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1.
Brown  J.  Madit  N.  Cole  E. T.  Wilding  I. R.  Cadé  D. 《Pharmaceutical research》1998,15(7):1026-1030
Purpose. To evaluate if the cross-linking of gelatin affects in vivo capsule disintegration. Methods. Scintigraphic investigation in nine healthy volunteers to provide for a real time visualisation of capsule disintegration. Results. The moderately stressed capsules failed the USP dissolution specification for acetaminophen capsule when tested in water and conventional SGF but passed with the addition of pepsin. Moderately stressed capsules started to disintegrate at 10 ± 6 minutes (range 6 to 24 minutes) compared to 8 ± 2 minutes (range 5 to 11 minutes) for the unstressed capsule. Conclusions. The results of the study clearly demonstrate that with the incisive technique of gamma scintigraphy there are no differences in the in vivodisintegration properties of moderately stressed and unstressed capsules.  相似文献   

2.
The aim of this study was to determine if the use of both enzyme and surfactant in the dissolution medium changes the in vitro drug release from cross-linked hard gelatin capsules containing a water-insoluble drug. Hard gelatin capsules were cross-linked by a controlled exposure to formaldehyde resulting in different stressed capsules and carbamazepine (CBZ) was chosen as a drug model. In vitro dissolution studies were conducted using simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) with enzymes. Sodium lauryl sulfate (SLS) was added in the dissolution medium at a concentration of 2% m/v both in SGF and SIF with pepsin and pancreatin, respectively. The percentage of CBZ dissolved was reduced by increasing the degree of gelatin cross-linking. For unstressed hard gelatin capsules, 36% of the CBZ was released after 1 h, lowering to 5% for highly stressed hard gelatin capsules in the SGF. A similar effect was observed with SIF. In the case of moderately stressed hard gelatin capsules, addition of enzyme in the dissolution medium enhanced the percentage of CBZ dissolved. The dissolution level increased from 12% to 39% in SGF with pepsin for hard gelatin capsules cross-linked with 1500 ppm formaldehyde. On the contrary, the use of enzyme in the dissolution medium did not increase the dissolution of CBZ from highly stressed hard gelatin capsules. Surprisingly, the addition of SLS in the medium did not allow the release of the CBZ both in SGF and in SIF. The results of this study demonstrate that the use of enzyme in the dissolution medium is justified for moderately cross-linked hard gelatin capsules. However, the action of a surfactant added in the medium containing enzyme remains unclear.  相似文献   

3.
Purpose: Evaluate if crosslinked hard gelatin capsules (HGCs) havingdifferent in vitro dissolution profiles changed in vivo release times oraltered bioavailability of a drug marker; assess if a two-tier dissolutiontest (with and without enzyme) predicted in vivo performance. Methods. Two classifications of stressed HGCs were artificiallyproduced by exposure to formaldehyde (HCHO). HGCs were categorizedas, a) pass/pass (p/p) which met in vitro dissolution criterion (75%drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p)which failed dissolution criterion in the absence of enzymes and passedin the presence of enzymes, and c) severely crosslinked fail/fail (f/f)which failed in vitro standards with or without enzymes. A six-way,single dose bioequivalence study (n = 10) administered the three HGCsunder the fasted and fed condition. In vivo capsule rupture and GItransit were monitored via gamma scintigraphy, and blood sampleswere collected through six hours. Results. Each crosslinked HGC was bioequivalent to the control p/pcapsule when using AUC(0–) and Cmax for comparison. Meanin vivo disintegration of the p/p capsule was 7 ± 5 min for the fastedcondition and 11 ± 7 min for the fed condition. In vivo rupture forthe f/p capsule was 22 ± 12 min and 23 ± 11 min for the fasted andfed studies, respectively, while the f/f HGC ruptured at 31 ± 15 minand 71 ± 19 min under the fasted and fed condition, respectively.Onset of amoxicillin absorption was dependent on in vivo HGC ruptureand subsequent entry of the released radioactive marker into the smallintestine. Consequently, fasted Tmax values were significantly laterfor the f/p HGC (1.62 ± 0.53 hr) and f/f HGC (1.85 ± 0.58 hr) ascompared to the p/p HGC (1.17 ± 0.30 hr). Fed Tmax values werestatistically different only for the f/f capsule (2.55 ± 0.44 hr) whereTmax values for the p/p and f/p HGCs under the fed condition were1.50 ± 0.47 hr and 1.60 ± 0.46 hr, respectively. Conclusions. A two-tier dissolution procedure that retested across-linked hard gelatin capsule with addition of gastric or intestinal enzymesprovided an adequate in vitro indicator of the formulation'sin vivo performance. The observed delays in the onset of amoxicillin absorptionand Tmax for the severely crosslinked f/f HGC was attributed todelayed in vivo capsule rupture, however, this delay did not adverselychange AUC(0–) nor Cmax.  相似文献   

4.
Purpose. To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR). Methods. HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25,4.60,9.42, 16.0 and 24.0 hours. The capsules were filled with fresh amoxicillin, placed in a 90° conical reflector cone, and scanned in a NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the intact capsules. Dissolution profiles were then obtained for each experimental group. Results. The dissolution of amoxicillin from the capsules at pH 1.2 was found to decrease with increasing time of exposure to the formaldehyde atmosphere. A set of principal components (PCs) was formed by a linear combination of the absorbance values at each wavelength scanned. A good correlation was established (r2 = 0.963) when PC values from the NIR spectra of the HGCs were regressed against percentage of amoxicillin dissolved at 45 minutes, at pH 1.2. Water content of the capsules was found to be the largest determinant in the variation between HGC spectra at each exposure time. Conclusions. NIR spectrophotometry, combined with PCR, was successful at not only predicting dissolution of HGCs exposed to formaldehyde, but also at determining which wavelengths contributed most to spectral variation of these stressed HGCs.  相似文献   

5.
Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.  相似文献   

6.
Purpose. To determine the extent of amino group crosslinking in gelatin matrices by chemical assay, and to compare these results to crosslinking evaluations from swelling measurements. Methods. Matrices crosslinked with a water soluble carbodiimide (EDC/G), glutaraldehyde (GTA/G), as well as a GTA crosslinked matrix prepared from gelatin modified to contain 230% greater crosslinking sites (GTA/Mod) were evaluated. Crosslinking extent, X c, was determined by a UV assay of uncrosslinked amino groups before and after crosslinking, and was used to obtain crosslinking densities. Equilibrium swelling ratios, Q m at 37°C in isotonic pH 7.4 were used to calculate crosslinking degree from the Flory equation for swelling of ionic polymers for comparison to the chemically determined crosslinking densities. Results. Of the original 33 × 10–5 moles -amino groups/g gelatin, 91 to 95% were crosslinked in EDC/G and GTA/G. GTA/Mod lost 95% of the original 108 × 10–5 moles amino groups/g gelatin. Crosslinking densities were 4.1 × 10–4 and 4.2 × 10–4 moles/mL for EDC/G and GTA/G, respectively. The value for GTA/Mod increased to 14.2 × 10–4 moles/mL. Values of Q m followed the same trend. The Flory crosslinking degrees for both gelatin matrices were 12 × 10–4 and 13 × 10–4 moles/mL, respectively. The value for the more extensively crosslinked GTA/Mod was 280 × 10–4moles/mL. Conclusions. The swelling and chemical evaluations of crosslinking are in general agreement for matrices with the lower of two crosslinking levels. The chemical determination appears suitable for evaluating amino group crosslinking in gelatin and it may be suitable for other proteinaceous materials.  相似文献   

7.
Abstract

Context: Drug polymorphism could affect drug product dissolution, manufacturability, stability and bioavailability/bioequivalence. The impact of polymorphism on the manufacturability and in vitro dissolution profiles of sulindac capsules has not been studied yet.

Objective: To evaluate the impact of polymorphism on the manufacturability and in vitro dissolution of sulindac hard gelatin capsules.

Materials and methods: Sulindac crystal forms I and II (SLDI and SLDII, respectively) were prepared and characterized. Powder formulations containing one of the polymorphs, lactose and magnesium stearate (at three different levels) were prepared and their flow properties determined. Hard gelatin capsules were filled with the formulations and tested for fill-weight variations. Drug dissolution for SLDI- and SLDII-containing hard gelatin capsules was determined.

Results: Differences in flow properties for each polymorph were observed, as well as for their formulations, which in turn affected capsule weight homogeneity. Statistically significant differences in the rate and extent of drug release were observed between SLDI- and SLDII-containing capsules.

Discussion: Formulations containing SLDI showed a better manufacturability and a better dissolution profile than those with SLDII.

Conclusion: Sulindac crystalline form I was the best candidate for hard gelatin capsule formulation because of its technological and in vitro dissolution properties.  相似文献   

8.
Purpose. Our laboratory has previously prepared gelatin/methotrexate (MTX) conjugates containing mixed conjugation sites and by-product crosslinking, both of which may alter conjugate effectiveness. In this study, we prepared and evaluated gelatin/MTX conjugates having specific conjugate bond sites and minimal by-product crosslinking. Methods. Opposite polarity conjugates were produced by coupling gelatin having blocked amino groups with MTX (G-MTX) and by coupling MTX having blocked amino groups with gelatin (M-GEL) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl. Amino groups were blocked using citraconic anhydride and deblocked under acidic conditions. Gelatin and MTX contents were determined spectrophotometrically. The stability of each conjugate was determined by evaluating their in vitro release of MTX in isotonic buffer at pH 7.4 and 37°C for 7 days. Results. The G-MTX and M-GEL conjugates contained 21 and 1.2 mole MTX/mole gelatin and released 12 and 17% MTX by 7 days resulting in pseudo-first order release rate constants of 0.76×10–3 and 1.0×10–3 hr–1, respectively. Alternate MTX species ( 10%) were detected during the release study and were attributed to low molecular weight gelatin/MTX fragments and MTX polymers. Conclusions. Gelatin/MTX conjugates having opposite conjugate bond polarities and minimal by-product crosslinking have been produced and slowly released MTX by hydrolytic cleavage indicating good stability for future cell culture studies.  相似文献   

9.

Purpose

Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with “superdisintegrants” to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect.

Methods

Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules.

Result

When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®.

Conclusion

Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin.
  相似文献   

10.
Purpose. To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for drugs with long half-lives and to study the relationship between Cmax and in vitro dissolution rates. Methods. Monte-Carlo simulations were conducted using actual mean plasma concentrations of five long half-life drug products. The simulations were based on a catenary pharmacokinetic system in which the drug disposition in the body was represented by a one-or two-compartment model, characterizing the observed mean profiles. The influence of dramatic changes in the in vitro dissolution rate constant kd, was simulated in scenarios consisting of 20 crossover trials with 24 subjects per trial, comparing a fast dissolving reference and a hypothetical, slow dissolving test formulation. Results. The AUC's truncated after the completion of distribution phase were found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the Cmax measure was insensitive to the changes in the in vitro dissolution rate. The Cmax measure was found to be useful in the bioequivalence assessment since it reflected both the rate and extent of absorption. (Cmax/AUCt) measure was specific to absorption rate. Conclusions. For the bioequivalence determination of long half-life drug products, (1) the use of truncated AUC's after completion of the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may be insensitive to input rate changes, if the absorption rate is not constrained by the input rate in relation to the distribution or elimination rate.(3) (Cmax/AUCt) may be more specific to ka differences, but Cmax reflects differences in both rate and extent of absorption.The views expressed in this paper are professional opinions and perspectives of the authors and do not represent the official policy of the U.S. Food and Drug Administration at this time.  相似文献   

11.
韩松  郑文杰  刘建平 《药学进展》2009,33(9):424-428
目的:考察中药麻黄软胶囊的溶出稳定性及影响因素,探讨中药软胶囊溶出迟缓机制。方法:采用加速试验,评价麻黄软胶囊的溶出稳定性;以平衡溶胀量和ε-氨基酸残基含量为指标,评价明胶囊壳的交联程度;应用红外光谱和醛类专属反应,鉴定麻黄提取物中醛类成分,并测定其含量。结果:在加速试验条件下(40℃,75%相对湿度),放置30天后,明胶囊壳的平衡溶胀量和ε-氨基酸残基含量均显著下降(P〈0.01),其交联度显著增加(P〈0.01);放置60天后,麻黄软胶囊溶出度显著下降(P〈0.01)。环境因素(高温/高湿)、溶媒介质(聚乙二醇)和药物成分(麻黄提取物)均可导致明胶交联度显著提高(P〈0.01),其中麻黄提取物的作用明显大于另两种影响因素。麻黄提取物中醛质量分数达约1.6%。结论:麻黄软胶囊溶出迟缓与囊壳明胶发生交联反应有关,而麻黄提取物中醛类成分是促进软胶囊发生交联反应、导致其溶出迟缓的主要原因。  相似文献   

12.

Purpose

To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding physiological environment in the stomach.

Methods

A capsule endoscopic method was developed. The disintegration time, dispersion characteristics and the impact of the physiological environment on different lipid based delivery systems in different gelatin capsules in the fasted stomach of nine healthy volunteers were visualized. Biorelevant dissolution studies using a USP II apparatus and a droplet size analysis of the released SNEDDS were performed.

Results

Visualization of the behavior of both hard and soft gelatin capsules formulations was possible. The disintegration and dispersion of EP oil in a soft capsule and SNEDDS in a hard shell capsule were visualized. The in vitro release rates were different from the in vivo release rates of the soft capsule due to volume, fluid composition and motility differences but not for the hard capsule containing SNEDDS.

Conclusions

A minimally-invasive capsule endoscopic method was developed for direct visualizing of drug delivery systems in the human stomach and maybe later, in the duodenum.  相似文献   

13.
Purpose. We assessed the application of water-soluble polymer-based nanofibers prepared by electrostatic spinning as a means of altering the dissolution rate of the poorly water-soluble drug, itraconazole. Methods. Organic solvent-based solutions of itraconazole/HPMC mixtures were electrostatically spun at 16 and 24 kV. The formed nanofibers were collected as a non-woven fabric. The samples were analyzed by scanning electron microscopy, differential scanning calorimetry, and dissolution rate. Results. Scanning electron microscopy showed fiber diameters of 1-4 m and 300-500 nm depending on the applied voltage. Differential scanning calorimetry measurements found that the melting endotherm for itraconazole was not present, suggesting the formation of an amorphous solid dispersion or solution. Dissolution studies assessed several presentations including direct addition of the non-woven fabrics to the dissolution vessels, folding weighed samples of the materials into hard gelatin capsules and placing folded material into a sinker. Controls included a physical mixture as well as solvent cast and melt extruded samples. Electrospun samples dissolved completely over time with the rate of dissolution depending on the formulation presentation and drug to polymer ratio. The physical mixture did not appreciably dissolve in these conditions. Conclusions. The application of electrostatic spinning to pharmaceutical applications resulted in dosage forms with useful and controllable dissolution properties.  相似文献   

14.
Purpose. The aim of the present work is to identify complex relationships between formulation variables and dosage form properties to aid the development of hard gelatin capsules. Methods. Multivariate statistical analysis was employed based on a statistical design, which considered drug solubility, particle size and concentration, type and concentration of filler and disintegrant, and concentration of standard lubricant and glidant as the main influence factors. Both the filling properties of the formulations and the disintegration/dissolution properties of the capsule content were studied. Results. From the two multivariate statistical methods used, nonparametric canonical analysis proved to be the superior method to deal with the complex information included in the data. While the filling performance of the formulation could clearly be attributed to the formulation variables such as drug particle size, type of filler, concentration of drug and glidant, the disintegration of the capsules and the dissolution of the drugs was not strongly related to the formulation variables chosen. In this respect as a trend, the drug solubility, and the type of disintegrant and filler appear to be more important factors. Conclusions. Based on an appropriate number of experiments, organised in a statistical design, nonparametric canonical analysis can be used to identify relationships in a set of data that is grouped in influence and response variables to aid the development of a dosage form.  相似文献   

15.
Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 – ) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 – ), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.  相似文献   

16.
Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0–) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0–) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.  相似文献   

17.
Incomplete in vitro capsule shell dissolution and subsequent drug release problems have recently received attention. A modified USP dissolution method was used to follow capsule shell dissolution, and a 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay was used to follow loss of epsilon-amino groups to study this shell dissolution problem postulated to be due to gelatin crosslinking. The dissolution problems were simulated using hard gelatin capsule (HGC) shells previously treated with formaldehyde to crosslink the gelatin. These methods were also used to study the effect of uncrosslinked HGC stored under stressed conditions (37 degrees C and 81% RH) with or without the presence of soft gelatin capsule shells (SGC). A 120 ppm formaldehyde treatment reduced gelatin shell dissolution to 8% within 45 min in water at 37 degrees C. A 200 ppm treatment reduced gelatin epsilon-amino groups to 83% of the original uncrosslinked value. The results also support earlier reports of non-amino group crosslinking by formaldehyde in gelatin. Under stressed conditions, HGC stored alone showed little change over 21 weeks. However, by 12 to 14 weeks, the HGC exposed to SGC showed a 23% decrease in shell dissolution and an 8% decrease in the number of epsilon-amino groups. These effects on the stressed HGC are ascribed to a volatile agent from SGC shells, most likely formaldehyde, that crosslinked nearby HGC shells. This report also includes a summary of the literature on agents that reduce gelatin and capsule shell dissolution and the possible mechanisms of this not-so-simple problem.  相似文献   

18.
ABSTRACT

Objective: The study examined relative bioavailability of a novel valproic acid (VPA) delayed-release (DR) soft gelatin capsule formulation to divalproex sodium DR tablet under fasting conditions and the effect of food on the bioavailability of the VPA DR soft gelatin capsule.

Method: This open-label, randomized three-way crossover study enrolled 36 healthy non-smoking adult volunteers. Treatments included a single 500 mg divalproex sodium DR tablet, fasting; a single 500 mg VPA DR soft gelatin capsule, fasting; and, a single 500 mg VPA DR soft gelatin capsule 500 mg, non-fasting. Analysis of variance was performed on the pharmacokinetic parameters. The ratio of geometric means and corresponding 90% confidence intervals (CI) were calculated on ln-transformed data for the area under the serum concentration-time curve (µg-hr/mL) from time zero to the time of the last quantifiable concentration (t) (AUC0–t), AUC0–∞ and maximum plasma concentration (Cmax). Bioequivalence was shown when 90% CIs were within the 80125% range.

Results: All subjects completed the study. The 90% CIs of VPA DR soft gelatin capsules compared to divalproex sodium DR tablets were within the 80–125% limits for AUC0–t, AUC0–∞, and Cmax. The time of maximum or peak concentration (Tmax) of VPA DR soft gelatin capsules was 2.3 hours versus 3.7 hours with divalproex sodium DR tablets. AUC0–t and AUC0–∞ of VPA soft gelatin capsules were not affected in the non-fasting condition, but Tmax occurred at 6.1 hours compared to 2.3 hours fasting. Eight subjects experienced a total of 10 adverse events; none were serious.

Conclusion: The VPA DR soft gelatin capsule formulation was shown to be bioequivalent to divalproex sodium DR tablet and no serious adverse events occurred. Because this was not a multiple-dose study, however, direct comparisons in chronic dosing were not possible. Administration with food affected rate but not extent of absorption of the VPA DR soft gelatin capsules, but comparisons with the reference product were not conducted under non-fasting conditions.  相似文献   

19.
Objective: Dose-dependent side effects related to myo-inositol (MI) oral administration represent a significant shortcoming for its clinical use. Aiming to search for a pharmaceutical form able to be better absorbed, the pharmacokinetic (PK) profile of the new manufactured MI soft gelatin capsule form was evaluated and compared with the commercially available MI powder.

Research design and methods: A single-dose relative trial, consisting of four phases, was performed on 20 healthy volunteers who received different doses of MI powder and MI soft gelatin capsules. PK profiles related to the two pharmaceutical forms were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared.

Results: The administration of MI powder and MI soft gelatin capsules resulted in a different bioavailability. MI soft gelatin capsule form showed similar PK parameters compared with three times higher doses of MI in powder form.

Conclusions: MI soft gelatin capsules displayed an improved bioavailability, allowing to substantially reduce the administered dose and to minimize the dose-dependent side effects. Considering the number of conditions in which MI supplementation is recommended, this evidence could support a broader use of MI in clinical practice.  相似文献   

20.
HPLC测定罗红霉素软胶囊的溶出度   总被引:1,自引:1,他引:0  
目的 采用HPLC测定罗红霉素软胶囊的溶出度。方法 以醋酸盐缓冲液(pH 5.5)为溶出介质,桨法,转速为100 r·min-1,60 min时取样,取样后采用HPLC测定。结果 罗红霉素在0.02~ 0.2 mg·mL-1内呈良好的线性关系(r=0.999 9),罗红霉素软胶囊的平均回收率为100.1%(RSD=0.6%),溶出液稳定,3批软胶囊在60 min时平均溶出度均在75%以上并且有较好的均一性。结论 该法可用于罗红霉素软胶囊溶出度的测定。  相似文献   

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