The preparation of capsaicin-chitosan microspheres (CCMS) enteric coated tablets.

This study aimed to research the preparation and content determination of capsaicin-chitosan microspheres (CCMS) enteric coated tablets. The core tablets were prepared with the method of wet granulation. Nine formulae were designed to determine the optimal formula of the core tablet. Eudragit L100 was used to prepare the CCMS enteric-coated tablets. The effect of enteric coated formulation variables such as content of talc (10%, 25% and 40%), plasticisers (TEC and DBS), dosage of plasticiser (10%, 20% and 30%) and coating weight (2%, 3% and 5%) were evaluated for drug release characteristics. The in vitro release was studied using 0.1 N HCl and pH 6.8 phosphate buffer. Enteric coated tablets without ruptures or swelling behaviour over 2 h in 0.1 N HCl indicated that these tablets showed acid resistance. The accumulated release rate in phosphate buffer (pH 6.8) revealed that the prepared tablets were able to sustain drug release into the intestine and a first-order release was obtained for capsaicin. This research is the first report of the preparation and content determination of CCMS enteric coated tablets. The sustained release behavior of enteric coated formulations in pH 6.8 phosphate buffer demonstrated that it would be a potential drug delivery platform for sustained delivery of gastric irritant drugs.

Population pharmacokinetics and IVIVC for mesalazine enteric-coated tablets.

Although in-vivo bioequivalence (BE) study serves as a golden standard for establishing interchangeability of oral dosage forms, it remains challenging for products with high inter-subject variability such as mesalazine enteric-coated tablet to fulfil the BE criteria set by regulatory authorities. Mesalazine, as a BCS class IV drug, targets to be delivered to distal ileum or colon with a pH-sensitive polymer coating for the remission of ulcerative colitis. Through population pharmacokinetic (PK) analysis and in-vitro in-vivo correlation (IVIVC) modeling on the dissolution and BE data of a generic enteric-coated product (EM) and its reference Salofalk® 250 mg tablet (SM), we for the first time revealed the underlying mechanism of the high inter-subject variability for such delayed-release formulation. It was also noted that the in-vivo start time of absorption (Ts) for EM and SM was positively correlated with their in-vitro lag time (Tlag) under the USP three-stage dissolution condition and reversely correlated with their in-vivo bioavailability. The varied oral bioavailability of mesalazine enteric-coated tablet was mainly due to the varied N-acetyltransferase activities along GI tract. Although such extensive intestinal first-pass metabolism with large individual differences led to a significant variation of mesalazine Cmax (coefficient of variation: 60-63.5%) and AUC0-t (coefficient of variation: 37.5-46.9%), the corresponding variations in the total absorbed mesalazine (mesalazine and its metabolite N-acetyl mesalazine) were significantly reduced by 12 to 45%. Since the BE purpose for mesalazine enteric-coated tablet focused on their comparable safety profiles, total absorbed mesalazine was recommended to be adopted for the development of the IVIVC model and BE evaluation for EM. All in all, our model-based approach has not only successfully identified the key factors that affect the BE of EM to guide its further formulation optimization, but also demonstrated the indispensable role of modeling in the development of generic pharmaceutical product at its early stages.

Partial tablet coating by 3D printing.

In the last decade 3D printing (3DP) technology has gained increasing interest in the pharmaceutical field addressing several novel challenges such as on-demand manufacturing at the point of need, customization of drug release profiles and patient-specific solutions as well as combinations of several APIs in one dosage form. Therefore, 3DP can become a new and promising path to drug product development and manufacturing, able to support specific therapies and improve compliance, safety and effectiveness. The aim of this work was to partially coat tablets with a glyceride, namely Precirol ATO 5 using a semi-solids 3D printer as an approach for tuning the release of two Active Pharmaceutical Ingredients (APIs), the hydrophilic methyl-levodopa hydrochloride (Melevodopa) and the lipophilic Acyclovir. Various parameters of the 3DP coating process were purposefully modified using experimental design techniques in order to customize the selected APIs release profile, without affecting the core composition of the formulation. The percentage of the tablet surface coated, the number of coating layers as well as the coated sides of the tablet where the parameters which controlled the release profile for both APIs. Different dissolution profiles have been achieved by tuning these simple parameters, which revealed a non-Fickian release mechanism regardless of the API.

Effect of Calcium Ions on the Disintegration of Enteric-Coated Solid Dosage Forms.

To investigate the effect of calcium ions on the disintegration of enteric-coated dosage forms, disintegration testing was performed on enteric-coated aspirin tablets in the presence and absence of calcium in the test media. The results show that the presence of calcium ions retards the disintegration of enteric-coated dosage forms. This finding, which has not been reported in scientific literature, sheds light on the importance of conducting well-designed detailed investigations into the potential of calcium from dietary sources, calcium supplements, antacids, and/or phosphate binders affecting the absorption of drugs formulated into enteric-coated dosage forms. Moreover, it shows the necessity to investigate the potential of the occurrence of additional nutrient-excipient interactions.

An investigation of the disintegration of tablets in biorelevant media.

The purpose of the study was to examine the disintegration of tablets in media designed to simulate conditions pertaining in the stomach. Although many studies have been performed to determine dissolution rates in these media, little work has been undertaken on the preliminary step in dissolution, namely disintegration. Two tablet formulations were prepared. One disintegrated rapidly (under 25 s in water) and the other more slowly (8 min in water). The disintegration times were measured by the BP 2000 test using discs. For the rapidly disintegrating tablets, disintegration times were similar in all media except for whole milk. This media is used to simulate the fed stomach and disintegration times were over five times longer than in the other media (P < 0.05). A similar effect was seen with the poorly disintegrating tablets in milk, and prolonged times were also observed in some of the other media. For these latter media, there was a good correlation between the penetration rate of the fluid into the tablet and the disintegration time. Penetration rates for milk were also slow which may be a reflection of its relatively high viscosity and low surface tension.

Development of an automation system for a tablet coater.

An instrumentation and automation system for a side-vented pan coater with a novel air-flow rate measurement system for monitoring the film-coating process of tablets was designed and tested. The instrumented coating system was tested and validated by film-coating over 20 pilot-scale batches of tablets with aqueous-based hydroxypropyl methylcellulose (HPMC). Thirteen different process parameters were continuously measured and monitored, and the most significant ones were logged for analysis. Laser profilometry was used to measure the surface roughness of the coated tablets. The instrumentation system provided comprehensive and quantitative information on the process parameters monitored. The measured process parameters and the responses of the film-coated tablet batches showed that the coating process is reproducible. The inlet air-flow rate influenced the coating process and the subsequent quality of the coated tablets. Increasing the inlet flow rate accelerated the drying of the tablet surface. At high inlet flow rate, obvious film-coating defects (ie, unacceptable surface roughness of the coated tablets) were observed and the loss of coating material increased. The instrumented and automated pan-coating system described, including historical data storage capability and a novel air-flow measurement system, is a useful tool for controlling and characterizing the tablet film-coating process. Monitoring of critical process parameters increases the overall coating process efficiency and predictability.

Mixing efficiency in side-vented coating equipment.

The purpose of this study was to evaluate tablet mixing within side-vented coating equipment by assessing the development of color uniformity during coating. A colorimetric method was used to evaluate the time for uniform coating for different mixing baffle systems at different scales of equipment. The influence of tablet size was also determined. The inclusion of rabbit ear baffles in the small-scale equipment reduced the time to achieve color uniformity by 20 minutes. The design of baffle influenced the time for uniform color with a mixing efficiency rank order of tubular > ploughshare > rabbit ear. Upon scale-up, the efficiency of mixing seen at development scale remained equivalent in terms of the influence of baffle design. The study into the influence of tablet size revealed the importance that the total batch surface area has on the time taken to achieve color uniformity, with 7-mm diameter tablets having a higher surface area for an equivalent volume of product and taking 15 to 20 minutes longer to achieve color uniformity than 16-mm diameter tablets.

Influence of formulation and process parameters on pellet production by powder layering technique.

The goal of the present study was to evaluate the influence of the formulation and operating conditions on pellet preparation by pan technique. To this end, a new pelletization process, typified by the application of powdered drug on sugar-based cores using the GS coating system was studied. Inert cores were intermittently treated with micronized drug powder and adhesive solution. This treatment led to the formation of multiple layers of drug particles around an inert core resulting in the production of pellets that can further be coated by different polymers to obtain modified release formulations. Different procedures have been used to evaluate a series of important parameters such as initial core weight; speed of powder application; speed, type, and position of the atomizers; atomization degree; temperature; and air cap. Good yield of drug layering was obtained by adjusting the quantity of both the drug powder to apply and the binder solution. Pellets obtained following the optimal operating conditions (defined in a pre-formulation study) were film coated with the acrylic polymer Eudragit L30D in order to produce a model formulation consisting of enteric polymer-coated pellets containing ibuprofen. During its preparation, the formulation showed no degradation of the drug; moreover, a low percentage of residual humidity was obtained, indicating that this system is very efficient for the production of highly stable formulations. This study showed the good performance of the GS automated pan-coating system in obtaining enteric coated pellets prepared by powder layering technique using aqueous solutions.

In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES) in multi-pH media using United States Pharmacopeia apparatus II and III.

United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating cylinder) coupled with automatic sampling devices and software were used to develop a testing procedure for acquiring release profiles of colon-specific drug delivery system (CODES) drug formulations in multi-pH media using acetaminophen (APAP) as a model drug. System suitability was examined. Several important instrument parameters and formulation variables were evaluated. Release profiles in artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. As expected, the percent release of APAP from coated core tablets was highly pH dependent. A release profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH 5.0 buffer was established. The drug release in pH 5.0 buffer increased significantly with the increase in the dip or paddle speed but was inversely related to the screen mesh observed at lower dip speeds. It was interesting to note that there was a close similarity (f2 = 80.6) between the release profiles at dip speed 5 dpm and paddle speed 100 rpm. In addition, the release rate was reduced significantly with the increase in acid-soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect. In conclusion, the established reciprocating cylinder method at lower agitation rates can give release profiles equivalent to those for the paddle procedure for CODES drug pH-gradient release testing. Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus III approach has better potential for in vitro evaluation of colon-specific drug delivery systems.

Factorial analysis of the influence of dissolution medium on drug release from carrageenan-diltiazem complexes.

This research studied the influence of buffer composition, pH, and ionic strength on the release of diltiazem hydrochloride from a complex of the drug with lambda carrageenan. Two viscosity grades of carrageenan were also compared. A factorial analysis was used to evaluate the influence of individual variables and their interactions. Both the complex solubility, measured as the drug concentration in equilibrium with the solid complex, and the drug release rate from constant surface area were considered. The increase of ionic strength significantly increased complex solubility in all the buffer systems. A significant effect of polymer grade on complex solubility was evidenced only in phosphate buffer with a pH of 6.8, indicating lower solubility of the complex when higher polymer molecular weight was involved. In most cases, drug release rate decreased when high polymer grade was involved in the complex. Ionic strength did not always have a significant effect on drug release rate and was quantitatively less important than for solubility. Ionic strength especially affected the drug release profiles. At higher ionic strength drug release was no longer constant, but decreased with time, probably because of lower polymer solubility.

Drug release from Kollicoat SR 30D-coated nonpareil beads: evaluation of coating level, plasticizer type, and curing condition.

A newly available polyvinylacetate aqueous dispersion, Kollicoat SR 30D, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound (diphenhydramine hydrochloride) from nonpareil-based systems. Kollicoat SR 30D premixed with a selected plasticizer (10% wt/wt propylene glycol, 2.5% triethyl citrate, or 2.5% dibutyl sebacate), talc, and red #30 lake dye was coated onto the drug beads in an Aeromatic Strea I fluid-bed drier with a Wurster insert using bottom spray. With propylene glycol as the plasticizer, increases in polymer coating level retarded drug release from beads in a stepwise fashion along with apparent permeability, indicating a consistent release mechanism. Stability studies at 40 degrees C/75% RH revealed gradual decreases in dissolution rate, and additional curing studies further confirmed the dependence of release kinetics on curing condition. Furthermore, the type of plasticizer was found to play a key role. Unplasticized formulations exhibited the fastest dissolution, followed by formulations plasticized with triethyl citrate, propylene glycol, and dibutyl sebacate. All 4 formulations (unplasticized and plasticized), nevertheless, revealed a marked difference between uncured and cured dissolution profiles. Kollicoat SR 30D has, thereby, been demonstrated to effectively retard drug release from nonpareil-based systems. However, selected plasticizer type and subsequent curing condition play important roles in controlling drug release from such a system.

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets.

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK(a) 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.

Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy.

PURPOSE: To validate Magnetic Moment Imaging (MMI) for the investigation of gastrointestinal transit and disintegration of solid dosage forms and to correlate the MMI findings with the corresponding gamma scintigraphic data. MATERIALS AND METHODS: Three magnetic tablets (MTs) were investigated using in vitro and in vivo tests. The clinical study was a four-way, crossover study with the following arms: (a) immediate-release tablets administered in fasted state; (b) immediate-release tablets administered after 400mL of Clinutren ISO; (c) enteric-coated tablets administered in the fasted state; and (d) non-disintegrating tablets studied in the lightly fed state (100mL of Clinutren ISO). RESULTS: In both the in vitro and in vivo studies, tablets were detected successfully by MMI and scintigraphy. There was a good correlation between gastric residence times and positional data (in the x, y and y, z-axes). In addition, MMI revealed early swelling behaviour of the tablet matrix. There was excellent agreement for the disintegration times of MT(A) in the fasted arm (scintigraphy 12.0+/-4.4min, MMI 11.8+/-4.4min). In the MT(A)-fed arm, onset times determined by scintigraphy were delayed in three subjects when compared to the corresponding MMI results. Delayed disintegration was observed with MT(A) administered after food (p<0.01) in both the techniques. CONCLUSION: The MMI device is a reliable imaging tool for tracking the transit and disintegration of a magnetic tablet through the gastrointestinal tract.