The influence of the type and ratio of hydrophilic polymers on the pharmaceutical-technological and biopharmaceutical characteristics of solid dispersions with clopidogrel hydrogen sulfate

[E. F. Osmanović Omerdić]

155 str.

Farmacija - Farmaceutska tehnologija / Pharmacy - Pharmaceutical technology

Razvoj formulacija lekova je poslednjih godina postao posebno izazovan zbog novih aktivnih supstanci koje imaju zahtevna fizičkohemijska svojstva, zbog potrebe farmaceutskih kompanija da se lekovi što pre plasiraju na tržište, kao i zbog sve strožijih zahteva regulatornih tela. Preko 40% aktivnih supstanci, koje se koriste u terapiji i preko 60% onih koji se nalaze u nekoj od faza istraživanja, spada u grupu slabo rastvorljivih aktivnih supstanci. Formulacija čvrstih disperzija je jedan od aktuelnih pristupa za povećanje rastvorljivosti i brzine rastvaranja slabo rastvorljivih aktivnih supstanci. Klopidogrel je inhibitor aktivacije i agregacije trombocita. Najčešće se koristi u obliku soli, klopidogrel-hidrogensulfata, koja ima nisku i pH-zavisnu rastvorljivost, što ograničava njegovu bioraspoloživost i terapijsku efikasnost. Klopidogrel je pro-lek, samo oko 2% primenjene doze klopidogrela se metaboliše u aktivni oblik i dospeva u sistemsku cirkulaciju, a uz to ima i izraženu interindividualnu varijabilnost. Iz navedenih razloga, cilj istrаživаnjа ove doktorske disertаcije bila je formulаcijа, izrаdа i fаrmаceutsko-tehnološkа i biofаrmаceutskа kаrаkterizаcijа čvrstih disperzijа sа slаbo rаstvorljivom model аktivnom supstаncom, klopidogrel-hidrogensulfаtom, u cilju povećаnjа brzine rаstvаrаnjа nаvedene аktivne supstаnce. U prvoj fazi eksperimentalnog rada formulisano je i izrađeno dvadeset čvrstih disperzija sa različitim hidrofilnim polimerima (kopovidon, makrogol 6000, poloksamer 407 i povidon K30) i različitim odnosima aktivna supstanca/polimer (1:1, 1;2; 1:3; 1:5 i 1:9), u cilju povećanja brzine rastvaranja aktivne supstance. Rezultati in vitro ispitivanja brzine rastvaranja su pokazali da vrsta i udeo hidrofilnog polimera imaju bitnu ulogu u povećanju brzine rastvaranja klopidogrel-hidrogensulfata. Najveći procenat klopidogrel-hidrogensulfata (96,38%, nakon 60 minuta) se rastvorio iz čvrste disperzije sa poloksamerom 407, pri udelu aktivna supstanca/polimer 1:9. U drugoj fazi istraživanja sprovedena je karakterizacija odabranih čvrstih disperzija primenom metoda diferencijalne skenirajuće kalorimetrije (DSC), infracrvene spektrofotometrije sa Furijeovom transformacijom (FT-IR) i difrakcije X-zraka na prašku (PXRD), kao i određivanje sadržaja klopidogrela. U svim ispitivanim uzorcima potvrđeno je prisustvo klopidogrel-hidrogensulfata u amorfnom obliku, a sadržaj klopidogrela je bio u dozvoljenim granicama odstupanja (± 5%). Rezultati ponovljenih ispitivanja, nakon 12 meseci skladištenja uzoraka pod kontrolisanim uslovima (25 ± 2 °C i vlažnost vazduha 60 ± 5%), ukazali su na njihovu dobru stabilnost. Međutim, rezultati ispitivanja in vitro brzine rastvaranja klopidogrel-hidrogensulfata iz čvrstih disperzija sa makrogolom 6000 su pokazali da je nakon 12 meseci došlo do velikog smanjenja količine rastvorenog klopidogrel-hidrogensulfata. Ovi rezultati su ukazali na neprihvatljivu stabilnost, odnosno na neprihvatljiv kvalitet čvrstih disperzija sa makrogolom 6000, pri odnosima aktivna supstanca/polimer 1:5 i 1:9. U trećoj fazi istraživanja ispitivane su karakteristike čvrstih disperzija prihvatljive stabilnosti (sa kopovidonom i poloksamerom 407, pri udelima aktivna supstanca/polimer 1:5 i 1:9) značajne za njihovu dalju obradu u finalni farmaceutski oblik (tablete i kapsule). Dobijeni rezultati ispitivanja veličine i raspodele veličina čestica, stvarne, nasipne i tapkane gustine, određivanja protočnosti, kompresibilnosti, poroziteta, sadržaja vlage i reoloških parametara su ukazali da ispitivane čvrste disperzije imaju prihvatljive osobine za obradu u finalni farmaceutski oblik. U četvrtoj fazi istraživanja, primenom kompjuterskog programa GastroPlus™, uspešno je razvijen i validiran klopidogrel-specifični, fiziološki zasnovan biofarmaceutski (PBBM) model, koji na odgovarajući način opisuje apsorpciju i distribuciju klopidogrela nakon intravenske i peroralne primene. Izgrađeni PBBM model je korišćen za ispitivanje uticaja vrste i udela hidrofilnih polimera na apsorpciju, distribuciju i posledično, bioraspoloživost aktivne supstance...

The development of drug formulations has become a particular challenge in recent years, as the physico-chemical properties of new active pharmaceutical ingredients are becoming increasingly complex, the pharmaceutical industry is demanding a rapid market launch and regulatory requirements are becoming ever stricter. More than 40 % of marketed active pharmaceutical ingredients and over 60 % of drug candidates in development belong to the class of poorly soluble substances. The formulation of solid dispersions is one of the current approaches to increasing the solubility and dissolution rate of poorly soluble active substances. Clopidogrel is an inhibitor of platelet activation and aggregation. It is most commonly used in the form of a salt, clopidogrel hydrogen sulfate, which has a low and pH-dependent solubility, limiting its bioavailability and therapeutic efficacy. Clopidogrel is a pro-drug, only about 2% of the clopidogrel dose administered is converted to an active form and enters the systemic circulation, and there is marked inter-individual variability. For these reasons, the research objective of this dissertation was the formulation, preparation and pharmaceutical-technological and biopharmaceutical characterization of solid dispersions with a poorly soluble model drug, clopidogrel hydrogen sulfate, in order to increase the dissolution rate of the listed active substances. In the first phase of the experimental work, twenty solid dispersions were formulated and prepared with different hydrophilic polymers (copovidone, macrogol 6000, poloxamer 407 and povidone K30) and different drug/polymer ratios (1:1, 1;2; 1:3; 1:5 and 1:9) to increase the dissolution rate of the drug. The results of the in vitro dissolution rate test showed that the type and ratio of hydrophilic polymer play an important role in increasing the dissolution rate of clopidogrel hydrogen sulfate. The highest percentage of clopidogrel hydrogen sulfate (96.38%, after 60 minutes) was dissolved from the solid dispersion with poloxamer 407 at a drug/polymer ratio of 1:9. In the second phase of the study, the characterization of the selected solid dispersions was carried out using the methods of differential scanning calorimetry (DSC), Fourier transform infrared spectrophotometry (FT-IR) and powder X-ray diffraction (PXRD), as well as the determination of the clopidogrel content. The presence of clopidogrel hydrogen sulfate in amorphous form was confirmed in all samples analysed, and the clopidogrel content was within the acceptable limits (± 5%). The results of repeated tests after 12 months of storage of the samples under controlled conditions (25 ± 2 °C and 60 ± 5 % RH) indicated their good stability. However, the results of testing the in vitro dissolution rate of clopidogrel hydrogen sulfate from solid dispersions with macrogol 6000 showed that there was a sharp decrease in the amount of dissolved clopidogrel hydrogen sulfate after 12 months. These results indicate an unacceptable stability, i.e. an unacceptable quality of the solid dispersions with macrogol 6000 at drug/polymer ratios of 1:5 and 1:9. In the third phase of the research, the characteristics of solid dispersions with acceptable stability (with copovidone and poloxamer 407, at a 1:5 and 1:9 drug/polymer ratio) were studied, which are important for further processing into the final pharmaceutical form (tablets and capsules). The results of testing the particle size and distribution of particle size, true density, bulk and tapped density, determination of flowability, compressibility, porosity, moisture content and rheological parameters showed that the solid dispersions tested had acceptable properties for processing into the final dosage form. In the fourth phase of the research, a clopidogrel-specific physiologically based biopharmaceutical model (PBBM) was successfully developed and validated using GastroPlus™ software. The model adequately described the absorption and distribution of clopidogrel after both intravenous and oral administration...

čvrste disperzije; hidrofilni polimeri; klopidogrel-hidrogensulfat, karakterizacija; in vitro brzina rastvaranja; reologija čvrstih disperzija; stabilnost; in silico fiziološki zasnovano biofarmaceutsko modelovanje

solid dispersions; hydrophilic polymers; clopidogrel hydrogen sulfate; characterization; in vitro dissolution rate; rheology of solid dispersions; stability; in silico physiologically based biopharmaceutics modeling

615.011(043.3)

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