Fixed-dose Combination Products Research Articles

Pharmacokinetics of a Fixed-Dose Combination Product of Amlodipine, Losartan, Ezetimibe, and Rosuvastatin and Its Comparison with Co-administration of Four Individual Components in Healthy Participants.

This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (Cmax) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. This trial (NCT04322266) was retrospectively registered on 9 September 2019.

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation

Fixed-dose combination (FDC) products represent a novel, safe, and cost-effective formulation. Combined use of anticoagulant and antiplatelet medications is common among comorbid cardiovascular patients. This study aimed to formulate FDC tablets for Apixaban and Clopidogrel, as prophylaxis and treatment of thrombo-embolic events. FDC tablets were developed by combining small tablets of Immediate-Release Clopidogrel 75 mg and Extend-Release Apixaban 5 mg through direct compression and wet granulation. Particularly, Apixaban tablets were developed using design expert software, and various types and concentrations of polymers were entered. For Clopidogrel tablets, various diluents were used to develop the formulation. Then, the dissolution profile for each formula was studied. Finally, the optimized formulations were encapsulated within hard gelatin capsules. Apixaban formulation followed zero-order with super case Ⅱ transport mechanism as the dominant mechanism of drug release. The Apixaban drug release rate was affected by the type and concentration of the polymers in the formulation (P < 0.05). As the HPMC concentration was increased, Apixaban release was retarded. For, Clopidogrel, the formulated tablets with spray-dried lactose filler and sodium stearyl fumarate lubricant were found to be stable with good properties. In conclusion, the optimum formulation yielded Clopidogrel and extended-release Apixaban for 24 h with the desired in vitro drug dissolution.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Formulary Management of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists

&#x0D; Health Canada has approved 4 sodium-glucose cotransporter-2 (SGLT2) inhibitors (ertugliflozin, dapagliflozin, canagliflozin, and empagliflozin) and 5 glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide, liraglutide, dulaglutide, lixisenatide, and exenatide), with 5 fixed-dose combination products (SGLT2 inhibitors: dapagliflozin-metformin, canagliflozin-metformin, and empagliflozin-metformin; GLP-1 receptor agonists: liraglutide–insulin degludec and lixisenatide–insulin glargine).&#x0D; Data protection has ended for all SGLT2 inhibitors in Canada as well as their fixed-dose combinations. Eleven dapagliflozin generics are currently available, and there are several canagliflozin and empagliflozin generics under review at Health Canada. Patent protection has not expired for GLP-1 receptor agonists.&#x0D; There is heterogeneity in public drug program reimbursement criteria for each SGLT2 inhibitor and GLP-1 receptor agonist ranging from restricted to unrestricted benefit.&#x0D; This Environmental Scan highlights that as SGLT2 inhibitors and GLP-1 receptor agonists have matured, additional indications (heart failure, chronic kidney disease, weight management) have been added to their initial Health Canada–approved indication (type 2 diabetes mellitus). SGLT2 inhibitors are beginning to lose their exclusivity status and are experiencing generic competition.&#x0D;

Fixed-Dose Combination Formulations in Solid Oral Drug Therapy: Advantages, Limitations, and Design Features.

Whilst monotherapy is traditionally the preferred treatment starting point for chronic conditions such as hypertension and diabetes, other diseases require the use of multiple drugs (polytherapy) from the onset of treatment (e.g., human immunodeficiency virus acquired immunodeficiency syndrome, tuberculosis, and malaria). Successful treatment of these chronic conditions is sometimes hampered by patient non-adherence to polytherapy. The options available for polytherapy are either the sequential addition of individual drug products to deliver an effective multi-drug regimen or the use of a single fixed-dose combination (FDC) therapy product. This article intends to critically review the use of FDC drug therapy and provide an insight into FDC products which are already commercially available. Shortcomings of FDC formulations are discussed from multiple perspectives and research gaps are identified. Moreover, an overview of fundamental formulation considerations is provided to aid formulation scientists in the design and development of new FDC products.

Curcumin-Based Fixed Dose Combination Products for Cholesterol Management: A Narrative Review.

Curcumin, a polyphenol compound that belongs to a class of molecules known as curcuminoids, may interact with various biological macromolecules in the body, including proteins, nucleic acids, and lipids. Curcumin-based fixed-dose combination (FDC) products enhance curcumin stability and bioavailability for better clinical use in cholesterol management. Preclinical studies on curcumin and cholesterol are mostly positive. Obstacles are the variable composition of the many different curcumin-based FDC products, the lack of standards, and the limitation of the randomized controlled trials (RCTs) conducted for specific products. Once these downfalls have been addressed, curcumin-based FDC products have great potential for cholesterol management. They can supplement the uptake of statins, reducing their dosage for the same controlling effects or even replacing them.

Correlation of effectiveness and tolerability assessments from a pharmacy-based observational study investigating the fixed-dose combination of 400 mg ibuprofen plus 100 mg caffeine for the treatment of acute headache

IntroductionObservational studies are valuable for investigating correlations between patient-reported treatment outcomes. In this study, we report a secondary analysis of a published pharmacy-based observational (patient-centered “real-world” outcomes) study on experiences reported by patients who treated their headache with an over-the-counter analgesic.MethodsA pharmacy-based exploratory survey was conducted in German community pharmacies. Patients buying a fixed-dose analgesic combination product (400 mg ibuprofen + 100 mg caffeine; IbuCaff) to treat their headache were offered a questionnaire that contained—among others—questions about time to onset of pain relief (OPR), assessment of time to onset of pain relief (AOPR), assessment of efficacy and tolerability, and pain intensity 2 h after intake. A correlation analysis of the data was performed. Moreover, perceived treatment effects compared to other acute headache medications used in the past were collected.ResultsThe correlation between OPR and AOPR was high (Spearman rank correlation r = 0.594, p &amp;lt; 0.0001). Headache patients assessed the onset of analgesic action within 15 min as “very fast” and within 30 min as “fast”. The other readouts were correlated as well [assessment of efficacy and % pain intensity difference (%PID) at 2 h: r = 0.487; OPR/AOPR and %PID at 2 h: r = 0.295/0.318; OPR/AOPR and assessment of tolerability: r = 0.206/0.397; OPR/AOPR and assessment of efficacy: r = 0.406/0.594; assessment of efficacy and assessment of tolerability: r = 0.608; p &amp;lt; 0.0001 for all correlations]. Compared to previous treatments, most patients (&amp;gt;89%) assessed the speed of analgesic action, efficacy, and tolerability of IbuCaff as equal to or better than for the previous treatment.DiscussionHeadache patients assessed the onset of analgesia within 15 min as “very fast” and within 30 min as “fast”. Efficacy assessments for acute headache medication appear to be highly correlated.

Simultaneous determination of tramadol and paracetamol in human plasma using LC-MS/MS and application in bioequivalence study of ­fixed-dose combination

The study aimed to develop a sensitive and high-throughput liquid chromatography coupled with tandem mass spectrometry method to quantify concentrations of tramadol and paracetamol simultaneously in human plasma. Sample preparation involved single-step protein precipitation using methanol and two deuterated internal standards, tramadol D6 and paracetamol D4. Agilent Poroshell 120 EC-C18 (100 × 2.1 mm, 2.1 µm) analytical column was employed to achieve chromatographic separation. Detection was in positive ion multiple reaction monitoring mode. A tailing factor (Tf) of <1.2, separation factor (K prime) of >1.5 from the column dead time and signal-to-noise (S/N) ratio >10, were obtained for analytes and internal standards. The standard curve was linear over the concentration range of 2.5–500.00 ng/mL for tramadol and 0.025–20.00 μg/mL for paracetamol. A small injection volume of 1 µL, low flow rate of 440 µL/min and short analysis time of 3.5 min reduced the solvent consumption, analysis cost and system contamination. The results of method validation parameters fulfilled the acceptance criteria of bioanalytical guidelines. The method was successfully applied to a bioequivalence study of fixed-dose combination products of tramadol and paracetamol in Malaysian healthy subjects.

Assessing Polymorphic Purity of Rifampicin in Double and Triple-Drug Fixed-Dose Combination Products

First-line tuberculostatic agents, Rifampicin (RIF), Isoniazid (ISH), Ethambutol (ETB), and Pyrazinamide (PZA) are generally administered as a fixed-dose combination (FDC) for improving patient adherence. The major quality challenge of these FDC products is their variable bioavailability, where RIF and its solid state are key factors. In this work, the analysis of the impact of the polymorphism in the performance of RIF in RIF-ISH and PZA-RIF-ISH combined products was carried out by an overall approach that included the development and validation of two methodologies combining near-infrared (NIR) spectroscopy and partial least squares (PLS) to the further evaluation of commercial products.For NIR-PLS methods, training and validation sets were prepared with mixtures of Form I/Form II of RIF, and the appropriate amount of ISH (for double associations) or ISH-PZA (for triple associations). The corresponding matrix of the excipients was added to the mixture of APIs to simulate the environment of each FDC product. Four PLS factors, reduced spectral range, and the combination of standard normal variate and Savitzky-Golay 1st derivative (SNV-D’) were selected as optimum data pre-treatment for both methods, yielding satisfactory recoveries during the analysis of validation sets (98.5±2.0%, and 98.7±1.8% for double- and triple-FDC products, respectively). The NIR-PLS model for RIF-ISH successfully estimated the polymorphic purity of Form II in double-FDC capsules (1.02 ± 0.02w/w). On the other hand, the NIR-PLS model for RIF-ISH-PZA detected a low purity of Form II in triple FDC tablets (0.800 ± 0.021w/w), these results were confirmed by X-ray powder diffraction. Nevertheless, the triple-FDC tablets showed good performance in the dissolution test (Q=99-102%), implying a Form II purity about of 80% is not low enough to affect the safety and efficacy of the product.

Skin Cancer and Hydrochlorothiazide: Novel Population-Based Analyses Considering Personal Risk Factors Including Race/Ethnicity.

Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity. We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.5 million individuals, 2010-2018), a subcohort with health risk assessment respondents (415, 330), and Medicaid (509, 767, 2011-2017). Adults (aged 18+ years) entered the respective cohort with a first-filled prescription (cohort entry) for hydrochlorothiazide (the exposure of interest) or angiotensin-converting enzyme (ACE) inhibitors (the active comparator), with ≥12 months of continuous enrollment with medical/pharmacy coverage at baseline. We excluded those who used hydrochlorothiazide/ACE inhibitor (including fixed-dose combination products) 12 months before cohort entry and those with prior skin cancer, HIV, or organ transplant. We compared the risk for hydrochlorothiazide versus ACE inhibitor using multivariate proportional hazards regression. Baseline characteristics were similar, aside from more Black individuals among hydrochlorothiazide users (43.3% [95% CI, 43.0%-43.6%]) than ACE inhibitor users (28.1% [95% CI, 27.9%-28.3%]). The hazard ratio (95% CI) for nonmelanoma skin cancer related to hydrochlorothiazide (versus ACE inhibitor) was 0.96 (0.91-1.00) in the Commercial cohort, 1.01 (0.77-1.32) for the health risk assessment subcohort, and 1.33 (0.77-2.29) for Medicaid. For melanoma, the respective hazard ratios were 1.07 (0.95-1.20), 0.85 (0.43-1.67), and 0.93 (0.51-1.67), respectively. Our evaluation using 3 different approaches, including adjustment for race/ethnicity, did not establish a clear difference between hydrochlorothiazide and ACE inhibitor in terms of skin cancer risk.

A comprehensive strategy for the identification of biologics by liquid-chromatography–mass spectrometry for release testing in a regulated environment

Identification (ID) testing is a regulatory requirement for biopharmaceutical manufacturing, requiring robust, GMP-qualified assays that can distinguish the therapeutic from any other in the facility. Liquid Chromatography-Mass Spectrometry (LC-MS) is a powerful analytical tool used to identify and characterize biologics. While routinely leveraged for characterization, LC-MS is relatively rare in Quality Control (QC) settings due to its perceived complexity and scarcity of MS-trained personnel. However, employing LC-MS for identification of drug products has many advantages versus conventional ID techniques, including but not limited to its high specificity, rapid turn-around time, and ease of method execution. In this work, we outline the development and implementation of a comprehensive LC-MS based ID strategy for biologics release testing. Two main workflows (WFs) were developed: i) WF1, a subunit-based assay measuring the molecular weight of the light chain (LC) and heavy chain (HC) of an antibody upon reduction, and ii) WF2, intact mass measurement of the biologic upon N-deglycosylation by PNGase F. The proposed strategy is shown to be applicable for over 40 diverse model biologics including monoclonal antibodies (mAbs), biobetters such as antibody prodrugs/afucosylated mAbs, fusion proteins, multi-specific antibodies, Fabs, and large peptides, all with excellent mass accuracy (error typically < 20 ppm) and precision. It requires a single-step sample preparation and a single click to run and process the data upon method setup. This strategy has been successfully implemented for release testing in GMP labs. Challenges and considerations for the establishment of QC-friendly methods are discussed. It is also shown that these methods can be applied to the ID of more analytically complex biotherapeutics, such as fixed-dose combination (FDC) and drug products co-formulated with trace-level additives.

Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison

A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences. This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions. Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n=40) and cohort 2 (n=39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful. The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM. gov identifier: NCT04856007.

Engineering of 3D printed personalized polypills for the treatment of the metabolic syndrome

Metabolic syndrome is a collection of abnormalities, including at least three of the following insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation, and non-alcoholic fatty liver disease. 3D printed solid dosage forms have emerged as a promising tool enabling the fabrication of personalized medicines and offering solutions that cannot be achieved by industrial mass production. Most attempts found in the literature to manufacture polypills for this syndrome contain just two drugs. However, most fixed-dose combination (FDC) products in clinical practice required the use of three or more drugs. In this work, Fused deposition modelling (FDM) 3D printing technology coupled with hot-melt extrusion (HME) has been successfully applied in the manufacture of polypills containing nifedipine (NFD), as an antihypertensive drug, simvastatin (SMV), as an antihyperlipidemic drug, and gliclazide (GLZ) as an antiglycemic drug. Hanssen solubility parameters (HSPs) were utilized as predictors to guide the formation of amorphous solid dispersion between drug and polymer to ensure miscibility and enhanced oral bioavailability. The HSP varied from 18.3 for NFD, 24.6 for SMV, and 7.0 for GLZ while the total solubility parameter for the excipient mixture was 27.30.5. This allowed the formation of an amorphous solid dispersion in SMV and GLZ 3D printed tablets compared to NFD which was partially crystalline. Popypill showed a dual release profile combining a faster SMV release (< 6h) with a 24 h sustained release for NDF and GLZ. This work demonstrated the transformation of FDC into dynamic dose-personalized polypills.

Antihypertensive Medication Regimens Used by US Adults With Hypertension and the Potential for Fixed-Dose Combination Products: The National Health and Nutrition Examination Surveys 2015 to 2020.

Background Fixed-dose combination (FDC) antihypertensive products improve blood pressure control and adherence among patients with hypertension. It is unknown to what degree commercially available FDC products meet the current hypertension management prescription patterns in the United States. Methods and Results This cross-sectional analysis of the National Health and Nutrition Examination Surveys 2015 to March 2020 included participants with hypertension taking ≥2 antihypertensive medications (N=2451). After constructing each participant's regimen according to antihypertensive classes used, we estimated the extent to which the 7 class-level FDC regimens available in the United States as of January 2023 would match the regimens used. Among a weighted population of 34.1 million US adults (mean age, 66.0 years; 52.8% women; 69.1% non-Hispanic White race and ethnicity), the proportions using 2, 3, 4, and ≥5 antihypertensive classes were 60.6%, 28.2%, 9.1%, and 1.6%, respectively. The 7 FDC regimens were among 189 total regimens used (3.7%), and 39.2% of the population used one of the FDC regimens (95% CI, 35.5%-43.0%; 13.4 million US adults); 60.8% of the population (95% CI, 57.0%-64.5%; 20.7 million US adults) were using a regimen not available as a class-equivalent FDC product. Conclusions Three in 5 US adults with hypertension taking ≥2 antihypertensive classes are using a regimen that is not commercially available as a class-equivalent FDC product as of January 2023. To maximize the potential benefit of FDCs to improve medication adherence (and thus blood pressure control) among patients taking multiple antihypertensive medications, use of FDC-compatible regimens and improvements in the product landscape are needed.

Co-delivery of an HIV prophylactic and contraceptive using PGSU as a long-acting multipurpose prevention technology

ABSTRACT Objectives Poly(glycerol sebacate) urethane (PGSU) elastomers formulated with 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), levonorgestrel (LNG), or a combination thereof can function as multipurpose prevention technology implants for prophylaxis against HIV and unintended pregnancies. For these public health challenges, long-acting drug delivery technologies may improve patient experience and adherence. Traditional polymers encounter challenges delivering multiple drugs with dissimilar physiochemical properties. PGSU offers an alternative option that successfully delivers hydrophilic EFdA alongside hydrophobic LNG. Methods This article presents the formulation, design, and characterization of PGSU implants, highlighting the impact of API loading, dimensions, and individual- versus combination-loading on release rates. Results Co-delivery of hydrophilic EFdA alongside hydrophobic LNG acted as a porogen to accelerate LNG release. Increasing the surface area of LNG-only implants increased LNG release. All EFdA–LNG, EFdA-only, and LNG-only formulated implants demonstrated low burst release and linear release kinetics over 245 or 122 days studied to date. Conclusion PGSU co-delivers two APIs for HIV prevention and contraception at therapeutically relevant concentrations in vitro from a single bioresorbable, elastomeric implant. A new long-acting polymer technology, PGSU demonstrates linear-release kinetics, dual delivery of APIs with disparate physiochemical properties, and biocompatibility through long-term subcutaneous implantation. PGSU can potentially meet the demands of complex MPT or fixed-dose combination products, where better solutions can serve and empower patients.

Fixed Dose Versus Loose Dose: Analgesic Combinations.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixed-dose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics.New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Antibiotska terapija kod kritično obolelih pacijenata sa sepsom - od koncepta FK/FD do novih lekova

Early detection of sepsis and its severity is critical for initiating proper therapy, including antibiotics, as soon as possible to maximize survival chances. Understanding the pathophysiological changes in septic shock that impact antimicrobial pharmacokinetics and pharmacodynamics (PK/PD), understanding the basics of PK/PD, and knowing PK-PD strategies in septic shock patients are all critical for appropriate therapy. By definition multi-drug resistant (MDR) microorganisms are those with acquired non-susceptibility to at least one agent in three or more antimicrobial categories. In the race between bacteria and novel antibiotics development, unfortunately, the number of new antibiotics/indications is not keeping pace with resistance and needs, especially for MDR Gram-negative microorganisms. When we fast forward to the approved antibiotics in the last five years, the list is rather short. Lefamulin is a novel pleuromutilin antibiotic which manifests activity against most Gram-positive pathogens. Cefiderocol is an injectable siderophore cephalosporin. Like other b-lactam antibiotics, it inhibits Gram-negative bacterial cell wall formation by binding to penicillin-binding proteins. Imipenem/cilastatin/relebactam is a new b-lactam/b-lactamase inhibitor combination with activity against MDR Gram-negative bacteria, including many CRE but excluding Metallo-b-lactamase (MBL)-producing Enterobacterales and CRAB. Those three antibiotics were FDA approved in 2019 and European Medicines Agency (EMA) approved in 2020. Plazomicin is a new semisynthetic aminoglycoside with activity against several MDR Gram-negative organisms, including CRE (FDA-approved in 2018). Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid b-lactamase inhibitor with potent activity against resistant Gram-negative bacteria like Klebsiella pneumoniae carbapenemase (KPC)-producing CRE; it is inactive against CRAB (FDA-approved in 2017; EMA-approved in 2018). Eravacycline is a new completely synthesized fluorocycline. It has a high level of effectiveness against Grampositive and Gram-negative bacterial strains that have developed tetracycline-specific resistance mechanisms; it is inactive against Pseudomonas aeruginosa (FDAand EMA-approved in 2018). Concluding this list of recently approved antibiotics is omadacycline, novel aminomethylcycline and a derivative of minocycline, with a chemical structure similar to tigecycline. Like other tetracyclines, omadacycline inhibits bacterial protein synthesis and possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria including CRAB. It is inactive against Pseudomonas aeruginosa (FDA-approved in 2018). There are three novel carbapenems sulopenem, tebipenem pivoxil hydrobromide and benapenem. There is a group of antibiotics in phase III clinical trials: the combination aztreonam/ avibactam, sulbactam/durlobactam, cefepime/enmetazobactam, cefepime/zidebactam, cefepime/taniborbactam. An interesting approach to antimicrobial treatment is antimicrobial drug repurposing. Drug combinations could be a strategy to extend the life of antibiotics in the XXI century due to the multi-targeting mechanisms of agents. New active substances are urgently required to stop the spread of antibiotic-resistant bacteria. However, it could be a rather cumbersome and expensive procedure. Antimicrobial misuse and/or overuse contribute greatly to this very important global healthcare problem.

Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs.

The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs. The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms. The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release. Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.

Spotlight on Calcipotriol/Betamethasone Fixed-Dose Combination in Topical Formulations: Is There Still Room for Innovation?

Psoriasis is a lifelong disease which requires treatment adherence for successful management. Considering the complexity of this pathology, the combination of active pharmaceutical ingredients with a synergistic mechanism of action can improve the safety and efficacy of the treatment with respect to the conventional monotherapy. Moreover, a fixed dose of therapeutic agents in a topical formulation offers the possibility to simplify administration, reduce the doses of each active ingredient, and improve patient’s compliance. Among the first-line treatments in mild to moderate psoriasis, the formulation of calcipotriol (Cal) and betamethasone dipropionate (BD) in a single vehicle is challenging due to their chemical incompatibility in an aqueous environment and the formation of degradation products. Based on these considerations, this review aims to provide an overview on the biopharmaceutical properties of Cal/BD fixed-dose combination products available on the market (namely ointment, oleogel, foam, and O/W cream), highlighting also the novel approaches under evaluation. The main differences among topical formulations are discussed considering the different features of the anatomic districts involved in psoriasis and the patient’s adherence. Moreover, since in vitro experiments are fundamental to evaluate the skin permeation profile during the development of an efficacious medicinal product, special emphasis is given to models proposed to mimic psoriatic lesions.

Effect of statin on age-related hearing loss via drug repurposing

Hearing loss in the elderly cause communication difficulties, decreased quality of life, isolation, loneliness and frustration. The aim of our study was to investigate the effect of drug repurposing candidates in aging mouse. The selected candidate drugs for age-related hearing loss (ARHL) included atorvastatin (AS) and sarpogrelate. Monotherapy or fixed dose combination (FDC) products were administered via oral gavage for 6 consecutive months. Auditory outcomes showed significant hearing preservation in AS-treated aging mice compared to aging control, especially in the early stages of ARHL in both 8 and 16 kHz frequencies. However, none of the FDC products were able to prevent ARHL regardless of AS involvement. In aging mice, damage and dysfunction of mitochondria was noted as well as reactive oxygen species overproduction leading to oxidative stress and intrinsic apoptosis. These processes of ARHL were significantly prevented with administration of AS. Normal structures of mitochondria were maintained, and antioxidant activity were proceeded by activation of HSF1/Sirt1 pathway. Our study suggests that AS is a promising drug repurposing candidate to delay the progression of ARHL.