Pulmonary Delivery Of Insulin Research Articles

Polysaccharide-Based Carriers for Pulmonary Insulin Delivery: The Potential of Coffee as an Unconventional Source.

Non-invasive routes for insulin delivery are emerging as alternatives to currently painful subcutaneous injections. For pulmonary delivery, formulations may be in powdered particle form, using carriers such as polysaccharides to stabilise the active principle. Roasted coffee beans and spent coffee grounds (SCG) are rich in polysaccharides, namely galactomannans and arabinogalactans. In this work, the polysaccharides were obtained from roasted coffee and SCG for the preparation of insulin-loaded microparticles. The galactomannan and arabinogalactan-rich fractions of coffee beverages were purified by ultrafiltration and separated by graded ethanol precipitations at 50% and 75%, respectively. For SCG, galactomannan-rich and arabinogalactan-rich fractions were recovered by microwave-assisted extraction at 150 °C and at 180 °C, followed by ultrafiltration. Each extract was spray-dried with insulin 10% (w/w). All microparticles had a raisin-like morphology and average diameters of 1-5 µm, which are appropriate for pulmonary delivery. Galactomannan-based microparticles, independently of their source, released insulin in a gradual manner, while arabinogalactan-based ones presented a burst release. The microparticles were seen to be non-cytotoxic for cells representative of the lung, specifically lung epithelial cells (A549) and macrophages (Raw 264.7) up to 1 mg/mL. This work shows how coffee can be a sustainable source of polysaccharide carriers for insulin delivery via the pulmonary route.

Integrated Continuous Crystallization and Spray Drying of Insulin for Pulmonary Drug Delivery

Pulmonary delivery of insulin in the form of a dry powder is an attractive alternative in comparison to conventional subcutaneous delivery. Insulin crystals have potential advantages such as sustained release and higher stability in comparison to amorphous particles. However, the design of crystallization processes that can reliably produce insulin crystals in a suitable size range for pulmonary delivery is challenging. A continuous process involving the integration of a tubular crystallizer and a spray dryer is characterized for the production of inhalable insulin. Supersaturation is created via cooling and a pH shift at the inlet of the crystallizer, aiming at a high nucleation rate. The recovery of insulin in the crystallizer exceeds 90%, and the insulin particles appear crystalline under most of the tested conditions. Integration with a spray dryer produces a dry powder with favorable properties for pulmonary drug delivery. The emitted fraction of insulin from a capsule in a commercial inhaler is in the range of 84.3–93.1%, which shows good powder dispersibility. Furthermore, the fine particle fraction of the insulin crystals ranges from 22.0% to 36.4%, which indicates a good potential for pulmonary delivery.

Recent Advances in Inhaled Formulations and Pulmonary Insulin Delivery Systems.

Insulin (INS) therapy played a great role in patients with type 1 and type 2 diabetes to regulate blood glucose levels. Although hypodermic injection was commonly used for insulin delivery, it had some disadvantages such as pain, needle phobia and the risk of infection. Therefore, pulmonary insulin delivery had been developed as an alternative method to overcome the therapeutic challenges in recent years since pulmonary insulin administration showed great improvements in rapid action and circumvention of first-pass hepatic metabolism. This review described the most recent developments in pulmonary insulin administration. Firstly, the structure and physiology of the lung cavity were introduced. Next, the advantages and disadvantages of pulmonary administration were discussed. Then some new dosage forms for pulmonary insulin were investigated including carriers based on surfactants and carriers based on polymers. Finally, innovate insulin inhalers and formulations were also described.

Insulin Therapy for Diabetes Epidemic: A Patent Review.

Diabetes is a serious and chronic problem that can be attributed to the insufficient release of the insulin or when body does not respond to the insulin which is already present. This disease has been targeted for corrective action and implementation among four non-communicable diseases by world leaders according to WHO report. The prevalence of diabetes has been estimated to be double from 4.7% of adult population in 1980 to 8.5% in the present scenario. The estimated deaths due to this epidemic disease were 1.5 million in 2012 alone. Currently, approximately 400 million people are suffering from diabetes worldwide. Although the factors leading to Type I diabetes are unknown, there are many therapies available in market for Type II disease which bags more than 90% of the total diabetes cases. But, the current treatment for this disease seems to be lacking in terms of proper management of disease, while insulin still remains the ultimate therapy to achieve comparatively effective glycemic control. In this review, an attempt has been made to summarize the patent applications filed in the field of pulmonary delivery of insulin as dry powder through an inhaler in various formulations. This review will provide an insight to the development and advancement for various formulations of insulin and the design of inhaler to improve the bioavailability of powder formulation of insulin, which would provide an alternate treatment with better acceptability or tolerability among the patients as compared to the intravenous delivery to offer better management of epidemic diabetes.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin.

Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time-action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time-action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control.

Preparation and characterization of spray-dried powders intended for pulmonary delivery of Insulin with regard to the selection of excipients

The aim of this study was to produce microparticles with optimal aerodynamic diameter for deep lung delivery (i.e., 1-3μm) of a protein drug intended for systemic absorption, using a combination of generally regarded as safe (GRAS) excipients. Based on the preliminary experiments, mannitol, l-alanine, sodium alginate, chitosan and dipalmitoylphosphatidilcholine (DPPC) were chosen as excipients and human insulin as a model protein drug. Dry powders were prepared by spray-drying. Powders with varying yields (29-80%) and low tapped densities (0.22-0.38 g/cm(3)) were obtained. Scanning electron microscopy (SEM) revealed distinctive particle morphologies among formulations from isolated spherical to highly folded particles. Aerodynamic properties were assessed by next generation impactor (NGI). Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) ranged from 2.1 to 4.6 μm and 46 to 81%, respectively. A comparative study of protein release from microparticles was conducted in vitro using an open membrane system with more than 50% cumulative release in all formulations which followed different kinetic models. Insulin's integrity was investigated by spectrofluorimetry and electrophoresis, and no tangible changes were observed in the structure of insulin. Of the formulations studied, the third, containing mannitol/sodium alginate/insulin/sodium citrate showed promising characteristics, optimal for systemic delivery of proteins via deep lung deposition.

One‐Step Formulation of Protein Microparticles with Tailored Properties: Hard Templating at Soft Conditions

AbstractFormulation of therapeutic proteins into particulate forms is a main strategy for site‐specific and prolonged protein delivery as well as for protection against degradation. Precise control over protein particle size, dispersity, purity, as well as mild preparation conditions and minimal processing steps are highly desirable. It is, however, hard to fit all these criteria with conventional preparation techniques. Here a one‐step hard‐templating synthesis of microparticles composed of functional, non‐denatured protein is reported. The method is based on filling porous CaCO3 microtemplates with the protein near to its isoelectric point (pI) followed by pH‐ or EDTA‐mediated dissolution of the tempplates. In principle, a wide variety of proteins can be converted into microparticles using this approach. The main requirement is an overlap of the protein insolubility and a template solubility for a certain parameter (here pH or EDTA). Here the formulation of insulin particles is studied in detail and it is shown that particles consisting of high molecular weight protein (catalase) can also be prepared. In this context, the synthesis of CaCO3 templates with controlled size, the mechanism of the protein microparticle formation and mechanical properties of the microparticles are discussed. For the first time, the fabrication of mesoporous monodispersed CaCO3 microtemplates with identical porocity but tuned diameter from 3 to 20 μm is demonstrated. The protein particle diameter can be adjusted by choosing the appropriate template size that is critical for successful pulmonary delivery of insulin. As a first step towards insulin delivery, the in vitro release of insulin at physiological conditions is studied.

Effect of carrier morphology and surface characteristics on the development of respirable PLGA microcapsules for sustained-release pulmonary delivery of insulin

The effect of morphology and surface characteristics of carriers were investigated for development of dry powder inhaler (DPI) formulation of insulin-loaded poly (D,L-lactic-co-glycolic acid) microcapsules for sustained-release pulmonary delivery of insulin. Microcapsule/carrier powder mixtures were prepared consisting of insulin-loaded PLGA microcapsules and sorbitol or mannitol as the carriers with various particle surface morphologies prepared by spray-drying and freeze-drying techniques. Powders were assessed by particle size analyzer, scanning electron microscopy, surface area analyzer, atomic force microscopy, helium pycnometer, X-ray diffraction, differential scanning calorimetery, bulk and tapped densitometers. Aerosol dispersion of microcapsules was examined by a twin impinger using Spinhaler device. The flowability results showed that the lowest (27.51+/-2.24%) and the highest (48.53+/-3.36%) Carr's indices were obtained for the samples containing sieved mannitol and spray-dried mannitol, respectively. The in vitro inhalation properties of the powder mixture prepared using various carrier shape and surface morphology were different, suggesting that the separation of microcapsules from carrier was a determining step to improve inhalation properties of DPIs. The results showed that the highest fine particle fraction (18.3+/-1.65%) and fine particle dose (62.22+/-3.74 microg) were obtained for the microcapsules formulated with sieved mannitol and these values were the lowest when the sieved mannitol was replaced by sieved sorbitol (10.5+/-0.86% and 35.70+/-2.51 microg). It was concluded that optimization of surface roughness is a critical parameter in development of DPIs. It also suggested that the elongation of carrier particles may play an important role in determining the aerosolization properties of the microcapsules. It seems that decrease in crystalline content of carriers may contribute to a decreased in fine particle fraction delivered.

Inhaled insulin: overview of a novel route of insulin administration.

Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular disease, both of which are affected by optimal diabetes control. Many individuals with diabetes rely on subcutaneous insulin administration by injection or continuous infusion to control glucose levels. Novel routes of insulin administration are an area of interest in the diabetes field, given that insulin injection therapy is burdensome for many patients. This review will discuss pulmonary delivery of insulin via inhalation. The safety of inhaled insulin as well as the efficacy in comparison to subcutaneous insulin in the various populations with diabetes are covered. In addition, the experience and pitfalls that face the development and marketing of inhaled insulin are discussed.

Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary insulin delivery

The pulmonary insulin delivery characteristics of liposomes were examined. Aerosolized liposomes containing insulin were administered into rat lungs and the enhancing effect on insulin delivery was evaluated by changes of plasma glucose levels. Liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhanced pulmonary insulin delivery in rats, however, liposomes with dilauroyl, dimyristoyl, distearoyl or dioleoyl phosphatidylcholine did not. Liposomes with DPPC also enhanced the in vitro permeation of FITC dextran (Mw 4400, FD-4) through the calu-3 cell monolayer by reducing the transepithelial electrical resistance and did not harm lung tissues in rats. These findings suggest that liposomes with DPPC enhance pulmonary insulin delivery by opening the epithelial cell space in the pulmonary mucosa not mucosal cell damage. Liposomes with DPPC could be useful as a pulmonary delivery system for peptide and protein drugs.

Is Relief from Diabetes Just a Breath Away … ?

Pulmonary insulin delivery is steadily emerging as a promising solution for the treatment of diabetes mellitus. The large as well as thin absorptive area of the lungs has not been explored until now for the treatment of systemic disease like diabetes. With an understanding of the lung anatomy and physiology and the transport mechanism of insulin through lungs, diabetic treatment through the pulmonary route may well become the reality of the 21(st) century. Though the transport of insulin through the lungs itself appears quite encouraging, potential problems concerning the formulation of a peptide like insulin in the form of an aerosol seem to be the most challenging. Stability aspects, stringent control of Mass Median Aerodynamic Diameter, antigenicity, insulin losses due to the device and impaction, sedimentation and diffusion in the nonabsorptive areas of the airway system (especially in the oropharynx) emerge as major concerns. This is in addition to the problems of lack of reproducibility of dose delivery by an inhaler where individual variations due to inspiratory differences and method of use of device come into play. Lung diseases and smoking may alter lung mechanisms and dose alterations are to be studied in such cases. Though almost equally effective, if not more, than the subcutaneous insulin route, even with proved short-term efficacy, insulin delivery through lungs is a potential but not a wholly proven means for blood glucose control.

Solid Lipid Nanoparticles as Insulin Inhalation Carriers for Enhanced Pulmonary Delivery

Growing attentions have been paid to the pulmonary route for systemic delivery of peptide and protein drugs, such as insulin. Advantages of this non-injective route include rapid drug deposition in the target organ, fewer systemic side effects and avoiding first pass metabolism. However, sustained release formulations for pulmonary delivery have not been fully exploited till now. In our study, a novel dry powder inhalation (DPI) system of insulin loaded solid lipid nanoparticles (Ins-SLNs) was investigated for prolonged drug release, improved stability and effective inhalation. Firstly, the drug was incorporated into the lipid carriers for a maximum entrapment efficiency as high as 69.47 +/- 3.27% (n = 3). Secondly, DPI formulation was prepared by spray freeze drying of Ins-SLNs suspension, with optimized lyoprotectant and technique parameters in this procedure. The properties of DPI particles were characterized for their pulmonary delivery potency. Thirdly, the in vivo study of intratracheal instillation of Ins-SLNs to diabetic rats showed prolonged hypoglycemic effect and a relative pharmacological bioavailability of 44.40% could be achieved in the group of 8 IU/kg dosage. These results indicated that SLNs have shown increasing potential as an efficient and non-toxic lipophilic colloidal drug carrier for enhanced pulmonary delivery of insulin.

Influence of Stabilizers on the Physicochemical Characteristics of Inhaled Insulin Powders Produced by Supercritical Antisolvent Process

To examine the effect of stabilizers on aerosol physicochemical characteristics of inhaled insulin particles produced using a supercritical fluid technology. Insulin with stabilizers such as mannitol and trehalose was micronized by aerosol solvent extraction system (ASES). The supercritically-micronized insulin particles were characterized for size, shape, aerosol behavior, crystallinity and secondary structure. Experimental results indicated that when insulin was incorporated with the most commonly used stabilizer mannitol (insulin/mannitol: 15/85 wt.%, designated IM), the particles formed were irregular and needle-shaped and had a tendency to agglomerate. With the incorporation of a second stabilizer trehalose (insulin/mannitol/trehalose: 15/70/15 wt.%, designated IMT), the particles were relatively uniform, more spherical, less cohesive, and less agglomerated in an air flow, when compared to IM particles. The mass median aerodynamic diameter of the IMT particles was 2.32 mum which is suitable for use in inhalation therapy. In vitro deposition test using micro-orifice uniform deposit impactor showed 69 +/- 7 wt.% of the IMT particles was deposited in stage 3, 4, 5 and 6 while 41 +/- 15 wt.% of the IM particles was deposited in the same stages. In terms of insulin stability, secondary structures of insulin particles were not adversely affected by the ASES processing studied here. When properly formulated (as in IMT particles), ASES process can produce particles with appropriate size and size distribution suitable for pulmonary insulin delivery.

Efficacy of pulmonary insulin delivery in diabetic rats: Use of a model-based approach in the evaluation of insulin powder formulations

The potential of N-trimethyl chitosan (TMC) with two degrees of quaternization (DQ), TMC20 (DQ 20%, as a mucoadhesive) and TMC60 (DQ 60%, as a mucoadhesive and a permeation enhancer), and dextran (as a non-mucoadhesive and non-permeation enhancer) microparticles as carriers for pulmonary delivery of insulin was studied in diabetic rats. The impact of the powder formulation on insulin bioavailability and its pharmacological effect was evaluated using a population pharmacokinetic-pharmacodynamic (PKPD) model. Insulin-loaded microparticles were prepared by a supercritical fluid (SCF) drying technique. They had a median volume diameter and median volume aerodynamic diameter of about 6-10 μm and 4 μm, respectively. The PK of insulin in the diabetic rats was analyzed by a one-compartment disposition model and the PD was described by the minimal model of glucose disappearance. The bioavailability of the pulmonarily administered dextran-, TMC20- and TMC60-insulin microparticles relative to subcutaneously (SC) administered insulin, was 0.48, 0.59 and 0.95, respectively. Histological examinations of the rats' lungs did not show any local adverse reactions after single administration of insulin powders. The pharmacodynamic model could describe the insulin-glucose relationship and pharmacodynamic efficiency of insulin formulations, which was about 0.6 ⁎10 - 5 ml/μU, irrespective of the formulations. The current findings suggest that TMC microparticles are a promising vehicle for pulmonary delivery of insulin.

Solid lipid nanoparticles for pulmonary delivery of insulin

Growing attention has been given to the potential of pulmonary route as an alternative for non-invasive systemic delivery of therapeutic agents. In this study, novel nebulizer-compatible solid lipid nanoparticles (SLNs) for pulmonary drug delivery of insulin were developed by reverse micelle-double emulsion method. The influences of the amount of sodium cholate (SC) and soybean phosphatidylcholine (SPC) on the deposition properties of the nanoparticles were investigated. Under optimal conditions, the entrapment delivery (ED), respirable fraction (RF) and nebulization efficiency (NE) of SLNs could reach 96.53, 82.11 and 63.28%, respectively, and Ins–SLNs remained stable during nebulization. Fasting plasma glucose level was reduced to 39.41% and insulin level was increased to approximately 170 μIU/ml 4 h after pulmonary administration of 20 IU/kg Ins–SLNs. A pharmacological bioavailability of 24.33% and a relative bioavailability of 22.33% were obtained using subcutaneous injection as a reference. Incorporating fluorescent-labelled insulin into SLNs, we found that the SLNs were effectively and homogeneously distributed in the lung alveoli. These findings suggested that SLNs could be used as a potential carrier for pulmonary delivery of insulin by improving both in vitro and in vivo stability as well as prolonging hypoglycemic effect, which inevitably resulted in enhanced bioavailability.

Insulin Antibodies with Pulmonary Delivery of Insulin

Delivery of insulin to the deep lung presents unique challenges to the body's mucosal defense system. Pulmonary mucosal defense has the ability to discriminate between self and non-self antigens and has the potential for induction of immunologic tolerance. Published data concerning the immunogenicity of inhaled human insulin in drug trials will be reviewed, and data regarding the possible adverse effects of anti-insulin antibody development will be presented. Examination of the immunologic safety of inhaled human insulin will include discussion of comparator studies, factors affecting immunogenicity, the effects of insulin immunity on glycemic control and pulmonary function, and the relationship of insulin antibodies to dose requirements, pharmacodynamics, and hypoglycemia. Inhaled human insulin, whether formulated as a powder or liquid, has been shown to be more immunogenic than comparator insulins given by subcutaneous routes; however, adverse effects of antibody formation have not been demonstrated.

Delivering Needle-Free Insulin Using AERx® iDMS (Insulin Diabetes Management System) Technology

Inhaled insulin has recently emerged as an alternative to subcutaneous insulin administration. One inhaled insulin device, AERx (a registered trademark of Aradigm Corp., Hayward, CA, or its affiliates in the United States and other countries) insulin diabetes management system (iDMS) (Novo Nordisk A/S, Bagsvaerd, Denmark), uses a unique liquid human insulin strip to deliver an aerosol of insulin to the lungs. AERx iDMS enables 1-unit increment dosing, and the device ensures that the insulin dose is released at the optimal point of inhalation for delivery to the lungs. Compared with subcutaneous human insulin, the pharmacokinetic and pharmacodynamic profile of inhaled insulin with AERx iDMS is similar, but with a more rapid onset of action. Data from these pharmacokinetic studies have also demonstrated that inhaled insulin dosing with AERx iDMS is as consistent and reproducible as subcutaneous human insulin. In individuals with diabetes, prandial inhaled insulin with AERx iDMS is as effective and well tolerated as subcutaneous prandial human insulin or insulin aspart in terms of glycemic control and overall hypoglycemia. No major safety concerns have been raised with respect to pulmonary function tests. Other clinical studies using AERx iDMS in special populations, such as smokers, people with asthma, or people suffering from upper respiratory tract infections, have provided important information regarding the use of inhaled insulin in these circumstances. Overall, pulmonary insulin delivery with the AERx iDMS device appears to be a promising safe and efficacious alternative to subcutaneous insulin injections.

Pulmonary Insulin Delivery—State of the Art 2007

Pulmonary Insulin Delivery—State of the Art 2007

Inhaled Insulin and the Lung

Pulmonary delivery of insulin is more than a promise in the treatment of diabetes mellitus. Inhaled insulin seems at least as efficacious as the conventional regimen of subcutaneous insulin and/or oral glucose-lowering agents in both type 1 and type 2 diabetes mellitus. Improved metabolic control and the use of a non-invasive route of administration represent the main benefits of this new treatment. Several physico-chemical factors could reduce the bioavailability of inhaled insulin. Indeed, both deep-lung deposition and adsorption of insulin variously depend on the type of propellants used, speed of air flow, particle size and velocity, drug deposition into the throat and larger bronchial tree. These factors, in turn, depend on the pulmonary delivery systems used and on respiratory mechanics and flows. Furthermore, the pharmacokinetics of inhaled insulin is affected by smoke, which increases its absorption, and by lung diseases, which decrease the available alveolar-capillary surface. Selected abnormalities of respiratory function complicate both type 1 and type 2 diabetes mellitus and a mild depression of carbon monoxide lung transfer after a 6-month period of treatment with inhaled insulin has been reported. Finally, results from some longitudinal studies suggest that diabetes might speed up the age-related decline of lung volumes and probably alter the pharmacokinetics of inhaled insulin, particularly in the elderly. Clarifying these issues is mandatory in order to define the indications and safety of inhaled insulin.