Aerosolization insulin

The standard mode of insulin therapy has traditionally been by subcutaneous injection using disposable needles/syringes. However, other routes of administration, including continuous subcutaneous insulin infusion pumps and inhalation of finely powdered aerosolized insulin, are currently being explored. 

Laube, B.L. 2001. Treating diabetes with aerosolized insulin. Chest 120 99S-106S. 

In order to overcome the inherent problem associated with pulmonary aqueous solution and dry powder aerosols, Choi et al. [2] developed an ethanol suspension of insulin for inhalation, in which the solid insulin is suspended in ethanol and aerosolized with a commercial compressor nebulizer. The aerosol insulin particles were found to be 1.5 pm, with a geometric standard deviation of 1.3 pm. Exposure of rats to 10 mg/mL insulin aerosol resulted in a drastic fall in blood glucose and a marked rise in serum insulin level. The bioavailability of insulin/ethanol aerosol was 33% relative to SC injection, and comparable to that of insulin aerosols in aqueous solution and dry powder form. No acute toxic effects were detected in the rat lungs or airways [2]. 

Dose reproducibility Several human studies comparing aerosol insulin administration to subcutaneously administered insulin showed that the variability in glucose response from a liquid nebulizer that utilized the standing cloud concept was equivalent or better than that seen with insulin injection. Inhale Therapeutics Systems, Inc. has adopted this standing cloud concept for its dry powder inhaler to achieve reproducibility of delivery of macromolecules to the systemic circulation that is equivalent to subcutaneous injections. 

Patton, J.S. Platz, R.M. Aerosol insulin—a brief review. Respiratory Drug Delivery IV 1994, 65-74. 

Insulin by Aerosol. Early studies showed that aerosolized insulin had a bioavailability of 57% after delivery via endotracheal tube into animals, about 10-fold higher than after instillation [125]. Human studies documented average time to peak insulin level at 40 min after aerosol inhalation by human diabetics and normalization of blood glucose [126]. Continuing research focuses on delivery systems [127-129] and particle modification [130,131] to enhance efficacy. Success of these new approaches will depend heavily upon their cost and convenience for patients. At this point, systems seem to depend upon nebulization, a distinct disadvantage for active people. Unless patients quickly recognize aerosolized insulin as distinctly superior to current therapy, e.g., subcutaneous insulin, the method will not gain acceptance. 

Inkjet technology was investigated for the adininistration of aerosol insulin and this technology was found to be an efficient administration system for protecting the quality and the biological activity of the adrninistered insulin (50). 

The recovered aerosolized insulin solution was similar to that of cells treated with a control insulin sample. Also the addition of additives used for the insulin aerosolization impair the plasma glucose-lowering action of subcutaneously injected insulin. For these reasons, the potential use of an inlqet device for insulin inhalation therapy for diabetes has been suggested (50). 

Colthorpe P, Farr SJ, Taylor G, Smith IJ, Wyatt D (1992) The pharmacokinetics of pulmonary delivered insulin a comparison of intratracheal and aerosol administration to the rabbit. Pharm Res 9 764-768. 

Inhalation Administration Aerosol particles of drug can be inhaled into the lungs. Because of the large surface area of the alveoli, absorption is rapid and effective. As the lungs are richly supplied with capillaries, distribution of inhalational drugs is very quick (refer to Exhibit 4.14 on inhalable insulin). 

Insulin (human) 5786 Da Aerosol (nebulized) Solution pH 7 20-25 % vs. s.c. injection... 

Evans and Farr [314] patented a process for preparation of aerosol inhalants containing proteins and peptides (with particular reference to insulin) solubilized in RMs. 

Colthorpe, R, Farr, S.J., Taylor, G., Smith, I.J., and Wyatt, D. (1992). Pharmacokinetics of pulmonary-delivered insulin Comparison of intratracheal and aerosol administration to the rabbit. Pharmaceut. Res., 9, 764—768. 

This route is currently being clinically tested as an application method to deliver insulin for the treatment of diabetes. The major problems in using drugs in nasal aerosols are finding the proper surfactant to breach the mucous membranes and avoiding excessive irritation of those membranes. 

Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (183). Methods of absorption other than subcutaneous, such as nasal insulin, buccal insulin, rectal insulin, and insulin in enteric-coated capsules, are still experimental. A problem in nasal administration is still how to get a daily reproducible dose (184). The frequency of hypoglycemia is comparable to the frequency with subcutaneous insulin (185). Nasal irritation, sometimes with congestion, and dyspnea (186) can occur. Pulmonary insulin, delivered by aerosol inhalation, is another experimental method. No lung obstruction was reported, but the uptake varied considerably (187). 

The risk of hypoglycemia with inhaled insulin has been reported to be similar to that with subcutaneous insulin (273). In an open study of 107 patients with type 2 diabetes, mean age 58 years, using liquid insulin aerosol droplets + subcutaneous NPH insulin (n = 54) compared with Actrapid + NPH (n — 53) for 24 weeks, there were three major episodes of hypoglycemia in two patients using inhaled insulin and none in the other group (268). 

Of 335 patients with type 1 diabetes randomized to receive preprandial inhaled insulin as a dry powder formulation via an aerosol delivery system (Exubera) plus bedtime subcutaneous Ultralente insulin, or to continue NPH and regular insulins subcutaneously, 170 received inhaled insulin (mean age 33 years) (272). Six discontinued inhaled insulin, one because of mild cough, two because of hypoglycemia, and three because of insufficient responses. The risk of hypoglycemia was slightly lower in those who used inhaled insulin, at 8.6 events per month compared with 9.0 events per month in the conventional insulin group. 

Laube BL, Georgopoulos A, Adams GK 3rd. Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients. JAMA 1993 269(16) 2106-2109. 

The active inhaler made by Nektar Therapeutics (formerly Inhale Therapeutic Systems, United States), called Pulmonary Delivery System (PDS), mechanically compresses a fixed volume of air required for delivery and dispersion of a premetered dry-powder unit dose by a spring-loaded pump (Fig. 8.10). Generation of the respirable aerosol cloud thus is independent of the inspiration effort exerted by the patient. The aerosol is generated in a transparent holding chamber that acts as a spacer from which the patient inhales the standing cloud of particles (Patton 1997). The PDS device is actually close to market for inhaled delivery of insulin under the trade name Exubera. 

Drugs are administered as a solid in the form of capsules, tablets, and pills (e.g., clonidine), a volatile liquid (e.g., halothane and enflurane), a solution (e.g., chlorpromazine), an aerosol (e.g., beclomethasone), a gas (e.g., oxygen and nitrous oxide), and a crystalline suspension (e.g., insulin). The route of administration is chosen based on the desired onset and duration of action of the drug, the nature of the drug, any special circumstances, and the bioavailability of the drug. 

AERx was developed by Aradigm Corporation in collaboration with Novo Nor-disk A/S. It is a liquid insulin formulation which can create aerosols of 1-3 pm particle diameter [62]. In a study involving 23 healthy volunteers, AERx was used to deliver aqueous insulin aerosols to the lungs at two concentrations (250 U/mL and 500 U/mL), and was compared with a SC injection of insulin solution. The results showed the absorption of insulin to be more rapid after pulmonary dosing... 

L. Schaupp, A. Siebenhofer, J.H. Jendle, J. Okikawa, and T.R. Pieber. 2001. Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients. Diabetologia 44 305-308. 

Because of its widespread use as a herbicide, the possibility exists of substantial paraquat contamination of food. Drinking water contamination by paraquat has also been observed. The chronic effects of exposure to low levels of paraquat over extended periods of time are not well known. Acute exposure of animals to paraquat aerosols causes pulmonary fibrosis, and the lungs are affected even when exposure is through nonpulmonary routes. Paraquat affects enzyme activity. Acute exposure may cause variations in the levels of catecholamine, glucose, and insulin. 

Key Words Dry powder inhalers (DPI) Pulmonary drug delivery Insulin Particle engineering Spray drying Liposomes Aerosol solvent extraction system (ASES) Technosphere insulin. 

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