Pharmacokinetics of nano- and microcrystal formulations of low solubility compounds after intramuscular injection to mice.

Objectives: The aim of this study was to investigate the pharmacokinetics (PK) of poorly soluble compounds when administered intramuscularly (i.m.) as crystalline particles of different sizes.

Case study: cremophor EL-based liquid formulations as simple substitutes for amorphous solid dispersions in early preclinical in vivo studies.

Objectives: The objective of the present case study was to increase the exposure of the poorly soluble crystalline compound A.

Methods: Mice received 10 mg/kg of crystalline compound A formulated in eight different cosolvent, oil, and cyclodextrin mixtures.

Key Findings: In all cases, AUC0-24h and maximum blood/plasma concentration (Cmax) were in the range of 6-16 µM × h and <1.

Investigation of supramolecular structures in various aqueous solutions of an amyloid forming peptide using small-angle X-ray scattering.

Aggregation of peptide molecules into amyloid fibrils is a characteristic feature of several degenerative diseases. However, the details behind amyloid-formation, and other self-assembled peptide aggregates, remain poorly understood. In this study, we have used small-angle X-ray scattering (SAXS), static and dynamic light scattering (SLS and DLS) as well as cryogenic transmission electron microscopy (cryo-TEM) to determine the structural geometry of self-assembled peptide aggregates in various dilute aqueous solutions.

The Fate of Polycatecholamine Coated Nanoparticles Is Determined by a Fibrinogen Enriched Protein Corona.

Polycatecholamine coatings have attracted significant attention in the past 10 years owing to their ability to functionalize a wide range of materials. Here we apply the use of such coatings to drug nanocrystals, made from a poorly soluble drug compound, to postfunctionalize the nanocrystal surface with the aim of providing steric stabilization and extending their circulation time after intravenous injection. We show that both polydopamine and polynorepinephrine can be used to successfully modify drug nanocrystals and subsequently incorporate end-functionalized PEG to the surface.

Supersaturated formulations of poorly soluble weak acid drugs evaluated in rodents; a case study.

In the present study we describe a way of working to overcome oral administration challenges in an early preclinical project. As candidate drugs were obtained, the preclinical delivery route was replaced by the intended route of the product and resources were allocated to optimize the oral absorption. Two main approaches were followed in order to formulate a selected weak acid, AZ'403, for oral administration in large scale toxicological studies and the early clinical phases.

A candidate drug administered subcutaneously to rodents as drug particles showing hepatic recirculation which influenced the sustained release process.

The aim of the present study was to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline AZ'72 nano- and microsuspensions to rodents.

Nano- and microcrystals of griseofulvin subcutaneously administered to rats resulted in improved bioavailability and sustained release.

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.).

Sustained release and improved bioavailability in mice after subcutaneous administration of griseofulvin as nano- and microcrystals.

The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice.

Nanoshells prepared by atomic layer deposition - Long acting depots of indomethacin.

There is a trend in pharmaceutical research and development to develop depot formulations with dosing once weekly, once monthly, or even less frequently. A novel approach to achieve long acting injectable suspensions is to produce dense inorganic nanoshells with atomic layer deposition (ALD) on active pharmaceutical ingredients. Such particles can be suspended in an aqueous vehicle and administered subcutaneously.

Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation.

Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics.

The crystalline salt form of a selected candidate drug showed photo-, thermal- and humidity induced form transitions.

AZ3411 was selected as a lead compound for the treatment of Inflammatory Bowel Disease (IBD). The present research aimed to perform an early pharmaceutical assessment of this NK antagonist candidate focusing on the challenging solid-state part of the evaluation. X-ray powder diffraction (XRPD), hot stage XRPD and microscopy, differential scanning calorimetry, thermogravimetrical analysis measurements, nuclear magnetic resonance spectroscopy and liquid chromatographic analysis were used to characterize AZ3411.

A case study where pharmaceutical salts were used to address the issue of low in vivo exposure.

The present active pharmaceutical ingredient (API) is a lipophilic compound with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The aim of the presented studies was to investigate whether three novel salts of a new selected candidate in the cardiovascular therapy area could be applied to improve intestinal absorption and the subsequent in vivo exposure. Three salts (chloride, hydrogen sulfate, and hemi-1.

Salt formation improved the properties of a candidate drug during early formulation development.

The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed.

A preformulation evaluation of a photosensitive surface active compound, explaining concentration dependent degradation.

A candidate drug within the cardiovascular area was identified during early research and evaluated for further development. The aim was to understand and explain the degradation mechanisms for the present compound. The stability of the active pharmaceutical ingredient (API) in solution and solid state was studied during different conditions.

Nanocrystal formulations of a poorly soluble drug. 2. Evaluation of nanocrystal liver uptake and distribution after intravenous administration to mice.

A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.

Preformulation investigation and challenges; salt formation, salt disproportionation and hepatic recirculation.

A compound, which is a selective peroxisome proliferator activated receptor (PPAR) agonist, was investigated. The aim of the presented studies was to evaluate the potential of the further development of the compound. Fundamental physicochemical properties and stability of the compound were characterized in solution by liquid chromatography and NMR and in solid-state by various techniques.

Nanocrystal formulations of a poorly soluble drug. 1. In vitro characterization of stability, stabilizer adsorption and uptake in liver cells.

In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v.

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs.

AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure.

Evaluation of preclinical formulations for a poorly water-soluble compound.

One central aim of the present work was to find a robust oral formulation approach for Compound A, both to achieve reliable pharmacodynamic read outs but also for long time safety assessment studies. The compound has low aqueous solubility (0.4μM at 37°C), is highly lipophilic and has high Caco-2 permeability, i.

Probing adsorption of DSPE-PEG2000 and DSPE-PEG5000 to the surface of felodipine and griseofulvin nanocrystals.

Nanosized formulations of poorly water-soluble drugs show great potential due to improved bioavailability. In order to retain colloidal stability, the nanocrystals need to be stabilized. Here we explore the use of the poly(ethylene glycol) (PEG) conjugated phospholipids DSPE-PEG2000 and DSPE-PEG5000 as stabilizers of felodipine and griseofulvin nanocrystals.

Discovery of AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP) for the treatment of inflammatory diseases.

A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog.

A small structural change resulting in improved properties for product development.

AZD9343 is a water-soluble gamma amino butyric acid (GABAB) agonist intended for symptomatic relief in gastroesophageal reflux disease (GERD) patients. The compound has good chemical stability in aqueous solutions, as well as in the solid state. Only one crystal modification has been observed to date.

Evaluation of systemic exposure of nanoparticle suspensions subcutaneously administered to mice regarding stabilization, volume, location, concentration and size.

Different routes of administration are likely to result in very different outcomes due to different availability or plasma profile. The objective of the present study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.

Subcutaneous administration of nano- and microsuspensions of poorly soluble compounds to rats.

The aim of the present study was to evaluate and interpret the pharmacokinetic profiles of two compounds after subcutaneous (s.c.) administration.