Formulation optimization of sustained-release ammonio methacrylate copolymer microspheres. Effects of log p and concentration of polar cosolvents, and role of the drug/copolymer ratio.

The objectives of this work were the formulation optimization of the preparation process parameters and to evaluate spray-dried sustained-release microspheres using ammonio methacrylate copolymer (AMC) as a polymer matrix. The effects of log P and the concentrations of the cosolvents (acetone, methyl ethyl ketone and n-butyl acetate) and different drug/copolymer ratios as independent variables on the physicochemical parameters (the W1/O emulsion viscosity, the microsphere production yield, the average particle size, the encapsulation efficiency) and the cumulative in vitro drug release as dependent variables were studied. The optimization was carried out on the basis of the 33 factorial design study. The optimization process results showed that addition of polar cosolvents proved effective, linear relationships were observed between the independent and the dependent variables. The best conditions were achieved by microspheres prepared by using a low/medium cosolvent log P, cosolvent concentration of 25-50% v/v and a drug/copolymer ratio of 1:16. The microspheres ensured sustained release with Nernst and Baker-Lonsdale release profiles.

Study of gel-forming properties of sucrose esters for thermosensitive drug delivery systems.

Sucrose esters (SEs) are non-toxic, biodegradable, non-ionic surfactants. They have a wide range of hydrophilic-lipophilic balance values (1-16) and are usually applied as surfactants, or as solubility or penetration enhancers. The aims of this work were to study the gelling behaviour of SEs and the effects of this property on drug release. The gelling characteristics of two different SEs (P1670 and S970) were investigated by rheological measurements, and compared with each other. The effects of the gel-forming SEs on model drug (paracetamol) release were evaluated by in vitro drug release studies. The kinetics of the dissolution process were studied by analysing the dissolution data through the use of various kinetic equations. The results revealed that the gelling of the SEs is temperature- and concentration-dependent. The examined sucrose stearate (S970) has a stronger gel structure than that of sucrose palmitate (P1670) and this behaviour has a significant effect on the drug release. The analysis of the dissolution kinetic data in this study revealed that the dissolution follows the Korsmeyer-Peppas (paracetamol-P1670) or Higuchi (paracetamol-S970) equations.

Intranasal delivery of human beta-amyloid peptide in rats: effective brain targeting.

(1) Intranasal administration is a non-invasive and effective way for the delivery of drugs to brain that circumvents the blood-brain barrier. The aims of the study were to test a nasal delivery system for human beta-amyloid (A beta) peptides, to measure the delivery of the peptides to brain regions, and to test their biological activity in rats. (2) A beta(1-42), in the form of a mixture of oligomers, protofibrils, and fibrils was dissolved in a nasal formulation containing hydrophobic, hydrophylic, and mucoadhesive components. The peptide solution was administered intranasally to rats as a single dose or in repeated doses. (3) Nasally injected A beta labeled with the blue fluorescent dye amino-methyl coumarinyl acetic acid (AMCA) could be detected by fluorescent microscopy in the olfactory bulb and frontal cortex. The concentration of the peptide was quantified by fluorescent spectroscopy, and a significant amount of AMCA-A beta peptide could be detected in the olfactory bulb. Unlabeled A beta also reached the olfactory bulb and frontal cortex of rats as evidenced by intense immunostaining. (4) In behavioral experiments, nasal A beta treatment did not affect anxiety levels (open-field test) and short-term memory (Y-maze test), but significantly impaired long-term spatial memory in the Morris water maze. The treatments did not result in A beta immunization. (5) The tested intranasal delivery system could successfully target a bioactive peptide into the central nervous system and provides a basis for developing a non-invasive and cost effective, new model to study amyloid-induced dysfunctions in the brain.

Sodium hyaluronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue.

Intranasal administration of molecules has been investigated as a non-invasive way for delivery of drugs to the brain in the last decade. Circumvention of both the blood-brain barrier and the first-pass elimination by the liver and gastrointestinal tract is considered as the main advantages of this method. Because of the rapid mucociliary clearance in the nasal cavity, bioadhesive formulations are needed for effective targeting. Our goal was to develop a formulation containing sodium hyaluronate, a well-known mucoadhesive molecule, in combination with a non-ionic surfactant to enhance the delivery of hydrophilic compounds to the brain via the olfactory route. Fluorescein isothiocyanate-labeled 4 kDa dextran (FD-4), used as a test molecule, was administered nasally in different formulations to Wistar rats, and detected in brain areas by fluorescent spectrophotometry. Hyaluronan increased the viscosity of the vehicles and slowed down the in vitro release of FD-4. Significantly higher FD-4 transport could be measured in the majority of brain areas examined, including olfactory bulb, frontal and parietal cortex, hippocampus, cerebellum, midbrain and pons, when the vehicle contained hyaluronan in combination with absorption enhancer. The highest concentrations of FD-4 could be detected in the olfactory bulbs, frontal and parietal cortex 4h after nasal administration in the mucoadhesive formulation. Intravenous administration of a hundred times higher dose of FD-4 resulted in a lower brain penetration as compared to nasal formulations. Morphological examination of the olfactory system revealed no toxicity of the vehicles. Hyaluronan, a non-toxic biomolecule used as a mucoadhesive in a nasal formulation, increased the brain penetration of a hydrophilic compound, the size of a peptide, via the nasal route.

Evaluation of the binding effect of human serum albumin on the properties of granules.

The main objective of this study was the application of a solution of human serum albumin as a granulating fluid. The properties of the granules formed were evaluated and compared with those when a conventional binder was applied in the same concentration. The powder mixture contained a soluble (mannitol) and an insoluble component (different types of cellulose). The protein solution applied exerted an appropriate aggregating effect if the system contained microcrystalline celluloses. Powdered cellulose was not suitable for the granulation with human serum albumin solution. As compared with the same concentration of the conventionally applied cellulose ethers as binder, the prepared granules exhibited a larger particle size, a significantly better compressibility, a higher breaking hardness and a favourable deformation process. These findings mainly reflect the good adhesive properties of the protein. The best compressibility and mechanical behaviour were attained on the application of the microcrystalline cellulose Vivapur type 105. This favourable behaviour may be connected with the wettability of cellulose. These results suggest that the formulation of tablets may be easier from an active agent in the serum that binds to albumin (e.g. interferon) since the amount of additives (binder) can be reduced.

Mucoadhesive behaviour of emulsions containing polymeric emulsifier.

Over the last two decades the attention has been focused on mucoadhesive dosage forms as a possibility to improve the residence time on a specified region of the body. In addition to bioadhesivity, controlled drug release from the dosage form is also desirable. Pemulen TR1 and Pemulen TR2 are cross-linked block copolymers of poly(acrylic acid) and hydrophobic long-chain methacrylates. They are able to stabilize o/w emulsions because their short lipophilic part integrates into the oil droplets whilst their long hydrophilic part forms a micro-gel around the droplet. In this study, correlations between the microstructure of these emulsions and the bioadhesive behaviour were found. Rheological and thermogravimetric methods were used to examine the microstructure of the emulsions. The mucoadhesive measurements were performed by tensile test and the bioadhesive bond between the polymer emulsifier and mucin was visualized by confocal laser scanning microscopy. It was established that (i) these emulsion form a special structure, which depends on the components, (ii) there were no remarkable changes in bioadhesive force and work when the oil content was increased in the emulsions, and (iii) the emulsions in which the polymeric emulsifier formed a special structure showed stronger adhesivity than the ones with simple polymer network.

[Gel-emulsion systems. I. Physical-chemical characterisation]. / Gél-emulziós rendszerek. I. Rész. Fizikai kémiai jellemzés.

Emulsion gels prepared with polyacrylic acid-alkyl acrylate diblock copolymer surfactants were studied. It was supposed that the polymer surfactants surrounding the oil droplets formed a microgel structure and this structure stabilized the emulsions sterically. This assumption was verified by thermoanalytic investigation. The effect of polymer concentration and the amount of oil on the rheological characteristics, the rate of water evaporation and droplet size distribution was analysed. It was established that gel emulsions had viscoelastic the properties, the viscosity increased exponentially with increasing emulsifier concentration and amount of oil. Water was present in two forms: i) in microgel surrounding oil droplets and ii) in dispersion medium. The distribution of droplet size was generally a monodisperse one, the average droplet size decreased with polymer concentration.

[Gel-emulsion systems. II. Stability]. / Gél-emulziós rendszerek. II. Rész. Stabilitás.

Viscosity, elastic character of gel emulsions containing polymeric emulsifiers and change of droplet size distribution under storage were studied. The quantitative change of free (non-bound) water and immobilized one in microgel form, and that of the evaporation rate under storage were examined. The phenomena were divided into two groups: change of i) macrostructure, and ii) microstructure. It was determined that macrostructure (e.g. average droplet size) was stable, it did not change during the 3 month storage period. On the other hand, the microstructure (e.g. viscosity, elastic character, solvation of polymer chains, immobilized water in microgel, rate of water evaporation) were characteristically changed during storage. These processes could be related to the sustained hydration of polymer chains.

[Formulation of an oral solid dosage form containing human interferon-alpha]. / Humán interferon-alpha orális szilárd gyógyszerformába történo feldolgozása.

The main objective of this study was to process the human alpha-interferon for the solid dosage form. The first step was the preparation of the intermediate product for the tablet making. Fluid bed apparatus with top spray method was applied for the layering of powdered cellulose with human alpha-interferon solutions. The intermediate product was compressed into tablet and an enteric solvent coating of the tablets was made in a fluid bed apparatus with Wurster method. The physical parameters were detected. These fitted the Ph. Eur. and the mechanical properties of the tablets were appropriate for coating in fluid bed apparatus. The tablets agree with the requirements of Ph. Eur. and the active agent was not dissolved in gastric juice. An animal test was also performed. The human alpha-interferon in the blood of the animals was detected with ELISA method. The human alpha-interferon specific kit was used. The active ingredient dissolved from the tablets was absorbed from the ileum. The solid dosage form containing human alpha-interferon was prepared; this can make oral application of human alpha-interferon possible.

[Optimatization of pellet preparation is CF-granulator with factorial design]. / CF-granulátorral történo pelletkészítés optimalizálása kísérlettervezéssel.

Lithium carbonate-containing pellets were made in a laboratory-scale centrifugal granulator in order to investigate the effects of the process parameters (rotor rotation speed, slit airflow rate and spray air rate) on the pellet shape and size distribution. The size distribution and the shape parameters (roundness, roughness, rectangularity and sphericity) of the pellets were measured, and an optimization parameter was then calculated from these shape parameters. The experiment was carried out and evaluated according to a 2(3) full factorial design. All three variables were found to exert a significant effect on the pellet shape. With use of the signs and magnitudes of the coefficients of the variables in the fitted linear model, the direction of the gradient was determined; two control measurements were made. These proved the accuracy of the applied model and the direction of the gradient. Overall, a high rotor rotation speed and low slit airflow rate and spray air rate furnished the best value of the optimization parameter.

An assessment of the interactions between diclofenac sodium and ammonio methacrylate copolymer using thermal analysis and Raman spectroscopy.

The objective of the work was to assess the possible interactions between the model drug diclofenac sodium (DS) and the water-insoluble ammonio methacrylate copolymer (AMC). Films with different drug/polymer ratios were therefore prepared by the solvent casting method and investigated as a preformulation study towards sustained release microparticles. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to investigate the dispersed/dissolved state of the DS in the preparation, the thermal stability and the properties of DS-containing AMC films; and Raman spectroscopy was used to confirm the possible interactions between DS and AMC. Thermoanalytical studies confirmed that the DS could behave as a plasticizer, which was indicated by decreasing glass transition temperature (Tg) of the AMC, depending on its dispersity level in the AMC matrix. Partially solid solutions were formed at DS/AMC ratios of 1:12, 1:8 and 1:6. The DS was mainly crystalline at DS/AMC ratio of 1:4, while it remained crystalline at a ratio of 1:2. The Raman spectra confirmed that none of the major structural changes revealed any significant difference, which can indicate a strong ionic interaction between the DS and the AMC. The investigations provided good facilities for the selection of a DS/AMC ratio, in the preformulation study of the microsphere preparation process, in conformity with the therapeutic aim.

Formulation of an intermediate product from human serum albumin for the production of a solid dosage form.

The main objective of this study was to evaluate and to increase the processibility of a model protein (human serum albumin (HSA)) for preparation of an intermediate for a solid dosage form. The applicability of the solid forms is easier, and therefore their formulation is a promising method for the application of proteins. The layering of powdered cellulose with HSA solutions of different concentrations in a fluid bed apparatus with the top spray method was applied. The yield of this technique was very good, independently of the concentration of the applied solution. The HSA covered the particles (the HSA layer formed was smooth), but it caused aggregation of the cellulose particles, and spray-dried microparticles also formed. The proportion of optimum-sized particles (200-315 microm) decreased. The largest amount was detected for the samples prepared with liquid containing 15% HSA (about 2 times higher than the second best). Not only the size, but also the shape of the particles was changed. The alteration in this parameter caused a change in the flowability. This was likewise the best for the samples prepared with the liquid containing 15% HSA. The concentration of HSA in the fraction containing smaller particles was higher, because of the abrasion of the particles and the enrichment of the spray-dried HSA. The distribution of HSA in the large particles was uneven. The layering of powder cellulose can be applied to produce an intermediate from HSA for solid dosage forms, but the appropriate concentration of this protein solution must be optimized previously because HSA can act as a binder. The formation of large agglomerates must be eliminated, because the distribution of the active agent in these is very inhomogeneous. The present results indicated that the best value can be achieved with liquid containing between 12.5% (most homogeneous distribution of HSA) and 15% HSA (best flowability).

[Determination of the gelatinization temperature of starches via thermoanalytical and rheological methods]. / Keményítok gélesedési homérsékletenek meghatározása termoanalitikai es reológiai módszerekkel.

This work provides a short review concerning the measuring techniques frequently applied to characterize the gelatinization behaviour of starches. The aim of the experiments was to determine the gelatinization temperatures of maize (A-type) and potato (B-type) starches via isothermal microcalorimetry and rheological methods (rotational viscosimetry and dynamic oscillatory testing). A significant difference was observed between the gelatinization temperatures of the aqueous starch suspensions, which can be attributed to the structural differences between A-type and B-type starches. Comparison of the applied measuring methods revealed a close correlation between the experimental data obtained by isothermal microcalorimetry and oscillatory testing, while rotational viscosimetry overestimated the gelatinization temperature. Additionally dynamic oscillatory tests provided valuable information not only on the gelatinization point, but also on the pasting temperature of the starch suspensions.

[Liberation of active substance from pharmaceutical suspensions I. Effect of surfactants on the active substance dissolving]. / Hatóanyag liberációja gyógyszeres szuszpenziókból I. Felületaktív anyagok hatása a hatóanyag kioldódására.

Liberation of active agent from suspensions containing sulfadimidine was investigated. There are three physico-chemical steps of the process: (i) dissolving active agent in the vehicle of suspension, (ii) partitioning dissolved molecules between the membrane and the suspension, and (iii) diffusion of active substance through membrane into the acceptor phase. The vehicle of suspensions contained surface active agents in 0.01 to 1.00 mass % concentration range. The liberation of active substance was examined with Hanson vertical diffusion cell. A multiplicative function, a square root one and an exponential equation were fitted at the analysis of results. It was established that the square root function and the exponential one fitted well to the measuring points. Relationships were found between the concentration and HLB values of surfactants and the rate constant of liberation. There is a characteristic correlation between the constants of Higuchi's equation and modified Weibull one, too.

[Investigation of the structure of macromoleculare gels II: analysis of viscosity curves]. / Makromolekulás gélek szerkezetének vizsgálata II. A viszkozitásgörbék elemzése.

Viscosity curves of gels from homo-and copolymers in aqueous medium reviewed in our previous paper were studied. Viscosity vs. rate of shear, and viscosity vs. shearing time were analysed. The viscosity curves can be described with multiplicative functions and the slope of these functions characterizes the orientation ability of polymer molecule-chains under shear. On the base of viscosity vs. shearing time functions the network formed from polymers can be classified into energetic structure, topologic one and/or friction one. It was also established, that the aqueous polymer network structures studied do not thixotropic systems.

[Surface active agents in drug forms and biological systems]. / Felületaktiv anyagok gyógyszerformákban és biológiai rendszerekben I.

The application areas of surface active agents in the pharmaceutical technology are surveyed. Three topics are summarized: (i) application of surfactant as traditional additives, (ii) the role of surfactant in modern drug delivery systems, and (iii) biopharmaceutical use of surfactants in different dosage forms. The team dealing with colloid carriers at the Pharmaceutical-Technological Department in Szeged has worked out several relationships in mathematical form. These relationships establish the formulation and give an exact character to it. Exponential functions were found between contact angle of wetting and the consistency parameters of water free coherent ointment-systems. There is an exponential relationship between contact angle and structure solidification of ointments measured during storage, between contact angle and structure-forming constant of coherent emulsions, and between contact angle and activation energy of thermostability. There is a linear relation between the contact angle of wetting and water uptake ability of absorbing ointments. On the investigation of emulsions a relationship was evaluated between the surfactant amount accumulated of the interface of oil and water phase and the viscosity and stability of emulsions. The amount of surfactant accumulated on the interface can determine the formation of multiple emulsions. On the area of solubilization there is a reciprocal relationship between the surface tension of surfactant solution and the solubilized amount of drugs. On the area of drug liberation a relationship characterized with a maximum curve can be described between the concentration of surfactant and the released drug. These functions can help the formulation of compositions having a suitable bioavailability.

[Investigation of structure of macromoleculare gels, I. Analysis of flow curves]. / Makromolekulás gélek szerkezetének vizsgálata I. A folyásgörbék elemzése.

Six polymers with different structure were investigated. The polymers studied were as follows: methylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, polyacrylate sodium-polyacrylamid copolymer (Hostacerin PN 73), poly(vinylpyrrolidone)-poly(vinylacetate) copolymer (Kollidon VA 64) and poly(ethylenoxide)-poly(propylenoxide) blockpolymer. Physical networks from polymers in aqueous media were prepared. The flow curves of these systems were determined. Polynoms, multiplicative functions and linear ones were fitted to the flow curves. The close packing was characterised by correlation coefficient. Physical content of function constants was delineated. Practically the constants expressing the binding forces has a great importance. It was established, that the binding forces in cellulose derivates gels and that of acrylic acid-acrylamide polymer gels are similar. Other structure binding forces act in the poly(ethylenoxide)-poly(propylenoxide) block-copolymer systems. The difference are well demonstrated by the constants values of functions.

[Preparation and investigation of gemfibrozil + dimethyl-beta-cyclodextrin products and solid dosage forms]. / Gemfibrozil es dimetil-beta-ciklodextrin termékek es szilárd gyógyszerformák eloállítása es vizsgálata.

Gemfibrozil is a lipid-regulating active substance. Dimethyl-beta-cyclodextrin products were prepared from this sparingly soluble pharmacon by means of methods such as physical mixing, kneading, spray drying and ultrasonication. Solid dosage forms (hydroxypropylmethyl cellulose /HPMC/ capsules and tablets) were prepared from the selected products on the basis of their dissolution profile and the in vitro membrane diffusion results. This publication details the results of electronmicroscopic morphological studies, particle size analysis and wetting contact angle determinations, and also the preparation and examination of the resulting solid dosage forms.

[Surfactants in dosage forms and biological systems. Part II]. / Felületaktív anyagok gyógyszerformákban es biológiai rendszerekben II.

The 2nd parts of publications are summarized the modern drug delivery systems contained surface active agents and the role of surfactants in the formation and stability of drug delivery systems. This paper reviews the structure and stability of multiple emulsions, and the different associates forming from surfactants. The solubilization is characterized and some mathematic functions between surface tension of surfactants and their solubilization capacity are introduced. Surfactants represent as important components of coherent emulsions, different vesicles and liposomes. The tensids have an important biopharmaceutical role. They can influenced the bioavailability by increase of thermodynamic activity of active substance and by change of permeability of cellular membranes.

[Monitoring the temperature distribution during dielectric drying]. / Mikrohullámú vákuumszárítás során kialakuló hoeloszlás követésének lehetosége.

Microwave assisted vacuum drying offers never questioned advantageous and it is getting more and more popular lately. In spite of its uniqueness there is a rightful resistance and mistrust because the temperature distribution of the workload is far from being homogeneous as a result of the existing inhomogeneous electromagnetic field. The aim of this study is to survey the heat thus field distribution in the workload to prevent local overheating that endangers the quality of the pharmaceutical product. Thermography as a non perturbing thermometrical method was used to map the heat distribution in the workload. To get a 3D information Teflon layers were used to form cross-sectional and photogenic surfaces about the dusty blend and a purpose-developed software to evaluate qualitatively the IR pictures.