The thrust of this thesis is to study oral solid dosage formulation using hot melt coating method and to use pharmacokinetic modeling and simulation (PK M&S) as a tool that can help to predict pharmacokinetics of a drug in human and the probability of passing various bioequivalence criteria of the formulation based on the PK of the drug.
Hot-melt coating using a new method, direct blending, was performed to create immediate and sustained release formulations (IR and SR). This new method was introduced to offer another choice to produce IR and SR drug delivery formulations using single and double coating layer of waxes onto sugar beads and/or drug loaded pellets.
Twelve waxes were applied to coat sugar cores. The harder the wax the slower the drug was released from single coated beads. The wax coating can be deposited up to 28% of the weight of the core bead with 58% drug loading efficiency in the coating
The cores were coated with single or double wax layers containing acetaminophen. Carnauba wax coated beads dissolved in approximately 6 hrs releasing 80% of loaded drug. However, when covered with another layer, the drug loaded beads released drug for over 20 hrs. When drug loaded pellets were used as cores, 33-58% drug loading was achieved. Double coated pellets exhibited a near zero order drug release for up to 16 hrs.
Hot melt coating by direct blending using waxes is a simple process compared to conventional hot melt coating using coating pan or fluid bed coating machines. It offers an alternative way of making immediate, sustained drug release (IR, SR) and modified release (IR+SR) oral dosage forms of drugs which are stable at high temperature (100°C). The pellet-containing-drug coated formulations provide options when higher drug loading is warranted.
It is required by the US Food and Drug Administration (FDA) that a new modified –release (MR) product or identical generic product be regarded as bioequivalent (BE) to the originators reference drug product. However, there are concerns that current regulatory criteria are not sufficient when evaluating bioequivalence (BE) for many MR products, and additional metrics for BE assessment of the products should be applied to ensure therapeutic equivalence. This study used pharmacokinetic modeling and simulation (M&S) to investigate 1) the probability of BE occurring between the MR test and reference products 2) the rates of false positive and true negative of the BE test; and 3) the estimation of the sample size in pivotal BE studies; all of which when partial area under the curves (pAUCs) were applied as additional BE criteria.
Reference data of two MR forms of methylphenydate HCl (MPH) were simulated and obtained from literature (formulation Q and Metadate CD, respectively). Monte Carlo simulations were performed to simulate the test drug concentration profiles and BE assessment was carried out utilizing the mean (method 1) and individual concentration time curves (method 2).
For formulation Q, adding pAUC₀₋[subscript Tmax] to current BE criteria reduced the possibility of passing BE from approximately 98% to 85%, with a true negative rate of 5%. The earlier the time points used to determine for pAUC before Tmax, the lower the chance of passing BE for the test product. The possibility of passing BE varied and depended on the coefficient of variations (CV) of T[subscript lag], K[subscript a] and K[subscript e] and that considerable variability in the parameters affected the earlier segments of the drug concentration profile curves more. Similar drug concentration time profiles between the test and reference products is recommended to ensure bioequivalence occurs with a reasonable subject sample size. A similar scenario was seen when Metadate CD was used as the reference product.
PK M&S can help provide appropriate additional metrics to assure the BE test is a better tool ensuring therapeutic equivalence for MR products with little negative impact to generic manufacturers. Predictions can also be made about the required sample size and the chances of passing BE with any addition to the conventional three criteria for the test product.
PK M&S was also used to predict drug concentrations of levofloxacin in tissue. Levofloxacin has been widely used in clinical practice as an effective broad-spectrum antimicrobial, however tendonitis and tendon rupture have been reported with increasing use of this agent. Here, these incidents will be assessed by investigating pharmacokinetic behavior of the compound to see if they are related to drug's tissue disposition. The PK model for levofloxacin was established. Mean concentration time profiles of single or multiple dosing of 500 mg levofloxacin following oral and IV infusion administration were simulated. Monte Carlo simulation was used to simulate the drug concentration time profiles in plasma (compartment 1) and tissue (compartment 2) after seven dosing regimens while varying the drug's elimination and distribution rates to see the effect of changing those rates have on the drug accumulation in tissue. Monte Carlo Simulation shows that low elimination rates affect the drug concentration in plasma and tissue significantly with the level in plasma rising up to 35 μg/mL at day 7. A normal elimination rate together with escalation of distribution rates from plasma to tissue could increase the tissue concentration after 7 doses to 9.5 µg/mL, a value that is more than twice that of normal. PK M&S can be used as an effective tool to evaluate drug concentration in different compartments (plasma and tissues, for example). The unexpectedly high concentration values in some cases may explain, at least in part, the reason of tendinopathy occurs in the clinical setting.