Milan D. Antonijevic

Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs.

Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w κ-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a Tg at 22.25 and 30.77°C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40 min of contact with dissolution medium simulating saliva.

Lyophilized wafers comprising carrageenan and pluronic acid for buccal drug delivery using model soluble and insoluble drugs

Lyophilized muco-adhesive wafers with optimum drug loading for potential buccal delivery have been developed. A freeze-annealing cycle was used to obtain optimized wafers from aqueous gels containing 2% κ-carrageenan (CAR 911), 4% pluronic acid (F127), 4.4% (w/w) polyethylene glycol with 1.8% (w/w) paracetamol or 0.8% (w/w) ibuprofen. Thermogravimetric analysis showed acceptable water content between 0.9 and 1.5%. Differential scanning calorimetry and X-ray diffraction showed amorphous conversion for both drugs. Texture analysis showed ideal mechanical and mucoadhesion characteristics whilst both drugs remained stable over 6 months and drug dissolution at a salivary pH showed gradual release within 2h. The results show the potential of CAR 911 and F127 based wafers for buccal mucosa drug delivery.

Sirolimus Encapsulated Liposomes for Cancer Therapy: Physicochemical and Mechanical Characterization of Sirolimus Distribution within Liposome Bilayers

Sirolimus has recently been introduced as a therapeutic agent for breast and prostate cancer. In the current study, conventional and Stealth liposomes were used as carriers for the encapsulation of sirolimus. The physicochemical characteristics of the sirolimus liposome nanoparticles were investigated including the particle size, zeta potential, stability and membrane integrity. In addition atomic force microscopy was used to study the morphology, surface roughness and mechanical properties such as elastic modulus deformation and deformation. Sirolimus encapsulation in Stealth liposomes showed a high degree of deformation and lower packing density especially for dipalmitoyl-phosphatidylcholine (DPPC) Stealth liposomes compared to unloaded. Similar results were obtained by differential scanning calorimetry (DSC) studies; sirolimus loaded liposomes were found to result in a distorted state of the bilayer. X-ray photon electron (XPS) analysis revealed a uniform distribution of sirolimus in multilamellar DPPC Stealth liposomes compared to a nonuniform, greater outer layer lamellar distribution in distearoylphosphatidylcholine (DSPC) Stealth liposomes.

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.

The stress stability of olanzapine: studies of interactions with excipients in solid state pharmaceutical formulations

Abstract Stress stability testing represents an important part of the drug development process. It is used as an important tool for the identification of degradation products and degradation pathways, as well as for the assessment of changes in physical form of drug molecules. The impact of excipients on the stability of olanzapine confirms that levels of impurities and degradants are limiting parameters and are therefore used for stability evaluation. The major degradation product of olanzapine was identified as 2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepine-4-one (III). The structure of III was determined by using LC-MS, IR and NMR. Compatibility and stress stability results demonstrated that tablet formulations of olanzapine are sensitive to temperature and moisture. In samples protected from moisture, the increase in concentration of III was shown to be highly temperature dependent and the degradation followed zero-order kinetics. In addition, studies of olanzapine with excipients and in formulated tablets revealed polymorphic phase changes in some samples, influenced by a combination of stress temperature and humidity conditions. Polymorphic transitions were monitored using x-ray powder diffraction (XRPD) analysis and exhibited no correlation between the phase change (appearance of a new polymorph) and the degradation process.

Phase behaviour of dehydrated phosphatidylcholines

Dehydrated DLPC, DMPC, DPPC and DSPC have been characterised at temperatures below the diacyl carbon chain-melting transition (Tm), using DSC. For the first time, the existence of pre-Tm transition processes, which are, usually, only observed in the colloidal/liposomal state of saturated phospholipids, has been detected for the dehydrated phosphatidylcholines. Temperature-modulated differential scanning calorimetry was used to characterise the several complexes, overlapping pre-Tm transition processes. Kinetic studies of the chain-melting (Tm) transition show the activation energy dependence on α (conversion rate), i.e. activation energy decreases as the transition progresses, pointing to the importance of initial cooperative (intra- and inter-molecular) mobility. Furthermore, the activation energy increases with increase in diacyl chain length of the phosphatidylcholines which supports the finding that greater molecular interactions of the polymer chain and its head groups in the dehydrated solid state lead to enhanced stability of dehydrated phosphatidylcholines.

Molecular mobility of hydroxyethyl cellulose (HEC) films characterised by thermally stimulated currents (TSC) spectroscopy.

Molecular mobility has long been established to relate to textural properties and stability of polymer films and is therefore an important property to characterise to better understand pharmaceutical film formulations. The molecular mobility of solvent cast hydroxyethyl cellulose (HEC) films has been investigated by means of thermally stimulated current (TSC) below the temperature at which the film was formed. Preliminary physical characterisation of the films was performed using XRPD, TGA, DSC and texture analysis (tensile properties). XRPD results showed the films to be completely amorphous with Tg determined by DSC to be 127 ± 1°C. TGA analysis showed the films to contain 8 ± 1% water and film was dried to only 0.06 ± 0.01% water content when heated to 160°C. Application of TSC detected molecular mobility in HEC films at sub-zero temperatures. Two motional transitions with average relaxation time of 50 ± 3s were identified; a β-relaxation at -57 ± 2°C, attributed to localised non-cooperative orientation of HEC polymer chain ends and the hydroxyethyl side groups and an α-relaxation, originating from cooperative segmental mobility, at -20 ± 2°C. The tensile properties i.e., elongation, tensile strength and elastic modulus of the HEC film have been related to the molecular relaxation processes detected by TSC.

Effect of Protonation State and N-Acetylation of Chitosan on Its Interaction with Xanthan Gum: A Molecular Dynamics Simulation Study

Hydrophilic matrices composed of chitosan (CS) and xanthan gum (XG) complexes are of pharmaceutical interest in relation to drug delivery due to their ability to control the release of active ingredients. Molecular dynamics simulations (MDs) have been performed in order to obtain information pertaining to the effect of the state of protonation and degree of N-acetylation (DA) on the molecular conformation of chitosan and its ability to interact with xanthan gum in aqueous solutions. The conformational flexibility of CS was found to be highly dependent on its state of protonation. Upon complexation with XG, a substantial restriction in free rotation around the glycosidic bond was noticed in protonated CS dimers regardless of their DA, whereas deprotonated molecules preserved their free mobility. Calculated values for the free energy of binding between CS and XG revealed the dominant contribution of electrostatic forces on the formation of complexes and that the most stable complexes were formed when CS was at least half-protonated and the DA was ≤50%. The results obtained provide an insight into the main factors governing the interaction between CS and XG, such that they can be manipulated accordingly to produce complexes with the desired controlled-release effect.

The influence of pyrolysis type on shale oil generation and its composition (Upper layer of Aleksinac oil shale, Serbia)

The influence of pyrolysis type on shale oil generation and its composition was studied. Different methods such as Rock-Eval pyrolysis, thermogravimetric analysis (TGA) and pyrolysis in the open and closed systems were applied. Samples from the Upper layer of Aleksinac oil shale (Serbia) were used as a substrate and first time characterized in detail. The impact of kerogen content and type on the shale oil generation in different pyrolysis systems was also estimated. Majority of the analysed samples have total organic carbon content > 5 wt. % and contain oil prone kerogen types I and/or II. Therefore, they can be of particular interest for the pyrolytic processing. Thermal behavior of analysed samples obtained by TGA is in agreement with Rock-Eval parameters. Pyrolysis of oil shale in the open system gives higher yield of shale oil than pyrolysis in the closed system. The yield of hydrocarbons (HCs) in shale oil produced by open pyrolysis system corresponds to an excellent source rock potential, while HCs yield from the closed system indicates a very good source rock potential. The kerogen content has a greater impact on the shale oil generation than kerogen type in the open pyrolysis system, while kerogen type plays a more important role on generation of shale oil than the kerogen content in the closed system. The composition of obtained shale oil showed certain undesirable features, due to the relatively high contents of olefinic HCs (open system) and polar compounds (closed system), which may require further treatment to be used.

Thermal decomposition of chlorogenic acid in different atmospheres

Purpose: To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant to the treatment of local conditions. Methods: We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal binding on the rate and depth of penetration of topical drugs into the underlying skin. We used this model to interpret literature in vivo human biopsy data on dermal drug concentration at various depths in the dermis after topical application of 6 substances. This interpretation was facilitated by our in vitro human dermal penetration studies in which dermal diffusion coefficient and binding were estimated. Results: The model shows that dermal diffusion alone cannot explain the in vivo data and blood and/or lymphatic transport to deep tissues must be present for almost all of the drugs tested. Conclusion: Topical drug delivery systems for deeper tissue delivery should recognise that blood/ lymphatic transport may dominate over dermal diffusion for certain compounds.