Non-disintegrating Tablets Research Articles

Bead Compacts. I. Effect of Compression on Maintenance of Polymer Coat Integrity in Multilayered Bead Formulations

Little information is available on the comparability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat®) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.

The effects of pharmaceutical excipients on small intestinal transit.

1. The effect of three iso-osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non-disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11-14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39-94-149 min, and 40-82-124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non-disintegrating tablet preparations, when co-administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Design and Evaluation of a Rotating Basket-Paddle Dissolution Apparatus

The rotating basket-paddle dissolution apparatus is a combination of the USP/NF rotating basket and rotating paddle. A comparative dissolution study was performed utilizing this new apparatus and the two USP/NF apparatus at various stirring speeds using non-disintegrating oxalic acid tablets and disintegrating aspirin tablets. The amount of drug released using the new apparatus was significantly higher than the rotating basket but significantly lower than the rotating paddle at each of the stirring speeds studied. The results obtained using this new apparatus were highly reproducible compared to the USP/NF apparatus.

Characterization of colonic transit of nondisintegrating tablets in healthy subjects

The transit of pharmaceutical dosage forms through the colon has been shown to be highly variable. The amount of fiber in the diet is known to alter gastrointestinal transit; however, the dietary intake of the subjects in previous studies was not adequately controlled. Using the technique of gamma scintigraphy, we have therefore characterized the variability in the colonic transit of nondisintegrating tablets, by strictly controlling the dietary fiber intake of the subjects. Eight healthy male subjects followed a diet containing 25 g dietary fiber per day, for six days prior to dosing. Each subject received five 6-mm nondisintegrating tablets on three consecutive days. Mouth-to-anus transit times exhibited a high degree of variability. Regional differences in colonic transit were evident. Tablet stasis appeared to occur mainly in the ascending colon and hepatic flexure. Despite the diets of the volunteers being identical, colonic transit was still observed to be highly variable, which suggests that this variability is intrinsic.

Influence of pH on Release of Phenytoin Sodium from Slow-Release Dosage Forms

Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic dissolution rate as functions of pH, type of dosage form, pH of dissolution medium used, and conversion of the sodium salt to free acid (phenytoin). The innovator’s product, Extended Phenytoin Sodium Capsule (Dilantin Kapseal, 100 mg, ParkeDavis), and two experimental formulations (one nondisintegrating tablet containing polymeric materials and the other a solid dispersion in an erodible matrix) served as the slow-release dosage forms. The sodium salt converts to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to such a conversion inside or at the surface of slow-release dosage forms, the release of drug in this pH range was incomplete. The extent of drug release also varied with the type of formulation used. In contrast, complete dissolution could be obtained in water because the pH of the medium gradually rose from -6 to -9.2 where the drug solubility was higher. Although several phenytoin sodium products might have similar dissolution rates in water, the extents of drug release under gastrointestinal pH conditions (pH 1 -8) could differ greatly, thus supporting the Food and Drug Administration recognition that the similarity in dissolution profiles in water does not assure that the products are bioequivalent. The reported lower steady-state level of phenytoin in human plasma following oral administration of a slow-release dosage form may be related to incomplete drug release.

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and td of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and td between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t1/2 (7.12 h), while apparent t1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for Cmax and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p < 0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the 'Levy's plot' (per cent released versus per cent absorbed) approach and provided further support for the correlation found.

The effect of meal composition on the gastrocolonic response: implications for drug delivery to the colon.

The response of the colon to eating, the gastrocolonic response (GCR), may have important implications for the design of drug dosage forms for selective delivery to the colon. Therefore, the effect of meal composition on the GCR and its relation to the transit of nondisintegrating tablets has been investigated. Eight healthy male volunteers each received 5 x 6-mm radiolabeled nondisintegrating tablets, and the transit was followed using a gamma camera. When the tablets reached the ileocolonic region, each volunteer received a test meal (1000 kcal) containing 70% carbohydrate, 15% fat, and 15% protein. The subsequent movement of the tablets was then monitored. The study was repeated using a 70% fat meal and a 70% protein meal, so that the effects of a high-carbohydrate, a high-fat, and a high-protein meal on the GCR could be compared. The incidence of GCRs was similar after all meals. Thus, there appeared to be no effect of meal composition on the movement of the tablets into the colon. This implies that the ingestion of food may not necessarily stimulate the passage of material across the ileocecal junction and that other factors may also be involved.

The transit rate of different-sized model dosage forms through the human colon and the effects of a lactulose-induced catharsis

Gamma scintigraphy has been used to compare the colonic transit rate of different sizes of radiolabelled model dosage forms in healthy human subjects. Studies simultaneously compared the ascending colon residence time of 111In-labelled 0.2 mm ion-exchange resin particles and 99mTc-labelled 5 or 8.4 mm non-disintegrating tablets. Under normal conditions, no difference was observed between the rate of transit through the ascending colon of 0.2 mm particlesvs 5 mm tablets ( n = 11) or 0.2 mm particles vs 8.4 mm tablets ( n = 10). The mean period of residence of 50% of the administered 0.2 mm particles in the ascending colon was 11.0 ± 4.0 h ( n = 21). Coadministration of the laxative, lactulose, to subjects receiving the 0.2 and 5 mm particles significantly accelerated colonic transit. Under these conditions, the ascending colon residence of the 0.2 mm resin was significantly shorter than for the 5 mm tablets, although the magnitude of the effect was small.

Evaluation of the gastric retention properties of a cross-linked polymer coated tablet versus those of a non-disintegrating tablet

The gastric emptying time of tablets coated with a cross-linked polymer that enabled them to balloon and float in gastric media has been compared with that of uncoated, non-disintegrating tablets in both fasted and fed states, with healthy human volunteers using gamma camera scintigraphy. In the fed state, the balloon tablets prolonged the gastric emptying time by an average of 6 h over that of the uncoated tablets. The emptying times for both coated and uncoated tablets were much shorter in the fasting state. The balloon tablet did not significantly prolong the gastric emptying time in the fasted state.

Coating of certain matrix cores with aqueous-based systems of acrylate methacrylate, a water-insoluble copolymer and drug release profiles

Abstract Physical mixtures of an acrylate methacrylate copolymer (in fine powder) and salicyclic acid (drug model) in a ratio of 1:4, have been compressed directly (i.e. without further granulation) to matrix (non-disintegrating) tablets to serve as core models. A coacervation technique was used to form an aqueous-based coating system consisting of a water-insoluble copolymer and sucrose in varying proportions. Film coatings were applied on the matrix cores to a thickness 75 ± 3 ωm (SEM). Drug-release rates increased as a linear function of the initial sucrose content in the film coatings. The amount of sucrose leached from the film coatings into the leaching fluid also increased linearly and in parallel with the increase in release rates. The release profiles obtained with cores with coating thickness of 75 μm were generally without a time-lag. Doubling the coating thickness introduced a time-lag (preceding the onset of release) of about 2.5 h, 1.3 h or 0.5 h for polymeric coatings without sucrose, or with sucrose 12.5% w/w, or 25% w/w, respectively. Coatings with a higher sucrose content did not display the release time-lag. Overall release rates were hardly affected by the increase in coating thickness.

Sustained-release dosage form of oxolamine citrate: preparation and release kinetics.

One of the principal uses of microencapsulation for pharmaceuticals has been the preparation of sustained-release dosage forms which have been usually presented in the form of a suspension or gel. However, a non-disintegrating tablet would be a better formulation to obtain sustained-release effect. Microencapsulation has been employed to provide protection of the core material against atmospheric effects, to cover the unpleasant taste and to enhance the stability. A number of drugs have also been encapsulated to reduce gastric and other GI tract irritations, to alter release properties and to change availability. Oxolamine citrate is one of the synthetic derivatives of 3,5-disubstituted 1,2,4-oxodiazole, used particularly for its antitussive activity. The usual dose of the drug is 200 mg given four times a day. Its use was limited by side-effects of nausea and vomiting. In order to prevent the disadvantages caused by taking the drug four times daily, and to reduce the side-effects, a sustained-release dosage form of oxolamine citrate was prepared by the microencapsulation technique and microcapsules thus formed were pressed into tablets. Dissolution tests were done with microcapsules and tablets formed by microcapsules by using the USPXXI paddle method and dissolution kinetics were studied and evaluated.

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

AbstractA comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.

Dissolution of solid dosage from. II. Equations for the dissolution of nondisintegrating tablet under the sink condition.

An equation for dissolution from the whole surface of a nondisintegrating single component tablet under the sink condition was derived. Also, equations for several dissolution manners of the tablet under the sink condition were derived in the postulation of the dominant dissolution rate constant which determines the dissolution manner. The applicability or validity of these equations were examined by the dissolution measurements with nondisintegrating single component tablets. About one-tenth the amount of the amount needed to saturate the solution was used to prepare a tablet, and dissolution measurements were carried out with the tablet whose flat or side surface was masked with an adhesive tape in accordance with the conditions for derivation of equations. Among the derived equations, dissolution from the whole surface of a tablet was expressed by a form similar to the cube root law equation for particles. Hence, a single component tablet compressed by the use of a suitable amount was thought to behave like a single crystal. Also, equations derived for several dissolution manners were thought to be applicable for the dissolution of a nonspherical particle and crystal concerning the crystal's habit and its dissolution property, and the extended applicability was examined by converting the crystal into a simplified or idealized form, i.e., rectangle or plate.

Correlation of the gastric emptying of nondisintegrating tablets with gastrointestinal motility.

The aim of the present study was to correlate the gastric emptying (GE) of nondisintegrating tablets with changes in gastrointestinal (GI) motility. Eight, healthy, male subjects each received 5 x 7-mm radiolabeled tablets, a radiolabeled meal, and a radiotelemetry capsule (RTC). Transit of the radiolabeled formulations was followed by gamma scintigraphy and the RTC detected contractile activity in the GI tract. The study demonstrated that 7-mm tablets can empty from the fed stomach, prior to the onset of interdigestive activity. Those tablets that were not emptied during fed activity were retained through the period of quiescence associated with the onset of the migrating myoelectric complex (MMC) and left the stomach during contractions associated with phase 2 and 3 activity. The RTC was retained in the stomach and was emptied only by large phase 3 contractions commonly termed the "housekeeper" wave. However, in one subject, the RTC was retained in the stomach for over 12 hr, during which time three distinct phase 3 complexes were monitored.

The effect of tablet size on the gastric emptying of non-disintegrating tablets

The gastrointestinal transit of non-disintegrating tablets of different sizes (7–13 mm diameter) was investigated in fed subjects using the technique of gamma scintigraphy. The 13 mm tablets took longer to empty from the stomach, with less variation between the individual data, than the smaller tablets.

Gastrointestinal transit of non-disintegrating tablets in fed subjects

The gastrointestinal transit of non-disintegrating tablets of different sizes (3–7 mm diameter) was monitored in fed subjects. Transit of the tablets was followed using the technique of γ-scintigraphy. Neither the gastric emptying nor small intestine transit of the tablets was affected by their size. However, the nature of the meal consumed had a marked effect on gastric emptying. The nature of the meal also appeared to influence the transit through the ileocaecal sphincter.

Gastric emptying and small and large bowel transit of non-disintegrating tablets in fasted subjects

The gastrointestinal transit of non-disintegrating tablets was investigated in fasted subjects. The tablets (5 × 5 mm diameter) were administered on 3 consecutive days. Transit of the tablets was monitored using γ-scintigraphy. The tablets emptied from the stomach and traversed the small intestine as a bolus. The rate of transit through the colon showed a large inter-subject variation. However, in all cases, the tablets dispersed throughout the colon.

Some Factors Influencing the Release of Drdg from Nondisintegrating Slow Release Tablets

AbstractThe purpose of this study was to investigate some factors that control the drug release from non disintegrating cylindrical slow release tablets using sodium salicylate as a model drug. The in vitro release of sodium salicylate was described adequately by a previously published cubic equation. It was found that the release of the drug from a nondisintegrating tablet is controlled by the factors such as porosity (e) of the tablet and the mass of drug present (A) per unit tablet volume. On the other hand, pH of the dissolution fluid had no influence on the release of sodium salicylate.

Relationship Between Planar and All-Surface Rate Constants for Drugs Formulated in Nondisintegrating Cylindrical Slow-Release Tablets

The release of drug through the planar surface of a nondisintegrating tablet with an insoluble matrix has been described mathematically using the Higuchi release rate constant (kH). The release of drug through a similar all-surface tablet has been described by using a cubic equation and the all-surface rate constant (kr). Using sodium salicylate and quinidine sulfate as model drugs, the relationship between kH and kr was verified for cylindrical slow-release tablets. Accordingly, the rate constant obtained from a single exposed planar surface can be used to predict the rate constant (kr) when all surfaces of the tablet are exposed to dissolution fluid.

In vitro assessment of the adhesiveness of film-coated tablets

A method has been developed to assess the adhesivity of capsules and film-coated tablets. The adhesiveness of tablets, a property important during aqueous film-coating processes and oesophageal transit, has been studied using a strain gauge device to measure the force required to detach the dosage form from a planar moist surface. The results obtained by this method correlate well with those obtained using an ex vivo method involving strips of porcine oesophageal mucosa. Non-disintegrating tablets were coated with hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) and the polymethacrylate copolymers Eudragit E100 and L100. The influence of film-coat thickness, and added poly(oxyethylene) glycol (PEG) of varying molecular weight was studied. While Eudragit polymers had little adhesive potential, HPC and HPMC film-coats became more adhesive with increase in film thickness, but the presence of PEG of molecular weight > 1000 markedly reduced adhesiveness.