pH= 1.2 pH= 6.5 pH= 7.5

pH = 1.2 pH = 6.5

CAPSULE DISSOLUTIONSize M capsules were filled with three varying powder formulations to determine if designed release formulations could be delivered in such a small capsule.

Eudragit® L100 coated capsules were exposed to a pH 1.2 media for 30 minutes and then transferred to a pH 6.5 media for 60 minutes during dissolution experiments.

Eudragit® S100 coated capsules were exposed to a pH 1.2 media for 30 minutes, a pH 6.5 media for 30 minutes, and then transferred to a pH 7.5 media for 60 minutes during dissolution experiments.

Application of Polymer Coatings on Non-banded Size M “Mouse” Capsules Containing Immediate and Extended-Release FormulationsIan McIntosh, Paul Sabo, Richard Goodin, Jason Vaughn; Pharmaceutical Development Services, Patheon Inc.; 2110 E Galbraith Road, Cincinnati, Ohio 45237, USA; www.patheon.com/

Poster #: AM-14-1477

ABSTRACT SUMMARY

This study was performed to evaluate and determine the feasibility of the application of

polymer coatings for Size M “Mouse” capsules. Due to the dimensions of the Size M

capsule, capsule filling and capsule coating become significantly more difficult compared to

conventional capsule sizes. For enteric and colonic delivery, Eudragit ® L100 and S100

were evaluated. Coating solution components were varied to determine optimal coating

conditions to provide targeted release profile with adequate physical stability for pre-clinical

studies.

An ethanol-based coating solution with triethyl citrate provided the best coating efficiency

and maintained capsule integrity after coating. Size M capsules were efficiently coated for

enteric/gastric delivery and able to deliver various delayed and extended-release

formulations.

INTRODUCTION

While easier to gavage or intubate mice than to administer a capsule, capsules are ideal for

materials that are insoluble, form poor suspensions, are affected by excipients, or are

odorous/distasteful. The utilization of capsules designed for mouse administration allows for

pharmacokinetic data utilizing minimal API amounts. The Size M capsules are manufactured

by Torpac and designed to be used for immediate release formulations. This experiment was

conducted to determine if the application of a enteric/colonic polymer coat to the capsule

was feasible.

SIZE M CAPSULE PROPERTIES

The size M capsules are manufactured to contain an internal volume of only 4µL! Depending on the density of the fill material, the estimated max fill weight it 4 mg (assuming 1 g/mL density). Size M capsules are currently only manufactured by Torpac®.

CAPSULE COATING

Confirmation of successful coating was initially determined through visual verification. Capsule coating integrity is typically most susceptible at the junction of the capsule body and cap. SEM images of the uncoated capsule show that there is ~30µm gap at the capsule junction.

SEM images of the capsule after 2 dips coats using the 12% w/w coating solution show complete capsule coating across the junction and the rest of the shell. Once a successful coating process was developed and confirmed visually, dissolution tests were performed to corroborate enteric/colonic protection and targeted dissolution profile.

CONCLUSION

With Size M capsules, modifications must be made to conventional coating methods. Due to

the size of the capsule, manual dip coating must be implemented with a more concentrated

coating solution that evaporates rapidly. It was determined that a 12wt% Eudragit® and 5wt

% triethyl citrate in ethanol coating solution provided the optimum coating of the capsule in

1-2 dip coating and drying cycles. SEM and dissolution tests were performed to determined

successful coating of the capsule and obtainment of target dissolution profile.

Eudragit® L100 coated capsules had successful enteric protection in a pH 1.2 dissolution

media for 30 minutes. Upon transfer to an intestinal pH environment the Eudragit® L100

coating dissolved and provided immediate release of neat ibuprofen and an ibuprofen SDD

formulation. Intimate mixing with a high molecular weight HPMC polymer provided significant

amount of gelling to occur to simulate a delayed-release profile in a Size M capsule.

Eudragit® S100 coated capsules had successful enteric protection in a pH 1.2 and pH 6.5

dissolution media for 30 minutes at each condition. Upon transfer to a colonic pH

environment the Eudragit® S100 coating dissolved and provided immediate release of neat

ibuprofen and an ibuprofen SDD formulation. Intimate mixing with a high molecular weight

HPMC polymer provided significant amount of gelling to occur to simulate a delayed-release

profile in a Size M capsule.

The results of this experiment have proven that coating of a Size M capsule can be successfully executed to provide either enteric or colonic protection. Experimentation also demonstrated that varying immediate and simple delayed-release formulations can be delivered in a coated or uncoated Size M capsule. The value of this technique enables new options at the early stages of development that closely represents a future dosage form.

REFERENCES1. Empty Porcine Hard Gelatin Capsule Size M Certificate of Analysis. Torpac Inc. Certified

January 12, 2014

2. Degussa; Enteric Coating of Hard Gelatin Capsules with Eurdragit® L 30 D-55. Pharma. Polymers January 2005

3. K. Thoma, K. Bechtold; Enteric Coated Hard Gelatin Capsules (1992) Capsugel Library BAS 146 E

4. Eudragit ® L100 and/or S100 Organic Coating for Gastro-Intestinal Targeting. Evonik Technical Information Sheet www.eudragit.com (Accessed March 10, 2014)

5. R. Dodds, F. Podczeck; Using a small-scale capsule dip coater to produce gastro-resistant hard capsules. Tablets and Capsules January 2008

ACKNOWLEDGEMENTSWe would like to thank Necati Neval and Edward Merino from the University of Cincinnati

COATING SOLUTION SCREENING

To determine the optimal coating solution for dip coating of the Size M capsules, several

coating solutions utilizing different solvents and polymer ratios were evaluated. 2,3

Due to the dimensions and sensitivity of the Size M capsules, a manual hand dip coating

method was utilized to coat the capsules. This method requires the solvent to rapidly evaporate

from the capsule shell in order to not affect the capsule integrity.

The vendor recommended coating solution4 is designed for spray coating of capsules and

didn’t provide sufficient evaporation. The solvent of the solution was modified to be ethanol-

based to provide improved evaporation rates (talc was also removed due to no tacking

concerns of the manual hand dipping process, and the plasticizer levels were increased).5

Trials using the “Test Coating Solution -1” required more than 7 dip coating and drying cycles to

achieve acceptable resistance in 0.1N HCl (aq) media. While sufficient coating was achieved,

the capsule integrity was significantly impacted and caused a high failure rate due to capsule

brittleness.

Ingredient %Composition (w/w)1

Gelatin Porcine 82.939%

Methyl Paraben (Methyl-4-hydroxybenxoate) 0.556%

Propyl Paraben (Propyl-4-hydroxybenxoate) 0.139%

Sodium Lauryl Sulphate 0.139%

Titanium Dioxide 2.728%

Vendor Organic Coating Solution4

Ingredient %Composition (w/w)

Eudragit® Polymer 6.25%

Triethyl Citrate 0.63%

Talc 3.13%

Acetone 34.29%

Isopropanol 51.42%

Water 4.29%

Test Coating Solution - 1

Ingredient %Composition (w/w)

Eudragit® Polymer 6.00%

Triethyl Citrate 2.50%

Ethanol 91.50%

Test Coating Solution - 2

Ingredient %Composition (w/w)

Eudragit® Polymer 12.00%

Triethyl Citrate 5.00%

Ethanol 83.00%

Coated Capsule

Coated CapsuleUncoated Capsule

Uncoated Capsule Uncoated Capsule

No. Formulation Dissolution Target

1 Ibuprofen (IBU) Immediate Release at high pH

2 10%A Ibuprofen:Kollidon® VA64 SDD (SDD) Immediate Release at low pH

3 50/50 Ibuprofen/HPMC K100M (HPMC Blend) Extended Release

Coated Capsule

Eudragit ® L100 Coated Capsules

Eudragit ® S100 Coated Capsules