Prolonged-release Formulation Research Articles

Effect over coagulation and fibrinolysis parameters of a prolonged release 24 + 4 daily use regime contraceptive formulation containing 2 mg dienogest/0.02 mg ethinylestradiol

Background A prolonged release combined oral contraceptive (COC) pill, containing 2 mg dienogest (DNG)/0.02 mg ethinylestradiol (EE) in a 24 + 4 daily dosing regimen has recently been approved in Europe. Objective To determine if this COC impacts coagulation and fibrinolytic factors in comparison to an immediate release COC containing 3 mg drospirenone (DRSP)/0.02 mg EE. Method Forty-four patients received the novel product, and forty-seven the comparator (immediate release formulation) during nine complete cycles. Coagulation and fibrinolytic parameters were evaluated: activated protein C resistance ratio, Antithrombin III (AT III), C-reactive protein, Factor VII, Factor VIII, and D-Dimer. Results Compared to baseline, at the end of the study both groups displayed significantly higher mean values for AT III: 1.06 mg/mL (standard deviation [SD], 95% CI, 0.98–1.15) for the DNG/EE formulation and 1.04 mg/mL (SD 95% CI, 0.96–1.12) for the comparator (p = 0.0006 and p = 0.0009, respectively). D-dimer showed a non-significant slight reduction in the DNG/EE group, from 276.62 ng/mL (SD, 95% CI, 228.92–334.26) before treatment to 243.98 ng/mL (SD, 95% CI, 192.45–309.31) ng/mL after treatment. Contrarily, the comparator displayed a non-significant rise in D-dimer values from 246.46 ng/mL (SD, 95% CI, 205.44–295.66) ng/mL to 275.30 ng/mL (SD, 95% CI 219.21–345.75; p = 0.4520). All other parameters showed no significant differences before and after the treatment for both groups. Conclusion The COC 2 mg DNG/0.02 mg EE was not associated with any meaningful changes in the analyzed coagulation and fibrinolytic parameters indicating that a prolonged release formulation does not impact on these factors. Clinical trial registry EudraCT: 2019-0018-77-97

Tragacanth Gum/Trimethyl Chitosan‐Derived Polyelectrolyte Complex as Potential Carriers in Drug Delivery Applications

ABSTRACTA three‐step procedure described in the literature has been used to create N,N,N‐trimethyl Ct a chitosan derivative that is extremely soluble in water. By combining two polymers in aqueous media, this derivative and tragacanth gum were able to form a new polyelectrolyte complex. The TGA, FTIR, and DSC analysis established the development of TMC/XG‐PEC. SEM was used to describe the TMC/TG‐PEC's surface morphology. The features of diffusion and swelling, such as the theoretical equilibrium ratio, initial swelling rate constant, and the process of water transportation into TMC/TG‐PEC, were established. The TMC/TG‐PEC swelling is seen to be pH‐dependent. It swells in the subsequent order: pH 7.4 > 6.8 > 1.2. At pH 1.2, 6.8, and 7.4, the TMC/TG‐PEC swelling ratio was found to be 6.5, 7.7, and 9.6 g/g, respectively. The second‐order kinetics of the swelling process is indicated by the linearity of the plot “t/SR” versus “t”. The TMC/TG‐PEC's n values under various pH circumstances ranged from 0.12 to 0.16, suggesting the Fickian water transport mechanism. The utility of complex as a matrix for KP formulations for sustained‐release tablets was investigated. It was discovered that 90.5% of KP was loaded into PEC. There is evidence that pH influences how much medicine is released. When the medium's pH was altered from acidic to neutral, the KP release was considerably boosted. The TMC/TG‐PEC demonstrated a maximum drug release of 7% in a pH 1.2 medium and between 85% and 90% in a pH 7.4 medium, demonstrating the TMC/TG‐PEC's potential as a matrix substance for the drug's prolonged release formulations of KP. The Fickian drug transport mechanism was indicated by the release exponent n, which was less than 0.5.

A Phase3, Open-Label, Single-Arm Trial of the Efficacy and Safety of Triptorelin 6-Month Formulation in Chinese Children with Central Precocious Puberty.

This phase3 study assessed the efficacy, safety, and pharmacokinetics of the 6-month prolonged release (PR) formulation in Chinese children with central precocious puberty (CPP). In this open-label study (NCT05029622), Chinese children (girls < 9years, boys < 10years) received two doses of triptorelin pamoate 22.5mg (day1 and month6). Primary endpoint was the proportion at month6 with luteinizing hormone (LH) suppression (stimulated peak LH ≤ 5IU/L after gonadotropin-releasing hormone stimulation). Secondary endpoints included safety assessments, hormone level changes, and clinical parameters from baseline. Overall, 66 children completed the study (93.9% girls; median age 8.0 [range 5-9] years). At month6, all patients had LH suppression; this was maintained at month12 in 98.5% of patients. Mean basal and peak LH and follicle-stimulating hormone levels were suppressed throughout follow-up. All patients at months3 to 12had sex hormone suppression to prepubertal levels. Stable or reduced breast development was seen for 98.4% and 93.5% of girls at month6 and 12, respectively; all boys had regression or stable genital development until month12. Compared with baseline (9.82cm/year), mean growth velocity was 5.88cm/year at month6 and 5.17cm/year at month12. Mean bone age/chronological age ratio decreased from 1.27 at baseline to 1.23 and 1.21 at month6 and 12, respectively. In girls, 64.5% showed decreased uterine length at month6 and 12 versus baseline, while 75.0% of boys showed stable testicular volume versus baseline. Thirteen patients (19.7%) had 22 drug-related treatment emergent adverse events (TEAEs); no grade ≥ 3 TEAEs were reported. The efficacy and safety profile of triptorelin 6-month PR in Chinese children with CPP was consistent with data previously reported in non-Chinese children with CPP, supporting this as a viable treatment option for Chinese children with CPP. Trial registration:ClinicalTrials.gov identifier, NCT05029622.

Liposomal bupivacaine for sleeve gastrectomy is associated with improved opioid outcomes and lower odds of opioid use disorder: claims-based analysis

BackgroundPatients undergoing bariatric surgery may be at increased risk for postsurgical opioid dependence, highlighting a need for opioid-sparing anesthesia. ObjectivesLiposomal bupivacaine (LB), a prolonged release formulation of bupivacaine, may improve postoperative pain management and reduce postsurgical opioid use. This retrospective claims-database study investigated the effects of LB versus non-LB analgesia on opioid use and healthcare resource utilization (HCRU) in patients receiving laparoscopic sleeve gastrectomy (SG). SettingRetrospective study using the IQVIA linkage claims database. MethodsData from patients aged ≥18 years and free of opioid prescriptions within the prior 6 months undergoing inpatient laparoscopic SG between January 1, 2016, and December 31, 2019, were analyzed. Outcomes included perioperative opioid use in oral morphine milligram equivalents (MMEs), opioid-related adverse events (ORAEs), postdischarge HCRU, continued (>2 weeks to 3 months postdischarge) and persistent (4–6 months postdischarge) opioid use, and opioid use disorder (OUD) at 6 months. ResultsOf 4298 patients (2149 in each cohort), LB was associated with significantly fewer perioperative opioids (100.53 versus 155.48 MMEs; mean difference, −54.95 [95% confidence interval (CI), −64.46, −45.45]; P < .0001), lower rates of in-hospital ORAEs (9.63% versus 13.82%; odds ratio [OR], .67 [95% CI, .55, .80]; P < .0001), significantly lower incidence of OUD (.09% versus .51%; OR, .18 [95% CI, .04, .82]; P = .026), shorter hospital length of stay (P = .0008), and significantly lower odds of 30-day postdischarge hospital readmissions (P = .025) versus non-LB analgesia. ConclusionsLB reduced opioid use, in-hospital ORAEs, OUD, and hospital readmissions after laparoscopic SG.

Glatiramer acetate in situ forming gel, a new approach for multiple sclerosis treatment.

Glatiramer acetate (GA), a commonly used treatment for multiple sclerosis (MS), requires long-term frequent injections to ensure its effectiveness. This often leads to adverse effects, patient noncompliance, and economic inefficiency. In this study, poloxamer, as a thermosensitive polymer modified by chitosan (CS) and hyaluronic acid (HA), was employed to prepare an in situ forming prolonged release formulation of GA to overcome the problems derived from frequent repeated injections and to enhance the patient compliance. The sol-gel formulation was produced through a cold method and optimized using design of experiments. The final product was characterized in terms of gelation time (GT), rheological behaviors, morphological properties, assay, and drug release kinetics. The in vitro release rate of GA during the first 24 h was quite rapid, but then it continued at a slower rate of 0.05 mg ml-1h-1. The in vivo analysis after the subcutaneous injections showed lower levels of IL-5, IL-13, and uric acid (UA) in mice treated with the gel formulation compared with those receiving free GA in the first few days. However, after 10 days, significantly higher concentrations were detected, which continued to increase slowly. It can be concluded that the designed thermosensitive sol-gel formula is capable of extending the effectiveness of GA and can be considered as a promising sustained release formulation for the treatment of MS.

P.182: Real world bioequivalence of prolonged release formulations of tacrolimus in renal transplant recipients. Is a determination needed before switching among them?

P.182: Real world bioequivalence of prolonged release formulations of tacrolimus in renal transplant recipients. Is a determination needed before switching among them?

Melatonin Bioavailability After Oral Administration of a New Delayed-Release Form in Healthy Male Volunteers.

Two main types of galenic formulation, immediate release and prolonged release, have been developed to optimize melatonin bioavailability. We recently described the kinetic profile of a prolonged-release form generating a peak of plasma melatonin 1 h (Tmax) after intake, followed by a prolonged decay over time. We have developed a new oral form of melatonin with the aim of producing a melatonin peak several hours after intake. The objective is to investigate melatonin bioavailability after administration of this new delayed-release form (DR form). In this single-centre open-label study, 12 healthy male volunteers received one tablet of the DR form containing 1.9 mg melatonin, 10 mg zinc and 200 mg lemon balm extract (Melissa officinalisL aerial parts). Blood samples were collected for 12 h, beginning at 8:00 am. Plasma concentrations of melatonin and 6-sulfatoxymelatonin (6-SMT), the main hepatic melatonin metabolite, were determined by radioimmunoassay. A progressive increase in plasma melatonin concentrations was observed from 20 min and a peak about 3 h after intake (Cmax 740 ± 824 pg/mL; Tmax 179 ± 60min). Concentrations remained high between 140 and 220 min, the concentration remaining physiologically significant (over 100pg/mL) up to 7 h after intake. The DR form was well tolerated. The melatonin release profile was consistent with what was anticipated for the DR form. The DR form generated a 2 h delayed Tmax compared with a prolonged-release form previously evaluated. This suggests that the DR form is suitable for the treatment of certain sleep disorders such as short sleep duration or early awakening. Registration number: NCT05419466.

#2830 Treatment of primary and secondary distal renal tubular acidosis with a prolonged release formulation of potassium citrate and potassium bicarbonate

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is a rare kidney disease. It can be inherited, i.e. primary (PdRTA), or acquired i.e. secondary (SdRTA). Secondary dRTA is more prevalent in the adult population and is usually caused by underlying autoimmune diseases (e.g. Sjogren syndrome). Both forms of dRTA are characterized by alkaline urine, kidney stone formation, nephrocalcinosis, chronic kidney disease, while metabolic acidosis can be variable. The treatment is based on the substitution of alkali substances. Our clinical study aims to describe a cohort of adult dRTA patients (both PdRTA and SdRTA) treated for 18 months by a prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate, in terms of electrolyte disbalance correction, metabolic control, nephrolithiasis complications and kidney function. Method Data from seven patients with dRTA (3 with PdRTA and 4 with SdRTA, mean age 44 years, women 71%) taking prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate in our center, were retrospectively collected and analyzed. The patients were previously treated with alkalizing agents (mostly sodium bicarbonate and potassium citrate). Patients were followed up for up to 18 months after inducing prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate was introduced. Kidney function, metabolic acidosis control (serum bicarbonate), serum electrolytes, urinary calcium excretion, and urinary citrate were measured. Nephrolithiasis complications and patient compliance were also evaluated. The urine and blood samples were analyzed two weeks after introducing the new drug and every 3 months afterward. Data are presented as mean ± standard error of the mean. Student T-test was used to calculate p values. Results The patients were taking on average 48 mEq of the drug (range 32-72 mEq), the dosage remained the same during the follow-up period (p = 0.365). The average follow-up period was 10 months (range 3-18 months). The metabolic acidosis was well controlled (serum bicarbonate was 24 ± 1.71 mmol/l at baseline, 24.4 ± 1.5 mmol/l at the end of follow-up, p = 0.680). Kidney function remained stable (GFR 73.5 ± 22.67 ml/min/1.73 m2 at baseline, 73 ± 22.69 ml/min/1.73 m2 at the end, p = 0.977). Serum potassium was also well controlled (4.07 ± 0.45 mmol/l at baseline, 4.32 ± 0.40 mmol/l at the end, p = 0.344), as well as calcium in 24-hour urine (2.75 ± 0.59 mmol/24-hour urine at baseline, 2.35 ± 0.12 mmol/24-hour urine at the end, p = 0.222). Urinary citrate levels (calculated as citrate/creatinine ratio) remained in the lower part of the reference range during the follow-up period (103.3 ± 68.3 mmol/mol at baseline, 114.6 ± 64.9 mmol/l at the end, p = 0.775). Two patients had acute renal colic caused by nephrolithiasis, without the need for surgical intervention. Safety and adherence to treatment remained good with no gastrointestinal side effects, one patient discontinued the drug due to headaches. Conclusion Our data show that treatment with a prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate in adult dRTA patients can achieve good control of metabolic acidosis and electrolyte disbalance with stable kidney function without the need to escalate the dose of the drug during the follow-up period. The adherence to the treatment remained good with no gastrointestinal side effects.

Development of Physiologically Based Biopharmaceutical Model (PBBM) for Felodipine Prolonged-Release Tablet as useful tool for prediction of formulation.

Physiologically Based Biopharmaceutical Models (PBBMs) are advanced tools that integrate physiological parameters with drug-specific properties to simulate drug behavior in vivo. In this study, we present the development of a PBBM specifically tailored for felodipine prolonged-release (PR) tablet formulations. Felodipine, a potent calcium channel blocker, is widely used for the treatment of hypertension and angina pectoris. Prolonged-release formulations aim to provide controlled drug release, ensuring sustained therapeutic effect with reduced dosing frequency and minimized adverse effects. Our PBBM incorporates key physiological processes such as gastrointestinal transit, drug dissolution, absorption, distribution, metabolism, and elimination. Data from in vitro dissolution studies, preclinical pharmacokinetics, and clinical observations are integrated to parameterize the model accurately. Special attention is given to the physicochemical properties of felodipine and the release characteristics of the PR tablet formulation. Validation of the PBBM is conducted against clinical pharmacokinetic data obtained from bioequivalence studies and population pharmacokinetic analyses of felodipine PR tablets. The model may demonstrate excellent predictive performance, accurately capturing plasma concentration-time profiles across different dosing regimens and patient populations. The developed PBBM provides valuable insights into the biopharmaceutical behavior of felodipine PR tablets, facilitating rational formulation design, dosage regimen optimization, and therapeutic individualization. It serves as a powerful tool for drug developers, regulatory agencies, and clinicians to enhance the efficiency and effectiveness of drug development and clinical pharmacotherapy

Formulation and Evaluation of Moxifloxacin Hydrochloride Loaded Cubosomal Gel for Ocular Delivery

This study aimed to develop and evaluate an ocular, prolonged-release cubogel formulation of moxifloxacin hydrochloride (MX) to treat conjunctivitis. Using glycerol monooleate and poloxamer 407 in varying concentrations, a cubosome containing the antibiotic MX was developed using a top-down approach. Further, by dispersing optimized cubosomes in a cold in-situ gelling system, MX cubogels were prepared. Following Higuchi's release kinetic model, formulations MA4, MA8, MA11, and MA14 released 95.84, 95.77, 97.45, and 97.68% of MX after 12 hours. The in-vitro corneal permeation study showed that the goat cornea absorbed 81% of MX cubogel than conventional formulations. From the results of antibacterial and histopathological studies, the selected formulations were safe for ocular administration. This study concluded that MX cubogel may be a suitable alternative to conventional eye drops due to its increased permeability and sustained release characteristics.&#x0D; Keywords: Conjunctivitis, Cubosome, Glycerol monooleate, Moxifloxacin hydrochloride Poloxamer 407

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Pregled lista i preporuka za zamenljivost lekova u izabranim evropskim zemljama

Generic substitution has been introduced in the healthcare systems of many countries to reduce the costs and ensure the continuity of drug market supply. Common and country-specific strategies on this topic have been presented for several European countries, as well as for the Republic of Serbia. The factors that need to be considered when assessing the interchangeability of medicines may be related to the medicine or the individual patient. Particular caution is required with narrow therapeutic index drugs, drugs with non-linear pharmacokinetics, antiepileptic drugs, medicines with prolonged release formulations, medicines administered in a specific way or with a medical device. Factors such as the different appearance of the medicines, excipients, packaging, indications, but also the patient's condition, age, concomitant diseases, pregnancy, hand function, vision, ability to swallow, and the patient's attitude towards the alternative medicines should also be taken into account. When substituting two generic medicines, it should be noted that those medicines may not be bioequivalent, since bioequivalence is confirmed between a generic medicine and a reference (usually original) medicine, and thus pose an additional risk to the patient's safety. Some countries have opted to form lists of interchangeable medicines and/or detailed guidelines regarding interchangeability to assist healthcare professionals in making decisions on drug substitution.

A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

Efficacy of Prolonged-Release Melatonin Administration in Elderly Patients With Treatment Resistant Insomnia: A Post-Hoc Analysis

Objective: Melatonin, both immediate and prolonged-release formulations, has been explored as an adjunctive treatment for insomnia, with prolonged-release melatonin demonstrating enhanced efficacy compared to its immediate-release counterpart. However, there remains a gap in understanding its effectiveness specifically in individuals with treatment-resistant insomnia, who continue to experience sleep difficulties despite using traditional hypnotic medications.Methods: An 8-week prospective, open-label, observational study was conducted on 115 patients aged 55 years or older with insomnia several years ago. This is a post-hoc analysis, which was performed on 63 out of 115 patients who were already taking hypnotics and still reported symptoms of insomnia. Per protocol (n=40) and last observation carried forward (LOCF) approaches (n=63) were used, assessing changes in sleep indicators after administering 2 mg of prolonged-release melatonin. Psychometric scales including Pittsburgh Sleep Quality Index (PSQI) and WHO-5 Well-Being Index were used for evaluation at baseline, week 4, and week 8.Results: The per protocol and LOCF analysis revealed substantial improvements in sleep latency, total sleep time, sleep efficiency, and total PSQI scores after 8 weeks of prolonged-release melatonin treatment. The LOCF analysis also revealed WHO-5 Well-Being Index significantly increased. Compared to prolonged-release melatonin monotherapy group with combination therapy group (adding prolonged-release melatonin to previous hypnotics) at baseline, 4 weeks, and 8 weeks after treatment, most variables did not differ between two groups in the per protocol and LOCF analysis. However, only WHO-5 Well-Being Index was higher in monotherapy group than in combination group at 4 weeks and 8 weeks after prolonged-release melatonin treatment in the per protocol analysis.Conclusion: Prolonged-release melatonin demonstrated notable efficacy in ameliorating sleep latency, duration, efficiency, and overall quality in treatment-resistant insomnia patients. The study highlights its potential as a treatment avenue for this challenging cohort, prompting further exploration into its benefits, particularly in improving overall well-being, and advocating for expanded research in this domain.

Dental Drug Delivery System used in Periodontitis

Periodontitis, a condition affecting the teeth’s supporting structures, affects people of all ages, ethnicities, races, and genders. There is a well-established link involving microbial infection and the progression of gum diseases and tooth cavities. There are different types of periodontal diseases caused by microbial infection. Aggressive periodontitis can be localized or generalized. Periodontal infection has been successfully treated with antibacterial medicines. The effectiveness of mechanical plaque debridement and regular use of topical and systemic medicines is limited due to a lack of access to infecting organisms into the periodontal tissues. Systemically administered drugs achieve effective concentration at the infected area, but only for a small period, necessitating multiple doses over extensive periods of time. Antimicrobials delivered locally have being studied to see if they can overcome the limits of conventional therapy. Anti-bacterial is delivered using prolonged release formulations. Anti-bacterial is increasingly being delivered at the infection site (periodontal pocket) through sustained release formulations. This review discusses the main drug delivery system used in periodontal disease, their advantages and evaluations. The usage of collagen dental cones after an infected tooth has been extracted is also discussed in this review. Periodontal regeneration, soft-tissue restoration, and wound healing are all aided by dental cones containing antibacterial and biodegradable polymers.

The role of tapentadol in cancer pain pharmacotherapy in patients with metastatic malignant disease.

The aim of this study was to establish the effects of prolonged formulation of tapentadol in combination with palliative radiotherapy on bone metastatic changes in oncology patients with primary breast cancer and proven bone metastases. The research was conducted as a prospective study at the Clinic for Oncology, University Clinical Center Nis, Nis, Serbia, during a three-month interval of monitoring the patients. The first group comprised 30 patients with mentioned malignancy for which tapentadol was prescribed, and they underwent palliative radiotherapy for bone metastatic changes. The second group comprised 30 patients with the same disease treated only with pain relief radiotherapy to metastatic changes. All the patients were interviewed using the Pain Detect questionnaire. Significantly more patients from the first group had severe pain in comparison to patients from the control group (χ2=16.596; p<0.001) at the second measurement and also at the third measurement (χ2=15.357; p<0.001). At the third measurement, pain with a neuropathic component was significantly more present in patients from the control group (χ2=8.541; p=0.014). There was a significant pain reduction in both groups - Tapentadol group (χ2=59.513; p<0.001) and control group (χ2=60.000; p<0.001) - and also a significant reduction of neuropathic pain component: Tapentadol group (χ2=56.267; p<0.001) and control group (χ2=60,000; p<0.001). There was a statistically significant positive correlation between tapentadol dose and pain intensity according to the numerical pain scale at all three measurements. Tapentadol prolonged-release formulation is an effective pharmacotherapy solution, along with palliative radiotherapy, for pain relief in patients with skeletal metastatic breast cancer. Palliative radiotherapy in these patients does not provide adequate neuropathic pain component relief.

Formulation and Evaluation of Microsponge Gel for Topical Delivery of Antifungal Drug

The quasi emulsion solvent diffusion technique was used to create the clotrimazole microsponges, which were eventually recognized as an efficient carrier for the topical delivery of the medicine. The characteristics of the created system were significantly affected by the drug:polymer ratio. It was discovered that microsponges made for prolonged release formulation were effective, and clotrimazole microsponges with gel produced results that were equivalent. Microsponge gel compositions that were prepared beforehand showed regulated medication release. It has been shown that microsponges can transport medications for topical antifungal therapy successfully. Given how well the formulations kept the medication on the skin, it appears that microsponge gel is a more effective drug delivery mechanism than ordinary gel.

Prolonged release pirfenidone pharmacokinetics is modified in cirrhosis GENESIS study

BackgroundIn both clinical and experimental trials, pirfenidone (PFD) showed anti-inflammatory and antifibrogenic effects. Considering the wide variation in hepatic functional reserve in patients with cirrhosis, we decided to learn more about the pharmacokinetics of a new formulation of prolonged release PFD in this population (PR-PFD), focusing on assessing changes on AUC0–∞, AUC0–t, and Cmax. MethodsIn this study, 24 subjects with cirrhosis were included: eight subjects with mild liver impairment (Child–Pugh A) and eight with moderate liver impairment (Child–Pugh B), and a third group of eight age-matched subjects without fibrosis. All participants were under fasting conditions before receiving orally two 600-mg tablets of a prolonged-release formulation of pirfenidone (PR-PFD) and remained in the clinical unit for 36 h after PR-PFD administration. Serial blood samples were collected after dosing (0.5-36 h). A validated high-performance liquid chromatography–mass spectrometry method was used to determine PFD plasma concentrations. ResultsThe exposure to PR-PFD was 3.6- and 4.4-fold greater in subjects with Child–Pugh A and Child–Pugh B than in subjects without cirrhosis, and Cmax was 1.6- and 1.8-fold greater in subjects with Child–Pugh B and Child–Pugh-A than in patients without cirrhosis, without significant differences between the two cirrhotic groups. PFD was well tolerated. ConclusionThe pharmacokinetic parameters of PR-PFD are significantly modified in patients with cirrhosis compared with those in controls, indicating that liver impairment should be considered in clinical practice.

Efficacy and Safety of Prolonged-Release Melatonin for Primary Insomnia in Elderly Patients

Objective: Insomnia, a prevalent sleep disorder affecting the elderly, necessitates effective and safe treatment options. This study explores the potential of the prolonged-release melatonin (Circadin&lt;sup&gt;®&lt;/sup&gt;) addressing insomnia in elderly patients.Methods: The 8-week prospective observational study involved 115 participants, assessing sleep parameters using the Pittsburgh Sleep Quality Index (PSQI) and WHO-5 Well-being Index. The prolonged-release melatonin (2 mg) was administered nightly, and assessments were conducted at baseline, 4 weeks, and 8 weeks.Results: Both per protocol and last observation carried forward (LOCF) analyses consistently revealed significant improvements in sleep latency, total sleep time, sleep efficiency, and overall well-being. Notably, sleep latency decreased after 4 and 8 weeks, while total sleep time and sleep efficiency increased, reflecting longer and more restful sleep. The WHO-5 Well-being Index exhibited noticeable enhancement. Adverse events, including dizziness and heartburn, were manageable. Despite a high dropout rate, this drug’s potential as an efficacious and safe treatment option for elderly insomnia patients was evident, aligned with prior research.Conclusion: The prolonged-release formulation’s resemblance to the natural circadian rhythm of melatonin release offers advantages over conventional medications. This study contributes to understanding the prolonged-release melatonin’s promise as a valuable therapeutic alternative, encouraging further investigation into its longterm effects and optimal implementation.