Enhancing solubility and bioavailability of coenzyme Q10: formulation of solid dispersions using Soluplus® as a carrier

Shrawani Lamichhane,Jo-Eun Seo,Taekwang Keum,Gyubin Noh,Santosh Bashyal,Seong-Wan Cho,Eun-Hee Lee,Sangkil Lee 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.1

Improving the aqueous solubility of poorlysoluble compounds have been a major issue in the pharmaceuticalindustry. In the present study, binary amorphoussolid dispersions (SDs) of Coenzyme Q10 (CoQ 10 ), a biopharmaceuticsclassifi cation system (BCS) II compound andSoluplus ® were prepared to enhance the solubility and pharmacokineticproperties compared to crystalline CoQ 10 . SDswere prepared with diff erent ratios of CoQ 10 and Soluplus ®(1:3, 1:5, and 1:7) using spray drying technology, and thephysicochemical properties of the SDs were evaluated. X-raypowder diff raction, diff erential scanning calorimetry, andscanning electron microscopy suggested the conversion ofthe crystalline form of CoQ 10 to a binary amorphous systemin the SDs. Fourier transform infrared spectroscopy revealedno potential interactions between CoQ 10 and Soluplus ® . The solubility of the optimal SD formulation (SD 1:7)was approximately 9000-fold higher than that of crystallineCoQ 10, and the increment was Soluplus ® concentrationdependent. As a result, optimized SD 1:7 also showed significantly enhanced dissolution rate where maximum drugrelease was observed within 30 min in two diff erent dissolutionmedia. Moreover, in contrast to crystalline CoQ 10, CoQ 10 SDs showed improved pharmacokinetic parameters. Thus, the SD 1:7 formulation is expected to improve biopharmaceuticalproperties and therapeutic effi cacy of CoQ 10 .

Recent progress in hydrophobic ion-pairing and lipid-based drug delivery systems for enhanced oral delivery of biopharmaceuticals

노규빈,금태광,Bashyal Santosh,Seo Jo-Eun,Shrawani Lamichhane,Kim Jeong Hwan,이상길 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.1

Background The biopharmaceuticals market has grown rapidly in recent years owing to the low toxicity and high therapeutic efficacy of peptide and protein drugs. However, due to their low stability, biopharmaceuticals have to be administrated via invasive routes, and there is an unmet need for alternative routes. The most familiar and preferred alternative route of administration is the oral route; however, peptide and protein drugs are readily affected by the harsh gastrointestinal environment, resulting in low oral bioavailability. Lipid-based drug delivery systems (LDDSs) for oral administration protect the incorporated drugs and enhance their absorption in the GI tract. However, only lipophilic substances can be stably incorporated in LDDSs, and hydrophilic peptides and proteins require lipidation via, e.g., hydrophobic ion pairing (HIP). Area covered This review discusses the issues that hamper the oral administration of peptides and proteins and introduces HIP and LDDSs as strategies to overcome these. The principle of HIP complexation, the parameters to be considered for complexation, and the various counterions used are described. As for LDDSs, the advantages of self-emulsifying drug delivery systems (SEDDSs), which are suitable for oral peptide and protein delivery, and in vivo study results are described. Expert opinion HIP complexes are prepared based on an understanding of the characteristics of drugs and counterions. HIP complexes of peptides and proteins in the oil phase of SEDDSs are protected from the GI environment and therefore, improved absorption is expected. Although their fundamental mechanisms remain unclear and require further study, HIPincorporated SEDDSs provide a potential strategy for oral peptide and protein delivery.

MicroRNA 452 regulates SHC1 expression in human colorectal cancer and colitis

Mo Ji-su,Lamichhane Santosh,Yun Ki-jung,Chae Soo-Cheon 한국유전학회 2023 Genes & Genomics Vol.45 No.10

Background Human microRNA 452 (MIR452) has been linked to both colorectal cancer (CRC) tissues and dextran sulfate sodium (DSS)-induced colitis. Objective We analyzed the correlation between MIR452 and its putative target gene in human CRC cells and in mouse colitis tissues. Methods Luciferase reporter assay confirmed that Src homologous and collagen adaptor protein 1 (SHC1) is a direct target of MIR452. Furthermore, the expression of proteins or mRNA was assessed by immunohistochemical analysis, Western blot, or quantitative RT-PCR (qRT-PCR). Results We found that MIR452 has a potential binding site at 3′-UTR of SHC1. Likewise, MIR452 or siSHC1 transfection dramatically reduced the level of cellular SHC1 in CRC cells. The expression of SHC1 was frequently downregulated in both human CRC tissues and mouse colitis tissues. In CRC cells, we demonstrated that MIR452 regulated the expression of genes involved in the SHC1-mediated KRAS-MAPK signal transduction pathways. Conclusion These findings suggest a potential defense mechanism in which MIR452 regulation of the adaptor protein SHC1 maintains cellular homeostasis during carcinogenesis or chronic inflammation. Therefore, MIR452 may have therapeutic value for human early-stage CRC and colitis.

Limonene Inhibits Methamphetamine-Induced Sensitizations via the Regulation of Dopamine Receptor Supersensitivity

( Sun Mi Gu ),( Sung Yeon Kim ),( Santosh Lamichhane ),( Jin Tae Hong ),( Jaesuk Yun ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.4

Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine- induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. The development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine- induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonenepretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity.

Increased intracellular Ca ²⁺ concentrations prevent membrane localization of PH domains through the formation of Ca ²⁺ -phosphoinositides

Kang, Jin Ku,Kim, Ok-Hee,Hur, June,Yu, So Hee,Lamichhane, Santosh,Lee, Jin Wook,Ojha, Uttam,Hong, Jeong Hee,Lee, Cheol Soon,Cha, Ji-Young,Lee, Young Jae,Im, Seung-Soon,Park, Young Joo,Choi, Cheol Soo National Academy of Sciences 2017 Proceedings of the National Academy of Sciences Vol.114 No.45

<▼1><P><B>Significance</B></P><P>Insulin resistance is a metabolic disorder in which target cells fail to respond to physiological levels of circulating insulin, leading to hyperinsulinemia and glucose intolerance. The molecular mechanism underlying insulin resistance is still largely unknown. Here, we found that intracellular Ca<SUP>2+</SUP> overloading in obesity attenuates insulin-stimulated phosphorylation of protein kinase B and its downstream signaling by preventing membrane localization of various pleckstrin homology (PH) domains. When at high intracellular levels, Ca<SUP>2+</SUP> binds tightly with phosphoinositides to yield Ca<SUP>2+</SUP>-phosphoinositides (PIPs), abrogating the membrane targeting of PH domains and disrupting insulin signaling. Thus, we identified a previously unknown physiological function of intracellular Ca<SUP>2+</SUP> as a critical negative regulator of insulin signaling, especially through the formation of Ca<SUP>2+</SUP>-PIPs.</P></▼1><▼2><P>Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca<SUP>2+</SUP> concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca<SUP>2+</SUP> homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca<SUP>2+</SUP> acts as a negative regulator of insulin signaling. Chronic intracellular Ca<SUP>2+</SUP> overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains. Pharmacological approaches showed that elevated intracellular Ca<SUP>2+</SUP> inhibits insulin-stimulated Akt phosphorylation and abrogates membrane localization of various PH domain proteins such as phospholipase Cδ and insulin receptor substrate 1, suggesting a common mechanism inhibiting the membrane targeting of PH domains. PH domain-lipid overlay assays confirmed that Ca<SUP>2+</SUP> abolishes the binding of various PH domains to phosphoinositides (PIPs) with two adjacent phosphate groups, such as PI(3,4)P<SUB>2</SUB>, PI(4,5)P<SUB>2</SUB>, and PI(3,4,5)P<SUB>3</SUB>. Finally, thermodynamic analysis of the binding interaction showed that Ca<SUP>2+</SUP>-mediated inhibition of targeting PH domains to the membrane resulted from the tight binding of Ca<SUP>2+</SUP> rather than PH domains to PIPs forming Ca<SUP>2+</SUP>-PIPs. Thus, Ca<SUP>2+</SUP>-PIPs prevent the recognition of PIPs by PH domains, potentially due to electrostatic repulsion between positively charged side chains in PH domains and the Ca<SUP>2+</SUP>-PIPs. Our findings provide a mechanistic link between intracellular Ca<SUP>2+</SUP> dysregulation and Akt inactivation in insulin resistance.</P></▼2>