Modifying the physicochemical properties of NSAIDs for nasal and pulmonary administration.

This review focuses on nasal and pulmonary delivery of NSAIDs (non-steroidal anti-inflammatory drugs) for fast-onset analgesia, for the potential prevention of Alzheimer's disease (AD), as well as for an add-on treatment in cystic fibrosis (CF) and non-small cell lung cancer (NSCLC). I discuss how the physicochemical properties of NSAIDs can be modified with respect to the biological characteristics of the target site. Innovative technology and/or dosage forms can promote an effective therapy.

Definition and validation of the Design Space for co-milled nasal powder containing nanosized lamotrigine.

OBJECTIVE: Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS. MATERIALS AND METHODS: Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the in vitro dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses. RESULTS: Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5 h, 400 rpm, 0.8 PVA:LAM ratio) showed around 100 nm drug particles and 97% drug release in five minutes. CONCLUSION: From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.

[Formulation of new generation drug delivery system for dry powder inhalation.] / Not available.

Based on the formulation method the dry powder inhalers (DPIs) can be divided in too types: carrier-based and carrier-free drug delivery systems. The newest researches report about several high potency carrier-free formulations, where the active ingredient and the excipients are together formulated to the DPI form. However, in Hungary the commercially available DPIs are carrier-based (e.g. lactose), which means that only the mic-onized active ingredient reaches the deeper lungs, the big carrier deposits in the upper airways. The present work is about formulating a high efficacy mannitol-based Pulmonary Drug Delivery System (PDDS), which is able to delivery different types of active ingredients to the deeper lungs with higher deposition rate. The present study involves the physico-chemical and aerodynamical characterisation of mannitol-based PDDS. The results demonstrated the use of the appropriate excipients (leucine, poly-vinyl-alcohol, cyclodextrine) and solvent combination (ethanol-water) during the co-spray drying, increases the inhalation properties of the mannitol. Such carrier systems with optimized properties can increase the aerolization efficacy of the active ingredient.

Cytotoxicity testing of carrier-based microcomposites for DPI application.

Inhalation is an attractive delivery route for systemic and local therapy. High local drug concentrations may permit non-invasive delivery, lower therapeutic doses, reduced systemic side-effects, and reduced metabolic degradation of the drug in the liver. In our earlier study, carrier-based microcomposites were prepared and investigated. The present study introduces studies of the cytotoxicity of meloxicam-containing microcomposites on monolayers of Calu-3 cells, in order to acquire information on its availability in pulmonary formulations. By relating cytotoxicity and drug dissolution, the appropriate amount of meloxicam for dry powder inhalation could be determined.

Lyotropic liquid crystal preconcentrates for the treatment of periodontal disease.

The aim of our study was to develop water-free lyotropic liquid crystalline preconcentrates, which consist of oils and surfactants with good physiological tolerance and spontaneously form lyotropic liquid crystalline phase in aqueous environment. In this way these preconcentrates having low viscosity can be injected into the periodontal pocket, where they are transformed into highly viscous liquid crystalline phase, so that the preparation is prevented from flowing out of the pocket due to its great viscosity, while drug release is controlled by the liquid crystalline texture. In order to follow the structure alteration upon water absorption polarization microscopical and rheological examinations were performed. The water absorption mechanism of the samples was examined by the Enslin-method. Metronidazole-benzoate was used as active agent the release of which was characterized via in vitro investigations performed by means of modified Kirby-Bauer disk diffusion method. On the grounds of the results it can be stated that the 4:1 mixture of the investigated surfactants (Cremophor EL, Cremophor RH40) and oil (Miglyol 810) formed lyotopic liquid crystalline phases upon water addition. Polarization microscopic examinations showed that samples with 10-40% water content possessed anisotropic properties. On the basis of water absorption, rheological and drug release studies it can be concluded that the amount of absorbed water and stiffness of lyotropic structure influenced by the chemical entity of the surfactant exerted major effect on the drug release.

Water-soluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation.

The majority of active pharmaceutical ingredients are poorly soluble in water. The rate-determining step of absorption is the dissolution of these drugs. Inclusion complexation with cyclodextrin derivatives can lead to improved aqueous solubility and bioavailability of pharmacons due to the formation of co-crystals through hydrogen-bonding between the components. Inclusion complexes of loratadine were prepared by a convenient new method involving microwave irradiation and the products were compared with those of a conventional preparation method. Dissolution studies demonstrated that the solubility and rate of dissolution of loratadine increased in both of the methods used. The interactions between the components were investigated by thermal analysis and Fourier Transform Infrared studies. The microwave treatment did not cause any chemical changes in the loratadine molecule.

In vitro and in vivo investigations on the binary meloxicam-mannitol system.

The objective of the study in rats was to investigate the anti-inflammatory effects of pure meloxicam (ME) with different particle sizes and of physical mixtures of the binary ME-mannitol system. The level of local inflammation was significantly decreased when the amount of mannitol was the highest and the particle size of ME was the lowest as well as the components had the interparticulate interaction. The same results were achieved in in vitro experiments.

Analysis of the polymorph changes of a drug candidate.

The effects of solvents, temperature and humidity on the stability of a former drug candidate obtained from Sanofi (Hungary) were examined by a slurry equilibration method, variable temperature and humidity X-ray powder diffractometry (VT/VH-XRPD) and differential scanning calorimetry (DSC). The VH-XRPD study showed that all 8 polymorphic forms of this material were stable in the interval 20-80 RH%. The VT-XRPD measurements indicated that all the polymorphs except Form II underwent changes in the range 30-200°C. The stable form was Form II, though Form IVb had almost the same stability. The investigation demonstrated that VT-XRPD is a very useful in situ method for relative stability studies.

Iron(II) sulfate release from drop-formed lipophilic matrices developed by special hot-melt technology.

Iron(II) sulfate-containing lipophilic matrices were developed by a special hot-melt technology (melt solidification in drops), using stearin, white wax and their mixture as conventional bed materials. The special technology resulted in spherical particles which can be filled directly into capsules; these store iron as a depot and ensure a slow and uniform release, whereby the irritation of the gastric mucosa by the iron can be decreased. The rates of dissolution of the iron(II) sulfate from the various lipophilic matrices were different, but fundamentally low. Kinetic calculations demonstrated that the rate of dissolution of the iron(II) sulfate was of approximately zero kinetic order. The results of in vivo experiments on rabbits correlated well with the in vitro data. The plasma curves for the animals treated with the iron(II) sulfate preparations varied with the excipients in the depot products. The properties and ratio of the bed materials influenced the release of the iron(II) sulfate. In all probability, the release of the active agent can be regulated through the use of a melt of stearin and white wax in different ratios. The development products functioned as a sustained-release system and ensured elimination of the irritation of the gastric mucosa. At the same time, the results justified the applicability of the special hot-melt technology in the development of the solid dosage form.

Study of in vitro and in vivo dissolution of theophylline from film-coated pellets.

Tests were performed on the influence of polymer coating films on the rates and the extents of in vitro and in vivo liberation of theophylline from pellets. Uncoated and coated pellets were used in the experiments. The coating material was Eudragit L; The film thickness was varied. The in vivo liberation of theophylline was studied in rabbits. The serum level of the released drug measured with a TDX Analyser. No appreciable difference was observed between the uncoated and the coated pellets as concern the maximum release data, but a significant shift was found in t(max) for Eudragit L coated pellets.

[The liberation of phenylbutazone from tablets]. / Untersuchung der Freisetzung von Phenylbutazon aus Tabletten.

The liberation of phenylbutazone from tablets prepared by wet granulation was examined. It was found that the solution process can be described by the equation c = cs (l-e-K.t alpha). The influence of the binder concentration and the disintegrant on the liberation rate was also studied. The increase of the Klucel MF concentration accelerated the liberation of the agents. Among the disintegrants Polyplasdone XL and cyclodextrin block polymer turned out to be very good.

[Study of the texture of furosemid tablets. Part 2 (author's transl)]. / Untersuchung der Textur von Furosemid-Tabletten. Teil 2.

The authors studied the alterations of the texture and of the physical properties of Furosemid tablets, which are prepared with the aid of hydroxypropylcellulose mucilage, that occur during storage. Klucel MF mucilage proved to be a very good binding agent. Though the film bursted on drying during storage, by which the pore volume of the tablets increased, the mechanical strength remained almost unchanged. The cause of this is the formation of solid bridges.

[Direct compression nitrazepam tablets]. / Untersuchung von direktverpressten Nitrazepamtabletten.

Tablets of nitrazepam were made by direct compression. The influence of different dry binders and other adjuvants on the physical parameters of the tablets and their texture (scanning electron microscope: SEM) were examined. Changes in the physical parameter can be explanded if the texture is known.

[The use of dry binding materials for the direct compression of phenylbutazone]. / Anwendung von Trockenbindemitteln für die Direktpressung von Phenylbutazon.

Direct compression of phenylbutazone is possible only with addition of excipients of several kinds, because its material properties are unfavourable. It is necessary to use besides disintegrant glidant, lubricant and antistatic agents too. The authors investigated the influence of two microcrystalline cellulose binders (Avicel and Heweten) for the pressability of phenylbutazone and on properties of the tablets, respectively. It was determined the physical parameters of the tablets and the dissolution characteristics of the active ingredient. It has been found, that Heweten optimized the exactness of dosage of the tablets as well as resulted in a faster dissolution than Avicel. Therefore, Heweten proved to be the more suitable binder.

[The polymorphism of drugs in powders and tablets. 1. The preparation and characterization of polymorphic modifications of phenobarbital]. / Untersuchungen zur Polymorphie von Arzneistoffen in Pulvern und Tabletten. 1. Mitteilung: Zur Herstellung und Charakterisierung polymorpher Modifikationen des Phenobarbitals.

The characterisation of three phenobarbital modifications by thermic examination procedures (DSC, DTA) is being described. Modification I was obtained by thermic treatment of the brands (modification II) from Hungary and the GDR. The spray product prepared, consisting of very fine hollow spheres, was identified as modification III. Besides the particle size distribution the form of the particle was determined by scanning electron microscopy (REM). The best results regarding saturation solubility and speed of dissolution were found for the spray product.

[The polymorphism of drugs in powders and tablets. 4. The effect of the polymorphism of drugs on the physical properties and drug release of phenobarbital tablets]. / Untersuchungen zur Polymorphie von Arzneistoffen in Pulvern und Tabletten. 4. Mitteilung, Einfluss der Polymorphie des Wirkstoffes auf die physikalischen Eigenschaften und die Wirkstofffreigabe aus Phenobarbitaltabletten.

Four products of phenobarbital (I, II1, II2, III) are manufactured into tablets with the dry binders Avicel PH 101 or Heweten 40 using different pressures by direct tabletting. The physical properties of the resulting tablets are different according to the modification of phenobarbital, the binders used and the pressure during tabletting. The dissolution behaviour of the drug may be changed by the different technological and physical parameters.

[The polymorphism of drugs in powders and tablets. 5. Preparation and characterization of polymorphic forms of tolbutamide]. / Untersuchungen zur Polymorphie von Arzneistoffen in Pulvern und Tabletten. 5. Mitteilung: Zur Herstellung und Charakterisierung polymorpher Formen des Tolbutamids.

The preparation of 4 modifications and 2 spray dried products of tolbutamid is described. The characterization is performed by thermoanalytical methods (thermomicroscopy, DSC). Scanning electron microscopy and investigations of solubility complete the results.

[Polymorphism of drugs in powders and tablets. 6. X-ray diffractometric studies of polymorphic modifications of tolbutamide]. / Untersuchungen zur Polymorphie von Arzneistoffen in Pulvern und Tabletten. 6. Mitteilung: Röntgendiffraktometrische Untersuchungen polymorpher Formen des Tolbutamids.

The modifications and spray dried products of tolbutamide published in a former article, are investigated furthermore by X-Ray diffraction. The indication of the reflexes in X-Ray diffraction patterns of 2 modifications is performed. Transformations of modification are provable in consequence of thermal stress.

Gas chromatographic-mass spectrometric analysis and subsequent quality improvement of plastic infusion packaging materials.

Although the opalescence of sterile transparent plastic materials utilized for the packaging of parenteral infusion drugs is a serious quality problem, most suppliers do not report the exact compositions of such polymers, and no literature data are available. Similarly, no information is available as concerns the potential incompatibility of the inner bag and the overpouch. Our gas chromatographic-mass spectrometric study revealed that the cause of the opalescence is the presence of a low-molecular-weight slip additive, 13-docosenamide (erucamide), which is transferred into the primary infusion bag from the overpouch during the heat-sterilization process. Autoclaving trials confirmed the analytical results. In view of these findings, a new slip additive-free overpouch has been produced as secondary packaging material, which does not give rise to opalescence.

Polymorph screening of an active material.

Polymorph screening is currently one of the most important tasks for innovators and for generic companies from both pharmaceutical and intellectual property rights aspects. The different polymorphs have different physicochemical properties, such as the crystal polymorph-dependent solubility which influences the bioavailability. A former drug candidate obtained from Sanofi Pharmaceutical Company (Hungary) was investigated to explore its polymorphism, to distinguish the morphologies generated by analytical examinations and to investigate their relative stabilities. An Avantium Crystal 16 automatic laboratory reactor system was used for the polymorph studies and the studies of their dissolution. Eight polymorphs were obtained by crystallization and transformation methods then characterized by XRPD, DSC, and Raman spectroscopy, scanning electron microscopy, and light microscopy. All the morphologies could be stored in solid without any form transformation for a long time (2 years investigated). According to the first relative stability results, Form I, III, IVa, V, VI, VII are unambiguously metastable forms. Form II and IVb have similar thermodynamic stabilities, that were higher than those of the other polymorphs. A special dissolution medium was developed in which the eight polymorphs showed clear differences in the rate of dissolution.