scholarly journals Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide

2020 ◽  
Vol 6 (14) ◽  
pp. eaba0145 ◽  
Author(s):  
Zhenhua Hu ◽  
Sara Nizzero ◽  
Shreya Goel ◽  
Louis E. Hinkle ◽  
Xiaoyan Wu ◽  
...  
Keyword(s):  
Oral Delivery ◽  
Oral Absorption ◽  
Chitosan Nanoparticles ◽  
Gastric Fluid ◽  
Molecular Targeting ◽  
Murine Models ◽  
Long Chain Fatty Acid ◽  
Poor Patient Compliance ◽  
Therapeutic Peptides ◽  
High Bioavailability

Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)–conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: Preparation, characterization, and pharmacokinetics

2020 ◽  
pp. 088532822094788
Author(s):  
Yanan Shi ◽  
Miaomiao Yin ◽  
Yina Song ◽  
Tengteng Wang ◽  
Shiqi Guo ◽  
...  
Keyword(s):  
Oral Delivery ◽  
Oral Absorption ◽  
Chitosan Nanoparticles ◽  
Relative Bioavailability ◽  
Oral Route ◽  
Significant Challenge ◽  
Imaging Results ◽  
Hydroxypropyl Methacrylamide ◽  
Carrier Materials

The delivery of peptides or protein drugs via the oral route has always presented a significant challenge. Here, nanoparticles for the oral delivery of liraglutide are prepared. The nanoparticles are composed of the biodegradable carrier materials chitosan and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA). In addition, CSKSSDYQC (CSK) and hemagglutinin-2 (HA2) are introduced into the particles to improve the in vivo bioavailability of liraglutide. The size of the nanoparticles is less than 200 nm, and the encapsulation efficiency is approximately 80%. Compared with the subcutaneously injected liraglutide solution group (100%), the relative bioavailability of the nanoparticle group modified with CSK and HA2 reached 10.12%, which is 2.53 times that of the oral liraglutide solution group. In vivo imaging results showed that pHPMA/HA2-CSK chitosan nanoparticles (pHPMA/HA-CCNPs) are retained in the gastrointestinal tract for up to 12 h, which is beneficial for oral absorption. CSK and HA2 modified pHPMA/chitosan nanoparticles significantly improved liraglutide oral bioavailability and therefore have the potential to be applied for oral administration of peptides and proteins.

scholarly journals Prediction of Permeation and Cellular Transport of Silybum marianum Extract Formulated in a Nanoemulsion by Using PAMPA and Caco-2 Cell Models

Planta Medica ◽  
2017 ◽  
Vol 83 (14/15) ◽  
pp. 1184-1193 ◽  
Author(s):  
Vieri Piazzini ◽  
Chiara Rosseti ◽  
Elisabetta Bigagli ◽  
Cristina Luceri ◽  
Anna Bilia ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Oral Delivery ◽  
Oral Absorption ◽  
Gastric Fluid ◽  
Simulated Gastric Fluid ◽  
Cellular Transport ◽  
Artificial Membrane ◽  
Silybum Marianum ◽  
Permeability Assay

AbstractThe present study explores the potential of nanoemulsion, a lipid drug delivery system, to improve solubility and oral absorption of Silybum marianum extract. The optimized formulation contained 40 mg/mL of commercial extract (4 % w/w) and it was composed of 2.5 g labrasol (20 %) as the oil phase, 1.5 g cremophor EL as the surfactant, and 1 g labrafil as the cosurfactant (mixture surfactant/cosurfactant, 20 %).The system was characterized by dynamic light scattering, transmission electron microscopy, and HPLC-DAD analyses in order to evaluate size, homogeneity, morphology, and encapsulation efficiency. Physical and chemical stabilities were assessed during 40 days at 4 °C and 3 months at 25 °C. Stability in simulated gastric fluid followed by simulated intestinal conditions was also considered. In vitro permeation studies were performed to determine the suitability of the prepared nanoemulsion for oral delivery. Different models such as the parallel artificial membrane permeability assay and Caco-2 cell lines were applied.The nanoemulsion showed a good solubilizing effect of the extract, with a pronounced action also on its permeability, in respect to a saturated aqueous solution. The Caco-2 test confirmed the parallel artificial membrane permeability assay results and they revealed the suitability of the prepared nanoemulsion for oral delivery.

Development and Oral Bioavailability of Self-Emulsifying Formulation of Ketoconazole

2013 ◽  
Vol 5 (4) ◽  
pp. 1858-1865
Author(s):  
Arundhati Bhattacharyya ◽  
M Bajpai
Keyword(s):  
Oral Bioavailability ◽  
Oral Delivery ◽  
Oral Absorption ◽  
Aqueous Suspension ◽  
Droplet Diameter ◽  
Tween 80 ◽  
Concurrent Administration ◽  
System Maintenance ◽  
Pure Drug ◽  
Ph Dependent

Ketoconazole is an imidazole antifungal drug belonging to the class II of Biopharmaceutic Classification System. Maintenance of gastric acidity is essential for adequate dissolution and absorption of ketoconazole. Concurrent administration of antacid and antiulcer preparations decreases the oral absorption of ketoconazole often causing therapeutic failure.  The aim of this study was to evaluate whether a self-emulsifying formulation of ketoconazole would be able to overcome the pH dependent dissolution and oral bioavailability. Self-emulsifying drug delivery system (SEDDS) was prepared after selecting the oil, surfactant and co-surfactant by solubility analysis. Optimum ratio of the components was finalized on the basis of drug content, self-emulsification and mean droplet diameter. The effect of pH on dissolution was studied in comparison to the pure drug. Oral bioavailability was determined in comparison to aqueous suspension in rats and the effect of co-administration of ranitidine hydrochloride solution and a commercially available liquid antacid preparation was studied. The optimized formulation containing 20% Capryol 90 and 40% each of Carbitol and Tween 80, exhibited 100% drug release regardless of the pH whereas the pure drug exhibited a highly pH dependent dissolution. The AUC0-24 resulted with oral administration of the SEDDS formulation was about 34%, 43% and 60% higher compared to the aqueous suspension when administered alone, administered with ranitidine and administered with antacid respectively. The results of the present study demonstrate that self-emulsifying formulations can be utilized for oral delivery of weakly basic drugs like ketoconazole which exhibit pH dependent dissolution.

scholarly journals Formulation of Quaternized Aminated Chitosan Nanoparticles for Efficient Encapsulation and Slow Release of Curcumin

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 449
Author(s):  
Ahmed M. Omer ◽  
Zyta M. Ziora ◽  
Tamer M. Tamer ◽  
Randa E. Khalifa ◽  
Mohamed A. Hassan ◽  
...  
Keyword(s):  
Slow Release ◽  
Sodium Tripolyphosphate ◽  
Chitosan Nanoparticles ◽  
Gastric Fluid ◽  
Release Profile ◽  
Simulated Gastric Fluid ◽  
Maximum Value ◽  
Structure Surface ◽  
Drug Encapsulation Efficiency

An effective drug nanocarrier was developed on the basis of a quaternized aminated chitosan (Q-AmCs) derivative for the efficient encapsulation and slow release of the curcumin (Cur)-drug. A simple ionic gelation method was conducted to formulate Q-AmCs nanoparticles (NPs), using different ratios of sodium tripolyphosphate (TPP) as an ionic crosslinker. Various characterization tools were employed to investigate the structure, surface morphology, and thermal properties of the formulated nanoparticles. The formulated Q-AmCs NPs displayed a smaller particle size of 162 ± 9.10 nm, and higher surface positive charges, with a maximum potential of +48.3 mV, compared to native aminated chitosan (AmCs) NPs (231 ± 7.14 nm, +32.8 mV). The Cur-drug encapsulation efficiency was greatly improved and reached a maximum value of 94.4 ± 0.91%, compared to 75.0 ± 1.13% for AmCs NPs. Moreover, the in vitro Cur-release profile was investigated under the conditions of simulated gastric fluid [SGF; pH 1.2] and simulated colon fluid [SCF; pH 7.4]. For Q-AmCs NPs, the Cur-release rate was meaningfully decreased, and recorded a cumulative release value of 54.0% at pH 7.4, compared to 73.0% for AmCs NPs. The formulated nanoparticles exhibited acceptable biocompatibility and biodegradability. These findings emphasize that Q-AmCs NPs have an outstanding potential for the delivery and slow release of anticancer drugs.

Assessment of chitosan nanoparticles in improving the efficacy of nitazoxanide on cryptosporidiosis in immunosuppressed and immunocompetent murine models

2021 ◽  
Author(s):  
Howayda Said Fouad Moawad ◽  
Mohamed Hegab Abd El-Hady Hegab ◽  
Maha Saber Reda Badawey ◽  
Shaimaa Elsayed Ashoush ◽  
Shereen Mahmoud Ibrahim ◽  
...  
Keyword(s):  
Chitosan Nanoparticles ◽  
Murine Models

New and novel approaches for enhancing the oral absorption and bioavailability of protein and peptides therapeutics

2020 ◽  
Vol 11 (11) ◽  
pp. 713-732
Author(s):  
Abhishek Kanugo ◽  
Ambikanandan Misra
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Oral Delivery ◽  
Oral Absorption ◽  
Enzyme Inhibitors ◽  
Oral Route ◽  
Limited Success ◽  
Physical Chemical ◽  
Novel Approaches ◽  
Active Research

The advancement of the oral route for macromolecules has gained a lot of attention due to its noninvasive nature, safe and challenging in active research but with limited success. Oral administration poses challenges due to poor solubility, short half-life, quick elimination and the physical, chemical and biological barriers of the gastrointestinal tract. Approaches of past for improving oral absorption, such as enhancers, mucoadhesive delivery and enzyme inhibitors have been taken over by novel approaches like advanced liposomes, self-nanoemulsifying drug delivery system, nanoparticles and targeted delivery. Eudratech™ Pep, Peptelligence, Rani Pill and Pharm Film are the emerging technologies for delivering oral proteins and peptide. Calcitonin, semaglutide and octreotide are the peptides available in the market for oral delivery as outcomes of these technologies.

scholarly journals Preclinical Evaluation of UDCA-Containing Oral Formulation in Mice for the Treatment of Wet Age-Related Macular Degeneration

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 561 ◽  
Author(s):  
Maharjan ◽  
Kim ◽  
Jin ◽  
Ko ◽  
Song ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Oral Delivery ◽  
Water Solubility ◽  
Vision Loss ◽  
Oral Absorption ◽  
Aqueous Solubility ◽  
Oral Formulation ◽  
Preclinical Study ◽  
Age Related Macular Degeneration ◽  
Age Related

As a posterior ocular disease, wet age-related macular degeneration (WAMD) has been known to be related to vision loss, accompanying ocular complications. The intravitreous injection of VEGF antibodies has been reported to be an effective treatment to relieve symptoms of WAMD. However, the limitations of this treatment are high costs and invasiveness. For this reason, oral delivery route can be considered as a cost-effective way and the safest method to deliver drug molecules to the eyes. Accordingly, ursodeoxycholic acid (UDCA) was included in the oral formulation as the potential substance for the cure of WAMD in the animal model. Various pharmacological activities, such as antioxidant or anti-inflammatory effects, have been reported for UDCA and recent reports support the effects of UDCA in ocular treatment. However, due to poor water solubility and low pKa (around 5.0), it has been challenging to formulate aqueous solution of UDCA in the neutral pH range. In the present study, we confirmed the aqueous solubility of the oral UDCA formulation and performed a preclinical study, including pharmacokinetic profiling and WAMD model efficacy study in mice after oral administration of the drug solution. The results demonstrated that the formulation improved bioavailability of UDCA and efficiently delivered UDCA to the eye tissues after oral absorption. UDCA formulation was found to have inhibitory effects of choroidal neovascularization with a functional recovery in mice retinas. Taken together, our results suggest that the oral UDCA formulation could be used as a potent supplement for the cure of WAMD and related retinal diseases.

scholarly journals Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 993
Author(s):  
Mie Kristensen ◽  
Ragna Guldsmed Diedrichsen ◽  
Valeria Vetri ◽  
Vito Foderà ◽  
Hanne Mørck Nielsen
Keyword(s):  
Oral Delivery ◽  
Molecular Size ◽  
Therapeutic Peptide ◽  
Enzymatic Stability ◽  
Therapeutic Peptides ◽  
Ph Dependent ◽  
Pharmacologically Active ◽  
High Degree

Oral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide penetratin was employed to investigate effects of co-administration with insulin and the pharmacologically active part of parathyroid hormone (PTH(1-34)) at pH 5, 6.5, and 7.4 with respect to complexation, enzymatic stability, and transepithelial permeation of the therapeutic peptide in vitro and in vivo. Complex formation between insulin or PTH(1-34) and penetratin was pH-dependent. Micron-sized complexes dominated in the samples prepared at pH-values at which penetratin interacts electrostatically with the therapeutic peptide. The association efficiency was more pronounced between insulin and penetratin than between PTH(1-34) and penetratin. Despite the high degree of complexation, penetratin retained its membrane activity when applied to liposomal structures. The enzymatic stability of penetratin during incubation on polarized Caco-2 cell monolayers was pH-dependent with a prolonged half-live determined at pH 5 when compared to pH 6.5 and 7.4. Also, the penetratin-mediated transepithelial permeation of insulin and PTH(1-34) was increased in vitro and in vivo upon lowering the sample pH from 7.4 or 6.5 to 5. Thus, the formation of penetratin-cargo complexes with several molecular entities is not prerequisite for penetratin-mediated transepithelial permeation a therapeutic peptide. Rather, a sample pH, which improves the penetratin stability, appears to optimize the penetratin-mediated transepithelial permeation of insulin and PTH(1-34).

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