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25% and 20% respectively, while estimates of the percentage of the dose reaching the lung were 12.0% and 8.8% respectively.

Many other tests could have been included to demonstrate the value of in vitro tests in quality control. Some, such as multistage impingers for aerosols, can be predictive of in vivo behaviour, or at least give an assurance of consistency of effect. An interesting test system for evaluating inhaled nasal delivery systems (Fig. 12.18) combines a physical device with cultured cells so that the interaction of microparticles with living cells can be studied directly. As new delivery systems appear, new tests will be required - as will ingenuity.

Figure 12.17 Impinger apparatus A, showing dimensions (mm) in order to ensure indenticality between equipment used in quality control.

Source: British Pharmacopoeia.

(similar to human dimensions). The upper impinger has a cut off at a particle size of ~6.4 ^m, with the first impact surface known as stage 1 and the last impact surface being in the lower impinger (stage 2), which is considered to be the respirable fraction.

Apparatus B (not illustrated) is made of metal and can be engineered to finer tolerances than the glass apparatus A; it is considered to be a superior apparatus for quality control testing and product release.

Typical of the result achieved with Apparatus B are those for two Intal formulations, Intal 1 and Intal 5. Intal 1 delivers 1 mg per shot and Intal 5 delivers 5 mg per shot. In vitro the respirable fraction was found to be a

Air-interfaced cells on Transwell insert

Microspheres deposited

Basolateral (receiver) chamber

Microspheres deposited

Figure 12.18 An in vitro technique for evaluating inhaled nasal delivery systems in which particles/microspheres are deposited on a cell monolayer. Drug that is absorbed through the monolayer can be arranged in the basolateral chamber.

Reproduced from B. Forbes, S. Lim, G. P. Martin and M. B. Brown, STP Pharma Sci, 12, 75-79 (2002).

In this chapter:

• We have seen a selection of tests which can be conducted to measure the key parameters of a variety of formulations.

• These tests are not necessarily predictive of performance in vivo, but can be used to ensure batch-to-batch consistency.

• When good in vitro-in vivo correlations have been established, laboratory based tests can be predictive of performance.

• Release tests can be applied to rectal and transdermal products by adapting methods used for oral products, altering the receptor phase to mimic the medium in which the formulation resides in vivo.

• Key parameters are different for different routes of delivery and different formulations: particle size is a key factor in inhalation products and in topical preparations where the drug is dispersed rather than dissolved in the vehicle.

• Adhesivity of oral dosage forms may be a factor in determining their efficacy (buccal delivery) or in causing adverse events (as in oesophageal injury); adhesion of transdermal patches to the skin is clearly important.

• The rheological properties of topical preparations and formulations for nasal delivery are important, and a key factor is the syringeability of injectables.

Finally, no laboratory test can mimic the complexity of the biological environment and the dynamic factors involved in drug absorption in patients, but well-designed in vitro experiments can elucidate whether different formulations are comparable in terms of their key features. At best, in vitro tests are predictors of quality of performance in the patient; at the least they can ensure consistency of response; where, for example, chemical assays of drug content in generic products may give identical results, release studies may show differences due to drug-excipient interactions which may be of significance.

References

1. W. A. Hanson. Handbook of Dissolution Testing, 2nd edn, Aster Publishing Group, Eugene, OR, 1991

2. G. L. Mattock and I. J. McGilveray. Comparison of bioavailabilities and dissolution characteristics of commercial tablet formulations of sulfamethizole. J. Pharm. Sci., 61, 746-9 (1972)

3. W. A. Ritschel and M. Banarer. Correlation between in vitro release of proxyphylline from suppositories and in vivo data obtained from cumulative urinary excretion studies. Arzneim Forsch., 23, 1031-5 (1973)

4. J. B. Taylor and D. E. Simpkins. Aminophylline suppositories: in vitro dissolution and bioavailability in man. Pharm. J., 227, 601-3 (1981)

5. J. A. Ostrenga, J. Haleblian, B. Poulsen, et al. Vehicle design for a topical steroid, fluocinolide. J. Invest. Dermatol., 56, 392-9 (1971)

6. H. Yoshida, S. Tamura, T. Toyoda, et al. In vitro release of Tacrolimus from Tacrolimus ointment and its speculated mechanism. Int. J. Pharm., 270, 55-64 (2004).

7. M. Corbo, T. W. Schultz, et al. Pharm Tech. Int., 17(9), 112 (1993)

8. M. Wolff, G. Cordes and V. Luckow. In vitro and in vivo-release of nitroglycerin from a new transdermal therapeutic system. Pharm.Res., 1, 23-9

9. M. Marvola, K. Vahervuo, A. Sothmann, et al. Development of a method for study of the tendency of drug products to adhere to the esophagus. J. Pharm. Sci., 71, 975-7 (1982)

10. H. Al-Dujaili, A. T. Florence and E. G. Salole. In vitro assessment of the adhesiveness of film-coated tablets. Int. J. Pharm., 34, 67-74 (1986)

11. M. Marvola, M. Rajaniemi, E. Marttila, et al. Effect of dosage form and formulation factors on the adherence of drugs to the esophagus. J. Pharm. Sci., 72, 1034-6 (1983)

12. H. Al-Dujaili, A. T. Florence and E. G. Salole. The adhesiveness of proprietary tablets and capsules to porcine esophageal tissue. Int. J. Pharm., 34, 75-9

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