Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole.

High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a "tapped basket" dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.

Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor.

We hypothesized that nanosuspensions could be promising for the delivery of the poorly water soluble anti-cancer multi-targeted kinase inhibitor, MTKi-327. Hence, the aims of this work were (i) to evaluate the MTKi-327 nanosuspension for parenteral and oral administrations and (ii) to compare this nanosuspension with other nanocarriers in terms of anti-cancer efficacy and pharmacokinetics. Therefore, four formulations of MTKi-327 were studied: (i) PEGylated PLGA-based nanoparticles, (ii) self-assembling PEG750-p-(CL-co-TMC) polymeric micelles, (iii) nanosuspensions of MTKi-327; and (iv) Captisol solution (pH=3.5). All the nano-formulations presented a size below 200 nm. Injections of the highest possible dose of the three nano-formulations did not induce any side effects in mice. In contrast, the maximum tolerated dose of the control Captisol solution was 20-fold lower than its highest possible dose. The highest regrowth delay of A-431-tumor-bearing nude mice was obtained with MTKi-327 nanosuspension, administered intravenously, at a dose of 650 mg/kg. After intravenous and oral administration, the AUC0₋∞ of MTKi-327 nanosuspension was 2.4-fold greater than that of the Captisol solution. Nanosuspension may be considered as an effective anti-cancer MTKi-327 delivery method due to (i) the higher MTKi-327 maximum tolerated dose, (ii) the possible intravenous injection of MTKi-327, (iii) its ability to enhance the administered dose and (iv) its higher efficacy.

Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues.

Supersaturating drug delivery systems (SDDS) hold the promise of enabling intestinal absorption for difficult-to-formulate, poorly soluble drug candidates based on a design approach that includes (1) converting the drug into a high energy or rapidly dissolving system which presents a supersaturated solution to the gastrointestinal environment and (2) dosage form components that act to stabilize the formed metastable drug solution through nucleation and/or crystal growth inhibition. The appropriate development and study of SDDS require that useful and biorelevant supersaturation and precipitation assays are available. This review summarizes different methodological aspects of currently available in vitro assays, including the generation of supersaturation (solvent shift, pH shift or formulation-induced), the quantification of supersaturation and the detection of precipitation. Also down-scaled approaches, including 96-well plate setups, are described and situated in the pharmaceutical development cycle based on their consumption of API as well as time requirements. Subsequently, the ability to extrapolate in vitro supersaturation assessment to the in vivo situation is discussed as are direct and indirect clinical tools that can shed light on SDDS. By emphasizing multiple variables that affect the predictive power of in vitro assays (e.g. the nature of the test media, hydrodynamics, temperature and sink versus non-sink conditions), this review finally highlights the need for further harmonization and biorelevance improvement of currently available in vitro procedures for supersaturation and precipitation evaluation.

Cyclodextrins as functional excipients: methods to enhance complexation efficiency.

Cyclodextrins have gained currency as useful solubilizing excipients with an ever increasing list of beneficial properties and functionalities. Although their use in liquid dosage forms including oral and parenteral solutions is straightforward, their application to solids can be confounded by the added bulk that is contributed to the formulation. This factor has limited the use of cyclodextrin in tablets and relates systems mainly to potent drug substances. Increasing the ability of cyclodextrins to complex with drug through a manipulation of their complexation efficiency (CE) may expand the use of these materials to the increasing list of drug candidates and marketed drugs who may benefit from this technology. This brief review assesses tools and materials that have been suggested for increasing the CE for pharmaceutically useful cyclodextrins and drugs. The relative importance of impacting the drug solubility (S(0) ) and phase-solubility isotherm slope is discussed in the context of drug ionization and salt use; the impact of polymers, charge interactions, and charge shielding; and the coincidental formation of other complex types in the media. The influence of drug form as well as supersaturation is also discussed in the context of the responsible mechanisms along with aggregation, inclusion, and noninclusion complex formation.

Supersaturating drug delivery systems: fast is not necessarily good enough.

An emerging technology subtype that has been adopted by formulators to address low-solubility issues is the supersaturating drug delivery system; this system is based on the "spring" and "parachute" design elements, which have been applied to lipid-based formulations, S(M)EDDS, solid dispersions, nano-based systems, and many others. This broad formulation approach attempts to delicately balance the need of creating intraluminal drug concentrations in excess of its thermodynamic solubility while at the same time providing for sufficient solution stability to allow for useful drug absorption. The conundrum created is that the higher the extent of supersaturation, the lower the physical stability of the metastable solution based on an increased tendency for a solubilized drug to precipitate. Traditional dissolution testing is a touchstone of formulation development based on the need for useful dissolution rates and drug availability. Dissolution testing is likewise important in the development and characterization of enabling and supersaturating drug delivery systems; however, their execution and interpretation are distinct from that associated with conventional dosage forms. The nature of the dissolution assay (sink versus nonsink, apparatus type, and rate and extent of supersaturation) can impact the ability to efficiently use the dissolution data in the configuration of these enabling formulations.

Self-assembly of cyclodextrin complexes: effect of temperature, agitation and media composition on aggregation.

Recently it has been shown that aggregation of drug/cyclodextrin inclusion complexes is strongly influenced by the drug molecule in addition to self-assembling tendencies of the cyclodextrin itself in aqueous media. Whereas the mechanistic basis of cyclodextrin self-assembly is known, the driving forces for complex aggregation are still unknown. In the present study, the influence of temperature on hydrocortisone/2-hydroxypropyl-ß-cyclodextrin complex aggregation is investigated as are influences associated with the addition of ethanol or water soluble polymers to the aqueous systems. Furthermore the effect of stirring on the aggregation is assessed. Size exclusion permeability studies were conducted to estimate complex aggregation tendencies. The results indicate that self-assembled complex aggregates are metastable and notably become smaller with increasing temperature and the addition of ethanol. Water soluble polymers also reduce the size of the complex aggregates. Specifically, hexadimethrine bromide had the greatest impact, since addition of this compound eliminated aggregates from the systems or reduced their size below the molecular weight cut-off of the sizing membrane (8 kDa). Similar observations are made when aqueous solutions of hydrocortisone and 2-hydroxypropyl-ß-cyclodextrin are equilibrated by stirred.

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

OBJECTIVES: Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories. KEY FINDINGS: Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. CONCLUSIONS: A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates.

Self-assembly of cyclodextrins: the effect of the guest molecule.

The principle action by which cyclodextrins solubilize compounds is via inclusion complex formation. However, data suggest that cyclodextrins and their complexes also aggregate in solution and this aggregation contributes to their ability to solubilize poorly water-soluble materials. The current effort aims at better understanding the role of guest molecule nature (i.e. its structural and functional peculiarities) in cyclodextrin complex aggregation as well as in the aggregate stability assessed using a cellophane membrane permeability assay. A test set of 11 acidic, basic and neutral drugs and antibacterial agents (i.e. guests) were examined with regard to their interaction with hydroxypropyl-ß-cyclodextrin (HPßCD) and the resulting ability of the formed aggregates to move through a semi-permeable membrane of various molecular weight cut-off values. The data suggested that the interaction of HPßCD with certain guests resulted in the formation of structure large enough to poorly penetrate semi-permeable membrane. The aggregates appeared to be highly dynamic in that there were no qualitative differences between systems that were diluted immediately prior to permeation experiments and those allowed to equilibrate. Pharmaceutical polymers which have been shown to enhance solubilizing efficiency of cyclodextrins had little or no effect on the stability of the aggregates using the permeability paradigm as an endpoint with the exception of carboxymethylcellulose.

Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes.

Cyclodextrins (CDs) are well known functional excipients for solubilization and stabilization of drugs in aqueous formulations as well as enabling adjuncts for increasing the oral bioavailability of solid dosage forms. More recently a number of the valuable properties of these CDs have been ascribed to nanoparticulate aggregation in addition to its ability to form molecular inclusion complexes. The purpose of this study is to identify and characterize the aggregation of CD inclusion complexes with a model drug, hydrocortisone, in saturated solutions which are more relevant to drug formulation than highly dilute systems. Penetration studies of complexes through membranes and phase solubility relationships were assessed for saturated hydrocortisone solutions with the parent CDs, namely αCD, ßCD, γCD or with various water-soluble derivatives, i.e., 2-hydroxypropyl-ßCD (HPßCD), 2-hydroxypropyl-γCD (HPγCD) or sulfobutyl ether-ß-CD (SBEßCD). The data indicate that ßCD and γCD form micro-aggregates with hydrocortisone resulting in non-linear phase-solubility relationships. By contract, the other studies of CDs or CD derivatives were found to form nanoaggregates with hydrocortisone resulting in linear solubilization relationships. Permeability profiles were evaluated for the systems formed and are described in three sections specifically a section (section I) where flux is linear (Fickian) as a function of CD concentration, a section (section II) where flux deviates in a negative fashion from linearity but still increases as the CD concentration increases and a section (section III) where flux is independent of the cyclodextrin concentration. Diminished values of flux can be interpreted based on the formation of nanoaggregates of hydrocortisone/CD complexes. Extrapolation of section I data made it possible to obtain theoretical flux values which could be used to estimate the fraction of complexes and drug which participate in aggregation. The CDs which appeared to demonstrate the lowest tendency to form complex aggregates were αCD and SBEßCD, due to their low complexation efficacy and repulsive forces, respectively. Complex aggregates with these CDs are also smaller with maximum size between 50 and 100 kDa. HPßCD and HPγCD complex aggregates manifested a maximum size above 100 kDa and the fraction of drug which participates in complex aggregation with these species is higher than for the other materials assessed. In the case of 90 mM HPγCD solution, data suggest that 87% of all hydrocortisone is tied up in the form of aggregates. These high concentrations were confirmed by TEM which found most particles in the 3-5 nm range but rarely particles as large as 10 and 20 nm. Speculation on the mechanism of the aggregation processes and equilibrium constants are provided but these tend to punctuate our limited understanding of these potentially important processes.

Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine.

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.

Pharmaceutical applications of cyclodextrins: basic science and product development.

OBJECTIVES: Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. KEY FINDINGS: There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. SUMMARY: We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as P(eff), flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB. Four PAMPA methodologies were evaluated in this study including: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (double sink) model, (3) a PAMPA-BBB (blood-brain barrier) model and (4) a PAMPA-BBB-UWL (unstirred water layer). Additionally, plasma protein binding (PPB) experiments and a Caco-2 assay were performed to determine the unbound fraction in plasma and the efflux ratio, respectively, for subsets of the selected compounds. This information was combined with the obtained PAMPA data in an effort to improve the predictions of LogBB. Taken in aggregate, the results presented, suggest that the PAMPA-BLM parameters are the most important contributors to predict the LogBB. The optimized multiple linear regression (MLR) relationship including the PAMPA-BLM properties demonstrated a slightly improved prediction compared to the model without the PAMPA-BLM parameters. Including the plasma protein binding of 15 compounds resulted in a significantly improved PAMPA-BLM prediction of LogBB, while integrating the efflux ratio with PAMPA-BLM or PAMPA-BBB P(eff) values, resulted in improved classification of brain permeable [BBB+(LogBB>/=0)] and impermeable [BBB-(LogBB<0)] compounds.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as Peff, flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB. Four PAMPA methodologies were evaluated in this study including: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (double sink) model, (3) a PAMPA-BBB (blood-brain barrier) model and (4) a PAMPA-BBB-UWL (unstirred water layer). Additionally, plasma protein binding (PPB) experiments and a Caco-2 assay were performed to determine the unbound fraction in plasma and the efflux ratio, respectively, for subsets of the selected compounds. This information was combined with the obtained PAMPA data in an effort to improve the predictions of LogBB. Taken in aggregate, the results presented, suggest that the PAMPA-BLM parameters are the most important contributors to predict the LogBB. The optimized multiple linear regression (MLR) relationship including the PAMPA-BLM properties demonstrated a slightly improved prediction compared to the model without the PAMPA-BLM parameters. Including the plasma protein binding of 15 compounds resulted in a significantly improved PAMPA-BLM prediction of LogBB, while integrating the efflux ratio with PAMPA-BLM or PAMPA-BBB Peff values, resulted in improved classification of brain permeable [BBB + (LogBB >or= 0)] and impermeable [BBB--(LogBB < 0)] compounds.

Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621.

The anti-cancer cyclin dependent kinase (CDK) inhibitors are poorly soluble drugs. The aims of this work were (i) to formulate a novel CDK inhibitor, JNJ-7706621, in polymeric micelles and nanoparticles, (ii) to compare passive and active targeting on tumor growth and (iii) to evaluate the potential synergy of JNJ-7706621 with Paclitaxel. Therefore, JNJ-7706621 was encapsulated in self-assembling diblock copolymers made up of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) (PEG-p-(CL-co-TMC)) polymeric micelles and in (poly(lactide-co-glycolide)) (PLGA)-based PEGylated nanoparticles (passive targeting) as well as in RGD-grafted nanoparticles (active targeting). In vivo, the transplantable liver tumor growth was more decreased by active targeting with RGD-grafted nanoparticles than by passive targeting with micelles or ungrafted nanoparticles. Moreover, a synergy between JNJ-7706621 and Paclitaxel was demonstrated. Therefore, active targeting of JNJ-7706621-loaded nanocarriers may be considered as an effective anti-cancer drug delivery system for cancer chemotherapy, particularly in combination with Paclitaxel.

Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability.

The Parallel Artificial Membrane Permeability Assay (PAMPA) has been successfully introduced into the pharmaceutical industry to allow useful predictions of passive oral absorption. Over the last 5 years, researchers have modified the PAMPA such that it can also evaluate passive blood-brain barrier (BBB) permeability. This paper compares the permeability of 19 structurally diverse, commercially available drugs assessed in four different PAMPA models: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (Double Sink) model, (3) a PAMPA-BBB model and (4) a PAMPA-BBB-UWL (unstirred water layer) model in order to find the most discriminating method for the prediction of BBB permeability. Both the PAMPA-BBB model and the PAMPA-BLM model accurately identified compounds which pass the BBB (BBB+) and those which poorly penetrate the BBB (BBB-). For these models, BBB+ and BBB- classification ranges, in terms of permeability values, could be defined, offering the opportunity to validate the paradigm with in vivo data. The PAMPA models were subsequently applied to a set of 14 structurally diverse internal J&J candidates with known log (brain/blood concentration) (LogBB) values. Based on these LogBB values, BBB classifications were established (BBB+: LogBB0 >or=; BBB-: LogBB<0). PAMPA-BLM resulted in three false positive identifications, while PAMPA-BBB misclassified only one compound. Additionally, a Caco-2 assay was performed to determine the efflux ratio of all compounds in the test set. The false positive that occurred in both models was shown to be related to an increased efflux ratio. Both the PAMPA-BLM and the PAMPA-BBB models can be used to predict BBB permeability of compounds in combination with an assay that provides p-gp efflux data, such as the Caco-2 assay.

Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability?

Contemporary pharmaceutical pipelines are often highly populated with poorly water-soluble drug candidates necessitating novel formulation technologies to provide dosage forms with appropriate biopharmaceutical properties. The configuration of supersaturating drug delivery systems (SDDS) is a promising concept to obtain adequate oral bioavailability. SDDS contain the drug in a high energy or otherwise rapidly dissolving form such that intraluminal concentrations above the saturation solubility of the drug are generated. For the strategy to be useful, the formed supersaturated solution must then be stabilized to allow for significant absorption and eventually sufficient bioavailability. The stabilization of a supersaturated solution can be accomplished by adding precipitation inhibitors which may act through a variety of mechanisms. The goal of this review is to assess methods and excipients associated with the development of SDDS and provide some context for their use. In addition, the future directions and factors likely to contribute to or detract from optimal dosage form selection are assessed. This includes a discussion on the potential effect of the gastrointestinal physiology on the ability to attain and maintain supersaturation as this information is essential in designing useful formulations based on the supersaturating concept.

Comparative interaction of 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions.

Cyclodextrins can increase the apparent solubility and dissolution rate of poorly water-soluble drug candidates improving their biopharmaceutical performance. The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth. To these points, the effects of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutylether-beta-cyclodextrin (SBEbetaCD) on equilibrium solubility was assessed via phase-solubility analysis as were the interactions of these excipients on drug solubility under conditions favoring supersaturation. Phase-solubility analysis indicated that different profiles were generated as a function of the cyclodextrin examined and the pH of the complexing medium. When kinetic solubility measurements were completed, the cyclodextrins were found to stabilize concentrations of itraconazole significantly in excess of their equilibrium solubility when supersaturated solutions were formed using the co-solvent/solvent quench approach. These solutions were stable over 240 min falling in concentration at the 24 h time point of the experiment unlike those formed using surfactants and other polymers which demonstrated a rapid decrease in concentration over time. These data suggest that hydrophilic cyclodextrins might be useful formulation adjuncts in supersaturating drug delivery systems.

Physicochemical properties of water and its effect on drug delivery. A commentary.

The structure and properties of water are integral to the existence and evolution of life on any number of levels. Consistent with this overarching statement, the unique physiochemical properties of water affect the pharmacological actions and delivery of drugs to the body whether they are administered orally, topically or by injection. This last topic is explored in the current review. While water is a group VIA hydride, it is distinct from other members of the class based on density, dielectric constant, surface tension as well as melting and boiling point. These differences are attributed to the ability of water to hydrogen bond to itself and other substrates resulting in the formation of strongly cohesive systems which molecularly resemble highly dynamic polymeric networks. As a consequence of these properties, hydrophobic compounds tend to aggregate in solution sometimes at the nanoscale. The practical consequence of this aggregation may be observed as spurious results associated with receptor-based high throughput screening assays as well as anomalies in phase-solubility analysis encountered in the study of hydrophobic materials with cyclodextrins. Other insights provided by a knowledge of the structure of water include the actions of excipients. Thus, materials that contribute to the hydrogen-bonding aqueous network (i.e., kosmotropes) will tend to salt more non-polar materials out of solution while material that destabilize the network structures (i.e., chaotropes) will tend to preferentially bind to solutes, reducing unfavorable interactions with water, resulting in solubilization. At membranes, the unique properties of water can affect drug absorption based on resistance in the unstirred water layer (UWL) which resides directly adjacent to the barrier. Depending on the nature of the membrane and the drug, the UWL can effectively reduce drug uptake and penetration. Furthermore, excipients that affect water structure can either contribute to or detract from the ability of a compound to pass the UWL and consequently the membrane. The increasing realization that water influences the actions and interactions drugs and excipients opens a variety of new avenues with regard to the rationale design of useful dosage forms.