Release Granules Research Articles

SUSTAINED-RELEASE FORMULATIONS FOR NIFEDIPINE

Three formulae of nifedipine sustained release granules were tried, each containing 10% of the drug. The former one was composed of nifedipine, lactose and PVP 40000, and prepared adopting moist granulation technique. In the second formula, the drug, PEG 6000 and HMPC were coprecipitated into microcrystalline cellulose. While the latter one was composed of nifedipine, and three components which are; HMPC; ethyl cellulose as binders; and corn starch as a filler. These granules and the plain nifedipine powder were investigated in vitro as well as in healthy subjects. The third formula showed pronounced dissolution rate compared to the other tested ones. The granules of the second and the third formulae were administered orally to healthy subjects and the plasma levels of nifedipine were compared with those after administration of nifedipine powder. Plasma levels following the administration of the granules were prolonged but a reduced level was observed. This indicates the sustained release of the drug from the granules in vivo. The plasma profiles of nifedipine indicated that the latter formula granules were superior to that with the second formula granules with respect to prolonging the effective plasma levels and to minimizing the intersubject variations.

Effect of Viscosity Increasing Agent and Electrolyte Concentration on the Release Rate of Theophylline from a HPMC Based Sustained Release Capsules

AbstractSustained release (SR) granules (250-650∼) containing theophylline were prepared using hydroxypropyl methylcellulose (HPMC) as a rate retarding polymer. The effect of variable ionic strength and viscosity increasing agent on the theophylline release rate have been investigated. Irrespective of dissolution media the theophylline release kinetics was found to be dependent on square root of time. Thc Higuchian release rate (K) was found to increase exponentially with the increase in ionic strength of the dissolution fluid. An opposite effect was observed with the viscosity increasing agent sodium carboxy methyl cellulose (Na-CMC) in the dissolution fluid. The release rate dccreased linearly with the increase of Na-CMC concentration in the dissolution fluid.

Hydrophilic matrices for the extended release of a model drug exhibiting pH-dependent solubility

After oral administration of basic drugs, the different pH values of the gastrointestinal tract can result in drastic changes in drug solubility, which can be very high at acidic pH values and dramatically low at neutral/basic pH, with consequent problems for the design of oral extended release formulations. In this paper, the preparation of an oral extended release formulation containing a basic drug is proposed, using dipyridamole as model. Three-component modified release granules capable of moderating the drastic dissolution behavior of dipyridamole were prepared by loading a swellable polymer (cross-linked sodium carboxymethylcellulose) with both the drug and an enteric polymer (cellulose acetate phthalate or cellulose acetate trimellitate). In vitro dissolution tests of modified release granules in USP gastric fluid showed a modulation of the high dissolution rate of dipyridamole at the acidic pH values, while in USP intestinal fluid a very marked improvement in drug dissolution was observed. Hydrophilic matrices containing the drug with the smoothed dissolution rate characteristics were prepared via mixing the granules with a gelling polymer (cellulose ether) and then tabletting the resulting mixture. In vitro release tests performed both at constant pH and with pH variation showed that the matrices are capable of providing extended drug release in both acidic and neutral/basic media.

Factors influencing release and distribution of carbofuran from granules into soils

Manipulation of soil concentrations of pesticides may he achieved by controlling the rate of release of the active agent from solid formulations. Such controlled release granules have reduced losses in delivery of soil pesticides, such as carbofuran, leading to lower application rates in the field and less leaching hazard. A high carbofuran content (35%) solid formulation was based on by-product lignin modified with polyvinyl chloride (10%) and which can degrade in the soil and thus release completely the active ingredient. As part of a series, studies on factors influencing the release and fate in soil of carbofuran delivered in this form were performed on granules and thin flake formulations of the lignin-based carbofuran matrix under static water and various non-leaching soil conditions at constant temperature. Two agricultural soils were used; one originating in Northern Britain and the other from Sudan. Release and distribution of the carbofuran from the formulations into the soil was evaluated over 17 weeks according to the soil type and water content. Comparison was also made for the two particle sizes used and with release under sink conditions of water immersion. Results indicated that certain soil properties influenced the release kinetics and that the rate was correlated with moisture content of each soil type. However, the kinetics fitted a model that was generally valid for all the environments studied.

Control of termites and other soil pests of groundnuts with special reference to controlled release formulations of non-persistent insecticides in India and Sudan

AbstractTrials for the control of soil pests, particularly of termites (Isoptera: Termiti-dae), in groundnuts (Arachis hypogaea) in India and Sudan used chlorpyrifos and isofenphos granules, chlorpyrifos, phorate, carbosulfan and carbofuran in controlled release formulations, and chlorpyrifos seed dressing. Their effects on foliar pests were also noted. Chlorpyrifos controlled release pellets were as effective as aldrin, used as a standard, in reducing root and pod attack and, like aldrin, doubled yields. Isofenphos and chlorpyrifos granules increased yields and reduced pod damage, but to a lesser extent. Other treatments were less effective. Carbosulfan and phorate controlled release and isofenphos granules reduced leaf miner attack. These trials establish the efficacy of controlling termites and other soil pests with controlled release formulations of otherwise non-persistent insecticides. However, the expensive formulation is unlikely to be cost-effective for rural farmers in developing countries and, in the case of chlorpyrifos, residue levels in kernels may be unacceptable. Future work should investigate other insecticides in the formulation and development of cheaper controlled release matrices.

５‐ＦＵ誘導体（ＳＦ‐Ｓ）の組織内濃度に関する検討

Thirty two patients with oral cancers were orally administered 600-800mg/day of SF-S which contains sustained release granules of tegafur before operation. Tegafur and 5-FU concentrations in serum, submandibular lymph nodes, normal and cancerous tissues were evaluated after SF-S administration by the method of chemical assay using HPLC and GC-MS.The mean tegafur concentrations in serum, submandibular lymph nodes, and normal and cancerous tissues were 15.1μg/m/, 9.91μg/g, 9.52μg/g, and 9.84μg/g, respectively. The mean tegafur concentration in serum was significantly higher than that in the other tissues (p<0.001). The mean 5-FU concentrations in serum, submandibular lymph nodes, and normal and cancerous tissues were 22.5 ng/m/, 171.9ng/g, 44.0ng/g and 173.9ng/g, respectively. The mean 5-FU concentration in cancerous tissues was much higher than 50ng/g which was reported to be the minimum effective concentration, and significantly higher than that in serum and normal tissues (p<0.001). Besides, the mean 5-FU concentration in submandibular lymph nodes was similarly higher than that in serum and normal tissues (p<0.01). With regard to the locations of cancerous tissue, the mean 5-FU concentrations in cancerous tissues of maxillary gingiva, mandibula gingiva, tongue, buccal mucosa, and oral floor were 158.8ng/g, 309.7ng/g, 94.1ng/g, 95.2ng/g, and 348.2ng/g, respectively. The mean 5-FU concentration in cancer tissues of mandibular gingiva was significantly higher than those of tongue and buccal mucosa (p<0.05).In conclusion, these results suggest that SF-S could also be effective against oral cancer.

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.These formulations were obtained in two different steps:a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.

Controlled release granules are an attractive alternative to conventional oral terbutaline

Controlled release granules are an attractive alternative to conventional oral terbutaline

FORMULATION OF CONTROLLED-RELEASE IBUPROFEN GRANULES AND EVALUATION OF THE ANTIINFLAMMATORY ANALGESIC ACTIVITIES

Two kinds of granules were prepared: one. with pH-dependent Release and the other with pH-in dependent release. The former was composed of ibuprofen, celluloseacetate phthalate, ethylcellulose and microcrystalline cellulose while the latter was composed of ibuprofen, hydroxypropyl methylcellulose, ethylcellulose and corn starch. The effects of mixing ratios of the polymers; pH of the release medium, and the drug content in the granules were examined in-vitro to investigate the release characteristics. In granules with pH-dependent, the release rate was decreased with the increment of ethylcellulose and as the pH of the release medium increased. While in granules with pH-independent, the release rate was decreased as the ratio of hydroxypropyl methylcellulose (HPMC) to ethylcellulose (EC) increased Analgesic activity of four seleted formulations of the controlled release was tested by two methods using p-benzoquinone (PB2) induced withing and the hot-plate. Also the anti-inflammatory activity of these formulations was examined after oral administration of the granules by using trypan-blue dye method. Results that the formulation of ibuprofen granules pH-independent containing HPMC and EC revealed in ratio of 3:1 had a delayed onset of anti-inflammatory and analgesic action extended for four hours or more while granules of ibuprofen with pH-dependent containing 4% ethylcellulose and 2% cellulose acetate phthalate were capable of increasing analgesic against thermal stimuli for four hours whereas lower percentage protection against PBO-induced wrifhing, was observed. Statistical analysis of the results were done using student's t-test. The pH- independent release granules were superior to the pH-dependent release granules with respect to prolonging the effective antiinflammatory action when administered orally to rats.

だ液中濃度測定による小児用Ｔｈｅｏｐｈｙｌｌｉｎｅ徐放性製剤の評価

The bioavailability of theophylline following administration of two pediatric sustained release tablets (Theona-P® and Theo-Dur®), two crushed sustained release tablets (crushed Theona-P® and crushed Theo-Dur®), and newly developed sustained release granules (E-0686-023, investigational drug) was studied in four volunteers by measuring salivary concentrations. The pharmacokinetic parameters tmax and MRT (mean residence time) for crushed Theona-P® and crushed Theo-Dur® were significantly shorter compared to Theona-P®, Theo-Dur®, and E-0686 granules, but the AUC0-∞ values were not different among them. The results show that each preparation is equivalent in the extent of bioavailability but not in the rate of bioavailability. More frequent administration is required when crushed Theona-P® or crushed Theo-Dur® are taken, and sustained release granules are desirable in children with chronic asthma who cannot swallow tablets.

Evaluation of Dissolution and Acid-resistance of L-Keflex Granule

L-Keflex granule is a sustained release preparation of cefalexin in rapid release granules (30%) and enteric coated granules (70%). The acid-resistance and the dissolution pattern of this preparation were measured with the U. S. P. dissolution tester in the following test solutions:(a) pH shift test solution in consideration of pH levels of gastrointestinal tract: pH of the medium was designed to rise gradually from 2.3 to 3.7 in the first 150 min, rapidly from 3.7 to 6.2 in the subsequent 30 min, and gradually up to 6.9 after 300 min.(b) Test solutions at pH 1. 2, 4. 5, 6.0 and 6.5. The following results were obtained: 1) In the pH shift test solution, the calculative dissolution rate rapidly increased to 30% in the first 20 min, unchanged in the subsequent 200 min, and again rapidly rose to 100% after 280 min. 2) At pH 1.2 and 4. 5, the calculative dissolution rapidly increased to 30% within 20 min, but the granules were not dissolved thereafter. At pH 6.0, the time required for 100% dissolution was about 140 min, and at pH 6.5, about 30 min. Thus, the dissolution of the rapid, release granules and the acidresistance and the dissolution of enteric coated granules were satisfactory, and the pH shift test method used above must be effective in a qualitative evaluation of granule preparations of such type.

Fluidized Bed Coating Technique for Production of Sustained Release Granules

A laboratory-scale instrument for fluid-bed spray coating of granules has been constructed. Its major advantage is its suitability for development work on small batches of granules or tablets of between 50 and 300 grams. Commercial equipment available at present requires minimum loadings of 0.5-1 Kg. for effective operation.The instrument has been successfully used for producing sustained-release products by coating granules of model drugs with EC, and data are presented which define important qualities of the products. In particular, the apparatus is capable of giving excellent batch homogeneity and reproducibility.One of the recent successful developments in pharmaceutical technology is the production of sustained-release dosage forms. The two main approaches utilized in the design of these products are (a) the introduction of a physical barrier preventing contact between the drug and the fluids of the digestive system, the effect of which is to reduce the rate of diffusion or leaching out of the drug from the dosage form (b) the addition of selected interactants to the formulation, such as ion-exchange resins or complexants, which form weak cnemical bonds with the drug.The present work is concerned with the first type of product which in practice may be produced using widely different technologies. The main ones are based on (a) coating techniques (b) embedding the drug in a wax or polymer matrix. Prior to 1956, coating was performed by means of the classical rotating pan-method, but in that year Spaulding (1) introduced a controlled spray technique for application of the coating solution to the pan contents, termed the rotating pan-spray technique.A new and major step in coating technology was the introduction into pharmaceutical manufacturing of the fluidized-bed technique. The term “fluidized-bed” has been defined in a number of ways (2-4); most simply, when a solid is “fluidized” in a process, it shows in its behaviour many of the physical characteristics of a liquid.In pharmaceutical production, fluidization methods are utilized in stages of drying (5-6), granulation (7) and coating (8-9). As a coating technique, its main advantages over the pan-coating method are as follows:a) irregular particles may be coated directly, b) loss of material is small, c) the process may be automated and does not require learning the “art” of coating, d) it is very rapid.The present work is a study of the preparation of sustained-release granules coated by means of the fluid-bed technique. Salicylic acid and caffeine were selected as model drugs, while ethyl cellulose (EC) with polyethylene glycol (PEG) were representative of coating materials.

Spermiogenesis in the Nine-Banded Armadillo

The testes of mature armadillos were fixed by either perfusion or immersion. The morphology of the seminiferous tubules and the process of spermiogenesis were studied.The developing spermatids are generally oval in shape and contain a centrally placed nucleus. A well-developed Golgi apparatus, scattered mitochondria, centrioles, smooth endoplasmic reticulum, and a chromatoid body are observed within the cytoplasm. Granules formed within the Golgi appear to coalesce to form the acrosomal granule, which is enclosed within a vesicle (Fi,g. 1). The acrosome adheres to the nucleus at the anterior pole of the developing spermatid. The acrosome vesicle collapses and extends over the anterior two-thirds of the nucleus (Fig. 2). As this vesicle expands, the Golgi continues to release granules into the vesicle. Concomitant with acrosome formation, the centrioles and chromatoid body migrate to the posterior pole of the developing cell.

Absorption of Nitroglycerin from the Alimentary Tract of the Rabbit

Nitroglycerin, either free or contained in controlled - release granules, when administered through the alimentary tract of the rabbit, caused dilatation of the vascular bed of the ear. Nitroglycerin, either free or contained in controlled - release granules, when administered through the alimentary tract of the rabbit, caused dilatation of the vascular bed of the ear.