Thomas Rades

Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers

Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution‐related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone‐co‐vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X‐ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physicochemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H‐bonding) between the carbonyl group of the pyrrole ring of the polymer and a H‐donor group of the drug. Indomethacin also showed evidence of H‐bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4–8 weeks at 25°C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25°C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H‐bonding between the components.

Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting--a review.

Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques for the physical characterization of pharmaceutical drug materials and final solid dosage forms, utilizing spectral information in the far infrared region of the electromagnetic spectrum. This review focuses on the development and performance of pharmaceutical applications of terahertz technology compared with other tools for physical characterization. TPS can be used to characterize crystalline properties of drugs and excipients. Different polymorphic forms of a drug can be readily distinguished and quantified. Recent developments towards a better understanding of the fundamental theory behind spectroscopy in the far infrared have been discussed. Applications for TPI include the measurement of coating thickness and uniformity in coated pharmaceutical tablets, structural imaging and 3D chemical imaging of solid dosage forms.

Emerging trends in the stabilization of amorphous drugs

The number of active pharmaceutical substances having high therapeutic potential but low water solubility is constantly increasing, making it difficult to formulate these compounds as oral dosage forms. The solubility and dissolution rate, and thus potentially the bioavailability, of these poorly water-soluble drugs can be increased by the formation of stabilized amorphous forms. Currently, formulation as solid polymer dispersions is the preferred method to enhance drug dissolution and to stabilize the amorphous form of a drug. The purpose of this review is to highlight emerging alternative methods to amorphous polymer dispersions for stabilizing the amorphous form of drugs. First, an overview of the properties and stabilization mechanisms of amorphous forms is provided. Subsequently, formulation approaches such as the preparation of co-amorphous small-molecule mixtures and the use of mesoporous silicon and silica-based carriers are presented as potential means to increase the stability of amorphous pharmaceuticals.

An overview of recent studies on the analysis of pharmaceutical polymorphs.

Pharmaceutical solids are well known to be able to exist in different solid-state forms and there are a wide variety of solid-state analytical techniques available to characterize pharmaceutical solids and solid-state transformations. In this review, the commonly used solid-state analytical techniques, the type of information collected, and advantages and disadvantages of each technique are discussed, with the focus on their application in solid-state characterization and monitoring solid-state transformations, such as amorphization, crystallization, hydrate formation/dehydration and cocrystal formation. The information gathered from recent literature is compiled in various tables to aid the reader to get a quick overall picture about what type of phenomena have recently been studied and which analytical technique(s) have been used.

Liposomal delivery of antigen to human dendritic cells

This study investigated whether formulation of antigen in mannosylated liposomes enhanced uptake and activation of dendritic cells (DC) and increased the ability of DC to induce primed T cell proliferation compared to formulation of antigen in unmodified liposomes or in solution. Immature human DC were generated from peripheral blood monocytes cultured with GM-CSF and IL-4. Uptake of antigen by DC and the degree of expression of the cell surface markers MHC class II, CD80, CD86 and the DC maturation marker CD83, was investigated by flow cytometry following incubation with liposomes or solution containing FITC-conjugated antigen. Exposure to liposomes containing FITC-ovalbumin resulted in enhanced expression of cell surface markers when compared to exposure to antigen in solution. Expression was highest following exposure to mannosylated liposomes. Mannosylated liposomes containing tetanus toxoid (TT) stimulated primed T cell proliferation more effectively than TT-neutral liposomes or TT-solution. This work suggests that mannosylated liposomes provide a versatile delivery vehicle for initiating enhanced immune responses to encapsulated peptide or protein vaccines.

New perspectives on lipid and surfactant based drug delivery systems for oral delivery of poorly soluble drugs

Objectives  The aim of this review is to highlight relevant considerations when implementing a rational strategy for the development of lipid and surfactant based drug delivery system and to discuss shortcomings and challenges to the current classification of these delivery systems. We also aim to offer suggestions for an improved classification system that will accommodate lipid based formulations that are not currently accommodated in the lipid formulation classification system.

Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen

One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T(g)), and the results were compared with predicted T(g)s from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T(g)s displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T(g)s.

Preparation of biodegradable insulin nanocapsules from biocompatible microemulsions

AbstractPurpose. To prepare poly(ethyl 2-cyanoacrylate) nanocapsulescontaining insulin by interfacial polymerization of spontaneously forming,biocompatible microemulsions. Methods. A pseudo-ternary phase diagram of a mixture of mediumchain glycerides (caprylic/capric triglycerides and mono-/diglycerides),a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) andwater was constructed. Polarizing light microscopy was used to identifycombinations forming microemulsions. Microemulsions werecharacterized by conductivity and viscosity to select systems suitable for thepreparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacialpolymerization. Nanocapsules were prepared by addition of 100 mgof ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsioncontaining 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. Thenanocapsules formed were characterized by photon correlation spectroscopy,freeze fracture transmission and scanning electron microscopy. Insulinnanocapsules were prepared by using an aqueous solution of insulin(100 units/ml) as the dispersed phase of the microemulsion. Theentrapment and the release of insulin from the nanocapsules were determined. Results. Three regions were identified in the pseudo-ternary phasediagram; a microemulsion region, a region in which liquid crystallinestructures were present and a coarse emulsion region. All systems inthe microemulsion region were water-in-oil dispersions.Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nmwere formed upon interfacial polymerization of the microemulsion.Nanocapsules were found to have a central cavity surrounded by apolymer wall. In excess of 80;pc of the insulin present in themicroemulsion was encapsulated upon interfacial polymerization. Conclusions. Interfacial polymerization of spontaneously formingwater-in-oil microemulsions represents a convenient method for thepreparation of poly(alkylcyanoacrylate) nanocapsules suitable for theentrapment of bioactive peptides.

Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen-cimetidine mixtures prepared by mechanical activation.

Naproxen, a non-steroidal anti-inflammatory drug (NSAID), is a biopharmaceutics classification system (BCS) class II drug whose bioavailability is rate-limited by its dissolution. Cimetidine is sometimes co-administered with naproxen for the treatment of NSAID-induced gastro-intestinal disorders. Hence, there is interest in the design of new formulations that offer (1) concomitant release of both drugs, and (2) an enhanced dissolution rate of naproxen. This study investigates the formation of amorphous binary systems with naproxen and cimetidine. The binary mixtures of all tested molar ratios were found to become amorphous upon co-milling for 60 min at 4 degrees C. In contrast, pure naproxen could not be transformed to the amorphous state by mechanical activation. The 1:1 sample was the most physically stable when stored for 33 days at 40 degrees C, even though it did not have the highest T(g) when compared to the 1:2 sample. The 1:1 sample was further stored for 186 days and remained amorphous under all conditions. Raman spectroscopy suggested a 1:1 solid-state interaction between the imidazole ring of cimetidine and the carboxylic acid moiety of naproxen in the co-milled amorphous sample. Thus, the stabilization of the amorphous binary system is dictated by molecular-level interactions rather than bulk-level phenomena. No recrystallization of either drug in the 1:1 co-milled sample was observed during dissolution testing, with naproxen and cimetidine having a four and two times higher intrinsic dissolution rate, respectively, compared to their crystalline counterparts. Further, the release of the two drugs could be synchronized using this formulation approach.

Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs.

A silica-lipid hybrid (SLH) microcapsule system for oral delivery of poorly water-soluble drugs is reported for the first time. For the model drug celecoxib (CEL), SLH microcapsules composed of medium-chain triglycerides, lecithin and silica nanoparticles; with an internal porous matrix structure, were shown to offer several physicochemical and biopharmaceutical advantages in comparison with unmodified drug, lipid emulsion, dry emulsion and the commercial product, Celebrex. DSC and XRD analyses confirmed non-crystalline CEL in SLH microcapsules and verified medium term physical stability. Dissolution under sink conditions revealed a 2- to 5-fold increase in dissolution efficiencies (%DE) and significantly reduced t(50%) (> or =50-fold) for CEL formulated as SLH microcapsules. Orally dosed in vivo studies in rats demonstrated superior pharmacokinetics for SLH microcapsules. Specifically, the fasted-state bioavailability (F) was statistically higher (p<0.05) than for aqueous suspension, lipid solution, o/w emulsion and a maltodextrin-stabilised dry emulsion, and was greater than for Celebrex. SLHs showed the highest maximum plasma concentration (C(max)) among all tested formulations (p<0.05). Linear correlations were observed between %DE and the pharmacokinetic parameters (F and C(max)). It is postulated that SLH microcapsules improve CEL oral absorption via dissolution enhancement, potentially in conjunction with other unexplored mechanisms, hence offering the possibility of dose reduction for improved therapeutic efficacy and cost-effectiveness of poorly soluble drugs.