Category: Formulation and Quality
Purpose: The United States Pharmacopeia (USP) defines delayed-release products as those which are “deliberately modified to delay the release of a drug substance for some period of time after initial administration”. This type of dosage form is often used to protect acid-labile drugs from degradation by the acidic gastric environment, to prevent irritation of the gastric mucosa by certain drugs, or to target the drug release to an specific intestinal region. A strategy frequently used to achieve such is to formulate oral drug products with an acid-resistant coat (commonly known as enteric coating) which is constituted of a polymer with a defined dissolution pH threshold. As the dosage form travels from the stomach to the intestine it is expected that the enteric polymer dissolves upon reaching a region that has a pH higher than its dissolution pH threshold. However, enteric-coated (EC) dosage forms tend to display an unpredictable in vivo behaviour, which, in some cases, can even impact their clinical efficacy.
The USP recommended dissolution method for EC products is a two-hour period in 0.1M HCl followed by phosphate buffer (about 50mM) pH 6.8. At this concentration, the buffering capacity of phosphate buffer is considerably high, which causes the pH around the polymer surface to be similar to the bulk pH. However, in vivo buffer capacity values are much lower and as a consequence a gap between the bulk and polymer surface pH may exist. The lower pH at the polymer-water interface can impact the coating dissolution, which may be one of the reasons for the inconsistent in vivo behaviour of EC drug products.
With this in view, the purpose of this work was to compare the in vitro performance of different marketed EC products with reported variable bioavailability. Both USP recommended method and bicarbonate buffer (BCB) at reported in vivo molarity and pH values were used.
Methods: The commercially available drug products tested were of different drug classes, presenting different physicochemical properties, coating material and manufacturers. The five EC products included aspirin (Bayer Inc., LOT: NAA68A2), diclofenac sodium (Sandoz Canada Inc., LOT: JN9884), pantoprazole (Teva, LOT: 0691118), esomeprazole (Apotex, LOT: NV2183) and sulfasalazine (PMS, LOT: 1037737) (Table 1). All dissolution tests were performed using an USP apparatus 2 (paddle), 900 mL dissolution media, 75 rpm rotation speed and temperature set at 37.0°C. The tablets were tested in both phosphate buffer ~50mM pH 6.8 (except sulfasalazine: medium pH of 7.2) and BCB 5mM pH 6.5 after being exposed to HCl 0.1M for two hours.
Results: All formulations displayed a fast release in phosphate buffer and complied with the USP performance specifications. On the other hand, they all had a delayed drug release in bicarbonate-based buffer compared with that in phosphate buffer. The rank order of onset of drug release was esomeprazole (30min) > pantoprazole (45min) > diclofenac = sulfasalazine (60 min) > aspirin (4 hours). The delay in BCB could be a consequence of the existing pH gap between the bulk pH and the coating-liquid interface pH (which has been reported to be lower). In addition, the coat neutralization doesn’t occur as readily at lower buffer concentrations compared to the USP phosphate buffer.
Interestingly, the products with the fastest onset of release in BCB contained basic drugs. Since the drug release from an EC product is depended upon the coat opening, the neutralization of the dissolving coat is essential. The basic properties of the drug molecules might have acted as an aid to the aforementioned neutralization but from the inner side of the coat. Likewise, the longer onset of drug release from EC products containing acidic drugs could be related to the acidic environment on the inner side of the coat. In this way, the coating neutralization would depend primarily on the medium it is exposed to.
Conclusion: The results from this study clearly indicate that the in vitro performance of enteric coated products is highly dependent on the ionic composition of the medium. Hence, the physiological aspect of bicarbonate buffer should be taken into account during the formulation development process, especially for acidic drugs, to avoid possible failures due to insufficient drug release. Therefore, a new physiologically relevant quality control test for enteric coated dosage forms needs to be developed.
Daniela Amaral Silva– Student, University of Alberta - DDIC, Edmonton, Alberta, Canada