Izdelava trdnih disperzij fenofibrata s koprocesirano pomožno snovjo in stiskanje orodisperzibilnih tablet

Pačnik, Nejc (author), Planinšek, Odon (mentor), Baumgartner, Ana (co-mentor)

Peroralna uporaba zdravil ostaja preferenčna zaradi enostavnosti in dobrega sodelovanja pacientov. Razvoj formulacij za peroralno aplikacijo velikokrat predstavlja izziv, saj je velik delež novih učinkovin v vodi slabo topnih. Eden od pristopov za izboljšanje topnosti in hitrosti raztapljanja ter posledično biološke uporabnosti takšnih učinkovin je priprava trdnih disperzij, saj s tem dosežemo njihovo pretvorbo v amorfno stanje. Ta način je primeren tudi za slabo topno učinkovino fenofibrat, ki jo uporabljamo za zmanjšanje koncentracije maščob v krvi. Cilj naše raziskave je bil izboljšati raztapljanje fenofibrata z izdelavo trdne disperzije s koprocesirano pomožno snovjo. Ta je sestavljena iz mezoporoznega silicijevega dioksida, ki smo ga granulirali z izomaltom. S tem smo izboljšali stisljivost in pretočnost delcev silicijevega dioksida, da smo lažje oblikovali končno farmacevtsko obliko, orodisperzibilne tablete. Z metodo odparevanja topila smo izdelali več različnih trdnih disperzij, ki so se razlikovale v uporabljenem topilu (aceton oziroma izopropanol) in temperaturi odparevanja topila (40 °C oziroma 70 °C). V trdnih disperzijah smo spreminjali tudi vsebnost, ki je znašala od 20 % do 50 % fenofibrata. Za vse izdelane trdne disperzije smo opravili termično analizo in test sproščanja v pufru s pH 1,2 ter ugotovili, da lahko na ta način dosežemo amorfizacijo učinkovine in izboljšamo sproščanje glede na čisti fenofibrat in njegove fizikalne zmesi s silicijevim dioksidom. Glede na rezultate sproščanja in rezultate diferenčne dinamične kalorimetrije smo za izdelavo orodisperzibilnih tablet z direktnim stiskanjem izbrali 30 % trdno disperzijo fenofibrata, pripravljeno z acetonom pri 70 °C. Z dodatkom 10 % superrazgrajevala natrijeve kroskarmeloze, 10 % manitola in 1 % magnezijevega stearata smo izdelali orodisperzibilne tablete in se uspešno približali profilu sproščanja čiste trdne disperzije. Po 5 tednih hranjenja vzorcev v hladilniku oz. pri temperaturi 40 °C in relativni vlagi 75 % smo preverili tudi stabilnost trdnih disperzij. Ugotovili smo, da povišana temperatura in relativna vlažnost znatno poslabšata stabilnost, medtem ko so vzorci v hladilniku v večini primerov ohranili svoje lastnosti. Pri izdelanih trdnih disperzijah uporabljeno topilo in temperatura odparevanja topila nista bistveno vplivala na rezultate sproščanja in analize z DSC.

• Language: Slovenian
• Keywords: trdna disperzija, fenofibrat, mezoporozni silicijev dioksid, koprocesirana pomožna snov, orodisperzibilne tablete
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-153044
• Publication date in RUL: 15.12.2023

Secondary language

• Language: English
• Title: Production of fenofibrate solid dispersions with coprocessed excipient and compression of orodispersible tablets

Abstract

Oral use remains preferable due to ease of use and patient compliance. However, development of oral formulations often presents a challenge, since approximately 40% of newly discovered active pharmaceutical ingredients are poorly water-soluble. To improve solubility and thereby bioavailability of such drugs, a great option remains formulation of amorphous solid disperisons. This approach is also suitable for the poorly soluble fenofibrate, which is used to lower the amount of fatty substances in blood. The aim of our research was to improve dissolution of fenofibrate by making solid dispersions with coprocessed excipient, which consisted of mesoporous silica, granulated with isomalt. Co-processing significantly improved compressibility and flowability of pure silica, which made it easier to produce final dosage form, orodispersible tablets. Solvent evaporation method was used to produce solid dispersions, which differed in the use of the solvent (acetone or isopropanol) and the solvent evaporation temperature (40 °C or 70 °C). We also varied the content of active ingredient in solid dispersions with 50%, 40%, 30% or 20% of fenofibrate. Solid dispersions were evaluated by thermic analysis and dissolution tests in buffer of pH 1.2 as the dissolution medium. Drug amorphisation as well as improved dissolution was achieved compared to dissolution of pure fenofibrate and physical mixtures. Based on results of dissolution testing and results of thermic analysis, solid dispersion containing 30% of fenofibrate prepared with acetone at 70 °C was chosen to formulate orodispersible tablets with direct compression. By adding 10% of superdisintegrant sodium croscarmellose, 10% of mannitol and 1% of magnesium stearate to formulation, the dissolution profile of tablets came close to the dissolution profiles of pure solid dispersion. After 5 weeks of storage in refrigerator and at 40 °C and 75% relative humidity, stability of prepared solid dispersions was evaluated as well. Elevated temperature and relative humidity significantly affected stability, while the samples stored in a refrigerator had comparable characteristics as freshly prepared samples. The solvent used and the solvent evaporation temperature did not significantly affect the results of dissolution testing and of thermic analysis.

• Keywords: solid dispersion, fenofibrate, mesoporous silica, coprocessed excipient, orodispersible tablets