ABSTRACT
Oral cannabidiol (CBD) is approved by the Food and Drug Administration (FDA) to treat patients with Dravet and Lennox-Gastaut syndromes and tuberous sclerosis complex. The therapeutic potential of oral CBD formulations is limited by extensive first-pass hepatic metabolism. Following oral administration, the inactive metabolite blood concentration is â¼40-fold higher than CBD. Inhalation bypasses the pharmacokinetic (PK) variability attributed to irregular gastrointestinal absorption and first-pass hepatic metabolism and may efficiently deliver CBD into systemic circulation. This phase 1 study compared the PK of a dry-powder inhaler (DPI) CBD formulation (10 mg powder containing 2.1 mg CBD) with an oral CBD solution (Epidiolex®, 50 mg) in healthy participants. Following a single dose of Epidiolex or DPI CBD (n=10 PK evaluable participants each), the maximum CBD concentration for the inhaled powder was 71-fold higher than that of Epidiolex while administering 24-fold less CBD. The mean time to reach maximum concentration was 3.8 min for the DPI CBD formulation compared with 122 min for Epidiolex. Both Epidiolex and DPI CBD were generally safe and well-tolerated. These data indicate that DPI CBD provided more rapid onset and increased bioavailability than oral CBD and support further investigations on the use of DPI CBD for acute indications.
Subject(s)
Cannabidiol , Administration, Inhalation , Administration, Oral , Biological Availability , Gastrointestinal Absorption , Humans , PowdersABSTRACT
In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 µm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).
Subject(s)
Aerosols/chemistry , Oxytocin/chemistry , Powders/chemistry , Administration, Inhalation , Calorimetry, Differential Scanning/methods , Chemistry, Pharmaceutical/methods , Desiccation/methods , Drug Compounding/methods , Drug Stability , Dry Powder Inhalers/methods , Excipients/chemistry , Hot Temperature , Nanoparticles/chemistry , Particle Size , Trehalose/chemistry , X-Ray Diffraction/methodsABSTRACT
Recent work has demonstrated that the route of administration affects the pharmacokinetics and biological activity of peptides. For example, the physiological profile of insulin consists of basal and prandial components with a small-scale oscillatory element. Insulin is used more efficiently when the pharmacokinetic profile mimics features of physiological release. Noninvasive administration of insulin by oral, transdermal, nasal and pulmonary routes resembles the relatively sharp peak and short duration of exposure of prandial release. The route of administration per se, can affect the response by avoiding first-pass metabolism or perhaps altering the timing in which the peptide reaches different sets of receptors. GLP-I delivered by injection and inhalation produces different side effect profiles. Nonclinical studies on two potential treatments for obesity, oxyntomodulin and PYY 3-36, are also presented to illustrate the relationship between exposure and effect as functions of route of administration.
Subject(s)
Drug Administration Routes , Drug Delivery Systems/instrumentation , Drug Delivery Systems/methods , Peptides/administration & dosage , Humans , Peptides/pharmacokineticsABSTRACT
The Annual Inhaled Drug Delivery Conference organized by Management Forum was held in London, UK, 9-10 November 2010. The meeting focused on a range of disease therapies from the pulmonary indications routinely treated with inhaled medicines (asthma, cystic firbrosis and chronic obstructive pulmonary disease) to novel applications of the inhalation route to treat systemic diseases (irritable bowel disease, schizophrenia, migraine, diabetes and obesity).
Subject(s)
Administration, Inhalation , Drug Delivery Systems , Humans , Pulmonary Disease, Chronic Obstructive/drug therapyABSTRACT
The 2011 Next-Generation Protein Therapeutics Summit integrated five promising strategic approaches to designing and realizing the next generations of protein and biologic drugs. The conference sessions focused on non-antibody and antibody therapeutics, innovations in improving the physicochemical properties of these drugs, routes of administration, methodologies for reducing unwanted immunogenic reactions, and novel drugs from non-natural amino acids.
Subject(s)
Antibodies/administration & dosage , Drug Design , Proteins/administration & dosage , Animals , Antibodies/adverse effects , Humans , Proteins/adverse effectsABSTRACT
The Natural Peptides to Drugs congress, held in Zermatt, Switzerland, included topics covering new therapeutic developments in the field of peptide- and protein-based drugs derived from natural products. This conference report highlights selected presentations on drug discovery from natural peptides, natural peptide-based drugs in preclinical and clinical development, and peptide candidates. Investigational drugs discussed include novel small peptides from KAI Pharmaceuticals Inc, XEP-018 (Atheris Laboratories), MKC-253 (MannKind Corp), AEZS-108 (AEterna Zentaris Inc) and XG-102 (Auris Medical AG/Xigen SA).
Subject(s)
Biological Products/pharmacology , Drug Design , Drug Discovery , Peptides/pharmacology , Animals , Drugs, Investigational , Humans , Peptide Library , Phytotherapy , Plant Preparations/pharmacology , Technology, PharmaceuticalABSTRACT
BACKGROUND: Technosphere Insulin (TI) is a novel inhalation powder for the treatment of diabetes mellitus. Technosphere Insulin delivers insulin with an ultra rapid pharmacokinetic profile that is distinctly different from all other insulin products but similar to natural insulin release. Such rapid absorption is often associated with penetration enhancers that disrupt cellular integrity. METHODS: Technosphere Insulin was compared to a panel of known penetration enhancers in vitro using the Calu-3 lung cell line to investigate the effects of TI on insulin transport. RESULTS: Measures of tight junction integrity such as transepithelial electrical resistance, Lucifer yellow permeability, and F-actin staining patterns were all unaffected by TI. Cell viability and plasma membrane integrity were also not affected by TI. In contrast, cells treated with comparable (or lower) concentrations of penetration enhancers showed elevated Lucifer yellow permeability, disruption of the F-actin network, reduced cell viability, and compromised plasma membranes. CONCLUSIONS: These results demonstrate that TI is not cytotoxic in an in vitro human lung cell model and does not function as a penetration enhancer. Furthermore, TI does not appear to affect the transport of insulin across cellular barriers.
