Claudia S. Leopold

Coated dosage forms for colon-specific drug delivery.

Coating materials used in the manufacture of colon-specific solid oral dosage forms include polymers with a pH-dependent solubility that rely on the difference in pH between the small and the distal large intestine (pH-controlled release), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion that take advantage of the constant small intestinal transit time (time-controlled release), polymers that are degradable by the microbial enzymes in the colon (enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase of the luminal pressure in the colon caused by peristaltic waves (pressure-controlled release). This review gives an overview of coated dosage forms that have been developed to achieve colon specificity.

An Attempt to Clarify the Mechanism of the Penetration Enhancing Effects of Lipophilic Vehicles with Differential Scanning Calorimetry (DSC)

In a previous in‐vivo skin penetration study, it was observed that certain lipophilic liquid vehicles enhanced drug penetration, whilst others did not.

Basic coating polymers for the colon-specific drug delivery in inflammatory bowel disease.

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit® E or AEA® in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100–200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.

Drug release from liquisolid systems: speed it up, slow it down

Introduction: Today, the properties of many new chemical entities have shifted towards higher molecular weights and this in turn increases the lipophilicity hence decreasing aqueous solubility. The low solubility of drugs usually has in vivo consequences such as low bioavailability, increased chance of food effect and incomplete release from the dosage form. Areas covered: The present review discusses the advantages of the liquisolid technology in formulation design of poorly water soluble drugs for dissolution enhancement and highly water soluble drugs for slow release pattern. Expert opinion: With the advent of high throughput screening and combinatorial chemistry, it has been shown that most of the new chemical entities have a high lipophilicity and poor aqueous solubility, hence poor bioavailability. In order to improve the bioavailability, the release rate of these drugs should be enhanced. Although there are multiple technologies to tackle this issue, they are not cost effective due to the involvement of sophisticated machinery, advanced preparation techniques and complicated technology. As the liquisolid technology uses a similar production process as the conventional tablets, this technology to improve the release rate of poorly water soluble drugs will be cost effective. This technology also has the capability to slow down drug release and allows preparing sustained release tablets with zero order drug release pattern. The excipients required for this technology are conventional and commonly available in the market. The technology is in the early stages of its development with extensive research currently focused on. It is envisaged that the liquisolid compacts could play a major role in the next generation of tablets.

Suitability of various excipients as carrier and coating materials for liquisolid compacts

Context: The liquisolid technology is a promising technique for the release enhancement of poorly soluble drugs. With this approach, liquids such as solutions or suspensions of poorly soluble drugs in a non-volatile liquid vehicle are transformed into acceptably flowing and compressible powders. As fast-release liquisolid compacts require a high amount of liquid vehicle, more effective tableting excipients for liquid adsorption are needed to reduce tablet weight. Objective: The aim of this study was to investigate the suitability of various novel tableting excipients as carrier and coating materials for liquisolid compacts. Materials and methods: Liquisolid compacts containing the liquid drug tocopherol acetate (TA) as model drug and various excipients were prepared. The effect of liquid drug content on the flowability and tabletability of the liquisolid powder blends as well as the disintegration of the liquisolid compacts was studied. From this data, the maximum liquid adsorption capacity of the respective mixtures of carrier and coating materials could be determined. Results and discussion: The liquid adsorption capacity depends on the specific surface area of the investigated excipients. Fujicalin® and especially Neusilin® are more effective carrier materials for liquid adsorption than Avicel®, which is often used for liquisolid systems. Moreover, Florite® and Neusilin® turned out to be more suitable as coating materials than the commonly used Aerosil® due to their better tableting properties. Conclusion: If Neusilin® is used as carrier and coating material instead of Avicel® (carrier material) and Aerosil® (coating material), the TA adsorption capacity is increased by a factor of 7.

Eudragit@ E as Coating Material for the pH-Controlled Drug Release in the Topical Treatment of Inflammatory Bowel Disease (IBD)

During an attack of ulcerative colitis the colonic pH of normally 6.4-7.0 drops to values of 2.3-4.7. The objective of this study was to investigate an acid-soluble polymer (Eudragit E) as coating material for multiple units (mini tablets) with regard to its ability to allow drug release only under the acidic conditions of the inflamed colon. Mini tablets (diameter 3 mm) containing 20% (w/w) of the model drug dexamethasone with or without the mucoadhesive swelling agent carbomer 934 (neutralized) were coated in a small coating pan with different amounts of an organic solution of Eudragit E leading to coating thicknesses of 150-400 microm. Drug release from the Eudragit E-coated cores at pH 2.0-5.0 starts after 10-50 min due to the rapid dissolution of the Eudragit E film. At pH 6.8 lag times of drug release depend on the composition of the cores and the thickness of the coating film: In the case of the carbomer-containing cores drug release is induced by disruption of the coating film due to swelling of the cores and lag times (up to 20 h) increase overproportionately with increasing coating thickness. With no swelling agent in the cores drug release at pH 6.8 is delayed due to the low erosion/dissolution rate of Eudragit E. Lag times of drug release (up to 33 h) increase in a linear manner with increasing coating thickness. Thus, Eudragit E, protected against dissolution in the stomach by an enteric coating, is a suitable coating polymer for drug release in acidic regions such as the inflamed colon.

Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach. Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.

Degradation of omeprazole induced by enteric polymer solutions and aqueous dispersions: HPLC investigations.

Two reversed-phase high-performance liquid chromatography (RP-HPLC) methods were developed to investigate the degradation of the acid-labile proton-pump-inhibitor omeprazole in organic polymer solutions and aqueous dispersions of enteric coating polymers (Eudragit® L-100, S-100, CAP, HP-55, HPMCAS-HF, -LF, and shellac). The overall goal of the study was to determine the influence of the polymer structure on the degradation of omeprazole, i.e., whether the acid structure of the enteric coating polymers caused an instability of the proton pump inhibitor. Moreover, it was investigated whether a difference in omeprazole degradation could be detected between organic polymer solutions and aqueous dispersions. pKa values of the polymers and pH values of the aqueous dispersions were determined to see whether there was a correlation with the extent of degradation of omeprazole induced by enteric polymers. As the polymers containing phthalate moieties are very susceptible to hydrolysis, the influence of free phthalic acid on omeprazole stability was investigated. Finally, the degradation kinetics of omeprazole in organic polymer solutions were determined. Omeprazole degradation is more pronounced in aqueous polymer dispersions than in organic polymer solutions. The influence of organic polymer solutions on the stability of omeprazole depends on the amount of acidic groups in the polymeric structure, whereas the influence of aqueous polymer dispersions depends on the pH value of the dispersion. The amount of free acids present in some polymers as by-products also cause a degradation of the proton pump inhibitor. Among all investigated polymers, shellac showed the least influence on the stability of omeprazole. The decomposition of omeprazole in organic polymer solutions followed first-order kinetics. The decrease of omeprazole peak area in organic polymer solutions was in the order Eudragit® L-100 > HPMCAS-HF > shellac.

Pharmacodynamics and dermatopharmacokinetics of betamethasone 17-valerate: assessment of topical bioavailability.

Background  The bioavailability of most topically delivered drugs is difficult to quantify, but is generally believed to be very low. With the exception of the vasoconstrictor assay for corticosteroids, no methodology to quantify the rate and extent of drug delivery to the skin has been validated. Recent research has examined the dermatopharmacokinetic (DPK) technique, which is based on stratum corneum (SC) tape‐stripping.

Investigation of the Formation Process of Two Piracetam Cocrystals during Grinding

Cocrystal formation rates during dry grinding and liquid-assisted grinding were investigated by X-ray powder diffractometry and Raman spectroscopy. Two polymorphic forms of piracetam were used to prepare known piracetam cocrystals as model substances, i.e., piracetam-citric acid and piracetam-tartaric acid cocrystals. Raman spectroscopy in combination with principal component analysis was used to visualize the cocrystal formation pathways. During dry grinding, cocrystal formation appeared to progress via an amorphous intermediate stage, which was more evident for the piracetam-citric acid than for the piracetam-tartaric acid cocrystal. It was shown that liquid-assisted grinding led to faster cocrystal formation than dry grinding, which may be explained by the higher transformation rate due to the presence of liquid. The cocrystal formation rate did not depend on the applied polymorphic form of the piracetam and no polymorphic cocrystals were obtained.