Modified release formulations

These enzymes (and transporters) exhibit differential expression at various sites throughout the GIT. For example, CYP3A4 expression is highest in the duodenum and lowest in the colon conversely, the expression of P-gp is greatest in the colon. This has implications for the gut wall first-pass extraction of drugs delivered by modified-release formulations, where the majority of the drug must be absorbed from the colon. 

The bacteria in the intestinal tract serve as another well-known source of luminal drug degradation [61], though this is only important for the colon region as the luminal concentration of bacteria is 104 to 109-fold higher in the colon compared with the small intestine. Thus, this aspect is only relevant for drugs that reach this region, for example, due to poor permeability, slow dissolution or delivery by modified-release formulations. Hydrolytic and other reductive reactions are predominantly mediated by bacterial enzymes, and a list of the most prominent types... 

There are a number of FDA regulatory guidances that are associated with IVIVC development and validation, as well as the application of IVIVC to SUPAC. The specific IVIVC guidance for oral modified-release formulations was first published in September 1997 (1). There are several guidances on SUPAC, including those for both modified release (2) and immediate-release solid oral dosage forms (3). The recent... 

Avinza- Avinza capsules are a modified-release formulation of morphine sulfate indicated for once-daily administration for the relief of moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time. Avinza capsules are to be swallowed whole or the... 

Indiplon is rapidly absorbed (1-2 h) and eliminated (ti/2 =1.3 h). In-vitro studies on indiplon show two major metabolites A-demethylation due to CYP3A4/5 and Ai-deacetylation by carboxylesterases. Its short half-hfe has enabled the development of two dosing paradigms with different formulations (1) an immediate release formulation to improve sleep initiation and for dosing in the middle of the night, and (2) a modified release formulation, which provides for immediate release and sustained release of the drug to help with sleep initiation, duration, maintenance, and sleep quality (Neubauer,... 

Trials of different modified-release formulations of zaleplon, zolpidem, and a similar selective GABA hypnotic, indiplon, are ongoing. These versions may help improve the sleep of those patients who have sleep maintenance insomnia or early-morning awakening. 

Markowitz JS, Straughn AB, Patrick KS, et al Pharmacokinetics of meth-ylphenidate after oral administration of two modified-release formulations in healthy adults. Clin Pharmacokinet 42 393 01, 2003... 

To determine precision at multiple collection time points for the dissolution profile of a modified release formulation, normalization to the final time point (or infinite time point) will eliminate tablet-to-tablet and lot-to-lot variation. Figure 4.1 illustrates the way that normalization is used to remove tablet-to-tablet variation. However, the normalization technique should be used during development only as a means of investigation of the profile. The final formulation should be sufficiently robust to produce complete release at its final time point. Normalization to remove lot-to-lot variation can be performed using the following equation ... 

Range. The results of the linearity, accuracy, and precision will help determine the range for the dissolution test (e.g., 25 to 125% of nominal for a single-point dissolution and 20% of the stated range for a dissolution profile for a modified release formulation). 

Modified-release formulations of metformin allow once daily dosage. In a double-blind, parallel-group comparison of an immediate-release and an extended-release formulation in 191 patients for 24 weeks adverse events did not differ between the groups (125). 

A once-daily modified-release formulation of gliclazide has been reviewed (157). It has a low tendency to cause hypoglycemia in all patients, including the elderly and patients with mild renal insufficiency. Arthralgia, arthritis, back pain, and bronchitis are its most commonly reported adverse effects, although it is not clear whether they are all related to gliclazide. 

Injection site reactions to somatropin are common and include nodules, pain, and erythema. They usually resolve spontaneously (25,34). In a 2-year study of once- or twice-monthly injections of a modified-release formulation of somatropin in 56 prepubertal children, injection site reactions were common, especially in the first year of treatment. These included skin nodules in 56% of injections, erythema in 49%, and lipoatrophy in 12% (70). 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

Modified-release formulations of nicotinic acid do not appear to be better tolerated than regular formulations, flushing and itching being the most common adverse effects (SEDA-19, 206). There have also been several reports of hepatotoxicity with this form of the drug (SEDA-16,438). Other adverse effects are hepatotoxicity (apparently a dose-related direct toxic effect), hyperglycemia, and hyperuricemia. It has been questioned whether the modified-release formulation, which is available over the counter in some countries, ought to continue to be available for self-medication in view of its serious adverse effects (2,3). 

Nicotinic acid is hepatotoxic, and it is suspected that the modified-release formulation increases the risk (SED-13,... 

Since nicotinic acid can cause unpleasant flushing and other symptoms of vasodilatation, attempts have been made to develop modified-release formulations. Modified-released nicotinic acid formulations may be better tolerated than the immediate-release formulation, because they reduce the vasodilatory effects of the drug. However, the low frequency of flushing produced by modified-release formulations may be offset by an increased risk of hepatotoxicity. Some reports have suggested a higher frequency of hepatic dysfunction with traditional modified-release nicotinic acid formulations compared with immediate-release products (2, 40). 

In a double-blind, placebo-controlled study of a modified-release formulation in 128 patients pruritus was reported in 10 patients taking nicotinic acid (11%) and rash in 9 patients (10%) there were no similar effects in those taking placebo (41). 

The efficacy and adverse effects of a modified-release formulation have been studied in 32 patients with type 2 diabetes (43). Of 22 patients who completed 6 months of therapy, 17 took 1000 mg/day, three 1500 mg/day, and two 2000 mg/day. Seven of 32 patients discontinued therapy. Of these, three withdrew after 2, 5, and 6 months because of flushing and itching. Three other patients withdrew within 2 months because of nausea, diarrhea, and dyspepsia. One patient withdrew after 7 days because of increased blood glucose concentrations. There were no significant increases in mean transaminase activities, which remained within the reference ranges in all patients. 

The pharmaceutical and biological availability of eight commercial furose-mide preparations was compared including two products with modified release properties [67], an enteric-coated tablet and a sustained-release preparation, in the form of a capsule containing diffusion pellets [28], A correlation between the rate of dissolution of different techniques and the area under the plasma concentration time curve was documented. The sustained-release preparation and the enteric-coated formulation clearly showed different pharmacokinetic behavior compared with conventional tablets. Although the literature mentions the maximal absorption at pH 5.5, the modified release formulations only showed a relative bioavailability of 80%. 

Immediate release tablets are formulated to release the (API) as soon as possible to hasten absorption. Modified release formulations release the API at a controlled rate. Modified release formulations can be classified into controlled release and extended release formulations. The intention of these formulations is to allow a reduction in dosing frequency or diminish the fluctuation of drug levels on repeated administration compared with that observed with the immediate release form of the drug. 

Greenblatt DJ, Legangneux E, Harmatz JS, et al. Dynamics and kinetics of a modified-release formulation of zolpidem comparison with immediate-release standard zolpidem and placebo. J Clin Pharmacol 2006 46 1469-1480. 

II.S.16 Special Situations for Drug Delivery Modified Release Formulations... 

One of the special situations for drug delivery is the assessment of the pharmacokinetic (PK) properties of a modified release formulation. Modified release products always gain importance if the PK/PD profile of a drug is not close to optimal for its target indication, mostly because the (short) PK or efficacy half-life does not match the intended dosing frequency. 

Soluble in organic solvents, insoluble in water and GI fluids used alone in modified-release formulations and in combination with water-soluble cellulose for immediate-release formulations Soluble in water and GI fluids... 

Hjartstam, J. (1998), Ethyl Cellulose Membranes Used in Modified Release Formulations, Chalmers University of Technology, Goteborg, Sweden. 

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