1 2002 Vol: 1(7):529-540. DOI: 10.1038/nrd836

New horizons — alternative routes for insulin therapy

Since the introduction of insulin therapy 80 years ago, the lives of millions of patients with diabetes have been saved, prolonged and immeasurably improved. However, restoring normal glucose levels in diabetic patients through administering insulin by subcutaneous injection has proved virtually impossible. The consequences for patients are serious complications, including diabetic retinopathy and nephropathy, which tend to result from persistent hyperglycaemia. Maximizing glucose control in diabetic patients requires several daily injections. In an effort to reduce this burden, alternative and less-intrusive routes for the administration of insulin are being explored.

Mentions
Figures
Figure 1: There are many alternative routes for the delivery of insulin.a | The pulmonary route might be the first of these to be used for clinical care of insulin-requiring patients with diabetes. Other options for the delivery of insulin include b | whole-organ pancreas transplantation, or c | transplantation of isolated islet cells or genetically modified stem cells. Other routes for the delivery of insulin include nasal, oral–gastrointestinal, buccal, rectal, vaginal, uterus, ocular and dermal. *The table shows surface areas of different sites in the body. Figure 2: The pulmonary tree provides a large surface area for drug/peptide delivery.Approximately 20% of insulin is absorbed into the systemic circulation after intrapulmonary delivery. Clinical studies have shown the potential usefulness of inhaled insulin for meal-related requirements. Figure 3: Pulmonary insulin-delivery devices.a | The Inhale Therapeutic Systems/Pfizer/Aventis Exubera inhalation system. An insulin-powder formulation that is contained in a single-dose blister is placed into a slot in the Inhale device, and an air-assisted mechanism is used to disperse the powder into a holding chamber from which the patient inhales the insulin. Reprinted with permission from Inhale Therapeutic Systems © (2002). b | The Novo Nordisk/Aradigm delivery system. A combination of single-use strips that contain a liquid-insulin formulation and a breath-activated, microprocessor-controlled device (shown in the figure) to optimize pulmonary delivery. Reprinted with permission from Novo Nordisk © (2002). c | The Aerodose/Aerogen delivery device. A breath-activated system, which uses a liquid formulation of insulin, and incorporates a titratable cartridge for dose adjustment. Reprinted with permission from Aerogen, Inc. © (2002). Aerogen and Aerodose are trademarks of Aerogen, Inc.; images and accompanying text supplied with permission by Aerogen, Inc., Mountain View, California. Figure 4: Modification of inhaled insulin particles.Technosphere–insulin particles (Pharmaceutical Discovery Corporation) comprise diketopiperazine derivatives and insulin, which self-assemble in an ordered lattice array, and lyophilize to particles of 2–4 m diameter. Reproduced with permission from Pharmaceutical Discovery Corporation © (2002).
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References
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    • . . . The identification of the pancreas as the site of the defect that causes diabetes mellitus by von Mehring and Minkowski in 1889 led eventually to the extraction of insulin by Banting and Best in 1921 (Ref. 1) . . .
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    • . . . However, despite these advances, replicating physiological patterns of insulin secretion has proved virtually impossible, and the goal of restoring and maintaining blood glucose at near-normal levels in diabetic patients has proved elusive2 (see Box 1 for insulin structure and for more on glucose homeostasis) . . .
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    • . . . However, this feature is central to the problem of glycaemic control, as the PHARMACOKINETICS of conventional insulin preparations that are given by this route make it difficult to replicate the normal pattern of nutrient-related and basal insulin secretion3, 4, 5 (Box 2) . . .
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    • . . . However, this feature is central to the problem of glycaemic control, as the PHARMACOKINETICS of conventional insulin preparations that are given by this route make it difficult to replicate the normal pattern of nutrient-related and basal insulin secretion3, 4, 5 (Box 2) . . .
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    • . . . However, this feature is central to the problem of glycaemic control, as the PHARMACOKINETICS of conventional insulin preparations that are given by this route make it difficult to replicate the normal pattern of nutrient-related and basal insulin secretion3, 4, 5 (Box 2) . . .
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    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
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    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
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    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Advances in insulin-infusion pumps have extended from the earlier, relatively bulky, external continuous subcutaneous insulin-infusion devices, such as the Mill Hill Infusor and Auto Syringe8, 9, to the present smaller, lighter and more reliable variable-rate pumps, such as MiniMed 508 and Disctronic H-Tron V100, which have improved catheters and inbuilt alarms10 . . .
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    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
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    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Advances in insulin-infusion pumps have extended from the earlier, relatively bulky, external continuous subcutaneous insulin-infusion devices, such as the Mill Hill Infusor and Auto Syringe8, 9, to the present smaller, lighter and more reliable variable-rate pumps, such as MiniMed 508 and Disctronic H-Tron V100, which have improved catheters and inbuilt alarms10 . . .
  11. Pickup, J. & Keen, H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 25, 593-598 , (2002) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Evidence indicates that patients with problems such as frequent, unpredictable hypoglycaemia could benefit from this approach11 . . .
  12. Buchwald, H. et al. A totally implantable drug infusion device: laboratory and clinical experiences using a model with single flow rate and new design for modulated insulin infusion. Diabetes Care 3, 351-358 , (1980) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Implantable insulin pumps have also been in development12, 13, but only the MiniMed Implantable Pump, which has a modified side-port catheter that uses a new insulin variant with improved stability (genapol insulin), is now available for clinical use in Europe14 . . .
  13. Irsigler, K. et al. Long-term continuous intraperitoneal insulin infusion with an implanted remote-controlled insulin infusion device. Diabetes 30, 1072-1075 , (1981) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
  14. Gin, H. et al. Clinical evaluation of a newly designed compliant side port catheter for an insulin implantable pump: The EVADIAC experience. Diabetes Care 24, 175 , (2001) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Implantable insulin pumps have also been in development12, 13, but only the MiniMed Implantable Pump, which has a modified side-port catheter that uses a new insulin variant with improved stability (genapol insulin), is now available for clinical use in Europe14 . . .
  15. Shimoda, S. et al. Closed-loop subcutaneous insulin infusion algorithm with a short-acting insulin analog for long-term clinical application of a wearable artificial pancreas. Front. Med. Biol. Eng. 8, 197-211 , (1997) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
    • . . . Ultimately, the goal is to develop either a miniature wearable or implantable 'closed-loop' system ('artificial pancreas'), which will include a glucose sensor to allow automatic infusion of insulin and maintenance of blood glucose within pre-defined limits15, 16 . . .
  16. Shichiri, M., Sakakida, M., Nishida, K. & Shimoda, S. Enhanced, simplified glucose sensors: long-term clinical application of wearable artificial endocrine pancreas. Artificial Organs 22, 32-42 , (1998) .
    • . . . Improvements have occurred as a result of several developments, including the introduction of rapid-acting and long-acting insulin analogues that are produced by genetic engineering6, 7, the use of advanced-formulation methods that combine different types of insulin (Boxes 3 and 4) and the use of pumps for the continuous infusion of insulin8, 9, 10, 11, 12, 13, 14, 15, 16 . . .
  17. Brange, J. & Langkjaer, L. in Protein Delivery: Physical Systems (eds Sanders, L. M. and Hendren, R. W.) 343-412 (Plenum, New York, 1997).An excellent and detailed review of insulin formulations and different routes of delivery that relate predominantly to animal studies , .
    • . . . Since then, almost every conceivable route has been tried, but with only limited success17, 18 (Fig. 1) . . .
    • . . . However, absorption of insulin from the rectum is poor and inconsistent, and requires the incorporation of enhancers into suppositories or gels to improve the absorption rate17, 18, 40, 41 (Box 5) . . .
    • . . . Since the 1980s, absorption enhancers, such as bile salts (1–4% sodium glycocholate and deoxycholate spray or drops, and 1% taurodihydrofusidate spray), surfactants (for example, 0.8% Laureth-9 spray) and phospholipids (for example, 2% didecanoyl-phosphatidylcholine spray), as well as various formulation methods, have been used to improve absorption and bioavailability17, 52, 53 (Table 1). . . .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  18. Chetty, D. J. & Chien, Y. W. Novel methods of insulin delivery: an update. Crit. Rev. Ther. Drug Carrier Syst. 15, 629-670 , (1998) .
    • . . . Since then, almost every conceivable route has been tried, but with only limited success17, 18 (Fig. 1) . . .
    • . . . However, absorption of insulin from the rectum is poor and inconsistent, and requires the incorporation of enhancers into suppositories or gels to improve the absorption rate17, 18, 40, 41 (Box 5) . . .
  19. Berger, M. in Frontiers in Insulin Pharmacology (eds Berger, M. & Gries, F.) 144-148 (Plenum, Stuttgart, 1993) , .
    • . . . Realizing the dream of administering insulin orally has met with little, if any, success, despite the use of many strategies to overcome the barriers to absorption that are presented by the gastrointestinal tract19 (Box 5) . . .
    • . . . For the moment, the goal of oral insulin administration is likely to remain unfulfilled for some time to come19. . . .
  20. Carino, G. P. & Mathiowitz, E. Oral insulin delivery. Adv. Drug Deliv. Rev. 35, 249-257 , (1999) .
    • . . . Enhancing the chemical stability of insulin, protecting against proteolytic enzymes, incorporating insulin into liposomes and using surfactants or emulsions to increase the permeability of the intestinal mucosa have achieved only variable success in improving absorption20, 21. . . .
    • . . . Considerable effort has also been made in the encapsulation of insulin, with or without protease inhibitors, into enteric-coated and pH-dependent biodegradable-polymer microspheres20, 24, some of which also show strong adhesive interactions with the intestinal mucosa . . .
  21. Damgé, C. in Biotechnology of Insulin Therapy (ed. Pickup, J.) 97-112 (Blackwell Scientific, Oxford, 1991) , .
    • . . . Enhancing the chemical stability of insulin, protecting against proteolytic enzymes, incorporating insulin into liposomes and using surfactants or emulsions to increase the permeability of the intestinal mucosa have achieved only variable success in improving absorption20, 21. . . .
    • . . . Entrapment of insulin into conventional 'liposomes' has been extensively investigated21, 22, and, more recently, liposomes that are made resistant to the gastrointestinal environment by polymerization have been developed23 . . .
  22. Patel, H. M. & Ryman, B. E. Orally administered liposomally entrapped insulin. Biochem. Soc. Trans. 5, 1739-1741 , (1977) .
    • . . . Entrapment of insulin into conventional 'liposomes' has been extensively investigated21, 22, and, more recently, liposomes that are made resistant to the gastrointestinal environment by polymerization have been developed23 . . .
  23. Langer, R. Drug delivery and targeting. Nature 392, 5-10.An important review of the different methodologies that are used for drug delivery and targeting. Current and future opportunities are discussed , (1998) .
    • . . . Entrapment of insulin into conventional 'liposomes' has been extensively investigated21, 22, and, more recently, liposomes that are made resistant to the gastrointestinal environment by polymerization have been developed23 . . .
  24. Mathiowitz, E. et al. Biologically erodable microspheres as potential oral drug delivery systems. Nature 386, 410-414 , (1997) .
    • . . . Considerable effort has also been made in the encapsulation of insulin, with or without protease inhibitors, into enteric-coated and pH-dependent biodegradable-polymer microspheres20, 24, some of which also show strong adhesive interactions with the intestinal mucosa . . .
    • . . . Non-degradable and degradable polymers have been used to produce microspheres in the nanometre size range that can be absorbed intact by the intestinal epithelium24. . . .
  25. Milstein, S. J. et al. Partially unfolded efficiently penetrated cell membranes - implications for oral drug delivery. J. Control. Release 53, 259-267 , (1998) .
    • . . . Non-acylated amino acids (Emisphere Technologies) are being evaluated as carriers for insulin, in which a non-covalent complex is formed that causes conformational change (unfolding) of the protein, thereby facilitating its passive diffusion through lipid bilayers (through exposure of hydrophobic side chains), before the complex dissociates after crossing the epithelial-cell membrane25 . . .
  26. Still, J. G. Development of oral insulin: progress and current status. Diabetes/Metabolism: Research and Reviews 18, S29-S37 , (2002) .
    • . . . Another approach is based on the modification of insulin by attachment of one or more AMPHIPHILIC oligomers (NOBEX Corporation), which are designed to both enhance absorption and improve resistance to enzymatic degradation26. . . .
  27. Crane, C. W., Path, M. C. & Luntz, G. R. W. N. Absorption of insulin from the human small intestine. Diabetes 17, 625-627 , (1968) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  28. Murlin, J. R. Effectiveness of peroral insulin in human diabetes. J. Clin. Invest. 19, 709-722 , (1940) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  29. Patel, H. M. et al. Intrajejunal absorption of liposomally entrapped insulin in normal man. Biochem. Soc. Trans. 6, 784-785 , (1978) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  30. Earle, M. P. Experimental use of oral insulin. Isr. J. Med. Soc. 8, 899-900 , (1972) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  31. Galloway, J. A. & Root, M.A. New forms of insulin. Diabetes 21 (Suppl. 2), 637-648 , (1972) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  32. Gwinup, G., Elias, A. N. & Domurat, E. S. Insulin and C-peptide levels following oral administration of insulin in intestinal enzyme protected capsules. Gen. Pharmacol. 22, 243-246 , (1991) .
    • . . . In the few studies that have been carried out in humans, little or no hypoglycaemic response has been achieved, irrespective of the method that was used to protect insulin and enhance intestinal absorption, and despite the use of high doses27, 28, 29, 30, 31, 32 . . .
  33. Nagai, T. & Machida, Y. Mucosal adhesive dosage forms. Pharm. Int. 6, 196-200 , (1985) .
    • . . . In animal studies, attempts to improve the ability of insulin to penetrate the mucosae of the mouth using absorption enhancers or bioadhesive delivery systems have shown reductions in blood glucose, but the results lacked reproducibility33, 34 . . .
  34. Aungst, B. J. & Rogers, N. J. Site dependence of absorption-promoting actions of laureth-9, Na salicylate, Na2EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery. Pharm. Res. 5, 305-308 , (1988) .
    • . . . In animal studies, attempts to improve the ability of insulin to penetrate the mucosae of the mouth using absorption enhancers or bioadhesive delivery systems have shown reductions in blood glucose, but the results lacked reproducibility33, 34 . . .
  35. Veuillez, F., Kalia, Y. N., Jacques, Y., Deshusses, J. & Buri, P. Factors and strategies for improving buccal absorption of peptides. Eur. J. Pharm. Biopharm. 51, 93-109.This is an expansive review of the many factors and strategies that are being used to enhance buccal absorption of peptides and other therapeutic agents , (2001) .
    • . . . Other potential options for improving absorption might involve the use of enzyme inhibitors or chemical modifications, such as acylation, to improve the lipophilicity of insulin molecules35 . . .
    • . . . Studies in humans have been limited, and have produced controversial results, with either no effect or limited effects on blood glucose using insulin mouth sprays35, 36 . . .
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    • . . . Studies in humans have been limited, and have produced controversial results, with either no effect or limited effects on blood glucose using insulin mouth sprays35, 36 . . .
  37. Schwartz, S. & Modi, P. Pharmacodynamics of oral insulin in healthy volunteers. Diabetologia 43 (Suppl. 1), A202 , (2000) .
    • . . . More recently, a liquid-insulin aerosol formulation known as Oralin has been developed, which is being evaluated in healthy and diabetic subjects37, 38. . . .
  38. Modi, P. & Mihic, M. A comparison of oral insulin versus subcutaneous injection in type 2 diabetic patients. Diabetologia 43 (Suppl. 1), A203 , (2000) .
    • . . . More recently, a liquid-insulin aerosol formulation known as Oralin has been developed, which is being evaluated in healthy and diabetic subjects37, 38. . . .
  39. Caldwell, L., Nishihata, T., Rytting, J. H. & Higuchi, T. Lymphatic uptake of water-soluble drugs after rectal administration. J. Pharm. Pharmacol. 34, 520-542 , (1982) .
    • . . . Administration of insulin by the rectal route is potentially advantageous because most of the insulin enters the systemic circulation through the lymphatic system, circumventing the hepatic extraction of insulin that occurs by other routes39 . . .
  40. Matsuda, H. & Arima, H. Cyclodextrins in transdermal and rectal delivery. Adv. Drug Deliv. Rev. 36, 81-99 , (1999) .
    • . . . However, absorption of insulin from the rectum is poor and inconsistent, and requires the incorporation of enhancers into suppositories or gels to improve the absorption rate17, 18, 40, 41 (Box 5) . . .
    • . . . Other pharmaceutical formulations, including lyophilized insulin in an aerosol powder, viscous polymer solutions, cyclodextrins or bioadhesive agents, such as starch microparticles and chitosan powder or spray, have also been investigated, predominantly in animals40, 41, 42, 60 . . .
  41. Yun, M.-O., Choi, H.-G., Jung, J.-H. & Kim, C.-K. Development of a thermo-reversible liquid suppository with bioavailabilty enhancement. Int. J. Pharm. 189, 137-145 , (1999) .
    • . . . However, absorption of insulin from the rectum is poor and inconsistent, and requires the incorporation of enhancers into suppositories or gels to improve the absorption rate17, 18, 40, 41 (Box 5) . . .
    • . . . Other pharmaceutical formulations, including lyophilized insulin in an aerosol powder, viscous polymer solutions, cyclodextrins or bioadhesive agents, such as starch microparticles and chitosan powder or spray, have also been investigated, predominantly in animals40, 41, 42, 60 . . .
  42. Yamasaki, Y. et al. The effectiveness of rectal administration of insulin suppository on normal and diabetic subjects. Diabetes Care 4, 454-458 , (1981) .
    • . . . In addition, bioavailability in humans is low (4–10%), and compared with subcutaneous injection, rectally delivered insulin acts more rapidly and is shorter lived42, 43 . . .
    • . . . Other pharmaceutical formulations, including lyophilized insulin in an aerosol powder, viscous polymer solutions, cyclodextrins or bioadhesive agents, such as starch microparticles and chitosan powder or spray, have also been investigated, predominantly in animals40, 41, 42, 60 . . .
  43. Hildebrant, R., Lius, A., Lotz, U. & Schliack, V. Effect of insulin suppositories in type 1 diabetic patients. Exp. Clin. Endocrinol. 873, 168-172 , (1984) .
    • . . . In addition, bioavailability in humans is low (4–10%), and compared with subcutaneous injection, rectally delivered insulin acts more rapidly and is shorter lived42, 43 . . .
  44. Raz, I., Bar-on, H., Kidron, M. & Ziv, E. Rectal administration of insulin. Isr. J. Med. Sci. 20, 173-175 , (1984) .
    • . . . An improvement in short-term glycaemic control has been shown with either a single or repeated doses during one day44, but long-term acceptance of this route of delivery among patients is unlikely. . . .
  45. Stephen, R. L., Petelenz, T. J. & Jacobsen, S. C. Potential novel methods for insulin administration: I. Iontophoresis. Biomed. Biochim. Acta 43, 553-558 , (1984) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
  46. Sage, B. H. Jr. Protein Delivery - Physical Systems (eds Saunders, L. M. & Hendren, R. W.) 319-341 (Plenum Publishing, New York, 1997) , .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
  47. Siddiqui, O., Shi, W. M. & Chien, Y. W. Transdermal iontophoretic delivery of insulin for blood glucose control in diabetic rabbits. Proc. Int. Symp. Control. Res. Bioact. Mater. 14, 174 , (1987) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
  48. Langkjaer, L., Brange, J., Grodsky, G. M. & Guy, R. H. Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pre-treatment. J. Control. Release 51, 47-56 , (1998) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
    • . . . Modified insulins, including the smaller, sulphated insulin and monomeric insulin analogues with increased negative charge, are transferred more efficiently (albeit across hairless skin that has been pretreated with absolute alcohol), although still at a rate that barely satisfies basal insulin requirements48 . . .
  49. Tachibana, K. Transdermal delivery of insulin to alloxan-diabetic rabbits by ultrasound exposure. Pharm. Res. 9, 952-4 , (1992) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
  50. Mitragotri, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850-853 , (1995) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
  51. Cevc, G. Transfersomes, liposomes and other liquid suspensions on the skin: permeation enhancement vesicle penetration and transdermal drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 13, 257-388 , (1996) .
    • . . . Several methods have been tested to improve transdermal transfer, including iontophoresis45, 46, 47, 48, low-frequency ultrasound (phonophoresis)49, 50 and drug-carrier agents, such as transfersomes51. . . .
    • . . . The effect lasts for 10 hours or more, and is equivalent to 75–100% of the hypoglycaemic action of soluble insulin injected subcutaneously51 . . .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  52. Gizurarson, S. & Bechgaard, E. Intranasal administration of insulin to humans. Diabetes Res. Clin. Pract. 12, 71-84 , (1991) .
    • . . . Since the 1980s, absorption enhancers, such as bile salts (1–4% sodium glycocholate and deoxycholate spray or drops, and 1% taurodihydrofusidate spray), surfactants (for example, 0.8% Laureth-9 spray) and phospholipids (for example, 2% didecanoyl-phosphatidylcholine spray), as well as various formulation methods, have been used to improve absorption and bioavailability17, 52, 53 (Table 1). . . .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  53. Hinchcliffe, M. & Illum, L. Intranasal insulin delivery and therapy. Adv. Drug Deliv. Rev. 35, 199-234.This review deals with the intranasal delivery of drugs with consideration to the structure and function of the nasal cavity , (1999) .
    • . . . Since the 1980s, absorption enhancers, such as bile salts (1–4% sodium glycocholate and deoxycholate spray or drops, and 1% taurodihydrofusidate spray), surfactants (for example, 0.8% Laureth-9 spray) and phospholipids (for example, 2% didecanoyl-phosphatidylcholine spray), as well as various formulation methods, have been used to improve absorption and bioavailability17, 52, 53 (Table 1). . . .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  54. Frauman, A. G., Jerums, G. & Louis, W. J. Effects of intranasal insulin in non-obese type 2 diabetics. Diabetes Res. Clin. Pract. 3, 197-202 , (1987) .
    • . . . Although these preparations have been effective, mucosal irritation has been a drawback54, 55, 56 . . .
    • . . . However, this failed to adequately control post-prandial glycaemia without repeated administration and the use of high doses54, 62, 63 . . .
  55. Drejer, K. et al. Pharmacokinetics of intranasally administered insulin with phospholipids as absorption enhancers. Diabetologia 53 (Suppl.1), A61 , (1990) .
    • . . . Although these preparations have been effective, mucosal irritation has been a drawback54, 55, 56 . . .
  56. Moses, A. C. Insulin administered intranasally as an insulin-bile salt aerosol - effectiveness and reproducibility in normal and diabetic subjects. Diabetes 32, 1040-1041 , (1983) .
    • . . . Although these preparations have been effective, mucosal irritation has been a drawback54, 55, 56 . . .
  57. Hirai, S., Ikenaga, T. & Matzuzawa, T. Nasal absorption of insulin in dogs. Diabetes 27, 296-299 , (1978) .
    • . . . Histological studies in animals have shown varied mucosal-cell damage after exposure to certain absorption enhancers57, 58, 59 . . .
  58. Duchateau, G. S. M. J. E. et al. Bile salts and intranasal drug absorption. Int. J. Pharmacy 31, 193-199 , (1986) .
    • . . . Histological studies in animals have shown varied mucosal-cell damage after exposure to certain absorption enhancers57, 58, 59 . . .
  59. Lee, W. A. et al. Histological studies of insulin absorption across the nasal mucosa in the presence of sodium taurodihydrofusidate (STDHF). Proc. Int. Symp. Control. Release Biochem. Mater. 15, 77 , (1988) .
    • . . . Histological studies in animals have shown varied mucosal-cell damage after exposure to certain absorption enhancers57, 58, 59 . . .
  60. Drejer, K. et al. Intranasal insulin administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects. Diabetic Med. 9, 335-340 , (1992) .
    • . . . Other pharmaceutical formulations, including lyophilized insulin in an aerosol powder, viscous polymer solutions, cyclodextrins or bioadhesive agents, such as starch microparticles and chitosan powder or spray, have also been investigated, predominantly in animals40, 41, 42, 60 . . .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  61. Pontiroli, A. E. et al. Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects. Br. Med. J. 284, 303-306 , (1982) .
    • . . . Clinical experience has shown that the pharmacokinetic profile of nasally administered insulin resembles intravenous insulin, but that bioavailability rarely exceeds 20%51, 53, 60, 61, and varies according to the type, volume and concentration of both the enhancer and the insulin17, 52, 53. . . .
  62. Bruce, D. G., Chishom, D. J., Storlien, L. H., Borkman, M. & Kraegen, E. W. Meal-time intranasal insulin delivery in type 2 diabetes. Diabetic Med. 8, 366-370 , (1991) .
    • . . . However, this failed to adequately control post-prandial glycaemia without repeated administration and the use of high doses54, 62, 63 . . .
  63. Coates, P. A. Intranasal insulin: the effect of three dose regimens on postprandial glycaemic profiles in type 2 diabetic subjects. Diabetic Med. 12, 235-239 , (1995) .
    • . . . However, this failed to adequately control post-prandial glycaemia without repeated administration and the use of high doses54, 62, 63 . . .
  64. Salzman, R. et al. Intranasal aerosalized insulin. Mixed-meal studies and long-term use in type 1 diabetes. N. Engl. J. Med. 312, 1078-1084 , (1985) .
    • . . . In longer-term studies (1–4 months) in patients with TYPE 1 DIABETES, the relatively short-lived effect of pre-prandial intranasal insulin was confirmed64, 65, 66 . . .
  65. Lassmann-Vague, V., Thiers, D., Vialettes, B. & Vague, P. Preprandial intranasal insulin. Lancet 13, 367-368 , (1988) .
    • . . . In longer-term studies (1–4 months) in patients with TYPE 1 DIABETES, the relatively short-lived effect of pre-prandial intranasal insulin was confirmed64, 65, 66 . . .
  66. Hilsted, J. et al. Intranasal insulin therapy: the clinical realities. Diabetologia 38, 680-684 , (1995) .
    • . . . In longer-term studies (1–4 months) in patients with TYPE 1 DIABETES, the relatively short-lived effect of pre-prandial intranasal insulin was confirmed64, 65, 66 . . .
    • . . . Patients who were given nasal insulin required an increased dose of basal insulin67 or suffered deteriorating metabolic control and withdrawal66 . . .
  67. Frauman, A. G., Cooper, M. E., Parsons, B. J., Jerums, G. & Louis, W. J. Long-term use of intranasal insulin in insulin-dependant diabetic patients. Diabetes Care 10, 573-578 , (1987) .
    • . . . Patients who were given nasal insulin required an increased dose of basal insulin67 or suffered deteriorating metabolic control and withdrawal66 . . .
  68. Lelej-Bennis, D. et al. Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic type 2 diabetic patients with oral drug failure: a cross over study. Diabetic Med. 18, 614-618 , (2001) .
    • . . . In more recent studies, which used an insulin–glycocholate freeze-dried formulation that was given before meals with subcutaneous insulin for basal requirements, glycaemic control that was comparable to subcutaneous administration was achieved in patients with type 2 diabetes68 . . .
  69. Lelej-Bennis, D. et al. Six month administration of gelified intranasal insulin in type 1 diabetic patients under multiple injections: efficacy versus subcutaneous injections and local tolerance. Diabetes Metab. 27, 372-377 , (2001) .
    • . . . More recently, a new, gel-based nasal insulin formulation that contains glycocholate and methyl-cellulose as absorption promoters has been tested in a small number of patients with type 1 diabetes69 . . .
  70. Holinger, M. A. Respiratory Pharmacology and Toxicology (W. B. Saunders, Philadelphia, 1985) , .
    • . . . The respiratory tree has a surface area of 140 m2 (Ref. 70), and offers the largest available surface area for drug delivery . . .
  71. Weibel, E. R. in Handbook of Physiology (eds Ferm, W. O. & Rahn, I. I.) 284-307 (Am. Physiol. Soc., Washington DC, 1964) , .
    • . . . Unlike the columnar epithelium of the gastrointestinal tract and nose, the alveolar epithelium — which represents 95% of the absorptive surface — provides an attractive option for the systemic delivery of drugs and polypeptide hormones71, 72, 73, 74 . . .
  72. Byron, P. R. Determinants of drug and polypeptide bioavailabilty from aerosols delivered to the lung. Adv. Drug Deliv. Rev. 5, 107-132 , (1990) .
    • . . . Unlike the columnar epithelium of the gastrointestinal tract and nose, the alveolar epithelium — which represents 95% of the absorptive surface — provides an attractive option for the systemic delivery of drugs and polypeptide hormones71, 72, 73, 74 . . .
    • . . . Deposition in the lung periphery (alveolar or deep lung) is optimal for aerosol particles with a MMAD of 1–3 m, and larger particles of 5–10 m or >10 m are deposited predominantly in the tracheobronchial or oropharyngeal regions, respectively, with the smallest particles (<1 m) being predominantly exhaled72. . . .
  73. Patton, J. S., Bukar, J. & Nagarajan, S. Inhaled insulin. Adv. Drug Deliv. Rev. 35, 235-247.This review addresses the many determinants of drug and peptide bioavailability, from aerosol delivery to the lung , (1999) .
    • . . . Unlike the columnar epithelium of the gastrointestinal tract and nose, the alveolar epithelium — which represents 95% of the absorptive surface — provides an attractive option for the systemic delivery of drugs and polypeptide hormones71, 72, 73, 74 . . .
    • . . . These include the particle size or aerodynamic diameter (a function of the geometric diameter of the particle and the mass density, which is designated the mass median aerodynamic diameter (MMAD)), surface morphology, charge, solubility, HYGROSCOPICITY and, less importantly, formulation, pH and concentration73, 74 . . .
  74. Patton, J. S. & Platz, R. M, Pulmonary delivery of peptides and proteins for systemic action. Adv. Drug Deliv. Rev. 8, 179-196.A discussion of the many barriers to the absorption of drugs and peptides to the lung, and the mechanisms of absorption , (1992) .
    • . . . Unlike the columnar epithelium of the gastrointestinal tract and nose, the alveolar epithelium — which represents 95% of the absorptive surface — provides an attractive option for the systemic delivery of drugs and polypeptide hormones71, 72, 73, 74 . . .
    • . . . The immunotolerant nature of the lung is also of considerable advantage74 (Fig. 2). . . .
    • . . . These include the particle size or aerodynamic diameter (a function of the geometric diameter of the particle and the mass density, which is designated the mass median aerodynamic diameter (MMAD)), surface morphology, charge, solubility, HYGROSCOPICITY and, less importantly, formulation, pH and concentration73, 74 . . .
  75. Von Heubner, W., de Jongh, S. E. & Laquer, E. Uber inhalation von insulin. Klin. Wochenschrift 51, 2342-2343 , (1924) .
    • . . . Early attempts to deliver insulin as an inhaled aerosol began in the 1920s75, 76 . . .
  76. Gansslen, M. Uber inhalation von insulin. Klin. Wochenschrift 4, 71 , (1925) .
    • . . . Early attempts to deliver insulin as an inhaled aerosol began in the 1920s75, 76 . . .
  77. Wigley, F. M. et al. Insulin across respiratory mucosae by aerosol delivery. Diabetes 20, 552-556 , (1971) .
    • . . . There was renewed interest in the subject in the 1970s77, but significant progress was not achieved until the 1990s, when the importance of aerosol dynamics was recognized . . .
  78. Byron, P. R. & Patton, J. S. Drug delivery via the respiratory tract. J. Aerosol Med. 7, 49-75 , (1994) .
    • . . . Many factors are now known to influence the amount and site of deposition of inhaled, aerosolized insulin78, 79, 80, 81 (Box 6) . . .
  79. Schultz, H. Mechanisms and factors affecting intrapulmonary particle deposition: implications for efficient inhalation therapies. Pharm. Sci. Technol. 1, 336-344 , (1998) .
    • . . . Many factors are now known to influence the amount and site of deposition of inhaled, aerosolized insulin78, 79, 80, 81 (Box 6) . . .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
    • . . . Extrusion of the insulin aerosol at the beginning of a slow inspiration, coupled with a large inhaled tidal volume, optimizes deep-lung deposition79, 80 . . .
  80. Farr, S. J. et al. Pulmonary insulin administration using the AERx™ system: physiological and physiochemical factors influencing insulin effectiveness in healthy fasting subjects. Diabetes Technol. Therapeutics 2, 185-197 , (2000) .
    • . . . Many factors are now known to influence the amount and site of deposition of inhaled, aerosolized insulin78, 79, 80, 81 (Box 6) . . .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
    • . . . Extrusion of the insulin aerosol at the beginning of a slow inspiration, coupled with a large inhaled tidal volume, optimizes deep-lung deposition79, 80 . . .
    • . . . The AERx iDMS pulmonary insulin delivery system combines single-use insulin strips that contain a liquid formulation with a breath-activated, microprocessor-controlled device that is designed to minimize variability due to patient technique80 . . .
    • . . . Studies in healthy subjects show that what is delivered with the AERx system is absorbed much more rapidly compared with subcutaneous injection — concentrations reach a maximum within 7–20 minutes compared with 100–120 minutes after subcutaneous injection80 . . .
  81. Katz, I. M., Schroeter, J.D. & Martonen, T. B. Factors affecting the deposition of aerosolized insulin. Diabetes Technol. Therapeutics 3, 387-397 , (2001) .
    • . . . Many factors are now known to influence the amount and site of deposition of inhaled, aerosolized insulin78, 79, 80, 81 (Box 6) . . .
  82. Martonen, T. B. Mathematical model for the selective deposition of inhaled pharmaceuticals. J. Pharm. Sci. 82, 1191-1199 , (1993) .
    • . . . Along with the mass output (particle mass and number of particles per unit volume) and the fine-particle fraction (FPF; respirable fraction), these are crucial determinants of the efficiency of the delivery device82, 83 . . .
  83. Martonen, T. B. et al. Human lung morphology models for particle deposition studies. Inhal. Toxicol. 12, 109-121 , (2000) .
    • . . . Along with the mass output (particle mass and number of particles per unit volume) and the fine-particle fraction (FPF; respirable fraction), these are crucial determinants of the efficiency of the delivery device82, 83 . . .
  84. Wollmer, P. & Evander, E. Biphasic pulmonary clearance of 99mTc-DPTA in smokers. Clin. Physiol. 14, 547-559 , (1994) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  85. Bradvik, I. One year follow-up of lung clearance of 99m c-diethylene traimine penta-acetic acid and diseases activity in sarcodisis. Vasc. Diffuse Lung Dis. 17, 281-287 , (2000) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  86. Jones, J. G., Royston, D. & Minty, B. D. Changes in alveolar-capillary barrier function in animals and humans. Am. Rev. Respir. Dis. 127, S51-S59 , (1983) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  87. Minty, B. D., Royston, D., Jones, J. G. & Hulands, G. H. The effect of nicotine on pulmonary epithelial permeability in man. Chest 86, 72-74 , (1984) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  88. Meignam, M. Exercise increases the lung clearance of inhaled technetium-99m DPTA. J. Nuclear Med. 27, 274-280 , (1986) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  89. Schmekel, B., Borgstrom, L. & Wollmer, P. Exercise increases the rate of pulmonary absorption of inhaled terbulatin. Chest 1, 742-745 , (1992) .
    • . . . Other important influences on pulmonary drug delivery include the pattern of breathing (inspiratory flow rate, inhaled volume and 'breath-hold' time)79, 80, the presence of airflow obstruction, asthma and interstitial lung disease84, 85, smoking86, 87 and exercise88, 89 . . .
  90. Fink, J. B. Metered-dose inhalers, dry powder inhalers, and transitions. Resp. Care 456, 623-635 , (2000) .
    • . . . In addition to the functionality of delivery devices, patient acceptance and ability to operate inhalers are key elements in determining overall efficiency90. . . .
  91. Smith, K. J., Chan. H. K. & Brown, K. F. Influence of flow rate on aerosol particle size distributions from pressurised and breath-actuated inhalers. J. Aerosol Med. 11, 231-245 , (1998) .
    • . . . These devices are limited by their dependence on the inspiratory flow rate91, and hence patient technique92, and are subject to large inter- and intra-subject variability93 . . .
  92. Corne, J., Gillespie, D., Roberts, D. & Younes, M. Effect of inspiratory flow rate in intubated ventilated patients. Am. J. Respir. Crit. Care Med. 156, 304-308 , (1997) .
    • . . . These devices are limited by their dependence on the inspiratory flow rate91, and hence patient technique92, and are subject to large inter- and intra-subject variability93 . . .
  93. Borgstom, L., Bengtsson, T., Derom, E. & Pauwels, R. Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and dry powder inhaler, Turbuhaler. Int. J. Pharm. 193, 227-230 , (2000) .
    • . . . These devices are limited by their dependence on the inspiratory flow rate91, and hence patient technique92, and are subject to large inter- and intra-subject variability93 . . .
  94. Maggi, L., Bruni, R. & Conte, U. Influence of the moisture on the performance of a new dry powder inhaler. Int. J. Pharm. 177, 83-91 , (1999) .
    • . . . DPI devices are further limited by powder hygroscopicity, which reduces the respirable fraction94. . . .
  95. Heise, T. Time-action profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin. Diabetes 39 (Suppl. 1), A10 , (2000) .
    • . . . The overall system efficiency relative to subcutaneous human insulin in healthy subjects is 10%95 . . .
  96. Gelfand, R. A., Schwartz, S. L., Horton, M., Law, C. G. & Pun, E. F. Pharmacological reproducibility of inhaled human insulin in patients with type 2 diabetes mellitus. Diabetologia 43, 773 , (2000) .
    • . . . The ability to reduce post-prandial hyperglycaemia is comparable to subcutaneous insulin96. . . .
    • . . . Essentially, the reproducibility of absorption, and frequency and severity of hypoglycaemic events, seem to be equivalent to that experienced with subcutaneous human insulin in patients with both type 1 and type 2 diabetes96, 97, 113. . . .
    • . . . So far, there is little evidence of local adverse reactions other than an increase in a throat-clearing-type cough that is associated with the act of inhalation, which occurs in 10% of patients96 . . .
  97. Skyler, J. S. et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet 357, 331-335.A pivotal clinical study that tested the hypothesis of pulmonary delivery of insulin in comparison to subcutaneous insulin for meal-related requirements in patients with type 1 diabetes. The formulation of insulin was a dry powder, which was packaged into a single-dose blister that was placed into a delivery device , (2001) .
    • . . . These features make inhaled insulin potentially suitable for delivering meal-related insulin requirements, and this possibility has been tested in several recently published, randomized clinical studies97, 99 . . .
    • . . . The use of the Inhale/Exubera system for meal-related insulin requirements was tested in a recently published 'proof-of-concept' study of 73 patients with type 1 diabetes97 . . .
    • . . . Essentially, the reproducibility of absorption, and frequency and severity of hypoglycaemic events, seem to be equivalent to that experienced with subcutaneous human insulin in patients with both type 1 and type 2 diabetes96, 97, 113. . . .
    • . . . Lung-function tests show some statistically insignificant changes after three months exposure in patients with both type 1 and type 2 diabetics97, 99, with a fall in DLCO in six-month studies in patients with type 1 diabetes . . .
  98. Quattrin, T. Efficacy and safety of inhaled insulin (Exubera) compared to conventional subcutaneous insulin therapy in patients with type 1 diabetes: results of a six month randomised trial. Am. Assoc. Clin. Endocrinol. Annu. Meet. Clin. Congr. Syllabus, 205 , (2002) .
    • . . . The promising metabolic results of this initial report have now been confirmed in a larger study of 335 patients with type 1 diabetes that was done over a six-month treatment period98 . . .
    • . . . Further investigations are needed to explain the change in the diffusing capacity of the lung that has been seen in some studies98, and to explore the potential clinical significance of the observation. . . .
  99. Cefalu, W. T. et al. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann. Int. Med. 134, 203-207 , (2001) .
    • . . . These features make inhaled insulin potentially suitable for delivering meal-related insulin requirements, and this possibility has been tested in several recently published, randomized clinical studies97, 99 . . .
    • . . . In a study of 26 patients who were given inhaled insulin at meal times with an injection of long-acting insulin at bedtime, improved levels of glycaemic control, shown by a reduction in HbA1c levels, were achieved99 . . .
    • . . . The reproducibility for the inhaled insulin was similar (20%) to subcutaneous administration for both insulin absorption and action99 . . .
    • . . . Lung-function tests show some statistically insignificant changes after three months exposure in patients with both type 1 and type 2 diabetics97, 99, with a fall in DLCO in six-month studies in patients with type 1 diabetes . . .
  100. Farr, S. J. et al. Comparison of in vitro and in vivo efficiencies of a novel unit-dose aerosol generator and a pressurised metered dose inhaler. Int. J. Pharm. 198, 63-70 , (2000) .
    • . . . The liquid-aerosol insulin that is generated by the device is released early in inspiration, but only when the inspiratory flow rate and inhaled volume are within acceptable ranges100. . . .
  101. Kipnes, M. Pharmacokinetics and pharmacodynamics of pulmonary insulin delivered via the AERx diabetes management system in type 1 diabetics. Diabetologia 43 (Suppl. 1), A201 , (2000) .
    • . . . SCINTIGRAPHIC studies in healthy subjects that compared a conventional pMDI to an early prototype of the AERx delivery system, in which both used microprocessor-controlled actuation, showed a more homogeneous pattern of distribution with the AERx system101 . . .
    • . . . When insulin is administered just before a test meal using the AERx iDMS, it achieves an affect on post-prandial glucose excursions that is equivalent to subcutaneous insulin injected 30 minutes before eating in patients with type 1 diabetes101 . . .
    • . . . Special caution also needs to be exercised when intrapulmonary insulin is used in patients who are smokers, due to the rapid rates of absorption101, 114, 115, 116 . . .
  102. McElduff, A. et al. Comparison of the pharmacokinetics and pharmacodynamics of subcutaneous and inhaled insulin lispro in healthy fasted volunteers. Diabetes 47, 413 , (1998) .
    • . . . Delivering the rapid-acting insulin analogue insulin lispro by inhalation results in an even earlier peak in plasma insulin concentrations102 . . .
  103. Jendle, J. et al. Pharmacokinetics of pulmonary insulin in healthy smokers and non-smokers. Diabetologia 44 (Suppl. 1), 816 , (2001) .
    • . . . As expected, inhaled insulin is absorbed much faster in individuals who are smokers, and a threefold higher peak insulin concentration is observed103 . . .
  104. Henry, R. et al. Pulmonary delivery of insulin using the AERx™ insulin diabetes management system in healthy and asthmatic subjects. Diabetologia 44 (Suppl. 1), 9 , (2001) .
    • . . . By contrast, asthmatic patients were shown to absorb less insulin than healthy individuals104. . . .
  105. Brunner, G. et al. Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients. Diabetologia 44, 305-308.An important study that used aerosolized liquid insulin in patients with type 1 diabetes. It clearly showed dose-response relationships in both bioavailability and activity of the inhaled insulin , (2001) .
    • . . . The pharmacokinetics and pharmacodynamics of insulin that is administered by the AERx iDMS inhaler have been investigated recently, and the results show the feasibility of the system105 . . .
  106. Fishman, R. S., Guinta, D., Chambers, F., Quintana, R. & Shapiro, D. A. Insulin administration via the Aerodose™ inhaler: comparison to subcutaneously injected insulin. Diabetes 49 (Suppl. 1), 38 , (2000) .
    • . . . Comparing the inhaler with subcutaneous injection, the time to reach maximum circulating insulin concentration is comparable (50 minutes compared with 85 minutes), and the estimates of bioavailability and biopotency over a 6-hour post-administration period were 9.3% and 10.3%, respectively106 . . .
  107. Heinemann, L. et al. Impact of particle size and aerosolisation time on the metabolic effect of an inhaled insulin aerosol. Diabetologia 44 (Suppl. 1), 10 , (2001) .
    • . . . Aerosolization time in relationship to inhalation was seen as a principal factor in determining the efficiency of the inhaled insulin107. . . .
  108. Edwards, D. A., Ben-Jerbria, A., Eskew, M. L. & Langer, R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85, 379-385 , (1998) .
    • . . . The particles, which are produced by encapsulating insulin into a biodegradable polymer matrix, have a reduced tendency to aggregate, which facilitates their dispersion and reduces susceptibility to local PHAGOCYTOSIS108 . . .
  109. Edwards, D. A. et al. Large porous particles for pulmonary drug delivery. Science 276, 1868-1871 , (1997) .
    • . . . In addition to rapid-acting insulin particles, a sustained-release formulation for basal-insulin supplementation has been produced using protamine– or zinc–insulin suspensions that are prepared by spray drying109, 110, 111 . . .
  110. Vanbever, R., Ben-jebria, A., Mintzes, J. D., Langer, R. & Edwards, D. A. Sustained release of insulin from insoluble inhaled particles. Drug Dev. Res. 48, 178-185 , (1999) .
    • . . . In addition to rapid-acting insulin particles, a sustained-release formulation for basal-insulin supplementation has been produced using protamine– or zinc–insulin suspensions that are prepared by spray drying109, 110, 111 . . .
  111. Hrkach, J. AIR insulin: complete diabetes therapy via inhalation of fact-acting and slow-acting dry powder aerosols. Diabetes 49 (Suppl. 1), 37 , (2000) .
    • . . . In addition to rapid-acting insulin particles, a sustained-release formulation for basal-insulin supplementation has been produced using protamine– or zinc–insulin suspensions that are prepared by spray drying109, 110, 111 . . .
  112. Steiner, S. et al. Technosphere™/insulin: bioavailibilty and pharmacokinetic properties in healthy volunteers. Diabetologia 43 (Suppl. 1), 771 , (2000) .
    • . . . Values for bioavailability and biopotency relative to subcutaneous insulin of 25.8% and 19%, respectively, were recorded over the defined time period of three hours112 . . .
  113. Perera, A. D. et al. Reproducibility of inhaled and subcutaneous insulin in type 2 diabetic patients. Diabetologia 44 (Suppl. 1), 815 , (2001) .
    • . . . Essentially, the reproducibility of absorption, and frequency and severity of hypoglycaemic events, seem to be equivalent to that experienced with subcutaneous human insulin in patients with both type 1 and type 2 diabetes96, 97, 113. . . .
  114. Kohler, D. Nicht radioaktives verfahren zur messung der lungenpermeabilitat: inhalation von insulin. Atemwegs Lungenkrankh 13, 230-232 , (1987) .
    • . . . Special caution also needs to be exercised when intrapulmonary insulin is used in patients who are smokers, due to the rapid rates of absorption101, 114, 115, 116 . . .
  115. Schmekel, B., Borgstrom, L. & Wollmer, P. Difference in pulmonary absorption of inhaled terbutaine in healthy smokers and non-smokers. Thorax 46, 225-228 , (1991) .
    • . . . Special caution also needs to be exercised when intrapulmonary insulin is used in patients who are smokers, due to the rapid rates of absorption101, 114, 115, 116 . . .
  116. Wise, S. D., Sathirakul, K., Yeo, K. P., Chien, J. Y. & Aftring, R. P. Smoking increases the bioavailibility of inhaled insulin, but relative insulin resistance ameliorates differences in action. Diabetologia 44 (Suppl. 1), 12 , (2001) .
    • . . . Special caution also needs to be exercised when intrapulmonary insulin is used in patients who are smokers, due to the rapid rates of absorption101, 114, 115, 116 . . .
  117. Weiss, S. R. et al. Adjunctive therapy with inhaled human insulin in type 2 diabetic patients failing oral agents: a multicenter phase II trial. Diabetes 48 (Suppl. 1), 48 , (1999) .
    • . . . Other concerns that have been expressed include the possibility of inducing pulmonary hypotension and pulmonary oedema due to the relatively high insulin concentration that is achieved in the pulmonary vascular bed, especially in patients with cardiac dysfunction117 . . .
  118. Chan, N. N. et al. Inhaled insulin in type 1 diabetes. Lancet 357, 1979-1980 , (2001) .
    • . . . The proinflammatory effects of insulin might also potentially unmask airway obstruction such as asthma, again emphasizing the need for both acute and long-term surveillance118. . . .
  119. Baker, E. H. & Phillips, B. J. Inhaled insulin in type 1 diabetes. Lancet 357, 1979-1980 , (2001) .
    • . . . Patients on inhaled insulin report improved satisfaction and quality of life compared with treatment by subcutaneous injection119 . . .
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