Hydroxyapatite microspheres coated with poly(D,L-lactide) as bone filler and antibiotic delivery system

Wciąż nie udało się otrzymać implantu kostnego, który charakteryzowałby się wysoką biozgodnością i bioaktywnością, osteokonduktywnością, odpowiednimi właściwościami mechanicznymi oraz dobrą poręcznością chirurgiczną. Dodatkową zaletą tego typu materiału powinna być możliwość dostarczenia antybiotyku w wybrane miejsce ludzkiego organizmu w celu zapobiegania rozwojowi potencjalnych infekcji związanych z jego wszczepianiem. Opracowano nowy kompozytowy nośnik leku, składający się z porowatych granul hydroksyapatytowych pokrywanych poli(D,L-laktydem) z klindamycyną, mający znaleźć zastosowanie jako implant kostny w chirurgii szczękowo-twarzowej. Właściwości materiałów wykorzystanych do produkcji implantu zostały zbadane z użyciem metodXRD, FTIR, BET oraz DSC. Rozmiar i morfologię granul (250-1000μm) określono za pomocą mikroskopii SEM. Technika ta posłużyła także do określenia rozmiaru (10-40 μm) oraz rozmieszczenia porów. Udział objętościowy porów został oszacowany za pomocą metody hydrostatycznej. Przygotowano cztery grupy granul z różną zawartością klindamycyny. Zbadano właściwości uwalniania (trwającego 15-22 dni) leku z warstwy polimerowej. Od pierwszej godziny, aż do końca eksperymentu, obserwowano aktywność bakteriobójczą uwolnionej klindamycyny. W przypadku dwóch grup granul przez pierwszych pięć dni szczep bakteryjny gronkowca złocistego wykazywał wrażliwość lub średnią wrażliwość na uwolniony lek. Przedstawione w niniejszej pracy wyniki badań dowodzą, że opisywany kompozyt może znaleźć zastosowanie jako potencjalny implant kostny i nośnik leków. Prowadzone są dalsze badania nad zaprezentowanym materiałem.The problem of developing the bone implant, characterized by high biocompatibility, bioactivity, osteoconductivity, suitable mechanical properties and good surgical handiness, is still not solved. Additional advantage of such material should be the capability of delivering an antibiotic to a chosen part of the human body in order to prevent occurrence of post-operative infections. A novel drug delivery system, composed of porous hydroxyapatite granules with poly(D,L-lactide) coating incorporating clindamycin, was engineered for use as a bone filler in oral and maxillofacial surgery. The properties of the materials, used to obtain the implant, were examined by the use of XRD, FTIR, BET and DSC methods. The size (250-1000μm) and morphology of granules were determined with SEM. This technique was also applied to investigate the size (10-40 μm) and distribution of pores. The solvent accessible pore volume was evaluated by the hydrostatic method. Four groups of granules with different concentrations of clindamycin were prepared. The properties of drug release (lasting 15 to 22 days) from the polylactide layer were studied. The antimicrobial activity of the released clindamycin was observed from the first hour till the end of the experiment. The Staphylococcus aureus strain was susceptible or intermediately susceptible to the released drug during first 5 days for two studied groups. These experimental results indicate that the studied composite material may be used as a potential bone implant and drug carrier. The described system is still under investigation

Ceramic-polylactide composite material used in a model of healing of osseous defects in rabbits

The growing demand for various kinds of bone regeneration material has in turn increased the desire to find materials with optimal physical, chemical, and biological properties. The objective of the present study was to identify the proportions of ceramic and polylactide components in a bone substitute material prepared in collaboration with the Crystal Chemistry of Drugs Team of the Faculty of Chemistry at the Jagiellonian University, which would be optimal for bone regeneration processes. Another goal was to provide a histological analysis of the influence of a ceramic-polylactide composite on the healing of osseous defects in rabbits. The study was performed on laboratory animals (18 New Zealand White rabbits). The following study groups were formed: – group A (study group, 9 animals) – in this group we performed a histological analysis of healing with a ceramic-polylactide composite based on an 80/20 mix of hydroxyapatite and polylactide; – group B (study group, 9 animals) – in this group we performed a histological analysis of healing with a ceramic-polylactide composite with a reduced amount of hydroxyapatite compared to the previous group, i.e. in a ratio of 61/39; – group K (control, 18 animals) – the control group comprised self-healing, standardised osseous defects prepared in the calvarial bone of the rabbits on the contralateral side. In the assessment of histological samples, we were also able to eliminate individual influences that might have led to differentiation in wound healing. The material used in the histological analysis took the form of rabbit bone tissue samples, containing both defects, with margins of around 0.5 cm, taken 1, 3, and 6 months after the experiment. The osseous defects from groups A and B filled with ceramic-polylactide material healed with less inflammatory infiltration than was the case with control group K. They were also characterised by faster regression, and no resorption or osteonecrosis, which allowed for better regeneration of the bone tissue. A statistical analysis of the study results revealed the increased resorptive activity of the composite in group B, which may have been due to its higher polylactide content. Simultaneously, we observed that healing of osseous defects filled with ceramic-polylactide composites in 80/20 and 61/39 ratios was comparable

Structure-reactivity study of O-tosyl Cinchona alkaloids in their new synthesis and in hydrolysis to 9-epibases : unexpected formation of cinchonicine enol tosylate accelerated by microwave activation

New methods for O - tosylation of the natural Cinchona alkaloids have been discovered as a biphasic processes with Bu 3 N as a catalyst. The optimized excess of tosy l chloride , necessary for transformation of each of the four alkaloid s into O - tosy l derivative , decreases in the following order : quinine, quinidine, cinchonidine and cinchonine . The same decreasing order has been noticed for the hy drolysis rate of the appropriate tosylates to 9 - epibases . D iffic ult conversion of O - tosy lcinchonine in the hydrolytic medium of aq ueous tarta ric acid gives 9 - epicinchonine together with parallel formation of cinchonicine enol tosylate. The latter product is obtained as the main when both cinchonine and cinchonidine tosylates react in the presence of salicylic acid under controlled microwave heating . On the basis of X - ray structure of the new alkene product, the stereoselective syn - E2 quinuclidine ring opening process , competing to the S N 2 hydrolysis is postulated for this transformation

N-(2-Bromobenzyl)cinchoninium bromide

The title compound {systematic name: 1-(2-bromobenzyl)-5- ethenyl-2-[hydroxy(quinolin-4-yl)methyl]-1-azabicyclo[2.2.2]- octan-1-ium bromide}, C 26 H 28 BrN 2 O + Br , is a chiral quater- nary ammonium salt of one of the Cinchona alkaloids. The planes of the quinoline and of the bromobenzyl substituent are inclined to one another by 9.11 (9) . A weak intra- molecular C—H O hydrogen bond occurs. The crystal structure features strong O—H Br hydrogen bonds and weak C—H Br interactions.The title compound {systematic name: 1-(2-bromo­benz­yl)-5-ethenyl-2-[hy­droxy(quinolin-4-yl)meth­yl]-1-aza­bicyclo­[2.2.2]octan-1-ium bromide}, C26H28BrN2O+·Br-, is a chiral quater­nary ammonium salt of one of the Cinchona alkaloids. The planes of the quinoline and of the bromo­benzyl substituent are inclined to one another by 9.11 (9)°. A weak intra­molecular C-H...O hydrogen bond occurs. The crystal structure features strong O-H...Br hydrogen bonds and weak C-H...Br inter­actions