Controlled-Release Oral Delivery Systems - ACS Symposium Series

Chapter 2

Controlled-Release Oral Delivery Systems Joseph A . Fix1, Kazuhiro Sako2, and Toyohiro Sawada

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1Yamanouchi Shaklee Pharma, 1050 Arastradero Road, Palo Alto, CA 94304 Novel Pharmaceutical Laboratories, Yamanouchi Pharmaceutical Company, Ltd., 180 Ozumi, Yaizu-shi, Shizuoka-ken 425, Japan 2

Downloaded by UNIV OF SYDNEY on May 3, 2015 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch002

The advantages of controlled-release oral delivery systems, particularly those achieving once-a-day efficacy, have long been recognized. Outcomes can include better therapeutic efficacy via improved control of plasma drug levels and reduced peak-associated side effects. Oral controlled-release dosage forms can also afford advantages in drug stability, patient compliance, and reduced total drug exposure. Applications for once-a-day administration must balance release kinetics, dosage form and in vivo drug stability, absorption kinetics and variable physiologic parameters such as g.i. transit, enzymes, pH, motility and fluid level. In spite of major efforts to develop once-a-day oral dosage forms, relatively few products have been introduced. In many cases, once daily therapeutic efficacy cannot be easily achieved due to poor control of drug release or poor drug absorption in the colon. Food effects can also introduce significant variability. O C A S is an oral controlled absorption gel matrix system that exhibits pH-independent, pseudo-zero order drug release with minimal food effects. The rapid hydration and formation of a rigid gel leads to effective drug release in the colon. Future advances in once-a-day oral delivery systems must address improving drug absorption in the colon and may extend applications of controlled-release technology to biomolecules.

Controlled-release oral delivery systems have been an integral part of pharmaceutical technology for several decades (I). Within the pharmaceutical industry, delivery systems and formulations have been developed which can provide

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

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a wide variety of drug release profiles, including systems designed for immediate, continuous, pulsatile, and delayed administration (2-4). For most traditional small molecule drug candidates, delivery systems can be designed which will release the candidate drug in the desired profile. In recent years, much of the focus in oral controlled-release technology has been directed toward site specific delivery in the gastrointestinal tract, chronobiology as related to oral delivery systems (5), and the development of technology to control the release and delivery of non-traditional drug candidates, i.e. peptides and proteins. Included in these various technologies are osmotically-controlled devices, matrix tablets, hydrogels, polymeric systems, multiparticulates, and erosion systems regulated by geometric design. Figure 1 depicts illustrative plasma profiles that can be achieved with existing oral technology.

In spite of the availability of numerous technologies to achieve up to 24 hour controlled drug release, relatively few products that are efficacious for once-a-day dosing have reached the market. Table I, although not inclusive, lists some of the products currently available where the recommended dose and administration guidelines indicate once-a-day efficacy. In some cases, controlled-release dosage forms that provide up to 24 hour in vitro drug release do not achieve the same release profile in vivo due to influences from the milieu of the gastrointestinal tract. Also, poor colonic drug absorption can effectively limit the once daily efficacy of dosage forms that otherwise afford 24 hour drug release.

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

16 Table I: Representative Once-a-Day O r a l Products Indocin SR® (Merck) DynaCirc CR® (Novartis) Toprol XL® (Astra U S A ) Adalat CC® (Bayer) Prelu-2® (Boehringer Ingleheim) Cardizem CD® (Hoechst Marion Roussel) Theo-Dur® (Key)


SOURCE: Physician's Desk Reference, 5 2 Co., Inc., Montvale, NJ

Verelan® (Lederle) Glucotrol XL® (Pfizer) Calan SR® (Searle) Theo-24® (UCB Pharma) Dilacor XR® (Watson) Lodine XL® (Wyeth Ayerst)

nd

Edition, 1998, Medical Economics

Physiologic Influences Once-a-day controlled release dosage forms are subject to numerous physiologic influences in the gastrointestinal tract, including pH, bile salts, fluidity, motility, enzyme activity, and absorption windows. Ideally, a once-a-day dosage form should function independent of variations in the parameters shown in Figure 2.

Figure 2: Quantitative trend analysis of gastrointestinal parameters that effect the performance of once-a-day dosage forms. During transit from stomach to lower colon, the p H exposure can range from p H 1.0 to p H 7.5 or greater. Bile salts and degradative enzymes are present in relatively high concentrations in the small intestine. Fluid content and gastrointestinal motility


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are high in the upper intestine and diminish in a distal direction. In order to reliably control drug release in an extended release product, the formulation would ideally function independent of these changing variables. Additionally, the decrease in fluid content in the colon, which is a water re-absorption site, can lead to altered drug release profiles (normally a decrease in the release rate if the release mechanism is dependent on the continued presence of high water content). The osmotically driven delivery systems pioneered by Alza have been quite effective in performing in a uniform fashion even in the presence of limited water availability (6). Other types of dosage forms do not always perform as well. Two examples are shown in Figure 3 where prospective once-a-day dosage forms do not achieve continuous drug release once the formulation reaches the colon.

Figure 3: A: Plasma nicardipine levels after oral dosing of controlled-release nicardipine hydrochloride to dogs and humans. B: In vitro and in vivo acetaminophen release from HPMC matrix sustained release tablets.

In Figure 3 A , the absorptive phase for nicardipine terminates upon arrival of the dosage form in the colon (as determined by scintigraphic imaging) of both dogs and humans. In Figure 3B, the in vivo release of acetaminophen (determined by deconvolution of plasma acetaminophen levels) only correlates with in vitro release while the dosage form is in the stomach or small intestine. Acetaminophen release dramatically decreased when the dosage form reached the colon. These data suggest that the release characteristics of these matrix tablets are not consistently maintained throughout the entire gastrointestinal tract. Several reasons may account for the discrepancies between in vitro and in vivo drug release, including effects of the gastrointestinal milieu on the controlled-release dosage form. In the colon, very little free water exists since the colon is a water absorptive region of the gastrointestinal tract. Those once-a-day dosage forms that are dependent on the continued presence of relatively significant amounts of water may be expected to experience altered drug release profiles once the dosage form reaches the colon. The osmotic systems developed by Alza Corporation have been shown to function well in low water environments, but other sustained release dosage forms (i.e. certain matrix tablets, hydrogels) are not always so robust in their In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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performance characteristics. The future development of once-a-day dosage forms depends on the ability to design and develop sustained-release dosage forms that will function independent of influences from the gastrointestinal milieu. Since sustainedrelease dosage forms spend the majority of their residence time in the colon, future once-a-day dosage forms must be designed to release drug in a predictable fashion in the relatively low water content of the colon.


Oral Controlled Absorption System (OCAS™)

In an effort to design a sustained-release formulation suitable for once-a-day dosing that will perform reproducibly whether in the small intestine or colon, modifications to gel-forming matrix tablets were investigated. The O C A S system described here contains, as its major components, the active drug, a gel-forming polymer (polyethylene oxide, PEO), and a gel-enhancing agent (polyethylene glycol, PEG). The design concept is to achieve rapid gelation, pseudo first-order drug release, consistent colonic drug release, and ease of manufacturing. A schematic, shown in Figure 4, describes the basic performance characteristics of O C A S .

Stomach

Small Intestine (Rapid gelation)

Colon (Fully hydrated)

Figure 4: Schematic of OCAS hydration and drug release in small intestine and colon. The schematic in Figure 4 depicts the design concept of O C A S in that the formulation achieves nearly complete hydration in the small intestine. Unlike O C A S , other gel-forming matrix tablets may only achieve incomplete hydration in the small intestine, resulting in a dosage form that retains a significant volume of residual nonhydrated drug/polymer core in the colon. In the absence of significant free water in the colon, drug release from these formulations may significantly decrease, resulting in a lack of correlation between in vitro drug release and in vivo drug absorption.


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The key to sustaining consistent drug release, as designed in the O C A S dosage form, is very rapid hydration of the gel matrix such that nearly complete hydration occurs prior to arrival of the dosage form at the colon. In most cases, the transit time for dosage forms from the stomach to the colon is approximately 3-4 hours, perhaps longer in the fed state depending on the extent of gastric retention. In order to ensure nearly complete pre-colonic hydration, fillers that could be combined with the gelforming polymer (PEO) were examined for their effects on gelation index (extent of gelation occuring within 2 hours). The results are summarized in Table II.

Table II: Effect of Fillers on Gelation Index of 1:1 PEO-Filier Matrix Tablets Additive

Gelation Index (Percent at 2 hours)

Lactose D-Mannitol PVPK30 PEG6000 D-Sorbitol

24.4 + 3.3 26.8 + 3.3 82.2 + 4.3 87.1 +0.4 97.0 + 0.8

None

29.7 + 5.0 Tablets were immersed in dissolution media for two hours. Gelation index was calculated by comparing ratios of the gel layer and non-gelated residual core thicknesses.

Without added filler, PEO matrix tablets exhibited only 30% gelation within two hours. This control gelation index was not significantly increased by the addition of lactose or mannitol. Ρ V P K30, PEG6000 and D-sorbitol each significantly increased O C A S gelation index, although P V P K30 required 2 ml of water per 1 g of solute whereas PEG6000 and D-sorbitol required only 1 ml of water per 1 g of solute to achieve similar results. PEG6000 was chosen as the desired filler because of its high gelation index and pharmaceutical acceptability. Utilizing PEG6000 as the filler for the gel-forming matrix tablets, four different gel-forming polymers were examined for their ability to achieve pseudo zero-order drug release for 12 hours. Matrix tablets were prepared from acetaminophen:PEG:polymer (1:1:2) and their in vitro release profiles determined by the paddle method. In addition, the release mechanism was described according to the following equation, D = kt n

where D is drug release at time t, k is the drug release rate constant, t is time, and η is the diffusional exponent number. As an approximation, η < 0.66 indicates diffusion dominated drug release while η > 0.66 indicates erosion dominated drug release (n =


20 0.5 for Fickian diffusion control and η = 1.0 for solvent front penetration control). The results from these studies are summarized in Table III.

Table III: Determination of In Vitro Release Mechanism of Acetaminophen from Drug:PEG:Polymer (1:1:2) Matrix Tablets


Gel-Forming Polymer Hydroxypropylcellulose (HPC) Hydroxyethylcellulose (HEC) Hydroxypropylmethylcellulose (HPMC) Polyethyleneoxide (PEO)

Diffusional Exponent Number (n) 0.59 0.61 0.61 0.76

PEG6000 used as filler in matrix tablet. The data shown in Table III indicate that tablets made fiom PEO were the only ones tested that exhibited erosion dominated drug release (n > 0.66). The other three polymers tablets (HPC, HEC, and HPMC) exhibited diffusion dominated drug release (n < 0.66). The actual release profiles (shown in Figure 5 for PEO and H P M C ) also demonstrated these differences in that a pseudo-zero order release profile was achieved only with PEO while the other polymers resulted in tablets exhibiting more non-linear release profiles.

Time (hr)

Ti

m e

(hr)

Figure 5: In vitro acetaminophen release profile from PEO and HPMC matrix tablets. The arrow shows the time of initiation (1 hour) of mechanical stress as described in the text.

The data shown in Figure 5 also demonstrate an additional important characteristic of the O C A S formulation. The arrows indicate the initiation of mechanical stress on the formulations. The mechanical stress involved shaking the formulations in dissolution medium at 320 strokes/min in the presence of 50 g of


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glass beads. Only a very minimal increase in drug release was observed utilizing PEO whereas an abrupt and dramatic increase in drug release was seen when H P M C was used as the gel-forming polymer. These data indicate that the gel formed with PEO possesses significant structural rigidity that is important in maintaining both physical integrity and consistent drug release during contractile activity present in the gastrointestinal tract. While in vitro release data are important in developing and characterizing sustained release dosage forms, the in vivo performance is the critical test of functionality. A comparison of in vitro and in vivo performance can be utilized to demonstrate that the dosage forms performs independent of gastrointestinal variables. Conventional PEO matrix tablets (gelation index = 21%) and O C A S PEO/PEG tablets (gelation index = 76%) were prepared and evaluated in both in vitro and in vivo models. Both formulations demonstrated reasonably pH-independent in vitro drug release between p H 1.2 and p H 6.8 over a 12 hour dissolution time. The release profile for O C A S was somewhat more linear than that observed with the conventional gel matrix tablet, especially between 8 and 12 hours, but both formulations achieved greater than 85% drug release within 10 hours. Two different in vivo experiments were conducted in dog models. In one study, both conventional and O C A S tablets were dosed at various times prior to necropsy and the tablets then retrieved and analyzed for in vivo drug release. In another experimental model, dogs received either conventional or OCAS tablets containing acetaminophen and plasma drug profiles determined. The pharmacokinetic parameters from this study are summarized in Table IV and a graphic summarization of all results is shown in Figure 6. The data presented in Table IV and Figure 6 clearly indicate that this conventional gel matrix tablet exhibits decreased in vivo drug release in the colon. In contrast, drug release from OCAS appears to remain consistent even when the dosage form enters the colonic region. It is proposed that the reason for the consistent O C A S performance is the fully hydrated state of the dosage form prior to its arrival in the "water-deficient" colon region. As mentioned in the introduction, the gastrointestinal variables that can impact the performance sustained-release once-a-day dosage forms are generally influenced by the presence of food. Enzyme activity, motility, pH, fluid content, and bile salts are all modified in the fed state versus the fasted state. In order to determine whether OCAS would perform independent of the effects of food, a dog study was conducted comparing nicardipine hydrochloride absorption from O C A S and conventional gel tablets. The resultant pharmacokinetic parameters are summarized in Table V . The data presented in Table V indicate that significantly greater absorption (AUC) is achieved with O C A S compared to the conventional gel and that the O C A S system is relatively free of food effects (547 vs 681 ng.hr./ml A U C for fasted vs fed, respectively). B y contrast, an approximate 2-fold food effect was observed with the conventional gel formulation. Again, it is likely that the very rapid hydration of the O C A S formulation is an underlying cause for the relative food effect independence.



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Table I V : Pharmacokinetic Parameters Formulation

AUCo-24hr (ng.hr./ml)

OCAS Conventional

2702+ 151 1470 + 537

Cmax (ng/ml)

Tmax (hr)

350 + 36.1 344 + 21.7

1.5 + 0.3 1.3 + 0.3

MET (hr) 7.0 + 0.3 4.0+1.2

Mean + S.E.

0

2

*

β

Time (hr)

β

10

12

14

0

2

4

β

β

10

12

14

Time (hr)

Figure 6: In vitro and in vivo release performance of OCAS and conventional gel tablets.


23 Table V : Pharmacokinetic Parameters of O C A S and Conventional G e l Nicardipine Hydrochloride Tablets in Fed and Fasted Dogs Formulation

Food

Fasted Fed Fasted Fed

OCAS Conventional

AUCo-24hr (ng.hr./ml) 547 + 180 681 + 108 125 + 32 239 + 62

Cmax (ng/ml) 82 + 14.8 87 + 17.8 54 + 12.5 47 + 12.6

Tmax (hr) 3.9 + 1.1 4.7 + 1.5 1.3 + 0.2 4.3 + 1.2


Ν = 6, mean + S.E.

In summary, O C A S is a rapidly hydrating gel matrix tablet that performs relatively independent of the effects of pH, mechanical stress, and location in the gastrointestinal tract. In addition, at least with the model compound employed, food effects appear minimal. As such, the technology represents an advance in sustained release formulations that might have applications in once-a-day drug therapy.

Future Challenges and Opportunities Sustained-release formulations for once-a-day therapy have been a target of pharmaceutical research and development for several decades with a limited variety available as marketed products. Advances as those described with O C A S represent attempts to further refine and develop new applications. Significant challenges and opportunities, however, still remain in this field and are summarized in Table VI. Although significant advances have been made in developing and commercializing once-a-day dosage forms, the field is still amenable to continued improvement and applications. Probably the two most critical fields for investigation are technologies for improving colonic absorption and applications of once-a-day technologies for biomolecules. Technologies such as O C A S can effective achieve drug release in the colon. However, until pharmaceutical approaches are available to improve colonic absorption, once-a-day products will be limited to those few drugs that exhibit high colonic permeability. In normal gastrointestinal transit, it can be expected that dosage forms will have approximately 4-6 hours available for drug release prior to arrival at the colon. This time window will continue to limit development of once-aday dosage forms unless colonic absorption improvement is adequately addressed. Finally, little progress has been achieved in oral delivery systems for biotechnology products, even with immediate release or targeted delivery systems. As more progress is achieved with this class of compounds, their in vivo behavior will be more fully understood. One can then anticipate extending that knowledge to once-a-day dosage forms in a manner similar to what has been done with traditional organic drug candidates. In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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Table V I : Future Challenges and Opportunities for Once-a-Day O r a l Delivery Systems Formulation design to optimize 24 hour absorption Biopharmaceutical techniques for improved colonic absorption Gastric retention techniques to minimize large intestine residence time Chronopharmaceutics Matching release/absorption profiles with therapeutic needs Technology improvements to minimize effects of gastrointestinal variables Applications to biotechnology products (i.e. peptides, proteins, genes, etc) Formulation strategies Stability Local therapy or systemic absorption

References 1. 2. 3. 4. 5. 6.

Chien, Y . C . Prog. Technol.1999 15,21. Shah, A.J.; Britten, N.J., Olanoff, L.S.; Badalamenti, J.N. J. Controlled Rel. 1989 9,169. Lee, V . H . L . ; Yamamoto, A . Adv. Drug Del. Reviews 1990 4, 171. Chien, Y . W . Novel Drug Delivery Systems; Marcel Dekker, Inc. New York, N Y , 1992, pp 139-196. Lemmer, B. J. ControlledRel.1991 16,63. Theeuwes, F. Drug Dev. Ind. Pharm. 1983 9,1331.


Controlled-Release Oral Delivery Systems - ACS Symposium Series

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