Excipients in Polymeric Drug Delivery and Formulations - Pharmaceutical Technology

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Excipients in Polymeric Drug Delivery and Formulations
A roundtable with John Doney, Jiao Yang, Hans Baer, and Elena Draganoiu.


Pharmaceutical Technology


Flexible pharmaceutical polymers

Baer: In solid-dosage forms, the chemical character of the active ingredient and its sensitivity to the conditions in the digestive tract often call for ingenious formulations, especially if the drug is to be set free at a specific site within the gastrointestinal (GI) tract (1). Multi-unit dosage forms have a low risk of dose dumping and a higher chance of therapeutic success. Multi-unit dosage forms release the active ingredient from a high number of subunits (e.g., coated granules or pellets.) The compression of coated subunits to multiparticulate tablets or coated capsules is a big challenge. The flexibility of the applied enteric layer is a major factor for the compression of coated pellets as well as for the pellet size and layer thickness. Known enteric polymers for oral applications are normally hard, brittle and less flexible (2).

For compression of coated pellets or particles, an elongation of at least 100% is necessary. Pure polymers are not able to fulfill this requirement. Instead, a certain amount of plasticizer or a mixture with very flexible sustained-release polymers (e.g., "Eudragit (R) NE 30 D" [poly(ethyl acrylate-co-methyl methacrylate 2:1, 800,000], Evonik, Essen, Germany]) is necessary to increase flexibility. With the use of "Eudragit (R) FS 30 D" [poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, 220,000, Evonik] or the addition of propylene glycol as a plasticizer, the elongation at break can be increased over 100%. Propylene glycol is a lightly volatile and low-boiling plasticizer. It will decrease the intermolecular forces of the film formers on the one side, and on the other side, it could lead to less storage stability. Therefore, a study was performed to identify the volatile tendency of propylene glycol (3).


Figure 1: Volatility of propylene glycol (PG) from anionic coatings. R.H. is relative humidity. DS is dry substance. (FIGURES ARE COURTESY OF EVONIK RÖHM GMBH.)
Soft-gelatin capsules were coated with a polymer weight gain of 10 mg/cm2 of "Eudragit (R) L 30 D-55 [poly(methacrylic acid-co-ethyl acrylate) 1:1, 250,000, Evonik]. Glycerolmonostearate was used as a glidant, and polysorbate 80 as an emulsifier. The plasticizer content was adjusted with four different values: 10, 15, 20, and 25% propylene glycol. After six-month storage, more than 80% of the theoretical amount of propylene glycol was evaporated (see Figure 1). The applied coating became brittle, and cracks were formed. Other well-known plasticizers such as triethyl citrate or polyethlyene glycol types were comparatively stable as observed in Figure 2. The results of this plasticizer study show that propylene glycol is not the best choice of a plasticizer for compression of coated subunits.


Figure 2: Volatility of triethyl citrate (TEC) or polyethylene glycol (PEG) from anionic coatings. R.H. is relative humidity. DS is dry substance. (FIGURES ARE COURTESY OF EVONIK RÖHM GMBH.)
Further studies showed that Eudragit (R) FS 30 D in combination with triethyl citrate or polymer combinations provide sufficient elongation at break for the compression of multiparticulate tablets (4).

Other factors for a successful compression process are the particle size and the applied-layer thickness. The type of polymer used and the layer thickness will have a significant influence on a successful multiparticulate formulation. Increased layer thickness leads to a more slowly active release. For evaluation of the coating performance, 25-μm and 50-μm layers were applied. The studies showed that coatings on small pellets were damaged more extensively than those on large pellets, independent of film thickness. Increased layer thickness leads to a slower release of the active ingredient (5).

Multi-unit dosage forms with a colon-targeting functionality have advantages for active ingredients redesigned for local treatment in the large intestine (such as Colitis ulcerosa, Crohn's disease, and colon cancer). Colon-targeting also makes sense or is required for several systemic substances. The colon is a preferred region for the absorption of peptidic drugs (peptides and proteins, including peptide hormones and antibodies) as they cannot be absorbed via the mucosa of the stomach or small intestine. The enzymes (proteases) there break down peptides and proteins. The colon, on the other hand, has physiological properties that enable absorption of both peptides and proteins. These properties include an approximately neutral pH, a long residence time, special absorption mechanisms for peptides, and a microflora that produces hardly any peptide-hydrolyzing enzymes (2).

To minimize systemic effects, the subunits need to release the active ingredient as close as possible to the affected colonic sites. Colon-delivery systems with Eudragit (R) FS 30 D have advantages with regard to compression flexibility and targeted drug release in the colon. To ensure the functionality of the dosage form, it is essential to select suitable polymers and/or ingredients that provide the required flexibility and storage stability.

Hans Baer is a senior scientist of the Pharma Polymer business line with Evonik Röhm GmbH.

References

1. Evonik Röhm GmbH, "Colon Targeting," Pharma Polymer News 7, 1 (2000).

2. M. Rudolph, "Entwicklung und in vitro Charakterisierung von per oralen multipartikulären Arzneiformen zur Optimierung der Therapie der Colitis ulcerosa und Morbus Crohn," PhD dissertation, J.W Goethe University Frankfurt, Institute of Pharmaceutical Technology, Frankfurt, 2002.

3. H. Baer et al., Effect of Different Plasticizers on the Storage Stability of Enteric Coated Soft Gelatine Capsules," poster presented at the 5th International Symposium on Solid Dosage Forms, Stockholm, 2007.

4. T. Beckert, "Verpressen von magensaftresistent überzogenen Pellets zu zerfallenden Tabletten," PhD dissertation, University of Tübingen, Institute of Pharmaceutical Technology, Tübingen, Germany, 1995.

5. Evonik Röhm GmbH, "Larger Pellets, Less Damages to Films," Pharma Polymer News, 6, 2 (1999).


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