Pengaruh Variasi Konsentrasi Kopolimer Polyethylene glycol-Poly(ε-caprolactone) (PEG-PCL) terhadap Karakteristik Formula Nanopartikel Klomifen Sitrat = Effect of Polyethylene Glycol–Poly(ε-caprolactone) (PEG-PCL) Copolymer Concentration Variation on the Characteristics of Clomiphene Citrate Nanoparticle Formulations

Polycystic Ovary Syndrome (PCOS) merupakan gangguan hormon endokrin yang memengaruhi jutaan wanita usia reproduktif di seluruh dunia, dengan jumlah kasus mencapai sekitar 69,47 juta. Clomiphene citrate (CC) dalam bentuk sediaan tablet menjadi terapi lini pertama untuk mengatasi infertilitas pada penderita PCOS. Namun, penghantaran CC secara oral memiliki keterbatasan karena mengalami metabolisme lintas pertama yang dapat menurunkan bioavailabilitasnya hingga 11% dan masih terdistribusi luas di sistemik sehingga konsentrasi CC di otak menjadi rendah. Kondisi ini juga menimbulkan efek samping berupa penipisan endometrium. Oleh karena itu, riset ini bertujuan untuk mengembangkan formula CC berbentuk nanopartikel (CC-NP) yang diinkorporasikan dalam sistem ion triggered in-situ gel (CC-NP-ITIG) dengan rute penghantaran intranasal untuk meningkatkan bioavailabilitas obat dan mengatasi penipisan endometrium. Metode riset dilakukan secara eksperimental yang diawali dengan sintesis polyethyleneglycol-poly(ε caprolactone) (PEG-PCL), formulasi dan karakterisasi CC-NP meliputi efisiensi penjerapan, pemuatan obat, ukuran partikel, indeks polidispersitas (PDI), SEM (scanning electron microscope), FTIR (fourier transform infrared), dan XRD (x-ray diffraction). Formula terbaik CC-NP kemudian diuji pelepasan secara in vitro, lalu diformulasikan dalam bentuk CC NP-ITIG berbasis natrium alginat dan beberapa variasi konsentrasi gellan gum. Formula CC-NP-ITIG yang dihasilkan dikarakterisasi secara fisika-kimia meliputi uji viskositas, sifat reologi, gelling time, uji pH, uji mukoadhesif, daya sebar, dan FTIR. Formula terbaik kemudian diuji permeasi secara ex vivo, uji hemolisis, potensi iritasi, serta uji farmakokinetika in vivo. Formula CC-NP terbaik diperoleh dengan konsentrasi polimer PEG-PCL 120 mg yang menunjukkan efisiensi penjerapan >60%, pemuatan obat 22,47 ± 1,57%, ukuran partikel <200 nm, nilai PDI <0,2 dan bentuk partikel bulat dalam skala nanometer. Hasil FTIR menunjukkan bahwa formula mengonfirmasi keberadaan CC yang diinkorporasikan. Selain itu, hasil XRD menunjukkan perubahan CC menjadi semikristalin. Profil pelepasan secara in vitro CC-NP menunjukkan pelepasan yang lebih terkontrol dan mampu bertahan hingga waktu ke-120 jam dengan konsentrasi 85,14 ± 2,34%. Formula CC-NP-ITIG dengan konsentrasi natrium alginat 1% b/b dan gellan gum 1% b/b memiliki karakteristik fisika kimia yang paling optimal dan tidak mempengaruhi struktur dari CC berdasarkan hasil FTIR. Hasil uji permeasi secara ex vivo menunjukkan kemampuan permeasi yang optimal (367,29 ± 12,64 µg/cm²) dalam melewati mukosa hidung dan uji hemolisis tidak menyebabkan lisis pada eritrosit serta tidak menyebabkan iritasi berdasarkan hasil uji potensi iritasi. Selain itu, uji in vivo menunjukkan konsentrasi CC yang tinggi di otak (2,64 ± 0,05 µg/ml) dan rendah di endometrium (0,37 ± 0,09 µg/ml). Oleh karena itu, formula CC-NP-ITIG yang dikembangkan terbukti lebih efektif menghantarkan CC secara selektif menuju hipotalamus, sehingga berpotensi sebagai terapi alternatif untuk pengobatan infertilitas pada penderita PCOS. Polycystic Ovary Syndrome (PCOS) is an endocrine hormone disorder that affects millions of women of reproductive age worldwide, with the number of cases reaching around 69.47 million. Clomiphene citrate (CC) in tablet form is the first-line therapy for treating infertility in women with PCOS. However, oral administration of CC has limitations due to first-pass metabolism, which can reduce its bioavailability to 11% and still be widely distributed in the systemic circulation, resulting in low CC concentrations in the brain. This condition also causes side effects in the form of endometrial thinning. Therefore, this study aims to develop a CC nanoparticle (CC-NP) formulation incorporated into an ion-triggered in-situ gel (CC-NP-ITIG) system with an intranasal delivery route to increase drug bioavailability and overcome endometrial thinning. The research methodology was experimental, beginning with the synthesis of polyethylene glycol-poly(ε-caprolactone) (PEG-PCL), formulation, and characterization of CC-NP included adsorption efficiency, drug loading, particle size, polydispersity index (PDI), SEM (scanning electron microscope), FTIR (Fourier-transform infrared), and XRD (X-ray diffraction). The optimal CC-NP formulation was then tested for in vitro release, followed by formulation into CC-NP-ITIG based on sodium alginate and several variations of gellan gum concentration. The resulting CC-NP-ITIG formula was characterized physically and chemically, including viscosity testing, rheological properties, gelling time, pH testing, mucoadhesive testing, spreadability, and FTIR. The best formula was then tested for ex vivo permeation, hemolysis testing, irritation potential, and in vivo pharmacokinetics. The best CC-NP formula was obtained with a PEG-PCL polymer concentration of 120 mg, which showed an absorption efficiency of >60%, drug loading of 22.47 ± 1.57%, particle size <200 nm, a PDI value <0.2, and spherical particle shape at the nanometer scale. FTIR results confirmed the presence of incorporated CC. Additionally, XRD results indicated a transition of CC to a semicrystalline state. The in vitro release profile of CC-NP showed controlled release and sustained release up to 120 hours with a concentration of 85.14 ± 2.34%. The CC-NP-ITIG formula with a sodium alginate concentration of 1% w/w and gellan gum 1% w/w has the most optimal physicochemical characteristics and does not affect the structure of CC based on FTIR results. The ex vivo permeation test results showed optimal permeation ability (367.29 ± 12.64 µg/cm²) in passing through the nasal mucosa, and the hemolysis test did not cause lysis in erythrocytes and did not cause irritation based on the irritation potential test results. In addition, in vivo tests showed high CC concentrations in the brain (2.64 ± 0.05 µg/ml) and low concentrations in the endometrium (0.37 ± 0.09 µg/ml). Therefore, the developed CC-NP-ITIG formulation proved to be more effective in selectively delivering CC to the hypothalamus, making it a potential alternative therapy for the treatment of infertility in PCOS patients.