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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.