ArticleLiterature Review

Novel strategies in the oral delivery of antidiabetic peptide drugs – Insulin, GLP 1 and its analogs

March 2017
European Journal of Pharmaceutics and Biopharmaceutics 115(4)

DOI:10.1016/j.ejpb.2017.03.015

Authors:

Ruba Ismail

AbbVie

Ildiko Csoka

University of Szeged

As diabetes is a complex disorder being a major cause of mortality and morbidity in epidemic rates, continuous research has been done on new drug types and administration routes. Up to now, a large number of therapeutic peptides have been produced to treat diabetes including insulin, glucagon-like peptide-1 (GLP-1) and its analogs. The most common route of administration of these antidiabetic peptides is parenteral. Due to several drawbacks associated with this invasive route, delivery of these antidiabetic peptides by the oral route has been a goal of pharmaceutical technology for many decades. Dosage form development should focus on overcoming the limitations facing oral peptides delivery as degradation by proteolytic enzymes and poor absorption in the gastrointestinal tract (GIT). This review focuses on currently developed strategies to improve oral bioavailability of these peptide based drugs; evaluating their advantages and limitations in addition to discussing future perspectives on oral peptides delivery. Depending on the previous reports and papers, the area of nanocarriers systems including polymeric nanoparticles, solid lipid nanoparticles, liposomes and micelles seem to be the most promising strategy that could be applied for successful oral peptides delivery; but still further potential attempts are required to be able to achieve the FDA approved oral antidiabetic peptide delivery system.

Strategy for designing oral antidiabetic peptide drug formulations

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New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs

Article

Full-text available

Mar 2024

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non‐pharmacological actions (e.g., diet and exercise) co‐associated with the administration of antidiabetic drugs. Metformin is the first‐line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon‐like peptide‐1 (GLP‐1) analogs have been explored for managing the disease. GLP‐1 analogs trigger insulin secretion and suppress glucagon release in a glucose‐dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP‐1 analogs have an extended plasma half‐life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase‐4. However, GLP‐1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP‐1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non‐invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP‐1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface‐conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP‐1 and GLP‐1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Hundred Years of Insulin: The Possibility of Development of Oral Dosage Form

Article

Full-text available

Dec 2021

Diabetes is one of the major medical problems in the world. The discovery of insulin was a milestone in the history of medical science. This legendary invention has completed 100 years of its journey. Through this 100-year journey, many important events have taken place, and many modifications have been made to make it convenient for commercialization and patient compliance. After the antidiabetic activity of the pancreatic extract was discovered, the bovine and pork insulin came into use. Then, recombinant human insulin was discovered. Now long-acting to rapid-acting insulin forms are available (e.g., insulin pens, insulin pumps, and the like), and different systems are in use to deliver them to the body, but all these insulins are in invasive dosage forms and have some disadvantages, too. As we are using the oral form of most medicines, we prefer the oral form of insulin. Therefore, the concern is now to develop the oral dosage form of insulin. Some proposed oral dosage forms are at different stages of the clinical trial such as classical dosage forms, enzyme inhibitors, unnatural amino acids, nanoparticles, cell-penetrating peptides, and so on. Since the oral forms of insulin create some limitations and confusion, further research is required to solve these problems. Accordingly, the aim of the review was to predict the possibility of developing marketable oral insulin.

Fabrication and Evaluation of a pH-Responsive Nanocomposite-Based Colonic Delivery System for Improving the Oral Efficacy of Liraglutide

Article

Full-text available

Jul 2023
INT J NANOMED

Purpose Oral administration of liraglutide, a protein drug, suffers from low intestinal absorption and instability in the gastrointestinal tract, resulting in low bioavailability. The present study aimed to develop a pH-responsive nanocomposite based-colonic delivery system to improve the oral efficacy of liraglutide. Methods Nanocomplex (AC-Lira) between aminoclay and liraglutide was prepared by a spontaneous self-assembly. After surface charge reversal using citric acid, AC-Lira was coated with poly(methacrylic acid-co-methyl methacrylate) (1:2). The fabricated nanocomplex underwent various in vitro studies to characterize its physicochemical properties, drug release, and cellular transport. In vivo efficacy studies were also conducted using streptozotocin-induced diabetic rats. Results Both uncoated (AC-Lira) and coated nanocomplex (EAC-Lira) achieved high entrapment efficiency (> 90%) and showed a narrow size distribution. While exhibiting low drug release at pH 1.2 (approximately 30%), EAC-Lira achieved rapid and extensive drug release (~90%) at pH 7.4, displaying pH-dependent drug release. EAC-Lira showed significant size reduction and surface charge reversal during dissolution at pH 7.4, probably due to the removal of the outer coating layer. Furthermore, EAC-Lira was effective at protecting the entrapped proteins against enzymatic degradation. EAC-Lira also increased the membrane transport of liraglutide by 3.5 folds in Caco-2 cells. Owing to enhanced membrane transport and metabolic stability, EAC-Lira improved in vivo efficacy of orally administered liraglutide, significantly reducing blood glucose concentrations, intake of food and water, and body weight in type 2 diabetes rats. Conclusion These results suggest EAC-Lira is a promising approach to improving the oral bioavailability and efficacy of liraglutide.

Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation

Article

Full-text available

Jun 2021

IntroductionOral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide pharmacokinetics were investigated.Methods Subjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose.ResultsIn the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration–time curve (AUC0–24h,semaglutide,day10) and maximum semaglutide concentration (Cmax,semaglutide,day10) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUC0–24h,semaglutide,day10 and Cmax,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p < 0.001).Conclusion Administration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label.Trial RegistrationClinicalTrials.gov identifiers NCT02172313, NCT01572753.

Microneedle Technology in Analgesic Therapy

Preprint

Aug 2024

Comprehensive ABC (HbA1c, blood pressure, LDL-C) control and cardiovascular disease risk in patients with type 2 diabetes mellitus and major depressive disorder in a South African managed healthcare organisation

Article

Mar 2024
Cardiovasc J South Af

Aim: Patients with type 2 diabetes mellitus (T2DM) who have suboptimal control of the triad of glucose (A), blood pressure (B) and lipid profile (C) have an increased risk of cardiovascular disease (CVD). Additionally, the presence of major depressive disorder (MDD) can lead to poor outcomes. Therefore, the aim of this study was to assess the role of MDD with ABC control in patients with T2DM in a South African private healthcare setting. Methods: Healthcare medical claims and electronic health records of 1 211 adult patients with T2DM and/or MDD were analysed for 2019. Results: Only 24% of the T2DM ± MDD patients reached a low-density lipoprotein cholesterol (LDL-C) target < 1.8 mmol/l, and only 13% of the T2DM + MDD and 7.1% of T2DM - MDD patients achieved simultaneous ABC targets. The proportion of patients admitted due to macrovascular complications was higher in the T2DM + MDD group (22.8%) compared to the T2DM - MDD (13.1%) and MDD group (9.9%) (p = 0.012). Multivariate logistic regression analysis showed that older patients with T2DM + MDD achieved better glycated haemoglobin and LDL-C control. Significantly more patients with T2DM + MDD (12%) had repeat macrovascular admissions in 2019 compared to the T2DM - MDD patients (2.9%) (p = 0.005). Conclusions: Despite a managed-care environment, the comprehensive ABC control among patients with T2DM was suboptimal, particularly in those with MDD, placing them at greater risk for CVD events.

Therapeutic Applications in Diabetes

Article

Full-text available

Nov 2023

Modern society gives great thought to the microparticulate drug delivery system (MDDS) because of its potential to solve the issues that have plagued conventional medicine for so long. Round particles with sizes between 10 and 1000 nm in diameter are called microparticles (MPs). MPs have the ability to encapsulate both soluble and insoluble substances. In clinical trials, MDDS were shown to be superior to conventional drug delivery methods in enhancing drug bioavailability, stability, targeting, and release control. By decreasing medication toxicity and dosing frequency, MPs also provide comfort, ease of administration, and enhanced patient compliance. This article discussed the production process, drug delivery, and potential therapeutic applications of MDDS. Drug release control via gastroretention, enhanced drug dissolution, reduced side effects, targeted drug delivery, mucosal drug delivery, natural products loaded with MPs, improved insulin stability, administration routes, andsustained drug release discussed in detail as therapeutic applications of antidiabetic drug-loaded MPs. The present scenario and potential future developments in creating MPs loaded with antidiabetic medicines also examined.

Therapeutic Applications in Diabetes

Article

Full-text available

Nov 2023

Oral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives

Article

Full-text available

Feb 2024

Diabetes, characterized by hyperglycemia, is a major cause of death and disability worldwide. Peptides, such as insulin and glucagon-like peptide-1 (GLP-1) analogs, have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body. Compared to subcutaneous injection, oral administration of anti-diabetic peptides is a preferred approach. However, biological barriers significantly reduce the efficacy of oral peptide therapeutics. Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes. This review will highlight (1) the benefits of oral anti-diabetic peptide therapeutics; (2) the biological barriers for oral peptide delivery, including pH and enzyme degradation, intestinal mucosa barrier, and biodistribution barrier; (3) the delivery platforms to overcome these biological barriers. Additionally, the review will discuss the prospects in this field. The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

Determination of vitamin D3 encapsulated in liprotide β-lactoglobulin crosslink oleic acid by HPLC and SEM

Article

Full-text available

Dec 2023

Vitamin D is an unstable compound to light, heat, and certain chemicals, so it is easily degraded under various conditions. Therefore, instability is achieved through the encapsulation method using complex protein carrier compounds with fatty acids known as liprotide. This study aims to determine vitamin D3. Method, the determination of vitamin D3 was analyzed, including the determination of vitamin D3 standard eluents, calibration curve, and determining the retention time of vitamin D3 encapsulated in liprotide using HPLC (High-Performance Liquid Chromatography). Morphology of vitamin D3 encapsulated in liprotide using SEM (Scanning Electron Microscopy). The results showed that the standard vitamin D3 HPLC analysis using acetonitrile: methanol and acetonitrile: aquabidest obtained two peaks. Butanol: n-hexane eluent obtained one peak with a retention time of 2,170 minutes. The results of the standard calibration curve for vitamin D3 at a linearity value of R2 = 0,9997 and f(x) = 14,928x-117,930. The same retention time was obtained for vitamin D3 encapsulated in liprotide. Conclusion, an enlargement of the cubic structure, which occurred due to the encapsulation of vitamin D3 by the liprotide-forming micelles.

Plant-derived cell-penetrating microprotein α-astratide aM1 targets Akt signaling and alleviates insulin resistance

Article

Full-text available

Sep 2023
CELL MOL LIFE SCI

Insulin-resistant diabetes is a common metabolic disease with serious complications. Treatments directly addressing the underlying molecular mechanisms involving insulin resistance would be desirable. Our laboratory recently identified a proteolytic-resistant cystine-dense microprotein from huáng qí (Astragalus membranaceus) called α-astratide aM1, which shares high sequence homology to leginsulins. Here we show that aM1 is a cell-penetrating insulin mimetic, enters cells by endocytosis, and activates the PI3K/Akt signaling pathway independent of the insulin receptor leading to translocation of glucose transporter GLUT4 to the cell surface to promote glucose uptake. We also showed that aM1 alters gene expression, suppresses lipid synthesis and uptake, and inhibits intracellular lipid accumulation in myotubes and adipocytes. By reducing intracellular lipid accumulation and preventing lipid-induced, PKCθ-mediated degradation of IRS1/2, aM1 restores glucose uptake to overcome insulin resistance. These findings highlight the potential of aM1 as a lead for developing orally bioavailable insulin mimetics to expand options for treating diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-023-04937-y.

Liposome optimisation for oral delivery of nutraceuticals in food: a review

Article

Jun 2023

A liposome is one of the most commonly used encapsulation technology with proven benefits, including high biocompatibility and improved solubility, but efficacy may be compromised when used for oral delivery, including application in food. The latter is an unfortunate but manageable setback compared to its promising compatibility with various nutraceuticals regardless of their solubility, which would be greatly useful in functional food production. Oral delivery presents several challenges, specifically the harsh environment in the gastrointestinal tract with enzymatic activities and pH changes and limited permeability of compounds across intestinal epithelia. To overcome these challenges, various efforts have been made to modify and strengthen liposomes as oral carriers. In this review, a brief introduction to liposomes and the challenges faced in the gastrointestinal tract is provided. A review of the existing modification efforts done to liposomes was to increase their stability and permeability for oral delivery.

ORAL DELIVERY OF PEPTIDE AND PROTEIN THERAPEUTICS: CHALLENGES AND STRATEGIES

Article

Full-text available

Jun 2023
J Exp Zool

This review explores the challenges and strategies in oral delivery of peptide and protein therapeutics. Physiological barriers such as the gastrointestinal tract, enzymatic degradation, poor permeability and proteolytic environment hinder effective delivery. Formulation approaches including bioavailability enhancement, mucoadhesive systems, nanoparticle-based, lipid-based, and polymer-based delivery systems have shown promise in improving solubility, stability, and permeability. Innovative technologies like nanotechnology-based delivery, targeted approaches, drug-device combinations, and bioadhesive/mucoadhesive technologies offer new avenues for overcoming challenges. Strategies to combat enzymatic degradation involve protease inhibitors, enzyme-resistant formulations, chemical modifications, and encapsulation strategies. Enhancing permeability across the intestinal epithelium can be achieved through absorption enhancers, carrier-mediated transport systems, tight junction modulators, and nanotechnology-based approaches. Preclinical and clinical studies provide insights into oral delivery efficacy, safety and patient acceptance. Future directions include advances in delivery, emerging technologies, regulatory considerations and patient compliance. This review offers a comprehensive overview for researchers and clinicians in the field.

Quantitative live cell imaging of lipidated peptide transport through an epithelial cell layer

Article

Full-text available

Jan 2023

Oral drug delivery increases patient compliance and is thus the preferred administration route for most drugs. However, for biologics the intestinal barrier greatly limits the absorption and reduces their bioavailability. One strategy employed to improve on this is chemical modification of the biologic through the addition of lipid side chains. While it's been established that lipidation of peptides can increase transport, a mechanistic understanding of this effect remains largely unexplored. To pursue this mechanistic understanding, end-point detection of biopharmaceuticals transported through a monolayer of fully polarized epithelial cells is typically used. However, these methods are time-consuming and tedious. Furthermore, most established methods cannot be combined easily with high-resolution live-cell fluorescence imaging that could provide a mechanistic insight into cellular uptake and transport. Here we address this challenge by developing an axial PSF deconvolution scheme to quantify the transport of peptides through a monolayer of Caco-2 cells using single-cell analysis with live cell confocal fluorescence microscopy. We then measure the known cross-barrier transport of several compounds in our model and compare the results with results obtained in an established microfluidic model finding similar transport phenotypes. This verifies that already after two days the Caco-2 cells in our model form a tight monolayer and constitute a functional barrier model. We then apply this assay to investigate the effects of side chain lipidation of the model peptide drug salmon calcitonin (sCT) modified with 4‑carbon and 8‑carbon-long fatty acid chains. Furthermore, we compare that with experiments performed at lower temperature and using inhibitors for some endocytotic pathways to pinpoint how lipidation length modifies the main avenues for the transport. We thus show that increasing the length of the lipid chain increases the transport of the drug significantly but also makes endocytosis the primary transport mechanism in a short-term cell culture model.

Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease

Article

Full-text available

Dec 2022

Diabetic kidney disease (DKD) is the main complication in diabetes mellitus (DM) and the main cause of end-stage kidney disease worldwide. However, sodium glucose cotransporter 2 (SGLT2) inhibition, glucagon-like peptide-1 (GLP-1) receptor agonist, mineralocorticoid receptor antagonists and endothelin receptor A inhibition have yielded promising effects in DKD, a great part of patients inevitably continue to progress to uremia. Newly effective therapeutic options are urgently needed to postpone DKD progression. Recently, accumulating evidence suggests that targeted drug delivery strategies, such as macromolecular carriers, nanoparticles, liposomes and so on, can enhance the drug efficacy and reduce the undesired side effects, which will be a milestone treatment in the management of DKD. The aim of this article is to summarize the current knowledge of targeted drug delivery strategies and select the optimal renal targeting strategy to provide new therapies for DKD.

Harnessing gut cells for functional insulin production: Strategies and challenges

Article

Full-text available

Dec 2022

Reprogrammed glucose-responsive, insulin + cells (“β-like”) exhibit the potential to bypass the hurdles of exogenous insulin delivery in treating diabetes mellitus. Current cell-based therapies-transcription factor regulation, biomolecule-mediated enteric signaling, and transgenics - have demonstrated the promise of reprogramming either mature or progenitor gut cells into surrogate “β-like” cells. However, there are predominant challenges impeding the use of gut “β-like” cells as clinical replacements for insulin therapy. Reprogrammed “β-like” gut cells, even those of enteroendocrine origin, mostly do not exhibit glucose – potentiated insulin secretion. Despite the exceptionally low conversion rate of gut cells into surrogate “β-like” cells, the therapeutic quantity of gut “β-like” cells needed for normoglycemia has not even been established. There is also a lingering uncertainty regarding the functionality and bioavailability of gut derived insulin. Herein, we review the strategies, challenges, and opportunities in the generation of functional, reprogrammed “β-like” cells.

Nanoparticles Containing Tamarind Isolate Protein Potentiate the Satiety without Promoting the Anti-Inflammatory Effect in a Preclinical Model of Diet-Induced Obesity

Article

Full-text available

Nov 2022

The study aimed to evaluate the nanoparticles (ECW) containing tamarind trypsin inhibitor (TTI) concerning the storage effect under different conditions on antitrypsin activity and the bioactive potential in a preclinical model. ECW was exposed to different pH and temperatures to evaluate the interaction between TTI and its encapsulating agents, monitored by antitrypsin activity. Wistar rats (n = 25) with obesity induced by diet were divided into groups: untreated; treatment with nutritionally adequate diet; treatment with nutritionally adequate diet and ECW/12.5 mg/kg; treatment with ECW/12.5 mg/kg; and treatment with TTI/25 mg/kg. The groups were evaluated over ten days with regards to satiety, zoometric, biochemical, and inflammatory parameters, using ten times less TTI (2.5 mg/kg) contained in ECW. TTI was protected and encapsulated in ECW without showing residual inhibitory activity. Only at gastric pH did ECW show antitrypsin activity. At different temperatures, it showed high antitrypsin activity, similar to TTI. The animals treated with ECW had significantly reduced body weight variation (p < 0.05), and only TTI treatment reduced the inflammatory parameters significantly (p < 0.05). The study showed that by using lower concentrations of TTI in ECW it was possible to perceive promising effects with perspectives of use in functional products for managing obesity and its complications.

Nanocarriers System for Vitamin D as Nutraceutical in Type 2 Diabetes: A Review

Article

Full-text available

May 2022

Incidence of diabetes are common among population around the world. Diabetes may lead to other complication and increasing morbidity and mortality. Many ways have been done to treat and prevent the development of diabetes. In addition of conventional pharmacotherapy, therapeutic therapy shown good opportunity to maintain and improve diabetic conditions. Vitamin D3 is known as nutraceutical and has good opportunity to develop the medication of type 2 diabetes. In another way, vitamin D3 naturally easy to damage by environmental condition. To overcome this weakness, researcher around the world have developed the method for protecting unstable compound as vitamin D3 with encapsulation. Liprotide is one of the various materials which can be used for encapsulation. Combination of lipid and protein molecules is expected to be a carrier and protector of vitamin D3 in gastrointestinal system. Here we review the research advances of liprotide as nanocarriers and vitamin D3 as nutraceuticals to discuss in applied on type 2 diabetes.

Liposomal Formulation for Oral Delivery of Cyclosporine A: Usefulness as a Semisolid-Dispersion System

Article

Full-text available

May 2022
PHARM RES-DORDR

Purpose This study aims to understand the process and mechanism of oral drug absorption from liposomes and to verify the usefulness of liposomal formulation for poorly soluble drugs. Methods Cyclosporine A (CsA) was used as a model drug and entrapped into Dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) liposomes. Molecular state of CsA in the liposomes was analyzed using powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). Release profiles of CsA from liposomes were observed in fasted state simulated intestinal fluid (FaSSIF). Oral absorption of CsA from liposomal formulations were investigated in rats. Results PXRD and PLM analyses suggested that CsA exists in the lipid layer of liposomes as a molecular dispersed state. Although both liposomes retained CsA stably in the simple buffer, DPPC liposomes quickly released CsA within 10 min in FaSSIF due to the interaction with bile acid. In contrast, effect of bile acid was negligible in DSPC, indicating a high resistivity to membrane perturbation. Oral bioavailability of CsA from liposomal formulations were almost comparable with that from a marketed product (Neoral). However, the absorption profiles were clearly different. CsA was absorbed quickly from DPPC liposomes and Neoral, while sustained absorption profile was observed from DSPC liposomes. Further study in which ritonavir was co-entrapped in the liposomes with CsA showed the higher efficacy of ritonavir to increase oral bioavailability of CsA. Conclusion Liposomes allows the appropriate formulation design for oral delivery of poorly soluble drugs, not only to increase the extent but also to control the rate of absorption.

Drug discovery of sclerostin inhibitors

Article

Full-text available

Jan 2022

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

Potentialities of nanomaterials for the management and treatment of metabolic syndrome: A new insight

Article

Full-text available

Mar 2022

Metabolic syndrome is a collection of abnormalities including insulin resistance, hypertension, dyslipi-demia, type 2 diabetes, obesity, inflammation, non-alcoholic fatty liver disease, etc. The metabolic syndrome results in a dramatic five-fold elevation in the risk of developing type-2 diabetes and a twofold heightened risk of developing cardiovascular diseases. It is fast becoming a major global health challenge, cause of mortality and morbidity. Regardless of advances in understanding the mechanisms involved in the pathogenesis of metabolic syndrome, available therapies are still not effective. Nanotechnology is marked as an upcoming tool with a wide range of applications in biomedicine, especially for the management of metabolic syndrome and its associated disorders such as diabetes, obesity, etc. because the nanotechnology utilizes nanoscaled drugs and therapeutics that can reach specific target sites, which helps in improving drug delivery systems, early disease detection and diagnosis using nano-imaging techniques. Therefore, nanotechnology increases bioavailability, permeability, compatibility, the effectiveness of treatment and reduced adverse effects. In this review, we will describe the role of nanomaterial-based therapeutics in managing metabolic disorders such as non-alcoholic fatty liver disease, obesity, insulin resistance, glucose intolerance which all increase the risk of developing car-diovascular diseases and diabetes.

Nanocarriers for oral delivery of biologics: small carriers for big payloads

Article

Sep 2021
TRENDS PHARMACOL SCI

Macromolecular therapeutics of biological origin, also known as biologics, have become one of the fastest-growing classes of drugs for management of a range of chronic and acute conditions. The majority of approved biologics are administered via the parenteral route and are thus expensive, have low patient compliance, and have high systemic toxicity. Therefore, tremendous efforts have been devoted to the development of carriers for oral delivery of biologics. This review evaluates key chemical (e.g. pH and enzymes) and physiological challenges to oral biologics delivery. We review the conventional formulation strategies and their limitations, followed by a detailed account of the progress on the use of nanocarriers used for oral biologics delivery, covering organic and inorganic nanocarriers. Lastly, we discuss limitations and opportunities presented by these emerging nanomaterials in oral biologics delivery.

Physicochemical Properties and Glucose-Lowering Effect of an Insulin-Aloe veraBuccal Delivery System

Article

Full-text available

Jun 2021

Subcutaneous insulin injection is one of the therapies in the treatment of diabetes mellitus. However, problems such as pain at the injection site and lipodystrophy present a challenge that will influence patient compliance. This study aims to develop and characterise buccal film formulations containing insulin, utilising the glucose-lowering and pharmaceutical properties of Aloe vera. Characterisation tests such as morphology, rheological measurement, pH value, mechanical properties, and permeation test were performed on the optimal formulation. Assessment of the glucose-lowering efficacy was performed using alloxan-induced diabetic rabbits. Composition of the final film formulation included 3% w/w sodium carboxymethyl cellulose, 40% v/v glycerol, 70% v/v Aloe vera, 0.5% w/v mannitol, 0.125% w/v aspartame, 0.125% v/v Tween 80 and 15.3 mg insulin. The drug content has been determined to be 56.77 ± 8.55%. The formulation shows a low variation in weight and thickness measurements and acceptable physicochemical properties, in addition to sustained drug release for 6 h. The final film formulation that combined insulin and Aloe vera was effective enough to reduce blood glucose levels compared to the negative control (p > 0.05), despite fluctuation in the blood glucose levels throughout the study, and did not show any enhancement in reduction compared to the insulin-only film. In conclusion, the developed buccal film formulation has the potential to be used as a vessel for the delivery of insulin. Nevertheless, further studies are required to ensure the stability of the insulin via buccal route and stabilisation of insulin within the formulation.

Challenge of diabetes mellitus and researchers’ contributions to its control

Article

Full-text available

May 2021

The aim of this review study was to assess the past significant events on diabetes mellitus, transformations that took place over the years in the medical records of treatment, countries involved, and the researchers who brought about the revolutions. This study used the content analysis to report the existence of diabetes mellitus and the treatments provided by researchers to control it. The focus was mainly on three main types of diabetes (type 1, type 2, and type 3 diabetes). Ethical consideration has also helped to boost diabetic studies globally. The research has a history path from pharmaceuticals of organic-based drugs to metal-based drugs with their nanoparticles in addition to the impacts of nanomedicine, biosensors, and telemedicine. Ongoing and future studies in alternative medicine such as vanadium nanoparticles (metal nanoparticles) are promising.

Long-Term clinical efficacy of liraglutide for type 2 diabetes: real-world evidence and outcomes from Pakistan

Article

Dec 2024

In Vitro Cellular Uptake and Insulin Secretion Studies on INS-1E Cells of Exendin-4 Loaded Self Nanoemulsifying Drug Delivery Systems

Article

Oct 2024
PHARM DEV TECHNOL

Exendin-4 (ex-4) is a peptide molecule that regulates blood glucose levels without causing hypoglycemia by providing insulin secretion from beta cells in the pancreas. Self-nanoemulsifying drug delivery systems (SNEDDS) attract attention for oral administration of therapeutic peptide/proteins because they protect therapeutic peptide/proteins from the gastric environment, reduce changes due to food effects, are easy to prepare and scale-up. Ex-4 has no commercial form that can be administered orally. In this study, the cytotoxicity, cellular uptake, and insulin secretion of ex-4 and ex-4/chymostatin (chym) SNEDDS were investigated on INS-1E rat pancreatic beta cells. The effect of ex-4 and ex-4/chym SNEDDS on cell viability in INS-1E cells increased when the dilution ratio higher. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 2.8 mM (low-dose) glucose-induced INS-1E cells 2.21-fold and 2.17-fold compared to control, respectively. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 16.7 mM (high dose) glucose-induced INS-1E cells compared to control, respectively. In cellular uptake studies, coumarin-6 solution penetrated the apical membrane of INS-1E cells and remained in the cytoplasm, while coumarin-6 loaded SNEDDS were visualized in the nuclei of the cell. These findings will likely be useful in the development of new formulations for the oral administration of peptides/proteins.

Nano-biomaterials: A Site-Targeted Approach to Antidiabetic Drug Delivery

Chapter

Jan 2024

Diabetes has become a global health crisis, marked by a significant increase in prevalence. This chapter delves into the distinct characteristics, prevalence, and complications of Type I and Type II diabetes, emphasizing the urgency of addressing this escalating epidemic. Current strategies to combat diabetes include public health campaigns, lifestyle interventions, early diagnosis, and improved healthcare access. The economic impact underscores the need for innovative solutions, and one promising avenue is the use of nano-biomaterials for targeted antidiabetic drug delivery. Nano-biomaterials, operating at the nanoscale, offer precision and effectiveness in drug delivery, potentially revolutionizing diabetes therapies. The chapter advocates for preventative measures, understanding economic implications, and exploring cutting-edge solutions like nano-biomaterials for targeted drug delivery to address diabetes as a global health crisis. Additionally, it delves into nanocarrier strategies for enhanced delivery of antidiabetic agents, exploring nanoparticulate approaches for improved therapy in hyperglycemic conditions. Nano-formulations, such as nanoparticles and nanostructured lipid carriers, offer advantages like reduced dosage, rapid onset of action, sustained release, targeted delivery, and improved bioavailability. Incorporating polymers, both synthetic and natural, enhances the design flexibility and biocompatibility of these delivery systems, showing promise in delivering antidiabetic phytocompounds. The comprehensive discussion on the utilization of nano-biomaterials and nanocarrier strategies sheds light on innovative approaches to diabetes management, holding the potential to offer more efficient, patient-friendly, and economically viable solutions amidst the diabetes pandemic. In conclusion, this chapter emphasizes the importance of a multidimensional approach, involving public health initiatives, socioeconomic considerations, and cutting-edge technologies to effectively address the challenges posed by diabetes globally.

Oral Delivery of Therapeutic Peptides: Strategies for Product Development

Chapter

Jan 2024

Puchun Liu

A Short Appraisal of Biological Macromolecules as Tethering Excipients for Improved Drug Delivery: Current Advances

Article

Oct 2023

Dilpreet Singh

A Comprehensive Review on Prospects of Polymeric Nanoparticles for Treatment of Diabetes Mellitus: Receptors-Ligands, In vitro & In vivo Studies

Article

Aug 2023

As per International Diabetes Federation Report 2022, worldwide diabetes mellitus (DM) caused 6.7M moralities and ~537M adults suffering from diabetes mellitus. It is a chronic condition due to β-cell destruction or insulin resistance that leads to insulin deficiency. This review discusses Type-1 DM and Type-2 DM pathophysiology in detail, with challenges in management and treatment. The toxicity issues of conventional drugs and insulin injections are complex to manage. Thus, there is a need for technological intervention. In recent years, nanotechnology has found a fruitful advancement of novel drug delivery systems that might potentially increase the efficacy of anti-diabetic drugs. Amongst nano-formulations, polymeric nanoparticles have been studied to enhance the bioavailability and efficacy of anti-diabetic drugs and insulin. In the present review, we summarized polymeric nanoparticles with different polymers utilized to deliver anti-diabetic drugs with in vitro and in vivo studies. Furthermore, this review also includes the role of receptors and ligands in diabetes mellitus and the utilization of receptor-ligand interaction to develop targeted nanoparticles. Additionally, we discussed the utility of nanoparticles for the delivery of phytoconstituents which aids in protecting the oxidative stress generated during diabetes mellitus.

Fundamental Uses of Peptides as a New Model in Both Treatment and Diagnosis

Article

May 2023

Hend Okasha

An amino acid short chain is known as a peptide. Peptide bonds are the connections that hold the amino acids of a peptide together in a particular order. Characteristically, the shorter length of peptides helps to identify them from proteins. Different ways are used to classify peptides, including chain length, source of peptides, or their biological functions. The fact that peptides serve several purposes suggests that there is a foundation for improvement in peptide production and structure to enhance action. This review aims to give an overview of peptides used recently in treatment and diagnosis.

Circumventing the Gastrointestinal Barrier for Oral Delivery of Therapeutic Proteins and Peptides (PPTS): Current Trends and Future Trajectories

Article

Apr 2023
Curr Drug Deliv

Therapeutic proteins and peptides (PPTs) have become one of the most important biological molecules for the management of many common and complex diseases due to their high specificity and high bioactivity. However, these biomolecules are mainly given by the hypodermic injection, which often leads to poor patient compliance due to the invasive nature of this route of administration. The oral route has been considered the most convenient and patient-friendly route for drug delivery relative to hypodermic injection. Despite the ease and simplicity conferred by oral administration, this drug delivery route suffers rapid peptide degradation in gastric fluid and low intestinal uptake. In order to circumvent these issues, several strategies, such as enzyme inhibitors, permeation enhancers, chemical modification, mucoadhesive and stimuli-responsive polymers, and specialised particulate formulation have been developed. Such strategies are designed with the aim of protecting proteins and peptides from the harsh gastrointestinal environment as well as providing a strategy to enhance the uptake of the therapeutic across the gastrointestinal tract. This review aims to provide an overview of the current development in enteral drug delivery strategies for proteins and peptides. The design of these drug delivery systems in overcoming physical and chemical barriers along the gastrointestinal tract while improving oral bioavailability will be highlighted and discussed.

In situ rearranged multifunctional lipid nanoparticles via synergistic potentiation for oral insulin delivery

Article

Mar 2023
INT J PHARMACEUT

Oral administration of therapeutic peptides/proteins (TPPs) is confronted with multiple gastrointestinal (GI) barriers such as mucus and intestinal epithelium, and the first-pass metabolism in the liver is also responsible for low bioavailability. In situ rearranged multifunctional lipid nanoparticles (LNs) were developed to overcome these obstacles via synergistic potentiation for oral insulin delivery. After the reverse micelles of insulin (RMI) containing functional components were gavaged, LNs formed in situ under the hydration effect of GI fluid. The nearly electroneutral surface generated by the rearrangement of sodium deoxycholate (SDC) and chitosan (CS) on the reverse micelle core facilitated LNs (RMI@SDC@SB12-CS) to overcome mucus barrier and the sulfobetaine 12 (SB12) modification further promoted epithelial uptake of LNs. Subsequently, chylomicron-like particles formed by the lipid core in the intestinal epithelium were easily transported to the lymphatic circulation and then into the systemic circulation, thus avoiding hepatic first-pass metabolism. Eventually, RMI@SDC@SB12-CS achieved a high pharmacological bioavailability of 13.7% in diabetic rats. In conclusion, this study provides a versatile platform for enhanced oral insulin delivery.

Lipid Nanocarriers as an Alternative for the Delivery of Bioactive Compounds Beneficial to Health

Article

Mar 2023

Bioactive compounds derived from food or plants have become a natural source with the potential for producing functional, nutraceutical, and pharmaceutical foods due to their biological functions and beneficial health effects. However, to perform such physiological processes, these compounds need to be absorbed through the gastrointestinal tract. Among the existing technologies, nanoencapsulation increases physical stability, protection, and the contact surface, facilitating the solubility and bioavailability of such compounds. In this type of encapsulation, lipid nanocarriers are promising carriers due to their lipid structure and containing hydrophilic surfactant, capable of facilitating the intestinal absorption of active compounds. However, in food or drugs, one of the significant challenges for applying bioactive compounds on a nanoscale is the lack of in vivo studies that establish safety limits for cytotoxicity. This review covered recent studies on the encapsulation of natural bioactive compounds in different types of lipid nanocarriers. In addition to methods for obtaining and characterizing nanocarriers, bioactivities with beneficial potential for human health, such as antioxidant, antimicrobial, antihypertensive, antidiabetic, and neuroprotective, are mentioned. The manuscript deals with the bioaccessibility of active compounds, new perspectives, and challenges for applying lipid nanocarriers.

Toxinology of Marine Venomous Snails

Article

Nov 2021

Design and characterization of lipid nanocarriers for oral delivery of immunotherapeutic peptides

Article

Dec 2022

The use of therapeutic proteins and peptides is of great interest for the treatment of many diseases, and advances in nanotechnology offer a path toward their stable delivery via preferred routes of administration. In this study, we sought to design and formulate a nanostructured lipid carrier (NLC) containing a nominal antigen (insulin peptide) for oral delivery. We utilized the design of experiments (DOE) statistical method to determine the dependencies of formulation variables on physicochemical particle characteristics including particle size, polydispersity (PDI), melting point, and latent heat of melting. The particles were determined to be non‐toxic in vitro, readily taken up by primary immune cells, and found to accumulate in regional lymph nodes following oral administration. We believe that this platform technology could be broadly useful for the treatment of autoimmune diseases by supporting the development of oral delivery‐based antigen specific immunotherapies.

Hydroxyethylcellulose-Based Hydrogels Containing Liposomes Functionalized with Cell-Penetrating Peptides for Nasal Delivery of Insulin in the Treatment of Diabetes

Article

Full-text available

Nov 2022

Liposomes functionalized with cell-penetrating peptides are a promising strategy to deliver insulin through the nasal route. A hydrogel based on hydroxyethylcellulose (HEC) aqueous solution was prepared, followed by a subsequent addition of liposomes containing insulin solution functionalized with trans-activator of transcription protein of HIV-1 (TAT) or Penetratin (PNT). The formulations were characterized for rheological behavior, mucoadhesion, syringeability, in vitro release and in vivo efficacy. Rheological tests revealed non-Newtonian fluids with pseudoplastic behavior, and the incorporation of liposomes (HLI, HLITAT and HLIPNT) in hydrogels did not alter the behavior original pseudoplastic characteristic of the HEC hydrogel. Pseudoplastic flow behavior is a desirable property for formulations intended for the administration of drugs via the nasal route. The results of syringeability and mucoadhesive strength from HEC hydrogels suggest a viable vehicle for nasal delivery. Comparing the insulin release profile, it is observed that HI was the system that released the greatest amount while the liposomal gel promoted greater drug retention, since the liposomal system provides an extra barrier for the release through the hydrogel. Additionally, it is observed that both peptides tested had an impact on the insulin release profile, promoting a slower release, due to complexation with insulin. The in vitro release kinetics of insulin from all formulations followed Weibull’s mathematical model, reaching approximately 90% of release in the formulation prepared with HEC-based hydrogels. Serum insulin levels and the antihyperglycemic effects suggested that formulations HI and HLI have potential as carriers for insulin delivery by the nasal pathway, a profile not observed when insulin was administered by subcutaneous injection or by the nasal route in saline. Furthermore, formulations functionalized with TAT and PNT can be considered promoters of late and early absorption, respectively.

Emerging Strategies to Improve the Stability and Bioavailability of Insulin: An Update on Formulations and Delivery Approaches

Article

Nov 2022
Curr Drug Deliv

One of the primary goals of diabetes management is to maintain blood glucose levels within a normal range, and insulin plays a vital role in achieving this. All Type 1 DM patients and advanced Type 2 DM patients require insulin. Insulin is administered subcutaneously, which may cause patient discomfort from the use of needles. Therefore, developing alternative routes of insulin administration has always been a major focus of diabetes research. This review aims to provide an update on the insulin formulations and delivery routes as well as strategies used to improve its stability and bioavailability for the treatment of diabetes.

Recent advances in bioactive peptides from cereal-derived Foodstuffs

Article

Jul 2022

Cereal-derived proteins account for a major part of human dietary protein consumption. Natural bioactive peptides (NBPs) from these proteins involve a variety of physiological activities and play an important role in the promotion of human health. This review focuses on the characteristics of NBPs obtained from cereals, and the commonly used methods for preparation, separation, purification, and identification. We also discussed the biological functions of cereal-derived NBPs (CNBPs), including the activities of antioxidant, immunomodulatory, antimicrobial, and regulation of hyperglycaemia and hypertension. The paper summarised the latest progress in the research and application of CNBPs and analysed the prospects for the development and application of several protein by-products, providing an important way to improve the added value of protein by-products in cereal processing.

Characterization and Impact of Peptide Physicochemical Properties on Oral and Subcutaneous Delivery

Article

May 2022
ADV DRUG DELIVER REV

Peptides, an emerging modality within the biopharmaceutical industry, are often delivered subcutaneously with evolving prospects on oral delivery. Barrier biology within the subcutis or gastrointestinal tract is a significant challenge in limiting absorption or otherwise disrupting peptide disposition. Aspects of peptide pharmacokinetic performance and ADME can be mitigated with careful molecular design that tailors for properties such as effective size, hydrophobicity, net charge, proteolytic stability, and albumin binding. In this review, we endeavor to highlight effective techniques in qualifying physicochemical properties of peptides and discuss advancements of in vitro models of subcutaneous and oral delivery. Additionally, we will delineate empirical findings around the relationship of these physicochemical properties and in vivo (animal or human) impact. We conclude that robust peptide characterization methods and in vitro techniques with demonstrated correlations to in vivo data are key routines to incorporate in the drug discovery and development to improve the probability of technical and commercial success of peptide therapeutics.

Oral Delivery of Food-derived Bioactive Peptides: Challenges and Strategies

Article

Apr 2022

Food-derived bioactive peptides (FBPs) have received widespread attention due to their various physiological functions. However, the realization of the potential biological effects of FBPs depends heavily on their ability to remain intact until reaching the target cells. The physicochemical nature of FBPs and the gastrointestinal tract (GIT) barrier can pose challenges in their delivery after oral administration. Over the past decade, many attempts, such as enzyme inhibitors, permeation enhancers, mucoadhesive polymers, and nanocarriers, have been made to improve the oral bioavailability of FBPs. Despite numerous efforts in FBPs delivery, the development of techniques for efficient delivery of FBPs remains an issue in food field. In this review, we summarize and discuss the challenges for oral delivery of FBPs, the most recent and promising techniques involved in the improvement of FBPs bioavailability, and future directions in the field of FBPs delivery.

New Kid on the Block: Semaglutide

Article

Apr 2022

Sattik Siddhanta

Development of drug alone and carrier-based GLP-1 dry powder inhaler formulations

Article

Feb 2022

The study aimed to develop two types of dry powder inhaler (DPI) formulations containing glucagon-like peptide-1(7-36) amide (GLP-1): carrier-free (drug alone, no excipients) and carrier-based DPI formulations for pulmonary delivery of GLP-1. This is the first study focusing on the development of excipient free GLP-1 DPI formulations for inhaled therapy in Type 2 diabetes. The aerosolisation performance of both DPI formulations was studied using a next generation impactor and a DPI device (Handihaler®) at flow rate of 30 L min-1. Carriers employed were either a 10% w/w glycine-mannitol prepared by spray freeze drying or commercial mannitol. Spray freeze dried (SFD) carrier was spherical and porous whereas commercial mannitol carrier exhibited elongated particles (non-porous). GLP-1 powder without excipients for inhalation was prepared using spray drying and characterised for morphology including size, thermal behaviour, and moisture content. Spray dried (SD) GLP-1 powders showed indented/dimpled particles in the particle size range of 1 to 5 µm (also mass median aerodynamic diameter, MMAD: <5 µm) suitable for pulmonary delivery. Across formulations investigated, carrier-free DPI formulation showed the highest fine particle fraction (FPF: 90.73% ± 1.76%, mean ± standard deviation) and the smallest MMAD (1.96 µm ± 0.07 µm), however, low GLP-1 delivered dose (32.88% ± 7.00%, total GLP-1 deposition on throat and all impactor stages). GLP-1 delivered dose was improved by the addition of SFD 10% glycine-mannitol carrier to the DPI formulation (32.88% ± 7.00% -> 45.92% ± 5.84%). The results suggest that engineered carrier-based DPI formulations could be a feasible approach to enhance the delivery efficiency of GLP-1. The feasibility of systemic pulmonary delivery of SD GLP-1 for Type 2 diabetes therapy can be further investigated in animal models.

B12-functionalized PEGylated liposomes for the oral delivery of insulin: In vitro and in vivo studies

Article

Jan 2022
J DRUG DELIV SCI TEC

Orally administered Insulin have to survive the harsh gastrointestinal tract condition, penetrate the enteric epithelia barrier and bypass first pass effect before reaching the bloodstream. To address this problem, PEGylated liposomal insulin was prepared and modified with B12 to improve stability and absorption of insulin in gastro intestinal environment. Liposomes were prepared by film method plus extrusion, linked to B12 and characterized for their particle size, zeta potential, encapsulation efficiency (EE%). The release profile in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was evaluated. The results indicated that B12 targeted PEGylated liposomes were more stable than non-functionalized-Lip-PEG in SGF and SIF. In vitro results showed significantly enhanced cellular uptake of B12 targeted PEGylated liposomes in Caco-2 cells compared to non-targeted liposomes. In the meantime, they had no toxicity on Caco-2 cells. In BALB/c mice, B12 targeted PEGylated liposomes showed higher insulin accumulation in intestine and liver. In diabetic rats B12 targeted PEGylated liposomes provided higher insulin bioavailability compared with other formulations. These findings suggest that B12-targeted liposomes could be an effective formulation for oral delivery of insulin and merits further investigations.

Nanopeptide CMCS-20H loaded by carboxymethyl chitosan remarkably enhances protective efficacy against bacterial infection in fish

Article

Jan 2022
INT J BIOL MACROMOL

Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease

Article

Full-text available

Nov 2021

Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.

Strategies for the delivery of antidiabetic drugs via intranasal route

Article

Sep 2021
INT J PHARMACEUT

Diabetes is a metabolic disorder defined by higher blood glucose levels in the body generally controlled by antidiabetic agents (oral) and insulin (subcutaneous). To avoid the limitations of the conventional routes such as lower bioavailability and pain at the site of injection in case of parenteral route modified delivery systems are proposed like transdermal, pulmonary and inhalation delivery and among the other delivery systems nasal drug delivery system that shows the advantages such as reduced frequency of dose, higher patient compliance, safety, ease of administration, prolonged residence time, improved absorption of drug in the body, higher bioavailability and stability. This review article discusses the strategies adopted for the delivery of antidiabetic drugs by the intranasal delivery system. The insulin and glucagon-like peptides on experimentation show results of improved therapeutic levels and patient compliance. The drugs are transported by the paracellular route and absorbed through the epithelial tight junctions successfully by utilising different strategies. The limitations of the nasal delivery such as irritation or burning on administration, degradation by the enzymes, mucociliary clearance, lesser volume of the nasal cavity and permeation through the nasal mucosa. To overcome the challenges different strategies for the nasal administration are studied such as polymers, particulate delivery systems, complexation with peptides and smart delivery using glucose-responsive systems. A vast scope of intranasal preparations exists for antidiabetic drugs in the future for the management of diabetes and more clinical studies are the requirement for the societal impact to battle against diabetes.

Preparation and characteristics of W/O microemulsion stabilized with polyglycerylpolyricinoleate as a potential system for oral insulin delivery

Article

Sep 2020

Aim. The aim of the present work was to develop the composition and study the characteristics of water-in-oil microemulsion stabilized with polyglycerylpolyricinoleate — Tween 80 — ethanol mixture as a potential system for oral insulin delivery. Materials and methods. To determine the boundaries of the regions of existence of water-in-oil microemulsion in the pseudo-three component systems water — polyglycerylpolyricinoleate (PG-3-PR, Gobiotics BV, Netherlands)/ Tween 80/ethanol — paraffin oil, mixtures of paraffin oil and surfactants with oil — surfactant ratios from 9.5:0.5 to 0.5: 9.5 (wt.) were thoroughly mixed and titrated with an aqueous phase (distilled water).Compositions with the value of hydrophilic-lipophilic balance of the PG-3-PR — Tween 80 mixture equal to 6.15 were studied. Among several types of formed systems, a single-phase region corresponding to a homogeneous, optically transparent, liquid water-in-oil microemulsion was determined. The kinetic and thermodynamic stability of a number of compositions, including those containing insulin (Actrapid HM, Novo Nordisk А/С, Denmark), was studied. The values of the effective viscosity of microemulsions at different ratios of surfactant — oil and surfactant — co-surfactant were determined using a vibration viscometer. Based on the results obtained, a composition was selected to study the kinetics of insulin release into a model environment that simulated the environment of the small intestine. Insulin solution (the control sample) and the insulin-containing microemulsion were placed in the dialysis bags and immersed in 50 mL of PBS (pH 7.4) in a shaking incubator at 180 rpm and 37 ° С. At predetermined intervals, the aliquots of dissolution media were withdrawn, and the concentration of the released peptide was determined by the Bradford assay using a UV spectrophotometer at 595 nm. Results. The composition with 9:1 surfactant — co-surfactant ratio, containing 10 % of the aqueous phase (an insulin solution with a concentration of 100 IU / ml), which remained stable both during three cycles of freezing/thawing and heating/cooling, and after long-term storage at room temperature, was selected to study the kinetics of in vitro release of the peptide into the model medium. The effective viscosity of the sample was 2.4±0.04 Pa.s. The microemulsion sample demonstrated a prolonged release of insulin within 48 hours of the experiment (43 %). Conclusions. As a result, the boundaries of the existence of microemulsion regions in pseudo-three — component systems water — polyglycerylpolyricinoleate / Tween 80 / ethanol — paraffin oil were established, as well as the values of the effective viscosity of a number of compositions were determined. The study of the kinetic and thermodynamic stability of the obtained systems, including those containing insulin, as well as the study of the kinetics of the release of biologically active substance from the microemulsion into the model medium, allowed us to determine the optimal composition for further development of nanoscale dosage forms intended for prolonged delivery of insulin to the gastrointestinal tract.

Assessment of Exenatide loaded Biotinylated Trimethylated Chitosan/HP-55 Nanoparticles

Article

Jun 2021
Curr Drug Deliv

Background Exenatide (EXE) is an anti-hyperglycemic agent approved for treating type 2 diabetes by the Food and Drug Administration (FDA). However, twice-daily injection of exenatide inconveniences most patients. Objective In this study, biotinylated trimethylated chitosan (Bio-TMC) based nanoparticles were proposed to promote oral absorption of exenatide. Realizing the oral administration of exenatide is very important to alleviate patient suffering and improve patient compliance. Methods Bio-TMC was synthesized, and the chemical structure was characterized by Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy. Nanoparticles were prepared through polyelectrolyte interaction in the presence of sodium tripolyphosphate (TPP) and Hydroxypropyl methylcellulose phthalate (HP-55). The formulations were physically and chemically characterized. In vitro release was investigated in different pH media. In vivo antidiabetic activities of biotin modified and non-biotin modified chitosan were evaluated in db/db mice. Results EXE-loaded Bio-TMC/HP-55 nanoparticles were spherical in shape with a mean diameter of 156.2 nm and zeta potential of +11.3 mV. The drug loading efficiency and loading contents were 52.38% and 2.08%, respectively. In vitro release revealed that EXE-loaded Bio-TMC/HP-55 nanoparticles were released faster in pH 1.2 than pH 6.8 (63.71% vs. 50.12%), indicating that nanoparticles had enteric characteristics. Antidiabetic activity study revealed that after oral administration to diabetic mice, the relative pharmacological bioavailability (FPharm%) of the biotin modified nanoparticles was found to be 1.27-fold higher compared with the unmodified ones and the hypoglycemic effect was also better. Conclusion Bio-TMC/HP-55 nanoparticles are feasible as oral drug carriers of exenatide and have the potential to be extended to other drugs that are not readily oral, such as monoclonal antibodies, vaccines, genes, etc., thus, this would be beneficial for pharmaceutical industries. Further research will focus on the biodistribution of Bio-TMC/HP-55 nanoparticles after oral administration.

Imaging therapeutic peptide transport across intestinal barriers

Article

Full-text available

Jun 2021

Oral delivery is a highly preferred method for drug administration due to high patient compliance. However, oral administration is intrinsically challenging for pharmacologically interesting drug classes, in particular pharmaceutical peptides, due to the biological barriers associated with the gastrointestinal tract. In this review, we start by summarizing the pharmacological performance of several clinically relevant orally administrated therapeutic peptides, highlighting their low bioavailabilities. Thus, there is a strong need to increase the transport of peptide drugs across the intestinal barrier to realize future treatment needs and further development in the field. Currently, progress is hampered by a lack of understanding of transport mechanisms that govern intestinal absorption and transport of peptide drugs, including the effects of the permeability enhancers commonly used to mediate uptake. We describe how, for the past decades, mechanistic insights have predominantly been gained using functional assays with end-point read-out capabilities, which only allow indirect study of peptide transport mechanisms. We then focus on fluorescence imaging that, on the other hand, provides opportunities to directly visualize and thus follow peptide transport at high spatiotemporal resolution. Consequently, it may provide new and detailed mechanistic understanding of the interplay between the physicochemical properties of peptides and cellular processes; an interplay that determines the efficiency of transport. We review current methodology and state of the art in the field of fluorescence imaging to study intestinal barrier transport of peptides, and provide a comprehensive overview of the imaging-compatible in vitro, ex vivo, and in vivo platforms that currently are being developed to accelerate this emerging field of research.

Development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride applying the quality by design approach

Article

Full-text available

Oct 2016

Pulmonary drug delivery of ciprofloxacin hydrochloride offers effective local antibacterial activity and convenience of easy application. Spray drying is a trustworthy technique for the production of ciprofloxacin hydrochloride microparticles. Quality by design (QbD), an up-to-date regulatory-based quality management method, was used to predict the final quality of the product. According to the QbD-based theoretical preliminary parameter ranking and priority classification, dry powder inhalation formulation tests were successfully performed in practice. When focusing on the critical parameters, the practical development was more effective and was in correlation with our previous findings. Spray drying produced spherical microparticles. The dry powder formulations prepared were examined by particle size analysis, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro drug release and aerodynamic particle size analyses were also performed. These formulations showed an appropriate particle size ranging between 2 and 4 μm and displayed an enhanced aerosol performance with fine particle fraction up to 80%.

Intestinal Permeation Enhancers for Oral Peptide Delivery

Article

Full-text available

Jun 2016

Intestinal permeation enhancers (PEs) are one of the most widely tested strategies to improve oral delivery of therapeutic peptides. This article assesses the intestinal permeation enhancement action of over 250 PEs that have been tested in intestinal delivery models. In depth analysis of pre-clinical data is presented for PEs as components of proprietary delivery systems that have progressed to clinical trials. Given the importance of co-presentation of sufficiently high concentrations of PE and peptide at the small intestinal epithelium, there is an emphasis on studies where PEs have been formulated with poorly permeable molecules in solid dosage forms and lipoidal dispersions.

Polymeric Nanoparticle Drug Delivery Technologies for Oral Delivery Applications

Article

Full-text available

Feb 2015

In vivo dual-delivery of glucagon like peptide -1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

Article

Full-text available

Apr 2016

Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding the nanosystems for oral protein delivery concerns in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems have been studied before, but the simulataneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the GLP-1 therapeutic efficacy. Four hours after oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4h, presenting half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6h after oral administration of the dual-drug composite system and, despite no statistic significant differences exists the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems

Article

Full-text available

Mar 2016

Unique characteristics, such as nontoxicity and rapid cellular internalization, allow the cell-penetrating peptides (CPPs) to transport hydrophilic macromolecules into cells, thus, enabling them to execute biological functions. However, some CPPs have limitations due to nonspecificity and easy proteolysis. To overcome such defects, the CPP amino acid sequence can be modified, replaced, and reconstructed for optimization. CPPs can also be used in combination with other drug vectors, fused with their preponderances to create novel multifunctional drug-delivery systems that increase the stability during blood circulation, and also develop novel preparations capable of targeted delivery, along with sustainable and controllable release. Further improvements in CPP structure can facilitate the penetration of macromolecules into diverse biomembrane structures, such as the blood brain barrier, gastroenteric mucosa, and skin dermis. The ability of CPP to act as transmembrane vectors improves the clinical application of some biomolecules to treat central nervous system diseases, increase oral bioavailability, and develop percutaneous-delivery dosage form.

Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease

Article

Full-text available

Feb 2016
INT J MOL SCI

Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects.

Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: Systematic review and meta-analysis of randomized trials

Article

Full-text available

Feb 2016
Br Med J

Objective To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes. Design Meta-analysis. Data sources and study selection PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease. Results The search yielded 19 randomized controlled trials that enrolled 25 414 participants with diabetes for a total of 95 910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease). Conclusions In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and β blockers at reducing the risk of hard cardiovascular and renal endpoints. These findings support the recommendations of the guidelines of the European Society of Cardiology/European Society of Hypertension and eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure to also use other antihypertensive agents in people with diabetes but without kidney disease.

Applications and Challenges for Use of Cell-Penetrating Peptides as Delivery Vectors for Peptide and Protein Cargos

Article

Full-text available

Jan 2016
INT J MOL SCI

The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs) constitute a promising tool and have shown applications for peptide and protein delivery into cells as well as across various epithelia and the blood-brain barrier (BBB). CPP-mediated delivery of peptides and proteins may be pursued via covalent conjugation of the CPP to the cargo peptide or protein or via physical complexation obtained by simple bulk-mixing of the CPP with its cargo. Both approaches have their pros and cons, and which is the better choice likely relates to the physicochemical properties of the CPP and its cargo as well as the route of administration, the specific barrier and the target cell. Besides the physical barrier, a metabolic barrier must be taken into consideration when applying peptide-based delivery vectors, such as the CPPs, and stability-enhancing strategies are commonly employed to prolong the CPP half-life. The mechanisms by which CPPs translocate cell membranes are believed to involve both endocytosis and direct translocation, but are still widely investigated and discussed. The fact that multiple factors influence the mechanisms responsible for cellular CPP internalization and the lack of sensitive methods for detection of the CPP, and in some cases the cargo, further complicates the design and conduction of conclusive mechanistic studies.

PLGA-based nanoparticles: A new paradigm in biomedical applications

Article

Full-text available

Dec 2015
TRAC-TREND ANAL CHEM

Polymers were first introduced three decades ago as bioresorbable surgical devices. Since then, polymer-based nanoparticles have been extensively studied in a variety of fields. Nanocarriers formulated with biocompatible and biodegradable polymers approved by the US FDA (Food and Drug Administration) and EMA (European Medicines Agency) are being studied for the controlled delivery of various therapeutic agents. Amidst the various polymers synthesized for formulating polymeric nanoparticles, poly(lactic-co-glycolic acid) (PLGA) is the most popular. PLGA has several interesting properties such as controlled and sustained release, low cytotoxicity, long-standing biomedical applications, biocompatibility with tissues and cells, prolonged residence time and targeted delivery. The main aim of this review was to comprehensively address the issues related to PLGA-based nanoparticles focusing on the methods of preparation, characterization techniques, surface modification, mechanism of drug release and the drawbacks. The review also critically addresses the developmental aspects of PLGA-based nanocarriers in terms of targeted drug delivery, as well as exploring their efficacy in vitro and in vivo.

Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides

Article

Full-text available

Dec 2015

The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.

A review of head-to-head comparisons of GLP-1 receptor agonists

Article

Full-text available

Oct 2015
DIABETES OBES METAB

Sten Madsbad

Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily (BID) and lixisenatide once daily (OD); and longer-acting liraglutide OD, exenatide once weekly (OW), albiglutide OW and dulaglutide OW. The phase 3 trial of a seventh GLP-1RA, taspoglutide OW, was stopped due to unacceptable adverse events (AEs). Nine phase 3 head-to-head trials and one large phase 2 study have compared the efficacy and safety of these seven GLP-1RAs. All trials were associated with notable reductions in HbA1c, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short-acting GLP-1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide BID but greater than those with exenatide OW, albiglutide and dulaglutide. The most frequently observed AEs with GLP-1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea; nausea, however, occurred less frequently with exenatide OW and albiglutide than exenatide BID and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than liraglutide and dulaglutide. GLP-1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP-1RAs and delivery methods may further expand future treatment options.

Cytotoxicity and Biological Efficacy of Exendin-4-Encapsulated Solid Lipid Nanoparticles in INS-1 Cells

Article

Full-text available

Sep 2015
J NANOMATER

Exendin-4 (Ex-4), a peptide of glucagon-like peptide-1 receptor agonist, is a potent insulinotropic agent and alternative drug delivery systems to increase therapeutic utility have been explored. We developed exendin-4-encapsulated solid lipid nanoparticles (Eudragit Ex-4 SLNs) and compared the effects of Eudragit Ex-4 SLNs with those of native Ex-4 on INS-1 cells. We observed no significant toxic effects of nanoparticles at concentrations from 1 nM to 100 nM. Similar to Ex-4, Eudragit Ex-4 SLNs stimulated the production of cyclic AMP at 10 nM. Moreover, unlike treatment with the vehicle, treatment with 10 nM Eudragit Ex-4 SLNs increased insulin mRNA levels and insulin secretion. These insulinotropic effects of Eudragit Ex-4 SLNs were comparable to those of Ex-4. Thus, our in vitro results suggest that the biological effects of Eudragit Ex-4 SLNs are similar to those of Ex-4, and further in vivo pharmacokinetic studies are required to propose an alternative sustained release drug system.

Mucoadhesive Drug Delivery System: A Review

Article

Jan 2011

Considerable attention has been focused in recent years on the delivery of drugs through the oral mucosa which have a high first pass metabolism or degrade in the gastrointestinal tract. Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, which presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption. Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. Buccal dosage forms can be of Matrix or Reservoir types. However, this route could become a significant means for the delivery of a range of active agents in the coming years, if the barriers to buccal drug delivery are overcome. © 2011 IGJPS. All rights reserved.

Development of nanostructured lipid carriers containing salicyclic acid for dermal use based on the Quality by Design method

Article

Dec 2016

The aim of our present work was to evaluate the applicability of the Quality by Design (QbD) methodology in the development and optimalization of nanostructured lipid carriers containing salicyclic acid (NLC SA). Within the Quality by Design methology, special emphasis is layed on the adaptation of the initial risk assessment step in order to properly identify the critical material attributes and critical process parameters in formulation development. NLC SA products were formulated by the ultrasonication method using Compritol 888 ATO as solid lipid, Miglyol 812 as liquid lipid and Cremophor RH 60® as surfactant. LeanQbD Software and StatSoft. Inc. Statistica for Windows 11 were employed to indentify the risks. Three highly critical quality attributes (CQAs) for NLC SA were identified, namely particle size, particle size distribution and aggregation. Five attributes of medium influence were identified, including dissolution rate, dissolution efficiency, pH, lipid solubility of the active pharmaceutical ingredient (API) and entrapment efficiency. Three critical material attributes (CMA) and critical process parameters (CPP) were identified: surfactant concentration, solid lipid/liquid lipid ratio and ultrasonication time. The CMAs and CPPs are considered as independent variables and the CQAs are defined as dependent variables. The 2(3) factorial design was used to evaluate the role of the independent and dependent variables. Based on our experiments, an optimal formulation can be obtained when the surfactant concentration is set to 5%, the solid lipid/liquid lipid ratio is 7:3 and ultrasonication time is 20min. The optimal NLC SA showed narrow size distribution (0.857±0.014) with a mean particle size of 114±2.64nm. The NLC SA product showed a significantly higher in vitro drug release compared to the micro-particle reference preparation containing salicylic acid (MP SA).

A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives

Article

Jan 2016

Peptides and proteins in pharmaceuticals

Article

Jan 2011

A REVIEW ON NOVEL APPROACHES FOR ORAL DELIVERY OF INSULIN

Article

Jul 2015

Objectives: A review article on novel approaches on oral insulin delivery. Data Sources: Review articles on oral insulin delivery, Books. Study selection: This review consist of importance as well as current approaches for oral insulin delivery like liposomes, nanospheres, nanocubeics, erythrocytes, thiolated chitosan tablets, chitosan microspheres etc. Summary of content article: Type 1 diabetes mellitus is a metabolic disorder which arouse as a major health problem worldwide. Clinical management of insulin is done by insulin replacement therapy and current route of its administration is through subcutaneous injection having many challenges. To overcome the problems associated with insulin injections novel approaches for insulin administration are being explored. If insulin is administered orally, in the stomach rapid enzymatic degradation of insulin occurs and in the intestine insulin is digested and hence inactivated by the action of proteolytic enzymes occurs. This review consist of importance as well as current approaches for oral insulin delivery like liposomes, nanospheres , nanocubeics, erythrocytes, thiolated chitosan tablets, chitosan microspheresetc. This review also gives the information about current market status of oral insulin⁵. Conclusion: The oral route is considered to be most acceptable and convenient route of administration for chronic therapy. Attempts have been made to achieve oral insulin delivery using various systems. Liposomes, microemulsions, nanocubicles, thiolated chitosan, chitosan microspheres and so forth have been prepared for the oral delivery of insulin. Keywords: oral insulin, approaches for oral insulin delivery , current market status.

Preparation of chitosan-based multifunctional nanocarriers overcoming multiple barriers for oral delivery of insulin

Article

Jan 2017
MAT SCI ENG C-BIO S

The application of P-gp inhibiting phospholipids as novel oral bioavailability enhancers — An in vitro and in vivo comparison

Article

Aug 2016

The efflux transporter P-glycoprotein (P-gp) significantly modulates drug transport across the intestinal mucosa, strongly reducing the systemic absorption of various active pharmaceutical ingredients. P-gp inhibitors could serve as helpful tools to enhance the oral bioavailability of those substances. As a membrane-associated protein P-gp is surrounded and influenced by phospholipids. Some synthetic phospholipids have been found to strongly reduce P-gp´s activity. In this study two representative phospholipids, 1,2-dioctanoyl-sn-glycero-3-phosphocholine (8:0 PC) and 1,2-didecanoyl-sn-glycero-3-phosphocholine (10:0 PC), were compared with Tween® 80 and Cremophor® EL, both commonly used surfactants with P-gp inhibitory properties. Their influence on the cellular transport of the P-gp substrate rhodamine 123 (RH123) was examined using Caco-2 cell layers. In addition, fluorescence anisotropy measurements were performed in order to investigate their effect on membrane fluidity. Finally, we compared the phospholipids with Tween® 80 and the competitive P-gp inhibitor verapamil in an in vivo study, testing their effects on the oral bioavailability of the P-gp substrate drug ritonavir. Both phospholipids not only led to the strongest absorption of RH123, but a permeability enhancing effect was detected in addition to the P-gp inhibition. Their effects on membrane fluidity were not consistent with their P-gp inhibiting effects, and therefore suggested a more complex mode of action. Both phospholipids significantly increased the area under the ritonavir plasma level curve (AUC) within 150 min by more than tenfold, but were inferior to Tween® 80, which showed superior solubilizing effects. Finally, these phospholipids represent a novel substance class showing a high permeabilization potential for P-gp substrates. Because of their physiological structure and intestinal degradability, good tolerability without systemic absorption is expected. Formulating P-gp substrates with an originally low oral bioavailability is a difficult task, requiring concerted interplay of all excipients. P-gp inhibiting phospholipids offer a new tool to help cope with these challenges.

Development and evaluation of viscosity-enhanced nanocarrier (VEN) for oral insulin delivery

Article

Jul 2016

Solid lipid nanoparticles (SLN) have demonstrated good potential for oral peptide delivery. However, their hydrophobic nature generally accounts for low peptide entrapment efficiency (EE%). In this study, a new strategy was adopted to improve peptide EE% by incorporating a hydrophilic viscosity-enhancing agent (VA) within SLN cores to develop viscosity enhanced nanocarriers (VEN). Three agents namely, propylene glycol (PG), polyethylene glycol (PEG) 400 and PEG 600, were tested with human insulin serving as a model peptide drug. The effects of VA were both concentration- and type-dependent. 70% w/w PG had achieved the highest EE% (54.5%), versus the two PEGs, compared to only 20.4% in unmodified SLN. PG based VEN had demonstrated good dispersion stability at gastrointestinal (GI) pHs and preferential uptake by intestinal Caco2 cells while showing low cytotoxicity. Additionally, they preserved the integrity of insulin and significantly protected it against GI enzymatic degradation. Freeze dried VEN had shown good stability upon storage at -20°C. Orally administered insulin-VEN had achieved good hypoglycemic effect in fasted rats with relative bioavailability of 5.1%. To conclude, an easily implementable technique to improve peptide entrapment within SLN has been validated, and the resulting VEN had proved promising efficacy for oral peptide delivery.

Development of amphoteric alginate/aminated chitosan coated microbeads for oral protein delivery

Article

Jul 2016
INT J BIOL MACROMOL

Abstract A new amphoteric biopolymer carrier based on alginate and aminated chitosan coated microbeads (Alg/AmCS) was developed and characterized for bovine serum albumin (BSA) protein delivery. The amphoteric character was investigated through studying the swelling and in vitro BSA release behaviors of the developed microbeads in simulated gastric (SGF; pH1.2), intestinal (SIF; pH6.8), and colonic (SCF; pH7.4) fluids. The pH sensitivity was found to depend on the amount of AmCS in the coating medium. The results were interpreted from the view of the individual pH sensitivity of alginate and aminated chitosan in addition to the ionic interaction between them under the studied pHs. Besides; it was found that the BSA loading efficiency (LE) exceeded 82% regardless of the initial concentration of BSA. The released amount of BSA reached approximately 63% and 86% in SIF and SCF, respectively, using 0.25% AmCS. The stability of alginate microbeads in SCF was improved with increasing AmCS concentration in the coating medium up to 2%. Furthermore, the developed microbeads demonstrated their ability for biodegradation in addition to their antibacterial activities against selected bacterial strains. The results clearly suggested that Alg/AmCS coated microbeads could be suitable carriers for site-specific protein delivery in the intestinal and colon tracts.

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

Article

Jul 2016

The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent. The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper. Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Freeze-dried eudragit-hyaluronan multicompartment liposomes to improve the intestinal bioavailability of curcumin

Article

Jun 2016

This work was aimed at finding an innovative vesicle-type formulation able to improve the bioavailability of curcumin upon oral administration. To this purpose, phospholipid, Eudragit® S100 and hyaluronan sodium salt were combined to obtain eudragit-hyaluronan immobilized vesicles using an easy and environmentally-friendly method. For the first time, the two polymers were combined in a system intended for oral delivery, to enhance curcumin stability when facing the harsh environment of the gastrointestinal tract. Four different formulations were prepared, keeping constant the amount of the phospholipid and varying the eudragit-hyaluronan ratio. The freeze-drying of the samples, performed to increase their stability, led to a reduction of vesicle size and a good homogeneity of the systems, after simple rehydration with water. X-ray diffraction study demonstrated that after the freeze-drying process, curcumin remained successfully incorporated within the vesicles. All the vesicles displayed similar features: size ranging from 220 to 287 nm, spherical or oval shape, multilamellar or large unilamellar morphology with a peculiar multicompartment organization involving 1 to 4 smaller vesicles inside. In vitro studies demonstrated the ability of the combined polymers to protect the vesicles from the harsh conditions of the gastro-intestinal tract (i.e., ionic strength and pH variation), which was confirmed in vivo by the greater deposition of curcumin in the intestinal region, as compared to the free drug in dispersion. This enhanced accumulation of curcumin provided by the eudragit-hyaluronan immobilized vesicles, together with an increase in Caco-2 cell viability exposed to hydrogen peroxide, indicated that vesicles can ensure a local protection against oxidative stress and an increase in its intestinal absorption.

A composite hydrogel system containing glucose-responsive nanocarriers for oral delivery of insulin

Article

Jun 2016
MAT SCI ENG C-BIO S

Development of an oral delivery strategy for insulin therapeutics has drawn much attention in recent years. In this study, a glucose-responsive nanocarriers for loading of insulin has been prepared firstly. The resultant nanocarriers exhibited relative low cytotoxicity against Caco-2 cells and excellent stability against protein solution. The insulin release behaviors were evaluated triggered by pH and glucose in vitro. In order to enhance the oral bioavailability of insulin, the insulin-loaded glucose-responsive nanocarriers were further encapsulated into a three-dimensional (3D) hyaluronic acid (HA) hydrogel environment for overcoming multiple barriers and providing multi-protection for insulin during the transport process. The hypoglycemic effect for oral delivery of insulin was studied in vivo. After oral administration to the diabetic rats, the released insulin from hydrogel systems containing insulin-loaded glucose-responsive nanocarriers exhibited an effective hypoglycemic effect for longer time compared with insulin-loaded nanocarriers.

Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies

Article

May 2016
MAT SCI ENG C-BIO S

This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their preparation, surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatology, bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biological barriers, resistance to chemical degradation, possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems.

Oral Delivery of Insulin via Polyethylene Imine-based Nanoparticles for Colonic Release Allows Glycemic Control in Diabetic Rats

Article

May 2016
PHARMACOL RES

In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Only the nanoformulation loaded into the three-layer pellets was able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption.

Enhancing insulin oral absorption by using mucoadhesive nanoparticles loaded with LMWP-linked insulin conjugates

Article

May 2016

Although significant progress has been made, effective oral delivery of protein drugs such as insulin by nanoparticle-based carrier systems still faces certain formidable challenges. Considerable amount of protein drug is released from the nanoparticles (NPs) in the gastrointestinal (GI) tract. Because of their low permeability through the intestinal mucosa, the released protein would be soon degraded by the large amount of proteases in the GI tract. Herein, we report an oral insulin delivery system that can overcome the above-mentioned problems by mucoadhesive NPs (MNPs) loaded with cell penetrating peptide-linked insulin conjugates. On one hand, after conjugation with low molecular weight protamine (LMWP), a cell penetrating peptide (CPP), insulin showed greatly improved permeability through intestinal mucus layer and epithelia. On the other hand, the mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles (MNPs) that were loaded with conjugates enhanced the retention in the intestinal mucus layer. By adopting this delivery strategy, the LMWP-insulin conjugates released from NPs could be deprived from enzymatic degradation, due to the short distance in reaching the epithelia and the high permeation of the conjugates through epithelia. The oral delivery system of insulin designed by us showed a long-lasting hypoglycemia effect with a faster onset in diabetic rats, with an oral insulin pharmacological availability being 17.98 ± 5.61% relative to subcutaneously injected insulin solution, as well as a 2-fold higher improvement over that by MNPs loaded with native insulin. Our results suggested that conjugation with CPP followed by encapsulation in MNPs provides an effective strategy for oral delivery of macromolecular therapeutics.

Novel Approaches for Oral Delivery of Insulin and Current Status of Oral Insulin Products

Article

Nov 2010

Diabetes mellitus is a serious pathologic condition that is responsible for major healthcare problems worldwide and costing billions of dollars annually. Insulin replacement therapy has been used in the clinical management of diabetes mellitus for more than 84 years. The present mode of insulin administration is by the subcutaneous route through which insulin is presented to the body in a non-physiological manner having many challenges. Hence novel approaches for insulin delivery are being explored. Challenges to oral route of insulin administration are: rapid enzymatic degradation in the stomach, inactivation and digestion by proteolytic enzymes in the intestinal lumen and poor permeability across intestinal epithelium because of its high molecular weight and lack of lipophilicity. Liposomes, microemulsions, nanocubicles, and so forth have been prepared for the oral delivery of insulin. Chitosan-coated microparticles protected insulin from the gastric environment of the body and released intestinal pH. Limitations to the delivery of insulin have not resulted in fruitful results to date and there is still a need to prepare newer delivery systems, which can produce dose-dependent and reproducible effects, in addition to increased bioavailability.

Cell penetrating peptides as an innovative approach for drug delivery; then, present and the future

Article

May 2016

With the rapid development of biotechnology, various macromolecules as therapeutic agents have made drug delivery an important field of research. However, these are being commercialized as injection form. Due to low patient compliance, various non-invasive routes emerge as a promising strategy. Cell penetrating peptides (CPPs) have shown to assist in efficient and non-toxic manner. They provide ample evidence to deliver of many cargoes ranging from small molecules to proteins and even nanocarriers for various applications. This review briefly discusses about introduction of CPPs, history, cellular uptake mechanisms and various possible alternative routes for CPP-conjugated drug delivery system. It also aims to give a perspective on present status of CPP-mediated research, clinical development, possible obstacles as well as future opportunities. Thus, development of novel CPPs that are safe, tissue-specific and highly efficient will be exemplified and become ideal vehicles for therapeutic delivery in near future.

Needle free drug delivery systems: A review

Article

Jan 2016

Oral hypoglycaemic effect of GLP-1 and DPP4 inhibitor based nanocomposites in a diabetic animal model

Article

Jun 2016
J CONTROL RELEASE

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is used for type 2 diabetes mellitus (T2DM) treatment because of its ability to stimulate insulin secretion and release in a glucose-dependent manner. Despite of its potent insulinotropic effect, oral GLP-1 delivery is greatly limited by its instability in the gastrointestinal tract, poor absorption efficiency and rapid degradation by dipeptidylpeptidase-4 (DPP4) enzyme leading to a short half-life (~2min). Thus, a multistage dual-drug delivery nanosystem was developed here to deliver GLP-1 and DPP4 inhibitor simultaneously. The system comprised of chitosan-modified porous silicon (CSUn) nanoparticles, which were coated by an enteric polymer, hydroxypropylmethylcellulose acetate succinate MF, using aerosol flow reactor. A non-obese T2DM rat model induced by co-administration of streptozotocin and nicotinamide was used to evaluate the in vivo efficacy of the nanosystem. The oral administration of H-CSUn nanoparticles resulted in 32% reduction in blood glucose levels and ~6.0-fold enhancement in pancreatic insulin content, as compared to the GLP-1+DPP4 inhibitor solution. Overall, these results present a promising system for oral co-delivery of GLP-1 and DPP4 inhibitor that could be further evaluated in a chronic diabetic study.

Dual Chitosan/Albumin-Coated Alginate/Dextran Sulfate Nanoparticles for Enhanced Oral Delivery of Insulin

Article

Jun 2016
J CONTROL RELEASE

The potential of nanoparticles (NPs) to overcome the barriers for oral delivery of protein drugs have led to the development of platforms capable of improving their bioavailability. However, despite the progresses in drug delivery technologies, the success of oral delivery of insulin remains elusive and the disclosure of insulin mechanisms of absorption remains to be clarified. To overcome multiple barriers faced by oral insulin and to enhance the insulin permeability across the intestinal epithelium, here insulin-loaded alginate/dextran sulfate (ADS)-NPs were formulated and dual-coated with chitosan (CS) and albumin (ALB). The nanosystem was characterized by its pH-sensitivity and mucoadhesivity, which enabled to prevent 70% of in vitro insulin release in simulated gastric conditions and allowed a sustained insulin release following the passage to simulated intestinal conditions. The pH and time-dependent morphology of the NPs was correlated to the release and permeation profile of insulin. Dual CS/ALB coating of the ADS-NPs demonstrated augmented intestinal interactions with the intestinal cells in comparison to the uncoated-NPs, resulting in a higher permeability of insulin across Caco-2/HT29-MTX/Raji B cell monolayers. The permeability of the insulin-loaded ALB-NPs was reduced after the temperature was decreased and after co-incubation with chlorpromazine, suggesting an active insulin transport by clathrin-mediated endocytosis. Moreover, the permeability inhibition with the pre-treatment with sodium chlorate suggested that the interaction between glycocalix and the NPs was critical for insulin permeation. Overall, the developed nanosystem has clinical potential for the oral delivery of insulin and prevention or therapy of type 1 diabetes mellitus.

Methocel-Lipid Hybrid Nanocarrier for Efficient Oral Insulin Delivery

Article

Mar 2016
J PHARM SCI-US

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40 %) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Chemically Modified Peptides and Proteins - Critical Considerations for Oral Delivery

Article

Mar 2016

Numerous approaches have been explored to date in the pursuit of delivering peptides or proteins via the oral route. One such example is chemical modification, whereby the native structure of a peptide or protein is tailored to provide a more efficient uptake across the epithelial barrier of the gastrointestinal tract via incorporation of a chemical motif or moiety. In this regard, a diverse array of concepts have been reported, ranging from the exploitation of endogenous transport mechanisms to incorporation of physicochemical modifications in the molecule, which promote more favourable interactions with the absorptive membrane at the cell surface. This review provides an overview of the modification technologies described in the literature and offers insights into some pragmatic considerations pertaining to their translation into clinically viable concepts.

Dextran-b-poly (Lactide-co-Glycolide) polymersome for oral delivery of insulin: In vitro and in vivo evaluation

Article

Feb 2016
J CONTROL RELEASE

Novel strategies in the oral delivery of antidiabetic peptide drugs – Insulin, GLP 1 and its analogs

Abstract and Figures

No full-text available