Maxim Puchkov

Drug loading into porous calcium carbonate microparticles by solvent evaporation

Drug loading into porous carriers may improve drug release of poorly water-soluble drugs. However, the widely used impregnation method based on adsorption lacks reproducibility and efficiency for certain compounds. The aim of this study was to evaluate a drug-loading method based on solvent evaporation and crystallization, and to investigate the underlying drug-loading mechanisms. Functionalized calcium carbonate (FCC) microparticles and four drugs with different solubility and permeability properties were selected as model substances to investigate drug loading. Ibuprofen, nifedipine, losartan potassium, and metronidazole benzoate were dissolved in acetone or methanol. After dispersion of FCC, the solvent was removed under reduced pressure. For each model drug, a series of drug loads were produced ranging from 25% to 50% (w/w) in steps of 5% (w/w). Loading efficiency was qualitatively analyzed by scanning electron microscopy (SEM) using the presence of agglomerates and drug crystals as indicators of poor loading efficiency. The particles were further characterized by mercury porosimetry, specific surface area measurements, differential scanning calorimetry, and USP2 dissolution. Drug concentration was determined by HPLC. FCC-drug mixtures containing equivalent drug fractions but without specific loading strategy served as reference samples. SEM analysis revealed high efficiency of pore filling up to a drug load of 40% (w/w). Above this, agglomerates and separate crystals were significantly increased, indicating that the maximum capacity of drug loading was reached. Intraparticle porosity and specific surface area were decreased after drug loading because of pore filling and crystallization on the pore surface. HPLC quantification of drugs taken up by FCC showed only minor drug loss. Dissolution rate of FCC loaded with metronidazole benzoate and nifedipine was faster than the corresponding FCC-drug mixtures, mainly due to surface enlargement, because only small fractions of amorphous drug (12.5%, w/w, and 8.9%, w/w, respectively) were found by thermal analysis. Combination of qualitative SEM analysis and HPLC quantification was sufficient to proof the feasibility of the solvent-evaporation method for the loading of various drugs into FCC. Mechanistic investigation revealed that a high specific surface area of the carrier is required to facilitate heterogeneous nucleation, and large pore sizes (up to 1 μm) are beneficial to reduce crystallization pressures and allow drug deposition within the pores. The solvent-evaporation method allows precise drug loading and appears to be suitable for scale-up.

Spray Freeze Drying in a Fluidized Bed at Normal and Low Pressure

The aim of this study is to develop the spray freeze drying process and its hardware and to investigate its capabilities to dry thermosensible substances such as pharma-proteins at normal and low pressures. As the result, the spray freeze fluidized–bed dryer was constructed. During the study, the drying kinetic comparison between classical and spray freeze–drying technologies was done. Spray freeze drying has shown short process times and allows advanced control, product particle shape and size uniformity, and high solubility. This shows that the fluidized-bed freeze-drying process could be an alternative for classical freeze-drying processes. Identified problems are the low yield of the primary drying phase and the strong electrostatic effects during the secondary drying step. However, the innovative process has shown an excellent capability to dry and stabilize the thermosensitive substances, such as pharma-proteins.

Floating gastroretentive drug delivery systems: Comparison of experimental and simulated dissolution profiles and floatation behavior

INTRODUCTION Gastroretentive drug delivery systems (GRDDS) play an important role in the delivery of drug substances to the upper part of the gastrointestinal tract; they offer a possibility to overcome the limited gastric residence time of conventional dosage forms. AIMS The aim of the study was to understand drug-release and floatation mechanisms of a floating GRDDS based on functionalized calcium carbonate (FCC). The inherently low apparent density of the excipient (approx. 0.6 g/cm(3)) enabled a mechanism of floatation. The higher specific surface of FCC (approx. 70 m(2)) allowed sufficient hardness of resulting compacts. The floating mechanism of GRDDS was simulated in silico under simulated acidic and neutral conditions, and the results were compared to those obtained in vitro. METHODS United States Pharmacopeia (USP) dissolution methods are of limited usefulness for evaluating floating behavior and drug release of floating dosage forms. Therefore, we developed a custom-built stomach model to simultaneously analyze floating characteristics and drug release. In silico dissolution and floatation profiles of the FCC-based tablet were simulated using a three-dimensional cellular automata-based model. RESULTS In simulated gastric fluid, the FCC-based tablets showed instant floatation. The compacts stayed afloat during the measurement in 0.1 N HCl and eroded completely while releasing the model drug substance. When water was used as dissolution medium, the tablets had no floating lag time and sank down during the measurement, resulting in a change of release kinetics. CONCLUSIONS Floating dosage forms based on FCC appear promising. It was possible to manufacture floating tablets featuring a density of less than unity and sufficient hardness for further processing. In silico dissolution simulation offered a possibility to understand floating behavior and drug-release mechanism.

Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface

In the present study, we aimed to characterize the compressibility and compactibility of the novel pharmaceutical excipient, functionalized calcium carbonate (FCC). We studied three FCC modifications and compared the values for compressibility and compactibility with mannitol, microcrystalline cellulose (MCC), and ground calcium carbonate (CC 330) as well as mixtures of paracetamol and MCC or FCC at drug loads of 0%, 25%, 50%, 75%, and 100% (w/w). We used Heckel analysis, modified Heckel analysis, and Leuenberger analysis to characterize the compaction and compression behavior of the mixtures. Compaction analysis of FCC showed this material to markedly differ from ground calcium carbonate, exhibiting properties, i.e. plastic deformability, similar to those of MCC. This effect was attributed to the highly lamellar structure of FCC particles whose thickness is of the order of a single crystal unit cell. According to Leuenberger parameters, we concluded that FCC-based tablet formulations had mechanical properties equal or superior to those formulated with MCC. FCC tablets with high tensile strength were obtained already at low compressive pressures. Owing to these favorable properties (i.e. marked tensile strength and porosity), FCC promises to be suitable for the preparation of solid dosage forms.

Efficacy and safety of oxantel pamoate in school-aged children infected with Trichuris trichiura on Pemba Island, Tanzania: a parallel, randomised, controlled, dose-ranging study

BACKGROUND Commonly used drugs for preventive chemotherapy against soil-transmitted helminths (ie, albendazole and mebendazole) show low efficacy against Trichuris trichiura. Recent studies with oxantel pamoate revealed good cure rates and high egg-reduction rates against T trichiura. We aimed to assess the nature of the dose-response relation to determine the optimum dose. METHODS We did a parallel, randomised, placebo-controlled, single-blind trial with oxantel pamoate in school-aged children (aged 6-14 years) infected with T trichiura on Pemba Island, Tanzania. Children were asked to provide two stool samples and children positive for T trichiura were eligible to participate in the trial. Children were excluded if they suffered from any systematic illness. Children were randomly assigned to six different oxantel pamoate doses (5-30 mg/kg) or a placebo. Randomisation was stratified by baseline infection intensity using random block sizes of seven and 14. The primary endpoints were cure rates and egg-reduction rates against T trichiura, both analysed by available case. Drug safety was assessed 2 h and 24 h after treatment. The trial is registered at www.isrctn.com, number ISRCTN86603231. FINDINGS Between Oct 14, and Nov 28, 2014, we enrolled 480 participants and randomly assigned 350 children to the different oxantel pamoate doses or the placebo. 5 mg/kg oxantel pamoate was the minimum effective dose (10 of 46 children cured [cure rate 22%, 95% CI 11-36]; egg-reduction rate 85·0%, 64·5-92·9). An increased probability of being cured and reduced egg counts with escalating doses was recorded. At 25 mg/kg oxantel pamoate 27 of 45 children were cured (cure rate 60%, 95% CI 44-65) with an egg-reduction rate of 97·5% (94·4-98·9), and at 30 mg/kg 27 of 46 children were cured (59%, 43-73) with an egg-reduction rate of 98·8% (96·8-99·6). Oxantel pamoate was well tolerated across all treatment groups; only mild adverse events were reported by the participants 2 h (27 [10%]) and 24 h (12 [4%]) after treatment. INTERPRETATION Our dose-finding study revealed an excellent tolerability profile of oxantel pamoate in children infected with T trichiura. An optimum therapeutic dose range of 15-30 mg/kg oxantel pamoate was defined. With a weight independent dose of 500 mg oxantel pamoate 95% of children aged 7-14 years in sub-Saharan Africa would receive doses of 11·7-32·0 mg/kg. Future research should include studies with oxantel pamoate in younger children and on different continents with the ultimate goal to be able to add oxantel pamoate to soil-transmitted helminth control programmes. FUNDING Swiss National Science Foundation.

Toward better understanding of powder avalanching and shear cell parameters of drug-excipient blends to design minimal weight variability into pharmaceutical capsules

Powder flow of mixtures is complex and not properly understood. The selection of drug-excipient blends with inadequate powder flow can lead to quality issues of the final dosage form. Therefore, this work aims at a better understanding of how changes in powder flow of binary blends can lead to weight variability in pharmaceutical capsule filling. We used image-analysis-based powder avalanching and shear cell testing to study blends of paracetamol and microcrystalline cellulose. A pilot-scale machine with dosator principle was employed for encapsulation. As a result, the powder flow properties improved generally with rising amounts of microcrystalline cellulose. However, a negative correlation was observed between avalanche angle and angle of internal friction. Results were discussed and percolation theory was considered to explain abrupt changes in the observed flow properties. This was particularly helpful for analysis of the capsule-filling data, since capsule weight variability displayed a threshold behavior as a function of the mixture fraction. The capsule weight variability correlated with the angle of internal friction as well as with the angle and the energy of avalanches. Based on the results we proposed a strategy of how to design minimal weight variability into powder-filled capsules.

Percolation theory and the role of maize starch as a disintegrant for a low water-soluble drug

The objective of the present work is to investigate the presence or absence of a critical concentration of maize starch according to the percolation theory for a truly ternary system with respect to a minimum disintegration time. The results of this study show that the application of percolation theory is not limited to the study of binary systems. In this work it is shown how it can be used to analyze the behavior of binary and ternary systems for caffeine and mefenamic acid formulations containing a starch-based disintegrant. The percolation threshold pc can be described by the volumetric ratio of the disintegrant to the drug substance being equal to pc = 0.2 (v/v) in in which both components have similar average particle sizes. In addition, the behavior of the disintegration time in the neighborhood of the percolation threshold can be mathematically modeled with the basic equation of the percolation theory yielding a critical exponent q = 0.28 ± 0.06.

Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.

Background Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies. Methodology We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d’Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel. Principal Findings 128 adolescents (age: 12–17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel). Conclusion/Significance Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni.

An Attempt to Calculate In Silico Disintegration Time of Tablets Containing Mefenamic Acid, a Low Water-Soluble Drug

Based on a Quality by Design (QbD) approach, it is important to follow International Conference on Harmonization (ICH) guidance Q8 (R2) recommendations to explore the design space. The application of an experimental design is, however, not sufficient because of the fact that it is necessary to take into account the effects of percolation theory. For this purpose, an adequate software needs to be applied, capable of detecting percolation thresholds as a function of the distribution of the functional powder particles. Formulation-computer aided design (F-CAD), originally designed to calculate in silico the drug dissolution profiles of a tablet formulation is, for example, a suitable software for this purpose. The study shows that F-CAD can calculate a good estimate of the disintegration time of a tablet formulation consisting of mefenamic acid. More important, F-CAD is capable of replacing expensive laboratory work by performing in silico experiments for the exploration of the formulation design space according to ICH guidance Q8 (R2). As a consequence, a similar workflow existing as best practice in the automotive and aircraft industry can be adopted by the pharmaceutical industry: The drug delivery vehicle can be first fully designed and tested in silico, which will improve the quality of the marketed formulation and save time and money.

Functionalized calcium carbonate microparticles for the delivery of proteins

Graphical abstract Figure. No Caption available. Abstract The recently introduced functionalized calcium carbonate (FCC), a porous microparticle with a nano‐structured, lamellar surface, shows promising properties in the field of oral drug delivery. In this work, FCC was loaded with biomolecules e.g. lysozyme (Lys) and bovine serum albumin (BSA) in order to investigate its suitability to deliver protein based drugs. Loading efficiency for our model proteins was >90% and enzyme activity was preserved as demonstrated by Michaelis‐Menten enzyme kinetic experiments. Circular dichroism analysis confirmed, that neither the structure of both model substances, nor the activity of Lys was affected by the loading process or the interaction with the surface of FCC. Electron microscopy (SEM) and mercury porosimetry were indicative of protein deposition on the particle surface as well as within the particle pores. Release properties were investigated in a customized flow cell, which simulates the conditions in the oral cavity. Depending on the isoelectric point of the investigated proteins, complete release was obtained within 1.5 h. This work shows, that FCC is a suitable pharmaceutical excipient for delivery of proteins.