Enteric-coated Formulation Research Articles

Pharmacokinetics of esomeprazole following intravenous and oral administration in healthy dogs.

Investigation into the pharmacokinetic profile of esomeprazole was conducted using eight healthy dogs after intravenous (IV) and oral (po) administration in a two-part randomized crossover study. The dogs were fasted for a minimum of 12 hours and then received esomeprazole either intravenously (dose range 0.93–1.48 mg/kg) or orally using an enteric-coated formulation (dose range 0.95–1.50 mg/kg). After a 1-week washout period, the dogs received an alternative treatment. Serial blood samples were collected at predetermined time points, and plasma esomeprazole concentrations were determined by using ultra-high-performance liquid chromatography–mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Then, the area under the plasma concentration/time curve (AUC) and maximal plasma concentration (Cmax) values were normalized to a 1.0 mg/kg dose of esomeprazole, that is, AUC/dose. Median (range) dose-normalized peak plasma concentration (Cmax) values for the IV and po formulations were 4.06 µg/mL (2.47–4.57 µg/mL) and 1.04 µg/mL (0.31–1.91 µg/mL), respectively. The median (range) time-to-peak concentration (Tmax) for the po formulation was 105 minutes (45–360 minutes). Median (range) plasma terminal half-life (t½) was 45.56 minutes (39.43–64.20 minutes) for the IV formulation and 63.97 minutes (44.02–109.94 minutes) for the enteric-coated po formulation. The median (range) po bioavailability was 63.33% (32.26%–79.77%). Clinically, both po and IV formulations were well tolerated with minimal side effects observed.

Effect of warning symbols in combination with education on the frequency of erroneously crushing medication in nursing homes: an uncontrolled before and after study

ObjectivesResidents of nursing homes often have difficulty swallowing (dysphagia), which complicates the administration of solid oral dosage formulations. Erroneously crushing medication is common, but few interventions have been tested to...

Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation?

While bioequivalence between enteric-coated and immediate-release formulations can be achieved in terms of AUC, gastric emptying of enteric-coated dosage forms is a stochastic event, usually leading to lower Cmax values than those observed with the corresponding immediate release. This article examines challenges of developing enteric-coated dosage forms which are bioequivalent to the corresponding immediate-release formulations in terms of both AUC and Cmax using rasagiline as a model compound. In vitro drug release profiles of enteric-coated formulations were obtained and compared to those of the immediate-release formulation by dissolution testing. Pharmacokinetics was evaluated in bioequivalence studies in healthy human volunteers after single oral administration of enteric-coated and immediate-release formulations. The initial enteric-coated pellet formulation prototype was equivalent in terms of AUC, but differed in Cmax ; a second formulation prototype, consisting of a single-unit core and enteric-coating film, proved to be bioequivalent to immediate-release rasagiline tablets in terms of AUC and Cmax . In vitro, it released rasagiline rapidly at a pH of 6.8. Despite differences in gastric emptying between disintegrating immediate-release and enteric-coated solid dosage forms, bioequivalence in pharmacokinetic studies was achieved.

Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438).

Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24h. Vonoprazan fumarate (TAK-438, hereinafter referred to as "vonoprazan") is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases. This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.

Toward Biopredictive Dissolution for Enteric Coated Dosage Forms.

The aim of this work was to develop a phosphate buffer based dissolution method for enteric-coated formulations with improved biopredictivity for fasted conditions. Two commercially available enteric-coated aspirin products were used as model formulations (Aspirin Protect 300 mg, and Walgreens Aspirin 325 mg). The disintegration performance of these products in a physiological 8 mM pH 6.5 bicarbonate buffer (representing the conditions in the proximal small intestine) was used as a standard to optimize the employed phosphate buffer molarity. To account for the fact that a pH and buffer molarity gradient exists along the small intestine, the introduction of such a gradient was proposed for products with prolonged lag times (when it leads to a release lower than 75% in the first hour post acid stage) in the proposed buffer. This would allow the method also to predict the performance of later-disintegrating products. Dissolution performance using the accordingly developed method was compared to that observed when using two well-established dissolution methods: the United States Pharmacopeia (USP) method and blank fasted state simulated intestinal fluid (FaSSIF). The resulting dissolution profiles were convoluted using GastroPlus software to obtain predicted pharmacokinetic profiles. A pharmacokinetic study on healthy human volunteers was performed to evaluate the predictions made by the different dissolution setups. The novel method provided the best prediction, by a relatively wide margin, for the difference between the lag times of the two tested formulations, indicating its being able to predict the post gastric emptying onset of drug release with reasonable accuracy. Both the new and the blank FaSSIF methods showed potential for establishing in vitro-in vivo correlation (IVIVC) concerning the prediction of Cmax and AUC0-24 (prediction errors not more than 20%). However, these predictions are strongly affected by the highly variable first pass metabolism necessitating the evaluation of an absorption rate metric that is more independent of the first-pass effect. The Cmax/AUC0-24 ratio was selected for this purpose. Regarding this metric's predictions, the new method provided very good prediction of the two products' performances relative to each other (only 1.05% prediction error in this regard), while its predictions for the individual products' values in absolute terms were borderline, narrowly missing the regulatory 20% prediction error limits (21.51% for Aspirin Protect and 22.58% for Walgreens Aspirin). The blank FaSSIF-based method provided good Cmax/AUC0-24 ratio prediction, in absolute terms, for Aspirin Protect (9.05% prediction error), but its prediction for Walgreens Aspirin (33.97% prediction error) was overwhelmingly poor. Thus it gave practically the same average but much higher maximum prediction errors compared to the new method, and it was strongly overdiscriminating as for predicting their performances relative to one another. The USP method, despite not being overdiscriminating, provided poor predictions of the individual products' Cmax/AUC0-24 ratios. This indicates that, overall, the new method is of improved biopredictivity compared to established methods.

Use of bicarbonate buffer systems for dissolution characterization of enteric-coated proton pump inhibitor tablets.

The aim of this study was to assess the effects of buffer systems (bicarbonate or phosphate at different concentrations) on the invitro dissolution profiles of commercially available enteric-coated tablets. In vitro dissolution tests were conducted using an USP apparatus II on 12 enteric-coated omeprazole and rabeprazole tablets, including innovator and generic formulations in phosphate buffers, bicarbonate buffers and a media modified Hanks (mHanks) buffer. Both omeprazole and rabeprazole tablets showed similar dissolution profiles among products in the compendial phosphate buffer system. However, there were large differences between products in dissolution lag time in mHanks buffer and bicarbonate buffers. All formulations showed longer dissolution lag times at lower concentrations of bicarbonate or phosphate buffers. The dissolution rank order of each formulation differed between mHanks buffer and bicarbonate buffers. A rabeprazole formulation coated with a methacrylic acid copolymer showed the shortest lag time in the high concentration bicarbonate buffer, suggesting varied responses depending on the coating layer and buffer components. Use of multiple dissolution media during invitro testing, including high concentration bicarbonate buffer, would contribute to the efficient design of enteric-coated drug formulations.

Evaluation of Acid Tolerance of Drugs Using Rats and Dogs Controlled for Gastric Acid Secretion

We attempted to establish animal models to evaluate the effects of drug degradation in the stomach on oral bioavailability. In addition, we assessed the utilization of animal studies in determining the need for enteric-coated formulations. In order to control the gastric pH in rats and dogs, appropriate dosing conditions were investigated using pentagastrin and rabeprazole, which stimulate and inhibit gastric acid secretion. Using animals controlled for gastric acid secretion, the area under curve (AUC) ratios (AUC with rabeprazole/AUC with pentagastrin) of all compounds unstable under acidic conditions were evaluated. The AUC ratios of omeprazole and erythromycin, which are administered orally to humans, as enteric-coated tablets, were greater than 1.9 in the rats and dogs controlled for gastric acid secretion. On the contrary, the AUC ratios of clarithromycin, azithromycin, and etoposide (commercially available as a standard immediate-release form) were less than 1.3 each. In conclusion, in vivo models using rats and dogs were optimized to evaluate the effects of gastric acid on the oral bioavailability of drugs, and demonstrated that in vivo models can lead to a better understanding of the oral bioavailability, with respect to the formulation development.

Effect of crofelemer extract on severity and consistency of experimentally induced enterotoxigenic Escherichia coli diarrhea in newborn Holstein calves

The objective of this study was to evaluate the effect of a standardized botanical extract of Croton lechleri, named crofelemer extract, on fecal dry matter and fecal scores on diarrheic newborn Holstein bull calves induced by enterotoxigenic Escherichia coli. A double-blinded randomized clinical trial was performed in which 60 newborn Holstein bull calves were clean caught and transported to an isolation facility where calves were individually housed and randomly assigned to 1 of 3 treatment groups: placebo (control), enteric-coated formulation of crofelemer extract (ECROF), and nonenteric-coated formulation of crofelemer extract (CROF). Diarrhea was induced at first feeding with an inoculum of the enterotoxigenic Escherichia coli (ATCC 31616) administered with a third of the recommended dose of a colostrum replacer. All calves enrolled in this study received treatments starting on the second feeding (diarrhea onset) and treatments were administered before feeding time (0600 and 1600h) for 6 feedings consecutively. All calves in this study had failure of passive transfer. The only cause of death in this study was due to septicemia, accounting for 1 death out of each treatment group. All the calves were examined twice daily, within 2h after feeding, from d 1 (prechallenge) until 10, on d 15, and a last examination on d 25 of life. Five parameters were evaluated during each examination; rectal temperature, clinical assessment of dehydration status, fecal scores, attitude, and appetite. No differences were observed between treatment groups for rectal temperature, attitude, and appetite. Fecal dry matter was analyzed as prechallenge fecal dry matter, dry matter during treatment, and fecal dry matter after treatment cessation. No difference in prechallenge fecal dry matter was observed and prechallenge fecal dry matter was used as a covariate in the models. Fecal dry matter during treatment was significantly higher for ECROF calves when compared with control calves and CROF calves. Additionally, ECROF fecal dry matter after treatment cessation had a statistical tendency to be higher when compared with control calves. Together, these results suggest that enteric-coated formulation of the standardized crofelemer extract, a natural-product with antisecretory properties, can significantly increase fecal dry matter of neonatal calves with experimentally induced enterotoxigenic Escherichia coli diarrhea. More research is needed to test the efficacy of enteric-coated crofelemer on incidence and severity of secretory diarrhea on calves under natural challenge conditions.

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors

Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients. A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design. The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37). These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.

Enteric-coated mycophenolate sodium given in combination with tacrolimus has a lower incidence of serious infections in Asian renal-transplant recipients compared with mycophenolate mofetil.

To compare the characteristics of the enteric-coated formulation of mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) given in combination with tacrolimus in Asian renal-transplant recipients. In a 24-month, single-centre, randomized, open-label, prospective study, 101 live-donor kidney transplant recipients were randomized to the EC-MPS (n = 50) or MMF (n = 51) group. The incidence of infection, therapeutic effect and adverse events were monitored. The incidences of infection were 40% and 49% for the EC-MPS and MMF groups, respectively (p = 0.362). However, serious infection was only observed in the MMF group (11.8%; p = 0.027). The incidences of gastro-intestinal adverse events (GI AEs) were 24% and 41.2% for EC-MPS and MMF, respectively (p = 0.066). However, serious diarrhoea only occurred in the MMF group (9.8%; p = 0.056). The trough level of FK 506 at the time of diarrhoea (13.22 ± 3.66 ng/ml) was significantly higher than the level within 1 month before (9.18 ± 1.12 ng/ml; p < 0.05) and 1 month after diarrhoea (9.13 ± 0.85 ng/ml; p < 0.05). The infection rate of patients with diarrhoea was significantly higher than those without diarrhoea (68%, 39%, p = 0.024). The serum creatinine level was 698 ± 60 μmol/l for EC-MPS and 673 ± 68 μmol/l for MMF from baseline (p > 0.05), and it decreased to 66 ± 6 μmol/l for EC-MPS and 69 ± 8 μmol/l for MMF at 24 months (p > 0.05). The incidences of biopsy proven acute rejection (BPAR) were 20% and 25.5% for EC-MPS and MMF, respectively (p = 0.511). Enteric-coated formulation of mycophenolate sodium, given in combination with tacrolimus, has a lower incidence of serious infection in Asian renal-transplant recipients compared with MMF, and the therapeutic effect of EC-MPS is similar to MMF. The clinical trial registration number is ChiCTR-IPR-14005509. The registry name is 'Effect of Enteric-coated mycophenolate sodium on posttransplant infection rate after renal transplantation compared with Mycophenolate mofetil'.

The Pharmacokinetic Profile of a New Gastroresistant Capsule Preparation of Eicosapentaenoic Acid as the Free Fatty Acid.

Supplementation with n-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for patients with inflammatory bowel diseases (IBD). In this study we analyzed the pharmacokinetic profile of eicosapentaenoic acid (EPA), as the free fatty acid (FFA), in an enteric-coated preparation, in 10 ulcerative colitis (UC) and 10 Crohn's disease (CD) patients and 15 healthy volunteers (HV). Subjects received 2 g daily of EPA-FFA for 8 weeks. Plasma phospholipid and red blood cell (RBC) membrane fatty acid content were measured by gas chromatography-mass spectrometry. There was a rapid incorporation of EPA into plasma phospholipids by 2 weeks and a slower, but highly consistent, incorporation into RBC membranes (4% total fatty acid content; coefficient of variation 10–16%). There was a concomitant reduction in relative n-6 PUFA content. Elongation and desaturation of EPA into docosahexaenoic acid (DHA) via docosapentaenoic acid (DPA) were apparent and DHA content also increased in membranes. EPA-FFA is well tolerated and no difference in the pharmacokinetic profile of n-3 PUFA incorporation was detected between IBD patients and HV. Our data support the concept that EPA can be considered the “universal donor” with respect to key n-3 PUFAs and that this enteric-coated formulation allows long term treatment with a high level of compliance.

Enteric coating can lead to reduced antiplatelet effect of low-dose acetylsalicylic acid.

Low-dose acetylsalicylic acid (ASA) is widely used as antithrombotic prophylaxis. Enteric-coated ASA has been developed to decrease the risk of gastrointestinal side effects. The consequences of enteric coating on pharmacokinetics and antiplatelet effect of ASA have not systematically been assessed. This MiniReview demonstrates that data from clinical trials indicate that enteric coating can reduce the antiplatelet effect of ASA compared to plain ASA. This is possibly due to decreased bioavailability of ASA caused by prolonged solvation and absorption of the enteric-coated formulations. Therefore, low-dose enteric-coated ASA might not be bioequivalent to plain ASA, entailing the risk of insufficient cardiovascular prophylaxis.

Changes in the Small Bowel of Symptomatic Kidney Transplant Recipients Converted from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium

Background/Aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions. Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

Comparison of the effect of two doses of omeprazole on the squamous gastric mucosa in thoroughbred racehorses

Omeprazole is widely used as a prophylactic agent against gastric ulceration in the horse, and doses of buffered omeprazole at 1 mg/kg per os once a day have been shown...

Efficacy of Omeprazole Powder Paste or Enteric‐Coated Formulation in Healing of Gastric Ulcers in Horses

BackgroundGastroGard, an omeprazole powder paste formulation, is considered the standard treatment for gastric ulcers in horses and is highly effective. Gastrozol, an enteric‐coated omeprazole formulation for horses, has recently become available, but efficacy data are controversial and sparse.ObjectivesTo investigate the efficacy of GastroGard and Gastrozol at labeled doses (4 and 1 mg of omeprazole per kg bwt, respectively, PO q24h) in healing of gastric ulcers.Animals40 horses; 9.5 ± 4.6 years; 491 ± 135 kg.MethodsProspective, randomized, blinded study. Horses with an ulcer score ≥1 (Equine Gastric Ulcer Council) were randomly divided into 2 groups and treated for 2 weeks each with GastroGard followed by Gastrozol (A) or vice versa (B). After 2 and 4 weeks, scoring was repeated and compared with baseline. Plasma omeprazole concentrations were measured on the first day of treatment after administration of GastroGard (n = 5) or Gastrozol (n = 5).ResultsCompared with baseline (squamous score (A) 1.65 ± 0.11, (B) 1.98 ± 0.11), ulcer scores at 2 weeks ((A) 0.89 ± 0.11, (B) 1.01 ± 0.11) and 4 weeks ((A) 1.10 ± 0.12, (B) 0.80 ± 0.12) had significantly decreased in both groups (P < .001), independent of treatment (P = .7). Plasma omeprazole concentrations were significantly higher after GastroGard compared with Gastrozol administration (AUCGG = 2856 (1405‐4576) ng/mL × h, AUCGZ = 604 (430‐1609) ng/mL × h; P = .03). The bioavailability for Gastrozol was 1.26 (95% CI 0.56–2.81) times higher than for GastroGard.Conclusions and Clinical ImportanceBoth Gastrozol and GastroGard, combined with appropriate environmental changes, promote healing of gastric ulcers in horses. However, despite enteric coating of Gastrozol, plasma omeprazole concentrations after single labeled doses were significantly higher with GastroGard.

Recent Advances in Pharmacotherapy of Ulcerative Colitis

Ulcerative colitis is a form of chronic inflammatory bowel disease (IBD) that produces inflammation and ulcers along the inside of the colon, which can interfere with the normal function of the colon. The disease typically starts to manifest in patients as young adults. Ulcerative colitis is an intermittent disease with periods of exacerbated symptoms, or flares, and periods that are relatively symptom-free. According to the Cohn’s and Colitis Foundation of America, several millions people suffer from ulcerative colitis worldwide. Current therapeutic approaches for ulcerative colitis are partially successful despites advances in GIT research. A significant proportion of patients with ulcerative colitis undergo colectomy. Nearly 50% patients do not achieve sustained remission, leading to impairment of physical and mental health, social life, employment issues and sexual activity. Budesonide is an oral, extended release synthetic corticosteroid that is recently approved for UC. Enteric-coated budesonide formulations resist gastric-acid degradation, delivering active drug to the small intestine and proximal colon. Budesonide is specifically indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide has a high first-pass metabolism with minimal systemic absorption. This review describes recent advances in the pharmacotherapy of ulcerative colitis and outlines why future studies targeting sustained suppression of inflammation could have an enormous impact on the natural course of the disease. Ulcerative colitis needs intense therapy and it should be maintained until sustained remission and mucosal healing has been reached.

Enteric-coated sustained-release nanoparticles by coaxial electrospray: preparation, characterization, and in vitro evaluation

Enteric-coated formulations can delay the release of drugs until they have passed through the stomach. However, high concentration of drugs caused by rapidly released in the small intestine leads to the intestinal damage, and frequent administration would increase the probability of missing medication and reduce the patient compliance. To solve the above-mentioned problems, aspirin-loaded enteric-coated sustained-release nanoparticles with core–shell structure were prepared via one-step method using coaxial electrospray in this study. Eudragit L100-55 as pH-sensitive polymer and Eudragit RS as sustained-release polymer were used for the outer coating and inner core of the nanoparticles, respectively. The maximum loading capacity of nanoparticles was 23.66 % by changing the flow rate ratio of outer/inner solutions, and the entrapment efficiency was nearly 100 %. Nanoparticles with core–shell structure were observed via fluorescence microscope and transmission electron microscope. And pH-sensitive and sustained drug release profiles were observed in the media with different pH values (1.2 and 6.8). In addition, mild cytotoxicity in vitro was detected, and the nanoparticles could be taken up by Caco-2 cells within 1.0 h in cellular uptake study. These results indicate that prepared enteric-coated sustained-release nanoparticles would be a more safety and effective carrier for oral drug delivery.

Aspirin therapy: Evaluating benefits and risks

The prevalence of OTC aspirin use is unknown, but with all the publicity about its potential benefit for cardiovascular health and cancer prevention, it's wise to assume many of your patients are using it. Recent data regarding aspirin therapy reinforce the need to evaluate potential benefits and risks in each patient. A recent study evaluated the overall benefit of aspirin use for primary prevention of cardiovascular events.1.JAMA. 2012;307(21):2286–94.Google Scholar Data for patients with and without diabetes who were taking placebo or aspirin were evaluated to determine the incidence of hospitalization for major bleeds (cerebral hemorrhage or gastrointestinal bleeds). The aspirin dose was less than 300 mg daily, and patient data were collected for a period of approximately 6 years. The researchers found that those taking aspirin and those with diabetes (regardless of aspirin use) had a significantly higher incidence of one of the adverse outcomes. These data reinforce the opportunities for pharmacists to counsel patients on the use of aspirin and potential risks to keep in mind. The data also suggest that individuals with diabetes, regardless of aspirin use, might benefit from a brief conversation about watching for increased risk of bleeding. The most recent guidelines for aspirin use from the American Diabetes Association suggested using low-dose aspirin (75–162 mg) as primary prevention for cardiovascular disease (CVD) in individuals with type 1 or type 2 diabetes and a 10-year cardiovascular risk greater than 10%.2.http://care.diabetesjournals.orgcontent/36/Supplement_1/S4.full.Google Scholar This would include most men older than 50 years and women older than 60 years with at least one additional risk factor (e.g., dyslipidemia, hypertension). Clinical judgment regarding the use of aspirin is recommended for those with a 10-year cardiovascular risk of 5% to 10%. Low-dose aspirin for secondary prevention also is recommended in patients with diabetes who have a history of CVD. Often the only evidence of aspirin's antiplatelet activity is increased bruising or bleeding. A recent evaluation was completed to determine if enteric coating/absorption affected response.3.Circulation. 2013;127(3):377–85Google Scholar A total of 400 patients took 325 mg aspirin in either immediate-release (IR) or enteric-coated (EC) formulation. Cyclooxygenase-1 activity was measured to evaluate response. Approximately 50% of patients taking 325 mg EC aspirin appeared to have aspirin resistance compared with no resistance among those taking the IR product. However, subsequent analysis revealed that rather than resistance, the issue was related to the type of aspirin used and the timing of administration. This study suggested that the IR formulation should be used to ensure absorption, and ultimately therapeutic benefit of antiplatelet activity, especially in patients using aspirin for secondary prevention only. CVD is the leading cause of death in women; thus, many are told to take aspirin for either primary or secondary prevention. In 2004 (survey 1) and 2009 (survey 2), women from 127 facilities were assessed for health attributes, including CVD risk factors and aspirin use.4.J Womens Health (Larchmt). 2012;21(4):379–87Google Scholar Slightly more than 218,000 women responded to the surveys, and 29,701 were told by their health care provider to take aspirin based on their profile and guidelines. The results showed that 41% of women who met criteria for primary prevention were taking aspirin as recommended, while 48% who met criteria for secondary prevention were taking aspirin as recommended. From survey 1 to survey 2, a significant increase was seen in use for primary prevention, but no change was seen in use for secondary prevention. These data suggest that pharmacists have an opportunity to identify women who should be using aspirin and educate those for whom aspirin therapy is recommended.

Quantitative analysis of erythromycylamine in human plasma by liquid chromatography-tandem mass spectrometry and its application in a bioequivalence study of dirithromycin enteric-coated tablets with a special focus on the fragmentation pattern and carryover effect

A liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of erythromycylamine, which is the predominant active metabolite of dirithromycin in human plasma. After solid-phase extraction, the analyte and internal standard (IS) were separated by using an isocratic mobile phase consisting of 20 mM ammonium acetate (pH 3.9, adjusted with formic acid)-acetonitrile (75:25, v/v) on a Phenyl-Hexyl column (150 × 2.1 mm, 3 μm) and then analyzed in positive ion mode under electrospray ionization. Azithromycin was selected as the IS because it has the most similar mass spectrometric and chromatographic behaviors to the analyte. The respective multiple reaction monitoring (MRM) transitions, m/z 368.5>83.2 for erythromycylamine and m/z 375.4>115.2 for IS were chosen to achieve high sensitivity and selectivity in determination. A more acidic mobile phase (pH 3.9) than those of previous reports and a special needle wash (ethylene glycol-acetonitrile-water, 50:30:20, v/v/v, adjusted to pH 3.9 using formic acid) were used to eliminate the carryover effects of the two macrolides. The method exhibited a linear dynamic range of 0.5-440.0 ng/mL for erythromycylamine in human plasma (r=0.9999). The lower limit of quantification (LLOQ) and limit of detection (LOD) were 0.5 and 0.05 ng/mL, respectively. The mean extraction recoveries were higher than 94.0% for the analyte and IS. The intra- and inter-day precisions ranged from 1.4 to 5.4% and from 1.6 to 4.0%, respectively. The accuracy varied between 91.2 and 101.2%. The established method was successfully applied to analyze the human plasma samples from 24 healthy subjects in a bioequivalence study of two dirithromycin enteric-coated formulations.

Association between Physician Specialty and Risk of Prescribing Inappropriate Pill Splitting

BackgroundPrescription errors that occur due to the process of pill splitting are a common medication problem; however, available prescription information involving inappropriate pill splitting and its associated factors is lacking.MethodsWe retrospectively evaluated a cohort of ambulatory prescriptions involving extended-release or enteric-coated formulations in a Taiwan medical center during a 5-month period in 2010. For this study, those pill splitting prescriptions involving special oral formulations were defined as inappropriate prescriptions. Information obtained included patient demographics, prescriber specialty and prescription details, which were assessed to identify factors associated with inappropriate pill splitting.ResultsThere were 1,252 inappropriate prescriptions identified in this cohort study, representing a prescription frequency for inappropriate pill splitting of 1.0% among 124,300 prescriptions with special oral formulations. Among 35 drugs with special oral formulations in our study, 20 different drugs (57.1%, 20/35) had ever been prescribed to split. Anti-diabetic agents, cardiovascular agents and central nervous system agents were the most common drug classes involved in inappropriate splitting. The rate of inappropriate pill splitting was higher in older (over 65 years of age) patients (1.1%, 832/75,387). Eighty-seven percent (1089/1252) of inappropriate prescriptions were prescribed by internists. The rate of inappropriate pill splitting was highest from endocrinologists (3.4%, 429/12,477), nephrologists (1.3%, 81/6,028) and cardiologists (1.3%, 297/23,531). Multivariate logistic regression analysis revealed that the strongest factor associated with individual specific drug of inappropriate splitting was particular physician specialties.ConclusionThis study provides important insights into the inappropriate prescription of special oral formulation related to pill splitting, and helps to aggregate information that can assist medical professionals in creating processes for reducing inappropriate pill splitting in the future.