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 dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values

Objectives : Enteric-coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Post-prandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0–6.0 for five currently available enteric-coated microsphere/microtablet pancreatin preparations.
Methods : The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 °C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2-mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times.
Results : All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher.
Conclusions : For the treatment of exocrine panceatic insufficiency conventional strength enteric-coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.     

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.     

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.     

Comparison of a high lipase pancreatic enzyme extract with a regular pancreatin preparation in adult cystic fibrosis patients

Background: Malabsorption due to exocrine pancreatic insufficiency is the main gastrointestinal problem in cystic fibrosis. Despite high doses of pancreatic enzyme supplements it is often not possible to normalize fat absorption. We compared a new high lipase pancreatic enzyme preparation (Pancrease-HL; Cilag, Brussels, Belgium), containing enteric coated microspheres with 25000 U of lipase, 22 500 U of amylase and 1250 U of protease per capsule, with regular Pancrease capsules, containing 5000 U of lipase, 2900 U of amylase and 330 U of protease per capsule. Methods: In a randomized double-blind crossover study, 13 cystic-fibrosis patients (6 male, 7 female, mean age 2 7.7 years) received either four capsules of Pancrease t.d.s. or one capsule of Pancrease-HL t.d.s. Patients took 20 mg omeprazole daily to raise intra-duodenal pH and thus optimize release of enzymes from the enteric coated microspheres. Results: With four capsules of Pancrease t.d.s., mean fat excretion was 15.4% and mean nitrogen excretion was 19.9% vs. 15.5% fat and 19.9% nitrogen excretion with one capsule Pancrease-HL t.d.s. Fat and protein energy loss (as a percentage of total daily intake) was 18.3% with Pancrease and 18.2% with Pancrease-HL. The differences were not statistically significant. Pancrease-HL was well tolerated, with no difference in abdominal pain or general well-being scores. The number and average weight of stools passed remained the same. Conclusions: One capsule of Pancrease-HL appears to be equivalent to four capsules of regular Pancrease. Treatment with less capsules per day with the same efficacy may facilitate patient compliance.     

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.     

Controlled release of lipase from Candida rugosa loaded into hydrogels of N-isopropylacrylamide and itaconic acid

The series of poly(N-isopropylacrylamide-co-itaconic acid) hydrogels, with lipase from Candida rugosa as a model protein, were synthesized by free radical copolymerization. The composition of hydrogels was varied by monomers ratio, crosslinking agent concentration and amounts of lipase, which was loaded by in situ polymerization. All samples were characterized regarding morphology. The investigation of hydrogel swelling properties revealed their pH and temperature sensitive character. Protein loading efficiency, release profiles and the specific activity yield of the released lipase were also investigated as a function of hydrogel composition, protein content and pH, at the physiological temperature of 37°C. Copolymers of N-isopropylacrylamide and itaconic acid presented high lipase loading efficiency. Another very important feature of these copolymers was that the protein release kinetic strongly depended on the pH value of the medium. The diffusion exponents values around 1 denoted that these hydrogel compositions could be adjusted to follow near zero-order kinetics. Namely, hydrogel formulations released low amounts of lipase at pH 2.20, but much higher released protein quantities were observed at pH 6.80 enabling these copolymers to be attractive candidates as site specific protein oral drug delivery systems.     

The dissolution of iron from various commercial preparations

The dissolution of iron in acetate buffer (pH 4.5) from commercially available preparations that contain several different types of iron salts in various dosage forms were compared. There were substantial differences in both rates and amounts of iron released in various products. The amount of iron released at 6 h ranged from a low of 0.5% to 99% of the label claim.     

Chemical reactivity of aluminium-based pharmaceutical compounds used as phosphate-binders

Several aluminium-containing substances, including antacids used as phosphate-binders in treating renal failure, have been analysed in-vitro under different pH conditions for the release of Al3+ ions and for binding of phosphate. Control experiments on different forms of pure aluminium hydroxide validated the methods. At pH 2 it was the most amorphous forms which released Al3+ most rapidly. These aluminium ions, available for absorption by the patient, were released from all antacids tested, but no firm phosphate-binding was detected while the pH remained at 2. Phosphate was bound at pH 8, by adsorption onto the surface of aluminium hydroxide. No significant amounts of free Al3+ exist in solution at pH 8, since at that pH aluminium hydroxide is precipitated. The most amorphous forms of this solid were the most efficient phosphate-binders. Alumino-silicate salts require prior exposure to acid to produce free Al3+ before they can act as phosphate-binders, whereas amorphous aluminium hydroxide acts as an efficient phosphate-binder without prior exposure to acid. Chemical principles are employed to show why aluminium release and phosphate-binding are separate and independent processes. Methods are proposed for maximizing the activity of phosphate- binders in-vivo, while minimising aluminium release.     

Parameters affecting the drug release from in situ gelling nasal inserts.

The purpose of the study was to investigate the influence of physicochemical drug properties, drug loading, and composition of the release medium on the drug release from in situ gelling nasal inserts. Sponge-like nasal inserts of carrageenan and HPMC K15M with the model drugs oxymetazoline HCl, diprophyllin, and acetaminophen (APAP) were prepared by lyophilization. Drug release studies at different drug loadings were performed in various release media. Raman analysis, DSC, and SEM were conducted to analyze the physical state of the drugs in the inserts. All drugs were dissolved in the solid HPMC inserts and were released at similar rates at all investigated loadings except for the least soluble APAP. APAP concentrations in the hydrating HPMC K15M inserts in excess of its solubility limit resulted in reduced relative release rates at higher drug loadings. Drug-polymer interactions (formation of less soluble drug-polymer salts) resulted in a slower release of oxymetazoline HCl from carrageenan inserts than from HPMC K15M inserts. Changes in the composition of the release medium affected the water uptake of carrageenan but not of HPMC K15M inserts. Oxymetazoline release from carrageenan inserts increased with higher Na+-content of the medium because of ion exchange and at low (pH 2) as well as at high pH (pH 10). The osmolality of the release medium had no effect. The solubility of the drug, its physical state in the polymer matrix, and drug-polymer interactions governed the drug release from nasal inserts. The release from inserts prepared with oppositely charged polymers and drugs was influenced by electrostatic drug-polymer interactions and by the composition of the release medium.     

Bupivacaine salts of diflunisal and other aromatic hydroxycarboxylic acids: aqueous solubility and release characteristics from solutions and suspensions using a rotating dialysis cell model.

In the search for poorly soluble bupivacaine salts potentially enabling prolonged postoperative pain relief after local joint administration in the form of suspensions the solubility of bupivacaine salts of diflunisal and other aromatic hydroxycarboxylic acids were investigated together with the release characteristics of selected 1:1 salts from solutions and suspensions using a rotating dialysis cell model. The poorest soluble bupivacaine salts were obtained from the aromatic ortho-hydroxycarboxylic acids diflunisal, 5-iodosalicylic acid, and salicylic acid (aqueous solubilities: 0.6-1.9 mM at 37 degrees C). Diffusant appearance rates in the acceptor phase upon instillation of solutions of various salts in the donor cell applied to first-order kinetics. Calculated permeability coefficients for bupivacaine and the counterions diflunisal, 5-iodosalicylic acid, and mandelic acid were found to be correlated with the molecular size of the diffusants. Release experiments at physiological pH involving suspensions of the bupivacaine-diflunisal salt revealed that at each sampling point the diflunisal concentration exceeded that of bupivacaine in the acceptor phase. However, after an initial lag period, a steady state situation was attained resulting in equal and constant fluxes of the two diffusants controlled by the permeability coefficients in combination with the solubility product of the salt. Due to the fact that the saturation solubility of the bupivacaine-salicylic acid salt in water exceeded that of bupivacaine at pH 7.4, suspensions of the latter salt were unable to provide simultaneous release of the cationic and anionic species at pH 7.4. The release profiles were characterised by a rapid release of salicylate accompanied by a much slower appearance of bupivacaine in the acceptor phase caused by precipitation of bupivacaine base from the solution upon dissolution of the salt in the donor cell.     

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.     

多糖凝胶骨架结肠定位给药缓释系统的体外释放研究

目的: 筛选多糖材料作为水凝胶骨架,以达到结肠定位释药目的.方法: 选用海藻酸钠、果胶、壳聚糖、瓜木耳胶与药物混和制粒,灌装肠溶或结肠溶胶囊,考察其在人工胃液,人工肠液及人工结肠液中的释放情况.结果: 难溶性药物的海藻酸钠骨架结肠溶胶囊在人工胃液和小肠液中均不释放,人工结肠液中3 h释药低于30%;果胶骨架肠溶胶囊在人工胃液亦不释药,人工肠液中5 h释药仅为15%.水溶性药物在人工肠液中5 h释放可达50%.结论: 难溶性药物的海藻酸钠/结肠溶胶囊和果胶/肠溶胶囊体外释放度结果符合结肠定位的要求,可以作为建立酶触发体外释放评价方法和体内评价的制剂形式.水溶性药物的果胶/肠溶胶囊是较理想的缓释剂型.     

复方自微乳中姜黄素和胡椒碱的体外释放研究

目的 考察复方自微乳中姜黄素和胡椒碱的体外释放行为.方法 采用动态透析法,分别以pH值为4.8、7.5的磷酸盐缓冲液并加入0.75％吐温-80作为漏槽条件,考察姜黄素和胡椒碱的体外释放特性.结果 姜黄素在pH 4.8和pH 7.5释放介质中108 h累积释放百分率分别为94.85％和84.38％.胡椒碱在上述介质中36...     

Effect of the dispersion of Eudragit S100 powder on the properties of cellulose acetate butyrate microspheres containing theophylline made by the emulsion-solvent evaporation method

The dispersion/incorporation of Eudragit S100 powder as a filler in cellulose acetate butyrate (CAB-551-0.01) microsphere containing theophylline was investigated as a means of controlling drug release. Microspheres of CAB-551-0.01 of different polymer solution concentrations/viscosities were prepared (preparations Z(0), Z(A), Z(B) and Z(C)) and evaluated and compared to microspheres of a constant concentration of CAB-551-0.01 containing different amounts of Eudragit S100 powder as a filler (preparations X(A), X(B) and X(C)). The organic solvent acetonitrile used was capable of dissolving the matrix former CAB-551-0.01 only but not Eudragit S100 powder in the emulsion-solvent evaporation method. The CAB-551-0.01 concentration in Z(A), Z(B) and Z(C) was equal to the total polymer concentration (CAB-551-0.01 and Eudragit S100 powder) in X(A), X(B) and X(C), respectively. Scanning electron microscopy (SEM) was used to identify microspheres shape and morphology. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at two successive different pH media (1.2 +/- 0.2 for 2 h and 6.5 +/- 0.2 for 10 h). Z preparations exhibited low rates of drug release in the acidic and the slightly neutral media. On the other hand, X preparations showed an initial rapid release in the acidic medium followed by a decrease in the release rate at the early stage of dissolution in the slightly neutral pH which could be due to some relaxation and gelation of Eudragit S100 powder to form a gel network before it dissolves completely allowing the remained drug to be released.     

Lung lipoprotein lipase: inhibition by barbiturates

The action of barbiturates on the enzymatic activity of lung lipoprotein lipase has been studied in vitro and in vivo. Mouse lung preparations can be separated into two fractions containing lipoprotein lipase activity and designated as soluble and membrane-bound. In vitro, both enzyme fractions were inhibited in a graded manner by the barbiturates when present in concentrations of 1-4 mg/ml. Experiments to determine the mechanism for the inhibition of lipoprotein lipase suggest that it may be related to non-specific binding of the drug to the enzyme since other drugs e.g., phenylbutazone and a coumarin derivative which bind non-specifically to serum albumin showed similar inhibitory activity. When rat lungs were perfused in situ with heparin, 49% of the total lipoprotein lipase activity was released into the perfusate. However, when pentobarbital was perfused prior to heparin, no lipoprotein lipase activity was observed in the perfusate. The possible clinical implications resulting from inhibition of pulmonary lipoprotein lipase by barbiturates are discussed in this paper.     

Fast and pH-dependent release of domperidone from orally disintegrating tablets

There has been growing interest in orally disintegrating tablets (ODTs) during the last decade due to their better patient acceptance and compliance. Further, drug dissolution and absorption may be significantly improved. This work describes the preparation of fast and pH-dependent release ODTs for domperidone by direct compression using crospovidone as superdisintegrant. Solid dispersions of domperidone and Eudragit L100-55, at different weight ratios, were prepared and characterized by DSC, TGA, X-ray diffraction, and FTIR, which indicated the presence of drug–polymer interaction. Disintegration time, friability, and hardness of ODTs were evaluated. In vitro drug release in 0.1N HCl and in phosphate buffer (pH 5.8 and 6.8) was investigated. All domperidone ODTs had fast disintegration times (6 KP) and acceptable friability (<1%). Drug release from fast release ODTs was highly improved; reaching 97% after 10?min in 0.1N HCl, compared to the dissolution of the free drug. Drug release from solid dispersions was pH dependent; showing higher release rates at pH 6.8 than at lower pH values. The controlled-release ODT resulted in 47% drug release in 0.1N HCl, with the rest of drug released at pH 6.8. Domperidone ODTs were considered suitable for ODT formulation.     

Dissolution of solid lipid extrudates in biorelevant media

Solid lipid extrudates with the model drug praziquantel were produced with chemically diverse lipids and investigated regarding their dissolution behaviour in different media. The lipids used in this study were glyceryl tripalmitate, glyceryl dibehenate, glyceryl monostearate, cetyl palmitate and solid paraffin. Thermoanalytical and dissolution behaviour was investigated directly after extrusion and after 3 and 6 months open storage at 40°C/75% RH. Dissolution studies were conducted in hydrochloric acid (HCl) pH 1.2 with different levels of polysorbate 20 and with a biorelevant medium containing pancreatic lipase, bile salts and phospholipids. Furthermore, the impact of lipid digestion on drug release was studied using in vitro lipolysis. The release of praziquantel from cetyl palmitate and glyceryl monostearate in the biorelevant medium was much faster than in HCl, whereas there was hardly any difference for the other lipids. It was shown that drug release from glyceryl monostearate matrices is driven by both solubilisation and enzymatic degradation of the lipid, whereas dissolution from cetyl palmitate extrudates is dependent only on solubilisation by surfactants in the medium. Moreover, storage influenced the appearance of the extrudate surface and the dissolution rate for all lipids except solid paraffin.     

Alkaline buffers release EDRF from bovine cultured aortic endothelial cells

1. Release of endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2) from bovine cultured aortic endothelial cells (EC) was measured by bioassay and radioimmunoassay, respectively. 2. Bradykinin (BK, 3-30 pmol), adenosine diphosphate (ADP, 2-6 nmol) or the sodium ionophore monensin (40-100 nmol) injected through a column of EC released EDRF. L-Arginine free base (FB; 10-20 mumol) or D-arginine FB (10-20 mumol) injected through the column of EC released similar amounts of EDRF and also caused an increase in pH of the Krebs solution perfusing the EC from 7.5-8.0 to 8.6-9.5. Sodium carbonate (Na2CO3) an alkaline buffer which caused the same changes in the pH of the Krebs solution also induced the same release of EDRF. The hydrochloride salts of L- or D-arginine did not cause either release of EDRF when injected through the column of EC or increases in the pH of the Krebs solution. 3. Inhibitors of either diacylglycerol lipase (RHC 80267) or kinase (R59022) inhibited the release of EDRF induced by BK or ADP but potentiated the release induced by L-arginine FB, monensin (40-100 nmol) or alkaline buffer (Na2CO3). R59022 and RHC 80267 infused through the EC increased the basal release of EDRF. 4. When calcium chloride was omitted from the Krebs solution the release of EDRF induced by alkaline buffer (Na2CO3; pH 8.6-9.5) or L-arginine FB (10-20 mumol) was selectively inhibited when compared to that induced by BK (3-30 pmol) or ADP (2-6 nmol). This inhibition was reversed when calcium (2.5 mM) was restored. 5. NG-monomethyl-L-arginine (NMMA; 30 microM) inhibited release of EDRF induced by BK (10-30 pmol) or alkaline buffers (Na2CO3 or D-arginine FB; pH 8.6-9.5). This inhibition was partially reversed by L- but not D-arginine FB or HCl (30-100 microM). 6. Prostacyclin was released when BK (10 pmol), ADP (2 nmol) or arachidonic acid (30 nmol) were injected through the column of EC. However, monensin (40 nmol) or alkaline buffers (pH 8.6-9.5) did not release detectable amounts of PGI2 as measured by radioimmunoassay for 6-oxo-prostaglandin F1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)