Oral Sustained Release Dosage Form Research Articles

Development of a Sustained Release Dosage Form for α‐Lipoic Acid. II. Evaluation in Human Volunteers

Within this study an oral sustained release dosage form of α‐lipoic acid (thioctic acid) has been generated and evaluated in healthy volunteers. A granulate comprising 56.8% α‐lipoic acid and 43.2% chitosan acetate was compressed to tablets (weight: 0.45 g; diameter: 10.0 mm; thickness: 4 mm). Three of these tablets were administered at once orally to each volunteer. Prior to administration and then every hour for 12 hours blood samples were taken from the antebrachial vein. α‐Lipoic acid concentrations in plasma were quantified via precolumn derivatization and reversed‐phase high‐performance liquid chromatography (HPLC). Results demonstrated that an increased plasma level of α‐lipoic acid can be achieved by this formulation for at least 12 hours. Within this time period at least two maximum plasma concentrations were reached. The first one is based on the release of α‐lipoic acid, which is not ionically and therefore only loosely bound to chitosan, whereas a second maximum is based on the release of the drug during the enzymatic degradation of the chitosan matrix in the colon. The AUC0→12 was determined to be 183.8 ± 101.4 µg × min/mL (mean ± SD; n = 8). Because of the pulsed sustained release of α‐lipoic acid, the dosage form described here seems to be highly beneficial in order to stimulate the glucose uptake in the case of diabetes type II.

Development and evaluation of a multiple-unit oral sustained release dosage form for S(+)-ibuprofen: preparation and release kinetics

Mini-matrix tablets containing S(+)-ibuprofen have been prepared by the wet granulation method. The hydrophilic matrix was formed with either xanthan gum, karaya gum or hydroxymethylcellulose (HPMC) together with a choice of additives from lactose, Encompress®, Avicel® PH101, talc and Lubritab®. Multiple unit dosage forms (MUDFs) were subsequently obtained by encapsulating the mini-matrix tablets into hard gelatin capsules. Preparation, in vitro release profiles and release kinetics are presented.

Evaluation of theophylline tablets compacted by means of a novel ultrasound-assisted apparatus

Abstract A model formulation containing theophylline and Eudragit® RL was compacted, at energies ranging between 15 and 150 J, by means of a laboratory-scale, novel tabletting machine in which compaction was effected by ultrasound, rather than by mechanical energy. Comparison of the technological and physico-chemical characteristics of the resulting tablets with those of tablets obtained with a conventional tabletting machine evidenced significant differences, suggesting sintering as the main mechanism operating in ultrasound-assisted compaction. The ultrasound-compacted tablets released the drug at lower rates with respect to conventional tablets. The novel technique migh prove useful for the development of sustained-release oral dosage forms containing theophylline or other suitable drugs.

Preparation and characterization of melatonin-loaded stearyl alcohol microspheres

A sustained release dosage form which delivers melatonin (MT), a pineal hormone, is of clinical value because of the short half-life of MT, for those who have a disordered circadian rhythm. The purpose of this study was to prepare MT-loaded microspheres by the emulsion melting/cooling method using stearyl alcohol (SA) and also dual walled chitosan and sodium alginate beads, and to evaluate the release characteristics in simulated gastric and intestinal fluid. The MT-loaded microspheres were spherical, ranging in diameter from about 250–750µm. When polyethylene glycol 4000 (PEG), as a water-soluble or aluminium tristearate (AT), as a water-insoluble additive, was incorporated, the surface roughness was further reduced resulting in a smooth matrix structure. The dual walled chitosan and sodium alginate beads entrapping small MT-loaded microspheres were not spherical in structure. As the additives incorporated into SA microspheres increased, the drug content decreased. The release profiles of the MT-loaded microspheres were independent of pH. When the melted SA solution was cooled rapidly in 10 min to 25 °C, the drug content increased but the release rate of MT-loaded microspheres decreased. The release rate of drug decreased as the amount of SA increased but an increase of agitation speed and amount of AT and PEG resulted in increased release rates. The release rate of drug from dual walled chitosan beads increased slightly but was retarded in the case of dual walled alginate beads when compared to MT-loaded microspheres. The emulsion melting/cooling method used to prepare MT-loaded microspheres using SA is simple and inexpensive, and may provide an alternative for the preparation of an oral sustained release dosage form of MT without using harmful organic solvents. The dual walled chitosan and sodium alginate beads may also provide a convenient way to control the release of drugs.

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.

Relative bioavailability of a novel sustained-release acetaminophen molded tablet

An experimental easily swallowable oral sustained-release dosage form of acetaminophen (APAP) that can be administered to patients every 12 hours was formulated and evaluated in 8 healthy, adult volunteers. The test product was compared to a well-characterized, commercially available immediate-release acetaminophen caplet. Multiple doses of these two products were administered to 8 healthy human subjects in a two-way cross-over design. Saliva samples were collected over a period of 24–48 h depending upon the administered treatment. The time course of acetaminophen concentrations in saliva was analyzed using non-compartmental methods. Results indicate that it is possible to maintain the desired therapeutic concentration over a 12-h dosing interval using the molded tablet dosage form.

Hydrophobic Aerosils as Dry Coating Agents for Sustained-Release Formulations

AbstractAn innovative and simple dry coating process for formulation of oral sustainedrelease dosage forms was developed. A hydrophobic aerosil (Aerosil® R972) was investigated as a dry coating agent. Aerosil® R972 particles adhered to the surface of acetaminophen particles upon dry coating. The release rate of the drug decreased with increased concentrations of aerosil. The release of acetaminophen from dry coated mixtures in capsules followed a square root of time release for the first 2 hours followed by zero-order release. A first-order relationship was found between the release rate and concentration of Aerosil® R972 in dry coated mixtures.

Glutaraldehyde cross-linked bovine casein microspheres as a matrix for the controlled release of theophylline: in-vitro studies.

A controlled release dosage form of theophylline in the form of microspheres using the milk protein casein as the matrix is described. Glutaraldehyde cross-linking of an aqueous alkaline solution of the protein containing the drug, dispersed in a mixture of dichloromethane/hexane having ca. 1% of an aliphatic polyurethane as the suspension stabilizer, led to the formation of the drug-loaded microspheres. Drug incorporation efficiency of around 80% could be achieved by the technique. Release profiles of the drug were examined in simulated gastric and intestinal fluids at 37 degrees C. It was observed that the release was diffusion-controlled and followed the Higuchi model. Release characteristics were influenced by the cross-linking density, particle size and the extent of loading. Data obtained indicate that the natural milk protein casein could be used as a matrix for sustained release oral dosage forms.

Microencapsulation studies on aminophylline involving spherical crystallization, spheronization and drug loading on to non-pareil seeds.

Aminophylline was formulated as small spherical cores for subsequent coating in an attempt to develop a competitor microencapsulated product to the commercial available sustained-release tablet, Phyllocontin. Optimum spherical crystallization conditions yielded cores of loosely adhering crystals of active, with highly irregular surface morphology and poor mechanical strength during pan coating. Aqueous spheronization yielded satisfactory cores in high yield when microcrystalline cellulose and liquid paraffin were used. However, application of large amounts of controlled-release coatings based on Eudragit RL and RS failed to produce a product with retarded drug dissolution comparable to the commercial product. Drug loaded non-pareils were easily formed, but required application of about 20 per cent Eudragit RL/RS coating to achieve adequate prolonged-release properties. Application of 10 per cent hydrogenated castor oil/ethylcellulose based coating gave acceptable in vitro release only if the microcapsules formed were tableted and annealed. All products investigated rapidly discoloured during storage and none were considered to represent a realistic alternative to tableting technology for the production of a sustained-release oral dosage form of aminophylline.

Gastrointestinal transit of pellets of differing size and density

The gastrointestinal transit of four multiple unit pellet dosage forms of two sizes 0.5 and 4.75 mm and two densities 1.5 and 2.6 g cm −3 was examined by gamma scintigraphy in eight healthy fasted subjects. The pellets were prepared by the processes of extrusion and spheronisation and radiolabelled with 99mTc or IIIIn. Small pellets of normal and high density were examined on one occasion and large pellets of normal and high density on another. The small and large pellet data from each administration were analysed separately, and then pooled to determine the overall effects of size and density on gastrointestinal transit. A distinct lag phase before gastric emptying commenced was observed for all pellets. The onset of emptying was not affected by size or density. Thereafter gastrointestinal transit did appear to be prolonged with an increase in density. This effect was more clearly demonstrated by the smaller pellets. Small pellet data and the pooled data indicated that an increase in density delayed gastric emptying and prolonged small intestinal residence time ( p < 0.05). The large pellet data alone, also indicated that the increase in density caused a delay in gastric emptying ( p < 0.05) but the prolongation of small intestinal residence time was not significant. Gastric emptying of the pellets was not affected by their size, although small intestinal residence time was prolonged by the large pellets ( p < 0.05). These results and those previously reported by the authors (Clarke et al., Int. J. Pharm., (1993 in press) suggest that there may be a threshold density, of the order of 2.4–2.6 g cm −3, above which gastric emptying is prolonged. The delayed gastric emptying and prolonged small intestinal residence time have important implications for the rational design of sustained release oral dosage forms.

The time to reach steady state after the administration of intravenous bolus, constant infusion, and oral immediate-release and sustained-release preparations.

Based on one-compartment pharmacokinetic model, the equations to calculate the specific fractional steady-state of drug level achieved at any time (FSS) after administration of intravenous bolus, constant infusion, and oral immediate-release preparations are reviewed. Also the equation to calculate FSS after administering an oral sustained-release dosage form is derived. From these equations, it can be shown that the drug FSS after these routes of administration is dependent primarily on the elimination rate constant (K). However, for a sustained-release preparation, the FSS is dependent on K, drug release rate constant (Kr), as well as the fraction of sustained release (Fs) of the dosage form. Using the new derived equation for FSS, several simulations were performed to evaluate the effects of Kr K, and Fs. These indicate that the time to achieve a given FSS is prolonged as Kr or K becomes smaller and as Fs becomes large.

Bioavailability study of Theo-dur tablets in the fasted cannulated dog

The present study uses the cannulated dog to verify the major elements of gastrointestinal (GI) motility affecting the performance of oral sustained release dosage forms. It appears that the residence time of a Theo-dur tablet in the fasted canine stomach and small intestine is dictated by the phasic activity of the motility pattern at the time of ingestion. The tablet does not disintegrate in vivo but undergoes surface erosion. Onset of tablet discharge corresponded with late phase II and phase III activity. The discharged eroded tablet was entrapped within mucus plugs. Mucus may play a significant role in the dissolution of administered tablets. There is little variability in the duodenal and ileal effluent pH, observed after onset of Theo-dur tablet discharge.

Sustained-release and intragastric-floating granules of indomethacin using chitosan in rabbits.

The release rate of indomethacin from chitosan granules was compared with that of conventional commercial indomethacin capsules and a sustained-release capsule. In contrast with the rapid release of a commercial conventional capsule form, sustained release from the chitosan granules was observed. Furthermore, the release rate could be controlled by changing the mixing ratio of drug and chitosan.The potential of chitosan granules as an oral sustained-release dosage form of indomethacin was investigated in rabbits. When a conventional commercial capsule was administered orally to rabbits, the plasma concentration reached the maximum level 1 h after administration. In the case of the granules with a 1: 2 mixture of drug and chitosan, the chitosan granules did not give a sharp peak of plasma concentration, but produced a sustained plateau level of indomethacin. The area under the plasma concentration curve (AUC)(0-8 h) value of chitosan granules showed a slightly higher value than that of commercial capsules. This may be due to the slow rate of release from the chitosan granules and the longer residence time in the stomach.Thus, in terms of decrease in the peak of plasma concentration and maintenance of indomethacin concentration in plasma, the chitosan granules were superior to the conventional commercial capsules. Indomethacin granule preparations using chitosan may be practically useful as oral preparations with reduced side effects and with prolonged action.

Pharmaceutical considerations of transdermal nitroglycerin delivery: The various approaches

When formulated as a sublingual or an oral sustained-release dosage form, nitroglycerin has certain shortcomings, i.e., decreased duration of antianginal action and extensive hepatic first-pass elimination, which limit its efficacy. The finding that administration of nitroglycerin in the form of topical ointment decreases the extent of hepatic first-pass elimination and increases the duration of therapeutic activity has pointed the way to the possibility of developing a more effective transdermal drug delivery device. Three such devices are the Nitrodisc, Nitro-Dur, and Transderm-Nitro systems. All three systems generate effective plasma drug levels within 30 minutes and maintain steady-state drug plasma levels as follows: the 16 cm 2 Nitrodisc at 280.6 ± 18.7 pg/ml for 32 hours; the 20 cm 2 Nitro-Dur at 201.4 ± 60.7 pg/ml for 24 hours; and the 20 cm 2 Transderm-Nitro system at 209.8 ± 22.8 pg/ml for 24 hours. In vitro studies show that the drug penetrates the skin with zero-order kinetics in all three systems, the rate for Nitrodisc being 20% greater than that of the other systems. When the daily nitroglycerin dose is calculated in terms of skin permeation rate and the device's surface area, the three transdermal systems become clinically interchangeable.

Greatly enhanced bioavailability of theophylline on postprandial administration of a sustained release tablet

The bioavailability of theophylline after oral administration of a new sustained release tablet Theograd-250 mg was studied in 7 healthy volunteers, under fasting and non-fasting conditions. Whilst fasting the bioavailability was moderate at 64 +/- 22% (mean +/- SD), whereas in the non-fasting state the relatively high bioavailability of 90 +/- 13% was found. The drug appeared to be significantly more slowly absorbed when a tablet was taken after a meal, than when it was ingested on an empty stomach. In the former case, the peak level was reached after 6.9 +/- 1.0 h, whereas in the fasting state the maximum serum concentration occurred 4.0 +/- 1.7 h after administration of the drug. Despite the slow absorption, the peak non-fasting level of 4.4 +/- 1.4 mg . 1(-1) was significantly higher than the 3.1 +/- 1.0 mg . 1(-1) observed in the fasting state. The profiles of the serum concentration-time curves showed that the concentration remained above 75% of Cmax for 8.7 +/- 1.3 h in the fasting and 9.0 +/- 1.1 h in the non-fasting state. It was concluded that to define the optimal dosage regime for sustained release oral dosage forms of theophylline, the influence of food on absorption from these preparations should be taken into account. Based on the present results, Theograd-250 mg tablets have predictable absorption and a high (90%) bioavailability if taken after a meal.

Evaluation of an Oral Sustained Release Dosage Form of Trimeprazine as Measured by Urinary Excretion

Effectiveness of sustained release dosage forms of trimeprazine tartrate, as pellets with varying thicknesses of a slowly digestible wax-fat mixture, is measured by determining the urinary excretion of the drug or its metabolites during specified periods after ingestion. Results are compared with in vitro tests.

Sulfaethylthiadiazole V : Design and Study of an Oral Sustained Release Dosage Form

An aueous sustained release suspension of sulfaethidole (sulfaethylthiadiazole or SETD) was prepared. The velocity constant ( K b ) for drug disappearance from blood in adult human subjects was utilized to approximate the quantity of drug to be administered every twelve hours in order to maintain free SETD blood concentrations near 10 mg. per cent. Dissolution characteristics of this sustained release suspension were also studied in vitro in three different test fluids. Possible relationships with the foregoing in vivo results are discussed.