In Vivo Assessment

Animals which have been used to obtain in vivo data on nasal drug absorption and pharmacokinetics include rats (100), rabbits (101) and sheep (58,102). The sheep has been used for nasal absorption studies as it has a nasal surface area per kilogram body weight that is similar to that of humans compared to other animals. For example, nasal mucosal surface area per kilogram of bodyweight (cm2/Kg) varies between 41.6 for rats, 22.0

100-,

90

80-

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70

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60

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50

H

40

T

30

Z

20

10

Time in minutes

Figure 4 In vitro release of the lyophilized nasal insert (♦) compared to conventional liquid (A) and powder (x) formulations (broken lines). Source: From Ref. 107.

for dogs, 20.3 for rabbits, 2.5 for humans, and 8.2 for sheep (103,104). It has been reported that nasal bioavailability results obtained in the sheep model closely mirror those obtained in man, and the sheep offers a reliable model for nasal absorption of all types of drug formulation (8). It has also been shown that when assessed using gamma scintigraphy, the clearance rate of a bioadhesive chitosan system in sheep was comparable with that found in humans, making the sheep a good predictive model for humans (105).

Sheep were therefore chosen as a pre-clinical model to assess nasal absorption from the lyophilized nasal insert formulation. Nicotine hydrogen tartrate, known to be readily absorbed from the nasal mucosa in sheep (106), was used as a model compound, and the lyophilized nasal insert formulation was compared with nasally administered conventional nicotine powder and solution formulations (99).

The mean plasma profiles obtained and relevant pharmacokinetic data are shown in Figure 5 and Table 2, respectively. The mean profile for the nasal insert shows a more gradual rise in plasma nicotine in comparison with the conventional nasal formulations, with significant levels sustained over approximately 2h, followed by a gradual decrease in plasma levels at a slower rate than for the other nasal preparations. The nasal insert formulation gave a relative bioavailability of 83.4%, compared to 51.5% and 27.2% for the nasal spray and powder respectively, a promising increase over the conventional nasal formulations. The extended absorptive phase of the nasal insert suggests prolonged nasal residence of the formulation, and continued absorption of nicotine suggests that the lyophilized insert remains in the nasal cavity releasing nicotine for approximately 2-3 h. In vitro

Time in minutes

Figure 5 Mean plasma concentration time profiles of different formulations following intranasal and intravenous administration of 4 and 1 mg respectively of nicotine in sheep. (O) IV; (♦) nasal insert; (A) nasal spray; (x) nasal powder. Source: From Ref. 107.

Time in minutes

Figure 5 Mean plasma concentration time profiles of different formulations following intranasal and intravenous administration of 4 and 1 mg respectively of nicotine in sheep. (O) IV; (♦) nasal insert; (A) nasal spray; (x) nasal powder. Source: From Ref. 107.

Table 2 Pharmacokinetic Parameters (mean values — s.d.) Following Intranasal (4mg) and Intravenous (1mg) Administration of Nicotine in Sheep

Formulation

Tmax (min)

Cmax (ng/ml)

AUC (ng.h/ml)

Frel(%)

IV

2.80 -1.40

9.4 - 5.8

16.3 - 32.25

100

Lyophilized insert

39.4 - 33.0

27.6 - 23.4

54.4-69.4

83.4

Spray

21.0 -13.4

45.6 - 24.0

33.6 - 32.7

51.5

Powder

20.0-7.7

36.4-19.4

17.7 - 6.40

27.2

Abbreviation: AUC, area under the curve. Source: From Ref. 107.

Abbreviation: AUC, area under the curve. Source: From Ref. 107.

observations show that a viscous bioadhesive gel is formed on hydration of the dosage form. If this gel is formed on administration of the insert to the sheep nasal cavity, then it would be expected to resist the rapid mucociliary clearance rate by adhering to the mucosa.

The literature reports the preparation of many other formulations designed to achieve bioadhesion for the enhancement of nasal absorption, with examples ranging from microspheres composed from various materials (8,102), resin complexes (106), nanoparticles (7), chitosans (105), and polycarbophil-cysteine conjugates for covalent bonding (68). However the major advantage of the formulation design of the nasal insert is the simple to administer, unit dosing that dispenses with the requirement for complex dosing devices. Lyophilization is a low temperature process and causes minimum damage and loss of activity of delicate heat labile materials, and further more may be used to achieve increased stability in comparison with liquid formulations. Owing to the wide range of pharmaceutical polymers available on the market, it is likely that for the majority of compounds and applications a formulation solution can be reached using the lyophilized nasal insert technology.

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