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ABSTRAK
PENGARUH PEMBENTUKAN DISPERSI PADAT
PERMUKAAN TERHADAP DISOLUSI DAN
KETERSEDIAAN HAYATI ASAM FENOFIBRAT
Oleh
Yulias Ninik Windriyati
NIM: 30714006
(Program Studi Doktor Farmasi)
Asam fenofibrat adalah metabolit aktif fenofibrat dan merupakan ligan
peroxisome proliferator activated receptor α (PPAR α) yang digunakan
sebagai antihiperlipidemia, penyakit jantung dan komplikasi diabetes.
Fenofibrat termasuk ke dalam daftar obat wajib dilakukan uji bioekivalensi
karena absorpsinya bervariasi dan eksipien serta proses pembuatannya
diketahui sangat mempengaruhi ketersediaan hayati, sedangkan asam
fenofibrat belum termasuk ke dalam daftar tersebut karena belum diketahui
pengaruh eksipien serta proses pembuatannya terhadap absorpsi dan
ketersediaan hayati. Asam fenofibrat tidak larut dalam pH lambung namun
larut dalam pH usus dan termasuk kelas II dalam Sistem Klasifikasi
Biofarmasetik, sehingga dilakukan pendekatan untuk meningkatkan disolusi
dan ketersediaan hayatinya. Penelitian ini bermaksud untuk mempelajari
pengaruh pembentukan dispersi padat permukaan terhadap disolusi dan
ketersediaan hayati asam fenofibrat untuk mendapatkan profil tablet asam
fenofibrat yang bioekivalen dengan inovator.
Dispersi padat permukaan asam fenofibrat dibuat dalam berbagai perbandingan
dengan eksipien yang mempunyai luas permukaan cukup besar dan lazim
digunakan dalam proses pembuatan tablet seperti microcrystalline cellulose,
colloidal silicon dioxide, crospovidone, croscarmellose sodium, dan sodium
starch glycolate menggunakan metode penguapan pelarut. Masing-masing
sistem dispersi padat permukaan diuji disolusi dalam medium dapar fosfat pH
6,8 dibandingkan dengan campuran fisiknya dan asam fenofibrat murni. Sistem
dispersi padat permukaan yang optimal meningkatkan disolusi asam fenofibrat
dianalisis karakteristiknya dengan XRD, DTA, FTIR dan SEM, lalu
dibandingkan dengan asam fenofibrat murni maupun campuran fisiknya.
Sistem dispersi padat permukaan tersebut dikempa menjadi tablet dan
dilakukan uji disolusi terbanding dalam berbagai medium dilanjutkan uji
ketersediaan hayati pada subjek laki-laki sehat kondisi puasa sesuai protokol
yang telah dikaji dan disetujui oleh Komisi Etik Penelitian Kesehatan.
Eksperimen menggunakan 2 sumber bahan baku asam fenofibrat yang berbeda
(Shijiazhuang dan BOC Sciences) menunjukkan bahwa dispersi padat
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permukaan asam fenofibrat dengan croscarmellose sodium rasio 1:1 dapat
meningkatkan disolusi secara signifikan dibandingkan campuran fisiknya
dengan nilai ED60 81,23% vs 61,74% untuk bahan baku dari Shijiazhuang,
sedangkan untuk bahan baku dari BOC Sciences 82,43% vs 67,70%.
Karakterisasi dengan SEM menunjukkan adanya perbedaan habit kristal antara
kedua bahan baku namun proses rekristalisasi saat pembentukan dispersi padat
permukaan telah mengubahnya menjadi habit kristal yang sama serta
menempatkannya pada permukaan partikel croscarmellose sodium. Foto SEM
juga menunjukkan penurunan ukuran dan deaglomerasi partikel asam
fenofibrat setelah proses pembentukan dispersi padat permukaan. Analisis
dengan XRD, DTA dan FTIR menunjukkan bahwa kedua bahan baku
merupakan polimorf yang berbeda. Pada dispersi padat permukaan terjadi
penurunan kristalinitas asam fenofibrat dibandingkan asam fenofibrat murni
karena keberadaan croscarmellose sodium. Selama proses pembentukan
dispersi padat permukaan tidak ada interaksi kimia antara asam fenofibrat dan
croscarmellose sodium serta tidak terjadi transformasi polimorf pada bahan
baku dari BOC Sciences, sedangkan pada bahan baku dari Shijiazhuang terjadi
transformasi polimorf. Sistem dispersi padat permukaan dengan bahan baku
dari BOC Sciences dibuat menjadi tablet.
Tablet dispersi padat permukaan asam fenofibrat memenuhi kriteria tablet yang
ditetapkan USP, dan disolusinya setara dengan inovator serta lebih baik
dibandingkan tablet konvensional yang dibuat dengan granulasi basah. Hasil
uji ketersediaan hayati menunjukkan tidak ada perbedaan signifikan pada
semua parameter ketersediaan hayati antara tablet dispersi padat permukaan,
tablet konvensional maupun inovator. Terdapat korelasi antara fraksi asam
fenofibrat yang terdisolusi dengan fraksi yang terabsorpsi hanya di awal waktu,
namun tidak ada korelasi dengan jumlah total asam fenofibrat yang terabsorpsi
dari sediaan tabletnya. Ketersediaan hayati tablet dispersi padat permukaan dan
tablet konvensional bioekivalen dengan inovator. Pembentukan dispersi padat
permukaan dengan croscarmellose sodium dapat meningkatkan disolusi asam
fenofibrat hingga mencapai ED60 2 kali lipat, namun tidak berpengaruh
terhadap ketersediaan hayati pada kondisi puasa.
Kata kunci: asam fenofibrat, dispersi padat permukaan, disolusi, ketersediaan
hayati.
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ABSTRACT
THE INFLUENCE OF FORMATION OF SURFACE SOLID
DISPERSION ON THE DISSOLUTION AND
BIOAVAILABILITY OF FENOFIBRIC ACID
By
Yulias Ninik Windriyati
NIM: 30714006
(Doctoral Program in Pharmacy)
Fenofibric acid is the active moiety of fenofibrate and is a peroxisome
proliferator-activated receptor α (PPAR α) ligand which is commonly used for
anti-hyperlipidemia, cardiovascular diseases and diabetes complications.
Fenofibrate is included in the list of drugs required for bioequivalence testing
due to the variety of absorption as well as the marked effect of the excipients
and their manufacturing processes on bioavailability. Fenofibric acid, on the
other hand, is still excluded in the list since the effect of the excipients along
with the manufacturing processes on both absorption and bioavailability
remains unknown. Fenofibric acid is insoluble in gastric pH, but soluble in
intestinal pH, and it is included in the Biopharmaceutical Classification System
(BCS) class II, meaning that an approach is needed to increase its dissolution
and bioavailability. This study aimed at investigating the influence of
formation of surface solid dispersion on dissolution and bioavailability of
fenofibric acid in order to obtain profile of fenofibric acid tablet that is
bioequivalent to an innovator.
Surface solid dispersions of fenofibric acid were made in numerous
comparisons using the solvent evaporation method. The excipients chosen in
this study covered microcrystalline cellulose, colloidal silicon dioxide,
crospovidone, croscarmellose sodium, and sodium starch glycolate, which
normally have large surface areas and are commonly used in the tablet
manufacturing process. Each surface solid dispersion was tested for
dissolution in phosphate buffer pH 6.8 and compared to the physical mixture
and pure fenofibric acid. The optimum surface solid dispersion that succeeded
to increase the dissolution of fenofibric acid was analyzed for characterization
by XRD, DTA, FTIR, and SEM, then compared to its corresponding physical
mixture and the pure fenofibric acid. Subsequently, it was compressed into
tablets, tested for dissolution in various medium, and evaluated for
bioavailability on healthy male subjects in fasting conditions in accordance
with the protocol reviewed and approved by the Health Research Ethics
Committee.
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In regard to dissolution, experiments with two different raw materials of
fenofibric acid, obtained from Shijiazhuang and BOC Sciences, showed that
the surface solid dispersion of fenofibric acid with croscarmellose sodium in
the ratio of 1:1 increased dissolution more significantly than that with the
physical mixture (DE60 81.23% vs 61.23% for raw material from Shijiazhuang
and 82,43% vs 67,70% for that from BOC Sciences). The characterization
using SEM indicated that these two raw materials had different crystal habits,
but the recrystallization process of forming the surface solid dispersion turned
the distinct crystal habits into the same and caused deposition on the particle
surface area of croscarmellose sodium. Additionally, the SEM images revealed
a decrease in terms of the size and deagglomeration of the fenofibric acid
particles after the surface solid dispersion was formed. Based on the analysis
with XRD, DTA and FTIR, both raw materials were of different polymorphs. In
relation to crystallinity, the surface solid dispersion of fenofibric acid
decreased crystallinity than that with pure fenofibric acid due to the presence
of croscarmellose sodium. No chemical interaction occurred between
fenofibric acid and croscarmellose sodium. However, polymorphic
transformation took place in the formation of surface solid dispersion with the
raw material from Shijiazhuang, but not with that from BOC Sciences. The
later surface solid dispersion was selected for tablet preparation.
The surface solid dispersion tablets of fenofibric acid fulfilled the
pharmaceutical requirements in USP and the dissolution was equivalent to that
of innovator tablets and even better than that of conventional tablets made with
wet granulation. The bioavailability test resulted in no significant differences
in the whole bioavailability parameters among surface solid dispersion tablets,
conventional tablets and innovator tablets. There was a correlation of the
dissolved fraction of fenofibric acid with the absorbed one, but there was no
correlation with the amount of the absorbed fenofibric acid from its tablet. The
surface solid dispersion and conventional tablets were bioequivalent to
innovator. The formation of surface solid dispersion with croscarmellose
sodium led to an increase in the dissolution of fenofibric acid (DE60 2 fold), but
it exerted no effect upon the bioavailability in the fasting condition.
Keywords: fenofibric acid, surface solid dispersion, dissolution,
bioavailability.