Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion

Hot-melt extrusion was applied to improve dissolution behavior of poorly soluble model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (PVCL-PVAc-PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1+3 (weighted parts) with varying amounts of PVCL-PVAc-PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissolution performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25°C/60%rH. The dissolution rate from extrudates was significantly increased when compared to pure fenofibrate powder or physical mixture of the components. A supersaturation of 7.6-12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystallization was observed after 26 weeks of storage for fenofibrate-COP extrudates 1+3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersaturation decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug-carrier mixture, the dissolution performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements.     

In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it

The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.     

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.     

Formulation and delivery of improved amorphous fenofibrate solid dispersions prepared by thin film freezing

The objective of this study was to prepare amorphous fenofibrate (FB) solid dispersions using thin film freezing (TFF) and to incorporate the solid dispersions into pharmaceutically acceptable dosage forms. FB solid dispersions prepared with optimized drug/polymer ratios were characterized by modulated differential scanning calorimetry (MDSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), Brunauer–Emmett–Teller (BET) specific surface area measurements, Fourier-transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR), and supersaturation dissolution testing. Furthermore, a dry granulation technique was used to encapsulate the TFF compositions for in vitro dissolution and in vivo animal pharmacokinetic studies. The results showed that the TFF process produced amorphous, porous, microstructured, and stable solid dispersions with high surface areas. Development of solid oral dosage forms revealed that the performance of the FB containing solid dispersions was not affected by the formulation process, which was confirmed by DSC and XRD. Moreover, an in vivo pharmacokinetic study in rats revealed a significant increase in FB absorption compared to bulk FB. We confirmed that amorphous solid dispersions with large surface areas produced by the TFF process displayed superior dissolution rates and corresponding enhanced bioavailability of the poorly water-soluble drug, FB.     

In Vitro System to Evaluate Oral Absorption of Poorly Water-Soluble Drugs: Simultaneous Analysis on Dissolution and Permeation of Drugs

Purpose. The aim of the present work was to develop a new in vitro system to evaluate oral absorption of poorly water-soluble drugs by utilizing Caco-2 monolayers. Methods. Caco-2 monolayer was mounted between side-by-side chambers, which enabled the simultaneous assay of dissolution and permeation of drugs (dissolution/permeation system; D/P system). Apical and basal sides of the chamber were filled with buffer solutions. Drugs were applied to the apical side as powder, suspension, or solution, and then, the permeated amounts into the basal side were monitored for 2 h. At the same time, dissolved amounts of drugs at the apical side were detected. The amount of drug applied to the D/P system was based on its in vivo clinical dose. Results. Sodium taurocholate (5 mM, apical side) and bovine serum albumin (4.5% w/v, basal side) increased the permeated amount of poorly water-soluble drugs. Both additives were considered to be effective at mimicking in vivo conditions of intestinal drug absorption. From the correlation between the permeated amount of 13 drugs (% dose/2 h) in the D/P system and their percentage dose absorbed in humans in vivo, this system was found to be useful in evaluating oral absorption of poorly water-soluble drugs. Conclusions. With attempts made to mimic the physiologic conditions of the human GI tract, in vivo oral absorption of drugs was quantitatively assessed in the D/P system in vitro. This system is quite useful to predict the oral absorption of poorly water-soluble drugs after administration as solid dosage forms.     

Dissolution of poorly water-soluble drugs in biphasic media using USP 4 and fiber optic system

A novel in-vitro dissolution system based on the principle of flow-through technique has been designed to evaluate the in-vitro release rate of poorly water-soluble compounds. The flow through apparatus (USP 4) has been coupled with the compendial dissolution apparatus (USP apparatus 2). A bi-phasic dissolution medium is used to achieve sink conditions. The dissolved drug is continuously removed from the aqueous phase into the organic phase of the dissolution medium, mimicking the process of absorption in the systemic circulation. The in vitro release profiles obtained from this dissolution model was able to distinguish the formulation changes of several poorly water-soluble drugs from their dosage forms. For AMG 517, the model drug, excellent rank order correlation has been obtained between the in-vitro release and the in-vivo absorption of the drug from several different dosage forms and their formulations. In addition, for several commercial formulations, the model successfully discriminated between the bioequivalent and non-bioequivalent formulations.     

Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system

The aim of the present work was to establish appropriate conditions for the dissolution/permeation system (D/P system) to estimate the effect of food intake on oral drug absorption. The D/P system is an in vitro assay system to evaluate the drug dissolution and permeation processes after oral administration. Caco-2 monolayer was used as a model membrane of the intestinal epithelium. In this study, two types of simulated intestinal fluid reflecting the fasted and the fed state conditions of the human gastrointestinal tract were used. Drugs were applied to the D/P system as a powder, then, permeated amounts of drugs into the basal side were monitored. A sigmoidal correlation was obtained between in vivo oral absorption (% absorbed of dose) and in vitro permeated amount (% of dose/2 h) under both states. From the D/P system, the estimated absorption of albendazole in both states was found to correspond well with in vivo observation. Moreover, the D/P system could estimate the effect of self-emulsifying formulation on the oral absorption of danazol, quantitatively. In conclusion, the D/P system was proved to be a useful assay system not only for the oral absorption of drugs, but also for the food effect on the absorption.     

Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system

This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22–55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69–85%) was slightly affected. Zafirlukast absorption (33–36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.     

Application of Dissolution/Permeation System for Evaluation of Formulation Effect on Oral Absorption of Poorly Water-Soluble Drugs in Drug Development

Purpose

The aim of the present study is to evaluate the formulation effect on the oral absorption of poorly water-soluble drugs using a dissolution/permeation system (D/P system).

Methods

This D/P system, consisting of apical and basal chambers and a Caco-2 cell monolayer mounted between chambers, can be used to perform simultaneous analysis of drug dissolution and permeation process of drugs applied as various dosage forms. Oral administration study with rats was also performed for both drugs as the same dosage forms.

Results

When danazol, a low-soluble and high-permeable drug, was applied to the D/P system as various formulations, dissolved and permeated amounts were significantly high compared with those from a suspension form. On the other hand, whereas the dissolved amount of pranlukast, a low-soluble and low-permeable drug, was significantly increased by formulations, there were no significant changes observed in the permeated amount between suspension and formulation. The oral availability of danazol was significantly increased by formulations but not pranlukast, which corresponded well to in vitro evaluations.

Conclusion

These results indicated that the D/P system might be applicable for selection of formulation on the basis of physicochemical drug properties.     

Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro–in silico–in vivo approach

Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO₄)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44 μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of C_max and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8–1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f₂ factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro–in silico–in vivo approach.     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz)

Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption.     

Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: Level A in vitro–in vivo correlation

The objective of the present study was to develop a novel in vitro system to simulate the process of dissolution and permeation of oral solid dosage forms in vivo, and to establish a correlation between in vitro permeation and in vivo absorption that could predict the bioavailability (BA) and bioequivalence (BE) of congeneric products. The in vitro dissolution and absorption kinetics of four dosage forms of isosorbide mononitrate (ISMN) were evaluated by the USP basket/paddle system and drug dissolution/absorption simulating system (DDASS). The corresponding pharmacokinetic study was performed in beagle dogs. A comparative study was carried out between the classical and the novel method to estimate the effectiveness of the modified DDASS in simulating the course of dissolution and absorption in vivo. Indeed, the correlation coefficients of in vitro dissolution and in vivo absorption obtained from DDASS and dogs were higher. Moreover, a higher level A in vitro–in vivo correlation (IVIVC) between DDASS permeation and dog absorption was established, with correlation coefficients of 0.9968, 0.9872, 0.9921, and 0.9728. The DDASS method was more accurate at modeling the process of dissolution and absorption in vivo for both immediate-release (IR) and sustained-release (SR) dosage forms of ISMN.     

The Use of Modeling Tools to Drive Efficient Oral Product Design

Modeling and simulation of drug dissolution and oral absorption has been increasingly used over the last decade to understand drug behavior in vivo based on the physicochemical properties of Active Pharmaceutical Ingredients (API) and dosage forms. As in silico and in vitro tools become more sophisticated and our knowledge of physiological processes has grown, model simulations can provide a valuable confluence, tying-in in vitro data with in vivo data while offering mechanistic insights into clinical performance. To a formulation scientist, this unveils not just the parameters that are predicted to significantly impact dissolution/absorption, but helps probe explanations around drug product performance and address specific in vivo mechanisms. In formulation, development, in silico dissolution-absorption modeling can be effectively used to guide: API selection (form comparison and particle size properties), influence clinical study design, assess dosage form performance, guide strategy for dosage form design, and breakdown clinically relevant conditions on dosage form performance (pH effect for patients on pH-elevating treatments, and food effect). This minireview describes examples of these applications in guiding product development including those with strategies to mitigate observed clinical exposure liability or mechanistically probe product in vivo performance attributes.     

Coaxial electrospray formulations for improving oral absorption of a poorly water-soluble drug

Development of oral dosage forms containing poorly water-soluble drugs is a major challenge in the pharmaceutical industry. This paper describes the use of coaxial electrospray deposition as a promising formulation technology for oral delivery of poorly water-soluble drugs. The technology produced core-shell particles composed of griseofulvin and poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100), with a diameter of around 1 μm. The drug phase was in an amorphous state when the griseofulvin core was coated with the Eudragit L-100 shell. The in vitro dissolution and in vivo oral absorption studies revealed that the core-shell formulation significantly improved dissolution and absorption behaviors, presumably because of a reduction in particle size, improvement in dispersity, and amorphization. Results demonstrated that coaxial electrospray deposition possesses great potential as novel formulation technology for enhancing oral absorption of poorly water-soluble drugs.     

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.     

Controlled Release Systems Containing Solid Dispersions: Strategies and Mechanisms

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.     

Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance.

PURPOSE: To develop lipid semisolid formulations of EMD 50733, a poorly soluble, neutral drug candidate and to develop an in vitro-in vivo correlation for these formulations using the dog as the in vivo model. METHODS: The model drug, EMD 50733, (with BCS Class II properties) was dissolved in molten lipid/surfactant mixtures and the melt was filled into hard capsules and allowed to re-solidify at room temperature. The dissolution profiles in bio-relevant dissolution media and the bioavailability in dogs were measured and compared to that of a standard formulation consisting of a lactose/drug mixture. RESULTS: The best results with respect to dissolution, stability upon storage and bioavailability were obtained with a formulation that contained a commercially available lipid mixture (Gélucire 44/14) and a solubilizing agent (2-vinylpyrrolidone). With this formulation it was possible to dissolve a typical drug dose in a fill volume suitable for a #0 capsule. Additionally, surface tension measurements showed that the formulation formed micelles during dissolution in aqueous media: the molecular dispersion of the drug in this self-micelle forming system is postulated to protect the drug from precipitation in vivo as well as in vitro. For other formulations tested, neither the in vitro nor the in vivo performance indicated sufficient drug solubilizing properties. CONCLUSION: To achieve adequate and reliable dissolution of poorly soluble drugs in vivo, lipid excipients should not only have appropriate solubilizing properties for the drug in the formulation, but should also assist in maintaining drug in solution during release in the GI tract.     

In vitro-in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers

The objective of the current study was to develop and evaluate the internal predictability for level C and A in vitro-in vivo correlation (IVIVC) models for prototype modified-release (MR) dosage forms of metformin. In vitro dissolution data for metformin were collected for 22 h using a USP II (paddle) method. In vivo plasma concentration data were obtained from 8 healthy volunteers after administration of immediate-release (IR) and MR dosage forms of metformin. Linear level C IVIVC models were developed using dissolution data at 2.0 and 4.0 h and in vitro mean dissolution time (MDT). A deconvolution-based level A model was attempted through a correlation of percent in vivo input obtained through deconvolution and percent in vitro dissolution obtained experimentally. Further, basic and extended convolution level A IVIVC models were attempted for metformin. Internal predictability for the IVIVC models was assessed by comparing observed and predicted values for C(max) and AUC(INF). The results suggest that highly predictive level C models with prediction errors (%PE) of <5% could be developed. Mean percent in vivo input for metformin was incomplete from all formulations and did not exceed 35% of dose. The deconvolution-based level A models for all MR formulations were curvilinear. However, a unique IVIVC model applicable to all MR formulations could not be developed using the deconvolution approach. The basic convolution level A model, which used in vitro dissolution as the in vivo input, had %PE values as high as 103%. Using an extended convolution approach, which modeled the absorption of metformin using a Hill function, a level A IVIVC model with %PE as low as 11% was developed. In conclusion, the current work indicates that level C and A IVIVC models with good internal predictability may be developed for a permeability- and absorption window-limited drug such as metformin.