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Objective:To prepare and preliminary verify dezocine polylactic acid-glycolic acid block copolymer (PLGA) microspheres.Methods:Preparation of dezocine PLGA microspheres Dezocine 120 mg, PLGA 0.1 g and the solubilizing additive poloxamer 0.1 g were dispersed in tetrahydrofuran solvent to form an organic phase solution. Sodium chloride and polyethylene glycol were dissolved in water for injection to form an inner aqueous phase solution and an outer aqueous phase solution. After the organic phase solution 20 ml was mixed with the inner aqueous phase solution 20 ml to form a water/oil colostrum, the water/oil colostrum was added to the outer aqueous phase solution to form a water/oil/water multiple emulsion, which was fully mixed with lyophilized powder protective agent and freeze-dried to prepare dezocine PLGA microspheres. Verification Eighteen clean-grade healthy male Sprague-Dawley rats, aged 10-12 weeks, weighing 220-260 g, were divided into 3 groups ( n=6 each) by a random number table method: control group (group C), dezocine ordinary preparation group (group D 1) and dezocine PLGA microspheres group (group D 2). Normal saline, dezocine injectio (dose 1 mg) and dezocine PLGA microsphere injectio (dose 0.2 μg) 0.2 ml were intramuscularly injected in C, D 1 and D 2 groups, respectively. The concentrations of dezocine in plasma were measured at 30 min and 1, 2, 3, 4, 5, 6, 7 and 8 h after administration, and thermal paw withdrawal latency was measured at T 1-T 3, T 5 and T 9. Tissues from the injection site were obtained on day 7 after intramuscular injection, and the inflammatory response was observed after HE staining. Results:Compared with group C, the thermal paw withdrawal latency was significantly prolonged at T 1-T 3 in group D 1 and at T 1-T 3, T 5 and T 9 in group D 2 ( P<0.05). Compared with group D 1, the thermal paw withdrawal latency was significantly prolonged at T 5 and T 9, and the plasma concentrations of dezocine were increased at T 6-T 9 in group D 2 ( P<0.05). Compared with the values at T 2, the plasma concentrations of dezocine were significantly decreased at T 4-T 9 in group D 1 ( P<0.05), and no significant change was found in the plasma concentrations of dezocine at T 3-T 9 in group D 2 ( P>0.05). On 7 days after injection, no inflammation was found in the local tissues in C, D 1 and D 2 groups, and no significant difference was found among the three groups. Conclusions:The sustained-release formulation of dezocine PLGA microspheres is successfully prepared, and it can maintain stable blood concentrations, effectively prolongs the action time of the drug and has significant sustained-release effect in rats.
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Methotrexate (MTX) injection has a short half-life and significant toxic side effects. In order to overcome the demerits of MTX injection, MTX@COF was prepared for subcutaneous injection by loading MTX in crosslinked cyclodextrin metal-organic framework (COF) in this study. The cationic lipid material (2, 3-dioleoyl-propyl)-trimethylamine (DOTAP) was then coated on the MTX@COF surface by solvent evaporation. Different surface charge characteristics were observed in the coated MTX@COF@DOTAP with no significant change in particle morphology. The in vitro release behaviors of sustained-release particles were investigated in water and phosphate buffer (pH 7.4), and the in vivo release characteristics were evaluated for pharmacokinetics in rats. The in vitro release results showed that the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 6 h was 92.70%, 36.31% and 18.19% in water, respectively; the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 4 h was 90.82%, 79.37% and 58.30% in phosphate buffer, respectively; the results showed that MTX@COF can significantly delay the release of MTX, the modification to MTX@COF by DOTAP can further delay the release of MTX. Pharmacokinetic studies in rats showed that the mean retention time [MRT(0-t)] and the time to peak (Tmax) of the subcutaneous injection of MTX@COF@DOTAP group were significantly prolonged compared with the MTX@COF group and the MTX group. The area under the concentration-time curve [AUC(0-t)] of the MTX@COF@DOTAP subcutaneous injection group was 1.8 times high as that of the MTX group. In this study, MTX@COF@DOTAP particles had a certain sustained-release effect, and could prolong the bioavailability of MTX by subcutaneous injection, which provided a new idea for the development of new MTX dosage forms.
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The aim of this study is to prepare acetaminophen sustained-release tablets by hot melt extrusion 3D printing technology based on the concept of "Quality by Design" (QbD). Firstly, the failure mode and effect analysis (FMEA) was used to determine the critical process parameters (CPPs), then full-factor experimental design was used to analyze the critical quality attributes (CQAs) and to establish the design space. The results showed that the content of plasticizer, the path spacing and the shell numbers are independent variable for the experimental design. The design space was concluded to be plasticizer content: 9%, and the shell number: 3-5, the path spacing: 1.05-1.2 mm. In this study, 3D printing technology was used to prepare acetaminophen sustained-release tablets in accordance with the concept of QbD, which improved the durability of the process and ensured the uniform and controllable quality of the preparation and also provided experimental basis for personalised medicine.
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Objective@#To optimize the formulation and preparation technology of hydroxy safflower yellow A solid lipid nanoparticles and evaluate its quality.@*Metheds@#Hydroxy safflower yellow A solid lipid nanoparticles were prepared by the method of hot melt emulsification ultrasonic-low temperature using hydroxypropyl methylcellulose as a lipid material and glyceryl monostearate as an emulsifier. Using entrapment efficiency as indexes, the amount of hydroxypropyl methylcellulose, purified water, glyceryl monostearate, and Tween 80 aqueous solution (1%) as factors, orthogonal test was applied to optimize the formulation and preparation technology. Dialysis method was used to measure encapsulation efficiency. The morphology and uniformity of the nanoparticles were observed by transmission scanning electron microscopy. The particle size, polydispersion index and Zeta potential were determined by nano-particle size analyzer. And hydroxy safflower yellow A solid lipid nanoparticles sustained releasing characteristics was evaluated by the percentage of cumulative drug release.@*Results@#The optimal process of prepared hydroxy safflower yellow A solid lipid nanoparticles was 5 mg of hydroxypropyl methylcellulose, 0.2 ml of purified water, 100 mg of glyceryl monostearate, and 1.8 ml of Tween 80 aqueous solution (1%). The size of the prepared nanoparticles was uniform and spherical. And the average particle size were (99.85 ± 3.04) nm, polydispersion index were (0.390 ± 0.021), Zeta potential were (-27.63 ± 2.12) mV, and the encapsulation efficiency of the hydroxy safflower yellow A solid lipid nanoparticles were (63.35 ± 2.65)%. The release rate of the nanoparticles was (44.35 ± 0.49)%.@*Conclusions@#The prepared hydroxy safflower yellow A solid lipid nanoparticles have good uniformity and good sustained release properties.
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Objective To optimize the formulation and preparation technology of hydroxy safflower yellow A solid lipid nanoparticles and evaluate its quality. Metheds Hydroxy safflower yellow A solid lipid nanoparticles were prepared by the method of hot melt emulsification ultrasonic-low temperature using hydroxypropyl methylcellulose as a lipid material and glyceryl monostearate as an emulsifier. Using entrapment efficiency as indexes, the amount of hydroxypropyl methylcellulose, purified water, glyceryl monostearate, and Tween 80 aqueous solution (1%) as factors, orthogonal test was applied to optimize the formulation and preparation technology. Dialysis method was used to measure encapsulation efficiency. The morphology and uniformity of the nanoparticles were observed by transmission scanning electron microscopy. The particle size, polydispersion index and Zeta potential were determined by nano-particle size analyzer. And hydroxy safflower yellow A solid lipid nanoparticles sustained releasing characteristics was evaluated by the percentage of cumulative drug release. Results The optimal process of prepared hydroxy safflower yellow A solid lipid nanoparticles was 5 mg of hydroxypropyl methylcellulose, 0.2 ml of purified water, 100 mg of glyceryl monostearate, and 1.8 ml of Tween 80 aqueous solution (1%). The size of the prepared nanoparticles was uniform and spherical. And the average particle size were (99.85 ± 3.04) nm, polydispersion index were (0.390 ± 0.021), Zeta potential were (-27.63 ± 2.12) mV, and the encapsulation efficiency of the hydroxy safflower yellow A solid lipid nanoparticles were (63.35 ± 2.65)%. The release rate of the nanoparticles was (44.35 ± 0.49)%. Conclusions The prepared hydroxy safflower yellow A solid lipid nanoparticles have good uniformity and good sustained release properties.
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Objective: With Bletillae Rhizoma gelatin as the main film-forming materials, Erhuangsan was developed into a sustained-release double-layer membrane for vagina. Method: Taking hydroxypropyl methyl cellulose(HPMC) and Bletillae Rhizoma gelatin as the film-forming materials of Coptidis Rhizoma-Alumen membrane layer, sodium carboxymethyl cellulose(CMC-Na) and Bletillae Rhizoma gelatin as the film-forming materials of Catechu membrane layer, glycerol as plasticizer, Erhuangsan Bletillae Rhizoma gelatin sustained release double-layer membrane was prepared.Central composite design-response surface methodology was used to optimize formulation of this preparation with appearance quality score, adhesion force and in vitro cumulative release as indexes. Result: Optimum formulation of Catechu membrane layer was 1.61% of CMC-Na, 3.81% of Bletillae Rhizoma gelatin and 8.49% of glycerol;optimum formulation of Coptidis Rhizoma-Alumen membrane layer was 1.15% of HPMC, 3.41% of Bletillae Rhizoma gelatin and 10.02% of glycerol. Conclusion: The optimized formulation is stable and feasible.Erhuangsan Bletillae Rhizoma gelatin sustained release double-layer membrane has characteristics of advanced dosage form and convenient use, providing a feasible modern Chinese medicine preparation for treatment of cervical cancer, and accumulating data for the research of Chinese medicine film agent.
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OBJECTIVE:To study the feasibility of overflow dissolution method for evaluating the drug in vitro sustained re-lease performance. METHODS:Overflow dissolution method was established by simulating the drugs elimination in vivo. Using Nifedipine sustained-elease tablets(Ⅰ)from 2 different manufacturers as model drug A,B,concentration-time curve,cumulative release rate- time curve,release velocity-time curve of model drugs in release pool at 3 different overflow speed (0,1.50,3.00 mL/min)were investigated. RESULTS:When overflow speed was 0,the cumulative dissolution was consistent with that of the con-ventional dissolution method. As the overflow speed increased,cmax of drug A,B was decreased [A:(8.89±0.20),(5.21±0.04), (3.51±0.03)μg/mL;B:(7.62±0.05),(4.80±0.09),(2.89±0.04)μg/mL];cumulative release rate was increased [A:(85.47± 2.45)%,(94.29 ± 2.44)%,(96.04 ± 2.56)%;B:(73.28 ± 1.13)%,(78.46 ± 1.94)%,(82.50 ± 1.69)%] ;tmax was ahead (A:1.5,1.0,0.5 h;B:2.0,1.0,0.5 h). CONCLUSIONS:Overflow dissolution method has avoided the inhibition of too large drug concentration on drug release,making complete drug release and more accurate evaluation of in vivo sustained release performance of the preparation.
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Controlled sustained-release preparation (CSRP) is a definitely important source of innovative medicines, however, its further researches and development are limited due to the complexity of Chinese medicine (CM) compositions, and a series of unclear key problems like the apparent properties from physical and chemical aspects. Combined with the CM characteristics of the multiple components and synergistic effect, a series of bottleneck problems in the preparation of CSRP were analyzed. Then the mechanism and influences of supermolecular chemical theory in the CSRP about the multiple-components overall-control were explored under the guideline of "overall control, synchronous dissolution" in CSRP, based on the previous explications about supramolecular chemistry theories and with the application of single component precision controlling technologies. The supermolecular mechanism of multi-component overall control and synchronous release of the CSRP was investigated, providing an useful academic reference for the research and development of the CSRP and laying the theoretical and technical foundation for the manufacturing process of CSRP.
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Tamsulosin hydrochloride is widely used for the treatment of lower urinary tract symptoms of benign prostatic hyperplasia ,requiring long-term medication .It reduces adverse reactions of hypotension and dizziness by rapid absorption from oral intake .The sustained-release (SR) formulation is recommended for clinical application .Currently in domestic and foreign market,SRproductsmainlyincludeSRcapsulesandSRtablets,likeFlomaxR○ andHarnalR○ .Thedomesticmarketmainlyuses the originally developed Harnal R○ SR capsules .In accordance with the drug′s potential market ,more and more SR studies have been done .This article reviews the research progress of tamsulosin hydrochloride sustained-release preparation .
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OBJECTIVE: To investigate the sustained-release ability of Na-montmorillonite (Na-MMT) on 1-deoxynojirimycin (DNJ) in mulberry leaf extract (MLE). METHODS: In order to prepare DNJ-MMT composite, DNJ was intercalated into the inter-layer of MMT by stirring. Time and temperature for adsorption and ratio of DNJ to MMT were determined by calculating the loading of DNJ, then in vitro release experiment was carried out to estimate the sustained-release characteristics of DNJ-MMT. RESULTS: DNJ-MMT composite with a drug loading of 111.64 mg·g-1 was obtained by stirring 5.00 g Na-MMT and 16.00 g MLE containing 4016.0 mg DNJ in 1000 mL deionized water at 100℃ for 1 h. The composite released DNJ quickly in water, potassium phosphate buffer (pH 7.4), and 0.1 mol·L-1 hydrochloric acid solution. With the increasing of volume of hydrochloric acid solution, the release ratio of DNJ also increased correspondingly. CONCLUSION: The sustained-release effect of Na-MMT on DNJ is proved. Na-MMT can be used for study of DNJ sustained-release preparations.
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Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64:16:20, w/w/w) loaded with 6 mg·g-1 of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8:3.2:16:20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC0-∞ of ISH2 group were increased significantly compared with that of SMH solution group and the AUC0-∞ of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.
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Components of matrix sustained-release preparation of Chinese materia medica (CMM) are complex, the multi-component and multi-target features of the pharmacological require the synchronous release of all the components, which are also influenced by the difference of their physicochemical properties. The article summarizes the effect of the multi-component on the synchronous release of CMM from hydrophilic matrix materials, infusibility matrix materials, bioerodible matrix materils, and mixed matrix materials by reviewing the related literatures, in order to provide the reference for the further research and development of multicomponent skeleton sustained-release preparation.
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The progress in the researches on film-controlled sustained-release preparations of Chinese material medica (CMM) for oral was introduced to provide the reference for further investigation and development of film-controlled sustained-release preparations of CMM for oral. This paper searched relevant literatures with sustained-release preparations of CMM. Choice of different coating material, coating thickness and preparation method can control the drug release rate of film-controlled sustained-release preparations of CMM for oral. This is beneficial to increasing operational regulation, so as to realize synchronized release of multi-component in the CMM.
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Optimization on sustained release preparation formulation is a multi-factor, multi-level complex optimiza-tion problem. Artificial neural network is very suitable for dealing with such complex multivariable nonlinear system. Based on analyzing the characteristics of sustained release preparation and the main influential factors of its quality, this paper focused on building a quality forecast model for sustained release preparation formulation by using BP neural network. The results showed that the BP neural network can effectively forecast the quality of sustained re-lease preparation formulation. It is a powerful optimization tool of sustained release preparation formulation.
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Background Scarring of the filtering bleb is a main cause of filtering surgical failure in glaucoma.It has been reposed that tetrandrine could suppress the proliferation of cultured human fibroblast of Tenons capsule in vitro and thus has the potential effect to prevent scarring after the filtering surgery. Objective Present study was to investigate the anti-cicatricial effect of tetrandrine drug delivery system(Tet DDS)during filtration surgery. Methods Filtration surgery was performed in bilateral eyes of 18 New Zealand white rabbits.The Tet DDS with 0.3 mg Tet,0.2 mg Tet or free-Tet were implanted subcunjunctially during the surgery.The filtering blebs were scored in 1 day,4,7,10,14 days after referring to the corneal thickness and bleb range under the slit-lamp biomicroscopy.The morphology of filtering bleb was assessed by in vivo confocal microscopy in 7 and 14 days after operation.The filtering bleb specimen was prepared in 7 and 14 days for the histopathological examination. Results The filtering bleb scores in Tet DDS implantation groups were significantly higher than those in free-Tet DDS group from 4 days through 14 days after trabeculectomy(P＜0.01),and the scores showed a considerably increase in 0.3 mg Tet DDS group compared with 0.2 mg Tet DDS group from 7 days through 14 days after trabeculectomy(P＜0.05).The filtering blebs of Tet DDS implantation groups were found with distinct subepithelial cystic spaces under the light microscopy and in vivo confocal microscopy on the 7th day and 14th day after surgery.Compared with free-Tet DDS group,the numbers of subepithelial mierocysts were much more(P＜0.01)and the area of microcysts was larger(P＜0.01)in Tet DDS group.The filtering tissue presented with more subepithelial microcysts and larger microcysts range in 0.3 mg Tet DDS group than 0.2 mg Tet DDS group in 7 and 14 days after operation(P＜0.05).The inflammatory cell infiltration wag milder in 0.3 mg Tet DDS group in comparison with 0.2 mg Tet DDS group and free-Ted DDS group.Conclusion Tet DDS has strong inhibitory effects on inflammatory cells activity and fibroblagt activity the early stage after filtering surgery and therefore improve the surgery success rate.
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AIM To evaluate bioavailability, biocompa- tibility and biodegradability of an injectable microsphere sustained release preparation of naltrexone(NTX) in 4 dogs. METHODS Pharmacokinetic data of NTX and remained NTX in microspheres in injection site were studied using high performance liquid chromatography(HPLC)-electrochemical detection with naloxone(NLX) as internal standard. Biocompatibility of the microspheres was assayed by histological examination. RESULTSPharmacokinetics of NTX after an intramuscular dose of 0.5 or 1.0 mg*kg-1 NTX indicated a plasma clearance range of 0.66 to 0.73 L*min-1 and a t1/2β range of 60.0 to 67.2 min. After a 1-week washout period without medication, NTX microspheres injection period about 4 weeks followed. After injection of 1.0 g of microspheres containing (296.5±2.1)mg of NTX, mean blood concentrations of NTX exceeded 1 μg*L-1 for 26-28 d, and cmax per dose (mg*kg-1) was only 1% of that after NTX dosing. It was estimated that approximately (93.0±4.1)% of the administered dose was absorbed after microspheres injection in 4 dogs. There were no serious adverse effects other than light tissue irritation. CONCLUSIONThis NTX microspheres preparation provides a safe, complete and sustained release of the drug for about one month.
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Objective To investigate the drug in vitro release behavior of gastric floating sustained-release preparation of Tripterygium wilfordii and establish their quality evaluating methods.Methods HPLC was Employed to gain the fingerprints of releasing medium of preparations.Triptolide was selected as marker to calculate the linear equation concerning peak area then the relative drug release and f2 simila-rity factor value were acquired.Results Various components in gastric floating sustained-release tablets and pellets of T.wilfordii could not release synchronously while sustained-releasing but all of them in the gastric floating sustained-release capsules of T.wilfordii prepared by using multiparticulate site-controlled release technology could release synchronously while sustained-releasing.Conclusion The quality and in vitro release behavior of gastric floating sustained-release preparation of T.wilfordii could be evaluated more scientifically and comprehensively by using HPLC fingerprints method.
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AIM: To study and evaluate release rules of Zuojin Sustained-Release Tablet(ZJSRT). METHODS: The total quantum statistical moment similarity(TQSMS)was used to evaluate similarity of the chromatographic fingerprints of ZJSRT in vitro dissolution; RESULTS: Compared with the chromatographic fingerprint of the complete dissolution sample,the averages of area under curve of total quantum,mean chromatographic retention time of total quantum and variance of mean chromatographic retention time of total quantum of the ZJSRT's release rules in vitro,from 1 to 12 h,were 2.620?10~8 ?v?sec,74.599 min and 252.481 min~2 respectively,meanwhile their RSD were 62.445%、1.268% and 2.777% coincidently,the similarities range from 0.947 to(0.991,)as average of 0.977 and RSD of 1.491%. CONCLUSION: It is suggested that the TQSMS can evaluate release rules of multicompon and control its quality.