Intranasal insulin delivery and therapy1
Introduction
The history of insulin as a therapeutic drug dates back to 1922 when it was first used successfully in humans to treat the symptoms of diabetes mellitus [1]. To this day, insulin is vital in the treatment of insulin-dependent diabetes mellitus (IDDM) and is also widely indicated in the treatment of non-insulin-dependent diabetes mellitus (NIDDM).
Although the oral route is preferred for the administration of drugs, particularly those required in chronic therapies, it is not feasible for the systemic delivery of most peptide and protein drugs including insulin 2, 3, 4, 5. The low bioavailability of drugs administered via the oral route is largely due to a number of physical and physiological factors such as chemical and enzymatic degradation in the gastrointestinal tract, low permeability across the gastrointestinal mucosa and those that are absorbed are subjected to `first pass' metabolism and clearance predominantly by the liver but also by the gut mucosa 6, 7.
As a consequence of poor oral bioavailability and the current lack of alternative delivery routes, insulin is presently administered parenterally. The subcutaneous route, requiring single or multiple daily injections, is the mainstay of conventional insulin therapy [8]. Subcutaneous insulin may also be delivered by continuous infusion, requiring a portable infusion pump attached to an indwelling needle inserted under the skin, although there are several disadvantages which limits its widespread application. Close control of insulin concentrations in the diabetic patient will usually require a daily injection regimen, close monitoring of blood glucose concentrations and a strict control of diet 9, 10.
There are numerous disadvantages to injectable insulin therapy. Poor patient compliance due to pain or discomfort during self-injection, particularly if multiple daily injections are required, can be problematic 10, 11, although the introduction of `user-friendly' portable pre-filled insulin pens has helped to improve patient compliance and reduce the stigma that many diabetics associate with injectable therapy [12]. A subcutaneous therapeutic regimen fails to deliver physiological patterns of insulin due to adverse insulin pharmacokinetics and hence normoglycaemia is seldom achieved 8, 10, 13, 14, 15. Also, in the majority of insulin-dependent diabetics, day-to-day metabolic variability in glycaemic control occurs despite consistency in the parenteral dosing regimen and site of injection 10, 13, 16. Insulin absorption via the subcutaneous route is generally slow and sustained and, thus, does not mimic the normal pulsatile pattern of endogenous insulin secretion in the non-diabetic. After a meal, the injection regimen should aim to provide peak post-prandial blood concentrations of insulin to match the post-prandial hyperglycaemia. However, due to the sustained absorption, insulin concentrations between meals (basal concentrations) may be inappropriately high which commonly results in episodes of hypoglycaemia. Subcutaneous or intramuscular injections of insulin will also result in peripheral hyperinsulinaemia which has been implicated in the exacerbation of the macrovascular complications of diabetes. The development of insulin analogues, such as Lys(B28)Pro(B29), which are more rapidly absorbed and have a shorter duration of action after subcutaneous injection than regular insulin and provide higher peak levels of insulin, have been reported [17]. These should improve the control of post-prandial hyperglycaemia in diabetics.
The difficulties in achieving a normal physiological profile of insulin by injectable therapy has led to the investigation of alternative, non-parenteral, routes for the delivery of insulin in an attempt to improve glycaemic control. Utilisation of the oral route for insulin delivery is fraught with enormous difficulty [15]. Consequently, the commercial development of a safe and reliable oral delivery system for insulin will probably never become a reality. There are a number of other non-parenteral routes other than the oral route which have been investigated for the systemic administration of peptide and protein drugs such as transdermal, ocular, buccal, rectal, vaginal, pulmonary and nasal routes 18, 19. Of these, the intranasal route is perhaps the most viable and favourable for chronic systemic medication of such drugs 20, 21, 22. As early as 1922, Woodyatt investigated the absorption of insulin via the nasal cavity [23]and over the years widespread interest has focused on the development of nasal delivery systems for insulin. Developing safe and effective nasal delivery systems for insulin is an exciting and demanding challenge and there is no doubt that the commercial availability of a nasal insulin formulation would represent a major breakthrough in the treatment of diabetes mellitus and help to improve the lives of millions of diabetics.
Section snippets
Rationale for the intranasal delivery of drugs
The nasal administration of drugs for systemic medication has been widely investigated and attempts have been made to deliver a large number of compounds, including peptides and proteins, by this route 20, 24, 25, 26. The accessibility of the nasal route facilitates self-medication thus improving patient compliance compared to parenteral routes [11]. The nasal cavity has a relatively large absorptive surface area and the high vascularity of the nasal mucosa ensures that absorbed compounds are
Structure and function of the nasal cavity
The anatomy, physiology and function of the adult human nasal cavity has been comprehensively reviewed in a number of publications 32, 33. The following description of the structure and function of the nasal cavity is based on several general publications 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44as well as specific sources of reference which will be given in the text.
Barriers to intranasal insulin absorption
It is generally recognised that the intranasal route has great potential for the delivery of peptide and protein drugs for systemic medication. However, the barriers which limit their absorption via this route are principally: (i) deposition and clearance from the nasal cavity; (ii) penetration of the mucus layer and the epithelial membrane; and (iii) enzymatic degradation.
Overcoming the barriers to nasal insulin absorption
The various absorption barriers must be overcome in order to achieve an effective degree of insulin absorption via the nasal route. The very low bioavailability of insulin, or indeed the majority of peptide and protein drugs, administered nasally severely restricts their commercial exploitation. Exceptions are compounds such as desmopressin, buserelin and calcitonin nasal sprays which, although poorly absorbed via the nasal route, are marketable owing to their high potency and relatively low
Intranasal insulin delivery in animals and humans
This section will review in detail the application of the various classes of absorption enhancers which have been investigated for the nasal delivery of insulin in humans and animal models. Systemic insulin absorption data following the nasal administration of some of the various types of absorption enhancer is shown in Table 2.
Concluding remarks
The pharmacokinetic profile of intranasal insulin is similar to that obtained by intravenous injection bearing relatively closer resemblance to the `pulsatile' pattern of endogenous insulin secretion than subcutaneous insulin which is the mainstay of current insulin therapy. Based on the results of the numerous studies reported in the literature, intranasal insulin therapy has considerable potential for controlling post-prandial hyperglycaemia in the treatment of both IDDM and NIDDM.
Effective
References (248)
- et al.
Routes of delivery: case studies. (5) Oral absorption of peptides and proteins
Adv. Drug Deliv. Rev.
(1992) - et al.
Systemic delivery of therapeutic peptides and proteins
Int. J. Pharm.
(1988) - et al.
The stability of peptides in nasal enzymic systems
Int. J. Pharm.
(1995) - et al.
Enkephalin hydrolysis in homogenates of various absorptive mucosae of the albino rabbit: similarities in rates and involvement of aminopeptidases
Life Sci.
(1986) - et al.
Aminopeptidases of newborn bovine nasal turbinate epithelial cell cultures
Int. J. Pharm.
(1991) - et al.
Hydrolysis of peptides in nasal cavity of humans
J. Pharm. Sci.
(1990) - et al.
Bioadhesive microspheres as a potential nasal drug delivery system
Int. J. Pharm.
(1987) - et al.
Intranasal administration of peptides: nasal deposition, biological response, and absorption of desmopressin
J. Pharm. Sci.
(1986) - et al.
Effects of concentration and volume on nasal bioavailability and biological response to desmopressin
J. Pharm. Sci.
(1988) - et al.
Effect of viscosity on particle size, deposition, and clearance of nasal systems containing desmopressin
J. Pharm. Sci.
(1988)
Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin
J. Pharm. Sci.
The influence of solution viscosity on nasal spray deposition and clearance
Int. J. Pharm.
Pharmacokinetics of intranasally applied medication during a cold
Antiviral Res.
Nasal absorption of propranolol in rats
J. Pharm. Sci.
Nasal absorption of propranolol in humans
J. Pharm. Sci.
Nasal absorption of propranolol from different dosage forms by rats and dogs
J. Pharm. Sci.
The history of insulin
Diabetes Care
Alternative delivery systems for peptides and proteins as drugs
Crit. Rev. Ther. Drug Carrier Syst.
Penetration and enzymic barriers to peptide and protein absorption
Adv. Drug Deliv. Rev.
Recent developments in insulin delivery techniques
Drugs
Alternative routes and methods of insulin delivery
Neth. J. Med.
Intranasal drug delivery: potential advantages and limitations from a clinical pharmacokinetic perspective
Clin. Pharm.
Monomeric insulins and their experimental and clinical implications
Diabetes Care
Intranasal insulin: clinical pharmacokinetics
Clin. Pharm.
Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients
Ann. Intern. Med.
Faster, shorter and more profound action of Lys(B28)Pro(B29) human insulin analogue compared to regular insulin irrespective of injection site
Diabetes
Nonparenteral administration of peptide and protein drugs
Crit. Rev. Ther. Drug Carrier Syst.
The clinical use of insulin
J. Metab. Res.
Intranasal drug delivery for systemic medications
Crit. Rev. Ther. Drug Carrier Syst.
Intranasal drug administration for systemic medication
Pharm. Int.
Lack of beneficial effect of intermittent subcutaneous insulin delivery by pump in Type-1 diabetic patients
Diabete Metabol.
Nasal and sublingual administration of insulin in man
J. Jpn. Diabetes Soc.
Insulin administered intranasally as an insulin–bile salt aerosol – effectiveness and reproducibility in normal and diabetic subjects
Diabetes
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Abbreviations: α-CD, α-cyclodextrin; β-CD, β-cyclodextrin; γ-CD, γ-cyclodextrin; AUC, area under the plasma/serum concentration versus time curve; Cmax, maximum or peak plasma/serum concentration; Cmin, minimum plasma/serum concentration; DDPC, didecanoyl-L-α-phosphatidylcholine; DM-β-CD, dimethyl-β-cyclodextrin; EDTA, ethylenediaminetetraacetic acid; FITC, fluorescein isothiocyanate; HLB, hydrophile–lipophile balance; hGH, human growth hormone; HP-β-CD, hydroxy-propyl-β-cyclodextrin; HPC, hydroxypropylcellulose; HSA, human serum albumin; Hyaff 11, hyaluronic acid ester; IDDM, insulin-dependent diabetes mellitus; Ig, immunoglobulin; Laureth-9, polyoxyethylene-9-lauryl ether; LPC, lysophosphatidylcholine; LPG, lysophosphatidylglycerol; MCC, microcrystalline cellulose; MTR, mucociliary transport rate; NIDDM, non-insulin-dependent diabetes mellitus; PC, phosphatidylcholine; RAMEB, randomly methylated β-cyclodextrin; SDC, sodium deoxycholate; SGC, sodium glycocholate; STDHF, sodium taurodihydrofusidate; 99mTc, 99mtechnetium; TER, transepithelial resistance.