Current methods for targeted drug delivery using enteric capsules face challenges including capsule leakage and breakage in the stomach. Researchers tested enteric capsules and enteric coated capsules containing a dye formulation using in vitro dissolution tests and a dynamic gastric model. The enteric capsules showed some dye leakage in the stomach while the enteric coated capsules performed better. However, in the dynamic gastric model the enteric capsules ruptured in the fasted state due to shear forces, while maintaining integrity in the fed state with reduced forces. Formulation optimization and advising patients to take capsules with food may improve enteric capsule performance.

1. RESEARCH POSTER
PRESENTATION DESIGN
© 2012
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New delivery technologies can be challenging to develop and meet acceptance in the pharmaceutical industry. Particularly when regulatory
pathways are known and established for similar dosage forms. Complications with regard to excipient monographs, and IPEC recognition create
some complications for novel excipient technologies, and at times can make the cost of introducing novel ingredients prohibitive for
development and use. Enteric capsule technologies for the targeted delivery of drugs sensitive to the harsh acidic conditions of the stomach
are being developed by several companies. However, several problems exist that are prohibitive to their more widespread use:
• Dosage form performance varies from enteric capsules and enteric coated capsules.
• Liquid ingress into the capsule in the stomach
• Leakage from the capsule in the stomach
• Breakage of the capsule before entering the intestine.
We have formulated a matrix powder containing a dye, as well as a dye directly blended with encapsulation grade MCC. These two different
powders were filled into enteric capsules (AR CAPS® from CapsCanada®) and HPMC capsules that were coated with an enteric polymer.
Comparisons of performance of the different formulation strategies in enteric coated capsules and enteric capsules were performed in order to
demonstrate approaches enabling the use of a new technology.
Abstract
Dye Matrix: Prepared as a high-shear solvent granulation with hydrophobic excipients which is milled and blended with diluents.
Dye Blend: Prepared as a direct blend of dye and microcrystalline cellulose (MCC).
Sample Capsule: AR CAPS® CapsCanada® Size 1 clear.
Control Capsule Uncoated: Capsulgel® Vcaps® HPMC Size 1.
Control Capsule Enteric Coated: Capsulgel® Vcaps® HPMC Size 1 white with Eudragit L-55 enteric coating.
Dissolution Testing: Capsule disintegration/dissolution was conducted according to USP requirements. Apparatus 2 paddles, RPM 100. 2 stage
dissolution: Stage 1 0.1N HCl pH 1.2 (750mL); Stage 2 addition of 250mL phosphate buffer solution pH adjusted to 6.8 (900mL total volume).
In-vitro Stomach Model: The Dynamic Gastric Model (DGM), diagram 1, was set to process under standard fasted and fed state conditions. The
capsules were dosed with 240 ml of water and simulated gastric fluid was continuously added at physiological rates along the sides of the
fundus part of the DGM. Approximately 6 aliquots of 40 mL were ejected from the DGM and collected at 4 to 5 minute intervals (1). The
housekeeper wave was applied at the end of the run to empty the entire contents of the DGM. The fed state experiments, a high-caloric, high
fat meal as recommended by the FDA for the evaluation of food effects. Each run consistent of n=3 capsules.
Dissolution
Enteric Capsules and coated capsules were tested for two stage dissolution in both Acid (0.1N HCl pH 1.2) and Neutral (pH. 6.8 Buffer). Stage 1
dissolution was the primary focus to understand AR CAPS® and formulation performance with enteric protection. Stage 1 dissolution results are
show in Figure 1 and Table 1. AR CAPS® with direct blend offered some protection to the dye reaching 11.4% release after 2 hrs in acidic media.
Formulation optimization resulted in greater protection of the dye in the matrix, with total release at 2 hours 7.0%, meeting the pass criteria of
NMT 10%. The control enteric coated capsules released 0% at 2 hrs. Uncoated capsules with dye matrix-powder results are shown to provide the
dye solubility in acidic media without protection. Capsule appearances post stage 1 dissolution are shown in figures 2 and 3, note both AR-
CAPS® and control enteric coated capsules allowed media ingress into the capsule.
Results
Conclusion
AR CAPS® allow more dye egress in the acidic stage than do
the control coated capsules. We have demonstrated the ability to
limit the leakage through formulation to meet specifications.
With further optimization this formulation approach should be
able to match the performance of current enteric coated capsule
technology. DGM offers a means of assessing the potential in vivo
performance of drug delivery and allows for formulation and
dosing protocol changes to optimize performance in clinical
trials. AR-CAPS® did rupture in the fasted state, however, capsule
integrity survived in the fed state, which is likely due to
reduction in shear forces.
Currently, issuing consumer medication information (CMI) (2)
guidance advising patients to “take with food” in order to reduce
shear force is a path forward for specific dosage forms identified
at CoreRX. Additional formulation development utilizing AR
CAPS® should provide a successful path forward to reduce
leakage and may allow for fasted DGM success. New technologies,
such as ARCAPS®, require formulators to adjust current
approaches within dosage forms to maximize the opportunities of
emerging technologies.
References
1. M. J. S. Wickham, R. M. Faulks, J. Mann, and G. Mandalari,
Dissolution Technologies,Aug 2012, 15-22
2. http://www.fda.gov/downloads/Drugs/GuidanceComplianceReg
ulatoryInformation/Guidances/ucm080602.pdf
Acknowledgements
Caps Canada® for material support.
1CoreRx Pharmaceuticals, Clearwater, Florida, USA 33760
2Bioneer A/S, Hørsholm, Denmark, DK-2970
adam.lambert@corerxpharma.com
A. Lambert1, M. Greene1, B. Hilker1, L. Saaby2, M. Fanø2, A. Müllertz2
Formulation Strategies for Enteric Capsule
Development
Current convention, methods and processes that are known to work are often selected over novel technologies that have potential to improve
product performance. Enteric capsules are a fairly new introduction to the array of formulation tools available for controlled delivery of drugs.
Presented here are some of the challenges and possible solutions for enabling the use of enteric capsules.
Diagram 1. Dynamic Gastric Model.
DGM Fed State
AR CAPS™ slowly leaked blue color over the duration of a fed state trial, but did
not rupture and survived into the antrum. One control enteric coated capsule
ruptured during the antral (Stage 2) processing. The rupture of the control
capsule passing into the antrum is likely due to the shear force breaking down
the capsule at the body/cap junction and occurred when leaving the stage 1
environment. Figure 6a shows AR CAPS® post fed state. The control capsule
which ruptured is shown recovered in figure 6b. Figure 7 and 8 show the
collected fractions for AR CAPS® and enteric coated capsules respectively.
Stage 1: Dissolution 0.1N HCl RPM 100
Time (hr)
AR CAPS® Matrix AR CAPS® -Direct Blend Enteric Coated Capsules Matrix-Powder
% Released % Released % Released % Released
1 0.8 4 0 82.4
2 7 11.4 0 81.7
Table 1. Stage 1 0.1N HCl dissolution profile comparison table.
Figure 1. Stage 1 0.1N HCl dissolution profile comparison chart. Figure 2. AR CAPS® post
stage 1 dissolution 0.1N HCl.
Figure 3. Control enteric coated capsule
post stage 1 dissolution 0.1N HCl
Figure 4. Fasted state AR CAPS® DGM samples.
Aliquots 1 – 6 shown.
DGM Fasted State
Difference between the control enteric coated capsules and
AR CAPS® was observed as the control capsule enteric
coated formulation withstood gastric processing while the
AR CAPS™ formulation ruptured within 5 minutes. AR
CAPS™ experienced shear forces resulting in rupture prior to
entry in the antrum. Figure 4 and 5 show the fasted state
collected aliquots for AR CAPS® and enteric coated
capsules respectively.
Figure 7. Fed state AR CAPS® DGM samples.
Aliquots 11 – 14 shown.
Figure 8. Fed state control enteric coated
capsule DGM samples. Aliquots 14-17
shown. 17 shows rupture.
Figure 5. Fasted state control enteric coated capsule
DGM samples. Aliquots 1 – 6 shown.
Figure 6a . AR CAPS® collected post
fed state.
1 2 3 4 5 6
1 2 3 4 5 6
14 15 16 17
11 12 13 14
Figure 6b . Ruptured enteric coated
capsule post fed state
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
0.8 1 1.2 1.4 1.6 1.8 2 2.2
%Q
Time (hours)
Disssolution: Stage1 0.1N HCl Paddles 100RPM
Matrix Powder
AR CAPS® Direct Blend
AR CAPS® Matrix
Control Enteric Coated Capsule
Introduction
Methods