Extruded and spheronized beads containing Carbopol 974P to deliver nonelectrolytes and salts of weakly basic drugs

The purpose of the study was to explore the utilization of Carbopol 974P, NF, resin in a bead dosage form manufactured by extrusion and spheronization. It was possible to prepare beads in this study by using calcium chloride to overcome the tack problem associated with wetted Carbopol 974P. The actives included both salts of weakly basic drugs (chlorpheniramine maleate and diphenhydramine hydrochloride) and nonelectrolytes (caffeine and dyphylline) which have a broad range of solubilities. Nonelectrolytes were released faster than the salts of weakly basic drugs. This is contrary to the behavior typically seen with a matrix system where the more soluble drug is released faster than a poorly soluble one. In the results of the present study, the solubility does not determine the drug release rate. Ionic interactions between the protonated amines of the salts and the carboxylates of the Carbopol resin are suggested to be the reason for the slower release of the salts of weakly basic drugs. Data from tack measurements confirm that this ionic interaction affects the behavior of the wetted Carbopol. In addition to the drug release profiles, bead average diameter, roundness, friability, and density were also determined.     

Influence of methyl-beta-cyclodextrin and liposomes on rheological properties of Carbopol 974P NF gels

The influence of positively-charged and sterically stabilized liposomes and/or methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels was investigated. All formulations have displayed a shear-thinning behavior of Carbopol gels, and the rate stress as a function of the shear rate was fitted using the Cross equation. An important loss of viscosity was observed when 1.5% Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was dissolved in buffer at 5% there was no additional effect on gel viscosity reduction. The incorporation of positively-charged and sterically stabilized liposomes at 2 mM of lipid concentration had no incidence on rheological properties of the Carbopol gels, whereas gel viscosity was significantly increased in the presence of positively-charged liposomes at 10 mM of lipid concentration. Finally, the viscosity of hydrogels containing both liposomes and methyl-beta-cyclodextrin tended to be close to control gels, remaining high and relevant for a topical delivery.     

Assay of amoxicillin sustained release from matrix tablets containing different proportions of Carbopol 971P NF

The sustained release of amoxicillin is desired because of its short biological half-life. Particularly to treat Helicobacter pylori infections, the sustained release is desired to be confined to the upper gastrointestinal tract. In vitro dissolution of amoxicillin has been evaluated utilizing a direct UV-absorption method. However, UV-absorption has been reported as not useful to determine amoxicillin in acidic dissolution test medium. To clarify the suitability of the assay method, the stability and dissolution behavior of amoxicillin sustained release tablets was determined by HPLC, iodometric titration and UV-absorption. Stability of amoxicillin studied under dissolution test conditions of pH 1.2, 37 degrees C and 50 rpm and determined by HPLC and titration showed considerable degradation of amoxicillin. On the other hand, the UV-absorption increased progressively as amoxicillin degradation proceeded. Amoxicillin release curves determined by different analytical methods show different release profiles, which can be corrected for amoxicillin degradation and change in the UV-absorption to produce similar dissolution results. Release curves determined by UV-absorption and obtained from tablets containing 1017 mg amoxicillin trihydrate and Carbopol 971P NF in a range from 180 to 680 mg showed increasing values of the exponent indicative of the release mechanism (n) and decreasing release constant values (k) as the matrix polymer content increased. The release constant (k) and the exponent (n) were found to be logarithmically related.     

Quantitative Determination of the Extent of Neutralization of Carboxylic Acid Functionality in Carbopol® 974P NF by Diffuse Reflectance Fourier Transform Infrared Spectrometry Using Kubelka-Munk Function

Purpose. The purpose of this study was to develop an analytical method for the quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF using Diffuse Reflectance Fourier Transform Infrared Spectroscopy (DRIFT) with Kubelka-Munk function analysis. Methods. Carbopol^® 974P NF is a high molecular weight, chemically crosslinked polymer of acrylic acid, that has the C=O stretching band of the unionized carboxylic acid function at 1695 cm^–1. The quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF is based upon the asymmetrical C =O stretching of the carboxylate anion at 1570 cm^–1 measured by DRIFT Spectroscopy. Results. To overcome spectral differences arising from sample preparation (powders, granules and tablets) and in an effort to increase the precision of the analytical method, the following approaches were used: (1) an internal standard, (2) first derivative of the spectrum to eliminate the effect of baseline drift and (3) the ratio of the first derivative of the C=O stretch of the carboxylate anion peak (1570 cm^–1) in the neutralized Carbopol^® 974P NF to that of the peak of the internal standard (866 cm^–1). The above data treatment techniques proved to be superior to the usual methods of peak height or peak area. The calibration curve of the ratio of the first derivative (1570 cm^–1/866 cm^–1) was a linear function of the mass of sodium carboxylate over the range from 0.0% to 100.0% neutralization of the carboxylic acid function in Carbopol^® 974P NF (Fig. la). No particle size or sample preparation effects were noted within the experimental error. Conclusions. DRIFT Spectroscopy using the Kubelka-Munk function is a powerful tool for the routine determination of the extent of neutralization of the carboxylic acid function in Carbopol^® 974P NF in complex pharmaceutical formulations.     

Formulation of rate-modulating pellets for the release of ibuprofen: an extrusion-spheronization process

Purpose: To develop a stable and reproducible modified release pellet formulation containing ibuprofen.Methods: Using extrusion-spheronization technology to produce pellets.Results: The percentage yield, size distribution and overall pellet shape within the desired size range of 1000-1400 microm was found to be dependent on various process variables. These include extrusion and spheronization speed, spheronization time and composition of the granulation fluid. Formulation factors such as viscosity grade of hydroxypropylmethylcellulose and concentration of microcrystalline cellulose were shown to influence the drug release rate of the pellets. In vitro dissolution studies revealed that the pellets behaved in a pH-dependent manner. Pellets exposed to different drying techniques exhibited an increase in drug release rate in the order corresponding to oven-dried, vacuum-dried, fluid bed-dried and freeze-dried pellets. In conjunction with scanning electron microscopy, kinetic modelling and statistical treatment of dissolution data, it was confirmed that the predominant release rate-controlling mechanism was diffusion, as evidenced from the power law expressions incorporating Fickian and relaxational parameters (M(t) /M(infinity) = K(1)t(n); M(t) /M(infinity) = K(1)t(2n)). Matrix swelling and erosion were not significant factors in modulating the drug release rate.Conclusions: The pH-dependent property of the pellets may be strategically employed towards development of a site-specific drug delivery system for non-steroidal anti-inflammatory agents. In general, targeting the delivery of an agent with potential for gastric irritation to the proximal intestine/colon may effectively reduce its ulcerogenic effect and ultimately contribute towards improved patient compliance.     

Production of inert cushioning beads: effect of excipients on the physicomechanical properties of freeze-dried beads containing microcrystalline cellulose produced by extrusion-spheronization

Conventional highly compactible fillers such as microcrystalline cellulose (MCC) can be mixed with drug-loaded membrane-coated beads and compressed to form a tablet. However, due to particle size differences, there is substantial risk of segregation leading to weight variation and content uniformity problems. Furthermore, whenever modified release beads are included in a tablet matrix, care must be taken to assure the integrity of the coated beads. This paper describes the development of placebo beads containing MCC whose properties make them uniquely suitable for tableting modified release beads. These placebo beads have high compactibility and the ability to rapidly disintegrate. They deform readily and may provide a high degree of protection to drug-loaded membrane-coated beads during compression ('cushioning effect'). They can be produced in size ranges that provide minimal segregation propensity. Beads containing different MCC/lactose ratios and different types and levels of superdisintegrants were produced by extrusion-spheronization followed by freeze drying. The presence of high levels of MCC and different superdisintegrants, especially croscarmellose sodium, increased the granulation liquid requirement, thus producing freeze-dried beads with higher porosities and compactibility. Athy-Heckel analysis studies revealed that beads rich in MCC exhibited lower mean yield pressures than those containing high levels of lactose. The freeze-dried beads exhibited both plastic deformation and brittle fracture characteristics.     

挤出滚圆法制备复方竹茶速释微丸

目的采用挤出滚圆法制备复方竹茶速释微丸。方法以圆整度及收率为指标,单因素考察投药量、辅料种类、辅料配伍比例、润湿剂种类及用量、挤出速度、滚圆速度及滚圆时间,正交试验考察润湿剂用量、滚圆速度及滚圆时间,优选工艺并采用大鼠LDL-R的ELISA试剂盒为检测方法测定高脂大鼠肝脏组织液中LDL-R含量。结果按最优处方工艺分别称取质量分数为20%的药物投药量、微晶纤维素(microcrystalline cellulose,MCC)与乳糖[m(MCC)∶m(乳糖)=4∶1]作为骨架材料,以12 m L水做黏合剂制软材后,置入挤出滚圆造粒机,以40 Hz的挤出速度,50 Hz的滚圆速度滚圆5 min,制得微丸。微丸的平均圆整度为9.8°,收率为93.7%。复方竹茶胶囊能促进肝脏对于脂质的代谢功能,从而起到了调控血脂水平的作用。结论此工艺条件下制备的微丸能起到调控血脂水平的作用。     

Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations

Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics.     

Formulation, characterization, and in vitro release of glyburide from proliposomal beads

The objective of our study was to formulate and evaluate proliposomes in the form of enteric-coated beads using glyburide as a model drug. The beads were enteric coated with Eudragit L-100 by a fluidized bed coating process using triethyl citrate as plasticizer. Content uniformity of glyburide was estimated using HPLC analysis of beads dissolved in methanol. These proliposomal beads formed liposomes on disintegration in phosphate buffered saline (pH 7.4), which was confirmed by transmission electron microscopy. The dissolution study of enteric-coated beads exhibited enhanced dissolution compared with pure drug and a marketed product. Liposomes can be successfully prepared for oral administration in the form of enteric-coated beads that may offer a stable system to produce liposomes for oral administration.     

Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant

Amorphous forms of poorly soluble drugs are more frequently being incorporated into solid dispersions for administration and extensive research has led to a reasonable understanding of how these dispersions, although still kinetically unstable, improve stability relative to the pure amorphous form. There remains however a paucity of literature describing the effects on such solid dispersions of subsequent processing into solid dosage forms such as tablets. This paper addresses this area by looking at the effects of the addition of common excipients and different manufacturing routes on the stability of a spray-dried dispersion (SDD) of the cannabinoid CB-1 antagonist, ibipinabant. A marked difference in physical stability of tablets was seen with the different fillers with microcrystalline cellulose (MCC) giving the best stability profile. It was found that minimising the number of compression steps led to improved formulation stability with a direct compression process giving the best results. Increased levels of crystallinity were seen in coated tablets most likely due to the exposure of the amorphous matrix to moisture and heat during the coating process. DSIMS analysis of the SDD particles indicated increased levels of polymer on the surface.     

Extruded and spheronized beads containing no microcrystalline cellulose: influence of formulation and process variables

The purposes of this study were to investigate the use of chitosan in the manufacture of beads by extrusion-spheronization without inclusion of microcrystalline cellulose, and to study the effect of formulation and process variables on the characteristics of the beads. Beads containing chitosan, fine particle ethylcellulose, hydroxypropyl methylcellulose (HPMC), and caffeine as the model drug were manufactured. Bead size, yield, shape, friability, density, porosity, and release studies were determined. Spherical beads with good mechanical properties could be manufactured without microcrystalline cellulose. Release studies showed that there was immediate release of drug from the beads. A five factor, half fraction screening design was employed to study the effect of formulation variables and process variables on the properties of the beads. Statistical analysis indicated that formulation variables such as the chitosan content, HPMC content, and water content, and process variables such as the spheronizer speed and extruder speed significantly affected the physical properties of the beads. The bead size decreased with an increase in chitosan content. Significant two-factor interactions exist between the variables for several of the measured responses. Beads with high percentage yield and high sphericity can be obtained at high chitosan content, and low HPMC content, water content, spheronizer speed, and extruder speed. Less friable beads can be obtained at high levels of studied formulation variables and low levels of studied process variables. Beads of high density and low porosity can be manufactured at high levels of the studied formulation and process variables. Regression equations were generated using Statgraphics Plus software that can be used to develop formulations with desired bead properties. Chitosan was useful to provide beads of acceptable physical properties using water as a granulating fluid in the extrusion-spheronization process.     

Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers.

General considerations concerning the stability of coated dosage forms are discussed, in order to avoid predictable interactions which may cause long-term stability problems. As polymers themselves maintain a high chemical stability and a low reactivity, instability phenomena mainly have to be explained by interactions of low molecular weight substances or physical changes. Possible interactions of functional groups can be predicted easily and insulating subcoates are proper countermeasures. Impurities, remaining in the polymeric material from the manufacturing process, may accelerate the hydrolysis of sensitive drugs. Instabilities of coated dosage forms are mainly based on physical interactions, caused by improper formulations of coating suspensions (i.e. plasticizers or pigments) or the film coating process. Residual moisture or solvents, probably enclosed in the core and migrating over time, may increase the permeability of coatings, due to plasticizing effects. The functionality of coatings from aqueous dispersions is linked to coalescence of latex particles. Thus any incomplete film formation, caused by too high or too low coating temperatures, may result in high permeable coatings. During storage, preferably under stress conditions this process will continue and thus change the release profile. Therefore bed temperatures of 10-20 degrees C above MFT must ensure the formation of homogeneous polymer layers during the coating process. Stability test procedures and packaging materials also need to be adapted to the physicochemical properties of the dosage form, in order to get meaningful results in stability tests.     

Formulation considerations for proteins susceptible to asparagine deamidation and aspartate isomerization

The asparagine (Asn) deamidation and aspartate (Asp) isomerization reactions are nonenzymatic intra-molecular reactions occurring in peptides and proteins that are a source of major stability concern in the formulation of these biomolecules. The mechanisms for the deamidation and isomerization reactions are similar since they both proceed through an intra-molecular cyclic imide (Asu) intermediate. The formation of the Asu intermediate, which involves the attack by nitrogen of the peptide backbone on the carbonyl carbon of the Asn or the Asp side chain, is the rate-limiting step in both the deamidation and the isomerization reactions at physiological pH. In this article, the influence of factors such as formulation conditions, protein primary sequence, and protein structure on the reactivity of Asn and Asp residues in proteins are reviewed. The importance of formulation conditions such as pH and solvent dielectric in influencing deamidation and isomerization reaction rates is addressed. Formulation strategies that could improve the stability of proteins to deamidation and isomerization reactions are described. The review is intended to provide information to formulation scientists, based on protein sequence and structure, to predict potential degradative sites on a protein molecule and to enable formulation scientists to set appropriate formulation conditions to minimize reactivity of Asn and Asp residues in protein therapeutics.     

Colon targeted beads loaded with pterostilbene: Formulation,optimization, characterization and in vivo evaluation

Background

Pterostilbene has a proven chemopreventive effect for colon carcinogenesis but suffers low bioavailability limitations and therefore unable to reach the colonic tissue.

Comparative scintigraphic assessment of the intragastric distribution and residence of cholestyramine, Carbopol 934P and sucralfate

It has been demonstrated that orally administered cholestyramine is distributed throughout the stomach and provides prolonged gastric residence via mucoadhesion. Gamma scintigraphy was used to compare the gastric emptying and residence of this resin with two formulations known to exhibit retentive or bioadhesive properties, Carbopol 934P and sucralfate. Fasted normal subjects received a single radiolabelled dose and gastrointestinal transit was monitored for 6 h. The subjects were fed after 4 h to determine the effects of inducing a fed pattern of motility on the retention of the formulations. Initial gastric emptying was similar (Mean T50+/-S.E.M.: cholestyramine=66.93+/-9.39 min; Carbopol=56.57+/-11.96 min; sucralfate=48.33+/-11.07 min; P=0.548: n=10), however, the emptying of cholestyramine slowed beyond 2 h. This resulted in greater residence for cholestyramine (Mean AUC0-6+/-S.E.M. (relative units)=11516+/-686 versus 7657+/-1170 versus 6170+/-998; cholestyramine versus Carbopol versus sucralfate; P=0.004: n=10), with approximately 25% remaining in the stomach at 6 h compared to 3.84 and 2.65% of Carbopol and sucralfate, respectively. Cholestyramine was also distributed widely throughout the stomach whereas Carbopol and sucralfate were concentrated in the body and antrum. Thus, as cholestyramine had a comparable emptying time to Carbopol and sucralfate but greater gastric residence and wider distribution, it could provide a potential mucoadhesive drug delivery system targeting the gastric mucosa for treatment of conditions such as Helicobacter pylori infection.     

Formulation and characterisation of beads prepared from natural cyclodextrins and vegetable, mineral or synthetic oils

A continuous external shaking for 2.5 days of a mixture composed of alpha-cyclodextrin (6%), soybean oil (19.6%) and water (74.4%) resulted in a calibrated lipid carrier namely bead with a high fabrication yield. The purpose of this work was to explore the possibility to substitute alpha-cyclodextrin by other natural cyclodextrins, i.e. beta- and gamma-cyclodextrin and then soybean oil by mineral (Primol) 352 and Marcol 82) or synthetic (Silicon 200) fluid 10, 50 or 100cSt) oils. Beads can be successfully prepared using Marcol 82 with alpha-cyclodextrin and Silicon 50 or 100cSt with gamma-cyclodextrin. The area inside oil/cyclodextrin/water ternary diagram corresponding to bead occurrence was superior for the Marcol 82/alpha-cyclodextrin couple compared to that observed with soybean oil/alpha-cyclodextrin couple. Only a few ratios of Silicon 50 and 100cSt/gamma-cyclodextrin/water led to beads. The combinations which did not induce bead occurrence gave either emulsions, two non-miscible liquids or a solid mixture. Whatever the materials used, beads exhibited similarities: presence of a crystalline organisation and viscoelastic properties. Manufacturing process of paraffin- and silicon-based beads need further optimisation to increase fabrication yield and later on, to take advantages from the high stability of both oils for the formulation of drugs with beads.     

Covalent coupling of concanavalin A to a Carbopol 934P and 941P carrier in glucose-sensitive gels for delivery of insulin

A novel glucose-sensitive gel formulation, containing concanavalin A and specific polysaccharides, was stabilised via covalent coupling to two structurally different carbomers. The bonding was done to minimise leaching of gel components thereby preventing toxicity and preserving the working mechanism of the gel. Increased gel stability was introduced by covalently bonding amine groups present on the lysine residues of concanavalin A to carboxylic moieties on Carbopol 934P NF and 941P NF using carbodiimide chemistry. The introduction of dextran then produced a glucose-sensitive formulation that transformed from gel to sol in the presence of free glucose. Rheological examination of glucose-sensitive gels stabilised in this way and containing varying concentrations of glucose was conducted with a cone and plate viscometer used in continual rotation mode. A decrease in viscosity over the chosen glucose concentration range was exhibited by both carbomer-stabilised formulations. The subsequent testing of such formulations in in-vitro diffusion experiments revealed that the leaching of concanavalin A from the covalently coupled gels is restricted significantly with respect to non-coupled formulations. In addition, insulin delivery in response to glucose in the physiologically relevant glucose concentration range has been demonstrated using the carbomer-stabilised gels at 37 degrees C. The performance of this self-regulating drug delivery system has been improved in terms of increased gel stability with reduced component leaching.     

Pharmaceutical acrylic beads obtained by suspension polymerization containing cellulose nanowhiskers as excipient for drug delivery

Direct compression is one of the most popular techniques to prepare tablets but only a few commercial excipients are well adapted for this process into controlled release formulations. In the last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluated the physicochemical and flow properties of new polymeric excipient of ethyl acrylate, methyl methacrylate and butyl metacrylate, synthesized by suspension polymerization using cellulose nanowhiskers as co-stabilizer, to be used as direct compression for modified release tablets. Infrared spectroscopy (FTIR) confirmed the success of the copolymerization reaction. Scanning electron microscopy (SEM) showed that excipient was obtained how spherical beads. Thermal properties of the beads were characterized by thermogravimetric (TG) analysis. Particle size analysis of the beads with cellulose nanowhiskers (CNWB) indicated that the presence of the nanowhiskers led to a reduction of particle size and to a narrower size distribution. In vitro test showed that the nanowhiskers and beads produced are nontoxic. Parameters such as Hausner ratio, Carr's index and cotangent of angle α were employed to characterize the flow properties of CNWB beads. Furthermore, the beads are used to produce tablets by direct compression contained propranolol hydrochloride as model drug. Dissolution tests performed suggested that beads could be used as excipient in matrix tablets with a potential use in drug controlled release.     

Formulation, characterization, and in vitro evaluation of bioadhesive gels containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16-18% w/w) either alone or in combination with HPMC K 15 M and Gantrez S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 x 10(-4) cm/s and 3.94 x 10(-5) cm/s, respectively, and differed significantly ( p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as non-Fickian diffusion.