Feasibility Assessment and Rapid Development of Oral Controlled

Chapter 8

Feasibility Assessment and Rapid Development of Oral Controlled Release Prototypes Avinash G. Thombre

Downloaded by UNIV OF MONTANA on February 24, 2016 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch008

Pfizer Inc., Central Research Division, Eastern Point Road, Groton, CT 06340

Several essential data and predictive methods are available to assess the feasibility of controlled release for a drug candidate in early development. These include physicochemical properties such as solubility and partition coefficient, and biopharmaceutical properties such as Caco-2 permeability. Feasibility assessment is important to aid in the selection of appropriate drug candidates that will benefit from novel drug-delivery approaches. The strategies to rapidly progress prototype oral controlled release dosage forms into clinical evaluation in the context of drug development in a large pharmaceutical company are discussed.

Advances in areas of combinatorial chemistry and high throughput screening (HTS) using receptor-site binding assays have made the drug discovery process increasingly efficient [1,2,3,4]. The efficiency has also been boosted by advances in the areas of bioinformatics, data mining, molecular modeling, and quantitative structure-activity relationships (QSAR). Thus, there are an unprecedented number of drug candidates in the development pipelines of major pharmaceutical companies. Although the emphasis is on orally absorbed compounds, not all drug candidates have the optimal solubility, permeability, and potency characteristics required for oral absorption. Furthermore, when one or more key physicochemical or biopharmaceutical property, e.g., the half-life of the drug candidate is not appropriate, then drug delivery approaches are frequently considered for these candidates as an alternative to the traditional discovery approach of seeking new drug candidates with an appropriate half-life. The drug delivery option is also increasingly being considered for early drug candidates to improve the efficacy and safety profiles including reduction of side-effects.

© 2000 American Chemical Society

In Controlled Drug Delivery; Park, Kinam, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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70 The consideration of the drug delivery or sustained release option for early drug candidates has resulted in the need to assess the feasibility of controlled release based on physicochemical and physiological measurements and to rapidly develop prototype dosage forms for clinical evaluation [5,6]. Frequently, physicochemical data such as solubility and partition coefficient are available for the drug candidate at an early stage of development as are some of the biopharmaceutical data such as Caco-2 permeability and bioavailability. In the absence of experimental data, predictive methods are available which can be used. For sustained release formulations, information on the regional absorption of the drug as a function of position in the gastrointestinal tract, and, in particular, colonic absorption is an important factor that may determine whether a long delivery duration corresponding to once-daily dosing is feasible or whether a shorter delivery duration with twicedaily dosing is the best option. Also, it is important to know the extent of first pass metabolism in relation to the rate of drug release as this may impact the bioavailability of the drug candidate from a sustained release dosage form. This paper presents an overview of the factors that should be considered as part of feasibility assessment and the strategies that can be employed to rapidly progress prototype controlled release dosage forms to clinical evaluation. The issues arising in the context of drug development in a large pharmaceutical company are discussed.

Discussion Key considerations in early drug candidate development The key considerations in the development of early drug candidates in a global pharmaceutical company and the strategy that can be employed are given in Table 1. In addition to the constraints of unknown dose strengths and unknown optimal release profiles, the quantity of bulk drug available for development is generally limited. Also, because of the team focus on the clinical testing of new hypotheses with molecules that exhibit a new pharmacology (i.e., first-in-class), the time available for development is short. The dosage form patent issues are less critical at tliis stage because the drug candidate is generally covered by a composition-of-matter patent. The recommended development strategy is as follows: • First, conduct a feasibility assessment of controlled release (CR) based on available physicochemical and biopharmaceutical data. The feasibility report should list the approaches considered and recommend the best approach to progress a CR formulation. It should provide a timeline and request that additional work be done to obtain key pieces of information that may not be available.


71 •

•

Second, conduct an experimental feasibility evaluation to confirm the "paper" feasibility analysis. The objective of the experimental evaluation is to determine the range of possible delivery durations and the doses that can be delivered. Third, develop prototype CR dosage forms for clinical evaluation. In the development of prototype formulations, the focus is on performance attributes such as the range of doses and release rates available, the chemical and physical stability of the dosage form, and, to a somewhat lesser extent, the manufacturability and scale-up of the formulation. The manufacturability considerations obviously become extremely important during the later stages of development.


Table 1. Key Considerations in Early Drug Candidate Development Consideration Pharmacology of the active agent is unknown. Unknown dose strengths and delivery duration.

Strategv Progress a dosage form rapidly into a human clinical study with prototypes if necessary. Choose technologies that allow dose flexibility.

Available quantity of bulk drug is small. Timing is critical.

Develop controlled release formulations in an efficient, optimized fashion. Consider prototypes.

Development process occurs in a team environment.

Manage team expectations. Educate what controlled release dosage forms can and cannot do.

Dosage form patent issues are less critical because the candidate molecule is generally patented.

Consider unpatented or "low tech" dosage forms. Remember that this can change at a later date.

Controlled Release Feasibility Assessment The feasibility of a controlled release dosage form of an early drug candidate can be considered at many different levels. The ability of the formulation to control the release rate of the drug with judicious choice of rate-controlling excipients and specific delivery technology or drug release device assures the in vitro feasibility. On the other hand, for in vivo feasibility, one has to consider drug absorption or biopharmaceutics, pharmacokinetic, and metabolism-related issues. From the standpoint of eventual commercialization of die formulation, factors such as the reliability and reproducibility of the dosage form, and the robustness of the manufacturing process as it is scaled up from the laboratory to pilot plant and then to production are critical issues. Finally, the pharmacological or clinical feasibility


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includes the medical rationale for controlled release and the pharmacodynamic aspects of the drug candidate.

Physicochemical Feasibility The physicochemical properties that have an impact of the feasibility of a controlled release formulation include molecular weight or size, partition coefficient, solubility, pKa, pH solubility profile, potential for solubilization, salt forms, polymorphs, particle size/distribution, and stability. In most cases, these properties directly influence whedier it is possible to obtain the desired in vitro release profile utilizing a given controlled release technology For example, the aqueous solubility of the drug will influence the rate of drug diffusion across a membrane barrier or a polymer gel. Thus, for commonly used hydrophilic matrix devices which release the drug by diffusion through a swollen polymer or by erosion of the matrix tablet, it may be difficult to obtain sustained release of a high dose over a prolonged duration for a highly water soluble drug. Osmotic systems that release the drug as a solution by a pumping mechanism may be limited by the availability of excipients with the proper solubility and osmotic properties. Such relationships between the excipients, delivery technology, and in vitro performance of the dosage form are generally well known to formulation scientists through the literature and from their own experiences. Most of the physicochemical property data required to assess the in vitro feasibility of controlled release is readily available for a given compound in the development pipeline. Generally, it is included in the Pharmaceutics Profile or equivalent report for the drug candidate. If a particular drug delivery technology requires a parameter that has not been measured, this can easily be accommodated. Experimental and computational approaches for estimating properties such as solubility and permeability have been extensively reviewed [7,5,9]. Biopharmaceutical Feasibility The biopharmaceutical and pharmacokinetic properties that have an impact of the feasibility of a controlled release formulation include gastrointestinal transit of the dosage form, food effect, intrinsic permeability, extent of first pass metabolism and oral bioavailability. The bioavailability and, hence, the biopharmaceutical feasibility is also dependent upon efflux mechanisms that may be relevant and the colonic absorption of the drug candidate. For example, if there is poor colonic drug absorption, it may not be feasible to have a long duration formulation for q.d. dosing without a significant loss of bioavailability, and, only a formulation with a short delivery duration suitable for b.i.d. dosing should be considered. The regional permeability of drugs in the rat jejunum, ileum, and colon have been determined for several drugs and attempts have been made to correlate the permeability values to physicochemical properties such as molecular weight and octanol-water partition coefficient [10,11,12,13], A literature survey also reveals that


73 the regional absorption of several drugs has been studied in humans by intubation methods (see Fig. 1) although formulations and protocols vary a lot between studies.


Flux measurements through Caco-2 monolayers have been used to predict absorption in humans [14,15,16,17,18] and there is a good understanding of the circumstances under which the predictions are less accurate. Many companies routinely determine Caco-2 permeability of drug candidates. Therefore, it is worthwhile to compile available data and correlate with performance of controlled release dosage forms. Depending on the available database and the correlation, "rules of thumb" can be developed for selection of controlled release candidates. The metabolism of the drug, particularly, its first pass extraction by hepatic and intestinal enzymes will also influence bioavailability and, hence, the feasibility of controlled release. Several in vitro and in vivo models are available to determine whether a given drug candidate is a substrate for cytochrome Ρ 450 oxidation. The role of isoenzymes CYP3A4 and CYP2C9 has also been recognized. [19]

Figure 1. Regional absorption of selected drugs in the human gastrointestinal tract


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If pharmacokinetic data from an immediate release dosage form is available, the plasma concentrations following administration of various controlled release dosage forms can be simulated. Based on these simulations, it may be possible to select the recommended drug delivery profile. For example, a mathematical model using STELLA® has been used to calculate drug absorption from the duodenum, jejunum, ileum, and colon. [20] Other models that take into account pH-dependent dissolution as well as GI transit times and regional absorption are also available. [21,22] Compared to the physicochemical feasibility, there is a somewhat greater uncertainty in determining the biopharmaceutical or in vivo feasibility. This is because the in vitro - in vivo correlation may be complex for many dosage forms and because of the added complexities of an in vivo situation compared to a well characterized in vitro system.

Technological Feasibility Selection of the drug delivery platform and the technology often depends on the physicochemical and biopharmaceutical properties of the drug candidate as well as the design parameters of the dose, delivery duration, and release profile. In addition to the drug and design parameters, prior experience with a technology and availability of in-house equipment and expertise may be important, as are financial constraints such as the need for the purchase of capital equipment for production. Depending on the in-house expertise and equipment availability, it may be necessary to consider an external collaboration with a drug delivery company. As stated earlier, the patent issues for early drug candidates may not be as important a factor as are reliability and reproducibility of dosage form performance, i.e., no dose-dumping or incomplete release, a robust manufacturing process, scaleup experience, and speed of development. Several oral drug delivery technologies are now available including those based on diffusion and erosion such as hydrophilic matrix tablets and osmotic systems such as Alza's OROS™ and GITS™. Pharmacological Feasibility The rationale for controlled release is generally based on an assumption. For example, a slow drug input rate will result in reducing the blood level fluctuations, which may be expected to decrease the side effects of a drug. However, it is possible that the peaks are pharmacologically important indicating the need for pulsatile delivery. Also, in certain cases, sustained release can cause down regulation or decrease in the number of receptors resulting from over-stimulation. In these cases, a controlled release dosage form may not be feasible. The continuous blood level of a hormone such as a corticosteroid might supress adrenocorticotropic hormone (ACTH) release from the pituitary gland, resulting in atrophy of the adrenal gland [23]. In most cases, such effects are difficult to predict a priori for early drug candidates and they become known only after extensive clinical testing.



75 Feasibility Assessment Report The Feasibility Assessment Report is a "paper" study to assess the feasibility of controlled release of a particular drug candidate. Ideally it is based on actual data, however, depending on when such a report is issued, it may have to rely on best guess estimates and institutional experience with similar compounds. The objectives of the feasibility report are to manage expectations of the candidate management team and educate its members on the pros and cons controlled release dosage forms. In addition to a discussion of the relevant physicochemical and biopharmaceutical properties that impact the feasibility of controlled release, the feasibility assessment should also include an estimate of the degree of difficulty and probability of success of the recommended approach. This is important information for line management for analyzing whedier this represents the best use of available resources. Furthermore, because die development generally occurs in a team environment, the feasibility assessment report should also address the quantity of bulk active that will be required and the timing for the various milestones. Information regarding the approaches considered versus those recommended is valuable to the formulator, as they will provide good starling points for die formulation development project. Depending on the stage of development of the compound, some key pieces of data may not be available when the controlled release feasibility assessment is performed. Therefore, the report should also include a recommended experimental plan. In particular, the experimental plan should address areas such as colonic intubation to determine whether a long duration sustained release formulation would be feasible. The major portion of the feasibility assessment report will provide physicochemical and biopharmaceutical data on the candidate and interpretation of these data in light of die performance of a controlled release formulation. Thus, for example, if die predicted (or actual) colonic permeability is poor, it may not be feasible to consider a long delivery duration (once-daily) for die compound and resources should be focused on a shorter delivery duration formulation that is likely to be dosed twice-daily. The feasibility assessment report should also include the biopharmaceutics classification system (BCS) for the candidate drugs. In this system, drugs are divided into four classes depending on their solubility and permeability [24,25].

Rapid Development of Controlled Release Prototypes The next step in the development of a drug candidate is to experimentally verify die controlled release feasibility assessment and to rapidly develop prototype formulations for clinical studies. In this phase, the important issues are speed (to shorten development time) and the quantity of bulk active required (to minimize resource/costs). Having prototype dosage forms for clinical evaluation is particularly


76 important in the case of compounds that are "first-in-class" or "best-in-class" because of the time pressure to move forward rapidly with such candidates.


Typical experiments diat are conducted in tiiis phase include the following: (a) an excipient compatibility screen; (b) the in vitro and in vivo (animal models such as dog or monkey) performance studies widi prototype formulations; (c) accelerated stability with the prototype formulations; and (d) a determination of scale-up issues and ease of manufacture. Based on the results of this experimentation, the range of feasible doses and delivery durations are determined. Also, the components of the formulations are identified although Uieir quantity in the formulations may change somewhat later on during process development. A worthwhile investment that can be made to reduce prototype development timelines is research geared towards developing a generic controlled release technology Uiat is broadly applicable to a variety of potential drugs with a range of physicochemical properties. If such a technology were available for the majority of the early drug candidates under consideration, the few drugs that required other technologies could be easily handled.

Conclusions The recommended strategy for the development of early drug candidates consists of assessing the feasibility of oral controlled release dosage forms followed by rapid development of prototype formulations for clinical testing. The state of the art for predicting whether the desired dose and delivery duration are feasible allows for a reliable assessment. Several tools are also available to determine the in vivo feasibility based upon biopharmaceutical factors. However, the data available in the literature needs to be analyzed further to ideally determine a set of rules that will help predict regional drug absorption for controlled release feasibility. Rapid development of oral controlled release prototypes for clinical testing is challenging in the case of early candidates given the various constraints imposed on development, including short timelines.

Acknowledgments The author would like to thank his colleagues in the Oral Controlled Release and Biopharmaceutics group for their contributions and useful discussions and Hope Carter for compiling the intubation data.


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References 1. Lipper, R. Α., Modem Drug Discovery, 1999, Jan/Feb, 55-60. 2. Lensey, M. S. Today's Chemist at Work, 1999, pp 36-43. 3. Smith, P. Adv. Drug Delivery Rev., 1997, 23,1. 4. See PhRMA Facts on http://www.pharma.org/facts/ 5. Lipinski, C. Α.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev., 1997 23, 3-25. 6. Stewart, Β. H.; Chan, O. H.; Jezyk, N.; Fleisher, D. Adv. Drug Delivery Rev., 1997 23, 27-45. 7. Yalkowshy, S. H.; Banerjee, S. Aqueous solubility; Marcel Dekker: New York, 1992. 8. Wessel, M . D.; Jurs, P. C.; Tolan, J. W.; Muskal, S. M.; J. Com. Inf. Comput. Sci., 1998, 38, 726-735. 9. Meylan, W. M.; Howard, P. H.; Boethling, R, S.; Environ. Tox. Chem., 1996 15, 100-106. 10. Ungell, A.-L.; Bergstrand, N. S.; Sjoberg, Α.; Lennernas, H. J. Pharm. Sci., 1998 87, 360-366. 11. Fagerholm, U.; Lindahl, Α.; Lennernas, H. J. Pharm. Pharmacol., 1997, 49, 687-690. 12. Lennernas, H. J. Pharm. Pharmacol., 1997,49,627-638. 13. Lennernas, H.; Lee, I.-D.; Fagerholm, U.; Amidon, G. L. J.Pharm.Pharmacol., 1997,49, 682-686. 14. Rubas W; Cromwell, Μ. Ε. M.; Adv. Drug Delivery Rev., 1997 23,157-162. 15. Rubas, W.; Cromwell M . E. M . ; Shahrokh, Z.; Villagran, J.; Nguyen, T.-N.; Wellton, M.; Nguyen, T.-H.; Mrsny, R. J. J. Pharm. Sci., 1996, 85, 165-169. 16. Yee, S. Pharm. Res., 1997, 14, 763-766. 17. Irvine, J. D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J. W.; Selick, H. E.; Grove, J. R. J. Pharm. Sci., 1999, 88 28-33. 18. Gan, L.-S. L.; Thakker, D. R. Adv. Drug Delivery Rev., 1997, 23, 77-98. 19. Thummel, K. E.; Kunze, K. L.; Shen, D. D. Adv. Drug Delivery Rev., 1997, 27, 99-127. 20. Grass, G. M . Adv. Drug Delivery Rev., 1997, 23, 199-219. 21. Yu, L. X.; Lipka, E.; Crison, J. R.; Amidon, G. L. Adv. Drug Delivery Rev., 1996, 19, 359-376. 22. GastroPlus™ Software from Simulations Plus, Inc., Lancaster, CA. 23. Shargel, L.; Yu, A.B.C. Applied Biopharmaceutics and Pharmacokinetics, Appleton & Lange, CT, 1993, p.248. 24. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. Pharm. Res., 1995, 12, 413-420. 25. Waterbeemd, H. Eur. J. Pharm.Sci.,1998, 7, 1-3.


Feasibility Assessment and Rapid Development of Oral Controlled

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