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1.
The aim of this study was to systematically evaluate the pelletization process parameters of κ-carrageenan-containing formulations. The study dealt with the effect of 4 process parameters—screw speed, number of die holes, friction plate speed, and spheronizer temperature—on the pellet properties of shape, size, size distribution, tensile strength, and drug release. These parameters were varied systematically in a 24 full factorial design. In addition, 4 drugs—phenacetin, chloramphenicol, dimenhydrinate, and lidocaine hydrochloride—were investigated under constant process conditions. The most spherical pellets were achieved in a high yield by using a large number of die holes and a high spheronizer speed. There was no relevant influence of the investigated process parameters on the size distribution, mechanical stability, and drug release. The poorly soluble drugs, phenacetin and chloramphenicol, resulted in pellets with adequate shape, size, and tensile strength and a fast drug release. The salts of dimenhydrinate and lidocaine affected pellet shape, mechanical stability, and the drug release properties using an aqueous solution of pH 3 as a granulation liquid. In the case of dimenhydrinate, this was attributed to the ionic interactions with κ-carrageenan, resulting in a stable matrix during dissolution that did not disintegrate. The effect of lidocaine is comparable to the effect of sodium ions, which suppress the gelling of carrageenan, resulting in pellets with fast disintegration and drug release characteristics. The pellet properties are affected by the process parameters and the active pharmaceutical ingredient used. 相似文献
2.
Summary and Conclusion The processing conditions has a pronounced effect on the pellet properties. Drying conditions influenced the mean size and
the drug release of the pellets. Because of the shrinking of the pellets upon drying at higher temperatures, the pellets also
showed increased densities. Freeze drying almost prevented shrinking and thus led to the highest drug release. With an increase
in the temperature of drying, the drug release rate decreased.
Both spheronization time and spheronization speed affected the shapes of pellets, and the changes in shapes then affected
the pellet flow properties. Within the studied range, the circularity of the pellets was affected more by the spheronization
time than by the spheronization speed. Drying conditions influenced pellet friability, which decreased with an increase in
drying temperature, indicating the formation of more dense structures at higher temperatures. The same result was obtained
with spheronization time. With an increase in spheronization time, the friability decreased, because of the formation of more
compact masses at higher spheronization time. Mean size was not affected by spheronization time or spheronization speed.
Published: March 9, 2007 相似文献
3.
Kalyan K. Saripella Nikhil C. Loka Rama Mallipeddi Anuja M. Rane Steven H. Neau 《AAPS PharmSciTech》2016,17(2):368-379
Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported. 相似文献
4.
Nikolett Kállai Oliver Luhn Judit Dredán Kristóf Kovács Miléna Lengyel István Antal 《AAPS PharmSciTech》2010,11(1):383-391
The objective of the present study was to investigate the effect of the pellet core materials isomalt, sugar, and microcrystalline cellulose on the in vitro drug release kinetics of coated sustained-release pellets as well as to evaluate the influence of different ratios of polymethacrylate copolymers exhibiting different permeability characteristics on the drug release rate. For characterization of the drug release process of pellets, the effect of osmolality was studied using glucose as an osmotically active agent in the dissolution medium. The pellet cores were layered with diclofenac sodium as model drug and coated with different ratios of Eudragit® RS30D and Eudragit® RL30D (ERS and ERL; 0:1 and 0.5:0.5 and 1:0 ratio) in a fluid bed apparatus. Physical characteristics such as mechanical strength, shape, and size proved that the inert cores were adequate for further processing. The in vitro dissolution tests were performed using a USP Apparatus I (basket method). The results demonstrated that, besides the ratio of the coating polymers (ERS/ERL), the release mechanism was also influenced by the type of starter core used. Sugar- and isomalt-type pellet cores demonstrated similar drug release profiles. 相似文献
5.
Pellets intended for oral dosing are frequently produced via extrusion/spheronization followed by drying. Typically, the last active process step, i.e., drying, is assumed to have little effect on the final dosage form properties (e.g., dissolution characteristics). Thus, there exist only a few studies of this subject. In the present study, calcium stearate/ibuprofen pellets were used as model system to investigate the impact of the drying conditions. Lipophilic calcium stearate matrix pellets containing 20% ibuprofen were prepared via wet extrusion/spheronization. Subsequently, desiccation, fluid-bed drying, and lyophilization were applied for granulation liquid removal. The impact of these drying techniques on the final pellet properties was evaluated. The in vitro dissolution behavior was dramatically altered by the drying techniques that were considered. The investigated pellets showed drug release rates that varied as much as 100%. As no polymorphic transitions occurred during drying, we focused on two possible explanations: (a) a change in the drug distribution within the pellets and (b) a change in pellet micro-structure (porosity, pore size). The ibuprofen distribution proved to be homogeneous regardless of the drying conditions. Pellet porosity and pore sizes, however, were modified by the drying process. Our results clearly demonstrate that a single process step, such as drying, can play a crucial role in achieving desired pellet properties and release profiles. 相似文献
6.
B. S. Schon K. Schrobback M. van der Ven S. Stroebel G. J. Hooper T. B. F. Woodfield 《Cell and tissue research》2012,347(3):629-642
Described here is a simple, high-throughput process to fabricate pellets with regular size and shape and the assembly of pre-cultured
pellets in a controlled manner into specifically designed 3D plotted porous scaffolds. Culture of cartilage pellets is a well-established
process for inducing re-differentiation in expanded chondrocytes. Commonly adopted pellet culture methods using conical tubes
are inconvenient, time-consuming and space-intensive. We compared the conventional 15-mL tube pellet culture method with 96-well
plate-based methods, examining two different well geometries (round- and v-bottom plates). The high-throughput production
method was then used to demonstrate guided placement of pellets within a scaffold of defined pore size and geometry for the
3D assembly of tissue engineered cartilage constructs. While minor differences were observed in tissue quality and size, the
chondrogenic re-differentiation capacity of human chondrocytes, as assessed by GAG/DNA, collagen type I and II immunohistochemistry
and collagen type I, II and aggrecan mRNA expression, was maintained in the 96-well plate format and pellets of regular size
and spheroidal shape were produced. This allowed for simple production of large numbers of reproducible tissue spheroids.
Furthermore, the pellet-assembly method successfully allowed fluorescently labelled pellets to be individually visualised
in 3D. During subsequent culture of 3D assembled tissue engineered constructs in vitro, pellets fused to form a coherent tissue,
promoting chondrogenic differentiation and GAG accumulation. 相似文献
7.
Ioannis Nikolakakis Athanasia Panagopoulou Andrea Salis Stavros Malamataris 《AAPS PharmSciTech》2015,16(1):129-139
Self-emulsifying pellets were prepared using microcrystalline cellulose, emulsions of caprylic/capric triglyceride, and three Cremophors (ELP, RH40, and RH60) at 1.5 and 2.3 weight ratios, and two drugs (furosemide and propranolol) of different lipophilicity. Droplet size, zeta potential (ζ) and viscosity of emulsions, and pellet size, shape, friability, tensile strength, disintegration, and drug migration in pellets were determined. Evaluation of reconstituted emulsions was based on droplet size and ζ. Factorial design and 3-way ANOVA was applied to estimate the significance of the effects of the drug, surfactant and oil/surfactant ratio. It was found that droplet size, viscosity and ζ of emulsions, and size, shape, and friability of pellets were affected by the studied factors and were significant interactions between their effects on pellet size and friability. Migration of drug towards the pellet surface was higher for the less lipophilic furosemide and higher oil content. Linear relationships were found between the emulsion viscosity and the shape parameters of the pellets (for the aspect ratio R2 = 0.796 for furosemide and R2 = 0.885 for propranolol and for the shape factor, eRR2 = 0.740 and R2 = 0.960, respectively). For all the formulations examined, an exponential relationship was found between migration (M%) and the product of viscosity (η) and solubility of drug in oil/surfactant mixture (S) (M% = 98.1e-0.016 [η•S], R2 = 0.856), which may be useful in formulation work.KEY WORDS: drug distribution, emulsion and pellet characterization, friability and tensile strength, furosemide and propranolol, self-emulsifying pellets 相似文献
8.
There is a growing interest for multiparticulate solid dosage forms such as pellets, because of their several advantages over tablets during drug therapy. It is essential to investigate the drug dissolution process which can be influenced by the composition and manufacturing process technology, too. This study was performed applying experimental design in order to evaluate the effects of independent process variables during high-shear pelletisation, taking the impeller speed (x1) and granulation binder flow rate (x2) as factors into consideration. Theophylline containing pellet formulation was prepared using a matrix consisted of ethylcellulose, microcrystalline cellulose and lactose. Dissolution profiles were modeled by the Weibull function to evaluate the power of process variables. Both process variables were powerful to influence the particle agglomeration. A linear regression was found between the particle size and the diffuse reflectance values after the Kubelka-Munk transformation. Differences in the diffuse reflectance spectra of pellet samples related to particle size offer a fast instrumental method for the in-process control. 相似文献
9.
Nastruzzi C Cortesi R Esposito E Genovesi A Spadoni A Vecchio C Menegatti E 《AAPS PharmSciTech》2000,1(2):14-25
The goal of the present study was to evaluate the influence of the formulation and operating conditions on pellet preparation by pan technique. To this end, a new pelletization process, typified by the application of powdered drug on sugar-based cores using the GS coating system was studied. Inert cores were intermittently treated with micronized drug powder and adhesive solution. This treatment led to the formation of multiple layers of drug particles around an inert core resulting in the production of pellets that can further be coated by different polymers to obtain modified release formulations. Different procedures have been used to evaluate a series of important parameters such as initial core weight; speed of powder application; speed, type, and position of the atomizers; atomization degree: temperature; and air cap. Good yield of drug layering was obtained by adjusting the quantity of both the drug powder to apply and the binder solution. Pellets obtained following the optimal operating conditions (defined in a pre-formulation study) were film coated with the acrylic polymer Eudragit L30D in order to produce a model formulation consisting of enteric polymer-coated pellets containing ibuprofen. During its preparation, the formulation showed no degradation of the drug, moreover, a low percentage of residual humidity was obtained, indicating that this system is very efficient for the production of highly stable formulations. This study showed the good performance of the GS automated pan-coating system in obtaining enteric coated pellets prepared by powder layering technique using aqueous solutions. 相似文献
10.
Lei Shang Niels Peter K. Nielsen Wolfgang Stelte Jonas Dahl Jesper Ahrenfeldt Jens Kai Holm Maria Puig Arnavat Lars S. Bach Ulrik B. Henriksen 《Bioenergy Research》2014,7(1):87-94
Combined torrefaction and pelletization is used to increase the fuel value of biomass by increasing its energy density and improving its handling and combustion properties. In the present study, a single-pellet press tool was used to screen for the effects of pellet die temperature, moisture content, additive addition, and the degree of torrefaction on the pelletizing properties and pellet quality, i.e., density, static friction, and pellet strength. Results were compared with pellet production using a bench-scale pelletizer. The results indicate that friction is the key factor when scaling up from single-pellet press to bench-scale pelletizer. Tuning moisture content or increasing the die temperature did not ease the pellet production of torrefied wood chips significantly. The addition of rapeseed oil as a lubricant reduced the static friction by half and stabilized pellet production; however, the pellet quality, strength, and density were negatively affected. The pellets produced from pine wood torrefied at 250 and 280 °C were shorter than pellets produced from untreated wood and their quality did not match conventional wood pellet standards. However, the heating value of the torrefied pellets was higher and the particle size distribution after grinding the pellets was more uniform compared to conventional wood pellets. 相似文献
11.
The aim of this study was to examine the effect of pellet size, pectin type, pectin concentration, and dissolution medium on the swelling and drug release behavior of spherical pellets containing theophylline and coated with 2 different calcium pectinates, using a multi-level factorial design approach. The spherical pellets were prepared by an extrusion-spheronization method and then coated with calcium pectinate using the diffusion-controlled interfacial complexation technique, which provides a defect-free and uniform coating on solid cores. Theophylline release from the pellets was slowed by the application of the coatings. The time to release 50% of the payload (ie, T50) in an acidic medium was approximately 7 minutes from uncoated small pellets and was 55 minutes after an amidated calcium pectinate coat was applied; a comparable coat on large pellets showed a T50 of 93 minutes. Drug release profiles of dry coated pellets showed a lag time (all less than 20 minutes) when the gel coat hydrated and swelled, followed by a zero-order release. It was found that the release rate was controlled by the pellet size, pectin type, pectin concentration, and dissolution medium. 相似文献
12.
This study examined the effect of rotor speed, amount of water sprayed, and atomizing air pressure on the geometric mean diameter
and geometric standard deviation of pellets produced in a fluid-bed rotor granulator using a 23 factorial design and an optimization technique.
Pellets were prepared by wet granulation. Equal amounts of microcrystalline cellulose, α-lactose monohydrate, and distilled
water were used as the granulation liquid. The size and the size distribution of the pellets were determined by sieve analysis.
The size of the pellets was found to be dependent on the amount of water added, while an increase in rotor speed decreased
their size. Both factors were found to be statistically significant (P<.05). The effect of atomizing air pressure on pellet size was not statistically significant. None of the 3 factors significantly
affected the geometric standard deviation of the pellets.
The rotor speed and the amount of water sprayed were further selected in order to construct a mathematical model that correlates
these factors with the geometric mean diameter of the pellets. For this purpose, the optimization technique 32 was used. The derived equation described the relationship between the the experimental design techniques applied were found
to be suitable in optimizing the pelletization process carried out in a fluid-bed rotor granulator. 相似文献
13.
Spherical granules (pellets) are quite useful in many pharmaceutical applications. The extrusion spheronisation technique is well established as a method of producing pellets of a spherical shape and narrow size distribution. After the extrusion, the cylindrical extrudates are transformed to spherical pellets by spheronisation. The frequently used models consider deformation and breakage during this process. However, the adhesion of fine particles has been neglected as a mechanism in spheronisation for many years. This study quantifies the mass transfer between pellets during spheronisation. During the investigation, the pelletisation aids (microcrystalline cellulose and kappa-carrageenan), the drug (acetaminophen and ibuprofen) and water content were varied systematically. A novel parameter, namely, the "mass transfer fraction" (MTF), was defined to quantify the mass transfer between the pellets. All four investigated formulations had an MTF between 0.10 and 0.52 that implies that up to 50 % of the final pellet weight was involved in mass transfer. Both pelletisation aids showed similar MTF, independent of the drug used. Furthermore, an increase of the MTF, with respect to an increase of the water content, was found for microcrystalline cellulose formulations. In conclusion, the mass transfer between the pellets has to be considered as a mechanism for spheronisation.KEY WORDS: carrageenan, MCC, mechanism, pellets, spheronisation 相似文献
14.
Both parallel fermentations with Aspergillus awamori (CBS 115.52) and a literature study on several fungi have been carried out to determine a relation between fungal morphology and agitation intensity. The studied parameters include hyphal length, pellet size, surface structure or so-called hairy length of pellets, and dry mass per-wet-pellet volume at different specific energy dissipation rates. The literature data from different strains, different fermenters, and different cultivation conditions can be summarized to say that the main mean hyphal length is proportional to the specific energy dissipation rate according to a power function with an exponent of -0.25 +/- 0.08. Fermentations with identical inocula showed that pellet size was also a function of the specific energy dissipation rate and proportional to the specific energy dissipation rate to an exponent of -0.16 +/- 0.03. Based on the experimental observations, we propose the following mechanism of pellet damage during submerged cultivation in stirred fermenters. Interaction between mechanical forces and pellets results in the hyphal chip-off from the pellet outer zone instead of the breakup of pellets. By this mechanism, the extension of the hyphae or hair from pellets is restricted so that the size of pellets is related to the specific energy dissipation rate. Hyphae chipped off from pellets contribute free filamentous mycelia and reseed their growth. So the fraction of filamentous mycelial mass in the total biomass is related to the specific energy dissipation rate as well.To describe the surface morphology of pellets, the hyphal length in the outer zone of pellets or the so-called hairy length was measured in this study. A theoretical relation of the hairy length with the specific energy dissipation rate was derived. This relation matched the measured data well. It was found that the porosity of pellets showed an inverse relationship with the specific energy dissipation rate and that the dry biomass per-wet-pellet volume increased with the specific energy dissipation rates. This means that the tensile strength of pellets increased with the increase of specific energy dissipation rate. The assumption of a constant tensile strength, which is often used in literature, is then not valid for the derivation of the relation between pellet size and specific energy dissipation rate. The fraction of free filamentous mycelia in the total biomass appeared to be a function of the specific energy dissipation in stirred bioreactors. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 715-726, 1997. 相似文献
15.
The objectives of this study were to develop and evaluate a novel self-emulsifying floating drug delivery system (SEFDDS)
that resulted in improved solubility, dissolution, and controlled release of the poorly water-soluble tetrahydrocurcumin (THC).
The formulations of liquid self-emulsifying drug delivery system (SEDDS; mixtures of Labrasol, Cremophor EL, Capryol 90, Labrafac
PG) were optimized by solubility assay and pseudo-ternary phase diagram analysis. The liquid SEDDS was mixed with adsorbent
(silicon dioxide), glyceryl behenate, pregelatinized starch, sodium starch glycolate, and microcrystalline cellulose and transformed
into pellets by the extrusion/spheronization technique. The resulting pellets with 22% liquid SEDDS had a uniform size and
good self-emulsification property. The microemulsions in aqueous media of different self-emulsifying floating pellet formulations
were in a particle size range of 25.9–32.5 nm. Use of different weight proportions of glyceryl behenate and sodium starch
glycolate in pellet formulations had different effects on the floating abilities and in vitro drug release. The optimum formulation (F2) had a floating efficiency of 93% at 6 h and provided a controlled release of THC
over an 8-h period. The release rate and extent of release of THC liquid SEDDS (80% within 2 h) and self-emulsifying floating
pellet formulation (80% within 8 h) were significantly higher than that of unformulated THC (only 30% within 8 h). The pellet
formulation was stable under intermediate and accelerated storage conditions for up to 6 months. Controlled release from this
novel SEFDDS can be a useful alternative for the strategic development of oral solid lipid-based formulations. 相似文献
16.
As a prelude to the understanding of mechanotransduction in human embryonic stem cell (hESC) differentiation, the mechanical
behavior of hESCs in the form of cell pellet is studied. The pellets were tested after 3 or 5 weeks of cell culture in order
to demonstrate the effect of the duration of cell culture on the mechanical properties of the pellets. A micromechanical tester
was used to conduct unconfined compression on hESC pellet, and experimental, numerical, and analytical methods were combined
to determine the mechanical properties of hESC pellet. It is assumed that the mechanical behavior of hESC pellets can be described
by an isotropic, linear viscoelastic model consisting of a spring and two Maxwell units in parallel, and the Poisson’s ratio
of the hESC pellet is constant based on pellet deformation in the direction perpendicular to the compression direction. Finite
element method (FEM) simulation was adopted to determine the values of Poisson’s ratio and the five parameters contained in
the viscoelastic model. The variations of Poisson’s ratio and the initial elastic modulus are found to be larger compared
with those of the four other parameters. Results show that longer duration of cell culture leads to higher modulus of hESC
pellet. The effect of pellet size error on the values of mechanical parameters determined is studied using FEM simulation,
and it is found that the effect of size error on Poisson’s ratio and initial elastic modulus is much larger than that on the
other parameters. 相似文献
17.
Many filamentous bacteria and fungi tend to form pellets, or mixtures of dispersed mycelium and pellets in liquid fermentation broths. In some cases, a specific kind of morphology is required for optimum product yield. When quantitative analysis and characterization of the pellet morphology are needed, an image processing system can be used. It allows a fast and reproducible analysis of the frequency distribution of pellet size, mean pellet size, contents of pellets, or their shape. The use of such a system allows for an on-line analysis. For a demonstration of the method, results of two fermentations of Streptomyces tendae are shown. 相似文献
18.
The effects of filler used in the pellet cores (ie, waxy cornstarch or lactose) and the enteric film coat thickness on the
diffusion and dissolution of a freely soluble drug were studied. Two kinds of pellet cores containing riboflavin sodium phosphate
as a model drug, microcrystalline cellulose (MCC) as a basic filler, and waxy cornstarch or lactose as a cofiller were film
coated (theoretically weight increase 20% or 30%) with an aqueous dispersion of cellulose acetate phthalate (CAP). The diffusion
of riboflavin sodium phosphate in aqueous enteric-coated pellets was investigated using noninvasive confocal laser scanning
microscopy (CLSM). The in vitro release tests were performed using a USP apparatus I (basket method). Diffusion of drug from
the core to the film coat was found to be greater with lactose-containing pellets than with waxy cornstarch-containing pellets.
The dissolution test showed that 30% enteric-coated waxy cornstarch pellets had a good acidic resistance in 0.1 N HCl solution
for at least 1 hour, while the other enteric pellet formulations failed the test. The waxy cornstarch-containing enteric pellets
dissolved at SIF in less than 10 minutes. Confocal images of film-coated pellets showed that waxy cornstarch-containing pellets
had less drug dissolved than respective lactose-containing pellets. The observations were further confirmed by measurement
of fluorescence intensity of riboflavin sodium phosphate in the film coat. The dissolution test was consistent with the confocal
microscopy results. In conclusion, waxy cornstarch as a cofiller in the pellet cores minimizes premature drug diffusion from
the core into the film coat layer. 相似文献
19.
T. J. Hanrahan 《Animal Feed Science and Technology》1984,10(4):277-283
An experiment involving 1360 growing finishing pigs was undertaken to examine the effect of pellet size and pellet quality, as measured by the Holmen pellet durability test, on pig performance. A barley and soya bean meal diet was used and pellets were of two sizes, 5 and 10 mm diameter. Pellet quality was varied to give two types of pellet by steam conditioning and screening procedure during the pelleting process. The mean difference obtained in pellet durability was 11%.
Pig performance between 30 and 80 kg liveweight was not affected by either pellet size or pellet quality. There were small non-significant trends in favour of both the smaller pellets and the lower quality pellets. These trends, of the order of 1% or less, followed the same pattern as the dry matter content of the diets. The smaller diameter pellets were dried more efficiently in the cooling process and the low durability pellets had less steam added during the manufacturing process, which was reflected in the dry matter content of the finished diets. 相似文献
20.
Wei He Min Yang Jun Hong Fan Cai Xia Feng Su Juan Zhang Jin Xu Wang Pei Pei Guan Wei Wu 《AAPS PharmSciTech》2010,11(3):1287-1293
Lansoprazole (LSP), a proton-pump inhibitor, belongs to class II drug. It is especially instable to heat, light, and acidic
media, indicating that fabrication of a formulation stabilizing the drug is difficult. The addition of alkaline stabilizer
is the most powerful method to protect the drug in solid formulations under detrimental environment. The purpose of the study
was to characterize the designed multiple coating pellets of LSP containing an alkaline stabilizer (sodium carbonate) and
assess the effect of the stabilizer on the physicochemical properties of the drug. The coated pellets were prepared by layer–layer
film coating with a fluid-bed coater. In vitro release and acid-resistance studies were carried out in simulated gastric fluid and simulated intestinal fluid, respectively.
Furthermore, the moisture-uptake test was performed to evaluate the influence of sodium carbonate on the drug stability. The
results indicate that the drug exists in the amorphous state or small (nanometer size) particles without crystallization even
after storage at 40°C/75% for 5 months. The addition of sodium carbonate to the pellet protects the drug from degradation
in simulated gastric fluid in a dose-dependent manner. The moisture absorbed into the pellets has a detrimental effect on
the drug stability. The extent of drug degradation is directly correlated with the content of moisture absorption. In conclusion,
these results suggest that the presence of sodium carbonate influence the physicochemical properties of LSP, and the designed
multiple coating pellets enhance the drug stability. 相似文献