Avinash Govind Thombre

Delivery of glipizide from asymmetric membrane capsules using encapsulated excipients

The aim of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH sensitive solubility such as glipizide. In order to obtain the desired delivery duration, the drug was solubilized with the use of a pH-controlling excipient. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Thus, highly water-soluble excipients are released much faster than the drug, which can limit their usefulness. In the case of the asymmetric membrane capsule, it was shown that this limitation could be overcome by encapsulating the pH-controlling excipient in a membrane and including the coated excipient in the asymmetric membrane capsule core to prolong its availability within the core. Thus, prolonged release of glipizide could be obtained with the asymmetric membrane capsule.

Asymmetric membrane capsules for osmotic drug delivery II. In vitro and in vivo drug release performance.

In a previous paper, we described asymmetric membrane capsules and a phase inversion process for manufacturing them. In this paper, we describe the in vitro and in vivo drug release characteristics from these capsules. The capsule formulations were developed with model drugs to understand the variables that influenced drug release. Studies were also conducted to understand the drug release mechanism and it was shown that osmotic drug delivery was possible with asymmetric membrane capsules.

Assessment of the feasibility of oral controlled release in an exploratory development setting

Controlled release (CR) formulations have generally been considered as follow-ons to conventional immediate release formulations to manage the life cycle of a product. Although significant opportunities exist to use CR as an enabling technology for certain exploratory drug candidates, they have not been fully exploited. However, progress made in assessing CR feasibility based on the physicochemical and biopharmaceutical properties of the drug, together with advances made in understanding the various CR technologies and developing formulations in a fast and efficient manner, have increasingly made it possible to consider CR in an exploratory development setting.

Improved Ziprasidone Formulations with Enhanced Bioavailability in the Fasted State and a Reduced Food Effect

ABSTRACTPurposeTo develop and characterize new formulations of ziprasidone with a reduced food effect achieved by increasing exposure in the fasted state.MethodsFormulations were developed utilizing the following solubilization technologies: inclusion complex of ziprasidone mesylate and cyclodextrin, ziprasidone free base nano-suspension, and semi-ordered ziprasidone HCl in polymer matrix. Pharmacokinetic studies were conducted with these formulations to examine the bioavailability of test formulations in fasted and fed state compared to commercial capsules (Geodon®) dosed in the fed state.ResultsAll formulations containing solubilized ziprasidone showed either no food effect or a reduced food effect compared to commercial capsules. Two formulations when taken in the fasted or fed state were comparable to the commercial capsules dosed in the fed state with respect to total exposure. However, peak concentrations were ~30–40% higher.ConclusionsPharmacokinetic studies indicated solubilization technologies can be employed to successfully increase the extent of ziprasidone absorption in the fasted state, thereby reducing the food effect. Such formulations could provide simple and convenient dosing while retaining the familiar safety and efficacy profile of currently marketed capsules.

In vitro and in vivo characterization of amorphous, nanocrystalline, and crystalline ziprasidone formulations

Ziprasidone, commercially available as Geodon capsules, is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. It is a BCS Class II drug that shows up to a 2-fold increase in absorption in the presence of food. Because compliance is a major issue in this patient population, we developed and characterized solubilized formulations of ziprasidone in an effort to improve absorption in the fasted state, thereby resulting in a reduced food effect. Three formulations utilizing solubilization technologies were studied: (1) an amorphous inclusion complex of ziprasidone mesylate and a cyclodextrin, (2) a nanosuspension of crystalline ziprasidone free base, and (3) jet-milled ziprasidone HCl coated crystals made by spray drying (CCSD) the drug with hypromellose acetate succinate. The formulations were characterized by in vitro methods appropriate to each particular solubilization technology. These studies confirmed that ziprasidone mesylate - cyclodextrin was an amorphous inclusion complex with enhanced dissolution rates. The ziprasidone free base crystalline nanosuspension showed a mean particle size of 274 nm and a monomodal particle size distribution. In a membrane permeation test, the CCSD showed a 1.5-fold higher initial flux compared to crystalline ziprasidone HCl. The three formulations were administered to fasted beagle dogs and their pharmacokinetics compared to Geodon capsules administered in the fed state. The amorphous complex and the nanosuspension showed increased absorption in the fasted state, indicating that solubilized formulations of ziprasidone have the potential to reduce the food effect in humans.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: Workshop summary report

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. Model development.

The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo‐equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design. Biotechnol. Bioeng. 2010; 105: 409–420.

Formulation design and pharmaceutical development of a novel controlled release form of azithromycin for single-dose therapy

Background: Azithromycins long serum half-life (∼68 hours) allows for a short 5-day, 3-day, and now 1-day course therapy with a large 2-g dose. Although the single-dose, 1-day therapy offers the advantage of 100% patient compliance, tolerance of such large dose becomes an issue. Methods: The dosage form discussed in this article employed a melt-congealing process to produce matrix microspheres with a 3-hour, first-order release. The vehicle blend included alkalizing agents to minimize GI side effects, minimize loss of bioavailability, and mask the bitter taste of azithromycin. Results: Azithromycin microspheres are small (∼200 μm) with a narrow particle size distribution. Drug release was optimized by controlling the amount of dissolution enhancer in the microspheres and by the addition of proper amount of alkalizing agents in the vehicle blend. The final formulation was selected based on a balance between bioavailability and tolerability. Conclusions: Drug release from the microspheres was shown to occur via diffusion through the larger pores formed by dissolution of azithromycin crystals and the smaller interconnected pores formed by dissolution of poloxamer. Several clinical studies have been conducted with the formulation to evaluate its pharmacokinetics and to demonstrate its safety and efficacy. The combined suspension formulation for a 2-g dose of azithromycin provided taste-masking and good tolerability.

Solid nanocrystalline dispersions of ziprasidone with enhanced bioavailability in the fasted state.

Reducing the absorption difference between fed and fasted states is an important goal in the development of pharmaceutical dosage forms. The goal of this work was to develop and characterize a solid nanocrystalline dispersion (SNCD) to improve the oral absorption of ziprasidone in the fasted state, thereby reducing the food effect observed for the commercial formulation. A solution of ziprasidone hydrochloride and the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) was spray-dried to form a solid amorphous spray-dried dispersion (SDD), which was then exposed to a controlled temperature and relative humidity (RH) to yield the ziprasidone SNCD. The SNCD was characterized using powder X-ray diffraction, thermal analysis, microscopy, and in vitro dissolution testing. These tools indicate the SNCD consists of a high-energy crystalline form of ziprasidone in domains approximately 100 nm in diameter but with crystal grain sizes on the order of 20 nm. The SNCD was dosed orally in capsules to beagle dogs. Pharmacokinetic studies showed complete fasted-state absorption of ziprasidone, achieving the desired improvement in the fed/fasted ratio.

Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation

A model was developed for predicting the influence of cyclodextrins (CDs) delivered as a physical mixture with drug on oral absorption. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. The purpose of this work is to compare the simulation predictions with in vitro as well as in vivo experimental results to test the models ability to capture the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution and absorption kinetics of low solubility drugs (Naproxen and Nifedipine) were tested in the presence and absence of CD in a simulated gastrointestinal environment. Model predictions were also compared with in vivo experimental results (Glibenclamide and Carbamazepine) from the literature to demonstrate the models ability to predict oral bioavailability. Comparisons of simulation and experimental results indicate that a model incorporating the influence of CD (delivered as a physical mixture) on dissolution kinetics and binding of neutral drug can predict trends in the influence of CD on bioavailability. Overall, a minimal effect of CD dosed as a physical mixture was observed and predicted. Modeling may aid in enabling rational design of CD containing formulations. Biotechnol. Bioeng. 2010; 105: 421–430.