Effect of Formulation Components on Drug Release from Multiparticulates

Abstract

The effect of excipients on the release of drug from multiparticulates or pellets coated and uncoated prepared by the extrusion/spheronization and centrifugal processes is reviewed in this paper. A processing viewpoint has been taken because of the relationship between a rugged scaleable process and reliable excipients. Only aqueous coating dispersions have been reviewed because of their increasing usage due to environmental and cost reduction programs.     

Effect of Formulation Components on Drug Release from Multiparticulates

The effect of excipients on the release of drug from multiparticulates or pellets coated and uncoated prepared by the extrusion/spheronization and centrifugal processes is reviewed in this paper. A processing viewpoint has been taken because of the relationship between a rugged scaleable process and reliable excipients. Only aqueous coating dispersions have been reviewed because of their increasing usage due to environmental and cost reduction programs.     

多孔羟基磷灰石微球的药物缓释性能

用锂钙硼（LCB）玻璃在磷酸盐溶液中的原位转化反应制备多孔羟基磷灰石（HA）微球,表征微球的物相组成、孔结构和形貌,以溶菌酶为药物模型研究了药物的缓释性能。结果表明,所制备的HA微球具有较好的孔结构。当溶菌酶溶液的浓度较低时,HA微球将溶菌酶吸附在微球的外表面;当浓度较高时,更多的溶菌酶扩散进入HA微球的微孔中,使缓释...     

Investigation of Hypromellose Particle Size Effects on Drug Release from Sustained Release Hydrophilic Matrix Tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

肝素/碳酸钙微囊的制备及其药物缓释性能

以药物HEP为有机基质,在CaCl2、Na2 CO3常温水溶液体系中制备碳酸钙微囊.分别采用SEM、流式细胞仪和紫外分光光度计等测试技术对微囊的形貌和结构进行了观察和表征.SEM结果表明,制备的HEP/CaCO3微囊平均直径为1.5μm,球形,分散性好;紫外分光光度法检测表明,微囊具有较高的药物装载量,肝素的包封率为80％;药物体外释放实验表明,HEP/CaCO3微囊的缓释性能受pH值的影响,在pH=1的PBS溶液中有明显的释放作用,随着释放溶液中pH值的减小,微囊的缓释效果越明显.本实验方法操作简单,所制备的药物微囊装载量高,在药物控释领域具有潜在的应用价值.     

Development of Hollow Microspheres as Floating Controlled-Release Systems for Cardiovascular Drugs: Preparation and Release Characteristics

Hollow microspheres of cellulose acetate loaded with four cardiovascular drugs (nifedipine [NFD], nicardapine hydrochloride [NCD], verapamil hydrochloride [VRP], and dipyridamole [DIP]) were prepared by a novel solvent diffusion-evaporation method. The oil-in-water emulsion prepared in an aqueous solution of 0.05% poly(vinyl alcohol) medium with ethyl acetate, a water-soluble and less toxic solvent, was used as the dispersing solvent. The yield of the microspheres was up to 80%. The microspheres had smooth surfaces, with free-flowing and good-packing properties. Scanning electron microscopy (SEM) confirmed their hollow structures, with sizes in the range 489–350 μm. The microspheres tended to float over the gastric media for more than 12 h. The drug loaded in hollow microspheres was in an amorphous state, as confirmed by differential scanning microscopy (DSC). The release of the drugs was controlled for more than 8 h. The release kinetics followed different transport mechanisms depending on the nature of the drug molecules.     

Effect of Drug Properties on Physical and Release Characteristics of Eudragit Microspheres Prepared by Spherical Crystallization Technique

Ten compounds having different solubilities and molecular weights were evaluated for incorporation into Eudragit microspheres using the spherical crystallization technique, and the effects of drug-related factors on the properties of Eudragit microspheres were investigated. The entrapment of the active compound within the microspheres was highly dependent on the acidic or basic characteristics of the drug. Structural changes were also observed on the microsphere surface prepared at different pH values. Microspheres prepared with slightly and very slightly soluble drugs such as salicylic acid, naproxen, piroxicam, indomethacin, and methylpred-nisolone indicated controlled-release properties. Generally, drug release from microspheres followed the Fickian diffusion model.     

Effect of Different Binders on Release Characteristics of Theophylline from Compressed Microspheres

Abstract

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.     

Effect of Different Binders on Release Characteristics of Theophylline from Compressed Microspheres

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.     

The Influence of Formulation Factors on the Kinetic Release of Metoprolol Tartrate from Prolong Release Coated Minitablets

The aim of this work was to study the possibility to obtain an oral extended-release dosage forms with zero order kinetic release by coating minitablets (containing metoprolol tartrate) with insoluble methacrylate film coating (Eudragit NE 40D) in a fluidized bed system. To achieve this aim a full factorial experimental design with two factors and three levels was used in order to study de influence of the amount of polymer film formatting (Eudragit NE 40D) and the amount of pore generating excipient in polymeric insoluble film (low viscosity hydroxypropyl methylcellulose-Methocel E 15LV) on the in vitro drug release profile.     

The Effect of Bases and Formulation on the Release of Indomethacin from Suppositories

The in vitro release characteristics of indomethacin from different suppository formulations were investigated using a dialysis method. Suppositories containing 100 mg of indomethacin were prepared by the fusion method in a variety of Witepsol and Novata bases with different hydroxyl values. The rate of release of indomethacin was found to be unexpectedly higher from oily bases with low hydroxyl values.

Furthermore, the effect of surface active agents and some excipients commonly used in suppository formulations on the release properties of indomethacin was determined. Colloidal silicon dioxide, sodium lauryl sulphate and cetyl alcohol had a slight effect, on the release of indomethacin, whereas dioctyl sodium sulphosuccinate significantly increased the amount of indomethacin released. White beeswax and Tween-80, however, resulted in a marked decrease in the release of indomethacin.

The in vitro release of indomethacin from five commercially available preparations was also determined using the same method. Suppositories formulated in PEG bases gave better release properties than those in oily bases.     

The Effect of Bases and Formulation on the Release of Indomethacin from Suppositories

The in vitro release characteristics of indomethacin from different suppository formulations were investigated using a dialysis method. Suppositories containing 100 mg of indomethacin were prepared by the fusion method in a variety of Witepsol and Novata bases with different hydroxyl values. The rate of release of indomethacin was found to be unexpectedly higher from oily bases with low hydroxyl values.

Furthermore, the effect of surface active agents and some excipients commonly used in suppository formulations on the release properties of indomethacin was determined. Colloidal silicon dioxide, sodium lauryl sulphate and cetyl alcohol had a slight effect, on the release of indomethacin, whereas dioctyl sodium sulphosuccinate significantly increased the amount of indomethacin released. White beeswax and Tween-80, however, resulted in a marked decrease in the release of indomethacin.

The in vitro release of indomethacin from five commercially available preparations was also determined using the same method. Suppositories formulated in PEG bases gave better release properties than those in oily bases.     

Some Factors Affecting the Release of Drug from Membrane Coated Slow Release Tablets

Tablets containing sodium salicylate were prepared by direct compression and coated with ethylcellulose and polyethylene glycol 3350. The effect of drug loading, direct compression carrier type, polymer ratio in the coating solution, pH of the dissolution medium, and agitation speed on the drug release were investigated using the USP XXI paddle method. It was observed that direct compression carriers, ratio of ethyl cellulose to polyethylene glycol, the amount of drug present in the tablet, and agitation speed used did not have any influence on the drug release from coated tablets, while the pH of the dissolution medium (gastric vs. intestinal fluids) was found to affect the drug release.     

Controlled Release of Cyclosporine from Microspheres

Abstract

A controlled release microsphere formulation of cyclosporine is reported for the first time. Ethylene-vinyl acetate copolymer was utilized to prepare microspheres containing cyclosporine. The polymer was dissolved in methylene chloride (10% w/v) to which different quantities of cyclosporine was added to give drug loadings of 5, 25 and 50% in the microspheres. The polymer-drug solution was extruded into ethanol, where gelling of the polymer was achieved at ?78°C in an ethanol-liquid nitrogen bath. Microspheres containing 25% of cyclosporine retained their shape and gave optimum results. Lower drug loadings (5% cyclosporine) resulted in deformed microspheres, whereas high drug loadings (50 % cyclosporine) produced tear drop shaped microspheres. This method used to prepare microspheres is simple, quick and inexpensive and can be used for drugs that are unstable to heat. Furthermore, the polymer used is bio-compatible and can be used to design formulations such as films containing cyclosporine which can then be used as subcutaneous implants.     

Effect of Spheronization Technique on Drug Release from Uncoated Beads

Spheronization techniques are finding increased utility in pharmaceutical research and production. In this investigation emphasis is on the effect of two different spheronization methods (pan versus marumerizer) on drug release from uncoated beads containing acetaminophen and microcrystalline cellulose at a 1:1 ratio. Drug release from the pan beads is much faster than that from the marumerizer beads. The pan beads disintegrate during the dissolution testing, while beads made via the extruder and marumerizer appear to behave as an inert matrix system.     

Formulation and Pharmacokinetic Studies of Acyclovir Controlled-Release Capsules

Acyclovir controlled-release capsules (CRCs) were prepared by a three-step process: [1] melt granulation of acyclovir; [2] coating of granules with ethylcellulose; [3] incorporation of coated granules into hard gelatin capsules. In vitro release experiments showed that the main factors affecting the release rate were the mean particle size of the acyclovir raw material and the amount of coating material applied. Release of acyclovir from the capsules was in accordance with the Higuchi equation. Pharmacokinetic studies in dogs after oral administration of acyclovir controlled-release capsules showed that the formulation was successful in providing slow release of acyclovir and was superior to a commercially available controlled-release formulation.     

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

Abstract

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

Formulation and Compaction of Microspheres

The factors affecting the tabletability of formulations containing uncoated and/or coated microspheres were discussed by presenting a case study. The size and shape, as well as surface properties of microspherical particles, the type and amount of coating agent, selection of the external additives, and the rate and magnitude of the pressure applied were found to be the most critical factors to be considered in order to obtain and maintain the desired drug release properties of the microspheres. It was found that microcrystalline cellulose was needed in order to produce satisfactory beads in terms of size, shape and surface characteristics. The microsphere formulations, which were found to be highly sensitive to lubrication, were more compressible than their powder forms, but produced much weaker tablets. When coated with Surelease, increasing the amount of coating on the pellets reduced the tensile strength of their compacts. Compaction of the microspheres at high velocities resulted in a decrease in the tensile strength values and an increase in the volumetric strain recovery values. Dissoultion studies revealed that, regardless of the amount of coating applied, the coated microspheres lost their sustained release properties during compaction.