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PubMed2006

Recent progress in the computational prediction of aqueous solubility and absorption.

The computational prediction of aqueous solubility and/or human absorption has been the goal of many researchers in recent years. Such an in silico counterpart to the biopharmaceutical classification system (BCS) would have great utility. This review focuses on recent developments in the computational prediction of aqueous solubility, P-glycoprotein transport, and passive absorption. We find that, while great progress has been achieved, models that can reliably affect chemistry and development are still lacking. We briefly discuss aspects of emerging scientific understanding that may lead to breakthroughs in the computational modeling of these properties.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

A critical review of analytical ultracentrifugation and field flow fractionation methods for measuring protein aggregation.

Analytical ultracentrifugation (AUC) and field flow fractionation (FFF) are 2 important biophysical methods for measuring protein aggregates. Both methods can separate protein monomer from its aggregate forms under a broad range of solution conditions. Recent advances in instrumentation and data analysis, particularly in the field of analytical ultracentrifugation technology, have significantly improved the capability and sensitivity of these biophysical methods for detecting protein aggregates. These advances have resulted in an increased use of these methods in the biopharmaceutical industry for characterization of therapeutic proteins. However, despite their many advantages over conventional methods, the difficulty in the use of the instrumentation and the complexity of data analysis process, have often hampered the widespread use and proper interpretation of data. This article reviews the recent progress in both technologies, and a few case studies are also presented to discuss their advantages and limitations.

Biological Products↗

PubMed2003

Colonic drug delivery: an updated review.

Specific targeting of drug to the colon is recognized to have several therapeutic advantages. Drugs that are destroyed by the acidic environment of the stomach or metabolized by pancreatic enzymes are only slightly affected in the colon. Sustained colonic delivery of drugs can be useful in the treatment of nocturnal asthma, angina, and arthritis. Treatment of colonic diseases such as ulcerative colitis, Crohn's disease, and colorectal cancer is more effective with direct delivery of drugs to the colon. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. The anatomy and physiology of the lower gastrointestinal tract is discussed; then the biopharmaceutical aspects are considered in relation to drug absorption in the colon. Various approaches to colon-specific drug delivery are discussed.

Chemistry, Pharmaceutical↗

PubMed2004

Permeability classification of representative fluoroquinolones by a cell culture method.

This study was undertaken to categorize representative fluoroquinolone drug substance permeability based on the methods outlined in the Food and Drug Administration's biopharmaceutic classification system (BCS) Guidance for Industry. The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones drugs demonstrated concentration-dependent permeability, indicating active drug transport. In comparing absorptive versus secretive in vitro transport, the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to labetalol, the high permeability internal standard, ciprofloxacin was classified as a low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were classified as high permeability drugs. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance.

Caco-2 Cells↗

PubMed2005

Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation.

Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline alpha-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1:1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.

Chemistry, Pharmaceutical↗

PubMed2005

Generalization of a prototype intelligent hybrid system for hard gelatin capsule formulation development.

The aim of this project was to expand a previously developed prototype expert network for use in the analysis of multiple biopharmaceutics classification system (BCS) class II drugs. The model drugs used were carbamazepine, chlorpropamide, diazepam, ibuprofen, ketoprofen, naproxen, and piroxicam. Recommended formulations were manufactured and tested for dissolution performance. A comprehensive training data set for the model drugs was developed and used to retrain the artificial neural network. The training and the system were validated based on the comparison of predicted and observed performance of the recommended formulations. The initial test of the system resulted in high error values, indicating poor prediction capabilities for drugs other than piroxicam. A new data set, containing 182 batches, was used for retraining. Ten percent of the test batches were used for cross-validation, resulting in models with R2 > or = 70%. The comparison of observed performance to the predicted performance found that the system predicted successfully. The hybrid network was generally able to predict the amount of drug dissolved within 5% for the model drugs. Through validation, the system was proven to be capable of designing formulations that met specific drug performance criteria. By including parameters to address wettability and the intrinsic dissolution characteristics of the drugs, the hybrid system was shown to be suitable for analysis of multiple BCS class II drugs.

Artificial Intelligence↗

PubMed2005

Diclofenac-beta-cyclodextrin binary systems: physicochemical characterization and in vitro dissolution and diffusion studies.

The aim of this work was to study the influence of beta-cyclodextrin (beta-CD) on the biopharmaceutic properties of diclofenac (DCF). To this purpose the physicochemical characterization of diclofenac-beta-cyclodextrin binary systems was performed both in solution and solid state. Solid phase characterization was performed using differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR). Phase solubility analyses, and in vitro permeation experiments through a synthetic membrane were performed in solution. Moreover, DCF/beta-CD interactions were studied in DMSO by 1H nuclear magnetic resonance (NMR) spectroscopy. The effects of different preparation methods and drug-to-beta-CD molar ratios were also evaluated. Phase solubility studies revealed 1:1 M complexation of DCF when the freeze-drying method was used for the preparation of the binary system. The true inclusion for the freeze-dried binary system was confirmed by 1H NMR spectroscopy, DSC, powder XRD, and IR studies. The dissolution study revealed that the drug dissolution rate was improved by the presence of CDs and the highest and promptest release was obtained with the freeze-dried binary system. Diffusion experiments through a silicone membrane showed that DCF diffusion was higher from the saturated drug solution (control) than the freeze-dried inclusion complexes, prepared using different DCF-beta-CD molar ratios. However, the presence of the inclusion complex was able to stabilize the system giving rise to a more regular diffusion profile.

Chemical Phenomena↗

PubMed2001

Effectiveness of repeated administration of a new oral naltrexone controlled-release system on morphine analgesia.

Naltrexone hydrochloride, an opioid antagonist used as an adjunct to the maintenance of the opioid-free state for detoxified individuals, was introduced into the polymeric structure of Eudragit L30D, an anionic copolymer based on polymethacrylic acid and ethylacrylate. From the results of a preclinical study, this complexation technique can be considered as a useful tool in the design of oral controlled-release systems (naltrexone-Eudragit L) capable of inducing long-lasting effects in-vivo. The biopharmaceutical characterization of the naltrexone-Eudragit L complex in comparison with naltrexone hydrochloride using the mouse hot-plate model has been previously carried out. The results showed a longer effect, an enhancement of 23.47% of the area under the curve of the inhibition of analgesic activity vs time, and a delay of 51.80% in the t1/2 value induced by the complex, compared with those induced by conventional naltrexone. In this study, a regimen of chronic administration of naltrexone-Eudragit L was established. Thus, in an 8-day treatment (4 doses in alternate days) this oral controlled-release system effectively antagonized the analgesic effect of morphine for 8 h, whereas naltrexone hydrochloride has to be administered over 16 days (8 doses in alternate days) to induce the same effect. In the 16-day schedule the complex-induced antagonism lasted over 14 h after administration.

Administration, Oral↗

PubMed2002

Biorelevant dissolution testing of St John's wort products.

In contrast to chemically defined drugs, most herbal medicinal products (HMPs) are poorly characterized in terms of their pharmaceutical properties. In many cases it is assumed that the plant extract as a whole is the active moiety, since it is often difficult to identify the individual components responsible for the pharmacological activity and even more difficult to assess synergies among the various components. However, where the active components have been identified, it should be possible to compare products with respect not only to content uniformity but also to their biopharmaceutical properties. The aim of this study was to investigate and compare the dissolution characteristics of several St John's wort products under biorelevant conditions. Components of St John's wort known, or suspected, to play a role in its antidepressant activity include phloroglucines, naphthodianthrones and the flavonoids. Since these groups have a broad spectrum of polarity and solubility, dissolution was studied for representative compounds from each group. Although the labelling indicates that several of the products studied should be pharmaceutically equivalent, dissolution under biorelevant conditions revealed that they have quite different release profiles and cannot be considered switchable. It was concluded that biorelevant dissolution testing can be a powerful tool for comparing HMPs as well as synthetically produced drug products.

Antidepressive Agents↗

PubMed2002

Solvent change co-precipitation with hydroxypropyl methylcellulose phthalate to improve dissolution characteristics of a poorly water-soluble drug.

Research compound GWX belongs to biopharmaceutical classification system type II, and hence shows dissolution-rate-limited absorption. To improve its dissolution performance, GWX was formulated as a co-precipitate with hydroxypropyl methylcellulose phthalate (HPMCP). Co-precipitates with various drug-HPMCP ratios were prepared and characterised using modulated differential scanning calorimetry (MDSC), X-ray powder diffraction, HPLC and dissolution testing. Co-precipitates with 1:9 and 2:8 drug-HPMCP ratios showed the highest extent of dissolution after both 5 and 90 min, followed by 3:7, 4:6, and 5:5 drug-HPMCP co-precipitates, in respective order. Co-precipitates with drug-HPMCP ratios of 6:4 and greater showed no significant improvement in dissolution over crystalline drug alone. The amounts of crystalline and amorphous drug in co-precipitates, as determined by MDSC, and HPLC quantification of the total amount of drug in co-precipitates were used to determine the amount of drug incorporated into solid solution. It was found that dissolution rate and extent was correlated to the amount of drug incorporated into amorphous solid solution for the 1:9 to 5:5 drug-HPMCP ratio co-precipitates. Amorphous drug alone and physical mixtures of drug and HPMCP showed very little and no significant improvement in dissolution rate or extent, respectively, above crystalline drug alone. Amorphous drug alone re-crystallized to a large extent within 1 min of contact with the dissolution medium, whereas 4:6 drug-HPMCP co-precipitate showed a lower degree of re-crystallization and 2:8 drug-HPMCP co-precipitate showed very little re-crystallization. It was concluded that the likely mechanisms of improved dissolution of low drug-HPMCP ratio co-precipitates were improved wetting or increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form and inhibition of re-crystallization, when drug was incorporated into solid solution.

Biological Availability↗

PubMed2004

Eudragit RL100 nanoparticle system for the ophthalmic delivery of cloricromene.

A Eudragit RL100 polymer nanoparticle system loaded with cloricromene was prepared and characterized on the basis of physicochemical properties, stability and drug release features. To investigate the ocular bioavailability of cloricromene after inclusion in the polymer matrix, the new nanoparticle system was topically administered in the rabbit eye and compared with an aqueous solution of the same drug. The nanoparticle system showed interesting size distribution and surface charge values, suitable for ophthalmic application. The results indicated that the dispersion of cloricromene within Eudragit RL100 polymer nanoparticles increased its ocular bioavailability and enhanced the biopharmaceutical profile. The new cloricromene-loaded nanoparticle system described here may be useful in clinical practice.

Acrylic Resins↗

PubMed2006

Fast-dissolving microparticles fail to show improved oral bioavailability.

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.

Administration, Oral↗

PubMed2006

In-vitro and in-vivo assays for angiogenesis-modulating drug discovery and development.

In the past 35 years, significant findings have been made in relation to angiogenesis, and how this usually normal physiological function is converted into an abnormal state in cancer. To search for agents that can inhibit angiogenesis, and thereby prevent a tumour from proliferation and spread that is ultimately fatal to the patient, various in-vitro assays have been developed. In addition, older assays have been refined usually into high throughput screening formats, mainly by the biopharmaceutical industry in their attempts to develop novel therapeutic molecules and maintain a pipeline of lead candidates. The central aim is to extract more accurate data that would facilitate the birth of innovative mechanisms to defeat aberrant angiogenesis in-vivo. At the same time, better in-vivo models have been established, with the goal to mimic as close as possible the natural progression of various types of neoplasms in response to a good angiogenic response. More clinically relevant models are needed as anti-angiogenesis drug discovery and drug development companies fast track their lead molecules from preclinical investigations to phase I clinical trials.

Angiogenesis Inhibitors↗

PubMed2007

Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule?

Sodium bicarbonate (sodium hydrogen carbonate) is used as an oral medication in disorders such as mild metabolic acidosis and chronic kidney disease. The two commercial products on the German market, bicaNorm and Nephrotrans, and also newly developed multiple-unit pellet formulations, have been characterized in these investigations by in-vitro methods like disintegration and dissolution testing. Both marketed products containing sodium bicarbonate are of sufficient pharmaceutical quality according to the European Pharmacopoeia. However, they and the novel pellet preparations showed different drug release at moderately elevated pH values. Early drug release may cause dose dumping in the stomach and adverse drug effects from the developed carbon dioxide. The soft capsule preparation (Nephrotrans) released the smallest amount of sodium bicarbonate at pH 1 and 4.5 of all formulations tested. It appeared that oral dosage formulations of sodium bicarbonate were an exception to the rule: the monolithic soft capsule seemed to be superior to an enteric-coated tablet as well as to multiple-unit pellet formulations from the biopharmaceutical point of view. Our results correspond with individual reports on adverse effects from patients treated with the sodium bicarbonate products.

Capsules↗

PubMed1998

Fractional absorption of L-carnitine after oral administration in rats: evaluation of absorption site and dose dependency.

We evaluated the fractional absorption of L-carnitine, a gamma-amino acid essential cofactor for the transfer of long-chain fatty acids, in rats in vivo after oral administration to determine its absorption behavior. At both low (0.05 micromol/rat) and high (100 micromol/rat) doses, L-carnitine was recovered only from the region of the cecum and below at 10 h after administration. During a major shift in distribution from cecum at 10 h to feces at 24 h, there was no significant change in the total recovery at each dose, suggesting that L-carnitine absorption is negligible in the cecum and the large intestine (colon and rectum). However, the recovery of L-carnitine was incomplete and the fraction recovered was larger at the high dose than at the low dose. The fractions absorbed were estimated to be 96.7 and 33.0% for the low and high doses, respectively, as these were the fractions that disappeared from the gastrointestinal tract. These values were comparable with 100 and 42%, respectively, of bioavailability values by the pharmacokinetic analysis of plasma concentration data in our preceding study [Matsuda et al., Biopharmaceutics & Drug Disposition, in press]. These results suggest that L-carnitine is significantly absorbed only in the small intestine, without undergoing first-pass degradation, and in a dose-dependent manner presumably due to the involvement of saturable transport by L-carnitine carriers. Consistent with the suggestions in vivo, L-carnitine absorption in the closed intestinal loop in situ was concentration-dependent in the small intestine but not in the large intestine, and the apparent membrane permeability in the large intestine was smaller by an order of magnitude than that of passive transport in the small intestine. These findings support our preceding kinetic modeling strategy assuming the small intestine to be the sole absorption site, and should be of help in guiding studies on development of more efficient oral L-carnitine delivery strategies.

Administration, Oral↗

PubMed1999

Structural characterization of recombinant human erythropoietins by fluorophore-assisted carbohydrate electrophoresis.

Routine analysis of the carbohydrate moieties of a glycoprotein is critical for ensuring the consistent quality of biopharmaceutical products. Fluorophore-assisted carbohydrate electrophoresis (FACE) is a recently introduced method for the separation, by polyacrylamide gel electrophoresis, of oligosaccharides labeled with 8-amino-naphthalene-1,3,6-trisulphonic acid (ANTS). In this study, we have evaluated the applicability of the FACE method to analysis of the carbohydrate moieties of three different recombinant human erythropoietins (rHuEPOs), two Chinese hamster ovary (CHO) cell-derived rHuEPOs, and one baby hamster kidney (BHK) cell-derived rHuEPO. The N-linked oligosaccharides released from the rHuEPOs were labeled with ANTS. Enzymic sequence analysis of the N-linked oligosaccharides was performed by the FACE method. The results showed that the FACE method was useful for the analysis of sialo-, asialo-, and agalacto-oligosaccharides in the same gel. Its usefulness for rapidly and reliably revealing the oligosaccharide profiles of given glycoproteins, and its reproducibility were also confirmed in this study. In conclusion, the method can be used for evaluating the quality consistency of recombinant glycoprotein products in terms of the carbohydrate moiety.

Animals↗

PubMed2004

Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib.

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.

Administration, Oral↗

PubMed2002

Development of a simple HPLC method for determination of paeoniflorin-metabolizing activity of intestinal bacteria in rat feces.

A simple and reproducible HPLC method for the determination of paeoniflorin (PF)-metabolizing activity of intestinal bacteria in rat feces was developed and validated. Orally administered PF, a major active constituent of Paeoniae Radix, is metabolized into a bioactive compound, paeonimetabolin I (PM-I) by intestinal bacteria. Direct determination of the PF-metabolizing rate into PM-I is hard to achieve by HPLC due to the lack of intense chromophore in PM-I. However, when PF was incubated with Lactobacillus brevis, an intestinal bacterium, in the presence of phenylmercaptan, the metabolizing rate of PF into 8-phenylthio-paeonimetabolin I (PT-PM-I) was found to be equivalent to that of PF into PM-I. Thus, the PF-metabolizing activity of intestinal bacteria in rat feces was determined by measuring the rate of biotransformation of PF into PT-PM-I, which was detected by HPLC at 255 nm. This method can be utilized in the biopharmaceutical study of traditional Chinese formulations containing Paeoniae Radix.

Animals↗