|Zusammenfassung||Use of unconventional polymer blends of Kollicoat® SR 30 D and Eudragit® RL 30 D:
Among the dissolution test conditions, hydrodynamic properties (agitation rate) and mechanical destructive force are important factors, which affect the dissolution behavior of the dosage form. In hydrogel-type tablets, in vivo drug release was much faster than that expected from in vitro dissolution tests due to the peristalsis of the gastrointestinal tract. Moreover, because single-unit reservoir tablets required a strong/flexible and permeable polymer, there are few publications in this respect, due to lack of polymer with these properties.
The main objective of this part was to use polymer blends of Kollicoat® SR 30 D and Eudragit® RL 30 D as coating materials to increase the mechanical robustness of HPMC matrix tablets and to prepare single-unit reservoir tablets. The effect of polymer blend ratio, curing conditions, coating level, drug content, drug solubility, ionic strength, pH, agitation rate, type of excipient and storage conditions on drug release were evaluated.
For coated HPMC matrix tablets, HPMC and film coat can control the drug release, which could easily be adjusted by varying the polymer blend ratio, which also affected the mechanical properties of the films. Flexibility increases as Kollicoat® SR 30 D increases and Young’s modulus increases as Eudragit® RL 30 D increases. At 8% w/w coating level, a force of 3.2 N was required to rupture the swollen tablet after 16 h in the release medium. The coated tablets were robust; coating level (6% to 10%, w/w) and agitation rate (50 rpm to 150 rpm) had no influence on the drug release. A water-insoluble model drug was not released; however, release of water-soluble drugs increased as the drug content increased and decreased as HPMC content increased. Curing at 40 °C/ 75% RH was required for polymer coalescence as it made the film more flexible.
However, for single-unit reservoir tablets, drug release significantly decreased when tablets were cured at 40 °C/ 75% RH for 24 h. Drug release was accelerated by increased Eudragit® RL content, buffer species (phosphate ≥ acetate ˃ chloride ion), drug solubility (diprophylline ˃ metoprolol ≥ theophylline), type of the excipient (MCC ˃ lactose) and increased drug content (50% to 80%, w/w). Ionic strength (0 M to 0.4 M), increased agitation rate of the dissolution medium (50 rpm to 150 rpm), and coating level (6% to 10%, w/w) showed no effect on drug release. In vitro release studies showed that the reservoir tablets were strong enough to withstand gastric destructive force.
Use of cellulose acetate butyrate (CAB-553-0.4) as a novel polymer in controlled-release drug delivery:
Advances in polymer science have led to the development of several novel drug-delivery systems. Cellulose acetate is an example that is used for preparation of osmotic tablet; however, toxic solvents and flammability hazard are the greatest disadvantages of the process. Hence, alternative polymers with sufficient strength, permeability, and solubility in a safer organic solvent (like alcohol) are desirable. The objective was to use CAB-553-0.4 (alcohol soluble) as a novel polymer. It was used as a coating material for preparation of osmotic tablets and multiparticulate pellets and as a carrier for high-dose matrix tablets.
For osmotic tablets, factors like polymer blend ratio, drug solubility, plasticizer, coating level, delivery orifice, medium molar concentration, pH, agitation rate, and storage conditions were investigated. With increasing Eudragit® RL PO/CAB ratios, higher medium uptake of the film was observed due to higher permeability of Eudragit® RL polymer, resulting in shorter lag times and faster drug release from the osmotic tablets. Replacing ethylcellulose with cellulose acetate butyrate as a coating material led to shorter lag times and faster drug release due to increased film permeability, moreover, films’ strength and flexibility increased. Drug release was osmotically controlled, and it was dependent on drug solubility (the higher the solubility, the faster was the release), buffer species (acetate > phosphate = chloride ion), and plasticizer content (increased plasticizer 10% to 20% w/w, drug release was faster, and rupture force was lower). The caffeine release rate was constant at 10% to 30% w/w coating level, 50 rpm to 150 rpm agitation rate, and 30% to 70% w/w core drug content. In vitro study showed that at a 20% w/w coating level, the tablet coat could tolerate forces of more than five times of the gastric destructive force. Drug release was unchanged when the tablets were kept under accelerated storage conditions for one month.
For multiparticulate pellets, other factors like pore-former, type and size of the starter core and compression force were studied (in addition to above factors). The diprophylline release from cellulose acetate butyrate coated pellets decreased, and lag time increased with increased coating level. The release from pellets with sugar nonpareil starter core was faster than with MCC cores, due to higher osmotic activity. The release of diprophylline was faster than caffeine and no release from carbamazepine pellets was seen. For water-insoluble drugs, release could be modified by addition of a pore-former. With increasing drug content (15%, 30% and 45%, w/w), diprophylline release was faster (1.0, 1.6 and 2.7 mg/h). Tableted pellets showed extended release with no effect of increased compression force from 10 kN to 20 kN and pellet content from 50% to 70%, w/w. Drug release from cellulose acetate butyrate coated pellets was stable during storage under stress condition (40 °C/ 75% RH).
The cellulose acetate butyrate matrix tablets were characterized with respect to the effect of granulation fluids, granule size, compression force, and SA/V ratio. An increased isopropanol content (0%, 50%, and 100% w/w) in the granulating fluid, resulted in decreased caffeine release. Nevertheless, no changes in the X-ray characteristic peaks and the crystalline structure of caffeine were noticed before and after granulation and compression. The mechanism of caffeine release was Fickian diffusion. Polymer content, drug content (up to 80% w/w), compression force (10 kN to 20 kN), granular size (0.15 mm to 1.4 mm) and surface area / volume ratio had no effect on drug release. However, drugs with higher solubility showed an increased release (diprophylline ˃ caffeine ˃ carbamazepine). The release of caffeine from the tablets was robust concerning the effect of the dissolution medium: increased ionic strength (0.4 M to 1.2 M), agitation rate (50 rpm to 150 rpm), and pH did not influence the release. Under accelerated stability conditions, the drug release was unchanged.
Increase tablettability of pellets through Eudragit® RL top coating
The major challenge during compression of coated pellets is the stress, which can rupture the coating and hence change the release characteristics of the formulations, in addition, the hardness of compacts decreased with increasing amounts of pellets.
In order to increase the tensile strength of tableted pellets (pellets’ content 70% w/w), pellets were top-coated with Eudragit® RL polymer. Effect of Eudragit® RL topcoat, vehicle type (aqueous or organic), and plasticizer content on drug release was investigated. The diprophylline release (from tableted cellulose acetate butyrate- and ethylcellulose-coated pellets) and tablets’ tensile strength increased as the compression force increased; however, tablets made of cellulose acetate butyrate-coated pellets were two times stronger than tablets made of ethylcellulose-coated pellets. Drug release from Eudragit® RL top-coated pellets was in the order of Kollicoat® SR˃ cellulose acetate butyrate ˃ ethylcellulose and similar to the release from Eudragit® RL top-uncoated pellets (tableted and un-tableted); however, at 5 kN compression force, Eudragit® RL top-coating increased tablets’ strength (8%, 135%, and 390%, respectively). For tableted enteric-coated (Eudragit® L and HPMCP) pellets, tablet’s strength increased (77% and 225%, respectively) and within 2 h in 0.1 N HCl, diprophylline release decreased (20% and 30%) when pellets were top-coated with Eudragit® RL. The plasticizer content (0, 10, and 20%) of Eudragit® RL top-coat did not influence the drug release; though, it increased tablet’s strength (29%, 88%, and 136%, respectively). Use of organic solution of Eudragit® RL instead of aqueous dispersion did not affect drug release and tablet’s strength. Cellulose acetate butyrate- and ethylcellulose-coated pellets were stable with or without Eudragit® RL top-coating, while the drug release increased with time from Eudragit® L- and HPMCP-coated pellets when top-coated with Eudragit® RL under accelerated stability conditions for twelve weeks.
Eudragit® matrix system:
The preparation of a controlled-release high-dose matrix tablets has always been a challenge due to the relatively large amount of excipients generally needed to provide a specific delivery profile resulting in too large dosage forms.
High dose ibuprofen loaded controlled-release matrix tablets were prepared and characterized; Eudragit® RL PO, Eudragit® RS PO, and ethylcellulose were used as carrier. In addition, the role of curing conditions for Eudragit® RL PO matrix tablets was evaluated.
Ibuprofen release from ibuprofen:Eudragit® RS or ibuprofen:ethylcellulose (95:5) matrix tablet was similar to the release from 100% ibuprofen tablet (no polymer). However, ibuprofen release significantly decreased from ibuprofen:Eudragit® RL at the same ratio (95:5), and tablet strength increased. Nevertheless, there was no drug-polymer interaction detected by IR. Increasing the ethanol content in the granulation fluid up to 20% w/w did not influence ibuprofen release from Eudragit® RL matrix tablet. For Eudragit® RS and ethylcellulose matrix tablet, increased ethanol content up to 30% w/w decreased ibuprofen release significantly, and increased tablet strength. Same release profile and release rate of ibuprofen were obtained from different polymers (Eudragit® RL, and ethylcellulose or Eudragit® RS) when different ethanol:water ratio was used (20:80 and 30:70, respectively) as granulation fluid. An increase of ibuprofen content (50%, 65%, and 80%) in the Eudragit® RL matrix decreased drug release rate and increased tablet strength; however, at 95% ibuprofen content, the drug release was faster and tablet’ strength was lower. An increase of compression force (5 kN to 15 kN), granule size (0.106 mm to 1.45 mm) and agitation rate (50 rpm to 150 rpm) had no impact on ibuprofen release. Increased surface area/volume ratio to 1.82 mm2/mm3 increased the ibuprofen release significantly. Furthermore, storage under accelerated stability conditions had no influence on ibuprofen release.
Increase ethanol content in the granulation fluid retards carbamazepine release from Eudragit® RL PO matrix tablets. Curing temperature had a crucial role in drug release retardation; at 70 °C/24 h, drug release followed zero-order kinetic because of polymer coalescence. Drug release profile from tablets cured at 70 °C was similar to release profiles of tablets cured at 40 °C/75% relative humidity. X-ray study showed no change in the crystalline structure of carbamazepine. As curing duration increased, moisture uptake increased and drug release was retarded more; beyond 24 h, curing had no further effect. Increased compression force increased tablet strength and decreased drug release rate. The larger the granules size, the slower was the drug release; increased compression force and curing duration for tablets prepared from small granules had no impact on drug release. Drug release proportionally changed with surface area/volume ratio, polymer permeability, and agitation rate. However, drug release was unchanged with increased drug content up to 50% w/w.