Pharmacokinetics of nifedipine sustained-release tablets in healthy Chinese volunteers

Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4.6 mm ×150 mm） column and a mobile phase of methanol： 0.01 mol·L^-1ammonium acetate （60：40, V/V） were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization （AP-ESI） mode and ion mass spectrum （m/z） of 314.9 [M＋H]^＋ for nifedipine, and 320.8 [M＋H]^＋ for lorazepam （Internal Standard, IS）. Results The linear range of nifedipine was 0.3 - 80 ng·mL^-1 （ r = 0.9997）, and the limit of quantitation （LOQ） was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test （T） or reference （R） were as the followings, t1/2 （6.73 ± 2.00） h and （7.04 ± 2.18） h, Tmax （4.28 ± 0.70） h and （4.48 ± 0.70） h, Cmax（39.66 ± 10.58） ng·mL^-1 and （40.19 ± 10.97） ng·mL^-1, AUC0-36 （391.63 ± 108.55） ng·mL^-1·h and （387.57 ± 121.51） ng·mL^-1·h, and AUC0-∞ （408.28 ± 121.16） ng·mL^-1·h and （406.15 ± 133.13） ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets （test） was （103.02 ± 13.93） %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.

Preparation and <i>in Vitro</i>Drug Release Evaluation of Once-Daily Metformin Hydrochloride Sustained-Release Tablets

The objective of this study was to develop once-daily metformin hydrochloride sustained-release tablets (MHSRT) and evaluate their in vitro release behavior. MHSRT were prepared by the film coating method. The in vitro drug release rate of MHSRT and the commercial tablets Fortamet? made in the United States of America in water was fitted with zero order kinetic equation, and Ritger-Peppas kinetic equation in 0.1 M HCl and pH 6.8-phosphate buffer, respectively. The similarity factor f2 values of MHSRT in three different dissolution medium were 82, 80 and 74, respectively in comparison with imported Fortamet?, which were all greater than 50. The results of storage-stability showed that MHSRT were stable for at least 6 months under stress condition (40℃ ± 2℃, RH 75% ± 5%). Therefore, in this study, MHSRT were successfully prepared using optimized formulation technologies that meet mass produce. The in vitro release behavior of MHSRT was almost similar to that of imported Fortamet?.

Preparation and evaluation of sustained-release azithromycin tablets in vitro and in vivo

The objective of this study was to prepare azithromycin(AZI)sustained-release products in order to allow for a high dose to be administered,reduce gastrointestinal side-effects and increase the compliance of patients.AZI sustained-release tablets with different release performance(F-I:T_(100%)=3 h and F-II:T_(100%)=8 h in pH 6.0 phosphate buffer)were successfully prepared by wet granulation.The in vitro release rate and drug release mechanism were studied.The release rate of F-Iwas affected by dissolutionmedia with different pH,but not for F-II.HixsoneCrowellmodel was the best regression fitting model for F-I and F-II.Additionally,F-I and F-II both belonged to non-Fick diffusion.Oral pharmacokinetics of the two tablets and one AZI dispersible tablet as reference were studied in six healthy beagle dogs after oral administration.Compared with the reference,the C_(max) of F-I and F-II were decreased,and the T_(max) were prolonged,in that case which meet the requirement of sustained-release tablets.The relative bioavailability of F-I and F-II were 79.12%and 64.09%.T-test ofAUC_(0-144),and AUC_(0-∞) for F-I and F-II indicated there was no significant difference between F-I and F-II.These mean that the extended release rate did not induce different pharmacokinetics in vivo.

Clinical observation of Baitou Weng Decoction combined with mesalazine sustained-release tablets in treating heat-toxic and smoldering ulcerative colitis

Objective:To observe the clinical efficacy of Baitou Weng Decoction combined with mesalazine sustained-release tablets in the treatment of ulcerative colitis with febrile heat and its effect on immune function and serum inflammatory factors.Methods: A total of 84 patients with ulcerative colitis were randomly divided into control group and treatment group, with 42 cases in each group. The control group was given mesalazine sustained-release tablets orally, while the treatment group was given Baitou Weng Decoction and mesalazine sustained-release tablets orally. The treatment period was 30 days and the patients were followed up for 3 months. After treatment, the clinical efficacy, quality of life, immune function and serum inflammatory factors of the two groups were observed.Results: The effective rate of treatment group (90.47%) was higher than that of control group (73.81%) (P<0.05);compared with before treatment, the scores of inflammatory bowel disease quality of life questionnaire scale in both groups were significantly improved (P<0.05), and the difference between the two groups was significant (P<0.05);after treatment, the plasma CD4+/CD8+ ratio and NK+ levels in both groups were significantly higher than those before treatment (P<0.05), and the treatment group was changed. The serum levels of tumor necrosis factor-α, interleukin-17 and interleukin-23 were significantly decreased in both groups after treatment (P<0.05), and the improvement was more significant in the treatment group (P<0.05). No significant adverse reactions were observed in the treatment group.Conclusions: Modified Baitou Weng Decoction combined with mesalazine in the treatment of heat-toxic and incandescent ulcerative colitis can significantly improve the clinical efficacy, improve the quality of life of patients, effectively regulate the expression level of serum inflammatory factors in ulcerative colitis patients, promote the recovery of patients' immune function, and have high drug safety.

Clinical observation on treatment of cancer pain with TCM oriented drugs combined with oxycodone sustained-release tablets and nimesulide sustained-release tablets

Objective： To study the effect of the transdermal preparation of traditional Chinese medicine in treating cancer pain. Methods： From October 2016 to January 2018, 126 patients with cancer pain were enrolled and divided into 4 groups, 39 patients in group A （directed TCM permeation）, 26 patients in group B （oxycodone sustained-release tablets）, 32 patients in group C （Chinese medicine directed drug penetration ＋ oxycodone sustained-release tablets）, and 29 patients group D （Chinese medicine directed drug penetration ＋ oxycodone sustained-release tablets ＋ nimesulide sustained release tablets）, according to KPS scores. Results： Transdermal preparations of traditional Chinese medicine can significantly alleviate cancer pain. For the treatment of moderate to severe cancer pain, the Chinese medicine transdermal preparation can reduce the dosage of oxycodone sustained-release tablets. At the same time, the patient＇s KPS and NRS scores were significantly reduced. Moreover, the transdermal preparation of traditional Chinese medicine has a better therapeutic effect on visceral pain. Conclusion： The traditional Chinese medicine tra_nsdermal preparation combined with western medicine for the treatment of cancer pain may be a new method for the treatment of cancer pain.

Pharmacokinetic Study on Lovastatin Sustained-release Tablet and Sustained-release Capsule in Begal Dogs

This study pharmacokinetically examined the lovastatin sustained-release tablet and sustained-release capsule in Beagle dogs. An reversed-phase HPLC method was established for the determination of lovastatin in Beagle dog plasma. Pharmacokinetic findings were compared among three preparation(lovastatin sustained-release tablet,T p; sustained-release capsule,T J and conventional capsule). Our results showed that the pharmacokinetic parameters in 6 dogs after single-dose oral administration of three perparations were calculated. T max, C max and MRT revealed significant difference (P<0.05). Relative bioavailability was 111.5±16.9 % (T P) and 110.4%±9.6 % (T J). The pharmacokinetic parameters in the 6 dogs after multiple-dose oral administration of three perparations, T max, C max MRT and DF had significant difference (P<0.05); C av , C min and AUC 0-24 h displayed no significant difference (P>0.05). It is concluded that the lovastatin sustained-release tablet and sustained-release capsule are able to maintain a sustained-release for 24 h.

Simultaneous Analysis of Indapamide and Related Impurities in Sustained-Release Tablets by a Single-Run HPLC-PDA Method

The contents of indapamide and related impurities in generic indapamide sustained-release tablets were simultaneously detected by a single-run high performance liquid chromatography equipped with photodiode array detector(HPLC-PDA)method for the quality control in this paper.The results showed the method had a good selectivity and was validated through linearity,limits of detection and quantification,recovery,and precision.The linear ranges of indapamide,2-methyl-1-nitroso-2,3-dihydro-1H-indole(impurity A,ImA),4-chloro-N-(2-methyl-1H-indol-1-yl)-3-sulphamoyl-benzamide(impurity B,ImB)and 4-chloro-3-sulfamoylbenzoic acid(impurity 1,Im1)were 0.028-1.80μg/mL(R=0.99995),0.060-1.20μg/mL(R=0.9996),0.0324-1.20μg/mL(R=0.99985)and 0.060-1.20μg/mL(R=0.9997)with detection limits of 0.0093,0.012,0.012 and 0.006μg/mL,respectively.ImA and Im1 were not detectable in the generic drug.The content of indapamide was 96.7%of the labeled amount with a relative standard deviation(RSD)of 1.30%,and the percentage of ImB relative to the labeled amounts of indapamide was 0.106%with an RSD of 1.82%.The content of other unspecified impurities all met the reference quality standards.The results provided references for the quality control and the quality standard study of generic indapamide sustained-release tablets.

硫酸沙丁胺醇气雾剂与茶碱缓释片治疗急诊老年哮喘的临床效果

目的 探讨硫酸沙丁胺醇气雾剂与茶碱缓释片治疗急诊老年哮喘的临床效果。方法 80例急诊老年哮喘患者,应用计算机随机数字表法将所有患者分成常规组与联合组,每组40例。常规组患者使用硫酸沙丁胺醇气雾剂吸入治疗,联合组患者采用硫酸沙丁胺醇气雾剂吸入治疗联合茶碱缓释片口服治疗。比较两组患者治疗前后第1秒用力呼气容积、炎性因子[白细胞介素(IL)-4、IL-13、γ-干扰素(IFN-γ)]水平以及临床疗效、不良反应发生率。结果 治疗4、8周,两组组患者第1秒用力呼气容积均高于治疗前,联合组第1秒用力呼气容积分别为(2.47±0.21)、(2.62±0.17)L,均高于常规组的(2.03±0.23)、(2.16±0.11)L(P<0.05)。联合组临床总有效率90.00%高于常规组的67.50%(P<0.05)。治疗2、8周,两组患者IL-4、IL-13、IFN-γ水平均低于治疗前,联合组患者IL-4分别为(12.03±1.52)、(10.47±1.61)pg/ml,低于常规组的(15.98±1.47)、(12.69±1.63)pg/ml, IL-13分别为(195.26±21.69)、(182.36±27.98)pg/ml,低于常规组的(213.98±21.66)、(200.48±26.39)pg/ml, IFN-γ分别为(8.36±0.62)、(5.17±0.32)pg/ml,低于常规组的(10.47±0.69)、(7.69±0.36)pg/ml(P<0.05)。联合组不良反应发生率22.50%与常规组的17.50%比较,差异无统计学意义(P>0.05)。结论 硫酸沙丁胺醇气雾剂联合茶碱缓释片用于治疗急诊老年哮喘既有较好的安全性,还能提升抑制炎症反应、提升呼吸功能的作用。

Qualitative and quantitative analysis of HPLC fingerprint of Wuji gastric floating sustained-release tablets

A qualitative and quantitative test method of fingerprint of Wuji gastric floating sustained-release tablets was established. High performance liquid chromatography （HPLC） was adopted, using Agilent ZORBAX SB-C18 column （250 mm×4.6 mm, 5 μm） as the chromatographic column, and acetonitrile-0.05 mol/L potassium dihydrogen phosphate solution as the mobile phase in a gradient elution with the flow rate of 1.0 mL/min. Sample solution （10 μL） was injected and was tested at the wavelength of 225 nm for 75 min at the column temperature of 30 ℃, Fingerprint similarity software （2004A version） was used to conduct data analysis. A total of 11 batches of Wuji gastric floating sustained-release tablets were tested and analyzed with HPLC fingerprint. Seventeen common peaks were found and the similarity of the 11 batches of agents was greater than 0.9, indicating that the production process of the agent is stable and feasible. The method is operable and could effectively control the quality of Wuji gastric floating sustained-release tablets.

布地格福吸入气雾剂联合茶碱治疗对COPD稳定期患者炎症因子水平的影响

目的探讨布地格福吸入气雾剂联合茶碱治疗在慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Dis-ease,COPD)稳定期患者中的应用价值,重点分析联合治疗对炎症因子水平的影响。方法目的选取2022年3月—2023年11月阜宁县人民医院收治的72例COPD稳定期患者为研究对象,按治疗方法不同分为两组,每组36例。对照组予以常规茶碱治疗,观察组在对照组基础上予以布地格福吸入气雾剂治疗,比较两组的白细胞介素(Interleukin,IL)-8、IL-10、呼吸峰流速(Peak Expiratory Flow,PEF)、用力肺活量(Forced Vital Capac-ity,FVC)、健康状况与生活质量、不良反应情况。结果观察组的IL-8低于对照组,IL-10高于对照组,差异有统计学意义(P均<0.05)。观察组的FVC、PEF水平高于对照组,健康状况与生活质量评分低于对照组,差异有统计学意义(P均<0.05)。两组的不良反应发生率对比(11.11%vs 8.33%),差异无统计学意义(χ^(2)=0.158,P>0.05)。结论在COPD稳定期,布地格福吸入气雾剂与茶碱缓释片合用能够改善患者的炎症因子水平、健康状况与生活质量,促进肺功能恢复,且用药安全性良好。

甘氨酸茶碱钠缓释片治疗支气管哮喘的效果及对氧化应激指标的影响

目的了解甘氨酸茶碱钠缓释片治疗支气管哮喘的效果及对氧化应激指标的影响。方法选择哮喘患者100例,作为研究样本。采用系统分配法将患者划分为两组(观察组50例,对照组50例)。观察组采用常规治疗加甘氨酸茶碱钠缓释片,对照组应用常规治疗,对比了解甘氨酸茶碱钠缓释片治疗效果。结果观察组患者治疗有效率(96.00%)比对照组(82.00%)更高(P<0.05)。观察组临床症状消失时间比对照组更短(P<0.05)。干预后观察组肺功能指标明显比对照组更优(P<0.05)。干预后观察组炎症因子比对照组更优(P<0.05)。干预后观察组患者氧化应激指标比对照组更优(P<0.05)。结论甘氨酸茶碱钠缓释片治疗支气管哮喘的效果显著,降低患者炎症因子,改善肺功能,优化氧化应激指标。

布地奈德福莫特罗吸入剂联合茶碱缓释片对COPD患者气道炎症及睡眠质量的影响

目的探究布地奈德福莫特罗吸入剂联合茶碱缓释片对慢性阻塞性肺疾病(COPD)患者气道炎症及睡眠质量的影响。方法选取2021年1月至2023年1月该院收治的COPD患者130例,采用随机数字表法分为观察组和对照组,每组65例。对照组给予布地奈德福莫特罗吸入剂治疗,观察组在布地奈德福莫特罗吸入剂治疗基础上给予茶碱缓释片治疗。比较2组患者治疗前后气道炎症指标[包括肿瘤坏死因子-α、白细胞介素-4(IL-4)、IL-6、IL-8等]、肺功能指标(包括1秒用力呼气量、用力肺活量、最大呼气流量等)、睡眠质量(匹兹堡睡眠质量指数评分)和并发症发生情况。结果观察组患者治疗后诱导痰中肿瘤坏死因子-α、IL-4、IL-6、IL-8水平,以及匹兹堡睡眠质量指数评分均明显低于治疗前和对照组,1秒用力呼气量、用力肺活量、最大呼气流量水平均明显高于治疗前和对照组,治疗期间夜间呼吸困难发生次数明显少于对照组,差异均有统计学意义(P<0.05);2组患者并发症发生率比较,差异无统计学意义(P>0.05)。结论布地奈德福莫特罗吸入剂联合茶碱缓释片可有效抑制COPD患者气道炎症,改善肺功能与睡眠质量,具有较高的安全性。

布地格福吸入气雾剂联合茶碱缓释片治疗COPD的效果

目的观察布地格福吸入气雾剂联合茶碱缓释片治疗慢性阻塞性肺疾病(COPD)的效果。方法选取2021年4月—2023年4月兴仁市人民医院收治的94例COPD患者,按照随机数字表法分为茶碱组和联合用药组,各47例。在常规治疗基础上,茶碱组患者采用茶碱缓释片,联合用药组患者在茶碱组基础上采用布地格福吸入气雾剂。2组患者均连续治疗12周。比较2组临床疗效,治疗前后肺功能指标[用力肺活量(FVC)、第1秒用力呼气容积(FEV_(1))、呼气流量峰值(PEF)]、血气指标[动脉血氧分压(PaO_(2))、动脉血二氧化碳分压(PaCO_(2))]、实验室相关指标[血清基质金属蛋白酶-9(MMP-9)、降钙素原(PCT)、白介素-18(IL-18)、C反应蛋白(CRP)]及不良反应。结果联合用药组临床总有效率为95.74%,高于茶碱组的82.98%(χ^(2)=4.029,P=0.045)。治疗12周后,2组FVC、FEV_(1)、PEF及PaO_(2)高于治疗前,PaCO_(2)低于治疗前,且联合用药组升高/降低幅度大于茶碱组(P<0.01);联合用药组血清MMP-9、PCT、IL-18、CRP水平低于治疗前,且联合用药组低于茶碱组(P<0.01)。联合用药组不良反应总发生率(10.64%)与茶碱组(8.51%)比较,差异无统计学意义(P=1.000)。结论布地格福吸入气雾剂联合茶碱缓释片治疗COPD的疗效显著,可有效改善患者肺功能,调节血气指标,缓解炎性反应,促进疾病恢复,且安全性较高。

茶碱缓释片联合噻托溴铵粉雾剂治疗慢性阻塞性肺疾病的效果分析

目的:分析茶碱缓释片联合噻托溴铵粉雾剂治疗慢性阻塞性肺疾病(COPD)的效果。方法:选取2022年10月—2023年12月遵义市道真自治县人民医院收治的COPD患者120例作为研究对象,采用随机数字表法分为对照组与观察组,各60例。两组均行常规治疗,对照组在常规治疗基础上联合茶碱缓释片治疗,观察组在对照组基础上联合噻托溴铵粉雾剂治疗。比较两组治疗效果、肺功能、临床症状。结果:观察组治疗总有效率高于对照组,差异有统计学意义(P=0.0153)。治疗前,两组第1秒用力呼气容积(FEV1)、用力肺活量(FVC)、FEV1/FVC比较,差异无统计学意义(P>0.05);治疗后,两组FEV1、FVC、FEV1/FVC升高,观察组高于对照组,差异有统计学意义(P<0.05)。治疗前,两组改良版英国医学研究委员会呼吸问卷(mMRC)、COPD患者自我评估测试(CAT)评分比较,差异无统计学意义(P>0.05);治疗后,两组mMRC、CAT评分降低,观察组低于对照组,差异有统计学意义(P<0.05)。结论:茶碱缓释片联合噻托溴铵粉雾剂治疗COPD的效果显著,可改善患者肺功能,缓解临床症状。

茶碱缓释片治疗支气管哮喘对患者小气道功能及气道壁细胞浸润的改善效果观察

目的:观察茶碱缓释片治疗支气管哮喘对患者小气道功能及气道壁细胞浸润的改善效果。方法:选取108例支气管哮喘患者为研究对象,按照治疗方式分为对照组和观察组,每组各54例。对照组给予布地奈德/福莫特罗粉剂治疗;观察组在对照组基础上给予茶碱缓释片治疗,疗程均为3个月。比较两组患者炎症相关因子[血清细胞间黏附分子-1(ICAM-1)、血管细胞粘附分子1(VCAM-1)、协同刺激分子(B7-H3)、白细胞介素5(IL-5)、IL-33]、呼出气NO含量(FeNO)及嗜酸性粒细胞(EOS)计数、肺功能[第1秒用力呼气量(FEV1)、用力肺活量(FVC)]、小气道功能[呼出25%肺活量的呼气流速(FEF25)、FEF50、FEF75]、生活质量[哮喘控制调查(ACT)评分及圣乔治呼吸问卷(SGRQ)评分]、治疗有效率及不良反应发生情况。结果:治疗后,两组患者VCAM-1、B7-H3、IL-5、IL-33、FeNO、EOS计数、FEF25、FEF50、FEF75测定值及SGRQ评分均降低,且观察组低于对照组(P<0.05);FEV1、FVC及ACT评分均升高,且观察组高于对照组(P<0.05)。观察组总有效率高于对照组,差异有统计学意义(P<0.05)。两组患者不良反应发生情况比较,差异无统计学意义(P>0.05)。结论:茶碱缓释片治疗支气管哮喘可减轻气道壁细胞浸润,并通过改善小气道功能进而提高肺功能,机制可能与减轻炎症反应有关。

基于QbD理念茶碱缓释片的处方开发及工艺优化

目的:探究茶碱缓释片的处方工艺。方法:基于“质量来源于设计”理念,以溶出度和相似因子(f_(2))为评价指标,对风险评估确定的高风险因素(制备工艺、乙基纤维素用量、乳糖用量、乙基纤维素粒径范围、黏合剂用量)进行考察,确定茶碱缓释片最佳处方工艺,并对优化的试验结果进行初步工艺放大考察其体外溶出。结果:制备工艺确定为湿法制粒工艺,乙基纤维素占比为17.5%,乙基纤维素粒径75~115μm,乳糖用量为15.0%,黏合剂用量为12%。体外溶出结果表明,工艺放大批次产品在体外溶出考察中f_(2)值大于50,溶出行为与参比制剂相似。结论:此研究获得的茶碱缓释片处方工艺在中试生产可行,可以为后续的工业化生产提供参考。

苏黄止咳胶囊联合茶碱缓释片治疗哮喘急性发作的临床疗效

目的分析苏黄止咳胶囊联合茶碱缓释片治疗哮喘急性发作的疗效及对促进病情转归的影响。方法将2019年6月—2022年6月在长沙市中心医院接受诊治的哮喘急性发作患者70例分为对照组和研究组各35例。对照组予以茶碱缓释片治疗,研究组加用苏黄止咳胶囊。比较两组临床疗效、肺功能、血清指标和预后恢复。结果治疗后,研究组临床治疗有效率显著高于对照组(P<0.05);研究组用力肺活量、第1秒用力呼气容积、最大呼气峰流速高于对照组(P<0.05);研究血清eotaxin-2、IL-33、SFRP1、TIM4指标低于对照组(P<0.05);研究组ACT评分、MiniAQLQ评分均高于对照组(P<0.05)。结论苏黄止咳胶囊联合茶碱缓释片治疗哮喘急性发作能够让病情得到理想控制,利于改善患者预后。

茶碱脉冲式控释片的研制

目的：探讨茶碱脉冲式控释片的处方组成和制备工艺。方法：以体外释药时滞和释药速率为指标，经拟水平均匀设计，计算机多元回归处理，筛选较佳处方。结果：体外释药时滞仅与处方组成有关而和释放介质无关。稳定性试验表明，研制的控释片在３７℃、ＲＨ７５％的条件下保存三个月，其含量、释放特征、时滞、硬度、脆碎度均无明显变化。家兔体内初步试验提示有脉冲式释药峰。

茶碱缓释片的人体生物利用度

用高效液相色谱（ＨＰＬＣ）法测定茶碱血药浓度。ＹＷＧ－Ｃ１８化学键合相为固定相，流动相为甲醇∶０．０５ｍｏｌ·Ｌ－１醋酸铵溶液（２５∶７５），内标为对乙酰氨基酚。ＵＶ２７３ｎｍ检测，线性浓度范围０．２～２０μｇ·ｍｌ－１，方法回收率９８．６７％～１０１．６８％。应用本法研究了茶碱缓释片研制品和对照品的人体生物利用度，结果表明，两种制剂的ＡＵＣ，Ｔｍａｘ，Ｃｍａｘ及波动系数之间差异无显著性。

羟丙基甲基纤维素对茶碱缓释片释放度的影响

利用均匀设计，考察羟丙基甲基纤维素对茶碱缓释片释放度的影响，给出羟丙基甲基纤维素、乳糖与茶碱缓释片释放度的关系．结果表明：用羟丙基甲基纤维素制备的茶碱缓释片，释放度数据较稳定，调整羟丙基甲基纤维素和乳糖量可调节释药速度．片剂硬度较低〔（３．２±０．５）ｋｇ〕和中等〔（６．１±０．９）ｋｇ〕时，对释放度无明显影响，硬度较大〔（１３．０±１．３）ｋｇ〕时，将减缓释药速度．