Optimization of Pramipexole-Loaded In Situ Thermosensitive Intranasal Gel for Parkinson's Disease.

The objective of the present work was to develop and optimize an intranasal in situ gel of Pramipexole dihydrochloride for enhanced drug delivery, better patient acceptability, and possible proper treatment of Parkinson's disease. Preliminary studies were performed to select formulation components and identify key variables affecting the formulation. The optimization of the in situ gelling system of Pramipexole dihydrochloride was achieved by applying 32 full factorial design using Design-Expert® software (Stat-Ease 9.0.6 version) and taking concentrations of Poloxamer 407 (X1) and HPMC K4M (X2) as independent variables. The gelling temperature, gel strength, and percentage of drug diffused after 8 h were taken as dependent variables. The software provided an optimized formulation, with 16.50% of X1 and 0.2% of X2 with the highest desirability. An in vivo drug retention time study was performed for the optimized formulation in Wistar rats. The results of the optimization process demonstrated that the selected gel formulation exhibited desirable characteristics, including gelation near body temperature, good gel strength, suitable viscosity, and sustained drug release. The optimized formulation displayed significantly higher drug retention, lasting about 5 h, versus the plain poloxamer gel formulation. Hence, it was concluded that the optimized formulation will remain affixed at the site of application for a significant time after intranasal administration and consequently sustain the release of the drug. The optimized formulation was found to be stable during the stability studies. The developed dosage form may improve patient compliance, enhance nasal drug residence, and offer sustained drug release. However, further clinical studies are necessary to validate these findings.

Cutaneous Pharmacokinetics of Topically Applied Novel Dermatological Formulations.

Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.

Design, preparation, and in vitro evaluation of gastroretentive floating matrix tablet of mitiglinide.

The present research is focused on developing floating matrix tablets of mitiglinide to prolong its gastric residence time for better absorption. Gastroretentive tablets were prepared using a direct compression technique with hydroxypropyl methylcellulose K15M (HPMC K15M) and sodium alginate as matrix-forming polymers and sodium bicarbonate as the gas-forming agent. A 32 full factorial design was adopted to optimize the flotation and release profile of the drug. The concentration of HPMC K15M and sodium alginate were taken as the independent variables, and the floating lag time, time required for 50% drug release, and time required for 90% drug release were taken as dependent variables. The compatibility between drug and excipients was assessed by Fourier transform infrared (FTIR) spectroscopy. The prepared tablets were evaluated for different parameters such as hardness, friability, drug content, floating time, in vitro dissolution, and stability. Dissolution data were analyzed using various kinetic models to ascertain the mechanism of drug release. Finally, a radiographic study was conducted to estimate the retention time of the optimized floating matrix tablets of mitiglinide inside the body. The results revealed that all the physical properties of the developed formulations were within standard limits. The formulation M3, with the maximum amount of both independent variables, was considered to be the optimized formulation based on the desirability value. In addition, the optimized M3 formulation showed stability for over 6 months, as evidenced by insignificant changes in lag time, drug release pattern, and other physical properties. Furthermore, radiographic examination indicated that the tablets remained afloat in gastric fluid for up to 12 h in the rabbit's stomach. In conclusion, the developed floating matrix tablet of mitiglinide could be regarded as a promising formulation that could release the drug in the stomach at a controlled rate and, hence, offer better management of type II diabetes.

Application of D-Optimal Mixture Design in the Development of Nanocarrier-Based Darifenacin Hydrobromide Gel.

BACKGROUND: Darifenacin hydrobromide, a BCS Class II drug, is poorly bioavailable due to extensive first-pass metabolism. The present study is an attempt to investigate an alternative route of drug delivery by developing a nanometric microemulsion-based transdermal gel for the management of an overactive bladder. METHODS: Oil, surfactant, and cosurfactant were selected based on the solubility of the drug, and surfactant: cosurfactant in surfactant mixture (Smix) was selected at a 1:1 ratio as inferred from the pseudo ternary phase diagram. The D-optimal mixture design was used to optimize the o/w microemulsion wherein the globule size and zeta potential were selected as dependable variables. The prepared microemulsions were also characterized for various physico-chemical properties like transmittance, conductivity, and TEM. The optimized microemulsion was gelled using Carbopol 934 P and assessed for drug release in vitro and ex vivo, viscosity, spreadability, pH, etc. RESULTS: Drug excipient compatibility studies showed that the drug was compatible with formulation components. The optimized microemulsion showed a globule size of less than 50 nm and a high zeta potential of -20.56 mV. The ME gel could sustain the drug release for 8 hours as reflected in in vitro and ex vivo skin permeation and retention studies. The accelerated stability study showed no significant change in applied storage conditions. CONCLUSION: An effective, stable, non-invasive microemulsion gel containing darifenacin hydrobromide was developed. The achieved merits could translate into increased bioavailability and dose reduction. Further confirmatory in vivo studies on this novel formulation, which is a cost-effective & industrially scalable option, can improve the pharmacoeconomics of overactive bladder management.

INSULIN GLARGINE 300 U/ML IS ASSOCIATED WITH LESS WEIGHT GAIN WHILE MAINTAINING GLYCEMIC CONTROL AND LOW RISK OF HYPOGLYCEMIA COMPARED WITH INSULIN GLARGINE 100 U/ML IN AN AGING POPULATION WITH TYPE 2 DIABETES.

OBJECTIVE: Assess efficacy, hypoglycemia, and weight gain in patients with type 2 diabetes (T2D) treated with insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) across different age groups. METHODS: Pooled data were generated for patients randomized to Gla-300 or Gla-100 in the EDITION 2 (NCT01499095) and 3 (NCT01676220) studies. In 4 age groups (<55, ≥55 to <60, ≥60 to <65, ≥65 years), glycated hemoglobin A1C (A1C), percentage of patients reaching A1C <7.5% (58 mmol/mol), weight change, confirmed hypoglycemia (blood glucose ≤70 mg/dL), and/or severe hypoglycemia (events requiring third-party assistance) were analyzed with descriptive statistics and logistic, binomial, and analysis of covariance regression modeling. RESULTS: A1C reductions from baseline and proportions of patients at target were similar for Gla-300 and Gla-100 across all age groups at 6 and 12 months, but hypoglycemia incidence and event rate were lower with Gla-300 at 6 (both P<.001) and 12 months ( P<.001 and P = .005, respectively). Patients on Gla-300 gained less weight than those on Gla-100 at 6 ( P = .027) and 12 months ( P = .021). Changes in weight and daily weight-adjusted insulin dose decreased with increasing age at 6 ( P<.001 and P = .017, respectively) and 12 months ( P<.001 and P = .011, respectively). CONCLUSION: Older patients with T2D may benefit from treatment with Gla-300, which is associated with a lower hypoglycemia rate and less weight gain with similar efficacy compared with Gla-100. ABBREVIATIONS: A1C = glycated hemoglobin A1C BMI = body mass index Gla-100 = insulin glargine 100 U/mL Gla-300 = insulin glargine 300 U/mL OAD = oral antidiabetes drug T2D = type 2 diabetes.

Chronic Obstructive Pulmonary Disease in Post-acute/Long-term Care Settings: Seizing Opportunities to Individualize Treatment and Device Selection.

INTRODUCTION: The burden of chronic obstructive pulmonary disease (COPD) in post-acute/long-term care (PA/LTC) settings is high, and many patients do not receive guideline-recommended care. METHODS: An interprofessional expert panel of PA/LTC professionals convened to discuss the unmet medical needs in patients with COPD in PA/LTC settings, and to make recommendations for the assessment of COPD patients to individualize the selection of maintenance treatment. RESULTS: Unmet needs observed in patients with COPD are described in addition to new tools for assessing individual patient abilities and appropriate device selection for maintenance treatment. CONCLUSION: COPD management in PA/LTC settings needs to be reevaluated and updated to help reduce exacerbations, hospitalizations, and readmissions.

Screening Tool of Older Person's Prescriptions/Screening Tools to Alert Doctors to Right Treatment Medication Criteria Modified for U.S. Nursing Home Setting.

OBJECTIVES: To develop a set of prescribing indicators measurable with available data from electronic nursing home (NH) databases by adapting the European-based 2014 Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tools to Alert Doctors to Right Treatment (START) criteria of potentially inappropriate and underused medications for the U.S. DESIGN: A two-stage expert panel process. In the first stage, the investigator team reviewed 114 criteria for compatibility and measurability. In the second stage, an online modified e-Delphi (OMD) panel was convened to rate the validity of criteria, and two webinars were held to identify criteria with highest relevance to U.S. NHs. PARTICIPANTS: Seventeen experts with recognized reputations in NH care participated in the e-Delphi panel and 12 in the webinar. MEASUREMENTS: Compatibility and measurability were assessed by comparing criteria with U.S. terminology and setting standards and data elements in NH databases. Validity was rated using a 9-point Likert-type scale (1 = not valid at all, 9 = highly valid). Mean, median, interpercentile ranges, and agreement were determined for each criterion score. Relevance was determined by ranking the mean panel ratings on criteria that reached agreement; the webinar participants reviewed and approved half of the criteria with the highest mean values. RESULTS: Fifty-three STOPP/START criteria were deemed to be compatible with the U.S. NH setting and measurable using data from electronic NH databases. E-Delphi panelists rated 48 criteria as valid for U.S. NHs. Twenty-four criteria were deemed to be most relevant, consisting of 22 measures of potentially inappropriate medications and two measures of underused medications. CONCLUSION: This study created the first explicit criteria for assessing the quality of prescribing in U.S. NHs.

Sliding Scale Insulin vs Basal-Bolus Insulin Therapy in Long-Term Care: A 21-Day Randomized Controlled Trial Comparing Efficacy, Safety and Feasibility.

INTRODUCTION: Sliding scale insulin (SSI) therapy remains a common means of insulin therapy in long-term care (LTC) for the management of type 2 diabetes mellitus, despite current recommendations not supportive of the form of therapy today. Lack of randomized trial data on the efficacy and safety of basal-bolus insulin (B-BI) therapy in nursing home residents may have precluded this form of insulin administration in the LTC setting. Our study is a comparison of the efficacy of SSI (control) and B-BI (intervention) therapies during a 21-day intervention trial in older nursing home residents. METHODS: Fourteen LTC facilities in the US participated; 110 residents with type 2 diabetes volunteered to participate; 35 failed inclusion criteria, 75 signed informed written consent, and 11 were discharged to home/hospital or withdrew consent; data from 64 participants are reported. Recent fasting blood glucose (FBG), hemoglobin A1c, and chemistries were obtained. Four glucose readings (prior to breakfast, lunch, dinner, and bedtime), oral antiglycemic drug, and insulin doses and changes, and all adverse events/serious adverse events, both those related to glucose control [hypoglycemic (<70 mg/dL) and hyperglycemic (>200 mg/dL) episodes] and those unrelated, were recorded daily. Patients were randomized to either remain on SSI or be shifted to the B-BI group. RESULTS: Nursing home residents 80 ± 8 (standard deviation) years, 66% female participated; Control and Intervention participants had similar age, gender, race distributions, comorbidity, and 3-day average pretrial FBG levels (all P > .05). At study end, B-BI volunteers had significantly lower 3-day average FBG levels vs pretrial (P = .0231) while SSI participants had no change in 3-day average FBG (P > .05). During the trial, participants from both groups had similar rates of hypoglycemia, hyperglycemia, other adverse events, and hospitalizations (serious adverse events) unrelated to glucose control (all P > .05). CONCLUSIONS: B-BI therapy produced significantly lower average FBG levels after 21 days compared with SSI therapy; both groups had similar rates of hypo- and hyperglycemia. Switching to B-BI therapy is feasible, safe, and effective in the LTC setting.

Efficacy and safety of insulin glargine compared to other interventions in younger and older adults: a pooled analysis of nine open-label, randomized controlled trials in patients with type 2 diabetes.

OBJECTIVE: Elderly patients with type 2 diabetes mellitus (T2DM) present therapeutic challenges related to co-morbidities, treatment adherence, and safety. This study examines the efficacy and safety of insulin glargine compared to other glucose-lowering interventions in younger and older adults. METHODS: In this pooled analysis of 24-week data from nine prospective open-label, multicenter, phase 3/4, two-arm, parallel-group, randomized controlled trials, patients with T2DM aged 18-80 years received insulin glargine (used as a basal insulin regimen) or comparators (including rosiglitazone, pioglitazone, insulin lispro, insulin lispro 75/25, NPH insulin, NPH insulin 30/70, and lifestyle/dietary measures). Endpoints included change from baseline to week 24 in: glycated hemoglobin; fasting plasma glucose; body weight; body mass index; insulin dose; incidence of nocturnal, daytime, or any hypoglycemia. Results were stratified by age (<65, ≥65, 65-74, and ≥75 years) and treatment (insulin glargine or comparator). RESULTS: A total of 2,938 patients were included (2,263 aged <65 years, 675 aged ≥65 years). Similar levels of glycemic control were achieved in both younger (<65 years) and older (≥65 years) patients with T2DM. Insulin glargine was associated with better glycemic control and a reduced incidence of daytime and any hypoglycemia versus comparator interventions in both younger and older T2DM patients. CONCLUSION: This analysis suggests that insulin glargine may represent a safe option to improve glycemic control in older patients with T2DM.

The role of cognitive impairment in the use of the Diskus inhaler.

BACKGROUND AND PURPOSE: Drugs delivered by metered-dose inhalers and dry powder inhalers (DPIs) are a mainstay in the treatment of chronic lung disease; however, previous studies suggest cognitive impairment hinders proper use of inhalers. The purpose of this study was to determine the relationship between the score on the Mini-Mental State Exam (MMSE) and the ability of nursing facility residents to complete the steps required for proper use of a multiunit-dose DPI (Diskus). METHODS: Nursing facility residents who had never used a multiunit-dose DPI (Diskus), who scored between 10 and 24 inclusive on the MMSE, and who were able to hold a breath for 10 seconds were recruited for an observational study to test their ability to use a placebo-loaded Diskus when supervised and assisted by personnel trained in the proper use the Diskus. Ability to use the DPI was assessed by the Diskus Evaluation Rating Scale (DERS), an instrument developed specifically for this study. Possible scores on the DERS ranged from 0 to 19, with a score of 0 indicating no limitations in any of the steps involved in using the Diskus and 19 indicating inability to do any of the steps after 3 supervised attempts. RESULTS: Forty Diskus-naïve nursing facility residents (86 ± 9 years of age; 32 women) with MMSE scores between 10 and 24 inclusive and the ability to hold a breath for 10 seconds were enrolled in the study. Mean MMSE scores were 17.4 ± 4.2, whereas the mean score on the DERS was 5.1 ± 3.2 (range 1-16). After controlling for age, gender, and education, a significant inverse relationship was noted between scores on the MMSE and the DERS such that for every 1-point increase on the MMSE, the subject's DERS score decreased by 0.345 points (P = .003). Overall, 38 of the 40 subjects with MMSE scores between 10 and 24 inclusive were able to use the Diskus successfully. CONCLUSION: For MMSE scores, the better the performance on the MMSE, the better the performance on the DERS. More important, 95% of the subjects in this study could use the Diskus successfully when properly supervised. In contrast to earlier studies, these findings suggest that a multiunit-dose DPI can be prescribed as one component of the regimen for chronic lung disease in patients with substantial cognitive impairment.

An open-label, randomized, multicenter, controlled study of epoetin alfa for the treatment of anemia of chronic kidney disease in the long term care setting.

OBJECTIVE: To evaluate the safety and efficacy of epoetin alfa administered in extended-dosing intervals to a target hemoglobin (Hb) level not exceeding 12.0 g/dL for the treatment of anemia in subjects with chronic kidney disease (CKD) not on dialysis. DESIGN: An open-label, randomized, multicenter, controlled study consisting of a 1-week screening phase and a 26-week open-label treatment phase. SETTING: Twenty-seven long term care (LTC) facilities in the United States. PARTICIPANTS: Subjects with CKD who were not receiving dialysis, who had not received an erythropoiesis-stimulating agent for 8 weeks before screening, and whose Hb levels were lower than 11.0 g/dL at screening were eligible. INTERVENTION: In the epoetin alfa group, subjects were administered 20,000 international units epoetin alfa subcutaneously every 2 weeks (Q2W). Dosing was based on the Hb concentration measurement obtained by HemoCue Hb201+System (Quest Diagnostics; Madison, NJ) at the time of the scheduled dose. When the Hb concentration was 11.0 to 11.5 g/dL on 2 consecutive biweekly measurements, the dose was doubled and administered on the day that the second consecutive measurement was obtained. The dosing interval was then extended to every 4 weeks (Q4W). Subjects in the standard of care (SOC) group received treatment for their anemia according to the practice of the LTC facility. MEASUREMENTS: Study visits were every 2 weeks, at which time blood was drawn and used for efficacy analysis. Measurements included: the Hb concentration change from baseline to the end of the study; the proportion of subjects who achieved an Hb response (defined as 2 consecutive Hb measurements at least 1.0 g/dL greater than baseline or 2 consecutive Hb measurements ≥11.0 g/dL at any time during the study); the time to the Hb response; the proportion of subjects who received a transfusion and the number of units of transfused; the proportion of epoetin alfa-treated subjects converting to Q4W dosing; and the proportion of subjects who converted to Q4W dosing and remained on Q4W dosing through the end of the study. RESULTS: A total of 157 subjects were randomized: 118 subjects to the epoetin alfa group and 39 to the SOC group. The mean change in Hb was significantly greater in the epoetin alfa group (0.9 g/dL) compared with the SOC group (0.3 g/dL) (P = .006). A significantly greater percentage of subjects achieved a Hb response in the epoetin alfa group (85.1%) compared with the SOC group (53.8%) (P < .001). The time to achieve a Hb response was significantly shorter in the epoetin alfa group (41 days) than in the SOC group (114 days) (P < .0001). There were no transfusions in the SOC group, whereas 4 subjects (3.5%) required transfusions in the epoetin alfa group. Of the 114 subjects receiving epoetin alfa, 33 (28.9%) subjects were converted to Q4W dosing, and all subjects who converted were able to be maintained on this schedule. CONCLUSIONS: The administration of epoetin alfa in extended-dosing intervals of Q2W followed by Q4W was safe and effective in the treatment of anemia in subjects with CKD who reside in LTC facilities.

Differences in diabetes management of nursing home patients based on functional and cognitive status.

OBJECTIVES: To describe practice patterns regarding diabetes management among nursing home (NH) physicians and to identify variation in this practice based on patient characteristics. DESIGN: Mailed survey. PARTICIPANTS: Nursing home physicians from the American Medical Directors Association (AMDA) Foundation Long-Term Care Research Network (n = 142), as well as other members of AMDA who were Certified Medical Directors (CMD) (n = 68) and members who were not CMD certified (n = 45). Response rates to the survey were 51%, 33%, and 23%, respectively. MEASUREMENTS: Physician and facility characteristics were queried. Responses to 12 items pertaining to diabetes management and 5 items pertaining to use of specific oral diabetes medications were evaluated in the context of 3 different patient profiles that reflected different combinations of functional and cognitive impairment. Responses were based on the physicians' perception of how they manage diabetes under these specified patient profiles. RESULTS: Responses from members of the Research Network indicated highly significant variability (P < .01) between the 3 patient profiles for all of the 12 management items. Ordering a special diet, monitoring lipid panel, and ordering routine ophthalmology was less likely for the patient profile with both functional and cognitive impairment (P < .01). These differences among the patient profiles for these 3 interventions were present in the responses from all 3 categories of physicians (Research Network, CMD, and non-CMD members of AMDA). There was no statistically significant variability among the 3 patient profiles for any of the 3 physician groups regarding the likelihood of using of any of the 5 classes of oral diabetic medications. Non-CMD physicians were more likely to have less NH experience; otherwise, there were no differences among the 3 physician groups. CONCLUSIONS: Nursing home physicians appear to alter the approach to diabetes management based on the functional and/or cognitive status of the patient. This was particularly true for those physicians who were members of the AMDA Foundation Research Network. These findings have implications for initiatives designed to guide clinical practice as well as efforts by regulatory bodies to evaluate appropriate care. Further research is needed to measure the actual impact of different approaches to diabetes management on relevant outcomes in this population.