12 research outputs found
Influence of additives on phase transformations in highly supersaturated solutions of poorly water-soluble drug compounds
No full textFormulation of poorly water-soluble drugs is a challenging problem encountered during the drug development process. To improve drug delivery, the amorphous form of a poorly water-soluble drug compound is often used to generate supersaturated solutions. The supersaturated solutions generated from the dissolution of amorphous solids may lead to an increase in absorption compared to that of a saturated solution if supersaturation can be maintained for a physiologically-relevant type period. . The phase behavior of supersaturated solutions is complex and poorly understood, with the formation of drug colloidal aggregates often being reported. Little is known about the mechanism by which colloidal aggregates are produced from supersaturated solutions, although it has been suggested that they are important to the bioavailability enhancement often seen with amorphous solid dispersions. However, in order to maintain supersaturation, crystallization must be prevented and so the presence of an effective crystallization inhibitor in solution is desirable to prolong supersaturation. Maintaining supersaturation by using polymeric additives depends on their ability to inhibit nucleation and crystal growth. Although the inhibition of crystallization from aqueous supersaturated solutions by polymeric additives has been extensively documented, there is very little mechanistic understanding of the underlying factors that affect the ability of polymeric additives to inhibit nucleation and crystal growth for a given drug compound. The insights into that mechanism of colloidal aggregate formation has important implications for understanding the phase behavior of amorphous solid dispersions upon dissolution as well as the delivery of compounds with low aqueous solubility. The elucidation of the key polymer properties important for crystallization inhibition of chemically and structurally different drug molecules will provide important insights about how polymers inhibit the crystallization of molecular crystals, and help to guide the development of new excipients with superior crystallization inhibitory properties
Effect of Binary Additive Combinations on Solution Crystal Growth of the Poorly Water-Soluble Drug, Ritonavir
No full textUnderstanding Polymer Properties Important for Crystal Growth InhibitionImpact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir
No full textThe use of supersaturating dosage forms, such amorphous
dispersions,
is an increasingly common approach for improving delivery of poorly
water-soluble drugs. Crystallization must be prevented to maintain
supersaturation, and so, the presence of an effective crystal growth
inhibitor in solution is desirable to prolong supersaturation. In
this study, the effectiveness of a group of chemically diverse polymers,
including a number of novel cellulose derivatives, at inhibiting the
crystal growth of ritonavir from solution was quantified, enabling
key polymer properties important for crystal growth inhibition of
ritonavir to be elucidated. In general, the greater effectiveness
of the cellulose derivatives relative to the synthetic polymers was
ascribed to a moderate level of hydrophobicity, the semirigid structure
of the cellulose polymers, and their amphiphilicity. Interestingly,
some of the novel cellulose polymers were found to be more effective
crystal growth inhibitors than commercially available cellulose derivatives.
Orthogonal partial least-squares analysis further pointed to the importance
of polymer hydrophobicity. These properties of the cellulose-based
polymers are likely to promote adsorption onto the crystallizing drug
surface. Given the diversity of impact of polymers on crystal growth
inhibition, it is clearly important to consider this factor when choosing
a polymer for a supersaturating dosage form
Effect of Binary Additive Combinations on Solution Crystal Growth of the Poorly Water-Soluble Drug, Ritonavir
No full textCombinations of additives (polymers and surfactants)
are often
used in pharmaceutical products to improve the delivery of poorly
water-soluble active pharmaceutical ingredients (API). Additive interactions
have not been widely studied and may promote or inhibit crystallization
(nucleation and crystal growth) in an unpredictable manner, which
in turn has an impact on the extent and duration of supersaturation.
In this study, the effect of a series of polymer/polymer and polymer/surfactant
combinations on crystal growth inhibition was investigated. Surprisingly,
the majority of the polymer/polymer combinations investigated had
a synergistic effect on crystal growth inhibition. The effectiveness
of the polymer/polymer combinations was ascribed to the formation
of interpolymer complexes through hydrophobic interactions that adsorb
and interact favorably with the crystallizing solute and/or, interaction
of individual polymers at different adsorption sites. The acceleration
of crystal growth in the presence of polymer/surfactant combinations
was attributed to weakened interactions between the polymer and the
surface of the crystallizing solute brought about by the presence
of surfactant molecules. Based on these observations, careful evaluation
of the impact of combinations of additives on crystallization behavior
is recommended in order to optimize the performance of supersaturating
dosage forms
Impact of Polymers on Crystal Growth Rate of Structurally Diverse Compounds from Aqueous Solution
No full textThe presence of an effective crystal
growth inhibitor in solution
is desirable to prolong supersaturation since residual crystalline
material in an amorphous formulation resulting from the manufacturing
process or formed during storage or dissolution can potentially have
a significant impact on the extent and duration of supersaturation.
In this study, the effectiveness of a group of chemically diverse
polymers, including several recently synthesized cellulose derivatives,
on solution crystal growth of three structurally diverse compounds
(celecoxib, efavirenz, and ritonavir) was quantified at different
extents of supersaturation and compared. Despite the different chemical
properties and structures of the model compounds, nonspecific hydrophobic
drug–polymer interactions appeared to be important in determining
the impact of a given polymer on crystal growth for of all these drug
compounds. Specific intermolecular interactions were also found to
be important for crystal growth inhibition of celecoxib and efavirenz
by the hydrophilic polymer, PVPVA. These interactive forceshydrophobicity
and specific intermolecular interactionsare likely to promote
adsorption of the polymer onto the surface of the crystalline drugs,
thus influencing crystal growth. The effectiveness of the polymers
also depended on the rate of crystallization of the drug molecules.
At a similar supersaturation ratio of ∼1.2, ritonavir and celecoxib
had slower normalized crystal growth rates (0.20 and 0.91 mg min–1 m–2, respectively), while the normalized
crystal growth rate of efavirenz was significantly higher (2.97 mg
min–1 m–2), resulting in lower
levels of crystal growth inhibition by the polymers for efavirenz
Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide‑1 Receptors
No full textPeptides are sustainable alternatives to conventional
therapeutics
for G protein-coupled receptor (GPCR) linked disorders, promising
biocompatible and tailorable next-generation therapeutics for metabolic
disorders including type-2 diabetes, as agonists of the glucagon receptor
(GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However,
single agonist peptides activating GLP-1R to stimulate insulin secretion
also suppress obesity-linked glucagon release. Hence, bioactive peptides
cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty
acid metabolism imbalance, tackling both diabetes and obesity to supersede
current monoagonist therapy. Here, we design and model optimized peptide
sequences starting from peptide sequences derived from earlier phage-displayed
library screening, identifying those with predicted molecular binding
profiles for dual agonism of GCGR and GLP-1R. We derive design rules
from extensive molecular dynamics simulations based on peptide–receptor
binding. Our newly designed coagonist peptide exhibits improved predicted
coupled binding affinity for GCGR and GLP-1R relative to endogenous
ligands and could in the future be tested experimentally, which may
provide superior glycemic and weight loss control
Computational peptide design cotargeting glucagon and glucagon-like peptide‑1 receptors
No full textPeptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide−receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.</p
Influence of Additives on the Properties of Nanodroplets Formed in Highly Supersaturated Aqueous Solutions of Ritonavir
No full textThe
formation of colloidal drug aggregates of lipophilic drugs
is thought to be of relevance for the oral delivery of poorly water-soluble
drugs. In this study, the underlying basis for colloid formation from
amorphous solid dispersions and the impact of additives on colloidal
stability were evaluated. A relationship was found between the concentration
at which colloidal droplets formed upon dissolution of an amorphous
solid dispersion and the liquid–liquid phase separation (LLPS)
transition concentration, whereby the latter is related to the theoretical
amorphous “solubility” value. The composition of the
dispersed phase in ritonavir–polymer–water solutions
was confirmed to be a noncrystalline, ritonavir-rich droplet phase.
Additives were found to impact the size, stability, and crystallization
behavior of the colloidal phase. In general, charged additives reduced
the kinetics of droplet coalescence, but had a variable effect on
crystallization kinetics, either promoting or inhibiting crystallization.
Through proper selection of formulation components, it thus appears
possible to promote the formation of ∼250–350 nm colloidal
droplets of ritonavir following dissolution of an amorphous solid
dispersion, and to inhibit coalescence and crystallization from these
two-phase supersaturated solutions
