Nano-precipitation is a versatile process based on pouring of an organic solution containing the drug and polymer into a dispersion phase that is miscible with the diffusing solvent yet non-solvent to the polymer (15).
Fessi et al. (7) reported the preparation of NPs by interfacial agitation produced through the diffusion of water-miscible solvent in the water. Having injected the organic phase into the water, a fast interfacial spreading was observed because of the mutual diffusion between the solvents, which supplies energy for oil droplet formation.
Here, the encapsulation efficiency was enhanced from 27.71% to 45.70%, as the amount of the polymer increased from 83.33% to 90%, which can be explained in three methods: Initially, the polymer precipitates quicker on the surface of the dispersed phase at high concentration, and inhibits drug diffusion through the phase boundary. Later, the viscosity of the solution is increased and diffusion of the drug into the polymer droplets is delayed at high concentration. Third, the large size of NPs can result in high concentration of polymer, leading to the loss of drug from the surface during NP washing as compared to the small NPs. Thus, size of NPs also affects the loading efficiency (16).
The small efficiency of drug incorporation can be ascribed to the water soluble properties of RHT.
Thereafter, entrapment of drug decreased from 45.70% to 27.71% (as P3 to P1) with further increases in the theoretical drug loading (from 10% to 16.67%). These results propose that there can be a relatively high amount of RHT that might be entrapped in the PLGA NPs (Figure 3).
Crystal morphology of RHT (Figure 2) showed a plate-like shape for form I. Besides, SEM studies showed that NPs are spherical and discrete in shape. Clearly, high RHT loadings reversely resulted the precipitation of PLGA polymer due to the production of spherical particles.
Zeta potential determinations showed low increases (from -10.5 mV to -2.28 mV) with an increase in polymer concentration (Table 2). These results are the opposite of what was anticipated, which is reduction in surface negativity owing to the interaction of carboxyl groups and the cationic drug on the particle surface. Blank NPs exhibited a negative surface charge of -11.1 mV, which might be due to the appearance of end carboxyl groups of the polymer at the NP surface, as formerly shown for drug-free NPs. An increased negative surface charge was also exhibited by Redhead (17) for Rose Bengal incorporation into PLGA NPs.
Notably, an increase in the theoretical drug loading from 10% to 16.67% w/w results in particle size reduction from 173 nm to 75.14 nm (Table 2). The size of NPs was found to increase with increasing concentration of polymer due to the increase in the viscosity of the organic phase, which renders solvent diffusion more difficult and results in larger NPs size. Average particle size of blank NPs was detected to be approximately the same to that of NPs containing the drug (154 nm).
The results of Table 2 suggest that the size of NPs can be tuned within a range of 75.14 - 173 nm with PDI (0.095 - 0.557). Particles produced with low PLGA concentration (10 mg/mL) were almost monodispersed (P1), showing a PDI of less than 0.1. However, the PDI steadily increased to more than 0.5 in a system with 18 mg/mL of PLGA. A decrease in NPs recovery was observed for NPs produced with different PLGA concentration (from P1 to P3). However, it may result from the increase of particle size as well as from the visually observed aggregation of the already formed particles as evidenced by the PDI value of 0.441 and 0.557 (for P2 and P3, respectively). The current study found that the recovery yield was also dependent on the PLGA concentration in the solvent phase.
The RHT formulations showed complete absence of the drug endotherm and an endothermic peak of PLGA was found at the range of 52.5 to 57.5°C. Besides, the peak at 126.22°C shown by RHT disappeared in the RHT NPs, indicating that RHT was encapsulated by the PLGA polymer. The loss of drug endotherm might be because of the perfect homogeneous matrix organization of the polymer with the drug or to the delusional effect of the polymer (Figure 4).
There may also be the possibility of overlapping of drug peaks by the background diffraction pattern of the amorphous structure (18). Thus, it can be concluded that the drug is present inside the NPs in the semi-crystalline to microcrystalline form. This finding was also in agreement with the rivastigmine tartrate (RT) loaded PLGA polymer nano-suspension, prepared by Joshi et al. (19).
By increasing the PLGA weight fraction from P1 to P3, the potency of typical drug peaks was decreased because of the delusional effect used by the polymer network. This supports the results obtained from FTIR and DSC.
The release behavior of RHT, illustrated in Figure 6, indicates a biphasic pattern (with an initial burst release followed by sustained release). Nano-particles released 9.58 - 21.95% of RHT (for P3 to P1) within 0.5 hours, which had a relationship with the onset of action (Table 3). Afterwards, the NPs exhibited considerable sustained release outcome by lengthening the release of drug at 69.98 - 89% for 24 hours. Using of the polymer PLGA significantly influences drug sustained release (69.98 ± 4.94%) over an extended time, yet the initial drug release of more than 21.95% within 0.5 hours may be ascribed to the portion of unencapsulated drug inward the polymer (Table 3). At first, the pure drug showed a risen release of RHT in comparison to the NPs, and after 0.5 hours it reached 101.20% (P < 0.05). The cumulative release was steady for the pure drug as observed, and did not increment with enhanced time, which improves the value of sustained release characteristic of the NPs. Enhanced drug release (89% ± 1.51) is associated with increased solubility, which may be due to the fact that lower particle size (75.14 nm) of the NPs (P1) effected an increment in the efficient surface area, which in turn increased the solubility (Tables 2 and 3). It is believed that the particle size is inversely proportional to the rate of dissolution and hence a higher rate of dissolution (P1 > P2 > P3) was observed with the NPs.
Figure 6.
Cumulative percent of RHT release from NPs with different polymer ratios and RHT untreated.
Table 3.
Comparison of Various Release Characteristics of RHT from Different NP Formulations and RHT Untreated and Fitting Parameters of the Release Data to Various Kinetic Models
Formulation | Rel0.5, % | Rel24, % | DE | T50%, min | f1 | ORDER | RSQ | n |
---|
P1 | 21.95 ± 1.64 | 89.00 ± 1.51 | 79.44 | 154.79 | 42.29 | Peppas | 0.915 | 0.572 |
P2 | 15.59 ± 1.34 | 83.89 ± 8.88 | 72.76 | 191.19 | 49.01 | Peppas | 0.964 | 0.680 |
P3 | 9.58 ± 0.31 | 69.98 ± 4.94 | 60.31 | 199.15 | 58.39 | Peppa | 0.974 | 0.787 |
RHT untreated | 101.20 ± 7.05 | 102.71 ± 7.15 | 101.61 | 15.44 | 0 | - | | |
Abbreviations: Rel0.25, amount of drug release after 0.5 hours; Rel, amount of drug release after 24 hours; DE, dissolution efficiency; T50%, dissolution time for 50% fractions; f1, Differential factor (0 < f1 < 15).
Furthermore, RHT NPs (P1) with lower PLGA showed higher dissolution efficiency and low Mid Dissolution Time (MDT) of 79.44% and 154.79 minutes, respectively (Table 3).
The drug was very gradually released at a later stage, the rate at which was measured by the diffusion (n < 0.5) of the drug in the inflexible structure of the matrix. The drug release following the Peppas kinetics and n values exhibited that it was a non-Fickian diffusion mechanism when the drug release occurred. Peppas kinetic model (Table 3) showed the highest correlation; as it is evident from the values of regression coefficients (R2) for P1, P2, and P3 NPs as 0.915, 0.964, and 0.974, respectively.
Multiple mechanisms, such as swelling, erosion, polymer relaxation, etc. might play a role in the drug release. This could be because rapid dissolution of poloxamer 407 from the surface of NPs created pores or channels and further drug release might have occurred through these pores or channels rather than by erosion. At the final dissolution, the rate of drug release was reduced with time due to the increment in the diffusion path length of the drug.
LEAVE A COMMENT HERE: