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.

Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice.

Introduction: We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS). Methods: Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control. Results: Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice. Conclusion: We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.

Solid self-microemulsifying drug delivery system (S-SMEDDS) prepared by spray drying to improve the oral bioavailability of cinnamaldehyde (CA).

The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.

The effect of polymeric binder type and concentration on flow and dissolution properties of SMEDDS loaded mesoporous silica-based granules.

Self-microemulsifying drug delivery systems (SMEDDS) are lipid-based formulations, designed to improve the solubility of poorly-water soluble drugs. Mesoporous silica is frequently used for SMEDDS solidification by various techniques. One of them is wet granulation, which enables achieving both high SMEDDS load and good flow properties. This study investigated the effect of six polymeric binders' addition to granulation dispersion (GD) (povidone K30, povidone K90, copovidone, Pharmacoat® 603, Pharmacoat® 615 and Methocel™ K100 Premium LV) on characteristics of produced SMEDDS granules, prepared by wet granulation. By incorporation of polymer in GD, it was possible to produce mesoporous silica-based free-flowing granules, with preserved self-microemulsifying properties, responsible for improved in vitro release of carvedilol. The incorporation of higher molecular weight binders resulted in slower in vitro release, while high binder concentration was related to faster drug release. The highest release rate was achieved with povidone K30 at 7.45 % binder concentration, as corresponding granules exhibited complete drug release already in 5 min. Granulation method (manual vs. high-shear) influenced the release rate of carvedilol as it was released slower from SMEDDS granules prepared using the granulator. Finally, SMEDDS tablet formulation was optimized to achieve maximum granule content and adequate tablet hardness. Increased granule content found to negatively influence tablet hardness, as maximum granule content of 25 % was needed to obtain appropriate hardness. Such tablets exhibited short disintegration time, so this final prototype can be considered as orodispersible tablet.

Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats.

Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting.

Omega-3 fatty acid-based self-microemulsifying drug delivery system (SMEDDS) of pioglitazone: Optimization, in vitro and in vivo studies.

Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose, improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of -20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0-24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.

Formulation and Evaluation of a Self-Microemulsifying Drug Delivery System of Raloxifene with Improved Solubility and Oral Bioavailability.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Lipid based formulations as supersaturating oral delivery systems: From current to future industrial applications.

Lipid-based formulations, in particular supersaturated lipid-based formulations, are important delivery approaches when formulating challenging compounds, as especially low water-soluble compounds profit from delivery in a pre-dissolved state. In this article, the classification of lipid-based formulation is described, followed by a detailed discussion of different supersaturated lipid-based formulations and the recent advances reported in the literature. The supersaturated lipid-based formulations discussed include both the in situ forming supersaturated systems as well as the thermally induced supersaturated lipid-based formulations. The in situ forming drug supersaturation by lipid-based formulations has been widely employed and numerous clinically available products are on the market. There are some scientific gaps in the field, but in general there is a good understanding of the mechanisms driving the success of these systems. For thermally induced supersaturation, the technology is not yet fully understood and developed, hence more research is required in this field to explore the formulations beyond preclinical studies and initial clinical trials.

Nanocellulose-Based Film-Forming Hydrogels for Improved Outcomes in Atopic Skin.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by impaired skin barrier function. Amongst the various dermal formulations that are being used and/or investigated for AD treatment, one of the advanced approaches is the use of hydrogels as film-forming systems that are applied directly to the skin and have the added value of providing a physical barrier, which is lacking in atopic skin. Novel film-forming hydrogels based on two different nanocrystalline celluloses (NCCs) in combination with one of two natural polymers (alginate or pectin) were developed for incorporation of betamethasone dipropionate (BDP). Initially, the low water solubility of BDP was resolved by prior dissolution in a self-microemulsifying drug delivery system (SMEDDS). The mixture of Kolliphor® EL/Capryol® 90 in a ratio of 8/2 was chosen on the merit of its high BDP-saturated solubility and no BDP precipitation upon water dilution, enabling BDP to remain dissolved after incorporation into hydrogels. The solvent evaporation method was used to prepare the films, and their high water retention capacity was confirmed in vitro on artificial membranes and pig ear skin. The presented results thus confirm NCC-based film-forming hydrogels as a very promising drug delivery system for AD treatment.

Design and Evaluation of Hydrophobic Ion Paired Insulin Loaded Self Micro-Emulsifying Drug Delivery System for Oral Delivery.

Despite several novel and innovative approaches, clinical translation of oral insulin delivery into commercially viable treatment is still challenging due to its poor absorption and rapid degradation in GIT. Thus, an insulin-SDS hydrophobic ion pair loaded self-microemulsifying drug delivery system (SMEDDS) was formulated to exploit the hypoglycemic effects of orally delivered insulin. Insulin was initially hydrophobically ion paired with sodium dodecyl sulphate (SDS) to enhance its lipophilicity. The successful complexation of Insulin-SDS was confirmed by FTIR and surface morphology was evaluated using SEM. Stability of insulin after its release from HIP complex was evaluated using SDS PAGE. Subsequently, Ins-SDS loaded SMEDDS was optimized using two factorial designs. In vitro stability of insulin entrapped in optimized SMEDDS against proteolytic degradation was also assessed. Further, antidiabetic activity of optimized Ins-SDS loaded SMEDDS was evaluated in diabetic rats. Insulin complexed with SDS at 6:1 (SDS/insulin) molar ratio with almost five-fold increased lipophilicity. The SMEDDS was optimized at 10% Labraphil M2125 CS, 70% Cremophore EL, and 20% Transcutol HP with better proteolytic stability and oral antidiabetic activity. An Ins-SDS loaded SMEDDS was successfully optimized. Compared with insulin and Ins-SDS complex, the optimized SMEDDS displayed considerable resistance to GI enzymes. Thus, the SMEDDS showed potential for effective delivery of macromolecular drugs with improved oral bioavailability.

Application of Design of Experiments in the Development of Self-Microemulsifying Drug Delivery Systems.

Oral delivery has become the route of choice among all other types of drug administrations. However, typical chronic disease drugs are often poorly water-soluble, have low dissolution rates, and undergo first-pass metabolism, ultimately leading to low bioavailability and lack of efficacy. The lipid-based formulation offers tremendous benefits of using versatile excipients and has great compatibility with all types of dosage forms. Self-microemulsifying drug delivery system (SMEDDS) promotes drug self-emulsification in a combination of oil, surfactant, and co-surfactant, thereby facilitating better drug solubility and absorption. The feasible preparation of SMEDDS creates a promising strategy to improve the drawbacks of lipophilic drugs administered orally. Selecting a decent mixing among these components is, therefore, of importance for successful SMEDDS. Quality by Design (QbD) brings a systematic approach to drug development, and it offers promise to significantly improve the manufacturing quality performance of SMEDDS. Furthermore, it could be benefited efficiently by conducting pre-formulation studies integrated with the statistical design of experiment (DoE). In this review, we highlight the recent findings for the development of microemulsions and SMEDDS by using DoE methods to optimize the formulations for drugs in different excipients with controllable ratios. A brief overview of DoE concepts is discussed, along with its technical benefits in improving SMEDDS formulations.

D-α-tocopherol polyethylene glycol 1000 succinate-based microemulsion delivery system: Stability enhancement of physicochemical properties of luteolin.

In the present study, D-α-Tocopherol polyethylene glycol 1000 succinate-based self-microemulsifying drug delivery systems (TPGS-SMEDDS) were introduced to enhance the solubility and stability of luteolin. The ternary phase diagrams were constructed to obtain the maximum area of microemulsion and suitable formulations of TPGS-SMEDDS. The particle size distribution and polydispersity index of selected TPGS-SMEDDS were analyzed to be less than 100 nm and 0.4, respectively. The thermodynamic stability results suggested that the TPGS-SMEDDS was stable during the heat-cool and freeze-thaw cycle. Moreover, the TPGS-SMEDDS exhibited excellent encapsulation capacity (51.21 ± 4.39 to 85.71 ± 2.40%) and loading efficiency (61.46 ± 5.27 to 102.86 ± 2.88 mg/g) to luteolin. In addition, the TPGS-SMEDDS showed an admirable vitro release ability with a ratio of more than 88.40 ± 1.14% for luteolin in 24 h. Therefore, TPGS-based SMEDDS might provide an effective role for the oral administration of luteolin and holds promise as a potential delivery for poorly soluble bioactive compounds.

Formulation and in vitro evaluation of meloxicam as a self-microemulsifying drug delivery system.

Background: The nonsteroidal anti-inflammatory medication meloxicam (MLX) belongs to the oxicam family and is used to reduce inflammation and pain. The aim of this study was to improve MLX's dispersibility and stability by producing it as a liquid self-microemulsifying drug delivery system since it is practically insoluble in water. Methods: Five different formulations were made by adjusting the amounts of propylene glycol, Transcutol P, Tween 80, and oleic acid oil and establishing a pseudo-ternary diagram in ratios of 1:1, 1:2, 1:3, 1:4, and 3:4, respectively. All of the prepared formulations were tested for a variety of properties, including thermodynamic stability, polydispersity index, particle size distributions, dilution resistance, drug contents, dispersibility, in vitro solubility of the drug, and emulsification time. Results: F5 was chosen as the optimal MLX liquid self-microemulsion due to its higher drug content (99.8%), greater in vitro release (100% at 40 min), smaller droplet size (63 nm), lower polydispersity index (PDI) value (0.3), and higher stability (a zeta potential of -81 mV). Conclusions: According to the data provided here, the self-microemulsifying drug delivery system is the most practical method for improving the dispersibility and stability of MLX.

Improved oral bioavailability of febuxostat by liquid self-micro emulsifying drug delivery system in capsule shells.

PURPOSE: Febuxostat is a non-purine xanthine oxidase inhibitor which belongs to the BCS class II. Main aim of this study is to enhance dissolution and bioavailability of a drug by formulating a liquid self-micro emulsifying drug delivery system (SMEDDS) in different capsule shells. METHOD: Compatability of gelatin and cellulose capsule shells was checked with different oils, surfactants and co-surfactants. Solubility studies were then carried out in selected excipients. Capryol 90, labrasol, and PEG 400 were used in a liquid SMEDDS formulation based on phase diagram and the drug loading. Further SMEDDS was characterized for zeta potential, globule size and shape, thermal stability and in vitro release. Based on the in vitro release, pharmacokinetic study was carried out using SMEDDS in gelatin capsule shells. RESULT: The diluted SMEDDS had globule size of 157.9±1.5d.nm, zeta potential of -16.2±0.4mV and they were thermodynamically stable. The formulation was found stable for 12 months in capsule shells. When tested in different media (0.1N HCl and pH 4.5 acetate buffer), the in vitro release of newly produced formulations differed substantially from that of commercially available tablets, while the release rate in alkaline medium (pH 6.8) was comparable and the highest. According to in vivo findings in rats, a threefold increase in plasma concentration, a fourfold increase in AUC0-t, and a reduction in oral clearance increased fuxostat's oral bioavailability. CONCLUSION: This investigation revealed that the novel liquid SMEDDS formulation sealed in capsules has considerable potential as a vehicle for enhancing the bioavailability of febuxostat.

Solid microemulsion preconcentrates on pH responsive metal-organic framework for tableting.

Poorly water-soluble drugs are frequently formulated with lipid-based formulations including microemulsions and their preconcentrates. We detailed the solidification of drug-loaded microemulsion preconcentrates with the acid-sensitive metal-organic framework ZIF-8 by X-ray powder diffraction and solid-state nuclear magnetic resonance spectroscopy. Adsorption and desorption dynamics were analyzed by fluorescence measurement, high-performance liquid chromatography, dynamic light scattering and 1H-DOSY experiments using the model compounds Nile Red, Vitamin K1, and Lumefantrine. Preconcentrates and drugs were successfully loaded onto ZIF-8 while preserving its crystal structure. The solid powder was pressable to tablets or 3D-printed into oral dosage forms. At low pH, colloidal solutions readily formed, solubilizing the poorly water-soluble compounds. The use of stimuli-responsive metal organic frameworks as carriers for the oral delivery of lipid-based formulations points towards solid dosage forms readily forming colloidal microemulsions.

Baicalein self-microemulsion based on drug-phospholipid complex for the alleviation of cytokine storm.

Cytokine storm is a phenomenon whereby the overreaction of the human immune system leads to the release of inflammatory cytokines, which can lead to multiple organ dysfunction syndrome. At present, the existing drugs for the treatment of cytokine storm have limited efficacy and severe adverse effects. Here, we report a lymphatic targeting self-microemulsifying drug delivery system containing baicalein to effectively inhibit cytokine storm. Baicalein self-microemulsion with phospholipid complex as an intermediate carrier (BAPC-SME) prepared in this study could be spontaneously emulsified to form 12-nm oil-in-water nanoemulsion after administration. And then BAPC-SME underwent uptake by enterocyte through endocytosis mediated by lipid valve and clathrin, and had obvious characteristics of mesenteric lymph node targeting distribution. Oral administration of BAPC-SME could significantly inhibit the increase in plasma levels of 14 cytokines: TNF-α, IL-6, IFN-γ, MCP-1, IL-17A, IL-27, IL-1α, GM-CSF, MIG, IFN-ß, IL-12, MIP-3α, IL-23, and RANTES in mice experiencing systemic cytokine storm. BAPC-SME could also significantly improve the pathological injury and inflammatory cell infiltration of lung tissue in mice experiencing local cytokine storm. This study does not only provide a new lymphatic targeted drug delivery strategy for the treatment of cytokine storm but also has great practical significance for the clinical development of baicalein self-microemulsion therapies for cytokine storm.

Cationic Solid SMEDDS of Efavirenz for Improved Oral Delivery: Development by Central Composite Design, In Vitro and In Vivo Evaluation.

Efavirenz (EFV) is an anti-HIV drug with high dose and 40% oral bioavailability (BA). The aim was to improve the bioavailability by designing cationic solid SMEDDS. Solubility data, ternary phase diagrams, and central composite design were employed in design. Globule size, TEM, DSC, and SEM studies were used for characterization. Optimized L-SMEDDS contained 20 mg of EFV, 10 mg of Peceol, 43.5 mg of Tween 80, and 40 mg of Labrafac Lipophile WL-1349 and the characters included mean globule size-94 nm, PDI-0.255, and ZP-28 mV. Later, octadecylamine was added to get L-SMEDDS with + 38 mV charge. L-SMEDDS was converted into solid S-SMEDDS by adsorbing onto silica carriers. Syloid XDP was preferred based on flow and oil adsorption capacity. The % drug (EFV) release from powder, L-SMEDDS, and solid SMEDDS were 14.04, 94.47, and 85 respectively in first 30 min. TEM picture showed dispersed globules. DSC and SEM studies indicated the loss of drug crystallinity in S-SMEDDS. Pharmacokinetic (PK) studies in Wistar rats revealed 4.12 fold hike in BA for optimized cationic S-SMEDDS when compared to EFV suspension. Increased absorption could be due to the positive charge on globules. Thus, cationic S-SMEDDS emerged as a potential novel delivery system for improvement in BA and has scope for reducing the high dose for AIDS patients by future clinical studies.

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.

Self-microemulsifying Drug Delivery System for Solubility and Bioavailability Enhancement of Eprosartan Mesylate: Preparation, In-vitro, and In-vivo Evaluation.

BACKGROUND: Formulations of eprosartan mesylate with a surfactant, like Kolliphor HS 15, an oil phase like Labrafil M 1944 CS, and a cosurfactant Transcutol HP by employing a liquid self-microemulsifying drug delivery system (SMEDDS) after screening several vehicles have been studied. OBJECTIVE: This study aimed to prepare a liquid self-microemulsifying drug delivery system for increasing the solubility and bioavailability of a poorly water-soluble eprosartan mesylate. METHODS: The micro-emulsion unit, achieved through the phase diagram and augmented with the central-composite design (CCD) surface response process, was adjusted into SMEDDS by lyophilization using sucrose as a cryoprotective agent. Particle size, self-emulsification time, polydispersion index (PDI), zeta potential, differential scanning calorimeter (DSC) screening, in-vitro drug release, and in-vivo pharmacokinetics were the essential features of the formulations. The subsequent DSC experimentation indicated that the drug was integrated into S-SMEDDS. Eprosartan mesylate loaded SMEDDS formulation showed greater in-vitro and in-vivo drug release than conventional solid doses. RESULTS: SMEDDS has reported effectiveness in reducing the impact of pH of eprosartan mesylate, thereby improving its release efficiency. The HPLC method was successfully implemented to assess eprosartan mesylate concentration in Wister rat plasma after oral administration of commercial tablet EM, SMEDDS, and eprosartan mesylate. The pharmacokinetics parameters for rats were Cmax 1064.91 ± 225 and 1856.22 ± 749 ngmL-1, Tmax 1.9 ± 0.3 hr, and 1.2 ± 0.4 hr and AUC0~t were 5314.36 ± 322.61 and 7760.09 ± 249 ng/ml hr for marketed tablets and prepared SSMEDDS, respectively. When determined by AUC0~1, the relative bioavailability of eprosartan mesylate S-SMEDDC was 152.09 ± 14.33%. CONCLUSION: The present study reports the formulation of a self-microemulsifying drug delivery system for enhancing the solubility and bioavailability of a poorly water-soluble eprosartan mesylate in an appropriate solid dosage form.

Development, characterisation, and in vitro anti-tumor effect of self-microemulsifying drug delivery system containing polyphyllin I.

Polyphyllin I (PPI), an effective active ingredient in Paris polyphylla, has a diverse set of pharmacological properties. However, due to its poor solubility and oral absorption, its application and development are limited. In the study, we were committed to improving the solubility of PPI by developing a self-microemulsifying drug delivery system of PPI (PPI-SMEDDS), screening the best preparation process, and evaluating the quality and the in vivo pharmacokinetics of PPI, and PPI-SMEDDS following oral administration to rats were also studied. In addition, the pharmacological activities against human lung adenocarcinoma cell A549 in vitro were assessed. The best formulation had 15.89% ethyl oleate, 47.38% Cremophor RH40, and 36.73% 1,2 propylene glycol. The produced PPI-SMEDDS was clear and transparent, with an average particle size of 24.51 nm and a zeta potential of -17.54 ± 0.51 mV. In vitro, the cumulative release rate of PPI-SMEDDS was nearly 80% within 2 h. PPI-SMEDDS had a substantially greater area under the curve than PPI following oral treatment in rats, and the relative bioavailability of PPI in rats was 278.99%. More importantly, the anti-tumor effect of PPI-SMEDDS in vitro was significantly greater than that of PPI. These findings suggested that PPI-SMEDDS has the potential to improve the solubility, oral bioavailability of PPI, and anti-tumor effect, laying the groundwork for future research on the new PPI dosage form.