Development and optimization of vildagliptin solid lipid nanoparticles loaded ocuserts for controlled ocular delivery: A promising approach towards treating diabetic retinopathy.

Diabetes mellitus (DM) is the most prevalent cause of diabetic retinopathy (DRP). DRP has been recognized for a long time as a microvascular disease. Many drugs were used to treat DRP, including vildagliptin (VLD). In addition to its hypoglycemic effect, VLD minimizes ocular inflammation and improves retinal blood flow for individuals with type 2 diabetes mellitus. Nevertheless, VLD can cause upper respiratory tract infections, diarrhea, nausea, hypoglycemia, and poor tolerability when taken orally regularly due to its high water solubility and permeability. Effective ocular administration of VLD is achieved using solid lipid nanoparticles (SLNPs), which improve corneal absorption, prolonged retention, and extended drug release. Ocuserts (OCUs) are sterile, long-acting ocular dosage forms that diminish the need for frequent dosing while improving residence time and stability. Therefore, this study intends to develop VLD solid lipid nanoparticle OCUs (VLD-SLNPs-OCUs) to circumvent the issues commonly associated with VLD. SLNPs were prepared using the double-emulsion/melt dispersion technique. The optimal formula has been implemented in OCUs. Optimization and development of VLD-SLNPs-OCUs were performed using a Box-Behnken Design (BBD). VLD-SLNPs-OCUs loading efficiency was 95.28 ± 2.87%, and differential scanning calorimetry data (DSC) showed the full transformation of VLD to an amorphous state and the excellent distribution in the prepared OCUs matrices. The in vivo release of VLD from the optimized OCUs after 24 h was 35.12 ± 2.47%, consistent with in vitro drug release data of 36.89 ± 3.11. The optimized OCUs are safe to use in the eye, as shown by the ocular irritation test. VLD-SLNPs-OCUs provide extended VLD release, an advantageous alternative to conventional oral dose forms, resulting in fewer systemic adverse effects and less variation in plasma drug levels. VLD-SLNPs-OCUs might benefit retinal microvascular blood flow beyond blood glucose control and may be considered a promising approach to treating diabetic retinopathy.

From cell factories to patients: Stability challenges in biopharmaceuticals manufacturing and administration with mitigation strategies.

Active ingredients of biopharmaceuticals consist of a wide array of biomolecular structures, including those of enzymes, monoclonal antibodies, nucleic acids, and recombinant proteins. Recently, these molecules have dominated the pharmaceutical industry owing to their safety and efficacy. However, their manufacturing is hindered by high cost, inadequate batch-to-batch equivalence, inherent instability, and other quality issues. This article is an up-to-date review of the challenges encountered during different stages of biopharmaceutical production and mitigation of problems arising during their development, formulation, manufacturing, and administration. It is a broad overview discussion of stability issues encountered during product life cycle i.e., upstream processing (aggregation, solubility, host cell proteins, color change), downstream bioprocessing (aggregation, fragmentation), formulation, manufacturing, and delivery to patients.

Advances in buccal and oral delivery of insulin.

Diabetes mellitus is a metabolic endocrine disease characterized by chronic hyperglycemia with disturbances in metabolic processes, such as those related to carbohydrates, fat, and protein. There are two main types of this disease: type 1 diabetes (T1D) and type 2 diabetes (T2D). Insulin therapy is pivotal to the management of diabetes. Over the last two decades, many routes of administration, including nasal, pulmonary, rectal, transdermal, buccal, and ocular, have been investigated. Nevertheless, subcutaneous parenteral administration is still the most common route for insulin therapy. To overcome poor bioavailability and the barriers to oral insulin absorption, novel approaches in the field of oral drug delivery and administration have been brought about by the coalescence of different branches of nanoscience and nanotechnology, such as nanomedicine, nano-biochemistry, and nano-pharmacy. Novel drug delivery systems, including nanoparticles, nano-platforms, and nanocarriers, have been suggested. The objective of this review is to provide an update on the various promising approaches that have been explored and evaluated for the safe and efficient oral and buccal administration of insulin.

Stabilization of insulin using low molecular weight chitosan carbonate nanocarrier.

The current study aims to design a nanoparticulate system that could encapsulate insulin and improve its stability. Nanoparticles were formulated by ionic cross-linking of chitosan (CS) with carbonate divalent anions. The interaction between the two moieties was evidenced by AFM, FTIR and surface tension measurements. CS carbonate nanoparticles were prepared with different mole fractions. The mole fraction of carbonate that produced the smallest size nanoparticles and highest zeta potential (40 nm and +39 mV, respectively) was determined. Circular dichroism (CD) studies revealed that insulin conformation was not affected by CS at 20 °C. However, the studies at elevated temperatures demonstrated that CS had a role in insulin stabilization. Fluorescence spectroscopy indicated the interaction between insulin and CS carbonate. The findings from this investigation showed the potential use of CS carbonate as an insulin stabilizer and at the same time as an insulin nanocarrier system.

Low Molecular Weight Chitosan-Insulin Complexes Solubilized in a Mixture of Self-Assembled Labrosol and Plurol Oleaque and Their Glucose Reduction Activity in Rats.

Oral insulin delivery that better mimics physiological pathways is a necessity as it ensures patient comfort and compliance. A system which is based on a vehicle of nano order where positively charged chitosan interacts with negatively charged insulin and forms a polyelectrolyte complex (PEC) solubilizate, which is then solubilized into an oily phase of oleic acid, labrasol, and plurol oleaque-protects insulin against enzymatic gastrointestinal reduction. The use of an anionic fatty acid in the oily phase, such as oleic acid, is thought to allow an interaction with cationic chitosan, hence reducing particle size. Formulations were assessed based on their hypoglycaemic capacities in diabetic rats as compared to conventional subcutaneous dosage forms. 50 IU/kg oral insulin strength could only induce blood glucose reduction equivalent to that of 5 IU/kg (1 International unit = 0.0347 mg of human insulin). Parameters that influence the pharmacological availability were evaluated. A preliminary investigation of the mechanism of absorption suggests the involvement of the lymphatic route.

Chitosan/lecithin liposomal nanovesicles as an oral insulin delivery system.

In the present work, insulin-chitosan polyelectrolyte complexes associated to lecithin liposomes were investigated as a new carrier for oral delivery of insulin. The preparation was characterized in terms of particle size, zeta potential and encapsulation efficiency. Surface tension measurements revealed that insulin-chitosan polyelectrolyte complexes have some degree of hydrophobicity and should be added to lecithin liposomal dispersion and not the vice versa to prevent their adsorption on the surface. Stability of insulin was enhanced when it was associated to liposomes. Significant reduction of blood glucose levels was noticed after oral administration of liposomal preparation to streptozotocin diabetic rats compared to control. The hypoglycemic activity was more prolonged compared to subcutaneously administered insulin.

Development of insulin loaded mesoporous silica injectable particles layered by chitosan as a controlled release delivery system.

The present work investigated the possibility of using mesoporous silica nanoparticles coated with low molecular weight chitosan as an injectable controlled release carrier of insulin. Insulin was totally encapsulated in particles. Surface tension measurements indicated that insulin was absorbed into mesoporous silica pores and interacted with chitosan. The stability of the encapsulated insulin was confirmed by different analytical methods such as RP-HPLC, FTIR and CD. Furthermore, the thermal stability using DSC was in the favor of the encapsulated insulin compared to free insulin. In vivo results indicated that insulin release was prolonged after loading into mesoporous silica nanoparticles. Such particles could be a potential carrier to control the release of insulin.

Chitosan-sodium lauryl sulfate nanoparticles as a carrier system for the in vivo delivery of oral insulin.

The present work explores the possibility of formulating an oral insulin delivery system using nanoparticulate complexes made from the interaction between biodegradable, natural polymer called chitosan and anionic surfactant called sodium lauryl sulfate (SLS). The interaction between chitosan and SLS was confirmed by Fourier transform infrared spectroscopy. The nanoparticles were prepared by simple gelation method under aqueous-based conditions. The nanoparticles were stable in simulated gastric fluids and could protect the encapsulated insulin from the GIT enzymes. Additionally, the in vivo results clearly indicated that the insulin-loaded nanoparticles could effectively reduce the blood glucose level in a diabetic rat model. However, additional formulation modifications are required to improve insulin oral bioavailability.

Formulation and characterization of an oily-based system for oral delivery of insulin.

The present work explored the possibility of formulating an oral insulin delivery system by combining the advantages of nanoencapsulation and the use of oily vehicle. The parameters affecting formulation such as association efficiency were characterized. The preparation was evaluated for its chemical, physical and biological stability. The preparation has unimodal particle size distribution with a mean diameter of 108+/-9 nm. Insulin was protected from gastric enzymes by incorporation into lipid-based formulation. The results of RP HPLC and ELISA indicated that insulin was able to withstand the preparation procedure. Insulin in the preparations was stable for a period of one month at storage temperatures of 4 and 25 degrees C. It was also biologically active and stable as demonstrated by the remarkable reduction of blood glucose levels of the STZ-diabetic rats after oral administration of the preparation. Moreover, hypoglycemic effect of nanoparticles administered orally was sustained for a longer period of time compared to the subcutaneous injection. These results clearly evidenced the ability of the nanoparticles to enhance the pharmacological response of insulin when given orally and could be used to deliver other peptides.

Enhancement of oral bioavailability of insulin in humans.

OBJECTIVE: The purpose of this study is to investigate oral absorption of 1, 2 and 3 U/kg oral insulin five test products with different particle sizes in comparison with 0.1 U/kg subcutaneous reference formulation. METHODS: Twenty five healthy volunteers participated in five studies using a two-phase, two-sequence crossover design with washout period of one day. Mean disposition kinetics was determined by non-compartmental analysis using Kinetica program. Absorption kinetics of insulin products were then determined using SIMCYP simulator utilizing ADAM model. RESULTS & CONCLUSIONS: Dimensional analysis results showed the superiority of formula 4:2 U/kg oral dose with 57 nm particle size over other oral formulations when compared with subcutaneous route. Optimized intestinal permeability coefficients (x10(-4)) of insulin best test and reference formulations were 0.084 and 0.179 cm/sec respectively. Total fraction of insulin dose absorbed (Fa) for the test and reference products were 3.0% and 19% respectively. Subcutaneous product exhibited higher absorption rate and extent than oral insulin. Yet that was compensated by the increase in other factors such as Fa*, Peff* and oral dose, leading to similar insulin plasma levels and similar effect on glucose infusion rates. Oral insulin bioavailability was shown promising for the development of oral insulin product.