Initial Risk Assessment as part of the Quality by Design in peptide drug containing formulation development.

Risk Assessment (RA) is the key element of the Quality by Design (QbD) approach recommended by the pharmaceutical regulatory bodies. This research paper aimed to implement the regulatory requirements, the QbD thinking and the RA from the first steps of the oral peptide formulation development. The authors intended to give a general recommendation about the application possibilities of this methodology, to demonstrate the risk factors and the required decision points. Later, this paper presents a concrete development in practice. This case study shows the QbD and RA based early phase development of the GLP 1 analog, Liraglutide, an antidiabetic peptide drug mainly used in the treatment of type 2 Diabetes Mellitus. The objective here was to design Liraglutide encapsulated polymeric nanoparticles for oral delivery and the progress of their RA based development is presented. In this case, the particle size, the encapsulation efficiency, and the drug loading were found as the most critical quality attributes, the polymer concentration, the drug concentration, the w2/o ratio, the stabilizer concentration and polymer type were identified by the criticality rating as having the greatest impact on the product quality among the critical material attributes, finally the sonication time and sonication power were selected as the most critical elements of the production process. The results showed the importance of the risk factor-focused development in the oral peptide pharmaceutical formulations, and underlined the importance of the profound planning phase even in such cases. The formulation of an oral peptide delivery system is associated with several risks, but their priority ranking helps to focus on the resources (human, financial, time) related to the final product quality aimed at.

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.

[Cluster headache]. / A "cluster" fejfájás.

In this article the main features of cluster headache are discussed by recent data of the literature. The authors describe the characteristics of the headache, the periodicity and the duration of the attacks, the diagnostic criteria. The theories about the pathomechanism and background of this type of headache are also discussed. They deal with the treatment of a single attack as well as the prophylaxis in detail.

Phosphorylation-induced conformational changes in the phosphorylase ab hybrid as revealed by resolution of pyridoxal 5'-phosphate with imidazole citrate and cysteine.

The accessibility of pyridoxal 5'-phosphates of the phosphorylase ab hybrid to resolution by imidazole citrate and cysteine was studied and compared with that of the b and a forms. Promotion of resolution of phosphorylated forms by raising the temperature or in the presence of glycogen indicates that the resistance of phosphorylase a and ab to resolution at 0 degrees C is due rather to their tetrameric state than their phosphorylation-related active conformation. The pattern of resolution of the ab hybrid was similar to that of the a and differed from that of the b forms in that it occurred at 30 degrees C and 37 degrees C but not at 0 degrees C, moreover, it did not show first-order kinetics. On the other hand, inhibition of resolution by ligands binding to the nucleotide site of phosphorylase reflected an intermediate sensitivity of the ab form between that of the b and a forms. We conclude that partial phosphorylation of phosphorylase b elicits conformational change(s) in both subunits which influence the monomer-monomer interactions and resolution of pyridoxal 5'-phosphates. Resistance of ab hybrid to monomerizing agents as imidazole citrate, comparable to that of other forms, argues for its stability, ruling out its reshuffling into mixtures of phosphorylase b and a.

Central core and nemaline rods in the same patient.

It is quite rare, that central cores and nemaline bodies occur in the same individual. We describe the case of a 12-year-old girl, who was born with bilateral congenital hip dislocation. Her early motor milestones were delayed. Due to proximal weakness of the lower extremities she has never been able to walk. The family history was negative. Muscle histology, histochemistry and electron microscopic studies showed a central core in nearly all muscle fibers, and nemaline rods in a few. The earlier literature and new genetical findings concerning these muscle abnormalities are also briefly summarized.