ISSUES RELATED TO DEVELOPING AN IVIVC FOR MODIFIED RELEASE PARENTAL DRUG DELIVERY SYSTEMS

3. ISSUES RELATED TO DEVELOPING AN IVIVC FOR MODIFIED RELEASE PARENTAL DRUG DELIVERY SYSTEMS

Although there are many modified release parental drug delivery systems, this chapter is unable to discuss the issues associated with each delivery system. Instead, this chapter will focus on some of the general IVIVC issues associated with some of these delivery systems.

3.1. Study Design The study design for modified release parenteral drug

delivery systems should be similar to the design for oral

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Figure 4 Output from the PDx-IVIVC software plot on plasma concentration vs. time for a formulation used for external prediction (CRB). Both observed data and the IVIVC model predicted plasma curve are presented.

Figure 5 Output from the PDx-IVIVC software showing the external prediction from Fig. 4. Observed and predicted C max and AUC are presented.

168 Young et al.

formulations, if logistically possible. Typically, two or more formulations with different release rates and formulation characteristics are administered to normal human volun- teers. Patients may be used in the study if administration of the drug to normal volunteers is unsafe or the patient population significantly handles the drug and =or delivery sys- tem differently. The active drug in solution (defined here as the reference formulation) is also administered i.v. or through the same route of administration as the modified release formulation in order to perform a Level A IVIVC. Although

a complete crossover study design is preferred, the logistical problems associated with running such a study may be diffi- cult given the time-course of in vivo delivery (e.g., implant delivery over a number of months). If the complete crossover study design is not possible, incomplete block and parallel designs have also been used. Regardless of the design, every subject should receive the reference formulation as the first arm of the study in order to define the unit impulse response and to ensure that a deconvolution can be performed even if a subject drops out after receiving only one of three modified release formulations.

3.2. In Vitro Release System Although IVR systems are well established for all types of oral

formulations, standard IVR systems for modified release parenterals do not exist. The literature reports a range of systems from destructive test tube systems to the USP 4 apparatus. Although the IVR system is critical to the IVIVC modeling, this chapter will concentrate on the modeling aspects and leave any further discussion of the IVR systems to other chapters.

3.3. IVIVC Using Time Scaling and Shifting With some of the modified release parenteral dosage forms,

IVR occurs over hours or days while complete in vivo release may take days, weeks, or months. The linear IVIVC models developed in the 1970s and 1980s could not deal with this time difference between the two releases. Over the last

Modified Release Injectable Drug Delivery Systems 169

decade, time-variant models (1,10) have been introduced and used to deal with the differences in the time course of release.

A model that has provided an enormous amount of flexibility in its ability to fit time-variant and linear time-invariant IVIVC data has been the model described by Gillespie (10) and others (9,11). Both time shifting and time scaling can

be described by the model, which allows the model to fit a wide variety of in vitro–in vivo profiles. The model used to describe both time shifting and scaling is presented in the following equation:

( 0 t <0 x vivo ðtÞ ¼

u ¼ T for t > T where x vivo (t) is the cumulative amount absorbed or released

a 1 þa 2 x vitro

1 þb 2 u Þ

in vivo, x vitro the cumulative amount released in vitro, a 1 the intercept for a linear IVIVC, a 2 the slope for a linear IVIVC, b 1 the coefficient representing a time shift between in vivo and in vitro, and b 2 is the coefficient representing a time scaling between in vitro and in vivo. If b 1

b 2 ¼ 0, the IVIVC is the linear ‘‘point-to-point’’ model that has been reported in the literature over the years. Predictable models have been developed using this approach for modified oral and parenteral drug delivery sys- tems. An example of the impact of these type of models can

be illustrated using Fig. 6 . The in vivo vs. IVR of four formula- tions are presented in Fig. 6. Two of the formulations (K1, K2) have faster in vivo release than in vitro while two of the for- mulations have faster IVR (K3, K4). It would be impossible to develop one model to describe all four formulations using a conventional linear time-invariant model. However, using

Eq. (2) to describe the shift and scaling, b 1 and b 2 can be estimated to obtain a single time-variant model for all four formulations. The %PE of C max and AUC for each formulation was <15% and the average %PE was <10% for both C max and AUC. These %PE met the FDA criteria for internal predict- ability.

170 Young et al.

Figure 6 Cumulative percentage absorbed vs. cumulative percen- tage dissolved with no time shifting.

3.4. Plasma Concentration Profiles There are two types of profiles ( Fig. 7 ) that have been seen

with modified release parenteral delivery systems: Type 1 with one peak and continuous delivery (Fig. 7, Product A), and Type 2 with an initial peak and a second peak at a later time (Fig. 7, Product B). The ideal approach to IVIVC model- ing is to develop one IVIVC model for the total plasma profile. This approach has been used to develop an IVIVC for Type 1 plasma profiles but has been less successful for Type 2 pro- files. Developing a single model to describe the in vitro–in vivo relationship for Type 1 formulations has been success- fully accomplished for multiple formulations (i.e., represent- ing an IVIVC) and for a single formulation. To illustrate a slightly different approach in developing a model between in vitro dissolution and the entire in vivo relationship for the

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Figure 7 Plot of plasma concentration vs. time after two different microsphere products were administered, Product A with an early peak and prolonged continued release and Product B with an initial release and a second release.

Type 1 curve, Fig. 8 shows the successful correlation between the percent of total AUC at each time point and the percent released in vitro for a microsphere drug delivery system (12). Although this example does not represent a true IVIVC since only one formulation was used, it illustrates how the entire in vivo curve can be related to the in vitro curve. Other approaches (e.g., two-stage approach and compartmental modeling) have also used to develop an IVIVC model for multiple formulations but have not been reported in the literature (13).

Investigators have attempted to develop a single IVIVC model for Type 2 plasma profiles using two-stage deconvolu- tion and compartmental modeling approaches (14). In order to develop a single model, the IVR system must be able to cor- relate to the very fast absorption rate of the first plasma peak

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Figure 8 Comparison of in vitro leuprolide release profile with in vivo release profile, the latter plotted as cumulative area under serum peptide curve—normalized as percent of the total area (large panel) and in vitro–in vivo correlation plot (small panel).

and the slower absorption rate of the second plasma peak. Figure 9 illustrates what type of in vitro curve is required in order to develop an IVIVC for the Type 2 dual peak plasma profile (13). Although a significant amount of time has been spent in trying to develop an IVIVC and IVR system for formu- lations with a Type 2 profile, at the present time an example of this type of in vitro system or a validated IVIVC model describ- ing both plasma peaks has not been reported in the literature.

For Type 2 plasma profiles, investigators have also attempted to develop an IVIVC for different parts of the plasma profile (14). This approach has also been difficult because the first peak and second peak represent different release mechanisms from the dosage form and the magnitude of the second peak appears to be related to the magnitude of

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Figure 9 Plot % released in vitro vs. time that is required to develop an IVIVC with Type 2, two peak plasma concentration profiles ( Fig. 7 , Product B).

the first peak. Investigators have attempted to use one IVR system as well as multiple IVR systems: the accelerated release IVR systems (e.g., higher temperature) and more phy- siologically relevant conditions. Although acceptable IVIVC models have been developed for formulation development work, IVIVC models that meet the strict predictability criteria of the FDA IVIVC Guidance have not been reported for the complete Type 2 plasma profile.

The major problem appears to be developing the relation- ship between the first peak and the IVR profiles. The in vitro profile in this situation represents the complete release of drug from the microsphere over time rather than the release of drug associated with the surface of the microsphere, usually the major source of drug for the first plasma peak.

Using time-invariant models, predictable IVIVC models have been successfully developed for the second peak. Table 1 illustrates how a time-variant model successfully related the IVR over 7 days to the in vivo release of a second peak that

174 Young et al. Table 1 Internal Validation of an IVIVC Model Relating the

Second Peak to In Vitro Release for Three Microsphere Formulations (A, B, C) that have Type 2 plasma Profiles (MAPPE is the Mean Absolute Percent Prediction Error of All Three Formulations)

Treatment

C max j%PEj

AUC j%PEj A 11.8 6.7

B 9.5 13.4 C 2.1 5.3 MAPPE

occurred 20–50 days after administration. The IVIVC model met the strict predictability criteria of the FDA IVIVC Guidance for both the C max and AUC of the second peak (14).

4. CONCLUSION The FDA IVIVC Guidance has described the basic approach

that all scientists have used to develop an IVIVC for all deliv- ery systems (1). This chapter has not presented all aspects of IVIVC but has provided some of the specific aspects of IVIVC modeling that are relevant to modified release parenteral drug delivery systems. Given the number of different parent- eral delivery systems, it is not possible to discuss or present examples for each system but the basic principles presented here apply to all parenteral delivery systems. In order to apply IVIVC models throughout the development and regula- tory cycle for all parenteral products, further IVIVC research is still required in order to develop appropriate in vitro systems as well as modeling the more complex relationship between the in vitro and in vivo processes.

ACKNOWLEDGMENTS The authors would like to thank Wendy Guy for her assis-

tance in preparing the chapter.

Modified Release Injectable Drug Delivery Systems 175

REFERENCES 1. Food & Drug Administration Guidance for Industry. Extended

Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro =In Vivo Correlations, CDER 09, 1997.

2. Food & Drug Administration Guidance for Industry. SUPAC- MR: Modified Release Solid Oral Dosage Forms, CDER 09, 1997.

3. Food & Drug Administration Guidance for Industry. SUPAC- IR: immediate Release Solid Oral Dosage Forms, CDER 10, 1997.

4. Food & Drug Administration Guidance for Industry. Bioavail- ability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations, CDER 10, 2000.

5. Burgess DJ, Hussain AS, Ingallinera TS, Chen M. Assuring quality and performance of sustained and controlled release parenterals. AAPSPharmSci 2002; 4(2):7 ( http: ==www.aaps pharmsci.org = ).

6. Burgess DJ, Crommelin DJA, Hussain AS, Chen M-L. Assuring quality and performance of sustained and controlled release parenterals: EUFEPS Workshop Report. AAPSPharmSci 2004; 6(1):11. Available at http: ==www.aapspharmsci.org= .

7. Young D, Devane JG, Butler J, eds. Advances in Experimental Medicine and Biology—Volume 23: In Vitro–In Vivo Correla- tions. New York: Plenum Press, 1997.

8. PDx-IVIVC 2 Tools for In Vitro–In Vivo Correlation; PDx by GloboMax.

9. Bigora S, Farrell C, Shepard T, Young D. IVIVC Applied Work- shop Manual – Principles and Hands-on Applications in Phar- maceutical Development; PDx by GloboMax.

10. Gillespie WR. Advances in Experimental Medicine and Biology—Volume 23: In Vitro–In Vivo Correlations; Chapter

5, Convolution-Based Approaches for In Vivo–In Vitro Correla- tion Modeling. New York: Plenum Press, 1997.

11. Devane J. Advances in Experimental Medicine and Biology— Volume 23: In Vitro–In Vivo Correlations; Chapter 23, Impact

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1997. 12. Woo BH, Kostanski JW, Gebrekidan S, Dani B, Thanoo BC,

DeLuca P. Preparation, characterization and in vivo evalua- tion of 120-day Ply (d,l-lactide) leuprolide microspheres. J Control Release 2001; 75:307–315.

13. Young D. Personal Communication, 2002. 14. Young D. Personal Communication, 2001.

SECTION II: DOSAGE FORMS

Coarse Suspensions: Design and Manufacturing

STEVEN L. NAIL and MARY P. STICKELMEYER Lilly Research Labs, Lilly Corporate Center,

Indianapolis, Indiana, U.S.A.