Abstract

Since Banting and Best first isolated Insulin in 1922, much progress has been made in its formulations (e.g. : long acting Insulins and Insulin analogues) and its delivery (e.g. via insulin pumps etc) however the subcutaneous route has remained the only option for administering it on long term basis. Every day millions of Diabetic patients around the world bear the burden of multiple subcutaneous injections of Insulin and this has led the scientists to continuously search for non-invasive modes of Insulin administration.

As early as 1971, Wigely et al showed that regular Insulin can be administered as an aerosol via a Nebuliser. Since then a number of Inhaled Insulins have been tried in clinical trials. In Jan. 2006, US FDA approved Insulin EXUBERA as the first inhaled Insulin for treatment of both type I and II diabetes mellitus, however other similar products in phase III trials are in the pipeline. Inhaled Insulins are as effective as Sub-cutaneous insulin and it works similarly to rapid acting Insulin as far as in its onset and duration of action is concerned.

The most common side effect observed in clinical trials was cough and it was shown to cause slight reduction in FEV1 and DLco but this occurred early, and was minimal and non-progressive, however larger trials of sufficiently long duration are needed to determine its pulmonary safety. The measures of patient’s satisfaction and quality of life showed that inhaled Insulins are well received in various populations of patients with diabetes. The article will review the efficacy and safety of inhaled Insulins with particular reference to Exubera Insulins.

Introduction

Currently a wide range of injectable Insulin products are available for treatment of diabetes, despite this, it has proved virtually impossible to replicate the physiological pattern of endogenous insulin secretion to maintain near normal levels of glycaemia and also many patients may fail to adhere to their regimens, particularly if they are prescribed to take several injections of Insulin a day. Consequently microvascular and macrovascular complication remain highly prevalent in type I and II DM. Attempts to develop noninvasive routes of insulin administration emerged soon after the introduction of insulin in 1922.

Wigley et al in 1971 showed that regular insulin given by an aerosol route via a nebuliser, lowered blood glucose levels in rabbits and healthy human volunteers. Later, Laube et al showed that nebulised porcine insulin lowered blood glucose. Degradation by the acidic environment of the stomach or by digestive enzymes in the upper gastrointestinal tract, active mucociliary clearance and presence of proteolytic enzymes in the nasal cavity, precluded successful delivery by oral, intestinal, intranasal, and transdermal routes.2 None of these obstacles apply to pulmonary delivery of Insulins. On the contrary, the lungs appear perfectly equipped for absorption of such Insulins especially with their large absorptive surface area approximately corresponding to half a tennis court.

Better understanding of aerosol dynamics and particle properties has contributed greatly to the current development of Inhaled Insulin preparations. Several pharmaceutical companies have collaborated with pulmonary drug delivery companies to develop an inhaled Insulin products and corresponding inhalation systems. At least one inhaled preparation EXUBERA was approved in June 2006 by FDA and has been released in market in Sept. 2006. The article will review the pharmacokinetics, safety and efficacy of inhaled Insulins particularly EXUBERA.

Pharmacokinetics

The surface area of the alveoli measures approximately 140 meter square and is lined by very thin and richly perfused, highly permeable monolayer of epithelium. Several factors affect the pulmonary delivery of inhaled Insulins and these include the efficiency of the inhaler, the size of the particles in the aerosol, and the breathing pattern. The efficiency of inhaled device reflects the percentage of dry powder emitted from the device by correct inhalation which is usually 80% to 95% for dry-powder inhalers, but can be as low as 20 to 30% for liquid nebulisers. Particle size and density play an important role in determining how far a drug is delivered into the lungs and how fast is it absorbed. Generally, particles larger than 2 micrometer are more likely to be deposited in the oropharynx or proximal bronchi tree instead of reaching the distal alveoli. However, larger particles can still be delivered consistently to the alveoli, if they are porus and less dense. Most inhaled human insulin products in development utilize particle size between 1 and 5 micrometer. The aerosol is best inhaled by slow inspiration with a large tidal volume. A good pulmonary function is a prerequisite for inhalation therapy. Forced inspiration, however, has an adverse effect on alveolar deposition and leads to particle loss in the oropharyngeal region.1 Transport of Insulin across the alveolar wall probably occurs by a paracellular process, although the exact process is still incompletely understood.2 There is evidence that only 20 to 40% of Insulin deposited in the lungs reaches the circulation. The remaining insulin undergoes cytosolic biodegradation or exits the lung via the mucociliary escalator.2 The bioavailability of Exubera is about 10% only.

Cigarette smoking enhances total systemic exposure of Exubera. In the trial of non-diabetic active smokers without pulmonary disease, the absorption rate of inhaled insulin was 50% higher than in the normal population; in addition, the time to reach peak concentration was reduced by about 40% (31.5 min versus 53.9 min).3 Structural lung damage secondary to smoking may also impact Exubera pharmacokinetics, but this has not been evaluated. Based on these observations and theoretical considerations, use of inhaled insulin is containdicated in smokers and subcutaneous administration of insulin may be a better option for smokers until more research is done in this area.

Absorption of inhaled Insulin occurs rapidly. The time to reach maximum Insulin concentration and glucose-lowering effect is similar to that of subcutaneous short-acting insulin analogues but shorter than that of subcutaneous regular Insulin. The duration of action of inhaled Insulin is four to six hours which is slightly longer than short-acting analogues and slightly shorter than subcutaneously injected regular insulin.4,5 These pharmacokinetic characteristics make inhaled insulin suitable as mealtime insulin only and not as a basal insulin. The safety in pregnancy and paediatric age group has not been established.

Products

Dry-powder formulations have superior room temperature stability, can deliver more insulin per inhalation, and are less prone to microbial growth, whereas liquid formulations are less susceptible to the influence of external humidity on dispersion (Table 1).

Exubera

The most thoroughly investigated inhaled pulmonary Insulin system is Exubera, which consist of dry-powder formulation with regular Insulin (approximately 60%) and stabilizers, primarily mannitol. It is packaged in 1 and 3 mg blisters that contain 3 and 8 units of Insulin respectively.

An individual blister pack is placed into a slot on the Inhaler device and is dispersed by the Pulmonary Inhaler device. The Dual blister is placed into a slot on the device and is dispersed by the inhaler into an aerosol cloud that is captured in a holding chamber for delivery. The patient inhales the aerosol at the beginning of a slow, deep breath in which air is drawn into the chamber, releasing the aerosol into the pulmonary system.5 Three 1 mg blister packs provide greater systemic insulin exposure than one three mg blister pack, and thus the Patient education and some minimal maintenance of inhalation are needed for proper functioning of device.

Studies that reported on the clinical efficacy of Exubera in type I DM include one small 12 week proof of concept study9 and two larger randomized trials,10,21 involving 735 patients in total. In these studies, the experimental group received inhaled insulin at mealtimes in combination with either subcutaneous ultralente insulin once daily or NPH insulin twice a daily. The comparator group either continued their subcutaneous insulin regimen of two to three times of insulin injections9,10 or received mealtime regular insulin in combination with NPH insulin twice daily. Inhaled therapy was found to be clinically equivalent to subcutaneous insulin treatment all of three studies.

In other study11 patients with type 2 DM inadequately controlled by diet only were divided in two groups, in one group inhaled Insulin was added and in other Rosiglitazone was added. After three months, the goal of HbA1c < 7% was achieved by 44% of patients in the inhaled insulin group compared with only 8% in the Rosiglitazone group. However, the study has been criticized for its relatively short duration, since Rosiglitazone may take longer time to achieve its full effect.
Hollander et al17 compared two regimes in 298 overweight patients with type 2 DM. In the first regime insulin Exubera with meals plus bed time ultralente was given and in the other regime twice daily doses of NPH and regular Insulin were given in a premixed ratio of 70:30. At the end of 6 months, the decreases in mean HbA1c was similar in both groups. However, the Insulin Exubera group has fewer episodes of hypoglycaemia and had more patients reaching HbA1c level of less than 7.0%. Weight gain was not seen with Inhaled Insulin, whereas the subcutaneous regimen was associated with an average of 1.5 Kg of weight gain.

In another trial with AERx inhaled insulin delivery system,13 107 patients with type 2 diabetes were given trial of intensive therapy with AERx insulin delivery system, which uses a liquid aerosol for 12 weeks. Patients were randomized to receive either prandial insulin AERx or prandial subcutaneous regular Insulin, both combined with bedtime NPH. Both groups achieved similar HbA1c levels, but the AERx group has less hypoglycaemia and lower fasting plasma glucose levels.13

Rosenstock et al14 randomized 309 patients who were taking two oral agents and had HbA1c ranging between 8% and 11% to either add Insulin Exubera to their regimen or continue their regimen unchanged, or stop their current regimen and take Exubera as monotherapy. The mean HbA1c level in the Exubera plus oral therapy group was 9.2% at the baseline and dropped to 7.3% at 12 weeks. Compared with the group who continued on oral agents alone, the adjusted mean absolute drop in HbA1c was 1.67% in the Exubera plus oral agents group and 1.18% in the Exubera monotherapy group. A HbA1c level; of less than 7% was achieved in 32% of patients in the Exubera plus oral agent group, 17% in the Exubera monotherapy group and only 1% of patients who continued with oral agents alone suggesting that exubera added to oral agents in Type II diabetes mellitus is very effective in accomplishing target HbA1c levels.

In inhaled treated type 2 diabetes patients, the combination of inhaled Insulin at mealtimes and ultralente insulin subcutaneously resulted in similar improvement of glycaemia as a subcutaneous regimen consisting of two to three injections of regular and NPH insulin.15

AERx iDMS

The AERx iDMS delivery system delivers liquid form of Human insulin. The device delivers the low velocity fine particle aerosol spray early during inhalation. The drug is delivered to the lungs only when breathing is correct which is the unique feature of this delivery system. This helps to minimize patient related variation in inhaled Insulin dose. The need for holding breath for better lung delivery is not needed with this system. The insulin is packaged in strips that contain an amount of insulin corresponding to approximately 1 unit subcutaneously. The bioavailability is shown to be about 13 to 17%5,6,17 respectively.

Human inhaled insulin powder (HIIP)

Advanced inhalation research developed large porous particles of low mass that consist of biodegradable polymer matrix than fast acting human insulin. The capsule contain HIIP as a dry powder in two dose strengths of either 0.9 mg or 2.6 mg, equivalent to 2 or 6 units of subcutaneous Insulin, respectively. A preliminary study involving 137 type I patients reported that premeal use of this inhaled insulin in combination with Glargine was clinically equivalent to a subcutaneous regimen of premeal regular or Lispro insulin and Glargine.18 Future development might involve production of sustained release preparation also of inhaled insulins.

Other products

Technospheres insulin is dry-powder pulmonary insulin packaged in microparticles to which an absorption enhancer is added. The particles rapidly dissolve in the alveolar space to release Insulin. The absorption of Technosphere Insulin occurs faster and more efficiently than the other inhaled Insulin products, with respect to time-to-peak insulin concentration (13 minutes), time to-maximal effect (39 minutes), and bioavailability relative to subcutaneous insulin (26%).19
Other inhaled insulin formulations under development are Aerodose, proMaxx, Kos Insulin and Spiros. Aerodose insulin which is designed to deliver the proprietary liquid formulation with dose adjustment facility according to dose requirement. A recent study has shown a bioavailability of above 21% with this device which appears promising.20

Safety Concerns

1. Hypoglycaemia : Several studies10,12,13 have reported a slightly lower relative risk for any hypoglycaemic event with use of inhaled vs. subcutaneous insulin.10 These data are at odds with studies reporting a doubling of the incidence of severe hypoglycaemic events (6.5 vs. 3.3 events per 100 patients-months)21 and a higher incidence of nocturnal hypoglycaemia.14 A Cochrane system review of six randomized controlled trials concluded that overall there was no or little difference in hypoglycaemic risk between inhaled and subcutaneous Insulins.22
2. Pulmonary Adverse Events : Although insulin has cell proliferative properties because it acts as a weak growth factor, to date malignant pulmonary tumours has not been reported in association with inhaled Insulins. The main adverse event reported by the users of dry powder inhaled insulin formulation is cough. In the trial with Exubera 8 to 27% of patients on inhaled insulin reported cough as compared to 1.5 to 7% of patients of comparator group treatment reported cough.10 The cough is reported to occur directly following inhalation and is characterized as mild to moderate. Shortness of breath was also more prevalent in the inhaled insulin group than in control group. However these adverse events rarely led to discontinuation of treatment. Neither cough nor shortness of breath was reported in excess by patients randomized to liquid inhaled insulin compared with subcutaneous insulin.22
   Pulmonary function tests have revealed a slightly greater reduction in both forced expiratory volume in one second (FEV1) and in carbonmonooxide diffusion capacity (DLco) in patients allocated to inhaled insulin treatment. The differences occur in the initial weeks of treatment and are small and non-progressive. In a study among type 2 diabetes patients, the difference in FEV1 and DLco observed between inhaled Insulin treatment group and control group treatment decreased gradually between week 24 and 104 and was no longer discernable 6-12 weeks after discontinuation.24 In addition, annualized decline of FEV1 and DLco during a four year extension study did not appear to continue in 159 type I diabetic patient who had chosen to continue inhalation therapy.25
   In view of the potential adverse pulmonary effects of inhaled insulin, the FDA has recommended pulmonary function testing when starting insulin Exubera, which should be repeated after 6 months, and then yearly regardless of pulmonary symptoms. The drug should not be used if FEV1 is less than 70% of predicted value at the start of therapy and stopped if FEV1 falls by 20% of baseline.26 At present as of now Exubera is contraindicated in patients with preexisting pulmonary disease like asthma and COPD and in those who develop respiratory infections while on inhaled insulin. It is advisable to shift to subcutaneous insulin till more studies are done on inhaled insulin in acute respiratory infections.
3. Insulin antibody response : In all studies inhaled insulin was found to produce larger insulin antibody responses, mainly of IgG class, than subcutaneous Insulin, irrespective of formulation.27-29
   Median antibody responses increased from 3 to 31% in patients with type I DM, and increased from 3 to 13%.30 The peak antibody response was observed after 6 to 12 months of treatment and then declined but did not touch the baseline. So far no relation has been found between presence of insulin antibodies and insulin dose requirements, fasting blood glucose, glycaemic control hypoglycaemia incidence or adverse effects therefore presence of Insulin antibodies appears to have no adverse clinical consequence but further studies are required to confirm that these antibodies do not act as reservoir for delayed release of insulin.
4. Patient preference and financial aspect: Studies in type 1 and type 2 diabetes show significantly more patients using inhaled insulin were satisfied overall than using subcutaneous Insulin.31-33 Since the bio-availability of inhaled insulin is very low, very high doses of inhaled Insulin (about eight times that of SC dose) may be needed and to achieve same glycaemic control. Due to high Insulin doses needed and the cost of development, it is anticipated that inhaled Insulin will cost considerably more than currently available subcutaneous Insulin preparations, but will cost the same as rapid acting anologues currently being used. Moreover extra costs would be incurred due to need of repeated pulmonary function monitoring.
   The “Real World Trial”, which aims to investigate the effect of introducing inhaled Insulin to clinical practice on health benefit and is clue to give its report in 2007, and that may provide some answers on the above issue.34

Conclusion

Overall, inhaled insulin represents an exciting new chapter in the management of diabetes and is likely to become an important tool in the management of both type 1 and 2 diabetes. Clinical studies in type 1 and 2 diabetes subjects indicate equivalence between inhaled insulin based regimens and subcutaneous insulin based regimens with respect to glycaemic control and incidence of hypoglycaemic events. Patients with ‘injection phobia’ or those with lipodystrophy due to subcutaneous insulin will greatly benefit.

Type II diabetes accounts for more than 90-95% of all diabetics. Switching to insulin in patient on oral treatment is often delayed. Reasons include fear of pain, hypoglycaemia, dependence and restricted life style with injectable insulin. Higher acceptance of inhaled insulins might encourage these patients to switch to insulin therapy at an early stage of diabetes and thus in the developing world the greatest impact it could have is to treat type 2 diabetes with insulin more aggressively and this in turn could significantly decrease diabetes related complications, but this is not likely in the near future in view of high costs involved and the likely limitation of supply.

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