Stability of Olmesartan Medoxomil Extemporaneous Suspensions.

Background: Olmesartan medoxomil (OLM) is only available in the United States as tablets. The United States Pharmacopoeia (USP) has placed OLM on its priority list of preparations that require stability data to support practitioner compounding. Objective: The purpose of the study was to develop a stability-indicating assay and then determine the beyond-use date (BUD) for an extemporaneous OLM suspension. Methods: A reverse-phase high-performance liquid chromatography (HPLC) assay was developed and validated according to guidelines for USP official compounded monographs. OLM 2 mg/mL suspensions were compounded with Ora-Sweet and Ora-Plus and stored at room temperature or in a refrigerator. Suspensions were assayed periodically over 90 days for OLM concentration and observed for physical stability. The pH was measured at the beginning and end of the study. Results: The OLM concentration remained above 97% of the starting concentration for 90 days when stored in the refrigerator and above 94% of the starting concentration for 90 days when stored at room temperature. The suspension pH did not change and indicators of physical stability were unchanged for 90 days. Conclusion: OLM 2 mg/mL suspensions were chemically and physically stable at room temperature and in the refrigerator for 90 days. The BUD may be set at 90 days under either storage condition.

Stability and Beyond-Use Date of a Compounded Thioguanine Suspension.

Background: Thioguanine (TG) is available only in the form of 40 mg tablets in the United States, and the patient population in which TG is used comprises mostly children. Recognizing its importance as a therapeutic agent and limited stability data for its compounded preparation, the United States Pharmacopoeia has listed TG in its priority list of compounded preparations monographs. Objective: The goal of the present study was to generate stability data and establish a beyond-use date for compounded TG suspension. Methods: Suspensions were compounded using TG tablets and ORA-Plus and ORA-Sweet as vehicles. A robust high-performance liquid chromatography method was developed and validated. TG and guanine (G) in suspensions were quantified immediately after compounding and at regular intervals for 90 days. Physical stability of suspensions was evaluated by observation of organoleptic properties. Results: Results from the study indicate that average TG levels in suspensions remained above 90% of the starting concentration and G formation was less than 2.5% for 90 days. There was no statistically significant difference in the amount of TG degraded over 90 days between suspensions stored at room temperature and in refrigerated conditions. There was also no statistically significant difference in G concentration of suspensions between day 0 and day 90. Conclusion: TG suspensions are stable for 90 days when stored at room temperature or refrigerated conditions and the beyond-use date can be set to 90 days.

Design and Performance of an Inexpensive Water Activity Meter.

Water activity refers to the amount of water in a system that is available for microbial growth. Commercial water activity meters are precision instruments with the ability to determine water activity to within 0.001 units and carry prices of $10,000 or more. The purpose of the study was to build a robust water activity meter from commercially available components and measure the water activity of liquids commonly used in compounded formulations. SHT-85 sensors were connected to an Adafruit Feather HUZZAH microcontroller. Standard salt slurries and common oral liquid vehicles were monitored in airtight containers until equilibrium was reached. Standard curves were used to convert sensor outputs to water activity values. The standard curves were linear with R2 >0.99. Oral liquid vehicles showed water activity values between 0.62 and 0.99. Samples equilibrated within 9.5 hours in 16-ounce jars or 2.5 hours in 20-mL vials. Stirring the sample during measurement reduced equilibration time in 16-ounce jars, but not in 20-mL vials. The inexpensive meter was accurate and precise in measuring the water activity of standards and selected oral vehicles. An accurate and precise water activity meter was constructed at a cost of approximately $150. Common oral formulation components have a water activity of >0.6, the United States Pharmacopeial threshold for requiring a preservative. Pharmacists should use caution when diluting preserved vehicles.

Patient Experiences with Compounded Topical Pain Creams.

Topical pain therapy offers several potential advantages as an alternative or adjunct to oral analgesic therapy, including decrease in concurrent oral drug use, lower abuse potential, lower side effects and toxicity, and localized effects. A variety of drugs and cream bases designed to promote transdermal delivery allow for unlimited customization of compounded topical pain creams (CTPC) for specific patients. The purpose of this study was to understand why patients begin CTPC therapy, their perceptions of CTPC therapy, and their level of satisfaction with CTPC therapy. A self-administered survey was distributed to patients receiving a compounded prescription. There were 107 responses from CTPC users. The typical CTPC user was a 67 year old woman with pain in the neck, back, or feet. The median duration of CTPC use was 4.5 months. Pain specialists, general practitioners, podiatrists, and orthopedists were the primary prescribers of CTPC. The prescriber was the first person to suggest CTPC for most patients. The majority of patients had insurance coverage for the CTPC and paid an average of $24.41 out of pocket per prescription. Most patients were highly satisfied with all aspects of CTPC and were more satisfied with CTPC than other medications they had used for the medical condition previously.

Patient experiences with compounded medications.

OBJECTIVES: There are few data directly from patients regarding their experiences with compounded prescriptions (CRx). The purpose of this study was to determine how patients initiated CRx use and how they perceived their CRx therapy. METHODS: A cross-sectional mailed national survey design was used. Participating pharmacies distributed questionnaires to their patients when dispensing CRx. The questionnaire contained items relating to patient demographics, previous use of CRx, how the patient came to use CRx, how the pharmacy was chosen, and satisfaction with the CRx. RESULTS: Four hundred ninety-four usable responses were received. Respondents were predominantly female (82.3%) with an average age of 60.5 years. Most respondents received their CRx by mail or delivery service (78.2%). The average duration of CRx use was 30 months. Patients with insurance paid an average of $50.04 for the CRx, whereas uninsured patients paid an average of $116.20. Hormone replacement therapy (HRT; 50.1%) and pain management (23.1%) were the most frequent indications for CRx therapy. CRx were primarily used to replace (68.1%) rather than supplement (31.9%) previous medications. The prescriber was the first person to suggest CRx therapy (78.9%), and the prescriber's recommendation was important in choosing the compounding pharmacy (89.6%) for most patients. More than 95% of patients were satisfied with all aspects of CRx therapy except cost. Patients judged CRx as equally good or better than previous medications they had used for their medical condition. CONCLUSION: Respondents used CRx for HRT, pain treatment, and a variety of medical conditions. CRx were used primarily to replace other medications because of treatment failure or intolerable adverse effects. Respondents were satisfied with all aspects of CRx therapy with the exception of out-of-pocket cost. The prescriber's recommendation was the single most important factor in a patient choosing to use CRx and in choosing a compounding pharmacy.

Kinetics of Tetracaine Solvolysis in Propylene Glycol.

Tetracaine is a potent ester-type local anesthetic. Recent publications describe the use of TC free base in topical anesthetic formulations containing propylene glycol. While solvolysis of tetracaine in propylene glycol solutions has been reported, there are no detailed reports on the kinetics of tetracaine reaction with propylene glycol. The objectives of the study were to characterize the kinetics and temperature dependence of tetracaine solvolysis in PG solutions. In this study, products of tetracaine degradation in propylene glycol solution at 60°C were collected and analyzed by high-performance liquid chromatographymass spectrometry and nuclear magnetic resonance. The kinetics of tetracaine reaction with propylene glycol was studied at 22°C, 30°C, 40°C, and 60°C. The reaction of tetracaine with n-propanol and isopropanol was also studied. Analysis was performed by high-performance liquid chromatography-mass spectrometry with ultraviolet detection using a gradient elution method. Tetracaine concentrations were quantitated using a four-point standard curve. Tetracaine degradation rates were consistent with apparent first order kinetics at all temperatures studied. The data indicated that tetracaine degrades via transesterification with propylene glycol. The rate constants ranged from 2.26 x 10-3 d-1 at 22°C to 7.06 x 10-2 d-1 at 60°C. Arrhenius analysis indicated an activation energy for the reaction of 74.1 kJ/mol, which is similar to published values for the hydrolysis of pharmaceutical esters.

Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet.

Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and ß-cell insulin content under nutrient overload.

Utilization and Costs of Compounded Medications for Commercially Insured Patients, 2012-2013.

BACKGROUND: Although compounding has a long-standing tradition in clinical practice, insurers and pharmacy benefit managers have instituted policies to decrease claims for compounded medications, citing questions about their safety, efficacy, high costs, and lack of FDA approval. There are no reliable published data on the extent of compounding by community pharmacists nor on the fraction of patients who use compounded medications. Prior research suggests that compounded medications represent a relatively small proportion of prescription medications, but those surveys were limited by small sample sizes, subjective data collection methods, and low response rates. OBJECTIVE: To determine the number of claims for compounded medications on a per user per year (PUPY) basis and the average ingredient cost of these claims among commercially insured patients in the United States for 2012 and 2013. METHODS: This study used prescription claims data from a nationally representative sample of commercially insured members whose pharmacy benefits were managed by a large pharmacy benefit management company. A retrospective claims analysis was conducted from January 1, 2012, through December 31, 2013. Annualized prevalence, cost, and utilization estimates were drawn from the data. All prescription claims were adjusted to 30-day equivalents. Data-mining techniques (association rule mining) were employed in order to identify the most commonly combined ingredients in compounded medications. RESULTS: The prevalence of compound users was 1.1% (245,285) of eligible members in 2012 and 1.4% (323,501) in 2013, an increase of 27.3%. Approximately 66% of compound users were female, and the average age of a compound user was approximately 42 years throughout the study period. The geographic distribution of compound user prevalence was consistent across the United States. Compound users' prescription claims increased 36.6% from 2012 to 2013, from approximately 7.1 million to approximately 9.7 million prescriptions. The number of claims for compounded medications increased by 34.2% during the same period, from 486,886 to 653,360. PUPY utilization remained unchanged at 2 prescriptions from 2012 to 2013. The most commonly compounded drugs were similar for all adult age groups and represented therapies typically indicated for chronic pain or hormone replacement therapy. The average ingredient cost for compounded medications increased by 130.3% from 2012 to 2013, from $308.49 to $710.36. The average ingredient cost for these users' non-compounded prescriptions increased only 7.7%, from $148.75 to $160.20. For comparison, the average ingredient cost for all prescription users' claims was $81.50 in 2012 and increased by 3.8% to $84.57 in 2013. CONCLUSIONS: Compound users represented 1.4% of eligible members in 2013. The average ingredient cost for compound users' compounded prescriptions ($710.36) was greater than for noncompounded prescriptions ($160.20). The 1-year increase in average compounded prescription costs (130.3%) was also greater than for noncompounded prescriptions (7.7%). Although prevalence of compound users and the PUPY utilization for compounded prescriptions increased only slightly between 2012 and 2013, the mean and median cost of compounded medications increased dramatically during this time. Text mining revealed that drug combinations characteristic of topical pain formulations were among the most frequently compounded medications for adults.

SR-135, a peroxynitrite decomposing catalyst, enhances ß-cell function and survival in B6D2F1 mice fed a high fat diet.

Peroxynitrite has been implicated in ß-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogs, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al., 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances ß-cell function and survival under nutrient overload.

Patient-centered care as value-added service by compounding pharmacists.

The term "value-added" is widely used to describe business and professional services that complement a product or service or that differentiate it from competing products and services. The objective of this study was to determine compounding pharmacists' self-perceptions of the value-added services they provide. A web-based survey method was used. Respondents' perceptions of their most important value-added service frequently fell into one of two categories: (1) enhanced pharmacist contribution to developing and implementing patient therapeutic plans and (2) providing customized medications of high pharmaceutical quality. The results were consistent with a hybrid community clinical practice model for compounding pharmacists wherein personalization of the professional relationship is the value-added characteristic.

The use of extemporaneously compounded 1% tetracaine to improve adherence with clotrimazole 1% topical solution in the treatment of ear infection: a case report.

For most medically amenable conditions, adherence to drug therapy is a necessary condition for a successful outcome. Drug side effects, especially pain, can interfere with the desired outcome. We report a case of non-adherence due to severe pain associated with the topical use of clotrimazole 1% solution in the ear. Instillation of tetracaine 1% solution prior to the administration of the clotrimazole blocked the pain sensation allowing the patient to successfully complete the antifungal therapy.

Assessment of the accuracy of pharmacy students' compounded solutions using vapor pressure osmometry.

OBJECTIVE. To assess the effectiveness of using a vapor pressure osmometer to measure the accuracy of pharmacy students' compounding skills. DESIGN. Students calculated the theoretical osmotic pressure (mmol/kg) of a solution as a pre-laboratory exercise, compared their calculations with actual values, and then attempted to determine the cause of any errors found. ASSESSMENT. After the introduction of the vapor pressure osmometer, the first-time pass rate for solution compounding has varied from 85% to 100%. Approximately 85% of students surveyed reported that the instrument was valuable as a teaching tool because it objectively assessed their work and provided immediate formative assessment. CONCLUSIONS. This simple technique of measuring compounding accuracy using a vapor pressure osmometer allowed students to see the importance of quality control and assessment in practice for both pharmacists and technicians.

An epidemiological model of spatial coupling for trips longer than the infectious period.

One of the standard methods of accounting for inter-population disease spread in equation-based epidemiology models is through a transportation operator. Implicit in the use of the transportation operator, however, is an assumption that daily travel volumes are small compared to overall population sizes, an assumption that can break down for modern rates of international travel or local commuter traffic. Alternative types of coupling have been proposed in the limit that trip durations are much shorter than the infectious period. We present an extension of these phenomenological models that relaxes both assumptions. We show that the approach produces more accurate results when assessing the impact of mitigative actions using modern travel volumes.

Stability of non-aqueous topical tetracaine and clotrimazole solutions in polypropylene droptainer bottles.

Tetracaine topical solution may improve patient adherence with topical clotrimazole therapy for fungal otitis externa. The chemical stability of tetracaine 1% and combination clotrimazole 1% with tetracaine 1% topical solutions was determined using a stability-indicating high-performance liquid chromatography assay. Propylene glycol and polyethylene glycol 400 were used as anhydrous solvents. Standard curves for tetracaine and clotrimazole were linear with r2 > or = 0.999. Clotrimazole did not degrade in either propylene glycol or polyethylene glycol 400 throughout the 90-day study period. Tetracaine degraded significantly in propylene glycol but not in polyethylene glycol 400. A beyond-use date of 90 days is supported for tetracaine and the combination clotrimazole-tetracaine solution in polyethylene glycol 400. A beyond-use date of 60 days is supported for tetracaine and the combination clotrimazole-tetracaine in propylene glycol.

ß-cell metabolic alterations under chronic nutrient overload in rat and human islets.

The aim of this study was to assess multifactorial ß-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in ß-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in ß-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 µM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets.

Stability of sodium bicarbonate solutions in polyolefin bags.

PURPOSE: The stability of sodium bicarbonate solutions in sterile water for injection or 5% dextrose injection stored at 21-24 degrees C or 2-4 degrees C was evaluated. METHODS: Sodium bicarbonate injection was obtained in 50-mL vials of 8.4% (1 meq/mL). A total of 50, 100, or 150 meq of sodium bicarbonate was added to each 1-L polyolefin bag of either sterile water for injection or 5% dextrose injection. All solutions were prepared in a laminar-airflow hood using aseptic technique. Bags were punctured once to remove headspace air and once for the addition of each 50 meq of sodium bicarbonate. Six replicates of each test solution were prepared. The solutions were stored at 21-24 degrees C and 2-4 degrees C. Control solutions (50 and 150 meq) were similarly prepared in triplicate. Control solutions were sparged with either nitrogen gas or oxygen gas before storage. Sodium bicarbonate stability was assessed by measuring solution pH. Bicarbonate content was measured utilizing titration. Both pH and bicarbonate concentrations were measured immediately upon preparation and on days 3, 5, and 7 for both test and control solutions. RESULTS: All 95% confidence interval values for sample solution pH remained within 7.0-8.5 for seven days at 2-4 degrees C. CONCLUSION: Sodium bicarbonate solutions of 50, 100, and 150 meq in sterile water for injection or 5% dextrose injection were stable for up to seven days when refrigerated. The 50-meq solution was stable for up to 48 hours when stored at room temperature, and the 100- and 150-meq solutions were stable for up to 30 hours when stored at room temperature.

Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX).

1,3-dipropyl-8-cyclopentylxanthine (CPX) has been shown to stimulate in vitro CFTR activity in F508 cells. Data from a phase I study demonstrated erratic bioavailability and no measurable clinical response to oral CPX. One cause for its poor bioavailability may have been dissolution rate limited absorption, but there is little published physicochemical data on which to base an analysis. The objective of this study was to determine the solubility and solid-state characteristics of CPX. CPX is a weak acid with pKa of 9.83 and water solubility at pH 7.0 of 15.6 microM. Both laureth-23 and poloxamer 407 increased the apparent water solubility linearly with increasing concentrations. CPX exists in two crystal forms, one of which (form II) has been solved. Form II is a triclinic crystal with space group P1 and calculated density of 1.278 g/cm(3). X-ray powder diffraction and differential scanning calorimetry studies (DSC) indicated that CPX crystals prepared at room temperature were mixtures of forms I and II. DSC results indicated a melting point of approximately 195 degrees C for form I and 198 degrees C for form II. Thermogravimetric analysis indicated no solvent loss upon heating. Dynamic water vapor sorption data indicated no significant water uptake by CPX up to 90% RH. Analysis of the data indicates that CPX may not be amenable to traditional formulation approaches for oral delivery.

Patient-centered care in the community-based compounding practice setting.

OBJECTIVE: To identify patient-centered care (PCC) functions delivered with compounded medications in the community pharmacy setting. DESIGN: Cross-sectional study. SETTING: United States during August to November 2007. PARTICIPANTS: 163 community pharmacist members of the International Academy of Compounding Pharmacists. INTERVENTION: Web-based questionnaire. MAIN OUTCOME MEASURES: Pharmacists' self-reported implementation and perceptions of the PCC process. RESULTS: Respondents were predominantly men (78.4%), independent pharmacy owners (84.0%), held a BPharm degree (78.5%), and dispensed an average of 746.6 prescriptions per week, including an average of 209.1 compounded medications. Respondents perceived a greater responsibility to provide PCC when dispensing a compounded medication compared with a manufactured product. Compounding pharmacists provided input into the prescribing process via frequent physician-initiated consultation. Respondents reported greater follow-up with patients and physicians regarding therapy with compounded medications than manufactured products. CONCLUSION: PCC is characterized by maintenance and frequent updating of detailed patient health records, routine counseling of patients on new and continuing drug therapies, monitoring of patient therapeutic outcomes, and participation in the prescribing process. Patients are drawn into a stronger relationship with pharmacists who provide these services. Provision of PCC services is associated with greater perceived quality of patient care and pharmacist professional satisfaction.