A comparison of two pancreatin microsphere preparations in cystic fibrosis.

OBJECTIVES: to compare the efficacy and tolerance of Creon and Pancrease in children and young adults with cystic fibrosis. METHODS: a double blind, crossover study of two pH sensitive microsphere preparations of pancreatin (Creon, Pancrease), given in equivalent lipase dosage to 27 children with cystic fibrosis, was conducted. RESULTS: at similar lipase activity no significant difference was found in the following: coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), weight gain, mean adequate daily intake for energy, and subjective symptoms. Three children who had a CFA less than 70% while receiving Pancrease all improved on Creon. No children had a CFA less than 70% while receiving Creon. A significant reduction in the number of capsules required daily to achieve similar control was possible when changing from Pancrease (mean 25/day) to Creon (mean 15/day). Seventy percent of patients preferred Creon and this was likely to be related to a perceived reduction in abdominal pain and stool frequency, and need for less capsules per day. CONCLUSION: Creon and Pancrease are equally effective at doses providing equal lipase activity, however, the reduced number of capsules, fewer symptoms, and possible improvement of more severe steatorrhoea result in an increased patient preference for Creon.     

In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability

Background  Various pancreatic enzyme preparations are used for the treatment of pancreatic insufficiency but their bioequivalence is often unknown.
Aim  To determine in vitro the pH-dependent release and acid resistance of enzymes from three commercially available pancreatin capsules, two containing enteric-coated (Creon 25000; Eurobiol 25000) and one uncoated (Eurobiol 12500) microspheres.
Methods  Dissolution experiments were performed at pH values ranging from 4.0 to 5.8. Lipase, chymotrypsin and amylase activities were measured in the solution as a function of time.
Results  Eurobiol 25000 started to release its enzymes significantly at pH 5.0 ( t _1/2 = 71 min), whereas the enzymes from Creon 25000 were only released at higher pH value (5.4; t _1/2 = 49.2 min). Unlike chymotrypsin, lipase and amylase were highly sensitive to acidic conditions at the lowest pH values tested. Both enzymes were also found to be sensitive to proteolytic inactivation at the highest pH values tested. Overall, Eurobiol 25000 released higher amounts of active amylase and lipase than Creon 25000 at the pH values usually found in duodenal contents. The uncoated Eurobiol 12500 preparation was, however, the only one that could immediately release rather high levels of active chymotrypsin and lipase at low pH (4.5).
Conclusion  These findings suggest that pH-sensitive enteric-coated pancreatin products containing similar amounts of enzymes might not be bioequivalent depending on the pH of duodenal contents.     

Pancreatin preparations used in the treatment of cystic fibrosis-- lipase content and in vitro release.

BACKGROUND: Pancreatic extracts are essential in the treatment of the majority of cystic fibrosis patients. The clinical response to different preparations is often unpredictable and at present there is no sure method of determining the best preparation for a particular patient. METHODS: Creon, Nutrizym GR, Pancrease and the high-lipase versions, Creon 25,000, Nutrizym 22 and Pancrease HL, were investigated for lipase content and resistance to simulated gastric conditions. The rates of lipase release in response to pH change, bile salts and duodenal solids were investigated. The stability of lipase and its binding to duodenal solids were also investigated. RESULTS: Declared values for lipase content were exceeded in all preparations. All preparations were acid resistant. The release of lipase in response to pH change showed notable differences in release rates. After 20 min at pH 5.5, Creon released three times the amount of lipase compared with Pancrease, the other preparations coming within the range. Above pH 5.75, the release rates were comparable amongst the preparations. Bile salts influenced release variably whilst release in a solid-rich duodenal fluid was much slower than in buffers. The released lipase was susceptible to proteolysis and pH-dependent binding to duodenal solids; these effects may compromise lipolysis. CONCLUSIONS: These results show some factors contributing to variable clinical responses to pancreatic supplements. Improvements may result if a patient is assessed on different preparations.     

A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency

BACKGROUND: Modern pancreatin preparations consist of enteric-coated microspheres to protect the enzymes from gastric acid. There are, however, no clinical trials comparing different sizes of pancreatin microspheres with regard to fat excretion and fat intake. AIM: To prove both equivalent efficacy and safety of conventional pancreatin microspheres and smaller pancreatin minimicrospheres in patients with exocrine insufficiency due to chronic pancreatitis. METHODS: In this prospective, randomized, double-blind, multicentre, crossover trial, patients with a stool fat excretion of > 7.5 g/day during a placebo period were randomly assigned either to the minimicrosphere/microsphere treatment sequence or vice versa. The primary end-point was the coefficient of fat absorption, which was calculated from fat excretion and fat intake during the course of a standardized diet. Stool weight, clinical symptoms and the safety of the preparations were also evaluated. RESULTS: Thirty-seven patients entered the study, of whom 23 fulfilled the criteria for the crossover period. In the per protocol analysis (n=18), the 90% confidence intervals for the coefficient of fat absorption of both crossover periods lay entirely within the equivalence range (P=0.02). The intention-to-treat analysis revealed similar results, but the equivalence range was slightly missed (P=0.07). Similar results were obtained for the secondary parameters and the reported adverse events. CONCLUSIONS: Pancreatin minimicrospheres have been shown to be equally effective as microspheres in improving the coefficient of fat absorption in patients with exocrine insufficiency due to chronic pancreatitis.     

Effects of product formulation on in vitro activity of pancreatic enzymes

The lipase activity of two enteric-coated and two uncoated pancreatic enzyme formulations was evaluated in vitro at different pH values and compared with postprandial duodenal pH data in cystic fibrosis patients. Lipase activity was measured over a pH range of 4-8 in four formulations: Viokase tablets and Viokase powder (Viobin), Cotazym-S (Organon), and Pancrease enteric-coated spherules (McNeil). A pH-stat technique was used in which the amount of hydroxyl ion that must be added to maintain a preset pH value is measured to determine the amount of lipase substrate (tributyrin) that is split into butyric acid. At least three determinations of activity were made at each pH. Six capsules of each enteric-coated formulation were subjected to disintegration testing at various pH values. These data were then compared with data available for postprandial duodenal pH in patients with cystic fibrosis. The lipase activity of all formulations studied decreased when pH decreased, especially when the pH was below 5.75. At a pH value between 5 and 5.5, which represents the postprandial duodenal pH in cystic fibrosis patients, activity was reduced 50% or more for all formulations tested. The two enteric-coated products displayed no activity at pH 5.5 and below because the coating did not dissolve in this pH range. Lipase activity in enteric-coated pancreatic enzyme preparations is limited because the enteric coating of these products dissolves slowly in the duodenal pH range (5-5.75) that is found in patients with cystic fibrosis.     

Study to compare the enzyme activity, acid resistance and dissolution characteristics of currently available pancreatic enzyme preparations

Anin vitro study of currently available pancreatic enzyme preparations was carried out to compare the three main types of product available, these being simple pancreatin preparations, enteric coated tablets and enteric coated granules. Two products from each of these types were analysed to compare their enzyme contents. The enteric coated preparations were tested for acid resistance and their pH dissolution profiles were also investigated. The measured enzyme contents were generally higher than the declared values but products' enzyme declarations remain valid for comparison. As the BP declaration for protease does not include total protease this value may be misleading. Acid resistance and pH dissolution profiles varied both between the types of preparation and between the actual products tested. The enteric coated granule preparations were more resistant to acid and released their enzyme more rapidly once the pH threshold of dissolution was reached. Of the two enteric coated granule preparations, Creon (Duphar) was more resistant to acid and released its enzyme from a slightly lower pH value.     

Site-specific drug delivery to the middle region of the small intestine by application of enteric coating with hypromellose acetate succinate (HPMCAS)

Enteric coatings that deliver drugs to specific regions of the small intestine were examined. Hypromellose acetate succinate (HPMCAS) with different values of succinoyl group contents was used. Decreasing the succinoyl group content resulted in an increase in the pH at which HPMCAS started to dissolve. Drug-containing granules with or without enteric coating were prepared and their in vitro dissolution in a simulated intestinal fluid of pH 6.8 was examined. Granules coated with HPMCAS having the succinoyl group content of 6.2% showed a lag time of about 30 min, although drug release from granules without coating was completed within 20 min. The time lag and dissolution rate were extended and reduced, respectively, as the succinoyl group content was decreased. Rat experiments indicated that enteric-coated granules disintegrated and the bulk of the drugs was immediately released when the granules reached a specific site of the small intestine where the pH corresponded to the pH at which the enteric coating agent started to dissolve. Similar results were observed in monkey experiments. It was suggested that HPMCAS with the succinoyl group content of about 5% was suitable as an enteric coating agent for delivering drugs to the middle-to-lower region of the small intestine.     

Preparation and evaluation of Eudragit S 100 microspheres as pH-sensitive release preparations for piroxicam and theophylline using the emulsion-solvent evaporation method

Microencapsulation of the anti-inflammatory drug piroxicam and the anti-asthmatic drug theophylline was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Microspheres of both drugs that are different in the chemical nature and size were successfully encapsulated at a theoretical loading of 25% with the pH sensitive Eudragit S 100 polymer using the emulsion-solvent evaporation method. Solvent composition, stirring rate and the volume of the external phase were adjusted to obtain reproducible, uniform and spherical microspheres. The size distribution of microsphere batches generally ranged from 125-500 microm with geometric means close to 300 microm. Optical light microscopy was used to identify the microsphere shape. Drug loading was determined by completely dissolving the microspheres in an alkaline borate buffer at pH 10. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at 100 rpm with USP Dissolution Apparatus II using the procedure for enteric-coated products at two successive different pH media (1.2 and 6.5). Both preparations exhibited an initial rapid release in the acidic medium with theophylline showing a larger increase in the amount released during this stage. The drug release was sustained for both preparations at pH 6.5 with theophylline microspheres, showing more extended release. Drug release rate kinetics followed a Higuchi spherical matrix model for both microsphere preparations.     

对某国产盐酸二甲双胍肠溶胶囊溶出度的评价研究

目的：评价盐酸二甲双胍肠溶胶囊在不同p H条件下的溶出曲线。方法：参照2010版《中华人民共和国药典》附录X B、XD,采用桨法考察盐酸二甲双胍肠溶胶囊在pH分别为1.0、4.0、纯水条件下2h后调节为pH6.8磷酸缓冲液再溶出1h的溶出性能, HPLC法测定溶出液中二甲双胍浓度,DDSolver 1.0对溶出曲线进行分析。结果：盐酸二甲双胍肠溶胶囊在pH1.0、pH4.0及纯水2h内几乎不释放,而在pH6.8的磷酸盐缓冲液中45min内释放达90%以上。经软件DDSolver1.0分析3种pH条件下的溶出曲线是相似的。结论：该二甲双胍肠溶胶囊在不同pH条件下的溶出曲线是相似的,对于不同患者溶出性能一致,药品品质较佳。     

Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations

Background : Intraduodenal proteases exert a negative feedback on pancreatic secretion.
Aim : To investigate the effect of two pancreatic enzyme preparations (enteric-coated tablets, and capsules with enteric-coated microtablets) on postprandial pancreatic and bile acid secretion, gastroduodenal motility and release of gastrin and pancreatic polypeptide in healthy humans.
Methods : Twenty healthy males were studied on two different days one week apart. After an overnight fast a nine-lumen motility tube was positioned with the distal tip at the Treitz angle. On each study day, 30 min after an interdigestive migrating motor complex-phase III, a semi-liquid test meal was given either alone ( n =20) or with enzymes (3 tablets ( n =10) or 2 capsules with microtablets ( n =10); 40000 U lipase and 2000 proteases) in a randomized order, and the study continued over 2 h. Motility was continuously recorded with four ports in the antrum and three in the duodenum, using a low-compliance pneumohydraulic perfusion system. Secretion of human-specific pancreatic elastase and bile acids was measured by a standard duodenal intubation perfusion technique. Plasma concentrations of gastrin and pancreatic polypeptide were measured by specific radioimmunoassays.
Results : Postprandial pancreatic secretion was significantly reduced by administration of microtablets (median 82 mg/2 h vs. 70 mg/2 h, P <0.02) but not by tablets (median 59 mg/2 h vs. 58 mg/2 h, N.S.). No changes were observed in bile acid secretion, antroduodenal motility or release of gastrin and pancreatic polypeptide.
Conclusions : Oral administration of pancreatic enzymes at normal therapeutic doses significantly inhibits postprandial pancreatic secretion in healthy humans, when capsules with enteric-coated microtablets are given. Exogenous pancreatic enzymes have no significant effect on bile acid secretion, gastroduodenal motility and hormone release.     

Treatment of steatorrhoea in cystic fibrosis: a comparison of enteric-coated microspheres of pancreatin versus non-enteric-coated pancreatin and adjuvant cimetidine

Enteric-coated microspheres of pancreatin were compared with non-enteric-coated pancreatin combined with cimetidine taken 40 min before meals in the treatment of patients with cystic fibrosis. Fourteen adults with steatorrhoea due to cystic fibrosis were investigated in an open, randomized crossover study, over two consecutive 28-day treatment periods. Lipase intake was adjusted to each patient's previous requirements and was the same during both months; they were instructed to continue with their normal diet. Patients collected faeces for 72 h at the end of each month and completed diary cards daily throughout. Bowel actions were less frequent on enteric-coated microspheres of pancreatin than on non-enteric-coated pancreatin/cimetidine (1.7 vs. 2.4/day; P less than 0.001) and stool character was improved (P less than 0.001). Mean daily faecal weight was similar on enteric-coated microspheres of pancreatin to that on the combination (254 g vs. 291 g; N.S.), whereas daily faecal fat excretion tended to be less on enteric-coated microspheres of pancreatin (21 g vs. 27 g; N.S.), and percentage fat absorption tended to be greater (81% vs. 73%; N.S.). Mean body weight increased by 0.3 kg on enteric-coated microspheres of pancreatin and fell by 0.1 kg on the combination (N.S.). These data indicate that enteric-coated microspheres of pancreatin are at least as effective as non-enteric-coated pancreatin with cimetidine in the treatment of steatorrhoea in cystic fibrosis.     

盐酸乙胺丁醇片在4种溶出介质中溶出曲线的比较研究

目的:比较自研盐酸乙胺丁醇片与国外原研药在4种不同pH的溶出介质中的体外溶出行为,为完善盐酸乙胺丁醇片的质量评价提供参考.方法:采用《中国药典》2015年版(四部)通则0931第二法(桨法),转速为50 r·min-1(45～60 min转速为250 r·min-1),分别以水、pH 1.2盐酸溶液、pH 4.0和pH...     

奥美拉唑在不同pH介质中的释放曲线及其在肠溶制剂质量评价中的应用

目的 探讨已上市肠溶制剂的质量评价方法.方法按照日本“药品品质再评价工程”的相关方法,测定奥美拉唑肠溶制剂在pH1.0、pH6.0、pH6.8缓冲液及纯化水中的释放曲线.结果奥美拉唑肠溶制剂在不同pH介质中的释放行为存在极显著性差异.结论采用不同pH介质中释放曲线的测定结果来评价肠溶制剂更能区分其内在质量.     

Impact of pharmaceutical dosage form on stability and dissolution of roxithromycin

The behavior of dispersible tablets containing enteric-coated pellets and oral suspension, both containing roxithromycin, was investigated using dissolution tests in different media. The dissolution test was performed under different pH conditions. For both dosage forms investigated, the test was conducted at pH 1.2, 4.5, and 6.8. Additionally, for dispersible tablets, the test involving increasing pH was performed at pH 1.2 (acid stage) and afterwards at pH 6.8 (buffer stage). The extent of dissolution was measured using high-performance liquid chromatography (HPLC). In all cases tested, roxithromycin underwent rapid degradation at pH 1.2. Dispersible tablets displayed the features of modified release preparations with a non-complete dissolution during the test times in all media. Conversely, the oral suspension behaved as an immediate release preparation, with degradation at pH 1.2. However, the dissolution of the oral suspension at pH 4.5 and 6.8 was rapid and complete. The role of enteric-coated pellets is to mask the bitter taste of the active substance upon administration. However, the coating showed lack of resistance to media at pH 1.2. Therefore, dispersible tablets containing enteric-coated pellets are not pharmaceutically equivalent to the immediate-release oral suspension.     

Development and in vitro evaluation of an enteric-coated multiparticulate drug delivery system for the administration of piroxicam to dogs.

The aim of the study was to develop enteric-coated pellets for the administration of piroxicam (a poorly water-soluble drug) to small animals in order to avoid local gastrointestinal irritation, one of the major side effects of nonsteroidal anti-inflammatory drugs after oral ingestion. Pellets were made by an extrusion-spheronization process. The influence of several excipients on the in vitro drug release was evaluated. Piroxicam release from the uncoated pellets was measured in phosphate buffer (pH 6.8) using the paddle dissolution method (USP XXIII). The enteric-coated pellets were tested in 0.1 N HCl and phosphate buffer, pH 6.8. The addition of sodium croscarmellose (Ac-Di-Sol) did not influence the piroxicam release from microcrystalline cellulose pellets. Sodium carboxymethyl starch (Explotab) increased the release from 30 to 65% at 45 min. The incorporation of sodium carboxymethyl cellulose on its own or as a co-processed blend with microcrystalline cellulose (Avicel RC 581 and CL 611) enhanced the release of piroxicam at 45 min from 30% (pure Avicel PH 101) to 95% (combination of Avicel PH 101 and CL 611 in a ratio of 1:3). Additional use of cyclodextrins had only a minor influence on the dissolution rate. An Eudragit L 30 D-55 and FS 30 D (6/4) film was applied to the core pellets (containing 2.5% (w/w) piroxicam and a combination of Avicel PH 101 and CL 611 in a ratio of 1:3) in order to obtain gastroresistant properties. The coated pellets retained their dissolution characteristics after compression into fast disintegrating tablets because waxy cushioning beads were added to minimize film damage.     

兰索拉唑肠溶微丸胶囊的体外释放度与其在犬体内吸收的相关性评价

目的:考察兰索拉唑肠溶微丸胶囊的体外释放度与其在犬体内吸收的相关性。方法:采用紫外分光光度法,在245 nm波长处检测兰索拉唑肠溶微丸胶囊在酸(pH1.2)中1 h的累积释放度,在284 nm波长处检测其在磷酸盐缓冲液(pH6.8)中1.25 h的累积释放度;采用高效液相色谱法检测犬(n=6)灌服兰索拉唑肠溶微丸胶囊12 h内的血药浓度,以Wagner-Nelson法计算其体内吸收分数(fa),考察fa与体外释放度(f)t的相关性。结果:兰索拉唑肠溶微丸胶囊在酸中1 h的累积释放度<3%,在磷酸盐缓冲液中1.25 h的累积释放度>90%;该胶囊在犬体内2.5 h fa达最高值;在0.75～2 h内,fa=1.017 6ft-16.654(r=0.954)。结论:兰索拉唑肠溶微丸胶囊体外释放度与在犬体内吸收的相关性良好。     

雷贝拉唑钠肠溶片的溶出度研究及方法学验证

目的：针对雷贝拉唑钠肠溶片在偏中性介质中不稳定及存在辅料干扰的情况,建立适宜的溶出度测定方法,考察雷贝拉唑钠肠溶片参比制剂及不同厂家仿制药的溶出度,并对该测定方法进行方法学验证。方法：利用紫外分光光度计,采用等吸收点-双波长吸收差值法测定参比制剂及国内A、B两个厂家仿制药在pH 1.2、pH 6.0、pH 6.8、水4种溶出介质中的溶出度,溶出方法为桨法,溶出介质体积为900 mL,转速为50 r·min^-1。结果：通过方法学验证,表明紫外分光光度法-等吸收点-双波长吸收差值法准确可靠,能测定出雷贝拉唑钠肠溶片的累积溶出量。结论：建立的溶出度测定方法适用于雷贝拉唑钠肠溶片溶出曲线的评估,可用于该产品的质量控制。     

尼美舒利颗粒溶出度测定方法研究

目的研究尼美舒利颗粒溶出度。方法以磷酸盐缓冲液(pH=8.8)为溶出介质,采用篮法进行溶出度测定,转速:100 r.min-1,用紫外分光光度法在393 nm波长处测定。结果绘制的溶出曲线表明20 min内尼美舒利颗粒可溶出80%以上,确定的溶出时间30 min,限度为80%。结论测定6批样品的溶出量均符合规定。     

Relationship between drug dissolution and leaching of plasticizer for pellets coated with an aqueous Eudragit S100:L100 dispersion

In order to investigate the relationship between drug dissolution and leaching of plasticizer, theophylline pellets coated with 30% (w/w) Eudragit S100:L100 (1:1) plasticized with different levels of triethyl citrate (TEC) were prepared. The influence of storage conditions on the dissolution profile of theophylline and leaching of TEC was determined. Theophylline was found to dissolve completely from pellets coated with Eudragit S100:L100 (1:1) plasticized with 50% TEC at pH 6.0 after 2h. The shape of the pellets was maintained during dissolution testing. Cracks due to the leaching of TEC were observed in the scanning electron micrographs (SEMs) following dissolution testing at pH 6.0. Both the dissolution of theophylline and the leaching of TEC decreased during storage due to further coalescence of the acrylic polymers. The dissolution profiles of theophylline showed a biphasic pattern and the lag times were estimated as the time points at which a second, rapid release of theophylline was initiated. Subsequently, the percent of TEC leached at the lag time was calculated. While the lag time was increased by storage time and humidity, the percent of TEC leached at the lag time was unchanged as a function of storage condition and was dependent on the initial TEC levels in the films. In conclusion, the plasticizer content in the film coating influenced the dissolution profile of theophylline from pellets coated with Eudragit S100:L100 (1:1). A large amount of the TEC was leached from the enteric films before drug release was initiated and a TEC level of approximately 30% in the films, based on the polymer weight, was the critical amount of TEC for initiating drug release during dissolution testing at pH 6.0. While enteric films are more soluble and dissolve faster at higher pH values, the kinetics of plasticizer release was one of the important factors controlling the dissolution of drugs at pH 6.0, at which pH the enteric polymers were insoluble.     

Preparation and characterization of biodegradable or enteric-coated microspheres containing the protease inhibitor camostat

We have produced biodegradable or enteric-coated microspheres containing camostat mesylate, a protease inhibitor, using a water-oil-water emulsion solvent evaporation method. The characteristics of the microspheres were determined. When polylactic acid, a biodegradable polymer, was used as a wall material, the optimized microsphere obtained showed a loading efficiency of almost 95% and had a mean diameter of 30 microm. This microsphere showed a sustained-release profile, with nearly 25% of drug being released at seven days in a dissolution test. When hypromellose acetate succinate (AS-HG type, with a high content of succinyl group) was used as an enteric wall material, optimized microspheres showed a loading efficiency of almost 80%. In this case, pH 3.0 citrate buffer was used as an internal aqueous phase, and citrate buffer containing 0.5% polyvinylalcohol was used as the external aqueous phase. These microspheres showed a rapid release profile in pH 6.8 buffer, whereas the release was extremely slow in pH 1.2 buffer. Hypromellose acetate succinate microspheres were also prepared containing 10% (w/w) N-benzoyl-dl-arg-4-nitroanilide as a model substrate for trypsin, with or without 5% (w/w) camostat. These microspheres were incubated in pH 6 or 7 buffer containing trypsin at 37 degrees C. When camostat was included in the microspheres, the substrate was protected from attack by trypsin, while in the absence of camostat, the released substrate was immediately attacked by trypsin to produce the degradation product N-benzoyl-dl-arginine.