Danina Krajišnik

Properties of diclofenac sodium sorption onto natural zeolite modified with cetylpyridinium chloride.

In this study an investigation of a model drug sorption onto cationic surfactant-modified natural zeolites as a drug formulation excipient was performed. Natural zeolite was modified with cetylpyridinium chloride in amounts equivalent to 100, 200 and 300% of its external cation-exchange capacity. The starting material and obtained organozeolites were characterized by Fourier transform infrared spectroscopy, zeta potential measurements and thermal analysis. In vitro sorption of diclofenac sodium as a model drug was studied for all surfactant/zeolite composites by means of sorption isotherm measurements in aqueous solutions (pH 7.4). The modified zeolites with three levels of surfactant coverage within the short activation time were prepared. Zeta potential measurements and thermal analysis showed that when the surfactant loading level was equal to external cation-exchange value, almost monolayer of organic phase were present at the zeolitic surface while higher amounts of surfactant produced less extended bilayers, ordered bilayers or admicelles at the zeolitic surface. Modified zeolites, obtained in this manner, were effective in diclofenac sodium sorption and the organic phase derived from adsorbed cetylpyridinium chloride was the primary sorption phase for the model drug. The Langmuir isotherm was found to describe the equilibrium sorption data well over the entire concentration range. The separate contributions of the adsorption and partition to the total sorption of DS were analyzed mathematically. Results revealed that that adsorption and partitioning of the model drug take place simultaneously.

Temoporfin-loaded liposomal gels: Viscoelastic properties and in vitro skin penetration

Temoporfin (mTHPC) is a potent second-generation photosensitizer. The primary object of this study was to develop a topical mTHPC-loaded liposomal hydrogel able to deliver mTHPC into the stratum corneum (SC) and deeper skin layers. This study was conducted (1) to determine the effect of carbomer concentration, used as a gelling agent, and the effect of phosphatidylcholine (PC) content of lecithin, used for the liposome preparation, on viscoelastic properties and viscosity of liposomal gels and (2) to determine the relationship between rheological properties of gels and the skin penetration of mTHPC. Liposomal hydrogels revealed plastic flow behaviour. The increase of carbomer concentration induced a domination of elastic over viscous behaviour of gels. There was an inverse relationship between the elasticity of gels and mTHPC-penetration. Viscosity also increased with the increment of carbomer concentration, reducing the mTHPC-penetration. Liposomal gels containing lecithin of smaller PC-content (i.e. smaller purity) exhibited a more elastic solid behaviour than gels containing lecithin with high PC-content, and showed smaller mTHPC-penetration. The gel containing 0.75%, w/w, carbomer and lecithin with high PC-content was considered to be the optimal formulation, since it delivered high amounts of mTHPC to the SC and deeper skin layers, and it possessed desirable rheological properties.

An investigation of formulation factors affecting feasibility of alginate-chitosan microparticles for oral delivery of naproxen

In the present work we investigated the feasibility of chitosan treated Ca-alginate microparticles for delivery of naproxen in lower parts of GIT and evaluated influence of formulation factors on their physicochemical characteristics and drug release profiles. Investigated factors were drug/polymer ratio, chitosan molecular weight, chitosan concentration in hardening medium, and hardening time. Sixteen microparticle formulations were prepared utilizing 24 full factorial design (each factor was varied at two levels). Microparticles size varied between 262.3 ± 14.9 and 358.4 ± 21.7 μm with slightly deformed spherical shape. Low naproxen solubility and rapid reaction of ionotropic gelation resulted in high encapsulation efficiency (> 75.19%). Under conditions mimicking those in the stomach, after two hours, less than 6.18% of naproxen was released. Significant influence of all investigated factors on drug release rate was observed in simulated small intestinal fluid. Furthermore, experimental design analysis revealed that chitosan molecular weight and its concentration had the most pronounced effect on naproxen release. Release data kinetics indicated predominant influence of a pH-dependent relaxation mechanism on drug release from microparticles.

Stability evaluation of temoporfin-loaded liposomal gels for topical application

Temoporfin (mTHPC) is a potent second-generation synthetic photosensitizer. Topical delivery of mTHPC is of great interest for the photodynamic therapy of psoriasis and superficial skin cancer lesions. The aim of this study was to evaluate the stability of hydrophilic gels containing mTHPC-loaded liposomes. Two different mTHPC-loaded liposome dispersions, composed of 15 % (w/w) nonhydrogenated soybean lecithin of different phosphatidylcholine content, were prepared and incorporated (2:1 w/w) into hydrogels of different carbomer concentrations (1.5, 2.25, and 3%; w/w). Obtained liposomal hydrogels, containing 0.15% (w/w) mTHPC, 10% (w/w) phospholipids, and 0, 0.5, or 1% (w/w) carbomer, were analyzed for flow properties, liposome particle size, and polydispersity index (PDI), pH value, and mTHPC content after their preparation and at predetermined time intervals during 6 months of storage at 4 and 23°C. All hydrogels showed, during the whole period of investigation, adequate characteristics for topical application (i.e., they revealed shear-thinning plastic flow behavior). Rheological parameters, particle size, and PDI of liposomes in hydrogels, mTHPC content, and pH value did not show remarkable changes during the storage of gels, which could make them unacceptable for topical use. The obtained results indicated physical and chemical stability of liposomal gels containing mTHPC during 6 months of storage at both temperatures.

Characterization of gelation process and drug release profile of thermosensitive liquid lecithin/poloxamer 407 based gels as carriers for percutaneous delivery of ibuprofen.

Suitability of liquid lecithin (i.e., solution of lecithin in soy bean oil with ∼ 60% w/w of phospholipids) for formation of gels, upon addition of water solution of poloxamer 407, was investigated, and formulated systems were evaluated as carriers for percutaneous delivery of ibuprofen. Formulation study of pseudo-ternary system liquid lecithin/poloxamer 407/water at constant liquid lecithin/poloxamer 407 mass ratio (2.0) revealed that minimum concentrations of liquid lecithin and poloxamer 407 required for formation of gel like systems were 15.75% w/w and 13.13% w/w, respectively, while the maximum content of water was 60.62% w/w. The systems comprising water concentrations in a range from 55 to 60.62% w/w were soft semisolids suitable for topical application, and they were selected for physicochemical and biopharmaceutical evaluation. Analysis of conductivity results and light microscopy examination revealed that investigated systems were water dilutable dispersions of spherical oligolamellar associates of phospholipids and triglyceride molecules in the copolymer water solution. Rheological behavior evaluation results indicated that the investigated gels were thermosensitive shear thinning systems. Ibuprofen (5% w/w) was incorporated by dispersing into the previously prepared carriers. Drug-loaded systems were physically stable at storage temperature from 5 ± 3°C to 40 ± 2°C, for 30 days. In vitro ibuprofen release was in accordance with the Higuchi model (rH>0.95) and sustained for 12h. The obtained results implicated that formulated LLPBGs, optimized regarding drug release and organoleptic properties, represent promising carriers for sustained percutaneous drug delivery of poorly soluble drugs.

Experimental Design in Formulation of Diazepam Nanoemulsions: Physicochemical and Pharmacokinetic Performances

With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1 M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195 -220 nm with polydispersity index below 0.15 and zeta potential between -30 and - 60 mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.

Cationic surfactants-modified natural zeolites: improvement of the excipients functionality

Context: In this study an investigation of cationic surfactants-modified natural zeolites as drug formulation excipient was performed. Objective: The aim of this work was to carry out a study of the purified natural zeolitic tuff with high amount of clinoptilolite as a potential carrier for molecules of pharmaceutical interest. Materials and methods: Two cationic surfactants (benzalkonium chloride and hexadecyltrimethylammonium bromide) were used for modification of the zeolitic surface in two levels (equal to and twice as external cation-exchange capacity of the zeolitic tuff). Prepared samples were characterized by Fourier transform infrared spectroscopy, thermogravimetric, high-performance liquid chromatography analysis, and powder flow determination. Different surfactant/zeolite composites were used for additional investigation of three model drugs: diclofenac diethylamine, diclofenac sodium, and ibuprofen by means of adsorption isotherm measurements in aqueous solutions. Results: The modified zeolites with two levels of surfactant coverage within the short activation time were prepared. Determination of flow properties showed that modification of zeolitic surface reflected on powder flow characteristics. Investigation of the model drugs adsorption on the obtained composites revealed that a variation between adsorption levels was influenced by the surfactant type and the amount present at the surface of the composites. Discussion and conclusion: In vitro release profiles of the drugs from the zeolite-surfactant-drug composites revealed that sustained drug release could be attained over a period of 8 hours. The presented results for drug uptake by surfactant-zeolite composites and the afterward drug release demonstrated the potential use of investigated modified natural zeolite as excipients for advanced excipients in drug formulations.

Inorganically modified diatomite as a potential prolonged-release drug carrier

Inorganic modification of diatomite was performed with the precipitation product of partially neutralized aluminum sulfate solution at three different mass ratios. The starting and the modified diatomites were characterized by SEM-EDS, FTIR, thermal analysis and zeta potential measurements and evaluated for drug loading capacity in adsorption batch experiments using diclofenac sodium (DS) as a model drug. In vitro drug release studies were performed in phosphate buffer pH6.8 from comprimates containing: the drug adsorbed onto the selected modified diatomite sample (DAMD), physical mixture of the drug with the selected modified diatomite sample (PMDMD) and physical mixture of the drug with the starting diatomite (PMDD). In vivo acute toxicity testing of the modified diatomite samples was performed on mice. High adsorbent loading of the selected modified diatomite sample (~250mg/g in 2h) enabled the preparation of comprimates containing adsorbed DS in the amount near to its therapeutic dose. Drug release studies demonstrated prolonged release of DS over a period of 8h from both DAMD comprimates (18% after 8h) and PMDMD comprimates (45% after 8h). The release kinetics for DAMD and PMDMD comprimates fitted well with Korsmeyer-Peppas and Bhaskar models, indicating that the release mechanism was a combination of non-Fickian diffusion and ion exchange process.

Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium.

Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (∼373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drugs XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier.

Chitosan oligosaccharide as prospective cross-linking agent for naproxen-loaded Ca-alginate microparticles with improved pH sensitivity

Objectives: The aim of the presented work was to develop Ca-alginate microparticles for oral administration of naproxen reinforced with chitosan oligosaccharide (COS) with a special interest to examine the potential of COS for improvement of microparticles stability in simulated intestinal fluid (SIF). Method: Microparticles were prepared according to the two-step procedure using an air-jet device with varying calcium chloride and COS concentration in the gelling medium. All prepared microparticles were subjected to size determination, morphology, surface, and inner structure analysis by scanning electron microscopy (SEM), drug loading (DL) and encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, in vitro swelling, and drug release studies. Results: In general, COS-treated microparticles were spherical in shape but somewhat deformed, exhibiting the surface roughness with the mean particle size less than 350 µm. FT-IR and DSC studies confirmed the formation of polyelectrolyte complex (PEC) between alginate and COS, whereas chemical properties and crystalline state of naproxen were unaffected by the encapsulation process. Low naproxen solubility in the gelling medium and rapid entrapment resulted in high encapsulation efficiency (>80.0%). The results of swelling studies demonstrated that COS-treated particles were less sensitive to swelling and erosion in SIF in comparison to the nontreated particles. This resulted in prolonged drug release in SIF, which was dependent on the COS/alginate ratio. Conclusion: The obtained findings proved that COS could be used as an effective cross-linking agent for improvement of Ca-alginate microparticles stability in SIF, allowing prolonged release of the encapsulated drug after oral administration.