AAPS PharmSciTech

The developed liposomal DPI of LEU (LLEUn-DPI) demonstrated approximately 50% bioavailability compared with SC route. The studies justify the role of the pulmonary route as a promising alternative to the presently available SC route. The components of liposomal vesicles may be suitably changed to achieve higher bioavailability. Pulmonary delivery of LEU is expected to help in improving patient compliance, self-administration and avoiding the complications related to injection procedure. The developed LEU-DPI may be employed for both male and female contraception and treatment of prostate cancer in men and early puberty in children. In women it may be used for ovarian, endometrial, pancreas, and breast cancer; endometriosis; Uterine Leiomyoma; and anemia due to uterine fibroid tumors. However, the role of LEU-DPI in clinical practice can only be justified only after in vivo studies on 2 species of animals followed by extensive clinical trials.

Excipients have always been a key input into pharmaceutical products, profoundly affecting product quality. Currently, most of our knowledge of excipient critical quality attributes is empirical, gained through experience, and shared through publications and other sources. The behavior of excipients is complicated, with many different failure modes that depend on the type of dosage form. Even within the same dosage form, there can be multiple failure modes depending on the manufacturing method. This complex behavior creates many possible combinations to assess when designing a formulation or evaluating regulatory submissions. Formulation science could be improved if data from different sources could be made widely available through an interactive system using a consistent, structured format to help formulators and regulators assess the risk of excipient usage for a particular dosage form with a particular manufacturing method. This paper describes a decision support system that was created for assessing excipient risk in different types of formulations and considering different types of manufacturing methods, dosage forms, and excipient functionality. The Excipient Risk Assessment System consists of a database that stores knowledge about factors that affect formulation design and a decision support processor that manages selections for creating formulation scenarios and assigning risk. Formulation and risk assessment data are provided by formulation science experts. This enables the system to assess compatibility among excipients, functionality, dosage forms, and manufacturing methods selected for formulations. The interface guides users through the creation of formulation scenarios and displays customized, interactive risk assessment reports for users to search and explore.

The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on–off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pHM). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pHM, so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release (“off” release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on–off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on–off release behavior of the drug and fumaric acid from coated tablets.

In vitro-in vivo correlation (IVIVC) analysis reveals a relationship between in vitro release and in vivo pharmacokinetic response of the drug of interest. Sandostatin LAR Depot (SLD) for endocrine tumors and acromegaly is a sustained-release formulation of octreotide, a cyclic oligomer of 8 amino acids, which prolongs therapeutic efficacy and enhances medication compliance of octreotide. Since the efficacy of SLD is dependent on the pharmacokinetic characteristics of octreotide released from a biodegradable matrix polymer, poly(lactide-co-glycolide)-glucose, of SLD, the IVIVC of SLD is critical for predicting an in vivo behavior of the octreotide. In this study, in vitro release of octreotide from SLD was investigated using the release test media each containing 0.02% or 0.5% surfactant and having different pH values of 7.4 and 5.5. In vivo pharmacokinetic profiles of SLD were determined by LC–MS/MS analysis of the systemic blood concentration of octreotide after the SLD injection to rodents. In IVIVC analysis, the Weibull model was adopted as a drug release model for biodegradable microsphere formulation. The IVIVC analyses revealed the in vitro release test condition of SLD with the highest IVIV correlation coefficient. By applying the in vitro release data to the model derived from the IVIVC analysis, pharmacokinetic parameters of SLD could be predicted with the prediction error of ± 10 ~ 15%. IVIVC analysis and pharmacokinetic prediction model of SLD in our study can be an efficient tool for the development of long-acting pharmaceutical dosage forms.

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106–500 μm) and coarse (500–1000 μm) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3–5 kDa to 12–14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.

The objective of this study was to determine the influence of mechanical stresses simulating gastrointestinal contraction forces of 2.0 N (stomach) and 1.2 N (intestine) on the gel properties and drug release characteristics from sustained release swelling and eroding hydrophilic matrices during dissolution studies. Two batches of tetracycline-sustained release tablets containing hydroxypropyl methyl cellulose (HPMC) were manufactured and subjected to USP apparatus II (pH 2.2 buffer) dissolution studies. Hydrated tablets were periodically removed, placed in a petri dish, and multiple times (six cycle) compressed with a flat-ended probe (diameter 1.3 cm) on a texture analyzer at preprogrammed force of either 2.0 or 1.2 N to determine force-distance profiles and changes in drug release rate. The calculated similarity factor values showed dissimilar dissolution profiles using standard dissolution profile as a reference. The similarity factor (f 2) values were especially lower than 50 at 2.0 N and, when profiles between the two batches compressed at 1.2 and 2.0 N, were compared with each other. The changes in dissolution pattern and release rate were significantly different after 4 h of dissolution. At 8 h, tablets were fully hydrated and no force could be detected by the probe, indicating a very soft gel matrix. It appears that the contraction forces in the stomach and intestine are capable of altering drug release from modified release hydrophilic matrices during transit in the human GI tract. Accounting for these forces during dissolution can enhance predictions of in vivo drug release, achieve better in vitro and in vivo correlation, introduce improvement in dissolution methods, and better understand the critical quality attributes (CQAs) and factors in quality by design (QbD) during the product development process.

Prior to compression in tablet manufacturing, a lubricant is added and mixed in a V-blender to ensure the mixture is ejected from the tablet die smoothly. Mixing is conducted batch-wise and must be analyzed offline afterwards to ensure the mixture is uniform and will produce desired tablet properties, thereby a costly and time-consuming step within the manufacturing process. To improve process efficiency, inline monitoring methods using passive acoustic emissions or vibration measurements could be implemented. Methods are non-destructive, non-invasive, and have a reduced capital cost compared to traditional methods. Using an accelerometer affixed to the lid of the V-shell, magnesium stearate was added to glass beads and monitored to determine the effect of loading configuration and fill level on mixing performance and measured vibrations. Axial loading configurations performed better than radial configurations due to the limited axial dispersion from the geometry of the V-shell. Mixing was hindered at an increased fill level due to convective and axial dispersion. The optimal fill level of a V-blender was found to be 21–23% by volume. Monitoring magnesium stearate mixing using passive vibration measurements is a non-intrusive and potentially inline method that could significantly improve pharmaceutical process efficiency.