FORMULATION AND EVALUATION OF PARENTERAL IN-SITU FORMING BIODEGRADABLE IMPLANT FOR CONTROLLED RELEASE OF LEVOTHYROXINE SODIUM

Öz

Objective: The objective of present research work is formulation and evaluation of parenteral in-situ forming biodegradable implant for controlled release of levothyroxine sodium.

Material and Method: The present study used N-Methyl pyrrolidone (NMP) and triacetin as solvents and PLGA as a biodegradable polymer to manufacture two biodegradable polymeric drug delivery systems, in-situ forming implant (ISFI) and in-situ micro particles (ISM). Other evaluation tests, such as sterility, percent drug entrapment capacity, and so on, were also carried out. ISFI and ISM were tested for up to one month at three different temperatures (4ºC, 25ºC, and 40ºC).

Result and Discussions: The drug release from both systems was compared. In batch F4, burst release was 10.72%, while in batch EP8, it was 8.16%. F4 was released 94.54% in roughly 30 days and EP8 was released 95.72%. The polymer content, type of solvent (hydrophilic or hydrophobic), and implant morphology all contributed to increased burst release in the ISFI formulation. Burst release was decreased using a combination of hydrophilic and hydrophobic solvents (NMP and Triacetin). When compared to other formulations, ISM had the lowest burst release. Both the ISFI and ISM formulations might deliver medications for up to 30 days. Both formulation show good drug entrapment efficiency F4 (87.74%) and EP8 (90.37%) respectively. Both formulations passed all their physicochemical proprieties included visual examination, pH, and injectability respectively. No visible growth of microorganisms was seen in growth media treated with both formulations after 30 days. The injection site (on the skin) and adjacent muscles showed no symptoms of irritation. It was confirmed when the results were compared to those of the control group. There was no hyperemia, discoloration, or necrosis at the site and no sign of irritation by both formulations. In the case of ISM (EP8), drug release follows zero order kinetics with an R2 value of 0.9814 and ISFI (F4) follows Korsmeyer peppas and both transport drug through Fickian diffusion mechanism. Both formulations were found to, be stable. Hence, Long-acting Levothyroxine sodium formulations (ISFI & ISM) may be a superior option for hypothyroidism treatment.

Anahtar Kelimeler

• Biodegradable polymers
• ISFI
• ISM
• in-situ implant
• solvent exchange technique

LEVOTİROKSİN SODYUMUN KONTROLLÜ SALIMI İÇİN IN-SITU PARENTERAL BİYOBOZUNUR İMPLANT FORMÜLASYONU VE DEĞERLENDİRİLMESİ

Öz

Amaç: Mevcut araştırmanın amacı, kontrollü levotiroksin sodyum salımı için parenteral in-situ oluşan biyobozunur implantın formülasyonu ve değerlendirilmesidir.

Gereç ve Yöntem: Bu çalışmada, in-situ implant (ISFI) ve in-situ mikro parçacıkları (ISM) şeklindeki iki biyobozunur polimerik ilaç taşıyıcı sistemi hazırlamak için çözücü olarak N-Metil pirolidon (NMP) ile triasetin ve biyobozunur polimer olarak da PLGA kullanılmıştır. Sterilite, etken madde yükleme kapasitesi yüzdesi ve benzeri diğer değerlendirme testleri de gerçekleştirilmiştir. ISFI ve ISM, bir aya kadar üç farklı sıcaklık (4ºC, 25ºC ve 40ºC) değerinde test edilmiştir.

Sonuç ve Tartışma: Her iki sistemden etken madde salımı karşılaştırıldı. F4 kodlu formülasyonda başlangıç doz boşalması %10.72 iken, EP8 kodlu da %8.16’di. Etken madde F4 koldu formülasyondan yaklaşık 30 günde %94.54 ve EP8 kodlu formülasyondan %95.72 düzeyinde açığa çıkmıştır. Polimer içeriği, çözücü tipi (hidrofilik veya hidrofobik) ve implant morfolojisi olmak üzere hepsi, ISFI formülasyonundan başlangıç doz boşalmasının artmasına katkıda bulunmuştur. Başlangıç doz boşalması, hidrofilik ve hidrofobik çözücülerin (NMP ve Triasetin) kombinasyonu kullanıldığında azaltılmıştır. Diğer formülasyonlarla karşılaştırıldığında, ISM en başlangıç doz boşalmasına sahiptir. Hem ISFI hem de ISM formülasyonları, etken maddeleri 30 güne kadar verebilmektedir. Her iki formülasyon da sırasıyla iyi etken madde yükleme etkinliği F4 (%87.74) ve EP8 (%90.37) göstermektedir. Her iki formülasyon da sırasıyla görsel inceleme, pH ve enjekte edilebilirlik dahil tüm fizikokimyasal özelliklerinden geçmiştir. 30 gün sonra her iki formülasyonla işleme tabi tutulan büyüme ortamındaki mikroorganizmaların gözle görülür bir büyümesi görülmedi. Enjeksiyon bölgesi (cilt üzerinde) ve bitişik kaslar hiçbir irritasyon belirtisi göstermedi. Sonuçlar kontrol grubu ile karşılaştırıldığında doğrulanmıştır. Her iki formülasyonda da irritasyon belirtisi ve enjeksiyon bölgesinde hiperemi, renk değişikliği veya nekroz yoktu. Her iki formülasyonun da stabil olduğu bulunmuştur. Bu nedenle, uzun etkili Levotiroksin sodyum formülasyonları (ISFI ve ISM), hipotiroidizm tedavisi için üstün bir seçenek olabilir.

Anahtar Kelimeler

• Biyobozunur polimerler
• ISFI
• ISM
• in-situ implant
• solvent değişim tekniği

Kaynakça

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