Development of Ethylcellulose Coating on Osmotic Pump Tablets

Sophie Zhai, 1 Robert Schmitt,2 Jennifer L’Hote-Gaston 3

1The
Dow Chemical Company, Shanghai, China
2The Dow Chemical Company, Bound Brook, NJ, USA
3The Dow Chemical Company, Midland, MI, USA

Objectives Figure 1. Process for preparing tablets. Figure 3. In-vitro drug release for tablets containing glipizide,
comparing tablets with an EC-based coating and commercial product
Acceptable similarity in verapamil HCl release was demonstrated for the optimum
tablets with an EC-based coating and commercial product under different media pH
• Develop an ethylcellulose (EC)-based coating Drug Layer Push Layer in different media conditions (f2>52). conditions. (Figure 6). Conditions included C, E, and F, as described earlier.
formulation for glipizide and verapamil HCl blending
120
Glucotrol A Figure 6. In-vitro drug release for tablets containing verapamil HCl,
osmotic pump tablets equivalent to commercially Blended Material Blended Material
100
Glucotrol B
Glucotrol C
comparing tablets with an EC-based coating and commercial product in
available drug products. granulation
Glucotrol D
Glucotrol E
different media conditions.

• Compare film properties, tablet stability, and in- Wet Granules Wet Granules 80
Glucotrol F
EC-based
100

Glipizide Released (%)

vitro and in-vivo drug release of osmotic pump drying
EC-based
EC-based
tablets coated with EC-based formulations to Dry Granules Dry Granules 60 EC-based
EC-based
80

those coated with cellulose acetate (CA)-based sieving

EC-based

Verapamil HCl Released (%)

formulations. Sized Dry Granules Sized Dry Granules
40 60

• Develop an application technology package to blending

20
provide best practice guidelines to customers. Granulation A Granulation B
40
Covera-HS
EC-based C, f2=63
0
Introduction tableting 0 4 8 12 16 20 20
EC-based E, f2=74
EC-based F, f2=92
The superior properties of osmotic pump technology make it possible to achieve 2-Layer Drug Core Time (h)
zero-order drug release in a controlled release dosage form. Interest in osmotic
coating
pump technology continues to grow as many of the main patents for this 0
Figure 4. In-vitro drug release for tablets containing glipizide,
technology have expired, making it more accessible to formulators. Coated Tablets 0 4 8 12 16 20
comparing tablets with an EC-based coating and commercial
POLYOX™ polyethylene oxide (PEO) and METHOCEL™ hypromellose are key Time (h)
orifice drilling product under simulated fasted and fed stomach states (f2>66).
functional polymers commonly used in osmotic pump formulations, which are then
typically coated using cellulose acetate. The purpose of this project was to develop Drilled Tablets 120
The pharmacokinetics analysis and the bioavailability evaluation showed the AUC,
a coating for the osmotic pump tablet based on ETHOCEL™ ethylcellulose with
drying Cmax, and Tmax for the tablets coated with reference (CA-based) and test (EC-
equivalent in-vitro and in-vivo performance to commonly used cellulose acetate- 100 based) formulations to be equivalent. The tablets coated with reference and test
coated tablets. Tablets
formulations demonstrated equivalent drug release in beagle dogs (Table 1).

Materials
80

Glipizide Released (%)

Table 1. Pharmacokinetic parameters for beagle dogs treated with
Active pharmaceutical ingredients (APIs) were glipizide (Beijing Honglin verapamil HCl with test and reference coating formulations (n=6).
Pharmaceutical, Inc.), 11 mg, and verapamil HCl (Tianjin Central Pharma Co., Ltd.), Results and Discussion 60
AUC(0-32) AUC(0→∝ ) Cmax T max Ke t 1/2 R*
240 mg. The drug layer included the API, POLYOX N80 (The Dow Chemical
Company, NaCl (China National Pharmaceutical Group Corp.), magnesium stearate
Glipizide Parameters (ng*h/mL) (ng*h/mL) (ng/mL) (h) (h-1) (h) (%)
40
Acceptable similarity in glipizide release was demonstrated for the tablets coated Reference mean 6757.0 7041.6 780.6 8 0.135 6.1 4.04
(China National Pharmaceutical Group Corp.), and Fe3O4 (China National Glucotrol XL FaSSIF
with the optimum EC-based coating and the equivalent commercial product (Figure (CA-based coating) SD 2008.0 2022.2 236.8 2 0.059 4.3 4.99
Pharmaceutical Group Corp.). The push layer included POLYOX Coagulant (The Dow Glucotrol XL FeSSIF
2). 20 Test mean 6697.6 6834 867.4 7 0.159 4.7 2.00
Chemical Company), POLYOX N750 (glipizide tablets only, The Dow Chemical EC-based FaSSIF
Company), METHOCEL E5 (The Dow Chemical Company), NaCl, Fe2O3 (China (EC-based coating) SD 1009.4 1086 117.4 3 0.051 1.9 2.17
EC-based FeSSIF
Figure 2. In-vitro drug release for tablets containing glipizide,
National Pharmaceutical Group Corp.), and magnesium stearate. The experimental 0
comparing tablets coated with an EC-based coating and commercial
coatings were based on ethylcellulose (The Dow Chemical Company) or cellulose 0 4 8 12 16 20
product. Verapamil HCl tablets coated with an EC-based coating showed stable drug release
acetate (Eastman Chemical Company). The NaCl was 80 mesh. Time (h)
Commercial tablets used for comparison purposes were Glucotrol XL (glipizide) 120 after storage for 6 months at both room temperature and accelerated conditions
and Covera-HS (verapamil HCl). Both products are osmotic products from Pfizer (data not shown). All drug release profiles demonstrated zero-order release and
and are coated with cellulose acetate. 100 Verapamil HCl were within the Covera-HS drug release specification.
Acceptable similarity in verapamil HCl release was demonstrated for the optimum
Methods tablets coated with an EC-based coating and the commercial product (Figure 5). No
80
film breakthrough was observed in the release evaluation. Conclusions
Glipizide Released (%)

Water permeation was measured on films of EC-based formulations according to

conventional methods. The optimum EC-based coating showed a six-fold Ethylcellulose-based coatings on glipizide osmotic pump tablets had equivalent drug
60 Figure 5. In-vitro drug release for tablets containing verapamil HCl, release performance as a commercial product under standard conditions, simulated
improvement in permeation over standard ethylcellulose.
comparing tablets coated with an EC-based coating and GI tract conditions, and simulated stomach states.
Tablet preparation proceeded as shown in Figure 1, resulting in a two-layer core
commercial product. Ethylcellulose-based coatings on verapamil HCl osmotic pump tablets had
which was coated with an EC-based coating and, in some cases, a CA-based 40
coating. Conventional methods were used for tablet pressing and coating and drug Glucotrol XL
100 equivalent drug release performance as the commercial product under standard
release testing. The similarity factor (f2) for drug release is calculated to determine Formulation 6-3-1, f2=75 conditions and in simulated GI tract conditions. In addition, in-vivo testing of the
if two profiles are equivalent. An f2 value greater than 50 means the two curves are 20 Formulation 6-3-2, f2=64 verapamil HCl tablets showed equivalence between the test (EC-based coating) and
equivalent. Formulation 6-3-3, f2=77 80 the reference (CA-based coating). A stability study indicated that the verapamil HCl
tablets coated with the EC based coating were stable for at least 6 months under
Verapamil HCl Released (%)

For drug release testing under different media conditions simulating the human 0
gastrointestinal tract, the following conditions were used: accelerated conditions.
0 5 10 15 20
A. hydrochloric acid solution (pH=1.2) 60
Time (h)
B. 1% hydrochloride sodium lauryl sulfate
C. acetic acid-sodium acetate buffer solution (pH=4.5)
D. 1% sodium lauryl sulfate acetic acid-sodium acetate solution 40
E. phosphate buffered solution (pH=6.8) Acceptable similarity in glipizide release was demonstrated for the commercial Covera-HS
F. hydrochloric acid solution (pH=1.2) for the first 2 h+ phosphate buffered product and the tablets coated with an EC-based coating under different media Formulation 11-1, f2=74
solution (pH=6.8) for remainder. conditions simulating the human gastrointestinal tract (Figure 3). 20 Formulation 11-2, f2=74
Acceptable similarity in glipizide release was demonstrated for the commercial Formulation 11, f2=74
Further details of the methods can be obtained from the authors. product and the tablets with an EC-based coating under similar fed (FaSSIF) and
fasted (FeSSIF) stomach states (Figure 4). 0
0 4 8 12 16 20 ™®Trademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow
Time (h)