Lipid-based systems with precipitation inhibitors as formulation approach to improve the drug bioavailability and/or lower its dose: a review.

Lipid-based systems, such as self-microemulsifying systems (SMEDDS) are attracting strong attention as a formulation approach to improve the bioavailability of poorly water-soluble drugs. By applying the "spring and parachute" strategy in designing supersaturable SMEDDS, it is possible to maintain the drug in the supersaturated state long enough to allow absorption of the complete dose, thus improving the drug's bio-availability. As such an approach allows the incorporation of larger amounts of the drug in equal or even lower volumes of SMEDDS, it also enables the production of smaller final dosage forms as well as decreased gastrointestinal irritation, being of particular importance when formulating dosage forms for children or the elderly. In this review, the technological approaches used to prolong the drug supersaturation are discussed regarding the type and concentration of polymers used in liquid and solid SMEDDS formulation. The addition of hypromellose derivatives, vinyl polymers, polyethylene glycol, polyoxyethylene, or polymetacrylate copolymers proved to be effective in inhibiting drug precipitation. Regarding the available literature, hypromellose has been the most commonly used polymeric precipitation inhibitor, added in a concentration of 5 % (m/m). However, the inhibiting ability is mainly governed not only by the physicochemical properties of the polymer but also by the API, therefore the choice of optimal precipitation inhibitor is recommended to be evaluated on an individual basis.

Supersaturation Behavior: Investigation of Polymers Impact on Nucleation Kinetic Profile for Rationalizing the Polymeric Precipitation Inhibitors.

BACKGROUND: Although nucleation kinetic data is quite important for the concept of supersaturation behavior, its part in rationalizing the crystallization inhibitor has not been well understood. OBJECTIVE: This study aimed to investigate the nucleation kinetic profile of Dextromethorphan HBr (as an ideal drug, BCS-II) by measuring liquid-liquid phase segregation, nucleation induction time, and Metastable Zone width. METHODS: Surfeit action was examined by a superfluity assay of the drug. The concentration was scrutinized by light scattering techniques (UV spectrum (novel method) and Fluorometer (CL 53)). RESULTS: The drug induction time was 20 min without polymer and 90 and 110 min with polymers, such as HPMC K15M and Xanthan Gum, respectively. Therefore, the order of the polymer's ability to inhibit nucleation was Xanthan Gum > HPMC K15M in the medium (7.4 pH). Similarly, the drug induction time was 30 min without polymer and 20, 110, and 90 min with polymers, such as Sodium CMC, HPMC K15M, and Xanthan Gum, respectively. Therefore, the order of the polymer's ability to inhibit nucleation was HPMC K15M > Xanthan Gum > Sodium CMC in SIFsp (6.8 pH), which synchronizes the polymer's potentiality to interdict the drug precipitation. CONCLUSION: The HPMC K15M and xanthan Gum showed the best crystallization inhibitor effect for the maintenance of superfluity conditions till the drug absorption time. The xanthan gum is based on the "glider" concept, and this shows the novelty of this preliminary research. The screening methodology used for rationalizing the best polymers used in the superfluity formulations development successfully.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.

Critical Strategies for Drug Precipitation Inhibition: A Review with the Focus on Poorly Soluble Drugs.

An oral route for drug administration is a more suitable route because of its ease of administration, pain avoidance, patient compliance, accommodation of various types of drug molecules, etc. But there are many factors affecting the oral absorption of the drugs. The main factor associated with oral absorption is drug solubility. Many new chemical molecules are poorly soluble in nature and can be included in BCS classes II and IV. For the administration of these drugs through the oral route, it was found that solubility is the rate limiting step. The low solubility of these drugs tends to cause precipitation in the gastrointestinaltract (GIT), affecting their bioavailability. Drug precipitation may be triggered by many factors such as insolubility of the drug in co-solvent, drug-excipient interactions, physiochemical properties of the drug, sudden change in the pH of the environment, incompatibility with the surfactant, etc. Precipitation of a drug may occur in two stages, formation of nucleation and crystal growth. To overcome precipitation, there are many strategies such as the use of polymers, the addition of surfactants, modulating drug loading and solubilizing capacity, change in the pH of the environment, etc. In this review, the causes of precipitation and diverse strategies of precipitation inhibition are critically reviewed.

Development of an enhanced formulation to minimize pharmacokinetic variabilities of a weakly basic drug compound.

Formulating poorly water soluble, weakly basic drugs with consistent exposure is often a challenge due to pH-dependent solubility. When the oral formulation is exposed to different pH ranges in the gastrointestinal (GI) tract, drug precipitation, or incomplete dissolution may occur resulting in decreased drug absorption and higher intra- and inter-patient pharmacokinetic (PK) variabilities. In the present study, a series of enhanced formulations containing organic acids and/or surfactants were developed and compared with conventional formulations with respect to their in vitro dissolution performance. The formulation containing 5% citric acid and 1% sodium lauryl sulfate (SLS) showed much less variations in dissolution performance at different pH conditions than a conventional formulation. The combination of citric acid and SLS demonstrated a synergistic effect as compared to use of citric acid alone or in combination with PEG4000 as a precipitation inhibitor. When compared with a conventional formulation and a spray-dried amorphous solid dispersion (ASD) formulation in a dog PK study, the enhanced formulation demonstrated the least AUC and Cmax variability between the two gastric pH-controlled groups. In conclusion, an enhanced formulation using a combination of organic acid and surfactant is recommended for weakly basic drug compounds to minimize drug PK variabilities in clinical studies.

Eutectic mixture and amorphous solid dispersion: Two different supersaturating drug delivery system strategies to improve griseofulvin release using saccharin.

This study evaluated the ability of different sweeteners to improve dissolution and to form and stabilize supersaturated solutions of griseofulvin (GSF), comparing a eutectic mixture and amorphous formulations. Among the sweeteners tested, only saccharin (SAC) was able to delay drug precipitation in buffer (area under the curve (AUC) increase of 40%) and in fasted state simulated intestinal Fluid (FaSSIF, AUC increase of 20%) compared to pure media. GSF solubility was not affected by the presence of isomalt (ISO), maltitol (MALT) and SAC in buffer pH 6.5 but was reduced in FaSSIF. The quenched cooled amorphous formulation GSF-SAC QC -with the carrier that forms a eutectic mixture with GSF -provided higher drug release in buffer than amorphous formulations with ISO and MALT. In FaSSIF, SAC slightly changed the microenvironment's hydrophobicity (observed in fluorescence studies) and both its amorphous formulation (GSF-SAC QC) and its eutectic mixture (GSF-SAC EM) dissolved at concentrations above drug solubility, achieving supersaturation ratio (SR, Eq. (1)) of 4.14 and 3.15, respectively. The main finding of this study was that for the first time a eutectic mixture acted as a supersaturating drug delivery system, emphasizing the importance of investigating EMs during preformulation studies of fast-crystallizing poorly water-soluble drugs.

Explicating the molecular level drug-polymer interactions at the interface of supersaturated solution of the model drug: Albendazole.

Supersaturation as a formulation principle relates to the aqueous solubility of poorly soluble drugs in solution . However, supersaturation state of drugs tends to crystallize because of its thermodynamic instability thereby compromising the solubility and biopharmaceutical performance of drugs. The present study aims to investigate the supersaturation potential of albendazole (ABZ) and its precipitation via nucleation and crystal growth. We hypothesized the use of polymers will avoid ABZ precipitation by interacting with drug molecules. The drug polymer interactions are characterized using conventional methods of Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR) and Polarized light microscopy (PLM). We have used a novel approach of sum frequency generation (SFG) vibrational spectroscopic in exploring the drug polymer interactions at air-water interface. Recently we have reported the SFG for e rifaximin-polymer interactions (Singh et al., 2021). The supersaturation assay, saturation solubility studies and nucleation induction time analysis revealed polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP K30) as effective precipitation inhibitors thereby enhancing the ABZ equilibrium solubility and in vitro supersaturation maintenance of ABZ. Further, modification in the solid state of ABZ has confirmed the influence of polymers on its precipitation behaviour. We conclude that PVA and PVP K30 act as nucleation and crystal growth inhibitor, respectively for the precipitation inhibition of ABZ.

Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems.

Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.

Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift.

Simple solvent shift is often used to induce supersaturation and investigate precipitation kinetics in early drug development as a substitute for amorphous dissolution. This study develops and compares a small-scale non-sink amorphous dissolution method to a solvent shift method as induction methods for supersaturation of the model drugs albendazole, felodipine and tadalafil with respect to the maximum dissolved drug concentration, and the solid form of the precipitate. The study also investigates the effect of pre-dispersed precipitation inhibitors (hydroxypropyl methyl cellulose (HPMC) or polyvinylpyrrolidone (PVP)) on tadalafil supersaturation induced by both amorphous dissolution and solvent shift with respect to maximum dissolved drug concentration, precipitation rate and solid form of the precipitate. The maximum drug concentrations achieved through solvent shift were 15.9, 208 and 108 µg/mL for albendazole, felodipine and tadalafil, respectively. Pre-dispersing 0.1% (w/v) HPMC or PVP, increased the maximum concentration by solvent shift of tadalafil to 180 µg/mL, for both polymers. Dissolution of up to 90 mg albendazole, 120 mg felodipine and 8.9 mg tadalafil could yield a maximum dissolved drug concentration of 76.1%, 87.9% and 102.5%, respectively, of the corresponding solvent shift maximum concentration. The maximum concentration achieved through amorphous dissolution of tadalafil with HPMC or PVP present in the dissolution medium was 87.1% and 88.7%, respectively of the solvent shift maximum concentration. Dissolution of 2 mg amorphous tadalafil with and without pre-dispersed polymer gave the same rank order of onset of precipitation as for the solvent shift method. The solid form of precipitate was the same for albendazole, felodipine, tadalafil and tadalafil with PVP for both methods. For tadalafil with HPMC, the precipitate was amorphous following solvent shift, but crystalline after amorphous dissolution. Overall, this study shows that the maximum concentration achievable through amorphous dissolution can be estimated when performing solvent shift and the precipitation inhibition of excipients assessed via solvent shift can be used to predict the effect on precipitation using amorphous dissolution.

The Opposed Effects of Polyvinylpyrrolidone K30 on Dissolution and Precipitation for Indomethacin Supersaturating Drug Delivery Systems.

Amorphous solid dispersions (ASD) are one of the most important supersaturating drug delivery systems (SDDS) for poorly water-soluble drugs to improve their bioavailability. As a result of thermodynamic instability, drug molecules tend to precipitate during storage and dissolution in gastrointestinal tract. Various precipitation inhibitors (PI) have been widely used to improve the stability in the past decade. However, most studies have investigated the inhibiting capability of PI on drug precipitation, rarely considering their potential hindering effect on the drug dissolution. The present study designed an ASD of Indomethacin (IND) and Eudragit® EPO by hot melt extrusion to investigate the influence of the added PI (PVP-K30) into ASD both on dissolution and precipitation. The precipitation study by solvent shift method indicated PVP-K30 could inhibit the precipitation of IND significantly. The dissolution study in different concentrations of PVP-K30 showed when the concentration increased above 50 µg/mL, PVP-K30 displayed an acceptable precipitation inhibition without drug concentration decline but an unexpected dissolution impediment with the reduction of maximum concentration platform. The dissolution tests of physical mixtures (PMs) of ASD and PVP-K30 also showed the precipitation inhibition and dissolution impediment when more than 2% PVP-K30 in PMs. This opposed effect of PVP-K30 was strengthen in ternary systems prepared by hot melt extruding the mixtures of IND, Eudragit® EPO and PVP-K30. All of these results proved the PI may be a double-edged sword for the opposed effects of precipitation inhibition and dissolution impediment, which should be carefully considered in the design and development of SDDS.

Classification of the crystallization tendency of active pharmaceutical ingredients (APIs) and nutraceuticals based on their nucleation and crystal growth behaviour in solution state.

Supersaturated drug delivery systems are commonly used to address the problems of poor aqueous solubility posed by most of the active pharmaceutical ingredients (APIs). However, the supersaturated systems are highly unstable due to their high free energy levels and demonstrate a tendency to precipitate. Understanding the crystallization tendency based on the mechanisms of crystallization, that is nucleation and crystal growth, is imperative to design formulation strategies and select appropriate precipitation inhibitors. This study aims to provide a classification system, based on both the nucleation and crystal growth tendency in the solution state of 60 APIs and nutraceuticals (in absence of polymer) from their desupersaturation profiles monitored by UV-Visible spectroscopy. The APIs and nutraceuticals are divided into four classes based on their induction time (tind) and crystal growth rate as fast nucleators-fast crystal growth (class I), fast nucleators-slow crystal growth (class II), slow nucleators-fast crystal growth (class III) and slow nucleators-slow crystal growth (class IV). Most of the molecules fall in the class I and class IV. An easy-to-use protocol for nucleation and crystal growth studies has been optimized. This protocol will find application to assess the crystallization tendency of the molecules in the preliminary screening stages, enabling appropriate formulation strategies to inhibit crystallization.

Improving the drug load and in vitro performance of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) using polymeric precipitation inhibitors.

In this study, the influence of the polymeric precipitation inhibitor (PPI) PVP/VA 64 (polyvinylpyrrolidone-co-vinyl acetate) on the physical stability and in vitro performance of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) containing the model drug simvastatin (SIM) was investigated. A heating-cooling cycle was employed to dissolve (i) the drug in the SNEDDS preconcentrate, generating super-SNEDDS, or (ii) the drug and PPI generating PPI super-SNEDDS, both containing drug loads of 200% and 250% (with regard to the equilibrium solubility of SIM in the blank SNEDDS). PPI super-SNEDDS were prepared at PPI concentrations of 1%, 10% and 20% (w/w), respectively. The formulations were characterized using polarized light microscopy, dynamic light scattering, rheological profiling and dynamic in vitro lipolysis. The physical stability of PPI super-SNEDDS correlated with an increase in viscosity due to the additionally dissolved PVP/VA 64. PPI super-SNEDDS with drug loads of 200% and 250% containing 20% (w/w) PPI showed no drug recrystallization after more than 6 months of storage at room temperature, whereas PPI-free super-SNEDDS (250% drug load) recrystallized within two hours after equilibration to room temperature. All formulations formed nanosized droplets after emulsification in Milli-Q water. The droplet size was not affected by the PPI, but increased slightly with increasing drug load (z-average of 47.3 ± 0.4 nm for SNEDDS with 200% drug load and 55.6 ± 1.3 nm for SNEDDS with 250% drug load). PPI super-SNEDDS with a drug load of 200% containing 20% (w/w) PVP/VA 64 showed an improved performance during dynamic in vitro lipolysis, maintaining a 2.5-fold higher degree of supersaturation after 15 min of digestion compared to PPI-free super-SNEDDS of the same drug load. In conclusion, the study demonstrated the feasibility of stabilizing higher drug loads and improving the in vitro performance of super-SNEDDS by incorporating PVP/VA 64 into the preconcentrate.

Polymeric precipitation inhibitor as an effective trigger to convert supersaturated into supersaturable state in vivo.

The supersaturated state of the drug in vivo is thermodynamically unstable resulting in a delayed response and reduced efficacy. The use of polymeric precipitation inhibitor (PPI) has been demonstrated as an effective trigger for the conversion of supersaturated state to supersaturable state for improving solubilization, thermodynamic maintenance of drug concentration and oral absorption of poorly water-soluble compounds. PPI retards drug precipitation and provides a kinetically stabilized supersaturation state for an extended period in gastric and intestinal fluids. However, the selection of appropriate PPI and understanding its mechanism is a challenge for formulating a stable pharmaceutical formulation. The present review is aimed at understanding the intricacies of selecting PPIs and their applications in pharmaceutical formulations.

Application of an automated small-scale in vitro transfer model to predict in vivo precipitation inhibition.

The majority of NCEs are weakly basic drugs. Consequently, their solubility is highly pH-dependent, with higher solubility in the acidic stomach and poor solubility in the neutral intestinal environment. The gastric emptying of dissolved drug can lead to the intestinal precipitation of the drug. One option of reducing this process is to formulate the drug together with a precipitation inhibitor (PI). The aim of this study was to investigate the effects of different PIs on the intestinal concentrations of ketoconazole and five orally administered kinase inhibitors (i.e. pazopanib, gefitinib, lapatinib, vemurafenib, and a Merck KGaA research compound, MSC-A) with the aid of a predictive small-scale in vitro transfer model. This screening revealed that HPMCAS and Soluplus® were the most effective PIs. Whereas all other drugs precipitated within several minutes, gefitinib expressed highly variable amorphous precipitation which was confirmed by PXRD. During the transfer model experiments, this intermediate supersaturated state was stabilized using HPMCAS and Soluplus®. The PI screening protocol described herein allows to study the effect of PIs for solubility and potential bioavailability improvement of poorly soluble drugs to support formulation development already in early stages.

Enhancing oral bioavailability of poorly soluble drugs with mesoporous silica based systems: opportunities and challenges.

Porous silica-based drug delivery systems have shown considerable promise for improving the oral delivery of poorly water-soluble drugs. More specifically, micro- and meso-porous silica carriers have high surface areas with associated ability to physically adsorb high-drug loads in a molecular or amorphous form; this allows molecular state drug release in aqueous gastrointestinal environments, potential for supersaturation, and hence facilitates enhanced absorption and increased bioavailability. This review focuses primarily on the ability of porous silica materials to modulate in vitro drug release and enhance in vivo biopharmaceutical performance. The key considerations identified and addressed are the physicochemical properties of the porous silica materials (e.g. the particle and pore size, shape, and surface chemistry), drug specific properties (e.g. pKa, solubility, and nature of interactions with the silica carrier), potential for both immediate and controlled release, drug release mechanisms, potential for surface functionalization and inclusion of precipitation inhibitors, and importance of utilizing relevant and effective in vitro dissolution methods with discriminating dissolution media that provides guidance for in vivo outcomes (i.e. IVIVC).

Intestinal mucus is capable of stabilizing supersaturation of poorly water-soluble drugs.

The utilization of polymers to stabilize drug supersaturation and enhance oral drug absorption has recently garnered considerable interest. The potential role of intestinal mucus in stabilizing drug supersaturation, however, has not been previously explored. The ability for intestinal mucus to stabilize drug supersaturation and delay drug precipitation is potentially useful in enhancing the absorption of orally dosed compounds from drug delivery systems that generate supersaturation within the gastrointestinal tract (e.g., solid dispersions, lipid-based drug delivery systems). This work aims to evaluate the precipitation-delaying abilities of intestinal mucus using carvedilol (CVDL) and piroxicam (PXM) as model drugs. In supersaturation-precipitation (S-P) experiments, CVDL and PXM supersaturation were induced in test media (0, 0.1, 0.2, 0.4%w/v mucin and 8%w/v native pig intestinal mucus (PIM)) via the solvent-shift method at supersaturation ratios (SSR) of 5 and 6, respectively. Time to drug precipitation was assessed using ion-selective electrodes and HPLC. The S-P experiments showed that increasing mucin concentration led to increasingly delayed CVDL precipitation, while PXM precipitation was prevented at all mucin concentrations studied. The ability of mucus-stabilized CVDL supersaturation to translate into enhanced CVDL absorption was evaluated in transport experiments using mucus-producing (90% Caco-2:10% HT29-MTX-E12 co-cultures) vs. non-mucus-producing intestinal monolayers (100% Caco-2 cultures). The absorption enhancement of CVDL (SSR = 5 relative to SSR = 1) was higher across mucus-producing than non-mucus-producing intestinal monolayers. This work demonstrates the potential for intestinal mucus to delay the precipitation and enhance the absorption of poorly water-soluble compounds, suggesting that drug supersaturation can be stabilized in close proximity to the absorptive site, thereby presenting a possible novel approach for targeted supersaturating drug delivery systems.

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation.

The ability of lipid-based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastrointestinal (GI) fluids has generated significant interest in the past decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs) to the formulation. In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid-soluble polymers Eudragit (EU) RL100 and poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water-soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure, and a good correlation was found between the degree of in vitro supersaturation and in vivo drug exposure. An improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors.

Poor water solubility is a bottle neck in the development of many new drug candidates, and understanding and circumventing this is essential for a more effective drug development. Zafirlukast (ZA) is a leukotriene antagonist marketed for the treatment of asthma (Accolate®). ZA is poorly water soluble, and is formulated in an amorphous form (aZA) to improve its solubility and oral bioavailability. It has been shown that upon dissolution of aZa, the concentration of ZA in solution is supersaturated with respect to its stable crystalline form (ZA monohydrate), and thus, in theory, the bioavailability increases upon amorphization of ZA. The polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), often used as stabilizers of the supersaturated state, are in the excipient list of Accolate®. It is not recommended to take Accolate® with food, as this reduces the bioavailability by 40%. The aim of this study was to investigate the effect of simulated fasted and fed state intestinal media as well as the effect of HPMC and PVP on the supersaturation and precipitation of ZA in vitro. Supersaturation of aZA was studied in vitro in a small scale setup using the µDiss Profiler™. Several media were used for this study: One medium simulating the fasted state intestinal fluids and three media simulating different fed state intestinal fluids. Solid state changes of the drug were investigated by small angle x-ray scattering. The duration wherein aZA was maintained at a supersaturated state was prolonged in the presence of HPMC and lasted more than 20h in the presence of PVP in a fasted state intestinal medium. The presence of PVP increased the concentration of drug dissolved in the supersaturated state. The duration of supersaturation was shorter in fed than in a fasted state simulated intestinal media, but the concentration during supersaturation was higher. It was thus not possible to predict any positive or negative food effects from the dissolution/precipitation curves from different media. Lipolysis products in the fed state simulated media seemed to cause both a negative effect on the duration of supersaturation, and an increased drug concentration during supersaturation. In contrast, when testing the effect of a fed state simulated medium compared to the fasted state medium, in the presence of PVP, a clear negative effect was seen on the dissolution/precipitation curved of the fed state medium. The drug concentration during supersaturation was marginally different in the two media, but a precipitation of ZA was seen in the fed state medium, which was not observed in the fasted state medium. Solid state transformation from aZA to ZA monohydrate (mhZA) upon precipitation of the supersaturated solutions was confirmed by small angle x-ray scattering. All of these results can explain the described in vivo behavior of ZA. For ZA simple dissolution experiments in vitro can be used to examine supersaturation, effectiveness of PI and potential food effects on these.

Self-microemulsifying drug delivery system (SMEDDS)--challenges and road ahead.

Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.

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.