Polymeric Precipitation Inhibitor Research Articles

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.

A study of hydrophobic domain formation of polymeric drug precipitation inhibitors in aqueous solution

Despite the widespread use of polymers as precipitation inhibitors in supersaturating drug formulations, the current understanding of their mechanisms of action is still incomplete. Specifically, the role of hydrophobic drug interactions with polymers by considering possible supramolecular conformations in aqueous dispersion is an interesting topic. Accordingly, this study investigated the tendency of polymers to create hydrophobic domains, where lipophilic compounds may nest to support drug solubilisation and supersaturation. Fluorescence spectroscopy with the environment-sensitive probe pyrene was compared with atomistic molecular dynamics simulations of the model drug fenofibrate (FENO). Subsequently, kinetic drug supersaturation and thermodynamic solubility experiments were conducted. As a result, the different polymers showed hydrophobic domain formation to a varying degree and the molecular simulations supported interpretation of fluorescence spectroscopy data. Molecular insights were gained into the conformational structure of how the polymers interacted with FENO in solution phase, which apart from nucleation and crystal growth effects, determined drug concentrations in solution. Notable was that even at the lowest polymer concentration of 0.01 %, w/v, there were polymer-specific solubilisation effects of FENO observed and the resulting reduction in apparent drug supersaturation provided relevant knowledge both from a mechanistic and practical perspective.

Development and characterization of solid lipid-based formulations (sLBFs) of ritonavir utilizing a lipolysis and permeation assay

As a high number of active pharmaceutical ingredients (APIs) under development belong to BCS classes II and IV, the need for improving bioavailability is critical. A powerful approach is the use of lipid-based formulations (LBFs) that usually consist of a combination of liquid lipids, cosolvents, and surfactants. In this study, ritonavir loaded solid LBFs (sLBFs) were prepared using solid lipid excipients to investigate whether sLBFs are also capable of improving solubility and permeability. Additionally, the influence of polymeric precipitation inhibitors (PVP-VA and HPMC-AS) on lipolysis triggered supersaturation and precipitation was investigated. One step intestinal digestion and bicompartmental permeation studies using an artificial lecithin-in-dodecane (LiDo) membrane were performed for each formulation. All formulations presented significantly higher solubility (5 to >20-fold higher) during lipolysis and permeation studies compared to pure ritonavir. In the combined lipolysis-permeation studies, the formulated ritonavir concentration increased 15-fold in the donor compartment and the flux increased up to 71 % as compared to non-formulated ritonavir. The formulation with the highest surfactant concentration showed significantly higher ritonavir solubility compared to the formulation with the highest amount of lipids. However, the precipitation rates were comparable. The addition of precipitation inhibitors did not influence the lipolytic process and showed no significant benefit over the initial formulations with regards to precipitation. While all tested sLBFs increased the permeation rate, no statistically significant difference was noted between the formulations regardless of composition. To conclude, the different release profiles of the formulations were not correlated to the resulting flux through a permeation membrane, further supporting the importance of making use of combined lipolysis-permeation assays when exploring LBFs.

Supersaturable Solid Self-microemulsifying Delivery Systems of Astaxanthin via Spray Drying: Effects of Polymers and Solid Carriers.

This study aimed to develop the solid astaxanthin-encapsulated self-microemulsifying delivery system (S-AST SMEDS) spray-dried particles and investigate the effect of materials in formulations on product characteristics. The optimized liquid AST SMEDS incorporated with a polymeric precipitation inhibitor (PI) was solidified with a solid carrier by spray drying. Physicochemical properties of S-AST SMEDS spray-dried powders including morphology, particle size and distribution, flowability, solid-state characters, moisture content, yield, loading capacity of AST, and reconstitution properties were examined. Polymeric PIs seemed to have an impact on particles' size, surface smoothness, and flowability while solid carriers had an effect on the particles' moisture content and droplet size of microemulsions obtained after reconstitution. The amount of AST encapsulated in S-SMEDS powder was influenced by both polymer and solid carriers. Dissolution and short-term stability of S-AST SMEDS were also studied. Our developed spray-dried solid SMEDS particles helped enhance AST dissolution rate.

Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs.

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition. Solutions of PVP K15, K30, K60 or K120 at concentrations of 0.1, 0.5 and 1% (w/v), as well as isoviscous solutions of PVP of increasing molecular weight, were prepared. Supersaturation of the three model drugs was induced by the use of a solvent-shift method. Precipitation of the three model drugs from supersaturated solutions in the absence and presence of polymer was investigated by the use of a solvent-shift method. Time-concentration profiles of the respective drugs in the absence and presence of polymer pre-dissolved in the dissolution medium were obtained by the use of a μDISS Profiler™ to determine the onset of nucleation and the precipitation rate. Multiple linear regression was used to evaluate the hypothesis that precipitation inhibition is influenced by the PVP concentration (i.e., the number of repeat units of the polymer) and the medium viscosity of the polymer for the three model drugs. This study showed that an increased concentration of PVP (i.e., an increased concentration of the PVP repeat units, independent of the molecular weight of the polymer) in solution increased the onset of nucleation and decreased the precipitation rate of the respective drugs during supersaturation, which can be explained by an increase in molecular interactions between the drug and polymer with increasing concentrations of polymer. In contrast, the medium viscosity had no significant influence on the onset of the nucleation and precipitation rate of the drugs, which can be explained by solution viscosity having a negligible effect on the rate of drug diffusion from bulk solution to the crystal nuclei. In conclusion, the precipitation inhibition of the respective drugs is influenced by the concentration of PVP, i.e., by molecular interactions between the drug and polymer. In contrast, the molecular mobility of the drug in solution, i.e., the medium viscosity, has no influence on the precipitation inhibition of the drugs.

Polymer-embedded deep eutectic solvents (PEDES) as a novel bio-enabling formulation approach

There is a growing interest in using deep eutectic solvents (DES) as a pharmaceutical delivery system for poorly water-soluble compounds. To reduce the risk of drug precipitation following oral administration, this study addresses the hypothesis that directly including a polymeric precipitation inhibitor (PI) in a DES mixture could obtain a polymer-embedded deep eutectic system (PEDES) as a novel bio-enabling formulation principle. Following broad formulation screening, a PEDES embedding 15% w/w of polyvinyl pyrrolidone K30 (PVP) in L-carnitine:ethylene glycol (1:4, molar ratio) DES was successfully formulated as a supersaturating formulation using indomethacin as model compound. The drug solubility of 175.6 mg/mL obtained in DES was remarkably high, and upon release (phosphate buffer, pH 6.5) a maximum supersaturation factor of 9.8 was recorded, whereby the release kinetics displayed a suitable “parachute effect”. The formulation was further characterized to include a molecular dynamics simulation. It can be concluded that PEDES appears to be a viable novel formulation approach, setting solid grounds for further research to assess the full potential of this novel type of supersaturating drug delivery system.

Carvedilol Precipitation Inhibition by the Incorporation of Polymeric Precipitation Inhibitors Using a Stable Amorphous Solid Dispersion Approach: Formulation, Characterization, and In Vitro In Vivo Evaluation.

An amorphous solid dispersion (ASD) of carvedilol (CVL) was prepared via the solvent evaporation method, using cellulose derivatives as polymeric precipitation inhibitors (PPIs). The prepared ASDs existed in the amorphous phase, as revealed by X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM). The Fourier-transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) results confirmed the compatibility between CVL and the polymers used. The ASDs characteristics were evaluated, with no change in viscosity, a pH of 6.8, a polydispersity index of 0.169, a particle size of 423-450 nm, and a zeta potential of 3.80 mV. Crystal growth inhibition was assessed for 180 min via an infusion precipitation study in simulated intestinal fluid (SIF). The interactions between the drug and polymers were established in great detail, using nuclear magnetic resonance (NMR) spectroscopy, nuclear Overhauser effect spectroscopy (NOESY), and Raman spectroscopy studies. Dielectric analysis was employed to determine the drug-polymer interactions between ion pairs and to understand ion transport behavior. In vivo oral kinetics and irritation studies performed on Wistar rats have demonstrated promising biocompatibility, stability, and the enhanced bioavailability of CVL. Collectively, the stable ASDs of CVL were developed using cellulose polymers as PPIs that would inhibit drug precipitation in the gastrointestinal tract and would aid in achieving higher in vivo drug stability and bioavailability.

Lipid-based solubilization technology via hot melt extrusion: promises and challenges

Introduction Self-emulsifying drug delivery systems (SEDDS) are a promising strategy to improve the oral bioavailability of poorly water-soluble drugs (PWSD). The excipients of SEDDS enable permeation through the mucus and gastro-intestinal barrier, inhibiting efflux transporters (e.g. P-glycoprotein) of drugs. Poor drug loading capacity and formulation instability are the main setbacks of traditional SEDDS. The use of polymeric precipitation inhibitors was shown to create supersaturable SEDDS with increased drug payload, and their solidification can help to overcome the instability challenge. As an alternative to several existing SEDDS solidification technologies, hot melt extrusion (HME) holds the potential for lean and continuous manufacturing of supersaturable solid-SEDDS. Despite being ubiquitously applied in solid lipid and polymeric processing, HME has not yet been widely considered for the preparation of SEDDS. Areas covered The review begins with the rationale why SEDDS as the preferred lipid-based delivery systems (LBDS) is suitable for the oral delivery of PWSD and discusses the common barriers to oral administration. The potential of LBDS to surmount them is discussed. SEDDS as the flagship of LBDS for PWSD is proposed with a special emphasis on solid-SEDDS. Finally, the opportunities and challenges of HME from the lipid-based excipient (LBE) processing and product performance standpoint are highlighted. Expert opinion HME can be a continuous, solvent-free, cost-effective, and scalable technology for manufacturing solid supersaturable SEDDS. Several critical formulations and process parameters in successfully preparing SEDDS via HME are identified.

In silico-assisted development of supersaturable preconcentrated isotropic mixture of atazanavir for augmenting biopharmaceutical performance in the presence of H2-receptor antagonist.

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1), has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization, and evaluation of hydroxypropyl methylcellulose acetate succinate (HPMC-AS)-based supersaturable preconcentrate isotropic mixture (SP-IM) containing long-chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing corn oil, oleic acid, Tween 80, and propylene glycol, evaluating various critical quality attributes (CQAs) like particle size, polydispersity index, self-emulsification time, % transmittance, and drug content. In silico analysis and in vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025N HCl and pH 6.8 over pure drug. Ex vivo permeation and in vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in Wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

Impact of Polymers as Precipitation Inhibitors on Physicochemical Properties of Spray-Dried Astaxanthin-Loaded Self-Microemulsifying Delivery Systems

Supersaturated astaxanthin (AST)-loaded self-microemulsifying delivery system (SMEDS) was developed and formulated with polymeric precipitation inhibitors (PPIs) to improve the dissolution profile of AST. Based on our preliminary in vitro polymer screening test, hydroxypropyl cellulose (HPC-L) and polyvinyl alcohol (PVA8/88) were selected as PPIs and studied further in this work. Microemulsions prepared from AST SMEDS (composed of AST, rice bran oil, Kolliphor® RH40, and Span® 20) were mixed with maltodextrin (MD) as a solid carrier and each PPI solution and then solidified using a spray drying technique. Particle size of spray-dried S-MD-HPC powder had larger circular equivalent (CE) diameter (14.69 ± 0.75 μm) than the other formula and showed particle agglomeration in SEM images. Spray-dried S-MD-PVA powder had 8.94 ± 0.37 μm CE diameter, and smooth surface of particles was observed. Amorphous phase transformation and chemical compatibility of both spray-dried powder formulations were detected by FT-IR, PXRD, and DSC. S-MD-HPC had marginally slower dissolution rate and release profile of AST compared to those of S-MD-PVA; however, both HPC and PVA polymers exhibited the ability for AST precipitation prevention and solubilization enhancement. Although AST degradation was caused by high temperature, physicochemical properties of the spray-dried AST SMEDS (S-MD-HPC and S-MD-PVA) powders after reconstitution were not significantly changed upon storage at 30°C/ RH 75%. This study illustrated a novel platform of spray-dried AST SMEDS in combination with HPC or PVA as a polymeric precipitation inhibitor for improvement of AST loading, solubility, and stability.

Polymeric precipitation inhibitor differently affects cocrystal surface and bulk solution phase transformations

During the dissolution of cocrystal particles, solution-mediated phase transformation (SMPT) can occur either on the particle surface (PS-SMPT) or in the bulk phase solution (BP-SMPT). In this study, we compared the effect of various polymers on PS-SMPT and BP-SMPT for the first time using carbamazepine saccharine cocrystal (CBZ-SAC) as a model drug. Polyethylene glycol 6000 (PEG), polyvinylpyrrolidone K-30 (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), amino methacrylate copolymer (EPO), and methacrylic acid copolymers (L100-55) were used as polymeric precipitation inhibitors. In the non-sink dissolution test, CBZ-SAC rapidly transforms to CBZ dihydrate (CBZ DH) via PS-SMPT in the absence of polymers. The polymers enhanced the dissolution rate and subsequent supersaturated CBZ concentration in the order of HPMC-AS > HPMC > EPO ≫ PVP ≈ L100-55 ≈ PEG. On the other hand, in the solvent-shift precipitation test, these polymers inhibited the precipitation of CBZ DH in a different order (EPO > HPMC > HPMC-AS ≫ L100-55 ≈ PVP ≫ PEG). The polymers affected the crystal habit of CBZ DH differently between PS-SMPT and BP-SMPT. Direct PS-SMPT observation by real-time polarized light microscopy (RT-PLM) showed that PS-SMPT was significantly inhibited by HPMC-AS, HPMC, and EPO, but less by PVP, L100-55, and PEG. Differences in solid surface pH and heterogeneous nucleation were discussed as the reason for the difference in the inhibitory effect between polymers in PS-SMPT and BP-SMPT. In conclusion, the inhibitory effect of polymers can differ between PS-SMPT and BP-SMPT. For the successful development of a cocrystal formulation, it is important to select a potent inhibitor of PS-SMPT.

In Vitro Evaluation of a Solid Supersaturated Self Nanoemulsifying Drug Delivery System (Super-SNEDDS) of Aprepitant for Enhanced Solubility.

Aprepitant (APR) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its low aqueous solubility. The objective of the current work is to develop self-nanoemulsifying drug delivery systems (SNEDDS) of APR to enhance its aqueous solubility. Preformulation studies involving screening of excipients for solubility and emulsification efficiency were carried out. Pseudo ternary phase diagrams were constructed with blends of oil (Imwitor® 988), cosolvent (Transcutol® P), and various surfactants (Kolliphor® RH40, Kolliphor® ELP, Kolliphor® HS15). The prepared SNEDDS were characterized for droplet size and nanoemulsion stability after dilution. Supersaturated SNEDDS (super-SNEDDS) were prepared to increase the quantity of loaded APR into the formulations. HPMC, PVP, PVP/VA, and Soluplus® were used as polymeric precipitation inhibitors (PPI). PPIs were added to the formulations at 5% and 10% by weight. The influence of the PPIs on drug precipitation was investigated. In vitro lipolysis test was carried out to simulate digestion of formulations in the gastrointestinal tract. Optimized super-SNEDDS were formulated into free-flowing granules by adsorption on the porous carriers such as Neusilin® US2. In vitro dissolution studies of solid super-SNEDDS formulation revealed an increased dissolution rate of the drug due to enhanced solubility. Consequently, a formulation to improve the solubility and potentially bioavailability of the drug was developed.

Polymeric Precipitation Inhibitor Based Supersaturable Self-microemulsifying Drug Delivery System of Canagliflozin: Optimization and Evaluation.

The present investigation attempts to optimize Supersaturable lipid based formulation (SS SMEDDS) of Biopharmaceutical Classification System (BCS) class IV drug canagliflozin (CFZ) and evaluating the oral bioavailability of the formulation. Preliminary screening revealed Poloxamer 188 to most effectively inhibit precipitation of CFZ after dispersion during in vitro supersaturation studies. Box Behnken Design was employed for designing different formulations, and various statistical analyses were done to select an appropriate mathematical model. The optimized formulation (OSS 1) was evaluated for in vitro drug release and ex vivo permeation studies to evaluate drug release and permeation rate. Pharmacokinetic studies have been carried out according to standard methodologies. The optimized formulation (OSS 1) containing 781.1 mg SS SMEDDS and 2.24% w/w Poloxamer 188 was developed at a temperature of 60°C, which revealed nano-globule size with negligible aggregation. Isothermal titration calorimetry revealed the thermodynamic state of formed microemulsion with negative ΔG. The optimized formulation was observed to possess physical stability under different stress conditions and acceptable drug content. In vitro dissolution of optimized SS SMEDDS revealed a higher dissolution rate of CFZ as compared to native forms of CFZ. The permeability of CFZ from optimized SS SMEDDS across various excised segments of rat intestine was observed to be multifold higher as manifested by 2.05-fold higher Cmax and 5.64- fold higher AUC0-36h following oral administration to Wistar rats. The results could be attributed to substantial lymphatic uptake and P-glycoprotein substrate affinity of CFZ in SS SMEDDS investigated through chylomicron and P-glycoprotein inhibition approach, respectively.

Interaction with biliary and pancreatic fluids drives supersaturation and drug absorption from lipid-based formulations of low (saquinavir) and high (fenofibrate) permeability poorly soluble drugs

Drug absorption from lipid-based formulations (LBFs) in the gastrointestinal (GI) tract is the result of a series of processes, including formulation dispersion, interaction with biliary and pancreatic secretions, drug solubilisation and supersaturation, and finally intestinal permeability. Optimal formulation design is dependent on a good understanding of the limitations to, and drivers of, absorption, but for LBFs the complexity of these processes makes data interpretation complex. The current study has re-examined a previous in vitro digestion–in situ perfusion model to increase physiological relevance and has used this model to examine drug absorption from LBFs. The composition of rat bile and jejunal fluid was also characterised to identify in vivo-relevant conditions. Digestion was initiated using rat bile/pancreatic fluid and the formulation and digestive enzymes mixed immediately prior to entry into the jejunum (allowing dilution/digestion to occur at the absorptive site). These conditions were employed to study drug absorption from LBFs of high (fenofibrate, FFB) and low (saquinavir, SQV) permeability compounds. The impact of polymeric precipitation inhibitors (PPIs) was also evaluated. For FFB, supersaturation, initiated by formulation interaction with biliary/pancreatic fluids, appeared to drive absorption and the addition of the PPIs poly(glycidyl methacrylate) (PPGAE) and hydroxypropylmethyl cellulose (HPMC), reduced drug precipitation, increased FFB supersaturation and increased absorption from a Type IV LBF of FFB. For a Type IIIB LBF however, PPIs were ineffective at increasing absorption. The impact of PPIs on the absorption of a less permeable drug, SQV, was similarly evaluated and again drug absorption appeared to be related to the extent of supersaturation, although in this case PPI were unable to promote absorption. For both FFB and SQV, drug absorption patterns obtained with the in vitro digestion–in situ perfusion mode, correlated well with in vitro supersaturation data and in vivo drug exposure data from oral bioavailability studies. The data are consistent with a mode of drug absorption where rapid dilution of LBFs with biliary and pancreatic secretions at the absorptive site in the upper small intestine drives transient supersaturation, that supersaturation is a significant driver of drug absorption for both low and high permeability drugs, and that PPIs delay drug precipitation, enhance supersaturation and promote drug absorption in a drug and formulation specific manner.

Polymeric Precipitation Inhibitor Assisted Supersaturable SMEDDS of Efavirenz Based on Experimental Observations and Molecular Mechanics.

Supersaturable SMEDDS, a versatile dosage form, was investigated for improving the biopharmaceutical attributes and eradicating the food effect of poorly water soluble drug efavirenz. The present research pursues the development of efavirenz loaded Supersaturable Self- Microemulsifying Drug Delivery System (SS SMEDDS) for improving biopharmaceutical performance. Preformulation studies were carried out to determine the optimized range of lipid excipients to develop stable supersaturated SMEDDS (ST SMEDDS). The SS SMEDD formulation was prepared by adding hydroxypropyl methylcellulose as a polymeric precipitation inhibitor. The developed SS SMEDDS were evaluated for supersaturation behavior by performing in vitro supersaturation studies and molecular simulations by in silico docking. Dissolution was performed in biorelevant media to simulate fed/fasted conditions in gastrointestinal regions. Absorption behavior was determined through in vivo pharmacokinetics approach. The optimized ST SMEDDS formulation containing Maisine® CC, Tween 80 and Transcutol-P exhibited thermodynamic stability with quick rate of emulsification. The optimized SS SMEDDS containing suitable polymeric precipitation inhibitor exhibited enhanced efavirenz concentration in in vitro supersaturation test. The theoretical simulations by molecular docking revealed strong intermolecular interactions with a docking score of -3.004 KJ/mol. The dissolution performance of marketed product in biorelevant dissolution media inferred the existence of food effect in the dissolution of efavirenz. However, in SS SMEDDS, no significant differences in drug release behavior under different fasted/fed conditions signify that the food effect was neutralized. In vivo pharmacokinetics revealed a significant increase in the absorption profile of efavirenz from SS SMEDDS than that of ST SMEDDS and marketed product. The designed delivery system indicated promising results in developing an effectual EFV formulation for HIV treatment.

Polymeric Precipitation Inhibitor–Based Solid Supersaturable SMEDD Formulation of Canagliflozin: Improved Bioavailability and Anti-diabetic Activity

The current investigation explores the enhanced biopharmaceutical attributes of solid supersaturable self-microemulsifying drug delivery system (Solid SS SMEDDS) for poorly water soluble drug canagliflozin (CFZ). Solid SS SMEDD formulation was prepared by spray drying using Neusilin US2 as an adsorbent. The developed SS SMEDDS were characterized for physicochemical and solid state characterizations. Theoretical molecular simulations were performed by in silico docking. BET measurements were done for evaluating surface area topography. In vitro dissolution, ex vivo permeation, and pharmacokinetics studies were performed to determine release rate, permeability, and absorption behavior, respectively. Anti-diabetic studies and histopathology were done as per standard protocols. The solid SS SMEDD formulation containing 320 mg Lauroglycol FCC, 1200 mg Tween 80, 480 mg Transcutol-P, and 2.24% w/v Poloxamer 188 as polymer-based precipitation inhibitor (PPI) was optimized. The solid state attributes of CFZ in solid SS SMEDDS revealed its molecularly dispersed state. The prepared formulation demonstrated uniform flow properties, nanoparticulate size distribution, and acceptable drug content. Theoretical simulations revealed strong intermolecular hydrogen bonding with a docking score of − 5.184 kJ/mol. In vitro dissolution studies depicted enhanced release of CFZ from solid SS SMEDDS in various dissolution media. Remarkable improvement in ex vivo permeability was observed across the jejunum segment of rat intestine. These studies revealed enhanced absorption of CFZ in rats following oral administration of solid SS SMEDDS, as compared with that of pure drug and marketed product. Pharmacological evaluation of optimized solid SS SMEDDS also revealed enhanced anti-diabetic activity, as evident from urinary glucose excretion studies and SGLT II protein expression in rat kidneys. Accelerated stability study confirmed the stability of the formulation up to 6 months storage period. The designed delivery system indicated promising results in developing an effective formulation of CFZ for diabetes mellitus.

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 6months 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±0.4nm for SNEDDS with 200% drug load and 55.6±1.3nm 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 15min 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.

Impact of amorphization and GI physiology on supersaturation and precipitation of poorly soluble weakly basic drugs using a small-scale in vitro transfer model.

Formulation of amorphous solid dispersions (ASD) is one possibility to improve poor aqueous drug solubility by creating supersaturation. In case of weakly basic drugs like ketoconazole (KTZ), supersaturation can also be generated during the gastrointestinal (GI) transfer from the stomach to the intestine due to pH-dependent solubility. In both cases, the supersaturation during dissolution can be stabilized by polymeric precipitation inhibitors. A small-scale GI transfer model was used to compare the dissolution performance of ASD versus crystalline KTZ with the polymeric precipitation inhibitor HPMCAS. Similar in vitro AUCs were found for the transfer from SGF pH2 into FaSSIF. Moreover, the impact of variability in gastric pH on drug dissolution was assessed. Here, the ASD performed significantly better at a simulated hypochlorhydric gastric pHof 4. Last, the importance of drug-polymer interactions for precipitation inhibition was evaluated. HPMCAS HF and LF grades with and without the basic polymer Eudragit EPO were used. However, EPO caused a faster precipitation probably due to competition for the interaction sites between KTZ and HPMCAS. Thus, the results are suited to assess the benefits of amorphous formulations vs. precipitation inhibitors under different gastrointestinal conditions to optimize the design of such drug delivery systems.

In Vitro and In Vivo Assessment of the Potential of Supersaturation to Enhance the Absorption of Poorly Soluble Basic Drugs

Delaying precipitation of weakly basic drugs in supersaturated state following their transition from the acidic gastric environment to the near-neutral proximal small intestinal fluid is emerging as a promising tactic for achieving higher transitional solubility and improving bioavailability of such drugs. The aim of this study was to assess the effect of supersaturation on drug dissolution and permeation in vitro, and to evaluate the in vitro-in vivo correlation of the supersaturation effect for the poorly soluble basic drug ketoconazole. We monitored dissolution of drugs in simulated gastric fluid followed by drug dissolution in simulated intestinal fluid and simultaneous permeation across Caco-2 cell monolayers using the IDAS2 experimental procedure. The pH shift from pH 1.6 to pH 6.5 (mimicking in vivo gastric to intestinal transition) was used to induce transient in vitro supersaturation of the tested weakly basic poorly soluble drugs. Polymeric precipitation inhibitor, hydroxypropyl methylcellulose acetate succinate (HPMCAS), was added to dissolution medium in order to increase the amplitude and duration of the pH-driven supersaturation of the weakly basic drug ketoconazole in the in vitro IDAS2 setting. The effect of HPMCAS on oral bioavailability of ketoconazole was demonstrated in the rat pharmacokinetic model. Drug supersaturation induced by pH shift was assessed in vitro by comparing drug dissolution and permeation under the 2-stage (pH shift from gastric pH 1.6 to intestinal pH 6.5) conditions vs. 1-stage (constant intestinal pH 6.5) conditions. Compared to the 1-stage conditions, 2-stage procedure increased in vitro dissolution AUC (area under the concentration-time curve) of the weakly basic drugs dipyridamole, ketoconazole, and itraconazole by 393%, 161%, and 71%, respectively, accompanied by corresponding 543%, 264%, and 46% increase in in vitro permeation. In contrast, the BCS 2 acidic drug warfarin exhibited 9% decrease in dissolution under 2-stage conditions, which was associated with a 21% decrease in permeation. None of the tested BCS 1 drugs (minoxidil and metoprolol) exhibited supersaturation after the gastric to intestinal pH shift; consistent with the absence of supersaturation, and the permeation of these drugs was not affected by the transition from simulated gastric to simulated intestinal environments. The polymeric precipitation inhibitor, HPMCAS, increased the in vitro dissolution and permeation AUC values of ketoconazole by 187% and 119%, respectively, and ketoconazole plasma AUC0-24h and Cmax by 54% and 49% following oral administration in rats. This study has shown that the novel in vitro dissolution-absorption methodology simulating the in vivo gastrointestinal environments that influence drug release and absorption of orally administered drugs constitutes a sensitive and physiologically relevant approach for investigating the potential utility of formulation excipients for exploiting supersaturation as a means to improve systemic drug absorption.

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.