Precipitation Inhibitor Research Articles

In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system

In order to characterize the in situ intestinal permeability and in vivo oral bioavailability of celecoxib (CXB), a poorly water-soluble cyclooxygenase (COX)-2 inhibitor, various formulations including the self-emulsifying drug delivery system (SEDDS) and supersaturating SEDDS (S-SEDDS) were compared. The S-SEDDS formulation was obtained by adding Soluplus as a precipitation inhibitor to SEDDS, composed of Capryol 90 as oil, Tween 20 as surfactant, and Tetraglycol as cosurfactant (1:4.5:4.5 in volume ratio). An in situ single pass intestinal perfusion study in rats was performed with CXB-dissolved solutions at a concentration of 40 μg/mL. The effective permeability (Peff) of CXB in the control solution (2.5 v/v% Tween 20-containing PBS) was 6.39 × 10(-5) cm/s. The Peff value was significantly increased (P < 0.05) by the lipid-based formulation, yielding 1.5- and 2.9-fold increases for the SEDDS and S-SEDDS solutions, respectively, compared to the control solution. After oral administration of various formulations to rats at the equivalent dose of 100 mg/kg of CXB, the plasma drug level was measured by LC-MS/MS. The relative bioavailabilities of SEDDS and S-SEDDS were 263 and 355 %, respectively, compared to the CXB suspension as a reference. In particular, S-SEDDS revealed the highest Cmax and the smallest Tmax, indicating rapid and enhanced absorption with this formulation. This study illustrates the potential use of the S-SEDDS formulation in the oral delivery of poorly water-soluble compounds.

Evaluation of the Structural Determinants of Polymeric Precipitation Inhibitors Using Solvent Shift Methods and Principle Component Analysis

The presence of polymers within solid dose forms, such as solid dispersions, or liquid or semisolid formulations, such as lipid-based formulations, can promote the maintenance of drug supersaturation after dissolution or dispersion/digestion of the vehicle in the gastrointestinal tract. Transiently stable supersaturation delays precipitation, increases thermodynamic activity, and may enhance bioavailability and reduce variability in exposure. In the current study a diverse range of 42 different classes of polymers, with a total of 78 polymers across all classes, grades, and molecular weights were examined, to varying degrees, as potential polymeric precipitation inhibitors (PPIs) using a solvent shift method to initiate supersaturation. To provide a deeper understanding of the molecular determinants of polymer utility the data were also analyzed, along with a range of physicochemical descriptors of the polymers employed, using principle component analysis (PCA). Polymers were selectively tested for their ability to stabilize supersaturation for nine poorly water-soluble model drugs, representing a range of nonelectrolytes, weak acids, and weak bases. In general, the cellulose-based polymers (and in particular hydroxypropylmethyl cellulose, HPMC, and its derivatives) provided robust precipitation inhibition across most of the drugs tested. Subsequent PCA indicate that there is consistent PPI behavior of a given polymer for a given drug type, with clear clustering of the performance of polymers with each of the nonelectrolytes, weak bases, and weak acids. However, there are some exceptions to this, with some specific drug type-polymer interactions also occurring. Polymers containing primary amine functional groups should be avoided as they are prone to enhancing precipitation rates. An inverse relationship was also documented for the number of amide, carboxylic acid, and hydroxyl functional groups; therefore for general good PPI performance the number of these contained within the polymer should be minimized. Molecular weight is a poor predictor of performance, having only a minor influence, and in some cases a higher molecular weight enhances the precipitation process. The importance of ionic interactions to the ability of a PPI to stabilize the supersaturated state was demonstrated by the advantage of choosing a polymer with an opposite charge with respect to the drug. Additionally, when the polymer charge is the same as the supersaturated drug, precipitation is likely to be enhanced. A PCA model based on polymer molecular properties is presented, which has a central oval region where the polymer will general perform well across all three drug types. If the polymer is located outside of this region, then they either show compound-specific inhibition or enhance precipitation. Incomplete separation of the PPI performance based on the molecular properties on the polymers indicates that there are some further molecular properties that might improve the correlation.

Correlating the Behavior of Polymers in Solution as Precipitation Inhibitor to its Amorphous Stabilization Ability in Solid Dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.

Drug precipitation inhibitors in supersaturable formulations

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.

Hydroxypropyl Methylcellulose Mediated Precipitation Inhibition of Sirolimus: From a Screening Campaign to a Proof-of-Concept Human Study

The aim of this study was to develop a sirolimus (BCS class II drug substance) solid oral dosage form containing a precipitation inhibitor, which would result in an improved sirolimus absorption in humans compared to the formulation containing nanosized sirolimus without a precipitation inhibitor, i.e., Rapamune. The selection of the precipitation inhibitor was based on the results of a screening campaign that identified two "hit" excipients: HPMC 603 (i.e., Pharmacoat 603) and Poloxamer 407. However, in a confirmatory precipitation inhibitor study using biorelevant media (Fa/FeSSIF) HPMC 603 more effectively inhibited sirolimus precipitation than Poloxamer 407. In the PAMPA assay, HPMC 603, but not Poloxamer 407, significantly increased the flux of the sirolimus across the membrane lipid layer. Additionally, a differential scanning calorimetry (DSC) and an infrared (IR) spectroscopy study revealed that interactions between the sirolimus and HPMC 603 were developed that could lead to the observed precipitation inhibition effect. Based on the above data, two formulations with HPMC 603-coated sirolimus particles were developed, namely, formulation A (d (0.5) = 0.21 μm) and formulation B (d (0.5) = 1.7 μm). A human pharmacokinetic study outlined that significantly higher AUC and Cmax were obtained for formulations A and B in comparison to Rapamune. This result could be attributed to the HPMC 603 (Pharmacoat 603) mediated sirolimus precipitation inhibition resulting in improved sirolimus absorption from the gastrointestinal tract in humans.

The effect of a new in situ precipitation inhibitor on chemical EOR

Divalent metals cations present in injection water can significantly influence the performance of alkali–surfactant–polymer (ASP) flooding. These cations such as calcium and magnesium react with the added chemicals to form their insoluble salts as precipitations. In this paper, an in situ precipitation inhibitor known as sodium acrylate is used to overcome the precipitation problems prevalent with ASP flooding. Fluid–fluid compatibility tests were performed to examine the performance of the in situ precipitation inhibitor using hard brine having large quantity of divalent metal cations. The effect of the precipitation inhibitor on interfacial tension was also investigated using various inhibitor concentrations. The in situ precipitation inhibitor showed an excellent performance in preventing calcium and magnesium precipitations and the solutions remained clear for 45 days at 80 °C. Further, as the inhibitor concentration increased to an optimal value, an ultra-low interfacial tension of 0.04 mN/m could be achieved. The advantage of the in situ inhibitor is the use of hard brines without the need for softening the injection water.

Using droplet-based microfluidic technology to study the precipitation of a poorly water-soluble weakly basic drug upon a pH-shift

The purpose of this study is to develop a droplet-based microfluidic device capable of monitoring drug precipitation upon a shift from gastric pH (pH 1.5) to intestinal pH (pH 6.5-7.0). The extent of precipitation occurring in droplets over time was measured using a novel on-chip laser scattering technique specifically developed for this study. The precipitation of ketoconazole, a poorly water-soluble basic drug, was investigated under different concentrations and pH values. It has been shown that the drug precipitates rapidly under supersaturation. Two water-soluble aqueous polymers, namely, polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) have been evaluated as precipitation inhibitors. HPMC was shown to be the most potent precipitation inhibitor. It is envisaged that the microfluidic pH-shift method developed in this study would form a proof-of-concept study, towards the development of a high throughput method for screening pharmaceutical excipients/precipitation inhibitors.

Enhanced dissolution of celecoxib by supersaturating self-emulsifying drug delivery system (S-SEDDS) formulation

A supersaturating self-emulsifying drug delivery system (S-SEDDS) was prepared and evaluated for enhanced dissolution of celecoxib (CXB), a poorly water-soluble drug. The selected CXB-dissolved SEDDS formulation consisting 10% Capryol 90 (oil), 45% Tween 20 (surfactant), and 45% Tetraglycol (cosurfactant) had the characteristics of small droplet size and great solubility as 208nm and 556.7mg/mL in average, respectively. CXB dissolution from SEDDS in simulated gastric fluid was increased to about 20% for the initial period of 5min, but decreased to a half level as time elapsed. Thus, precipitation inhibitors were screened to stabilize the supersaturation. The stabilizing effect of Soluplus, an amphiphilic copolymer, was concentration-dependent, revealing the greatest dissolution of approximately 90% level with delayed drug crystallization by the addition of the copolymer. CXB dissolution from S-SEDDS was pH-independent. We concluded that S-SEDDS formulation would be very useful in the future for developing oral delivery product of poorly water-soluble drugs.

Technical Note: Non-Sink Dissolution Media for Identification of Functional Formulation Excipients—The Case of a Precipitation Inhibitor

INTRODUCTION Due to the abundance of dissolution methodology and media available to pharmaceutical development and quality scientists, it is advisable that method selection criteria be dictated by the purpose of the measurement. This is particularly important when dissolution is used as a tool to guide formulation design. These cases often require the use of conditions that are relevant to the in vivo situation, but most critically, they are chosen to tease out an excipient’s ability to perform its intended function. This note aims to illustrate how purposeful media selection can help probe the functionality of an excipient to be used in a solid oral dosage form of a low solubility compound. In this example, the active pharmaceutical ingredient (API) is a crystalline potassium salt of a weak acid with a pKa = 6.8, and the excipient in question is hydroxypropyl methylcellulose (HPMC). The API has relatively high solubility, 71 mg/ mL in water or at a pH > pKa, which drops to 0.01 mg/ mL (the equilibrium solubility of the protonated free form measured more than 24 h after the crystalline salt was introduced in aqueous medium) at pH < 6.8, the pH expected in the gastrointestinal (GI) tract (1). The HPMC excipient was chosen for its potential ability to act as an antinucleating agent (2), inhibit precipitation of the drug at a pH < pKa, and induce super saturation, thus enhancing in vivo solubility and absorption. To assess the utility of the excipient for an oral dosage form, in vitro dissolution of the neat API is carried out under non-sink conditions, at a pH < pKa and a dose-relevant concentration, in the presence and absence of HPMC. Next, dissolution of the formulated API is carried out under non-sink conditions, over a pH range that is GI relevant, at dose-relevant concentrations. Subsequently, preclinical models are used to assess further the in vivo utility of the HPMC excipient before defining a formulation for human trials. A range of drug and excipient concentrations may be explored in vitro depending on predicted clinical doses and dosage form considerations, respectively. Two examples of in vitro measurements of neat and formulated API are presented below.

The Application of Acrylic Acid as Precipitation Inhibitor for ASP Flooding

Alkaline-Surfactant-Polymer (ASP) flooding has shown incredible successes for enhancing oil recovery for both sandstone and carbonate reservoirs. However, the main constraint of ASP flooding in carbonate reservoirs is the presence of undesired minerals either within the reservoir rock or reservoir brine. These minerals could react with the added chemicals to form their insoluble salts as precipitations. In this paper, the performance of the acrylic acid was evaluated in the presence of sodium metaborate as an alkaline, alpha olefin sulfonate as a surfactant and AN-125 SH as a polymer. The effect of various acrylic acid concentrations on alkalinity, interfacial tension reduction and polymer viscosity were investigated using hard brine with a total salinity of 59,940 ppm. Fluid-fluid compatibility test indicates that acrylic acid has the potential to prevent any precipitation when hard brine is used. The acrylic acid to alkali ratio of 0.6:1 was found to be the optimum ratio for keeping the solution without precipitations for 30 days at 80oC. It was also observed that the combination of ASP with acrylic acid has a positive effect on interfacial tension and solution viscosity. This makes the new system more flexible for offshore application in which hard brine or sea water could be used to prepare ASP slug without any negative effects.

TECHNIQUES FOR SOLUBILITY ENHANCEMENT OF POORLY SOLUBLE DRUGS: AN OVERVIEW

A success of formulation depends on how efficiently it makes the drug available at the site of action. Solubility is the phenomenon of dissolution of solid in liquid phase to give a homogenous system. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects for drugs. This is true for parenterally, topically and orally administered solutions. Hence various techniques are used for the improvement of the solubility of poorly water soluble drugs include hydrotrophy, use of salt form, use of precipitation inhibitors, alteration of pH of the drug micro-environment, solvent deposition, precipitation pH adjustment, co-solvency, micellar solubilization, super critical fluid techniques, solid dispersion, complexation, micro-emulsion, solid solution, eutectic mixture, selective adsorption on insoluble carriers, evaporative precipitation into aqueous solution, use of surfactants, use of amorphous, anhydrates, solvates and nanonisation

Evaluation of a High-Throughput Screening Method for the Detection of the Excipient-Mediated Precipitation Inhibition of Poorly Soluble Drugs

The objective of the present study was to develop and evaluate a high-throughput (HT) precipitation inhibitor screening method that can be used for the identification of the excipient-mediated precipitation inhibition of poorly soluble drugs. The impact of incubation temperature, shaking intensity, phase separation, inter- and intraday variability, cosolvent, and plate selection on the HT screening method performance was investigated. Additionally, the pipetting quality of the automated workstation, the correlation with the classical laboratory approach, and the practical implementation of the developed HT screening method using two model compounds are disclosed. Investigation of the HT method resulted in optimized experimental conditions, which showed low inter- and intraday variability (relative standard deviation [RSD]<5.88%). Higher shaking intensity (7 Hz) and incubation temperature (37°C) resulted in a lower likelihood of obtaining false-negative results. The acceptable dimethyl sulfoxide concentration in the precipitation inhibitor screening assay was set to ≤1% (v/v). All liquid dispensing steps resulted in an RSD of <3.4%, and an excellent correlation (R(2)=0.96, P<0.01) with the classical laboratory method was obtained. The practical implementation of the developed HT method was demonstrated by investigating the impact of 23 diverse excipients on the precipitation inhibition of two poorly soluble drugs (fenofibrate and carbamazepine). The screen resulted in the identification of hit excipients, which were not identical for fenofibrate and carbamazepine. This outcome emphasized that the HT screening approach is a reasonable starting point for searching for effective precipitation inhibitors, especially because the excipient-mediated precipitation inhibition effect is case specific and cannot be predicted in a straightforward manner.

Enhanced dissolution performance of curcumin with the use of supersaturatable formulations

The goal of this research was to employ formulation strategies to develop supersaturatable formulations for curcumin, a poorly water-soluble drug to improve the in vitro dissolution performance. Self-emulsifying lipid-based formulations and hydrophilic carrier formulations with polymeric precipitation inhibitors were designed to achieve supersaturation upon dilution. In vitro dissolution of curcumin from each formulation was performed, in addition to assessment of the utility of polymers such as polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC) as precipitation inhibitors. For the hydrophilic solvent formulation, it was observed that the presence of 10% w/w polymer results in curcumin concentrations almost 100-fold greater compared to the formulation without the polymer. Incorporation of polymer in the SEDDS formulation results in a supersaturated solution of curcumin with concentrations identical to the theoretical starting dose. The high drug concentrations were sustained for 3 h as compared to the self-emulsifying formulation without the polymer. The low dissolution of curcumin in the neat hydrophilic solvent and self-emulsifying formulation is attributed to the uncontrolled precipitation of the drug upon mixing with the dissolution media, which is a result of formation of an unstable supersaturated solution. Upon relative assessment, the rank order in which the polymers inhibited precipitation was PVP-K30 < PVP-K90 < HPMC.

Drug precipitation–permeation interplay: Supersaturation in an absorptive environment

PurposeThe present study investigated the interplay between supersaturation, absorption, precipitation, and excipient-mediated precipitation inhibition by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment. Loviride and HPMC-E5 were selected as poorly soluble model drug and precipitation inhibitor, respectively. MethodTo investigate supersaturation in an absorptive environment, supersaturation was induced at different degrees (DS), using a solvent shift method, in shaken Caco-2 Transwell® inserts containing fasted state simulated intestinal fluid (FaSSIF); to simulate a non-absorption environment, the inserts were parafilm-sealed and did not contain a cell monolayer. Donor and acceptor compartments were sampled as a function of time to determine precipitation kinetics and transport, respectively. ResultsIn absence of precipitation, loviride transport increased proportionally with the initial DS; however, precipitation limited the supersaturation-induced transport enhancement. Loviride precipitation was found to be less extensive in an absorption environment compared to a non-absorption environment. As a result, the optimal DS obtained in a non-absorption environment (highest amount maintained in solution) did not correlate with the highest transport in an absorption environment. In addition, the impact of HPMC-E5 on loviride transport was inferior to its precipitation inhibitory capacity observed in a non-absorption environment. ConclusionFor the first time, the present study explicitly demonstrated that implementation of permeation in precipitation assays is critical to predict the impact of supersaturation, precipitation, and precipitation inhibition on the absorption of poorly soluble drugs.

Characterization of Supersaturatable Formulations for Improved Absorption of Poorly Soluble Drugs

With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum. This is intended to design the formulation to yield significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and thus to enhance the intestinal absorption. The major challenges faced by scientists developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. This review is intended to cover publications on this topic since April 2009. Scientific publications associated with characterization of supersaturatable systems and related preclinical and clinical pharmacokinetics (PK) studies are reviewed. Specifically, this review will address issues related to assessing the performance of supersaturatable systems including: (1) Diversified approaches for developing supersaturatable formulations, (2) meaningful in vitro test methods to evaluate supersaturatable formulations, and (3) in vivo PK study cases which have demonstrated direct relevance between the supersaturation state and the exposure observed in animal models and human subjects.

Lipid Digestion as a Trigger for Supersaturation: Evaluation of the Impact of Supersaturation Stabilization on the in Vitro and in Vivo Performance of Self-Emulsifying Drug Delivery Systems

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S(M)DIGEST). The ability of the formulation to maintain solubilization in vitro decreased as the S(M) of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where S(M)DISP < 3.5 and S(M)DIGEST < 4. In the presence of polymer, some degree of supersaturation was maintained up to S(M)DIGEST ∼ 8. Differentiation in the ability of SEDDS to maintain drug solubilization stems from the ability to stabilize supersaturation and for MC SEDDS, utilization of lower drug loads, higher surfactant levels (balanced against increases in S(M)DISP), lower cosolvent and the addition of PPI enhanced formulation performance. In vivo studies confirmed the ability of PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation). At higher drug loads (80% saturation) and in lipid-free SEDDS, this effect was lost, suggesting that the ability of PPIs to stabilize supersaturation in vitro may, under some circumstances, overestimate utility in vivo.

Synthesis of Monolithic Hierarchically Porous Iron-Based Xerogels from Iron(III) Salts via an Epoxide-Mediated Sol–Gel Process

Various iron-based polycrystalline monoliths, Fe3O4, iron, and Fe3C, with hierarchically distributed pores have been synthesized from ionic precursors using a sol–gel process accompanied by phase separation. Propylene oxide acts as a proton scavenger to increase pH moderately and uniformly in a reaction solution, which leads to homogeneous gelation. On the other hand, poly(acrylamide) works as a phase separation inducer as well as a precipitation inhibitor. Appropriate choice of iron precursor, solvent, polymer, and epoxide allowed the formation of iron(III)-based xerogels with cocontinuous macroporous structures. The dried gels were amorphous, whereas heating in air above 300 °C led to the formation of α-Fe2O3. Calcination under an inert condition above 400 °C formed Fe3O4, iron, and Fe3C without collapse of macrostructures. Examination has been carried out using SEM, TG-DTA, FT-IR, Hg intrusion, pH measurement, X-ray diffraction, and N2 adsorption–desorption.

Enhanced Bioavailability of a Poorly Water-Soluble Weakly Basic Compound Using a Combination Approach of Solubilization Agents and Precipitation Inhibitors: A Case Study

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.

Green Amorphous Nanoplex as a New Supersaturating Drug Delivery System

The nanoscale formulation of amorphous drugs represents a highly viable supersaturating drug-delivery system for enhancing the bioavailability of poorly soluble drugs. Herein we present a new formulation of a nanoscale amorphous drug in the form of a drug-polyelectrolyte nanoparticle complex (or nanoplex), where the nanoplex is held together by the combination of a drug-polyelectrolyte electrostatic interaction and an interdrug hydrophobic interaction. The nanoplex is prepared by a truly simple, green process that involves the ambient mixing of drug and polyelectrolyte (PE) solutions in the presence of salt. Nanoplexes of poorly soluble acidic (i.e., ibuprofen and curcumin) and basic (i.e., ciprofloxacin) drugs are successfully prepared using biocompatible poly(allylamine hydrochloride) and dextran sulfate as the PE, respectively. The roles of salt, drug, and PE in nanoplex formation are examined from ternary phase diagrams of the drug-PE complex, from which the importance of the drug's charge density and hydrophobicity, as well as the PE ionization at different pH values, is recognized. Under the optimal conditions, the three nanoplexes exhibit high drug loadings of ~80-85% owing to the high drug complexation efficiency (~90-96%), which is achieved by keeping the feed charge ratio of the drug to PE below unity (i.e., excess PE). The nanoplex sizes are ~300-500 nm depending on the drug hydrophobicity. The nanoplex powders remain amorphous after 1 month of storage, indicating the high stability owed to the PE's high glass-transition temperature. FT-IR analysis shows that functional groups of the drug are conserved upon complexation. The nanoplexes are capable of generating prolonged supersaturation upon dissolution with precipitation inhibitors. The supersaturation level depends on the saturation solubility of the native drugs, where the lower the saturation solubility, the higher the supersaturation level. The solubility of curcumin as the least-soluble drug is magnified 9-fold upon its transformation to the nanoplex, and the supersaturated condition is maintained for 5 h.

Evaluation of Carbamazepine (CBZ) Supersaturatable Self-Microemulsifying (S-SMEDDS) Formulation In-vitro and In-vivo.

The supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) represents a new thermodynamically stable formulation approach wherein it is designed to contain a reduced amount of surfactant and a water-soluble polymer (precipitation inhibitor or supersaturated promoter) to prevent precipitation of the drug by generating and maintaining a supersaturated state in-vivo. The supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) of CBZ was evaluated in-vitro and in-vivo. Three different formulations of CBZ were prepared and drug precipitation behavior, dissolution rate in-vitro and particle size distribution were evaluated. Studies on CaCO-2 permeability of three formulations were also carried out. Pharmacokinetic studies were conducted in beagle dogs with administration dose of 200mg to assess bioavailability in-vivo compared with commercial tablet. The results showed that the presence of a small amount of polymeric precipitation inhibitor (PVP) effectively sustained supersaturated state by retarding precipitation kinetics. The mean particle size after dispersion was about 33.7 nm and the release rate from S-SMEDDS was significantly higher than the commercial tablet in-vitro. S-SMEDDS formulation with precipitation inhibitor decreased impairment to cells due to a lower surfactant level compared to SMEDDS. The absorption of S-SMEDDS in-vivo resulted in about 5-fold increase in bioavailability compared with the commercial tablet and the reproducibility of plasma concentration profiles intra-individual was improved remarkably. This study demonstrates that S-SMEDDS technology provide an effective approach for improving the extent of absorption of poorly-soluble drugs with low level of surfactant.