Drug Pellets Research Articles

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD

Purpose: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. Methods: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). Results: Conventionally cured Aquacoat/hydroxypropyl methylcellulose-coated pellets were storage stable at ambient conditions and 25°C/60% relative humidity (RH) but showed a decreasing drug release at 40°C/75% RH, which is a required test condition according to ICH guidelines. Conclusion: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60°C/75% RH or 80°C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.

A novel, dual acting, soft pellet formulation, combining cushioning and rapid disintegration properties, and their incorporation into tablet formulations containing film-coated drug pellets

This work reports the concept of a novel, dual-acting, 'soft' pellet formulation, which protects film-coated 'hard' pellets during tabletting. The novel 'soft' pellets were designed to both cushion film-coated pellets during tabletting and ensure rapid disintegration of the tablets when in contact with water. The deformability and disintegration properties of these pellets were controlled using olive oil. 'Hard' pellets, produced by extrusion/spheronisation, were optimised and characterised and were film coated with Kollicoat® SR30D, containing triethyl citrate as plasticiser and fluorescein sodium as marker substance. Several coating thicknesses and plasticiser concentrations were studied using a statistically designed experiment. 'Soft' pellets produced using extrusion/spheronisation or granulation/spheronisation, were tabletted with either film-coated ibuprofen pellets or theophylline pellets and their dissolution and disintegration properties were determined. Granulation/spheronisation was the preferred method of manufacture of the soft pellets and lower percentages of olive oil were found to be more beneficial to the disintegration properties of the compacts.

Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer

Hyaluronic acid–coupled chitosan nanoparticles bearing oxaliplatin (L-OHP) encapsulated in Eudragit S100–coated pellets were developed for effective delivery to colon tumors. The in vitro drug release was investigated using a USP dissolution rate test paddle-type apparatus in different simulated gastrointestinal tract fluids. In therapeutic experiments the pellets of free drug, and hyaluronic acid–coupled and uncoupled chitosan nanoparticles bearing L-OHP were administered orally at the dose of 10 mg L-OHP/kg body weight to tumor-bearing Balb/c mice. In vivo data showed that hyaluronic acid–coupled chitosan nanoparticles delivered 1.99 ± 0.82 and 9.36 ± 1.10 μg of L-OHP/g of tissue in the colon and tumor, respectively after 12 hours, reflecting its targeting potential to the colon and tumor. These drug delivery systems show relatively high local drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which provides a potential to enhance antitumor efficacy with low systemic toxicity for the treatment of colon cancer. From the Clinical Editor In this study, a nanoparticle system was developed to deliver oxaliplatin to colorectal tumors. In murine models, the drug delivery system showed relatively high local drug concentration in colonic tumors with prolonged exposure time, which provides a potential for enhanced antitumor efficacy with low systematic toxicity.

Obtenção de pellets por extrusão e esferonização farmacêutica. Parte II: avaliação das características física de pellets

O processo de peletização, abordado na Parte I, consiste na aglomeração por via úmida de pós de uma substância ativa e excipientes sob a forma de unidades esféricas denominadas por pellets. Os pellets diferem de grânulos não apenas pela técnica utilizada para a produção, mas também no que respeita as características físicas conseguidas. O presente trabalho, o segundo de uma série de dois, apresenta uma revisão das características físicas e das técnicas para a caracterização física de pellets farmacêuticos abordando as principais necessidades posteriores a produção dessas multi-unidades, nomeadamente revestimento com película, enchimento de cápsulas, compressão, manuseamento, armazenamento e transporte.

Drug-Polymer Mixed Coating: A New Approach for Controlling Drug Release Rates in Pellets

A new approach to developing a drug-polymer mixed coat for highly water-soluble diltiazem pellets was investigated at different coating levels. Drug layering and the coating procedures were performed using a bottom spray fluidized bed coater. Drug pellets were coated with Eudragit NE40 (NE40) alone and in combination with diltiazem and hydrophilic cellulose derivatives. Dissolution studies revealed that incorporation of hydrophilic substances such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and the drug itself considerably increased the release rates. The release from mixed polymer coatings was fast compared to pellets coated with NE40 only. The major portion of the drug was released in about 2 hours in case of MC and NE40 mixed coat compared to hours from coated pellets containing HPMC or diltiazem. Incorporation of 15% to 25% drug with respect to the polymer coat helped to achieve a drug-release profile at a desirable rate over a 12 hour period. Moreover, the test formulation comprising 25% diltiazem with respect to 7% NE40 had a dissolution profile that matched the commercial product, Herbesser SR capsules. The release of diltiazem from the coated pellets was slightly affected by the pH of dissolution media.

Investigation of the Effect of Various Shellac Coating Compositions Containing Different Water-Soluble Polymers on In Vitro Drug Release

In this study drug pellets were coated with aqueous shellac coating formulations containing different amounts of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carbomer 940. The coating level needed for enteric coating was determined. The influence of different amounts of PVA, HPMC, and carbomer on drug release and mechanism; the porosity, and the stability of shellac coatings was investigated. The results show that the incorporation of different concentrations of HPMC into shellac coatings, due to the increasing of pores, could considerably increase the drug release from the pellets in purified water. Moreover, the swelling effect of carbomer 940 leads to much more diffusivity through shellac coatings in water. In addition, PVA results in small cracking in the films and much more diffusion of drug in water. Furthermore, all coating systems containing different hydrophilic polymers that were used in the present work could prevent the dissolution of drug in simulated gastric juice for 2 hours. On the other hand, a rapid and complete release of drug within 45 minutes was observed in simulated intestinal fluid. Drug release from shellac coated pellets and ones containing different amounts of carbomer was affected between 3–6 months, whereas shellac coatings containing different amounts of PVA or HPMC show the same dissolution profiles with small deviation after 12 months.

Preparation of Indapamide slow-release pellets

During the process of developing a slow-release formulation of indapamide, researchers created a drug-containing pellet coated with Eudragit RS100 (Rohm GMbH & Co. KG, Darmstadt, Germany) to control the rate at which the drug was released. The two main variables were the agglomerants used in the pellet preparation and the amount of Eudragit RS100 used to coat them. The optimal outcome was indicated by the greatest number of drug-containing pellets recovered through an 18- to 24-mesh sieve and a satisfactory 24-hour release curve. The kinetics of dissolution fit the Higuchi kinetics model. Stability tests of the drug pellets showed no notable changes in the rate of drug release, related substances (mean byproducts or impurities from interactions or decompositions), and drug content.

Drug release from reservoir pellets compacted with some excipients of different physical properties.

The aim of the present study was to investigate the influence of the size and the porosity of excipient microcrystalline cellulose (MCC) particles on the densification and the deformation during compaction and the consequent effect on the drug release from reservoir pellets. Drug pellets consisting of salicylic acid and microcrystalline cellulose were prepared by extrusion-spheronisation and spray-coated with ethyl cellulose (ethanol solution). Excipient pellets of different size and porosity were prepared by extrusion-spheronisation or direct spheronisation. Five binary mixtures of reservoir pellets and excipient particles were prepared in the proportion 1:7 and lubricated. After compaction the reservoir pellets were retrieved and analysed to determine the intragranular porosity, surface area, shape and drug release. The reservoir pellets were shown to undergo extensive deformation and densification during compaction, resulting in a preserved or even prolonged drug release time. The mode of deformation of the reservoir pellets seems to be critical for the compression-induced change in drug release. Formation of large indents has a negative effect on the release time, while the use of small particles or small deformable agglomerates has a protective effect. We also hypothesize that the coating structure changes during compaction and the final structure of the coating is the net effect of two parallel processes, one reducing and one prolonging the drug transport time across the coating.

Powdered cellulose as excipient for extrusion–spheronization pellets of a cohesive hydrophobic drug

This study compared a powdered cellulose (PC) and a microcrystalline cellulose (MCC) as sole excipients in the preparation of furosemide pellets by extrusion–spheronization. Pellets prepared with PC and 25 or 50% furosemide showed smaller mean size, a broader particle size distribution, similar sphericity, greater surface roughness and higher friability than equivalent pellets prepared with MCC. Furosemide release rate was markedly higher from PC pellets, which may be attributable to their higher micropore volume.

Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets

Purpose : We evaluated the use of a subcutaneously (s.c.) implantable, biodegradable pellet as a drug delivery system for the radioprotector amifostine. Materials and methods : Mice were implanted s.c. with either the custom-made biodegradable amifostine drug pellet or the placebo pellet without amifostine, exposed to cobalt-60 γ-radiation (bilateral, 1 Gy min -1, 7-16 Gy), and the 30-day survival rate was monitored. The non-irradiated mouse was used for pharmacokinetic and behavioural tests. Results : Significant radioprotection (85-95% survival) at 10 Gy was observed in the three-amifostine pellet implanted group 3-5 h after implantation. LD 50/30 was 7.97, 8.74 and 16.64 Gy for the control, three-placebo pellet (dose reduction factor, DRF=1.10, p <0.01), and three-amifostine pellet (DRF=1.79, p <0.01) groups respectively in mouse exposed to radiation 2h after implantation. Radioprotection at 12 Gy was observed up to 4h after s.c. amifostine administration and up to 3h after implantation. Pharmacokinetic data revealed that the three-amifostine pellet group had sustained blood WR-1065 levels at 2 h after implantation, in contrast to the reported sharp peak at 30 min for s.c. administration. Although locomotor activity was significantly reduced (p <0.01) in the amifostine pellet group, the onset of the locomotor decrement was delayed as compared with groups that received 400 and 750 mg kg -1 s.c. amifostine. Conclusions : Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.

Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: its properties, degradation behavior, and utilization for drug formulation

A segmented polyurethane containing azo aromatic groups in the main chain was synthesized by reaction of isophorone diisocyanate with a mixture of m,m′-di(hydroxymethyl)azobenzene, poly(ethylene glycol) (Mn=2000), and 1,2-propanediol. This polyurethane was soluble in various solvents and showed a good coating and film-forming property. A solution-cast film of this polyurethane was found to be degraded in a culture of intestinal flora with the azo group reduction to hydrazo groups, not to amino groups. The film degradation, therefore, was attributed to the decreased cohesive energy in the hydrazo polymer compared with that in the original azo polymer. Then, the drug pellets containing water-soluble drugs (ONO-3708 and OKY-046) were undercoated with (carboxymethyl)(ethyl)-cellulose and overcoated with the azo polymer in order to examine the drug-releasing profiles in the culture of intestinal flora. The releasing rate of drugs from these double-coating pellets was found to depend on the molecular weight and the composition of the polyurethane used as the overcoat as well as the hydrophilicity of the incorporated drugs. Since the polyurethane was glassy and its segment motion or conformational change is frozen, the structure change should be retarded even after partial reduction of the azo groups, resulting in the effective prevention of the drug leakage. These data suggested that the present azo-containing polyurethanes are applicable as coating material of drug pellets in a colon-targeting delivery system.

Compaction of, and drug release from, coated drug pellets mixed with other pellets

Tablets have been prepared at known compaction force from three types of pellets in different proportions: (1) pellets containing 80% theophylline as a model drug coated with different thicknesses of a polymer film coat, (2) pellets containing glyceryl monostearate as a deformable material, and (3) pellets containing a disintegrant. The breaking load, friability, disintegration and drug release properties were evaluated, the latter as a mean dissolution time (MDT) and its variance (VDT). The mechanism of dissolution was assessed from the value of the relative dispersion (RD) of the mean dissolution time. The possible relationship between the properties of the pellets and those of the tablets was evaluated by canonical analysis followed by multiple regression analysis. It was found that only about 51% of the tablet properties could be predicted from the properties of the pellets. The quantitative relationship between pellet properties and tablet properties was found to vary in type and level of quality. Reduction of breaking load, friability and disintegration was less predictable than that of dissolution represented as the MDT. The values of RD for the different preparations clearly identified those preparations where the film coat still retained control of the dissolution process. Such formulations contained at least 40% of soft pellets and coated pellets with at least a weight gain of 8%.

Swelling of pellets coated with a composite film containing ethyl cellulose and hydroxypropyl methylcellulose

The swelling behaviour of membrane-coated drug pellets has been investigated. A coating membrane containing ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) in the range of 10–24% was used. By measuring the release rate of a drug during swelling experiments, it is possible to obtain an insight into the release mechanisms that are involved. The results revealed that the swelling of the membrane coat increased as the amount of HPMC increased. The expansion of the pellets continued until the release of the drug began. We have also evaluated the swelling of pure EC/HPMC, where no change in volume occurred. It is believed that the swelling of the pellet coat is a result of water imbibition due to osmotic pressure.

Bioabsorbable Polymers for Implantable Therapeutic Systems

For a long time, subcutaneous implantable drug pellets using nondegradable polymers have been used for long-term, continuous drug administration. The procedure requires surgical implantation and removal of the drug-containing devices or polymeric matrices, which has a significant negative impact on the acceptability of the product candidate. In addition, the release profile from such devices is neither constant nor readily controlled in terms of precision of rate of release and duration of action. These facts have led to the research and development of novel, controllable, nonirritating, noncarcino genie, biocompatible, and bioabsorbable drug delivery systems for overcoming the drawbacks of nondegradable implantable pellets for prolonged continuous release. Biodegradable implantable systems release the drug over a long period of time with simultaneous or subsequent degradation in the tissue of the polymer to harmless constituents, thus avoiding removal once the therapy is complete. This approach has considerably improved patient acceptability and patient compliance. Various bioabsorbable polymers have been evaluated for controlled implantable drug delivery, including hydrogels, copolymers ofpolylactic and polyglycolic acids, polylactic acid, poly(orthoesters), polyanhydrides, poly(E-capro-lactone), and polyurethanes. Their characteristics have been studied using a variety of drugs, like anticancer agents, hormone agonists and antagonists, nonsteroidal anti-inflammatory agents, neuroleptics, contraceptives, and others. The present paper describes the current research on implantable therapeutic systems, the bioabsorbable polymers, and the biologically active agents being used in this approach.

Influence of disintegrant type and proportion on the properties of tablets produced from mixtures of pellets

The influence of the composition and properties of pellets on the properties of the tablets prepared from their mixtures has been evaluated. Three types of pellets were prepared, (a) those containing a model drug readily identifiable by colour, to evaluate tablet consistency; (b) those containing a deformable material, glyceryl monostearate, to provide pressure absorbing and binding properties, and (c) those containing an inorganic disintegrating agent. Tablets from various mixtures of these pellets, in a statistical designed manner, were prepared at a known compression force and their weight uniformity, friability, diametral breaking load and disintegration times were measured. The uniformity of composition of selected tablets was also determined. Analysis of variance established that the disintegrant type, the proportion of drug pellets and the proportion of disintegrant pellets influenced the breaking load and the disintegration time of the tablets. The proportion of drug and disintegrant pellets influenced the tablet friability whereas the type of disintegrant did not. Canonical analysis failed to establish an exact relationship between pellet properties and tablet properties. However some conclusions can be drawn from this analysis. First, an increase in either the amount of drug pellets or disintegrant pellets decreases the tablet breaking load, and the disintegration times are reduced. Secondly, disintegration times are increased with disintegrants of a high density. Thirdly, larger amounts of drug and disintegrant pellets increase the tablet friability.

The Effect of Polymer Coating Systems on the Preparation, Tableting, and Dissolution Properties of Sustained-Release Drug Pellets

The preparation of sustained-release (SR) drug pellets and their tablets was evaluated. Pellets containing indomethacin, pseudoephedrine hydrochloride (P-HCl), or pseudoephedrine (P) base were prepared by spraying a mixture of drug, Eudragit S-100 resins, dibutyl sebacate, and alcohol onto nonpareil seeds via the Wurster-column process. The oven-dried drug/Eudragit S-100 (DS) pellets were coated with different levels of Eudragit RS and Eudragit S-100 acrylic resins. Tablets containing P-HCl or P-base SR pellets, microcrystalline cellulose, and Methocel K4M were compressed. The solubility of the drug entity in the polymer solution was found to be the most critical factor affecting the yield and the physical properties of the resultant DS pellets. Dissolution studies of Eudragit RS coated drug pellets demonstrated that the release profiles depended not only on the physicochemical properties of the drug, particularly aqueous solubility, but also on the coating levels. The release rate profiles of the matrix tablets can be modified by varying the types of P-HCl or P-base SR pellets in the formulation. The release of drug from the matrix tablets is primarily matrix controlled.

Chronic Perioperative Steroids and Colonic Anastomotic Healing in Rats

Objective: To develop a rat model of long-term high-dose perioperative steroids and to evaluate the effects of these steroids on a colonic anastomosis in this model. Design: Prospective randomized. Methods: Twenty-six male Sprague–Dawley rats, weighing 270 to 330 g, were randomized into two groups. The first group (steroid group) (13 rats) received a time-release drug pellet (200 mg cortisone acetate in a 60-day release form) placed in the subcutaneous tissue of the posterior neck for an average daily dose of 3.3 mg. The second group (control group) (13 rats) received a placebo. At 6 weeks, blood cortisol levels were measured, and a colonic anastomosis was performed 2.5 cm distal to the cecum. Steroid group animals also received cortisone acetate (5 mg intramuscularly) immediately before surgery. Colonic bursting strength (mmHg) was measured at the anastomosis site and in the normal distal left colon using a saline infusion system at 8 and 12 days postoperatively. Results: Blood cortisol levels were significantly higher in the rats in the steroid group than in the rats in the control group. The anastomotic bursting strength was significantly lower in the steroid group at Days 8 and 12. The bursting pressure of the unoperated left colon was not significantly different when the groups were compared. Also, in the steroid group, healing of the pellet insertion wounds in the neck was impaired. Conclusion: The time-release drug pellet is a reliable method of administering long-term steroids. Long-term perioperative steroids impaired colonic anastomotic healing, while normal tissue strength (left colon) was not significantly changed.

Development and in Vitro Evaluation of a Novel Multiparticulate Matrix Controlled Release Formulation of Theophylline

A novel multiparticulate matrix controlled release preparation of theophylline was formulated and evaluated in-vitro. The preparation which consisted of spherical drug pellets in a size range of 1.18-1.70 mm diameter was produced using an extrusion-spheronisation technique. The drug was embedded in a mixture of nonsoluble matrix materials forming the pellets to control the drug release. For this purpose, microcrystalline cellulose (MCC) and its mixture with glyceryl monostearate (GMS) were evaluated. When microcrystalline cellulose was used alone, the drug release was not sufficiently sustained and was essentially complete within 6 hours. However, incorporation of glyceryl monostearate significantly retarded the rate of drug release. Moreover, the rate of drug release could be readily modified in a predictable manner by varying the amount of glyceryl monostearate. The rate of the drug release was relatively insensitive to changes in the drug to matrix ratio. Drying of the drug pellets at temperatures below the melting point of glyceryl monostearate (approximately 57°C) has no effect on the rate of drug release. In addition, the rate of drug release was found to be stable after storage for 6 months and was essentially independent of pH and agitation rate.

Controlled Drug Delivery of Ph Dependent Soluble Drug-Pindolol

Pindolol, a pH dependent soluble beta adrenoceptor blocker has been formulated into a controlled drug delivery system. Drug pellets were prepared by extrusion spheronization technique. These were coated with different retardant polymers, namely ethylcellulose and Eudragit RS 100. The effect of different variables such as coating level and pH of dissolution medium have been studied. Drug release from pellets were found to be influenced by the pH of the dissolution medium. A flux release of the drug in the acidic buffer was observed from pellets coated with these polymers. To avoid this flux, a top coat using different pH sensitive polymers, namely Hydroxypropylmethyl cellulose phthalate (HPMCP 55) and Eudragit S 100 was successfully attempted and the drug release from the pellets was modified.

Gastrointestinal transit and absorption of theophylline from a multiparticulate controlled release formulation

The gastrointestinal transit and absorption of theophylline from a novel multiparticulate controlled release formulation were investigated under fed and fasted conditions. The drug pellets of high drug loading were prepared using an extrusion spheronisation technique, and coated with a methylcellulose-ethylcellulose mixture to control the drug release. Transit of the dosage form in the gastrointestinal tract, determined using a gamma scintigraphic method, revealed that the presence of food delayed the gastric emptying, but was without influence on the small intestinal transit time. The delay in gastric emptying was associated with a delay in drug absorption. However, the overall rate and extent of drug absorption were essentially unaffected by the presence of food. For both fed and fasted conditions, the rate of absorption whilst the pellets were in the stomach was slower than when the pellets were in the small intestine. The pellets were less well dispersed in the stomach than in the small intestine or colon. Moreover, whereas only 14% of drug was released in the stomach, 47% was released in the small intestine. It is interesting that the remaining 39% of the drug was taken up from the colon, which thus acts as a significant site of absorption.