Rate-controlled drug release

The rate of drug release (E) from the eroding matrix is controlled by (a) the chemical properties of the system - the hydrolytic and the neutralizing process at the boundary of the device, catalytic degradation of the polymer and the intrinsic backbone reactivity, and (b) several concomitant physical processes such as water diffusivity, water solubility, water partitioning, etc. 

A reported application of canonical analysis involved a novel combination of the canonical form of the regression equation with a computer-aided grid search technique to optimize controlled drug release from a pellet system prepared by extrusion and spheronization [28,29]. Formulation factors were used as independent variables, and in vitro dissolution was the main response, or dependent variable. Both a minimum and a maximum drug release rate was predicted and verified by preparation and testing of the predicted formulations. Excellent agreement between the predicted values and the actual values was evident for the four-component pellet system in this study. 

With continuous development of systems for controlled drug release, new materials are being used whose influence on peptide stability must be carefully examined. Thus, the model hexapeptide Val-Tyr-Pro-Asn-Gly-Ala (Fig. 6.30) embedded in poly (vinyl alcohol) and poly(vinyl pyrrolidone) matrices had rates of deamidation that increased with increasing water content or water activity, and, hence, with decreasing glass transition temperature (Tg). However, the degradation behavior in the two polymers differed so that chemical reactivity could not be predicted from water content, water activity, or T% alone. Furthermore, the hexapeptide was less stable in such hydrated polymeric matrices than in aqueous buffer or lyophilized polymer-free powders [132],... 

The provision of rate-controlled drug action (such as various controlled-release tablets, capsules, and suspensions)... 

Buccal dosage forms can be of the reservoir or the matrix type. Formulations of the reservoir type are surrounded by a polymeric membrane, which controls the release rate. Reservoir systems present a constant release profile provided (1) that the polymeric membrane is rate limiting, and (2) that an excess amoimt of drug is present in the reservoir. Condition (1) may be achieved with a thicker membrane (i.e., rate controlling) and lower diffusivity in which case the rate of drug release is directly proportional to the polymer solubility and membrane diffusivity, and inversely proportional to membrane thickness. Condition (2) may be achieved, if the intrinsic thermodynamic activity of the drug is very low and the device has a thick hydrodynamic diffusion layer. In this case the release rate of the drug is directly proportional to solution solubility and solution diffusivity, and inversely proportional to the thickness of the hydrodynamic diffusion layer. 

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]. 

Oral controlled drug-release systems are increasingly used for short half-life drugs to reduce peak blood levels and side-eflfects, to maintain optimum drug concentration and to stimulate patient compliance. In order to maintain a constant blood-level of the drug during an extended period, a constant in vitro drug release rate is desired. The most popular controlled-release system is the matrix tablet (Desai et al., 1965). Te Wierik et al. (1996) reported on... 

Alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) are bioerodible acidic polymers that are used to control drug release. In biological fluids with poor buffering capacity, drug release from the polymers and their dissolution are slowed owing to the lower pH on the polymer surface. We studied whether the release of timolol from matrices of monoisopropyl ester of PVM-MA in vitro and in vivo in rabbits eyes could be affected by disodium phosphate in the matrices. Addition of disodium phosphate to the matrices doubled the release rate of timolol in vitro, but it did not affect the bulk pH of the dissolution medium. On the basis of the timolol concentrations in the tear fluid and in systemic circulation, disodium phosphate seems to accelerate drug release in vivo also. Disodium phosphate probably affects the rate of dmg release by increasing the microenvironmental pH on the polymer surface. 

Bioerodible alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) (Fig. 1) can be used to control drug release. Being acidic, ionizable polymers the pH of the disolution medium affects the rate of polymer dissolution [1]. 

During polymer dissolution, the pH on the polymer surface decreases. This decreases the rate of polymer dissolution. When buffer is added to dissolution medium, hydrogen ions are neutralized by the buffer on the surface of the polymer. The buffer concentration thus affects the rates of polymer dissolution and erosion-controlled drug release [1]. In biological fluids with poor... 

For water-insoluble drugs, dissolution-controlled systems are an obvious choice for achieving sustained-release because of theirslow dissolution rate characteristics. Theoretically, the dissolution process at steady state can be described by the Noyes-Whitney equation as shown in Equation 22.7. The rate of dissolution of a compound is a function of surface area, saturation solubility, and diffusion layer thickness. Therefore, the rate of drug release can be manipulated by changing these parameter. 

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). 

Subcutaneous administration involves injecting the drug directly under a patient s skin. Subcutaneous and IM injections are similar. Bioavailability is high but lower than administration directly into the bloodstream. The rate of drug release can be somewhat controlled by the formulation of the drug. The pH of the injected solution must be close to physiological pH otherwise, severe skin irritation can result. 

---