systems is available [47],... 

Beside mid-IR, near-IR spectroscopy has been used to quantitate polymorphs at the bulk and dosage product level. For SC-25469 [34], two polymorphic forms were discovered (a and /3), and the /3-form was selected for use in the solid dosage form. Since the /3-form can be transformed to the a-form under pressure by enantiotropy, quantitation of the /3-form in the solid dosage formulation was necessary. Standard mixtures of both forms in the formulation matrix were prepared, and spectra were measured in the near-IR via diffuse reflectance. Utilizing a standard, near-IR multiple linear regression, statistical approach, the a- and /3-forms could be predicted to within 1% of theoretical. This extension of the diffuse reflectance IR technique shows that quantitation of polymorphic forms at the bulk and/or dosage product level can be performed. 

It is important to keep in mind that safety assessment is only one of many components involved in the discovery and development of new pharmaceuticals. The entire process has become enormously expensive, and completing the transit of a new drug from discovery to market has to be as efficient and expeditious a process as possible. Even the narrow part of this process (safety assessment) is dependent on many separate efforts. Compounds must be made, analytical and bioanalytical methods developed, and dosage formulations developed, to name a few. One needs only to refer to Beyer (1978), Hamner (1982), Matoren (1984), Sneader (1986) (a good short overview), Zbinden, (1992) or Spilker (1994) for more details on this entire process and all of its components. 

A preservative is a substance that prevents or inhibits microbial growth and extends the shelf life of the drug products. In most pharmaceutical drug products, only a few compounds are typically selected as preservatives. For efficiency, a generic method should be developed for the types of preservatives that are more commonly used. For example, butylated hydroxytoluene (BHT) is an antioxidant commonly used in many solid dosage formulations to retard oxidative degradation of the excipients. 

TABLE 6 Direct Infusion FTMS Results on a Stressed Solid Dosage Formulation... 

Since the bottleneck on the clinical trial for taxol was in the supply, the NCI turned in 1989 to industrial partners, and issued a request for a Cooperative Research and Development Agreement, and selected Bristol-Myers Squibb (BMS) in 1991 as the partner in taxol development. BMS would take responsibility for the short-term supply of taxol, and NCI would sponsor research to deal with long-term supply. BMS collected 750,000 lbs of dried T. brevifolia bark from 38,000 trees during the 1991 growing season, sufficient to yield 25 kg of pure taxol to treat about 12,000 cancer patients. Hauser Chemical Research of Boulder, Colorado, was overseeing collection of yew bark and processing of the bark to extract taxol. BMS prepared the final dosage formulation and delivered it to the NCI for use in clinical studies. 

PHARMACOLOGY, TOXICOLOGY THERAPEUTIC DOSAGE FORMULATIONS, AND CLINICAL RESPONSE... 

The impact of formulation on protein absorption and disposition is also an important factor in the development and use of biologic molecules. Stability of the protein drug in subcutaneous or muscle tissues and absorption rates directly influence the overall response. Various physical and chemical approaches are used to stabilize proteins and other macromolecules as a part of optimizing dosage formulations. 

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