Development and evaluation of C10 and SNAC erodible tablets for gastric delivery of a GIP/GLP1 peptide in monkeys.

The permeation enhancers (PEs) sodium caprate (C10) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) have been utilized for the intestinal and gastric delivery of macromolecules, respectively. However, the potential of C10 for the gastric delivery of a peptide and the ability of SNAC to deliver other peptides to the stomach beyond semaglutide have not been investigated. In this study, we have developed and evaluated C10 and SNAC-containing erodible tablets for the gastricdelivery of a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP1) dual agonist peptide (LY) in cynomolgus monkeys.

Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide.

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs.

Identification of a Multi-Component Formulation for Intestinal Delivery of a GLP-1/Glucagon Co-agonist Peptide.

Purpose: Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine.

Methods: An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.

Vitamin C Improves Dasatinib Concentrations Under Hypochlorhydric Conditions of the Simulated Stomach Duodenum Model.

Purpose: pH-dependent drug-drug interactions (DDIs) with poorly soluble, weakly basic drugs may lead to clinical implications. Dasatinib is a tyrosine kinase inhibitor with reduced absorption in patients on acid-reducing agents (ARAs). The objective of this study is to investigate the influence of gastric pH on dasatinib supersaturation and determine if vitamin C (L-ascorbic acid) can improve dasatinib concentrations under simulated hypochlorhydric gastric conditions.

An IQ Consortium Perspective on Connecting Dissolution Methods to In Vivo Performance: Analysis of an Industrial Database and Case Studies to Propose a Workflow.

Assessment of bioperformance to inform formulation selection and development decisions is an important aspect of drug development. There is high demand in the pharmaceutical industry to develop an efficient and streamlined approach for better understanding and predicting drug product performance to support acceleration of clinical timelines. This manuscript presents an effort from the IQ Formulation Bioperformance Prediction Working Group composed of members from 12 pharmaceutical companies under the IQ Consortium to develop a database around the topic of formulation bioperformance prediction and report findings from the database analysis.

Microstructures and pharmaceutical properties of ferulic acid agglomerates prepared by different spherical crystallization methods.

Spherical agglomerates of an active pharmaceutical ingredient, ferulic acid (FA), were prepared using four different spherical crystallization methods, i.e., quasi-emulsion solvent diffusion (QESD), anti-solvent, pH shift, and the direct method.

Direct Compression Tablet Containing 99% Active Ingredient-A Tale of Spherical Crystallization.

Direct compression (DC) is the easiest and most cost-effective process for tablet manufacturing, because it only involves blending and compression. However, active pharmaceutical ingredients generally exhibit poor mechanical and micromeritic properties, which necessitate dilution and the use of high percentage of excipients to enable a robust DC manufacturing process. Consequently, drug loading in DC tablets is usually low (typically <30%, w/w).

A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules.

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration-time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines.

Relative Bioavailability Risk Assessment: A Systematic Approach to Assessing In Vivo Risk Associated With CM&C-Related Changes.

Relative bioavailability (RBA) studies are often carried out to bridge changes made between drug products used for clinical studies. In this work, we describe the development of a risk assessment (RA) tool that comprehensively and objectively assesses the risk of noncomparable in vivo performance associated with Chemistry, Manufacturing, and Controls (CM&C)-related changes. The RA tool is based on a risk grid that provides a quantitative context to facilitate discussions to determine the need for an in vivo RBA study.

A mesoporous silica based platform to enable tablet formulations of low dose drugs by direct compression.

Achieving adequate content uniformity (CU) is a significant challenge in the development and manufacturing of low dose oral tablets. Using four model active pharmaceutical ingredients (APIs), we show that loading APIs into a grade of mesoporous silica, Aeroperl®, is effective for achieving excellent CU. All APIs in the Aeroperl® composites were amorphous.

Development of an in vivo-relevant drug product performance method for an amorphous solid dispersion.

The purpose of this work was to develop a meaningful in vitro dissolution method for evacetrapib spray-dried dispersion (SDD) tablets that is discriminating for crystalline drug substance (DS) content. Justification of the method conditions included evaluation of dissolution media, rotation speed, surfactant selection and level of surfactant to achieve sink conditions. Discrimination was illustrated by testing SDD tablets spiked with 10%, 20%, and 30% crystalline DS.

Particle Engineering for Enabling a Formulation Platform Suitable for Manufacturing Low-Dose Tablets by Direct Compression.

Maintaining good content uniformity (CU) is a significant challenge for low-dose oral tablets in particular when using direct compression (DC). Using 6 model active pharmaceutical ingredients, we show that a platform DC tablet formulation suitable for developing low-dose API with excellent CU can be developed. This platform formulation is enabled by particle engineering, where an API of interest is loaded in a suitable porous carrier to form a uniform API-carrier composite.

Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility.

Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability.

Identification and Prevention of Particulates in a Parenteral Solution of a Protein Kinase B Inhibitor.

The aim of this work was to identify the root cause of particulates in a parenteral solution formulation of a protein kinase B inhibitor (AKT inhibitor) and to devise a formulation fix. While standard potency/purity analyses did not reveal degradation, it was determined that the mass of the particulates corresponds to that of a "dimer-like" degradation product. The dimer-like molecule manifested itself as particulates rather than impurities in standard HPLC analysis.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated.

Leveraging BCS in Development: A Case Study.

In this work, we discuss leveraging the Biopharmaceutics Classification System (BCS) in the development of edivoxetine HCl, a selective norepinephrine reuptake inhibitor. First, the biopharmaceutical and in vivo data are presented and discussed. Solubility studies indicate that edivoxetine HCl meets the BCS "highly soluble" criteria.

Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone).

The log-linear cosolvency model was applied for estimating the solubility of four drugs: ritonavir, griseofulvin, itraconazole and ketoconazole in poly(vinylpyrrolidone) (PVP). Cosolvent mixtures consisted of PVP mixed in different proportions with N-ethylpyrrolidone, which served as the monomeric analogue of the repeating unit of the polymer. Solubility in the monomer-polymer mixtures was determined by HPLC.

A novel method for determining the solubility of small molecules in aqueous media and polymer solvent systems using solution calorimetry.

Purpose: To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material.

Methods: A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone.

Results: Dissolution end point was clearly ascertained when heat generation stopped.

Analysis of magnesium from magnesium stearate in pharmaceutical tablet formulations using hydrophilic interaction liquid chromatography with nano quantity analyte detection.

This study demonstrates the use of hydrophilic interaction liquid chromatography with a nano quantity analyte detector for the retention, separation and detection of magnesium from magnesium stearate in tablet formulations for a drug product formulation blend containing a hydrochloride salt of a weakly basic compound as the active ingredient. The nano quantity analyte detector can provide direct detection of inactive excipients and inorganic salts lacking ultraviolet chromophores, as well as, all non-volatile compounds. The separation was accomplished using a SeQuant ZIC-HILIC column and mobile phase consisting of 32.

Use of first derivative of displacement vs. force profiles to determine deformation behavior of compressed powders.

Displacement (D) vs. force (F) profiles obtained during compaction of powders have been reported by several researchers. These profiles are usually used to obtain mechanical energies associated with the compaction of powders.

Quantitative mineralogical properties (morphology-chemistry-structure) of pharmaceutical grade kaolinites and recommendations to regulatory agencies.

The physical and chemical characteristics of kaolinite (kaolin) may be variable, and minor amounts of other clay minerals, nonclay minerals, and other impurities may affect the properties of kaolinites. Thus specific technical properties of pharmaceutical grade kaolinites become very important because these clays are used in medical applications, e.g.

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media.

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g.

Physical stability of salts of weak bases in the solid-state.

When selecting the physical form of an active pharmaceutical substance, there is often a question of when a molecule's pKa renders it too low for salt formation and formulation into a product that will be sufficiently physically stable to provide adequate shelf life. In the paper, a graph is provided that tabulates pKa values of active pharmaceuticals versus the salt or free base form that was chosen to be developed as an orally administered drug product. Tabulation of the data provides insight into where, if any, practical cutoff exists, under which salt formation should not be considered.

Interpreting deformation behavior in pharmaceutical materials using multiple consolidation models and compaction energetics.

Tableting behavior is often characterized using qualitative analyses of compactibility and compressibility measurements. More quantitative methods use consolidation models to estimate parameters indicative of the predominating deformation mechanism exhibited by a material. It will be shown that a concerted approach, using multiple consolidation models and mechanical energy analysis, presents a more reliable way of evaluating the relative plasticity of pharmaceutical materials and identifying complicating behaviors.

Effect of storage conditions on compaction behavior of two grades of spray-dried lactose.

In this work we examine the effect of storage conditions (moisture exposure) on the compression behavior of 2 grades of spray-dried lactose (Pharmatose DCL 11 and Pharmatose DCL 14) under 2 different circumstances. The first was to expose powder samples to moisture, then compress them. The second was to expose precompressed tablets to moisture.