Preparation and characterization and release properties of Eudragit RS based ibuprofen pellets prepared by extrusion spheronization: effect of binder type and concentration

Objective: The effects of type and concentration of binding agent on properties of Eudragit RS based pellets were studied.

Materials and methods: Pellets containing ibuprofen (60%), Eudragit RS (30%), Avicel (10%) were prepared by extrusion spheronization. PVP K30, PVP K90, HPMC 6cp, HPMC K100LV or HPMC K4M were used as binders in concentrations of 2, 4 or 6% based on the total weight of formulation. The process efficiency, pellet shape, size distribution, crushing strength, elastic modulus and drug release were examined. The effect of curing on pellet properties was also investigated.

Results: The process of extrusion spheronization became difficult with increase in binder viscosity and/or concentration. An increase in binder viscosity and/or concentration resulted in reduction in the yield of pellets, wider particle size distribution and departure from spherical shape especially in the case of HPMC binder. The crushing strength and elastic modulus of pellets decreased with increase in PVPs concentration. However this was not the case for pellets containing HPMCs. Drug release rate increased as the concentration of binder increased. Pellets containing 2%w/w of PVP K30 showed the slowest release rate. For those pellets with brittle nature, curing changed the behavior of pellet under mechanical test to plastic deformation. Yield point and elastic modulus of all formulations decreased after curing. Curing decreased the drug release rate.

Conclusion: Binder type and concentration significantly affected the properties of pellets. For production of sustained release ibuprofen Eudragit RS based pellets lower viscosity binders (PVP K30) with concentrations less than 4%w/w was optimum.     

Extrusion-Spheronization of Blends of Carbopol 934 and Microcrystalline Cellulose

We evaluated the effects of several process variables on the pharmaceutical and drug release properties of extrusion-spheronization pellets of blends of Carbopol 934 and microcrystalline cellulose (MCC) containing a high proportion of Carbopol. The model drug was theophylline. Rheological monitoring during mixing was by mixer torque rheometry. Carbopol:MCC blends wetted with a CaCl₂ solution showed different rheological behavior compared to blends with a high proportion of MCC wetted with water only. In contrast to previous suggestions, the optimal wetting point for extrusion did not coincide with the point of peak torque, but occurred just beyond this point, at much lower torque. The influence of process variables on blend properties was investigated with a three-variable factorial design (Carbopol:MCC ratio, wetting liquid proportion, CaCl₂ :Carbopol ratio), and the influence of process variables on pellet properties with a four-variable design (the variables listed plus extrusion screen hole diameter). Blend torque values were strongly influenced by CaCl₂ proportion, while mean pellet diameter was influenced by Carbopol:MCC ratio. Mean pellet diameter also differed depending on whether the pellets contained theophylline. The observed among-formulation differences in theophylline release kinetics were largely explained by differences in pellet size and theophylline hydration state. Compaction of pellets to form tablets markedly modified the drug release profile, making it biphasic.     

Extrusion-Spheronization of Blends of Carbopol 934 and Microcrystalline Cellulose

We evaluated the effects of several process variables on the pharmaceutical and drug release properties of extrusion-spheronization pellets of blends of Carbopol 934 and microcrystalline cellulose (MCC) containing a high proportion of Carbopol. The model drug was theophylline. Rheological monitoring during mixing was by mixer torque rheometry. Carbopol:MCC blends wetted with a CaCl₂ solution showed different rheological behavior compared to blends with a high proportion of MCC wetted with water only. In contrast to previous suggestions, the optimal wetting point for extrusion did not coincide with the point of peak torque, but occurred just beyond this point, at much lower torque. The influence of process variables on blend properties was investigated with a three-variable factorial design (Carbopol:MCC ratio, wetting liquid proportion, CaCl₂ :Carbopol ratio), and the influence of process variables on pellet properties with a four-variable design (the variables listed plus extrusion screen hole diameter). Blend torque values were strongly influenced by CaCl₂ proportion, while mean pellet diameter was influenced by Carbopol:MCC ratio. Mean pellet diameter also differed depending on whether the pellets contained theophylline. The observed among-formulation differences in theophylline release kinetics were largely explained by differences in pellet size and theophylline hydration state. Compaction of pellets to form tablets markedly modified the drug release profile, making it biphasic.     

New co-processed MCC-based excipient for fast release of low solubility drugs from pellets prepared by extrusion-spheronization

In this study, a new co-processed excipient composed of microcrystalline cellulose (MCC), sorbitol, chitosan and Eudragit® E, easily obtained by wet massing, to increase the dissolution rate of active ingredients of low water solubility from pellets prepared by extrusion–spheronization is evaluated. Indomethacin, nifedipine, furosemide, ibuprofen, prednisolone and hydrochlorothiazide are used as model drugs of different solubility. All pellet formulations evaluated showed adequate morphological, flow and mechanical properties. Pellets prepared with the co-processed excipient show a higher drug dissolution rate than those prepared with MCC and even higher than the pure drug powder. The fast drug dissolution and the complete disintegration (<3?min) of the pellets can be explained by the great porosity of the formulations, the high solubility of the sorbitol, the disintegrant capacity of the chitosan and the distribution of the Eudragit® E polymer particles in-between the other components of the co-processed mixture. In conclusion, this new co-processed excipient is very suitable to increase the dissolution rate of poorly soluble drugs from pellets prepared by extrusion–spheronization. Moreover, the drug release rate can be estimated from the Ln of the drug solubility in acidic medium.     

Modulated release of 5-fluorouracil from pH-sensitive and colon targeted pellets: An industrially feasible approach

Pellets, reliant on pH-sensitivity and time-dependency for drug delivery, provide one of the most versatile opportunities for targeting colon. 5-Fluorouracil (5-FU) loaded pellets were prepared by extrusion-spheronization using Avicel^® PH101 as a spheronization aid and hydroxypropylmethylcellulose K4M (HPMC K4M) solution as a binder. A 3² full factorial design was employed to optimize spheronization speed and time. Obtained pellets were evaluated for flow properties, pellet size, roundness and aspect ratio. Optimized batch was coated in a bottom-spray fluidized bed processor (FBP) with an inner coat of sustained release polymer Eudragit NE30D and an outer coat of pH-sensitive polymer Eudragit FS30D. The coating levels were statistically optimized and in vitro drug release was monitored by changing pH media method. Optimized system with 15% inner and outer coating levels revealed t_50% (time required for 50% drug release) to be about 9?h while almost complete drug was released in 24?h (98.71?±?1.33%) with highest dissolution efficiency (DE_24h) of 58.71%. The optimization model was validated; the predicted and experimental/actual values for validation batch (M1) were in close tolerance and the standard error (SE) was also small. Drug release was also studied at pH 7.4. Scanning electron microscopy (SEM) demonstrated average coating thickness to be 32.50?±?3.0 µm. Hence, the present study provides constructive results for colon targeting of 5-FU pellets with industrially feasible processes.     

Application of similarity factor in development of controlled-release diltiazem tablet

Controlled-release grade hydroxypropylmethylcellulose (HPMC) or xanthan gum (XG) and microcrystalline cellulose (MCC) were employed to prepare controlled-release diltiazem hydrochloride tablets. The similarity factor f₂ was used for dissolution profile comparison using Herbesser 90 SR as a reference product. Drug release could be sustained in a predictable manner by modifying the content of HPMC or XG. Moreover, the drug release profiles of tablets prepared using these matrix materials were not affected by pH and agitation rate. The f₂ values showed that only one batch of tablets (of diltiazem HCl, HPMC or XG, and MCC in proportions of 3.0:3.0:4.0) was considered similar to that of the reference product, with values above 50. The unbiased similarity factor f^*₂ values were not much different from the f₂ values, ascribing to a small dissolution variance of the test and reference products. The amount of HPMC or XG incorporated to produce tablets with the desired dissolution profile could be determined from the curves of f₂ versus polymer content. Hence, the f₂ values can be applied as screening and optimization tools during development of controlled-release preparations.     

Effect of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer on bioadhesion and release rate property of eplerenone pellets

Abstract

The present study involved the design and development of oral bioadhesive pellets of eplerenone. A solid dispersion of eplerenone was developed with a hydrophilic carrier, polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®). Bioadhesive pellets were prepared from this solid dispersion using a combination of HPMC K4M and Carbopol 934P. Both the solid dispersion and the pellets were evaluated for various physicochemical properties such as solubility, entrapment efficiency, drug content, surface morphology, mucoadhesion and swelling behavior. Analysis carried out using FT-IR, DSC and XRD found no interaction between the eplerenone and excipients. The solid dispersion had irregular-shaped smooth-surfaced particles of diameter 265?±?105.5?μm. In TEM analysis, eplerenone particles of size 79–120?nm were found. The solubility and dissolution of eplerenone in the Soluplus^®-based solid dispersion were 5.26 and 2.50 times greater, respectively. Investigation of the swelling behavior of the pellets showed that the thickness of the gel layer increased continuously over the duration of the study. Moreover, a correlation was observed between the thickness and strength of the gel layer and the percentage release. The mechanism of drug release was found to be non-Fickian (anomalous), with the release kinetics approaching first-order kinetics. The bioavailability of the eplerenone bioadhesive pellet formulation was studied using Wistar rats and was found to be improved. An in vivo mucoadhesion study showed that the pellets are retained for 24?h in rabbits. It was concluded that Soluplus^® had a positive effect on the solubility and dissolution of pellets without affecting the bioadhesion.     

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.     

Application of Similarity Factor in Development of Controlled-Release Diltiazem Tablet

Controlled-release grade hydroxypropylmethylcellulose (HPMC) or xanthan gum (XG) and microcrystalline cellulose (MCC) were employed to prepare controlled-release diltiazem hydrochloride tablets. The similarity factor f₂ was used for dissolution profile comparison using Herbesser 90 SR as a reference product. Drug release could be sustained in a predictable manner by modifying the content of HPMC or XG. Moreover, the drug release profiles of tablets prepared using these matrix materials were not affected by pH and agitation rate. The f₂ values showed that only one batch of tablets (of diltiazem HCl, HPMC or XG, and MCC in proportions of 3.0:3.0:4.0) was considered similar to that of the reference product, with values above 50. The unbiased similarity factor f*₂ values were not much different from the f₂ values, ascribing to a small dissolution variance of the test and reference products. The amount of HPMC or XG incorporated to produce tablets with the desired dissolution profile could be determined from the curves of f₂ versus polymer content. Hence, the f₂ values can be applied as screening and optimization tools during development of controlled-release preparations.     

Pellet Starters in Layering Technique Using Concentrated Drug Solution

Characteristics of inert starters in drug solution layering are important for successful active pellet formation. Four types of starters composed of sucrose or microcrystalline cellulose (MCC) or lactose and MCC were compared in our study. The active pellets were prepared using Wurster type apparatus. Yield and pellet quality parameters were determined. The highest yield (85.66–89.41%) was obtained for cores composed of MCC due to their insolubility in water (the drug solvent) and good mechanical properties. On the contrary, soluble and brittle sucrose cores dissolved partially during the process forming undesirable agglomerates and giving lower yield (76.2%). All pellet samples showed good flow properties and drug content from 82.4 to 94.5% of the theoretical drug amount.     

Pellet starters in layering technique using concentrated drug solution

Characteristics of inert starters in drug solution layering are important for successful active pellet formation. Four types of starters composed of sucrose or microcrystalline cellulose (MCC) or lactose and MCC were compared in our study. The active pellets were prepared using Wurster type apparatus. Yield and pellet quality parameters were determined. The highest yield (85.66-89.41%) was obtained for cores composed of MCC due to their insolubility in water (the drug solvent) and good mechanical properties. On the contrary, soluble and brittle sucrose cores dissolved partially during the process forming undesirable agglomerates and giving lower yield (76.2%). All pellet samples showed good flow properties and drug content from 82.4 to 94.5% of the theoretical drug amount.     

Comparative study of drug release from pellets coated with HPMC or Surelease

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.     

Use of к-carrageenan,chitosan and Carbopol 974P in extruded and spheronized pellets that are devoid of MCC

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol^® 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.     

Development of a tamsulosin hydrochloride controlled-release capsule consisting of two different coated pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol(R) 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit NE30D and Eudragit L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f(2)) was employed to choose the optimum proportion compared with the commercial product (Harnal capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER = 2:1 using a centrifugal coater (f(2) = 61.93) and SR:ER = 3:1 using a fluidized coater (f(2) = 66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.     

Preparation of theophylline-hydroxypropylmethylcellulose matrices using supercritical antisolvent precipitation: a preliminary study

Several controlled release systems of drugs have been elaborated using a supercritical fluid process. Indeed, recent techniques using a supercritical fluid as a solvent or as an antisolvent are considered to be useful alternatives to produce fine powders. In this preliminary study, the effect of Supercritical Anti Solvent process (SAS) on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC) was investigated. Two grades of HPMC (HPMC E5 and K100) as carriers were considered in order to prepare a sustained delivery system for theophylline which was used as a model drug. The characterization of the drug before and after SAS treatment, and the coprecipitates with carriers, was performed by X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). The dissolution rate of theophylline, theophylline-coprecipitates, and matricial tablets prepared with coprecipitates were determined. The physical characterizations revealed a substantial correspondence of the drug solid state before and after supercritical fluid treatment while drug-polymer interactions in the SAS-coprecipitates were attested. The dissolution studies of the matrices prepared compressing the coprecipitated systems showed that the matrices based on HPMC K100 were able to promote a sustained release of the drug. Further, this advantageous dissolution performance was found to be substantially independent of the pH of the medium. The comparison with the matrices prepared with untreated substances demonstrated that matrices obtained with SAS technique can provide a slower theophylline release rate. A new mathematical model describing the in vitro dissolution kinetics was proposed and successfully tested on these systems.     

Development of an osmotically-driven pellet coated with acrylic copolymers (Eudragit® RS 30 D) for the sustained release of oxymatrine,a freely water soluble drug used to treat stress ulcers (I): in vitro and in vivo evaluation in rabbits

Purpose: To develop an osmotically-driven pellet coated with polymeric film for sustained release of oxymatrine (OMT), a freely water soluble drug.

Methods: Pellet containing OMT and sodium chloride (NaCl), an osmotically active agent, were prepared by extrusion/spheronization and then coated with acrylic copolymers (Eudragit^® RS 30 D) by the fluidized bed coating process. In vitro release and swelling behavior studies were employed to optimize and to evaluate the sustained-release behavior from the osmotically-driven pellets with film coated. Finally, in vivo evaluation in rabbits was employed to investigate the sustained plasma level of OMT and its active metabolite matrine.

Results: It was found that the F3 formulation, prepared with 20% NaCl and an 8% coating level, showed a continuous NaCl-induced water influx into the pellets providing a gradual sustained release of OMT for over 12?h. Finally, we confirmed that oral OMT with sustained release led to a gradual sustained plasma profile of both OMT, with a reduction in its bioavailability, and MT with an increase in the bioavailability compared with that of oral OMT with immediate release. Conclusions: The pharmaceutical parameters obtained suggested the potential usefulness of oral OMT with sustained release for the treatment of stress ulcers, as well as reducing the risk of MT-induced side effects.     

Preparation of the traditional Chinese medicine compound recipe heart-protecting musk pH-dependent gradient-release pellets

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100-Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100-Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

Preparation of the Traditional Chinese Medicine Compound Recipe Heart-Protecting Musk pH-Dependent Gradient-Release Pellets

ABSTRACT

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100–Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100–Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

Study of Drug Release from Pellets Coated with Surelease Containing Hydroxypropylmethylcellulose

The release of metoclopramide hydrochloride (a very water soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with Surelease containing hydroxypropylmethylcellulose (HPMC) at different coating loads was investigated. The release rates of either drug at each coating composition decreased as the coating load increased. Inclusion of HPMC E15 increased the release rates of both drugs compared to pellets coated only with Surelease. This was thought to be due to the leakage of the soluble part of the film (HPMC E15) during dissolution, which left pores for drug release. The Surelease:HPMC E15 ratio had a major role in the release rates of drugs. Addition of HPMC E15 into Surelease did not change the release mechanism for metoclopramide hydrochloride (the mean value of n ≈ 0.57) from that of Surelease alone, and diffusion remained the main mechanism controlling the release. However, the release exponent (≈1.28) increased for diclofenac sodium on addition of HPMC E15, indicating a dissolutioncontrolled mechanism. Despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride from pellets coated with Surelease containing HPMC E15 at equivalent coating loads.     

Sustained-release alginate-chitosan pellets prepared by melt pelletization technique

Context: Alginate-chitosan pellets prepared by extrusion-spheronization technique exhibited fast drug dissolution.

Objective: This study aimed to design sustained-release alginate pellets through rapid in situ matrix coacervation by chitosan during dissolution.

Methods: Pellets made of alginate with chitosan and/or calcium acetate were prepared using solvent-free melt pelletization technique which prevented reaction between processing materials during agglomeration and allowed such reaction to occur only in dissolution phase.

Results: Drug release was retarded in pH 2.2 medium when pellets were formulated with calcium acetate or chitosan till a change in medium pH to 6.8. The sustained-release characteristics of calcium alginate pellets were attributed to pellet dispersion and rapid cross-linking by soluble Ca²⁺ during dissolution. The slow drug release characteristics of alginate-chitosan pellets were attributed to polyelectrolyte complexation and pellet aggregation into swollen structures with reduced erosion. The drug release was, however, not retarded when both calcium acetate and chitosan coexisted in the same matrix as a result of chitosan shielding of Ca²⁺ to initiate alginate cross-linkages and rapid in situ solvation of calcium acetate induced fast pellet dispersion and chitosan losses from matrix.

Conclusion: Similar to calcium alginate pellets, alginate-chitosan pellets demonstrated sustained drug release property though via different mechanisms. Combination of alginate, chitosan and calcium acetate in the same matrix nevertheless failed to retard drug release via complementary drug release pattern.