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As a depot drug delivery system, injectable polylactide-polyglycolide (PLGA) sustained-release microspheres have been successfully used to treat many diseases since the first microsphere product Lupron depot was approved for marketing in the United States in 1989. It has the ability of long-term release in the body for several days to several months, which can not only reduce the times of administration, but also reduce the drug blood concentration fluctuations, significantly improve the safety and patient compliance. In vitro-in vivo correlation (IVIVC) makes the development of microspheres more possible. It can describe the dynamic information of drug release in vivo through the in vitro release behavior of microspheres, and can reduce the workload of each stage and shorten the time span while characterizing the performance of microspheres. IVIVC can provide guidance or support for drug development, production changes, supervision and management. This article summarizes the release mechanism of injectable PLGA sustained-release microspheres, common measurement methods and theories of in vitro and in vivo release. And we also focus on the establishment and application of IVIVC, especially A level IVIVC in the field of microsphere preparations, to provide a reference for further study on in vitro-in vivo correlation of microspheres.
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OBJECTIVE@#Traditional Chinese medicine (TCM) has been widely used throughout China to prevent and cure diseases for thousands of years, and now it is a part of the integrative medicine field that is available in Western societies. To ensure the safety and quality of the herbal medicines that are a major part of the TCM tradition, they must be held to modern pharmaceutical standards. Erzhi pill (EZP) is a Chinese Pharmacopeia-listed herbal preparation that is used in the long-term clinical management of post-menopausal symptoms, osteoporosis and menstrual disorders. Until now, whether the drug release mechanism of EZP is in line with its intended TCM usage has not been studied.@*METHODS@#The release of specnuezhenide from three EZPs (self-made, Leiyunshang and Renhe) in simulated gastric fluid (SGF), acetate buffer (pH 4.5 buffer) and simulated intestinal fluid (SIF) was investigated in a dissolution test. The water uptake capacity and erosion extent of the three EZPs were investigated using swelling and erosion studies. The drug release mechanism was further assessed through statistical model fitting, using DDSolver software.@*RESULTS@#The release of specnuezhenide from all three EZPs in SGF was less than 50% within a 4 h period. However, over 70% of the specnuezhenide was released from each EZP in both pH 4.5 buffer and SIF in the same time. Analysis of the swelling and erosion behaviors and the drug release mechanism of the three EZPs confirmed that the release rate from EZP followed a sustained release profile, which was an interactive combination of swelling and erosion.@*CONCLUSION@#This study showed that the release pattern from the pills was in line with the intended TCM use of EZP. TCM had not only theoretically considered sustained release from the pills, but also formulated them to achieve this release pattern. When establishing quality control standards for pills, the theoretical TCM usage and the actual release patterns need to be considered.
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Background The time rhythm of human body is associated with the occurrence and development of manydiseases, and it also affects the efficacy and pharmacokinetic characteristics of the corresponding therapeuticdrugs. Therefore, the chronopharmacological drug delivery system has potential applications. Aim In this work, it is proposed to develop a kind of pulsatile release tablet of simple structure and preparingprocess, thus to provide an alternative drug delivery system for therapeutic agents used in treatment of diseasesof typical onset biorhythm at period inconvenient to take drug.Methods Metoprolol tartrate (MT), a drug widely used clinically to treat cardiovascular diseases was selected asa model drug for developing pulsatile tablets of time-controlled explosive system (TES). The MT pulsatile tabletswere ethyl cellulose (EC) coating tablets produced by pan coating process, and the core tablets were preparedby direct compression. The formulation and process was optimized by single factor test and orthogonal design.Also, the pulsatile release mechanism of the tablets was discussed through investigating the water absorptionand swelling capacity of tablets as well as the mechanical properties of EC free film.Results A kind of pulsatile tablets of MT were developed with a drug release lag time around 7 h and a fastrelease of drug after lag time. When the swelling force of core tablet caused by water uptake was high enoughover the tensile strength of EC coating film, the MT pulsatile tablets demonstrated a shell-type exploding rupturedue to the great rigidity and weak flexibility of EC film, and then a fast pulsatile release of drug was observed.Both the swelling capacity of core tablet and the thickness of coating film together controlled the lag time of drugrelease. The lag time showed a good linear relationship with the thickness of coating film (r = 0.9984, P < 0.01).The sort and amount of fillers and disintegrants dominated the release behaviour after lag time.Conclusion The developed MT pulsatile tablets can exert a timely release of drug before peak onset period ofhypertension and angina pectoris early in the morning after drug taking around 22:00 P.M the night before. Thegood linear relationship between lag time and coating thickness enabled the pulsatile tablets to be used fordelivery of other therapeutic agents of similar chronotherapy demand by adjusting the coating thickness toachieve the appropriate lag time of drug release to match the different high attack rhythm of the exact diseases.
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Objective: To optimize the formulation of paeonol lipid microspheres (Pae-LM) through central composite design- response surface method and determine its in vitro release characteristics. Methods: Using the mean particle size and centrifugal stability constant (Ke) as evaluation indexes, the oil phase type and the ratio of composite oil, the amount of phospholipid and stearic acid, the type of emulsifier, the type and amount of stabilizer, the quality of PC and CH, the high-speed shear temperature and time, the homogenization pressure and time was screened in prescription process. Effects of dosage of paeonol and high pressure homogenizing pressure on the properties of Pae-LM preparation were investigated by central composite design-response surface method. The binomial model and multivariate linear regression model were used to establish the mathematical relationship between the indexes and the factors. According to the best mathematical model of evaluation index, the response surface was depicted and the best prescription was analyzed by the response surface method. According to the optimized formulation Pae-LM, the in vitro drug release characteristics were investigated. Results: The best prescription of Pae-LM was basically round, with mean particle size of (149.32 ± 0.57) nm, Zeta potential of (-36.01 ± 3.09) mV, encapsulation rate of (98.24 ± 0.32)% and drug-loading rate of (11.94 ± 0.04)%. There was a credible quantitative relationship between Ke and the two factors, and the binomialmodel was more reliable than the multivariate linear model. The cumulative release of paeonol drug substance at 12, 24 and 36 h were 71.84%, 85.21% and 95.07%, while the cumulative release of Pae-LM was only 57.21%, 59.66%, and 63.91% at 12, 24 and 36 h, respectively. The drug release was in accordance with the Ritger-peppas model. Conclusion: Central composite design-response surface method can be applied to optimize prescription of lipid emulsion microspheres. The optimized particle size of Pae-LM was suitable with a higher encapsulation rate, which can provide a reference for the development of paeonol cardiovascular delivery system.
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Objective: To prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. The factors that might influence drug release and release mechanism were studied in present study. Methods: High pressure homogenization method was used to prepare tilianin nanosuspension. Lactose and mannitol (3:1) were employed as freeze-drying protective agent to prepare lyophilized powder. HPMC was used as framework material to prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. Based on single factor test, the effects of proportion and amounts of HPMC K4M and HPMC K15, amounts of PEG 4000 and magnesium stearate on in vitro drug release of sustained-release tablets were investigated. Orthogonal test was designed to gain the optimum prescription. Results: The particle size and zeta potential of tilianin nanosuspension were (164.41 ± 9.72) nm and (-37.21 ± 2.38) mV, respectively. The particle size and zeta potential of re-dispersed freeze-drying products were (211.83 ± 11.26) nm and (-31.66 ± 2.92) mV, respectively. The optimum prescription was as follow: the proportion and amounts of HPMC K4M and HPMC K15 were 2:1 and 40 mg, amounts of PEG 4000 was 20 mg, and amounts of magnesium stearate were 0.5%. Sustained release tablets of tilianin nanosuspension were well accorded with Higuchi kinetics model. The equation was Mt/M∞ = 0.286 8 t1/2-0.073 8, r2 = 0.981 4. And the cumulative release could achieve 92.36% in 12 h. The drug release from the tablets was controlled by diffusion and degradation of the matrix. Conclusion: The preparation technology of sustained release tablets of tilianin nanosuspension lyophilized powder has good reproducibility. This sustained release tablets could control the release of tilianin
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In the present experimental investigation an attempt has been made to assess the utility of Crushed Puffed Rice (CPR)-High Molecular Weight Chitosan (HMWCH)-Hydroxypropyl Methylcellulose K15M (HPMC K15M) as a polymeric carrier for the sustained stomach delivery of Piroxicam (PRX). A total of nine formulations were prepared by using 3 (2) Taguchi factorial design, physically blending drug and polymer(s) followed by encapsulation into hard gelatin capsules size 1. The prepared capsules were evaluated for various performance such as weight variation, drug contents, in vitro buoyancy and drug release in 0.1 M HCl. The effect of drug loading on in vitro performance of the formulations was also determined. Crushed puffed rice (CPR) remained buoyant for up to average time span of 06 hr as an unwetted irregular mass in 0.1 M HCl. However, when combined with HMWCH or HPMC K15M or HPMC K15M + HMWCH a low -density cylindrical raft type hydrogel was formed which remained buoyant for up to 12 hr and released up to 99% drug in a sustained manner from 8 to 12 hr following zero order release kinetics. It was also observed that drug release from drug + CPR matrices followed Fickian mechanism. Combination of CPR + HMWCH or HMWCH + HPMC K15M also follows Fickian mechanism. Obtained data from the research work suggests that CPR in combination with HMWCH or HPMC K15M or HPMC has sufficient potential to be used as a carrier for stomach specific delivery of gastric irritant drug like PRX
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Objective To prepare brucine solid lipid nanoparticles (SLN) and its lyophilized powder, and then hydrogel matrix sustained-release tablets (HMST) of brucine SLN (SLN-HMST) were prepared. The factors that may influence drug release in vitro and release mechanism were also investigated in present study. Methods Based on single factor test, orthogonal test was designed to gain the optimum prescription. Zero-order, First-order and Higuchi models were used for the model fitting of drug release. Ritger-Pappas models were employed to study release mechanism of brucine SLN-HMST. Results Brucine SLN-HMST was better agreed with First-order kinetics model. The equation was ln(1-Mt/M∞) = -0.212 1 t + 0.106 4 (r = 0.992 3). The cumulative release could achieve 91.48% in 12 h. The sustained release features were obviously. The drug release from the tablets was controlled by diffusion and degradation of the matrix. Conclusion The prepared brucine SLN-HMST can deliver drug continually for 12 h with good reproducibility.
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Objective:To prepare febuxostat nanosuspension and prepare sustained-release pellets,and investigate the in vitro dis-solution.Methods: Febuxostat nanosuspension was prepared by a high pressure homogenization method. Febuxostat nanosuspension pellets were prepared by fluidized bed coating technique. Eudragit RL30D and Eudragit RS30D were used to prepare the sustained-re-lease pellets. The dissolution mechanism of febuxostat nanosuspension sustained-release pellets was evaluated. Results: The average particle size of the prepared febuxostat nanosuspension was (212.5 ± 36.3) nm, PdI was (0.193 ± 0.018), zeta potential was ( -12.4 ± 0.3) mV,and the scanning electron microscopy showed that the particle size distribution of febuxostat nanosuspension was narrow. The in vitro dissolution of febuxostat nanosuspension sustained-release pellets was more stable and conformed to the first-order release model. Conclusion: The in vitro dissolution of febuxostat nanosuspension sustained-release pellets is more stable, and the preparation provides a new choice for febuxostat clinical application.
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OBJECTIVE:To optimize the formulation of Cilnidipine sustained-release tablet,and study its drug-release mecha-nism. METHODS:Solvent method was adopted to prepare the cilnidipine solid dispersion,then Cilnidipine sustained-release tablet was prepared by using hypromellose K4M(HPMC K4M)as release material. Using comprehensive scores of cumulative release de-gree in 2,6,12 h as indexes,single factor method and Box-Behnken response surface method were used to screen the amounts of HPMC K4M and ethyl cellulose (EC),lactose-microcrystalline cellulose (MCC) ratio in formulation of Cilnidipine sustained-re-lease tablet,and verification test was conducted. The drug-release mechanism of Cilnidipine sustained-release tablet was investigat-ed by model fitting way. RESULTS:The optimal formulation was as follow as 25％ of cilnidipine solid dispersion,30％ of HPMC K4M,10％ of EC,lactose-MCC ratio of 1:1(m/m). The adhesive was 5％ PVPP ethanol solution and the lubricant was 0.5％magnesium stearate. The cumulative release degrees of prepared sustained-release tablet in 2,6,12 h were(21.4±3.3)％,(62.9± 2.8)％,(85.4±0.5)％(n=3),relative error of which to predicted value 25％,60％,90％were 14.4％,4.8％and 5.1％. Release curve showed the highest fitting degree with the first-order release model,conforming to non-Fick diffusion. CONCLUSIONS:Cil-nidipine sustained-release tablet with sustained-release effect is successfully prepared by optimized formulation.
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OBJECTIVE: To optimize the prescription and preparation process of garcinia glycoside bilayer tablets and study the drug release mechanism in vitro. METHODS: Solid dispersions were prepared by using water soluble carrier material polyethylene glycol (PEG) and then used to prepare the rapid release layer. Hydroxypropylmethyl cellulose (HPMC) was used as main sustained release material to prepare the sustained release layer. The formulations of rapid release layer and sustained release layer were optimized by using univariate analyses. DDslover software was used to fitting drug release curve. RESULTS: The content of the garcinia glycoside in the bilayer tablets was 98.5% and its release rate was consistent with the rule of release in vitro. The release behavior of the sustained release layer in vitro followed Higuchi equation (r=0.998 3). The main mechanism of drug release was the synergistic action of diffusion and dissolution. CONCLUSION: Garcinia glycoside bilayer tablets prepared by this method can achieve the goal of both rapid-acting and long-acting.
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@#3D printing is rapidly developing in various areas of science and technology. Owing to its advantages such as simplicity, flexibility, reproducibility and suitability, 3D printing technology is utilized in the field of advanced pharmaceutical preparations. The literatures are mainly related to the formulations with a variety of release mechanism, including conventional-release formulations, controlled-release formulations, implants and compound preparations. Herein the latest 3D printing technology in the advanced preparations is presented and the related developing trends and challenges are also addressed.
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Objective To optimize the prescription of GA and GB hydrophilic gel matrix tablets; To study the in vitro release mechanism. Methods On the basis of the results of the mono-factor investigation, mixture uniform design was used to optimize the handicraft molding prescription of GA and GB hydrophilic gel matrix tablets. The release mechanism was investigated by the vitro of the GA and GB hydrophilic gelmatrix tablets to accumulate releasing rate to conduct linear fitting. Results The optimized prescription of GA and GB hydrophilic gel matrix tablets was: powder: HPMC: lactose=23:24:53. Conclusion Mixture uniform design can be used to optimize the prescriptions of GA and GB hydrophilic gel matrix tablets, and the results are accurate. The hydrophilic gelmatrix tablets release medicine by non-Fick mechanism, and the medicine release is in accordance with zero-order.
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@#The formulations of pramipexole hydrochloride sustained-release tablets were screened by single factor test and optimized by Box-Behnken design. The effects of the viscosity and content of hydroxypropyl methyl cellulose, as well as the insoluble sustained-release material combined with HPMC K100M on the in vitro release behavior were investigated. After single factor screening, a three-factor, three-level Box-Behnken design was used for optimization using the contents of HPMC K100, Eudragit RSPO and Eudragit L100 as independent variables, and the cumulative release at different time as responses. The optimal range of the three-factor optimized by Box-Behnken design, one of the optimized formulations was achieved with HPMC K100M of 101. 5 mg, Eudragit RSPO of 98 mg, and Eudragit L100 of 13. 7 mg, and the observed responses of the optimized formulation were very close to the predicted values. The in vitro drug release mechanism of the tablet was studied by drug released model fitted with different equations. The results explained that Eudragit RSPO promoted the release of the pramipexole hydrochloride, while Eudragit L100 blocked the release, and there was an antagonism between them. In conclusion, the drug release behavior of optimized formulations prepared by Eudragit RSPO/L100 was stable, less pH-dependent, which improved the drug bioavailability in vivo.
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Objective: To prepare silybin (SLB) controlled-release formulations with the utilization of solid dispersion and effervescent technology and to study their release mechanism. Methods: To determine the optimal formulation and preparation of SLB controlled release formulations was by using single factor test depending on drug release in vitro. The similarity factor method was used to explore the release mechanism of the controlled release formulations prepared. Results: The SLB controlled release formulations cores were prepared using SLB-polyethylene glycol 6000 solid dispersion (1: 2) as main drug, tartaric acid and sodium bicarbonate as effervescence, sodium carboxymethyl cellulose as blockers. The tablets were prepared using cellulose acetate as coating materials, polyethylene glycol 400 as porogen. SLB controlled release formulations released at a rate of zero-order. In the research on the release mechanism, the coating solution with/without porogen, tablet cores with/without blockers and effervescence had a significant impact on the drug release. On the contrary, the speed of the dissolution tester and the pH value of the release medium had no significant effect on the drug release. Conclusion: The preparation process of SLB controlled release formulations is simple. SLB controlled release formulations release with zero-order release in 12 h (r > 0.996 5).
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Aim: The application of factorial experimental design to evaluate the effect of particle size, capsule surface coating and binder concentration on the in vitro controlled release profile of metronidazole from encapsulated granules. Methodology: Metronidazole granules were prepared by the wet granulation technique and encapsulated in hard gelatin capsule shells. Eudragit® L-100 and Landolphia owariensis latex served as primary and secondary coatings respectively on 50 or 75% of capsule surface. The three formulation factors (% capsule surface coating, matrix former concentration and particle size) were subjected to a 2x3x4 factorial design experiment using the software (JMP 4.0.4, SAS Inc. USA). Gradient drug release studies were conducted in three media; firstly in media of pH 1.2 for 2 h, pH 6.8 for 3 h and finally pH 7.4 until exhaustion of drug release. The drug release data were subjected to kinetic treatment to establish operational release kinetics such as zero order, first order, Higuchi, Hixon Crowell and Kitazawa, while the power law enabled the prediction of mechanism of drug release. Results: Results showed that % capsule surface coated with Landolphia owariensis latex and particle size significantly (p<0.05) contributed to time of drug release (T7.4) at pH 7.4. In tandem with this, maximum amount of drug released (D7.4) at pH 7.4 was significantly (p<0.05) affected by particle size alone. A few batches were characterized by anomalous transport while over 80% were associated with super case 11 type of release. Conclusion: We therefore conclude that, factorial experimental design identified Landolphia owariensis latex coating and particle size of granules as being chiefly responsible for drug release variations.
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Nanogels based materials have high drug loading capacity, biocompatibility, and biodegradability which are the key points to design a drug delivery system effectively. The pursuit of this review article is to concisely describe the recent development of nanogel drug delivery system in terms of drug loading and swelling of drug from nanogels. Furthermore, biomedical application and current clinical trial studies of nanogel are summarized briefly. Here, different types of nanogels along with the synthetic procedure and mechanism of drug release from nanogel carrier are mainly focused. An intensive study of clinical trial in future will confirm nanogel as a suitable carrier for drug delivery.
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Controlling In-vitro drug release profiles for a system of PLGA/PLA microparticles encapsulating a hydrophobic drug. Challenges with the diversity of drug properties, microencapsulation methods, are evaluated with a focus on decreasing the time to lab-scale encapsulation of water-insoluble drug candidates in the drug development stage. The development of biodegradable microparticles systems that combined the beneficial properties of polymeric microparticles for hydrophobic drug delivery were reviewed here. Injectable biodegradable and biocompatible copolymers of lactic and glycolic acid are important advanced delivery system for week too month controlled release of hydrophobic drug (e.g., from biopharmaceutical classification system class IV), which often display poor oral bioavailability. Finally, three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating, . This review focuses on the microencapsulation of hydrophobic drugs, describes a variety of techniques for their preparation and analytics.
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Voltage-sensitive release mechanism was pharmacologically dissected from the Ca2+-induced Ca2+ release in the SR Ca2+ release in the rat ventricular myocytes patch-clamped in a whole-cell mode. SR Ca2+ release process was monitored by using forward-mode Na+-Ca2+ exchange after restriction of the interactions between Ca2+ from SR and Na+-Ca2+ exchange within micro-domains with heavy cytosolic Ca2+ buffering with 10 mM BAPTA. During stimulation every 10 s with a pulse roughly mimicking action potential, the initial outward current gradually turned into a huge inward current of -12.9+/-0.5 pA/pF. From the inward current, two different inward INCXs were identified. One was 10 muM ryanodine-sensitive, constituting 14.2+/-2.3%. It was completely blocked by CdCl2 (0.1 mM and 0.5 mM) and by Na+-depletion. The other was identified by 5 mM NiCl2 after suppression of ICaL and ryanodine receptor, constituting 14.8+/-1.6%. This latter was blocked by either 10 mM caffeine-induced SR Ca2+-depletion or 1 mM tetracaine. IV-relationships illustrated that the latter was activated until the peak in 30~35 mV lower voltages than the former. Overall, it was concluded that the SR Ca2+ release process in the rat ventricular myocytes is mediated by the voltage-sensitive release mechanism in addition to the Ca2+-induced-Ca2+ release.
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Animales , Ratas , Potenciales de Acción , Cloruro de Cadmio , Citosol , Células Musculares , Características de la Población , Canal Liberador de Calcio Receptor de Rianodina , TetracaínaRESUMEN
OBJECTIVE:To prepare diclofenac sodium controlled release pellets and investigate the mechanism of re?lease.METHODS:Single-factor method was used to investigate the influence of the composition of solvent system in coating solution,the concentration of coating material,porogenic agent and plastifier on the release rate of drug.RESULTS:When the concentration of coating material and the proportion of water increased,the release rate of pellets was increased;the release rate was further increased with PVP K30 added.CONCLUSION:The pellets belongs to the matrix-coating pellets,and the release mechanism varies with the change of coating thickness.
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To elucidate the Ca2+ release mechanisms in the rabbit coronary artery, arterial preparations were permeabilized with beta-escin and changes in tension were measured under varying experimental conditions. Additionally, we investigated properties and distribution of two kinds of Ca2+ release mechanisms, Ca2+-induced Ca2+ release (CICR) and IP3-induced Ca2+ release (IICR). The results obtained were summarized as follows; 1. When a rabbit coronary artery was incubated in a relaxing solution containing 30 microM beta-escin for 40 min. sensitivity to externally added Ca2+ was much higher in beta-escin permeabilized muscle than in intact preparations. The contractile effect of IP3 in beta-escin permeabilized muscle was also demonstrated; 2. Caffeine and IP3 contracted coronary arteries were permeabilized with beta-escin, but the amplitude of contraction was much larger in the presence of caffeine than of IP3. 3. Intracellular heparin completely inhibited the contractions induced by IP3, but not those by caffeine. On the other hand, procaine inhibited the responses to caffeine, but not those to IP3. Ryanodine inhibited both the caffeine- and IP3-induced contractions. 4. The amplitude of contractile responses was much larger to the maximal stimulation of CICR by applying caffeine than to the maximal stimulation of IICR by applying IP3. After the maximal CICR stimulation by caffeine, the activation of IICR by IP3 without the reloading of Ca2+ could no longer evoke contraction. On the other hand, after the maximal IICR activation, the activation of CICR could still evoke contraction although the amplitude of the contraction was smaller when compared with the case without the initial IICR stimulation. 5. Acetylcholine contracted coronary artery smooth muscles were permeabilized with beta-escin. However, in the absence of added guanosine triphosphate (GTP), the responses were very small. Acetylcholine-induced contraction was inhibited by heparin, but not by procaine. From the above results, it may be concluded that there are two kinds of mechanisms of Ca2+ release, CICR and IICR, in the rabbit coronary artery smooth muscle cell. Also, whereas the CICR mechanism distributes on the membrane of the whole smooth muscle Ca2+ store, the IICR mechanism distributes only on a part of it.