N.G.M. Schipper

Nasal mucociliary clearance as a factor in nasal drug delivery

The nasal mucociliary clearance system transports the mucus layer that covers the nasal epithelium towards the nasopharynx by ciliary beating. Its function is to protect the respiratory system from damage by inhaled substances. Impairment of nasal mucociliary clearance can result in diseases of the upper airways. Therefore, it is important to study the effects of drugs and drug excipients on nasal mucociliary clearance. A large number of methods are used to assess mucociliary clearance. These methods study the effects of drug and excipients on the mucociliary system in vitro or in vivo in animals and humans. In some cases, the results of different in vitro and in vivo measurements do not correlate well. In vitro methods, especially ciliary beat frequency measurements, have been demonstrated to be valuable tools for toxicity screening. However, in vivo studies are essential to confirm the safety of nasal drug formulations. Nasal mucociliary clearance also has implications for nasal drug absorption. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in fast systemic drug absorption. Several approaches are discussed to increase the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. However, more experimental evidence is needed to support the conclusion that this improved absorption is caused by a longer residence time of the nasal drug formulation.

Cyclodextrins in nasal drug delivery.

Nasal drug delivery is an attractive approach for the systemic delivery of high potency drugs with a low oral bioavailability due to extensive gastrointestinal breakdown and high hepatic first-pass effect. For lipophilic drugs nasal delivery is possible if they can be dissolved in the dosage form. Peptide and protein drugs often have a low nasal bioavailability because of their large size and hydrophilicity, resulting in poor transport properties across the nasal mucosa. Cyclodextrins are used to improve the nasal absorption of these drugs by increasing their aqueous solubility and/or by enhancing their nasal absorption. With several cyclodextrins very efficient nasal drug absorption has been reported, but also large interspecies differences have been found. Studies concerning the safety of cyclodextrins in nasal drug formulations demonstrate the non-toxicity of the cyclodextrins and also clinical data show no adverse effects. Therefore, some cyclodextrins can be expected to become effective and safe excipients in nasal drug delivery.

The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.

ABSORPTION ENHANCING EFFECT OF CYCLODEXTRINS ON INTRANASALLY ADMINISTERED INSULIN IN RATS

The absorption enhancing effect of α-, β-, and γ-cyclodextrin (CD), dimethyl-β-cyclodextrin (DMβCD), and hydroxypropyl-β-cyclodextrin (HPβCD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DMβCD to the insulin solution resulted in a high bioavailability, 108.9 ± 36.4% (mean ± SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% α-CD gave rise to an insulin bioavailability of 27.7 ± 11.5% (mean ± SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the α-CD-containing solution as compared to the DMβCD preparation. The other CDs, HPβCD (5%), β-CD (1.8%), and γ-CD (5%), did not have significant effects on nasal insulin absorption. DMβCD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DMβCD is a potent enhancer of nasal insulin absorption in rats.

Absorption enhancers in nasal drug delivery: efficacy and safety

Abstract Efficacy and safety of nasal absorption enhancers depend on many different parameters, such as their influence on nasal epithelial membrane barriers, the enzymatic activities in the nasal cavity, and the mucociliary clearance. Large interspecies differences appear to exist in the nasal absorption of drugs. Nasal absorption enhancers, although very effective in some cases, differ substantially in efficacy and safety. For a number of enhancers like surfactants, bile salts and fusidate derivatives a good relationship (similarity in rank order) can be established between the morphological damage and the influence on the ciliary beat frequency (CBF) of nasal epithelial tissue, making CBF measurements a valuable tool in the search for safe nasal absorption enhancers.

Nasal Insulin Delivery with Dimethyl-β-Cyclodextrin as an Absorption Enhancer in Rabbits: Powder More Effective than Liquid Formulations

The nasal absorption of insulin using dimethyl-β-cyclodextrin (DMβCD) as an absorption enhancer in rabbits was studied. The nasal administration of insulin/DMβCD liquid formulations did not result in significant changes in serum insulin and blood glucose concentrations. In contrast, previous experiments in rats showed that the addition of DMβCD to the liquid nasal formulation resulted in an almost-complete insulin absorption, with a concomitant strong hy-poglycaemic response. Apparently, the effect of the cyclodextrin derivative on insulin absorption differs between animal species following nasal delivery of insulin/DMβCD solutions. On the other hand, nasal administration of the lyophilized insulin/DMβCD powder dosage form in rabbits resulted in increased serum insulin concentrations, and a maximum decrease in blood glucose of about 50%. The absolute bioavailability of the nasally administered insulin/DMβCD powder was 13 ± 4%, compared to 1 ± 1% for both an insulin/ DMβCD liquid and an insulin/lactose powder formulation. It is concluded that insulin powder formulations with DMβCD as an absorption enhancer are much more effective than liquid formulations.

NASAL ABSORPTION OF 17-BETA-ESTRADIOL AND PROGESTERONE FROM A DIMETHYL-CYCLODEXTRIN INCLUSION FORMULATION IN RATS

Abstract The nasal absorption of progesterone was studied in male Wistar rats, using dimethyl-β-cyclodextrin (DMsCD) as an absorption enhancer. DMsCD solubilizes steroids which are poorly water soluble by formation of inclusion complexes. Drug preparations with a molar ratio of steroid to DMsCD of 1:2 were used in these experiments. The systemic bioavailabilities of progesterone with DMsCD, and a progesterone suspension were compared. DMsCD increased the bioavailability of progesterone from 18 ± 13% for the suspension to 58 ± 16% for the inclusion complex. The nasal absorption of simultaneously administered estradiol and progesterone with DMsCD as absorption enhancer was also studied, in order to investigate the potential use of this combination in the treatment of postmenopausal disorders. The bioavailabilities of estradiol and progesterone were high, 59 ± 16 and 67 ± 23%, respectively. They were not significantly different from those achieved after separate administration. The combined preparation had only a mild effect on the ciliary beat frequency of human nasal adenoid tissue in vitro.

The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects

Abstract The bioavailability of intranasally administered insulin in humans is very low, because insulin is a high molecular weight and hydrophilic substance. In healthy volunteers and diabetes patients some absorption enhancers proved to be very effective, including the bile salts sodium deoxycholate and glycocholate, sodium taurodihydrofusidate (STDHF), laureth-9 and didecanoyl- l -α-phosphatidylcholine (DDPC). Several studies reported an insulin bioavailability in the order of 5–10%. However, some of these absorption enhancers may be harmful for nasal epithelial membranes, because in vitro studies showed morphological damage and severe inhibition of nasal ciliary movement. In vivo, laureth-9 and sodium deoxycholate are associated with nasal irritation, and STDHF leads to painful stinging and lacrimation. Cyclodextrins, especially dimethylated β-cyclodextrin (DMβCD), improve the nasal absorption of insulin in rats. This compound is relatively non-toxic, as has been shown in various studies concerning its effect on nasal epithelial tissue. Nasal administration of liquid insulin-DMβCD solution in rats results in an almost complete insulin absorption. In contrast, experiments in rabbits and man with the same formulation show no nasal insulin absorption. However, the nasal administration of a lyophilized insulin-DMβCD powder formulation results in a rapid nasal insulin absorption with a peak level reached after about 10 min. In diabetic patients the mean absolute bioavailability of insulin with this formulation was 5.1%. Only a slight initial itch was reported. Rapid absorption of intranasally administered insulin provides a pharmacokinetic profile similar to intravenous insulin and the postprandial endogenous insulin secretion by the pancreas. Therefore, its potential may be considered as an adjunct to subcutaneous treatment. Although the results so far with a few absorption enhancers are encouraging, the nasal insulin bioavailability is very low and the long-term safety of nasal insulin therapy has to be proven. Therefore, an intranasal insulin formulation is still far away from reaching the market.

Methylated ?-cyclodextrins are able to improve the nasal absorption of salmon calcitonin

The absorption enhancing effect of methylated β-cyclodextrins on the nasal absorption of salmon calcitonin (sCT) was studied in rats and rabbits. The nasal absorption of sCT following administration without additives was low in both species. The absorption in rats could be largely improved by coadministration of cyclodextrins as apparent from the effect on serum calcium concentrations. Trimethyl-β-cyclodextrin (TMβCD), at a concentration of 5% (w/v), was the least potent enhancer. Randomly methylated-β-cyclodextrin (RMβCD) and dimethyl-β-cyclodextrin (DMβCD), all at a concentration of 5% (w/v), were almost equally effective in decreasing serum calcium levels, and the hypocalcemic responses were similar to those of i.v. and s.c. injected sCT. Absorption enhancement was already achieved with 1% DMβCD added to the nasal formulations. In rabbits, only the effect of DMβCD on the nasal sCT absorption was investigated. A total serum calcium decrement in 4 hours of 9.4±3.9% (mean±SD) was observed following nasal administration of 12.6 IU/kg sCT with 5% DMβCD, comparable to that of i.v.-injected sCT. In conclusion, the methylated cyclodextrins DMβCD and RMβCD are suitable absorption enhancers for nasal sCT administration, which is expected to have a clinical impact on the therapy with calcitonin.

Absorption enhancers in nasal insulin delivery and their influence on nasal ciliary functioning

Abstract A major drawback in current insulin therapy is the lack of an efficient non-parenteral delivery system. Among other routes nasal administration of insulin has extensively been investigated as an alternative route for delivery. Insulin is poorly absorbed from the nasal mucosa, and it is necessary to use an absorption enhancing compound to facilitate its absorption. Many enhancers of widely differing chemical structure have been investigated in this respect. Recently, it was demonstrated that the cyclodextrin derivative, dimethyl-β-cyclodextrin (DMβCD), at a concentration of 5% (w/v) strongly improved nasal insulin absorption in rats. In the present study the effect of different concentrations of DMβCD on the absorption of intranasally administered insulin in rats was studied. Administration of 2 IU/kg insulin with 5% (w/v) DMβCD resulted in a bioavailability of approx. 100%. The minimal concentration of DMβCD required to improve the insulin absorption was 2% (w/v). Increasing the concentration to 3, 4, and 5% (w/v) resulted in a more pronounced insulin absorption, but the area under the serum concentration-time curve measured up to 1 h post administration was not significantly different from 2% DMβCD. DMβCD decreased the ciliary beat frequency of both chicken embryo trachea and human adenoid tissue in vitro. The effect was concentration dependent. For 2% DMβCD the ciliary activity was still 40% of the initial frequency at 60 min incubation in both ciliated tissue models. In conclusion, DMβCD is a potent enhancer of nasal insulin absorption in rats, already effective at concentrations that show a mild effect on in vitro ciliary movement.