Time-controlled Drug Release

Time-controlled drug release with pH-induced drug delivery is a delivery method that does not depend on changes in the luminal pH of the GI tract but on a pH change within the dosage form itself. 

Swelling sustained-release coating polymers such as Eudragit NE 30 D, i.e. poly(ethyl-acrylate-methylmethacrylate) [101,102] or Eudragit RS [90], lead to a delay in drug release which is dependent on the thickness of the coating since these films have slow rates of swelling. 

For an erosion-induced drug delivery system compactable cellulose ethers are suitable polymers [103]. Drug release, which is controlled by the erosion/dissolution of these polymeric layers, may be pH-dependent if an acid or basic polymer is used. 

In summary, the lag time of drug release may be controlled by the rate at which water penetrates through the coating or shell, the rate of fluid absorption of the polymer layer, the osmotic activity of salts and osmopolymers, the erosion and dissolution rate of the polymer layers and the thickness of the layers or coatings. 

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Most of the drug delivery systems that have been studied for clinical application are capable of rate- and/or time-controlled drug release. The therapeutic advantages in these approaches lie in the in vivo predictability of release rate, minimized peak plasma levels, predictable and extended duration of action and reduced inconvenience of frequent re-dosing and hence, improved patient compliance [1]. 

The relatively constant transit time in the small intestine of approximately 3-4 h is another physiological characteristic which can be exploited to achieve colon specificity (time-controlled drug release). After gastric empt5ung, a time-controlled drug delivery system is intended to release the drug after a predetermined lag phase. 

Vladimir, S. K., Serquei. M. D. and Elena, V. K. (2002). A method to fabricate porous spherical hydroxyapatite granules intended for time controlled drug release. Biomaterials, 23 3449-3454. 

Langoth et al. [86] studied the properties of matrix-based tablets containing the novel pentapeptide leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) that has been shown to have pain-modulating properties. The matrix-based tablets were made with the thiolated polymer PCP. The covalent attachment of cysteine to the anionic polymer PCP leads to an improvement of the stability of matrix tablets, enhances the mucoadhesive properties, and increases the inhibitory potency of PCP towards buccal enzymes. All these factors lead to stability of the peptide and a controlled drug release for the peptide was obtained for more than 24 h. Also, the tablets based on thiolated PCP remained attached on freshly excised porcine mucosa 1.8 times longer than the corresponding unmodified polymer. 

Conventional systems do not offer sufficient flexibility in controlling drug-release rate and sustaining the release over time periods extending from days to months. Therefore specific modified release vaginal delivery systems are continuously under development and are based on mucoadhesive systems. Penetration enhancement may represent a necessary feature for certain delivery systems, particularly when the absorption regards a macromolecule (such as a peptide or a protein). 

Prolonged intestinal residence time Protective effect towards an enzymatic attack Controlled drug release... 

This arbitrary recommendation does not rely on strict theoretical and experimental findings and is based only on the fact that completely different physical conditions have been postulated for the derivation of the equivalent (4.2) and (4.3), while the underlying mechanism in both situations is classical diffusion. In this context, a linear plot of the cumulative amount of drug released q (t) or the fraction of drug released q (f) /f/,Xj (utilizing data up to 60% of the release curve) vs. the square root of time is routinely used in the literature as an indicator for diffusion-controlled drug release from a plethora of delivery systems. 

From the values of A listed in Table 4.1, only the two extreme values 0.5 and 1.0 for thin films (or slabs) have a physical meaning. When A = 0.5, pure Fickian diffusion operates and results in diffusion-controlled drug release. It should be recalled here that the derivation of the relevant (4.3) relies on short-time approximations and therefore the Fickian release is not maintained throughout the release process. When A = 1.0, zero-order kinetics (Case II transport) are justified in accord with (4.4). Finally, the intermediate values of A (cf. the inequalities in Table 4.1) indicate a combination of Fickian diffusion and Case II transport, which is usually called anomalous transport. 

Disadvantages of Controlled Drug Release. Potential disadvantages of controlled release dosage forms include the possibility of dose dumping, less facile dose adjustment, increased potential for hepatic first-pass metabolism, possible delay in onset of action, possibly lower system availability, and time of drug release limited to residence time of formulation in the optimum absorption region(s) of GI tract. 

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