Enteric-coated Products Research Articles

Practices of tablet splitting and dose uniformity of fragments at public hospitals in Ethiopia: A cross-sectional study supported by experimental findings.

To assess the practices and dose uniformity of tablet splitting at selected public hospitals in Northwest Ethiopia. A hybrid study method was employed to see the overall practices of tablet splitting. A prospective cross-sectional study was conducted to explore the practices of tablet splitting by administering structured questionnaires to patients and pharmacy professionals. Experimental data on dose and content uniformity of split tablets were obtained from the results of drugs split by study subjects. The content uniformity assay was performed using UV/Vis spectrophotometry. A total of 241 patients and 82 pharmacy professionals participated in the cross-sectional study. The majority of patient participants (51.3%) faced problems while splitting their tablet medications and this had a significant association with the education level of the patients (χ2 = 60.5; p = 0.001). Enteric-coated formulations were dispensed to be split, despite the precaution given by the manufacturers against splitting or crushing these products. Splitting of enteric-coated products accounts for 11% of the total drugs that were dispensed to be taken after a split. The mean of weight variation test for the half tablets does not meet the specifications set in pharmacopoeias when splitting was done by patients. The unscored haloperidol tablets were hard to split and resulted in a significant weight variation of half-tablets than the scored furosemide tablets. Moreover, the weight of 4 out of 20 fragments that were split by patients deviated at least by 15%. This finding showed that the tablet-splitting practices are poor and do not meet the specifications set by pharmacopoeias. Splitting by patients resulted in significantly higher dose variation and weight loss of fragments than splitting by pharmacists.

Assessing the Potential of Untargeted SWATH Mass Spectrometry-Based Metabolomics to Differentiate Closely Related Exposures in Observational Studies.

Mass spectrometry (MS) is increasingly used in clinical studies to obtain molecular evidence of chemical exposures, such as tobacco smoke, alcohol, and drugs. This evidence can help verify clinical data retrieved through anamnesis or questionnaires and may provide insights into unreported exposures, for example those classified as the same despite small but possibly relevant chemical differences or due to contaminants in reported exposure compounds. Here, we aimed to explore the potential of untargeted SWATH metabolomics to differentiate such closely related exposures. This data-independent acquisition MS-based profiling technique was applied to urine samples of 316 liver and 570 kidney transplant recipients from the TransplantLines Biobank and Cohort Study (NCT03272841), where we focused on the immunosuppressive drug mycophenolate, which is either supplied as a morpholino-ester prodrug or as an enteric-coated product, the illicit drug cocaine, which is usually supplied as an adulterated product, and the proton pump inhibitors omeprazole and esomeprazole. Based on these examples, we found that untargeted SWATH metabolomics has considerable potential to identify different (unreported) exposure or co-exposure metabolites and may determine variations in their abundances. We also found that these signals alone may sometimes be unable to distinguish closely related exposures, and enhancement of differentiation, for example by integration with pharmacogenomics data, is needed.

Enteric-Coated Polymers Past and Present - A Review

Abstract: Tablet coating has evolved over the years, and today, there are various types of coating for the delayed release of a drug. Drugs can be enteric-coated to provide delayed release, protect the active pharmaceutical ingredients, minimize undesirable effects, and modify the pharmacokinetic properties of a drug, which will have clinical impacts. Certain types of drugs need to be enteric-coated for various reasons, such as gastric irritants or acid-liable drugs. This article will review ethylcellulose and polymethacrylate, their role in an enteric coating, and their process coating pa-rameters. Ethylcellulose can provide a short delayed release; it can be modified by adding pH-dependent polymers such as sodium alginate and hydroxypropyl methylcellulose phthalate for a long delayed release. On the other hand, polymethacrylate can also be employed to enteric coat drugs without additional polymers. Polymethacrylate, such as Eudragit®, comes in different grades with varying proportions of polymer ratio, allowing for targeted delayed drug release. These will impact which polymer to be employed. Upon choosing the coating material, modeling can also pre-dict in vitro and in vivo correlation as enteric-coated products can have unpredictable in vivo phar-macokinetic profiles. Today, the trend is moving away from the traditional coating, and towards new polymers, and with digitalization, there is a focus to start using data from laboratory experi-ments to be integrated with computational modeling, artificial intelligence, and machine learning to accurately predict key process parameters and film properties for high-quality products.

Population pharmacokinetics and IVIVC for mesalazine enteric-coated tablets.

Although in-vivo bioequivalence (BE) study serves as a golden standard for establishing interchangeability of oral dosage forms, it remains challenging for products with high inter-subject variability such as mesalazine enteric-coated tablet to fulfil the BE criteria set by regulatory authorities. Mesalazine, as a BCS class IV drug, targets to be delivered to distal ileum or colon with a pH-sensitive polymer coating for the remission of ulcerative colitis. Through population pharmacokinetic (PK) analysis and in-vitro in-vivo correlation (IVIVC) modeling on the dissolution and BE data of a generic enteric-coated product (EM) and its reference Salofalk® 250mg tablet (SM), we for the first time revealed the underlying mechanism of the high inter-subject variability for such delayed-release formulation. It was also noted that the in-vivo start time of absorption (Ts) for EM and SM was positively correlated with their in-vitro lag time (Tlag) under the USP three-stage dissolution condition and reversely correlated with their in-vivo bioavailability. The varied oral bioavailability of mesalazine enteric-coated tablet was mainly due to the varied N-acetyltransferase activities along GI tract. Although such extensive intestinal first-pass metabolism with large individual differences led to a significant variation of mesalazine Cmax (coefficient of variation: 60-63.5%) and AUC0-t (coefficient of variation: 37.5-46.9%), the corresponding variations in the total absorbed mesalazine (mesalazine and its metabolite N-acetyl mesalazine) were significantly reduced by 12 to 45%. Since the BE purpose for mesalazine enteric-coated tablet focused on their comparable safety profiles, total absorbed mesalazine was recommended to be adopted for the development of the IVIVC model and BE evaluation for EM. All in all, our model-based approach has not only successfully identified the key factors that affect the BE of EM to guide its further formulation optimization, but also demonstrated the indispensable role of modeling in the development of generic pharmaceutical product at its early stages.

Physiologically relevant dissolution conditions towards improved in vitro - in vivo relationship – A case study with enteric coated pantoprazole tablets

There are many hurdles in the development of generic formulations. In vitro biopredictive dissolution conditions together with alternative in vitro - in vivo relationship (IVIVR) approaches can be a powerful tool to support the development of such formulations. In this study, we hypothesized that the release profile of enteric coated (EC) formulations of pantoprazole in physiologically relevant bicarbonate buffer (BCB) would detect possible performance differences between test and reference formulations resulting in more accurate IVIVR results and predictability when compared to a pharmacopeial dissolution test. We correlated the in vitro performance of test and reference formulations (both in BCB and pharmacopeial phosphate buffer) with the in vivo data from a failed bioequivalence study. Test and reference formulations of EC pantoprazole tablets passed the USP dissolution criteria. However, they failed statistical similarity in vitro both in compendial and BCB. Bicarbonate buffer was additionally more discriminative while being more physiologically relevant. Having BCB as an additional test to evaluate EC products in vitro might improve the comparison of formulations. This can de-risk the development of generic EC formulations.

Toward Mechanistic Design of Surrogate Buffers for Dissolution Testing of pH-Dependent Drug Delivery Systems.

The in vivo dissolution of enteric-coated (EC) products is often overestimated by compendial in vitro dissolution experiments. It is of great interest to mimic the in vivo conditions as closely as possible in vitro in order to predict the in vivo behavior of EC dosage forms. The reason behind this is the overly high buffering capacity of the common compendial buffers compared to the intestinal bicarbonate buffer. However, a bicarbonate-based buffer is technically difficult to handle due to the need for continuous sparging of the media with CO2 to maintain the desired buffer pH. Therefore, bicarbonate buffers are not commonly used in routine practice and a non-volatile alternative is of interest. A mathematical mass transport modelling approach was previously found to enable accurate calculation of surrogate buffer molarities for small molecule compounds; however, the additional complexity of polymeric materials makes this difficult to achieve for an enteric coat. In this work, an approach was developed allowing relatively rapid screening of potential surrogate buffers for enteric coating. It was found that the effective buffering pKa of bicarbonate at the surface of a dissolving enteric polymer tended to be around 5.5, becoming higher when the dissolving enteric polymer formed a gel of greater firmness/viscosity and vice versa. Using succinate (pKa 5.2 under physiological ionic strength) and/or citrate (pKa 5.7 under physiological ionic strength) at conjugate base molarities corresponding to bicarbonate molarities in the intestinal segments of interest as an initial “guess” can minimize the number of experimental iterations necessary to design an appropriate surrogate.

Mechanistic understanding of underperforming enteric coated products: Opportunities to add clinical relevance to the dissolution test

Over the last 70 years several cases of in vivo failure of enteric coated (EC) formulations have been reported. The observed failures seem to be due to the slower than expected in vivo performance of EC products. Upon reaching the intestinal lumen, the dosage form is exposed to a bicarbonate buffered environment at much lower interfacial buffering capacity compared to those applied in compendial phosphate buffers. Hence, there is an urgent need to understand the behavior of EC products in bicarbonate buffer (BCB) and to revaluate the current dissolution methods used for such products. The current pilot study mechanistically investigated the performance of five EC products available in the Canadian market. The evaluated parameters were the buffer system (bicarbonate buffer vs. phosphate buffer), buffer capacity and medium pH. We hypothesized that the performance of EC products in BCB would be different compared with compendial phosphate buffer, giving more physiological insight, and that API properties would impact the dissolution behavior in BCB. The objective of this study was to examine the effect of the aforementioned parameters on the drug release applying physiologically relevant conditions (bicarbonate buffer at low molarities). A first step towards making the use of bicarbonate-based systems more feasible in a quality control setting is also reported. All formulations displayed a fast release in phosphate buffer and complied with the compendial performance specifications. On the other hand, they all had a much slower drug release in bicarbonate buffer and failed the USP acceptance criteria. Also, the nature of the drug (acid vs base) impacted the dissolution behavior in BCB. This pilot study indicates that compendial dissolution test for enteric coated tablets lacks physiological relevance and it needs to be reevaluated. Thus, an in vivo relevant performance method for EC products is needed.

Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications

Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings’ performance in vivo. This is attributed to the relatively low bicarbonate molarities in human intestinal fluids. Further, the hydration and dehydrations kinetics of carbonic acid and carbon dioxide are not sufficiently rapid to reach equilibrium in the diffusion layer surrounding a dissolving ionizable solid. This results in the effective pKa of bicarbonate in the diffusion layer being lower than that determined potentiometrically at equilibrium in the bulk surrounding fluid. These results demonstrate the importance of thoroughly investigating the intestinal bicarbonate concentrations and using bicarbonate buffers or properly designed surrogates (if possible) when evaluating enteric drug products during product development and quality control.

Unpredictable Performance of pH-Dependent Coatings Accentuates the Need for Improved Predictive in Vitro Test Systems.

First introduced in the second half of the 19th century, enteric coatings are commonly used to protect acid-labile drugs, reduce the risk of gastric side effects due to irritating drugs, or for local drug delivery to the lower gastrointestinal (GI) tract. The currently available enteric-coatings are based on pH-sensitive weakly acidic polymers. Despite the long history of their use, the causes behind their performance often being unpredictable have not been properly investigated with most of the attention being focused only on the gastric emptying. However, little attention has been given to the postgastric emptying disintegration and dissolution of these dosage forms. This lack of attention has contributed to the difficulty in predicting the in vivo behavior of these dosage forms and to cases of bioavailability problems with some enteric-coated products. Therefore, increased attention needs to be given to this issue.

The interprocess NIR sampling as an alternative approach to multivariate statistical process control for identifying sources of product-quality variability

We are presenting a new approach of identifying sources of variability within a manufacturing process by NIR measurements of samples of intermediate material after each consecutive unit operation (interprocess NIR sampling technique). In addition, we summarize the development of a multivariate statistical process control (MSPC) model for the production of enteric-coated pellet product of the proton-pump inhibitor class. By developing provisional NIR calibration models, the identification of critical process points yields comparable results to the established MSPC modeling procedure. Both approaches are shown to lead to the same conclusion, identifying parameters of extrusion/spheronization and characteristics of lactose that have the greatest influence on the end-product’s enteric coating performance. The proposed approach enables quicker and easier identification of variability sources during manufacturing process, especially in cases when historical process data is not straightforwardly available. In the presented case the changes of lactose characteristics are influencing the performance of the extrusion/spheronization process step. The pellet cores produced by using one (considered as less suitable) lactose source were on average larger and more fragile, leading to consequent breakage of the cores during subsequent fluid bed operations. These results were confirmed by additional experimental analyses illuminating the underlying mechanism of fracture of oblong pellets during the pellet coating process leading to compromised film coating.

Distinct Pharmacokinetic Profile and Safety of a Fixed‐Dose Tablet of Sumatriptan and Naproxen Sodium for the Acute Treatment of Migraine

To describe the pharmacokinetic and safety profiles of sumatriptan 85 mg formulated with RT Technology (RT) and naproxen sodium 500 mg in a fixed-dose combination tablet (sumatriptan/naproxen sodium) that targets both serotonergic dysmodulation and inflammation in migraine. Six open-label, crossover studies were conducted in healthy volunteers (Studies 1, 2, 3, 4, 5) or patients with migraine (Study 6). Consistently across studies, naproxen administered as a component of sumatriptan/naproxen sodium demonstrated a delayed-release profile similar to that of an enteric-coated product. Naproxen from the combination tablet showed a delayed time to peak plasma concentration and lower peak plasma concentration while exposures (area under the plasma concentration-time curve) were similar. The peak plasma concentration for naproxen was approximately 36% lower and the time to peak plasma concentration approximately 4 hours later when naproxen was administered as sumatriptan/naproxen sodium compared with a single naproxen sodium 550 mg tablet. Sumatriptan peak plasma concentration and area under the plasma concentration-time curve after administration of sumatriptan/naproxen sodium (containing sumatriptan 85 mg) were comparable to those after administration of a commercially available sumatriptan 100 mg (RT) tablet. Sumatriptan time to peak plasma concentration occurred, on average, 30 minutes earlier with sumatriptan/naproxen sodium compared with sumatriptan 100 mg (RT). No clinically significant differences between sumatriptan/naproxen sodium and sumatriptan tablets 100 mg (RT) were identified with respect to electrocardiograms, blood pressure, or heart rate. In addition, food had no significant effect on the bioavailability of naproxen or sumatriptan after administration of sumatriptan/naproxen sodium but slightly delayed the time to peak plasma concentration of sumatriptan by approximately 40 minutes. The pharmacokinetics of sumatriptan and naproxen did not differ according to whether sumatriptan/naproxen sodium was administered during a migraine attack or a migraine-free period. The pharmacokinetics of 2 sumatriptan/naproxen sodium tablets administered 2 hours apart were consistent with the pharmacokinetic predictions from a single dose of the combination tablet. The adverse-event profile of the sumatriptan/naproxen sodium combination tablet did not appear to differ from that of the individual components of the same or similar dosage strengths administered alone or in combination. In addition, the incidence of adverse events with 2 sumatriptan/naproxen sodium tablets administered 2 hours apart was lower than that with the single dose. The combination tablet of sumatriptan/naproxen sodium has unique pharmacokinetic properties. The rapid absorption of sumatriptan with the delayed-release properties of naproxen sodium from sumatriptan/naproxen sodium might contribute to its therapeutic advantage over monotherapy with either component. No clinically meaningful effects of food, administration during a migraine attack, or administration of a second tablet (2 hours after initial dose) on the pharmacokinetics or safety of sumatriptan/naproxen sodium were observed.

Dissolution test of various low-dose acetylsalicylic acid preparations marketed in Indonesia

Aim To compare the dissolution profi les of various enteric-coated low-dose acetylsalicylic acid (ASA) tablets marketed in Indonesia. Methods The dissolution study was carried out according to US Pharmacocopoeiae (USP) /European Pharmacopoeiae, method A, using USP apparatus 1 (basket) 100 rpm, with 2 media: 0.1 N HCl, 120 minutes for acid stage, and phosphate buffer pH 6.8, 90 minutes for buffer stage. The sampling points were 120 minutes for the acid stage, and every 10 minutes until 90 minutes for the buffer stage. The acetylsalicylic acid was assayed using spectrophotometry at 280 nm for the acid stage, and at 265 nm for the buffer stage. The free salicylic acid was determined only at the end of the buffer stage with HPLC method. There were 6 test products (Cardio Aspirin® 100 mg, Aptor® 100 mg, Ascardia® 80 mg, Thrombo Aspilet® 80 mg, Astika® 100 mg and Farmasal® 100 mg), 3 batches for each product, and 6 units for each batch. Results The amount of ASA released from each ASA product tested at the end of acid stage (120 minutes) ranged from 1.79% for Cardio Aspirin® to 6.92% for Thrombo Aspilet®, all conformed to the compendial requirement for enteric-coated product (< 10%). The amount of salicylic acid observed at the end of the dissolution test ranged from 3.47% for Cardio Aspirin® to 10.90% for Astika® and 11.90 % for Thrombo Aspilet®. Thrombo Aspilet® showed sustained-release properties, causing high variability in ASA release, such that one of the 3 batches tested did not fulfill the compendial requirement of more than 75% (the release was only 55.11%). High variability in ASA release between batches was also found with Farmasal® at 10, 20, and 30 minutes in buffer medium. The lowest effective dose of ASA as an antiplatelet drug for longterm use is 75 mg of plain ASA, and this is equivalent to 100 mg of enteric-coated ASA. Conclusions All of the low-dose ASA preparations marketed in Indonesia are enteric-coated products, while Thrombo Aspilet® is not only an enteric-coated but also a sustained-release product. Cardio Aspirin®, followed by Aptor®, has the right dose for low-dose enteric-coated preparation (100 mg), produces consistent ASA release between batches, and the most stable towards deacetylation (antiplatelet inactivation). (Med J Indones 2009;18:159-64)

Pediatric Patients Have Shorter Lansoprazole Half-Life Than Previously Reported

Purpose: Traditional pharmacokinetic teaching suggests that the elimination rate (half-life) of drugs is related to patient age. However, the package insert for lansoprazole, a common proton-pump inhibitor (PPI) drug, reports that its “pharmacokinetics in pediatric patients aged 1 to 17 years [are] similar to those observed in healthy adult subjects.” Numerous recent articles, in contrast, suggest that higher dosages are needed for children, although these articles establish no definite pharmacokinetic relationship between patient age and drug half-life. Establishing the correct half-life is important for appropriate dosage regimen development for PPI drugs. Methods: Evaluation of previously published literature reveals an unusually large degree of variability in most studies. This variation can be caused by: (1) rapid versus slow metabolizer status based on genetic variation in Cytochrome P450, (2) immature hepatic function, (3) hepatic dysfunction, and (4) errors related to timing of blood draws with enteric-coated products. Meanwhile, when the ages of the patients in the same studies are plotted against the respective half-lives of lansoprazole, an increase in half-life with age is observable. After removing data involving patients with immature hepatic function and eliminating outlying points by using statistically acceptable methods, the relationship between age and half-life becomes even more evident.TableTo further investigate this relationship between age and half-life, a single dose of buffered lansoprazole suspension was administered to six children and pharmacokinetics were evaluated by standard methods. The drug was delivered in caracream, a flavored suspension that is buffered with sodium bicarbonate (which causes immediate release of lansoprazole into the bloodstream and, therefore, the elimination phase is discrete from the absorption phase and timing of blood draws is much simpler). Results: The half-life of the drug in each of the six patients was much lower than in other studies involving adults; furthermore, almost no variability was evident. When this data is compared with previously published data in pediatrics, it becomes clear that lansoprazole half-life increases with age. Conclusion: These results explain why many clinicians find a need for larger daily doses of PPIs in children and the consideration of such factors is critical in the effort to control Gastroesophageal Reflux Disease in children.

Development and characterization of multivesicular liposomes bearing serratiopeptidase for sustained delivery

Serratiopeptidase exhibits proteolytic activity and is used in the therapy of inflammation. It is rapidly degraded under harsh gastric environments; hence it is conventionally delivered as an enteric-coated product. There is severe loss of enzyme activity during the compression of tablets. Therefore, it is pivoted to develop a delivery system, which could sustain therapeutic blood and tissue level of drug for an extended period of time and avoids frequent dosing and loss of its proteolytic activity. The present study aimed to prepare and characterize serratiopeptidase bearing multivesicular liposomes for sustained delivery of serratiopeptidase. Multivesicular liposomes (MVLs) bearing serratiopeptidase were prepared using the double emulsification technique using amphipathic lipid, cholesterol, neutral oil and negatively charged lipid and characterized for their shape, size, drug entrapment and in vitro drug release. In vivo performance of multivesicular liposomes bearing serratiopeptidase was evaluated by assessing anti-inflammatory activity using the carrageenan-induced rat paw edema volume method and the cotton pellet granuloma method. The results thus obtained were compared with those of conventional drug solution and conventional liposomes containing serratiopeptidase in equal amounts. Optimized formulation parameters resulted in homogenous population of multivesicular liposomes having high encapsulation efficiency and spherical vesicle morphology. Vesicle size was found to be in the range 4.30 ± 0.25 μm to 19.61 ± 0.42 μm. The MVLs were found to be sensitive to osmotic pressure, responding by shrinking when the osmolarity of the medium was increased. Drug encapsulation was observed at 24.6 ± 0.99% in the case of conventional liposomes while it increases to 86.5 ± 4.24% in MLVs (SP MVL-S-b). The in vitro release reveals that conventional liposomal formulation releases more than 80% drug within 48 h while MVL formulations release the same amount of drug in 120 h. In vivo data reveal that reduction in inflamed paw volume with the MVLs formulation was not rapid but effect was maintained for prolonged period and even after 6 h there was 68 ± 1.26% reduction in inflamed paw volume. MVLs formulation shows 66.48 ± 1.82% inhibition in weight of granuloma in three days. MVL formulation showed more sustained and prolonged anti-inflammatory effect as compared to conventional drug and conventional liposomal formulation.

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 µm with geometric means close to 300 µm. 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°C (±0.5°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.

Dissolution test for liquid formulations of omeprazole enteric-coated products

Dissolution test for liquid formulations of omeprazole enteric-coated products

Effects of Garlic Preparations on the Gastrointestinal Mucosa

The effects of garlic preparations, including dehydrated raw garlic powder (RGP), dehydrated boiled garlic powder (BGP) and aged garlic extract (AGE), on the gastric mucosa were determined using a newly established endoscopic air-powder delivery system, which can deliver solid materials directly into the stomach. Among the three preparations, RGP caused severe damage, including erosion. BGP also caused reddening of the mucosa, whereas AGE did not cause any undesirable effects. The safety of enteric-coated garlic products was also determined. Direct administration of pulverized enteric-coated products on the gastric mucosa caused reddening of the mucosa. When an enteric-coated tablet was administered orally, it caused loss of epithelial cells at the top of crypts in the ileum. These results suggest that caution be used with regard to safety and effectiveness when choosing a garlic preparation because some preparations may have undesirable effects, including gastrointestinal problems.

Dissolution of Omeprazole from Delayed-Release Solid Oral Dosage Forms

The evaluation of the biopharmaceutical quality of omeprazole enteric-coated products (granules in capsules) with respect to its dissolution characteristics is not specifically regulated in any of the most common official pharmacopoeia. USP 23 includes a general monograph for enteric-coated products. This paper reports the evaluation of the medium pH effect on the dissolution rates of omeprazole from four omeprazole-containing products of different manufacturers. It is concluded that the USP 23 recommended dissolution procedure for enteric-coated products is not suitable due to the degradation of omeprazole under such conditions. Furthermore, the medium with pH 8.0 showed different dissolution rates not observed at pH 7.4, allowing discrimination between products of different manufacturers.

Treatment Failure After Substitution of Generic Pancrelipase Capsules

To the Editor.— The report of treatment failure after substitution of generic pancrelipase capsules 1 clearly illustrates the need for regulatory oversight in the manufacture of enteric-coated dosage forms. The Food and Drug Administration categorizes enteric-coated formulations as and not equivalents because these products differ in some aspect of formulation. Accordingly, the Food and Drug Administration does not evaluate the bioequivalency of pharmaceutical alternates in its list of therapeutically equivalent drug products, 2 in part due to the lack of systematic comparisons on which evaluation could be based. Pharmaceutical alternates (same drug, different formulation) constitutes a gray area between generic alternates (same drug, same formulation, different manufacturer) and therapeutic alternates (different drug). In addition to enteric-coated products, other types of pharmaceutical alternates include different dosage forms (tablets, capsules, and liquids), derivatives of the same active ingredient (esters, salts, acids, and bases), sustained-release formulations that use different technologies

Oral naproxen formulations.

The absorption of naproxen is dependent on the gastric emptying and the dissolution of the drug product in the small intestine. Enteric-coated granules designed to dissolve at pH 5.5 have a delayed absorption profile when given orally. Delivered directly into the duodenum, however, rapid absorption is obtained, indicating that the gastric emptying is the rate-limiting step. By varying the coating layer, it is possible to monitor the dissolution of enteric-coated products within a pH range from 4.5 to 7.0. The onset of absorption can be delayed by increasing the pH resistance of the coating, without affecting the extent of absorption.