Release, drug formulation immediate

As mentioned before, nifedipine was the first marketed dihydropyridine CCB. Initially, the drug indication was exclusively for angina, but the more recently developed extended release (ER) formulations are used off-label primarily for hypertension (Bayer, 2004). The extended-release tablets use a cellulose coat that extends their release time. The half-life of the ER formulation is reported as 7 h, whereas the immediate-release formulation has a half-life of 2 h (Bayer). 

We include certain excipients in a formulation specifically because they interact with the physiological fluids and the bodily functions in a certain way. For example, as discussed above, we include disintegrants in immediate release tablet and capsule formulations, because we know that when they encounter the aqueous environment of the stomach, they will cause the tablet or capsule to disintegrate and thereby aid dissolution of the API. Another example is the general case of hydrophilic colloid matrices used as prolonged release drug delivery systems. We know that when these materials contact the aqueous environment of the GIT they swell and create a diffusion barrier that slows the rate of dissolution of the dissolved drug. 

This guidance provides recommendations to sponsors of new drug applications (NDA s), abbreviated new drug applications (ANDA s), and abbreviated antibiotic applications (AADA s) who intend, during the postapproval period, to change 1) the components or composition 2) the site of manufacture 3) the scale-up/scale-down of manufacture and/or 4) the manufacturing (process and equipment) of an immediate release oral formulation. 

Oxycodone is a semisynthetic opioid derived from thebaine and used for oral pain relief. It is commonly formulated as an immediate-re lease medication with acetaminophen or aspirin. A con-trolled-release oxycodone formulation is used for the treatment of moderate to severe pain it provides controlled drug delivery over 12 h. The oral bioavailability of this formulation is 60 to 87%.35 The results of clinical studies of patients with postoperative and cancer pain show that oxycodone has a potency 1.5 times that of morphine. 

An NDA can be submitted for a previously unapproved new molecular entity, or for a new salt, new ester, prodrug, or other noncovalent derivative of a previously approved new molecular entity, formulated as a modihed-release drug product. The first modified-release drug product for a previously approved immediate-release drug product should be submitted as an NDA. Subsequent modified-release products that are pharmaceutically equivalent and bioequivalent to the listed drug product should be submitted as ANDAs. BA requirements for the NDA of an extended-release product are listed in 320.25(f). The purpose of an in vivo BA study for which a controlled-release claim is made is to determine if all of the following conditions are met. 

For low-dose, immediate-release drug products, the formulation should be designed with cohesive diluents, such as lactose, to enhance ordered mixing prior to the dry granulation process. Based on the two case studies reported here, it was also demonstrated that this formulation approach reduced the propensity for the powder blend to segregate. 

Bioavailability studies quantify rate and extent of absorption. They compare the efficiency of the disposition of several drug formulations, e.g. immediate-release vs. extended-release or capsule vs. tablet or tablet A vs. tablet B etc., or they compare the disposition of different routes of administration, e.g. oral vs. subcutaneous or oral vs. intravenous. According to the definition, a comparison to the intravenous bolus injection yields the absolute bioavailability. 

The study described here has a very complex design for its exploratory approach. It combines four different extended release formulations, each tested under fasting and non-fasting conditions, and compares the results to the immediate release drug product as the reference formulation. The bilayer tablets combines an immediate release component and an extended release component in one vehicle. In this project a close cooperation between the galenics department and the clinical pharmacokinetic function was mandatory. The in vitro/in vivo correlation was done by means of the deconvolution which is an appropriate surrogate to describe the in vivo dissolution. 

Multiporous oral drug absorption system. A single-unit, immediate-release tablet formulation consisting of an inner core, containing active drug plus excipients, surrounded by a non-disintegrating, timed release coating. 

Eorster, A. Rades, T. Hempenstall, J. Selection of suitable drugs and excipient candidates to prepare glass solutions by melt extrusion for immediate release oral formulations. Pharm. Tech. Eur. 2002, 27-57. 

Acetyltriethyl citrate is used to plasticize polymers in formulated pharmaceutical coatings. The coating applications include capsules, tablets, beads and granules for taste masking, immediate release, sustained-release and enteric formulations. It is also used in diffusion-controlled release drug... 

Level C correlation This correlation describes a relationship between the amount of drug dissolved (e.g., percent dissolved in one hour) at one time point and one pharmacokinetic parameter [e.g., either area under the curve (AUC) or Cmaxl-Level C correlation is considered the lowest correlation level as it does not reflect the complete shape of the plasma concentration time curve. Similarly, a multiple Level C correlation relates one or more pharmacokinetic parameters to the percent drug dissolved at several time points of the dissolution profile and thus may be more useful. Levels B and C correlations can be useful in early formulation development, including the selection of the appropriate excipients, optimization of manufacturing processes, for quality control purposes, and characterization of the release patterns of newly formulated immediate-release and modified-release products relative to the reference. 

The pharmacokinetics of the drug administered as IV or immediate release (IR) or drug released from the extended release (ER) formulation are indistinguishable. In others words, once a drug molecule released from the IR or ER formulations is absorbed into the systemic circulation, it behaves just like an intravenously administered one. 

Figure 3 Pharmacokinetic/pharmacodynamic relationship and enantiospedfic first-pass metabolism of verapamil. A prototype category HI racemic drug. Unlike propranolol, with verapamil the EC50 value for the PR prolongation, determined on the basis of the nonenantiospecific assay, is higher after the oral dose than after the intravenous dose (upper panel). This is attributed to the greater first-pass metabolism of the more active S-enantiomer (lower panel). Slowing the oral input rate by switching from an immediate- (IR) to a sustained-release (SR) formulation results in a significant ( = P < 0.05 by paired t test) decrease in the proportion of the more active S-enantiomer at maximum concentration (Cmax R + S). (From Ref 26, with permission.)...

Drug formulations The feasibility of immediate overnight switching from slow-release... 

ControUed-release oral formulation of morphine sulfate is not indicated for pain in the immediate postoperative period (the first 12-24 horns following sm-gery) in patients not previously taking the drug, because its safety in this setting has not been established. 

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