2.3.1. The Effect of the OKG Weight Ratio
In order to investigate the pH sensitive of the CTS-OKG polymers, the release profile of diclofenac in SGF (pH 1.2) from diclofenac-loaded CTS and CTS-OKG films at 37 ± 2 °C for 24 h were performed. The release profiles are shown in
Figure 5.
The cumulative release profiles of DFNa from the CTS and CTS-OKG polymer film revealed that both polymer films can prolong release of diclofenac. After two hours, the release rate of diclofenac from the CTS film is faster than that from the CTS-OKG and significantly different after the sixth hour (about 1% for CTS-OKG and 6% for CTS). The results suggested that the CTS-OKG can more retard the release of diclofenac in SGF than that of CTS film even, the solubility of diclofenac sodium is very low in the acidic condition. This is attributed from the amino groups in the CTS polymer film have been protonated to –NH
3+ in the SGF (pH 1.2), resulted in the repulsions between the amino groups and allowed the water molecule to penetrated in the polymer matrix, hence swollen as shown in
Figure 6.
In case of the CTS-OKG polymer film, some of amino groups of CTS reacted with aldehyde groups of OKG to give imine bonds, so the amine groups in CTS-OKG polymer film are less than that in the native CTS, consequently, less swollen. Therefore CTS-OKG polymer film can more control the release of DFNa from the polymer film in SGF (pH 1.2) (Shown in
Scheme 3).
The release profiles of DFNa from the DFNa-loaded CTS-OKG polymers formulated with varying amounts of OKG were evaluated in a crude simulated gastrointestinal system of using a 2 h exposure to simulated gastric fluid (SGF; pH 1.2) followed by 24 h in simulated intestinal fluid (SIF; pH 7.4), all at 37 °C. The results are shown in
Figure 6.
The cumulative release profiles of DFNa from encapsulation in the different CTS:OKG (w/w) ratio polymer films revealed a sustained DFNa release profile in all cases. In common, all formulations released almost no DFNa in the SGF (pH 1.2) at less than 1% in 2 h, but the release rates of DFNa from the formulations in SIF (pH 7.4) varied with their CTS:OKG proportions. The formulation without OKG (0OKG) showed by far the fastest DFNa release rate of all the samples, with DFNa release starting within the first hour of exposure to SIF (pH 7.4) and attaining a rate of around 6.2% of the total DFNa level released per hour over the first 8–10 h. A relatively much slower release of DFNa was recorded from the OKG containing composites, with negligible DFNa release in the first two hours at pH 7.4. Thereafter, the order of the DFNa release rate was (highest to lowest) OKG > 1OKG >> 3OKG polymers, with an average DFNa release rate over the 2–8 h period in pH 7.4 of about 3.2%, 2.1% and 0.75% of the total DFNA released per hour, respectively. In the subsequent period of 8–24 h at pH 7.4 (10–26 h total assay time) DFNa was still released from all composites but at a slower rate, and attained approximately 90% total release rate in the OKG free formulation (0OKG) compared to ~60%, 50% and 19% for the 2OKG, 1OKG and 3OKG composites, respectively.
The high OKG proportion (2:1 (w/w) OKG:CTS in 3OKG) in the polymer matrix causes a delay in the kinetics of DFNa release, presumably due to the increased crosslink density that was present. However, that the formulation 2OKG that contains a two-fold higher proportion of OKG than formulation 1OKG gave a slightly higher DFNa release rate might be due to the higher amount of CTS (1:0.5 (w/w) CTS:OKG). In this scenario, the molar excess of then free CTS amine groups remaining in the matrix can form strong hydrogen bonds in the polymeric chains, helping to delay the release rate of the DFNa. These results are consistent with the results obtained when varying the proportion of CTS (section 2.3.2). When the proportion of OKG was higher than that for CTS (1:2 (w/w) ratio of CTS:OKG), the DFNa release profiles may thus be dependent upon the hydrogen bonding between the hydroxyl groups of OKG and the amine groups of CTS.
2.3.2. The Effect of the CTS Weight Ratio
As mentioned in section 2.3.1, the proportion of OKG in the formulation clearly affected the DFNa release profile. Therefore, the relative proportion of CTS is likely to be an important factor and was investigated. The release profiles of DFNa from the DFNa-loaded CTS-OKG polymer formulations with varying amounts of CTS (from 0.5:1 to 2:1 (w/w) CTS:OKG) at a fixed 1:1 (w/w) ratio of OKG:DFNa were evaluated in the same simulated gastrointestinal system (SGF (pH 1.2) for 2 h and then SIF (pH 7.4) for the next 24 h). The results are shown in
Figure 7.
As observed before (section 2.3.1), DFNa was hardly released at all from all three DFNa-loaded CTS-OKG polymer composites in the SGF buffer (less than 1% of the total amount of loaded DFNa over the 2 h). In the SIF buffer, the DFNa release rates for the three formulations were either very small (<4%; 1CTS) or negligible (2OKG and 2CTS) in the first two hours, and then showed a relatively slow release of DFNa from the CTS-OKG polymer matrix, in the order of 1CTS > 2OKG >> 2CTS (containing 0.5:1, 1:1 and 2:1 (w/w) ratios of CTS:OKG, respectively) over the next six hours (2–8 h total time in pH 7.4) averaging 7.0%, 4.3% and 1.8%, or 5.8%, 3.8% and 1.3% of the total DFNa released per hour over these 4 and 6 h, respectively. Thereafter, DFNa was still released from all three formulations, with around 78%, 60% and 41% of the total DFNa loaded being released by 24 h in pH 7.4.
The results indicated that the DFNa release rate is affected by the CTS content in the CTS-OKG polymer matrix. A high CTS content causes a delay in the kinetics of DFNa release, because, as the proportion of CTS is increased so is the crosslink density and then also so is the amount of free amine groups for hydrogen bonding with the OKG hydroxyl groups increased.
2.3.3. The Effect of the DFNa Weight Ratio
In the view of the fact that the amount of DFNa in the CTS-OKG polymer may affect its release rate, the release profiles of DFNa from DFNa-loaded CTS-OKG polymer formulations with varying amounts of DFNa from 0.5:1 to 2: 1 (w/w) DFNa:CTS-OKG were evaluated with a 1:1 (w/w) fixed weight ratio of CTS:OKG, using the same simulated gastrointestinal system at 37 °C. The results are shown as the DFNa cumulative release profiles in
Figure 8.
As observed before (sections 2.3.1 and 2.3.2), almost no DFNa was released from the three DFNa-loaded CTS-OKG polymers in the two hours in SGF (<1% total level of loaded DFNa) and in the first two hours in the SIF. Thereafter, DFNa was released at a slow rate from all three CTS-OKG polymer compositions over the next six hours (4–10 h total time), with the rate of DFNa release being related to the amount of DFNa loaded in the composite, in the order (highest to lowest release rate) of 1DFNa > 2OKG > 2DFNa with average release rates over the 6 h from 4 to 10 h total time of approximately 5.7%, 4.0% and 1.7% of the total DFNa loaded per hour for 1DFNa, 2OKG and 2DFNa, respectively, and a total release after 26 h of ~73%, 61% and 43%, respectively.
Thus, OKG as a crosslinking polymer with CTS can control the DFNa release at pH 1.2 to a minimal level over 2 h but maintain a sustained release of DFNa over more than 8 h in pH 7.4 media, releasing from at least 43 to 73% of the loaded dose of DFNa.
Finally, the formulations for each effect that gave the minimum and maximum DFNa release in the SGF (pH 1.2) and SIF (7.4) buffers, respectively, were selected to compare with that for the two commercial DFN drugs (Diclosian and Voltaren tables) in the same mock gastrointestinal system (
Figure 9).
In common with the DFNa-loaded CTS-OKG polymers noted before (sections 2.3.1–2.3.3 and
Figure 9), both commercial drugs (Diclosian and Voltaren) released less than 1.0% of the total DFNa loaded in the SGF dissolution medium over 2 h. However, in contrast to the DFNa-loaded CTS-OKG polymers when immersed in the SIF dissolution medium, the commercial drugs released DNFa faster and sooner with a significant release amount of ~35%, ~65% and >87% of the total amount of DFNa loaded being released from both formulations after one, two and four hours in pH 7.4, respectively. As presented before (section 2.3.1), the CTS matrix without OKG (0OKG) presented a significantly faster DFNa release than the OKG containing CTS-OKG polymers, but this was still slower than that of the two commercial tablets taking more than 10 h to release >90% of the DFNa. Comparing the DFNa release from the four different DFNa-loaded CTS-OKG polymers, it is clear that the release rate is affected by the CTS, OKG and DFNa proportions in the polymer matrix.
In addition, the release of DFNa from the DFNa-loaded CTS-OKG composite polymers is also clearly depended on the pH of the release medium, with essentially no release in the SGF buffer (pH 1.2) over two hours compared to the significant release in the SIF buffer (pH 7.4). Release rates in the SGF were not assayed beyond two hours as the stomach contents are retained in the stomach for about 2 h before passing to the duodenum.
The DFNa release rates are summarized for all composites in
Table 2. In comparison with the % EE of DFNa (
Table 1), it can be deduced that the formulation 3OKG had the slowest release rate and gave the highest % EE. Therefore, the 3OKG formulation may be appropriate for further study as a model drug controlled release model for a longer period of time, such as three days released model, although it remains to be established that the total DFNa released would improve from the 19% seen at 24 h to a more acceptable 50% at 3 days. Alternatively, for shorter sustained delivery models, for example, formulation 2OKG would still offer benefits over the two commercial DFNa drugs.