Highly compressible ethylcellulose for tableting

Details Highly compressible ethylcellulose for tableting Highly compressible ethylcellulose for tableting

2001-10-15

2003-07-15

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S406000, C424S464000, C424S465000, C424S480000

Reexamination Certificate

active

06592901

ABSTRACT:

FIELD OF INVENTION
The present invention relates to the use of a type of ethylcellulose that is highly compressible and compactible in the manufacture of pharmaceutical solid dosage forms.
BACKGROUND
Ethylcellulose (EC) is frequently used in the pharmaceutical industry as an excipient to provide a diffusion barrier function, thus limiting the diffusion of aqueous fluids into a system and limiting diffusion of dissolved actives out of the system. This functionality can be utilized in areas such as controlled release, stabilizing film coatings, and taste masking. Additionally, EC is utilized as a binder in compressed tablet systems where the high plasticity of EC contributes to the cohesion and mechanical strength of the tablet compact.
In order to incorporate EC into a product, a number of different processes can be used. Organic solvent-based processes are frequently utilized for film coating and microencapsulation (Morse et al, U.S. Pat. No. 3,860,733 (1972); Kent, D. J. and Rowe, R. C., “Solubility Studies on Ethylcellulose used in Film Coating”, J. Pharm. Pharmacol., Vol. 31, 1978, pp. 808-819). Alternately, EC can be dispersed in aqueous based latex systems for film coating. EC may also be thermally processed, as in melt extrusion or injection molding. Lastly, direct compression and wet granulation tablet manufacturing processes that produce either monolithic or multi-layer systems have been exploited in the pharmaceutical arena (Dahlinder, L. E., Graffner, C., and Sjoregen, “Strength of the Insoluble Residues of Plastic Matrix Slow Release Tables (Duretter) In Vitro and In Vivo”, Acta Pharm. Suec., Vol. 10, 1973, pp. 323-332; and Shlieout, G. and Zessin, G., “Investigation of Ethylcellulose as a Matrix Former and a New Method to Regard and Evaluate the Compaction Data”, Drug Development Ind., Vol. 22, No. 4, 1996, pp. 313-319; Colombo, P. et al, “System for the Controlled-rate Release of Active Substances”, European Patent 0 226 884 B1, 1990.)
Tablets based on inert plastic deforming polymers such as EC (also referred to as “inert plastic matrix tablets”) were first introduced in 1960 and have found extensive clinical application (Chang, R. K. and Robinson, J. R., Sustained Drug Release from Tablets and Particiles through Coating in “Pharmaceutical Dosage forms: Tablets”, (Lieberman, H. A., Lachman, L. and Schwartz, J. B. Eds.), 2
nd
Ed., Marcel Dekker, New York, N.Y., 1990, pp. 239-241). In particular in the area of direct compression, a number of reports have been published describing the use of EC in directly compressed tablet systems. Upadrashta, S. M., Katikaneni, P. R., Hileman, G. A. and Keshary, P. R., (in “Direct Compression Controlled Release Tablets using Ethylcellulose Matrices”, Drug Dev. Ind. Pharm. Vol. 19, 1993, pp. 449-460) report a systematic study of the effect of different types of EC (N-type, 48.0-49.5% ethoxyl content) on directly compressed matrix tablets in combination with varying proportions of theophylline or indomethacin to make controlled release matrix tablets. They observed that EC of low (10 cps) viscosity (low viscosity corresponds to low molecular weight) resulted in harder tablets than when high 100 cps) viscosity EC was used and compressed at the same pressure. Furthermore, the greater mechanical strength was correlated with greater drug release retardation. Upradashta, S. M., Katikaneni, P. R., Hileman, G. A., Neau, S. H. and Rowlings, C. E., (in “Compressibility and Compactibility Properties of Ethylcellulose, Int. J. Pharm. Vol. 112, 1994, pp. 173-179) further reported on the compressibility and compactibility of N-type (48.0-49.5% ethoxyl content) EC. Based on hardness-compression force profiles, Heckel plots, and force-displacement profiles, Upradashta et al. again concluded that lower viscosity (lower molecular weight) EC yields harder tablets. Furthermore, lower molecular weight was correlated with lower mean yield pressures, indicating greater plasticity, while higher molecular weight EC was associated with an increase in elastic work. Shliehout and Zessin (ibid) who studied EC (48.0-49.5% ethoxyl content) independently confirmed these findings with EC of 7, 22 and 100 cps viscosities.
Katikaneni, P. R., Upadrashta, S. M., Rowlings, C. E., Neau, S. H. and Hileman, G. A., (in “Consolidation of Ethylcellulose: Effect of Particle Size, Press Speed and Lubricants, Int. J. Pharm., Vol. 117, 1995, pp. 13-21) further reported on the effect of particle size and press speed on the consolidation of the above mentioned EC N-types. As particle size was decreased from 420-840 &mgr;m to 105-149 &mgr;m, the tablet hardness was markedly increased. Simultaneously, mean yield pressure was found to decrease with decreased particle size. Conversely, the elastic work increased with the use of larger particle size EC.
In an attempt to advance the utility of EC in direct compression and particularly for controlled release dosage forms, micronized ethylcellulose (48.0-49.5% ethoxyl content, 7-41 &mgr;m average particle size) has been proposed as a directly compressible matrix former by Pollock, D. K. and Sheskey, P. J., (in “Micronized Ethylcellulose: Opportunities in Direct Compression Controlled Release Tablets”, Pharm. Tech., Vol. 20 (9), 1996, pp. 120-130). These authors compared various viscosity types (7, 10, and 100 cps). Furthermore, a comparison was made with analogous ethylcellulose in granular form (average particle size 310-465 &mgr;m). Diphenhydramine was used as a water-soluble model drug. Their findings were that higher EC concentration and smaller EC particle size led to a marked reduction in EC drug release rates. Furthermore, they found that micronized EC achieved greater tablet hardness than granular EC when the same compression force was used. This greater tablet hardness was again observed to lead to lower release rates (greater prolongation of release duration). A further finding was that the drug release rate was lower from tablets containing micronized EC when compared to tablets containing granular EC, where the two types of tablets were compressed to the same hardness. Apparently, these differences in tablet properties were caused by the differences between the particle sizes of the drug and the two types of EC studied.
However, in the above study as well as in other studies where micronized EC has been used, tablets were prepared manually, “one at a time”, using a hydraulic laboratory press. A key requirement for large-scale commercial tablet manufacturing using an automated rotary press is that the powders that are to be compressed should have fast and relatively unimpeded and uniform flow under gravity. Without this prerequisite, powder flow from the hopper of a tablet press into the tablet feedframe and then into the die cavities will not be fast and uniform enough to ensure uniform and reliable tablet weight and hardness. Furthermore, uniform flow is needed to avoid damage to the tooling due to insufficient filling of the die cavities resulting in contact between the upper and lower punches (Banker, G. S. and Anderson, N. R., Tablets in “The Theory and Practice of Industrial Pharmacy” (Lachman, L., Lieberman, H. A. and Kanig, J. L., Eds.), Edition, Lea and Febiger, Philadelphia, Pa., 1986, pp. 293-345). Particle size is one of the key parameters affecting powder flow. It is generally accepted that as particle size decreases, powder flowability improves with the optimum occurring in the size range of about 100-400 &mgr;m (Fassihi, A. R. and Kanfer, I., “Effect of Compressibility and Powder Flow Properties on Tablet Weight Variation”, Drug Development Ind. Pharm., Vol. 12, 1986, pp. 1947-1958). Below this level, decreased particle size can lead to rapid increase in inter-particle interaction resulting in an increase in cohesive forces (Randall, C. S., Particle Size Distribution in “Physical Characterization of Pharmaceutical Solids”, (Brittain, H. G., Ed.), Marcel Dekker Inc., New York, 1995, pp. 180-182). Due to its fine nature, micronized EC (particle size 7-41 &mgr;m) is a cohesive powder, which is generally prone to p

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