Active Drug Substance Research Articles

Innovative Discovery Studies of Anti Lungs Cancer Active Drug Substances in Medicinal Chemistry

The discovery study of anti cancer active drug substance of (2S,2′S)-2,2′-[[2,2′- Diamino-4,4′,6-trioxo-1,4,4′,6,7,7′-hexahydro-1′H,5H-5,6′-bipyrrolo[2,3-d]pyrimidine-5,5′- diyl]bis(ethylenebenzene-4,1-diylcarbonylimino)] dipentanedioic acid was synthesized and characterized by medicinal chemistry bath way, also this product was obtained via the associated with the synthesis of pemetrexed disodium was performed. The possibility of (2S,2′S)-2,2′-[[2,2′-Diamino-4,4′,6-trioxo-1,4,4′,6,7,7′- hexahydro-1′H,5H-5,6′-bipyrrolo[2,3-d]pyrimidine-5,5′-diyl]bis(ethylenebenzene-4,1-diylcarbonylimino)] dipentanedioic acid forming has been mentioned in literature, but no study on this structure has been published yet. This paper describes the development of the synthesis methods and preclinical studies for this compound and discusses their structure elucidation on the basis of NMR experiments and MS data. The identification of anti cancer drug activity of this compound by preclinical test, it should be useful for identify the new anticancer drug in pemetrexed generation.

An eco-friendly smartphone based HPTLC method versus conventional densitometric one for determination of Naltrexone and Bupropion

The rapid uprising technologies of smartphone applications and software introduced a new era for analytical detection techniques. It has transformed bench-top laboratory methods into simpler ones depending on cost-effective, portable, and widely accessible devices. In this work, two high performance thin layer chromatographic (HPTLC) methods were developed based on smartphone’s camera detection and either ImageJ desktop software or Color-Picker smartphone’s application as alternative techniques to conventional densitometric detection. A mixture of Naltrexone hydrochloride (NAL) and Bupropion hydrochloride (BUP) was chromatographed on HPTLC- plates using ethyl acetate, methanol, acetone, and glacial acetic acid (3:6:1:0.5, by volume) as a developing system. The developed plates were scanned at 203 nm for the densitometric analysis, then visualized by modified Dragendorff’s reagent and shot by a smartphone’s camera. The captured images were uploaded to either ImageJ software or Color-Picker application to detect the separated spots. The results derived from the three detection methods were compared over the concentration range of 0.4–24 & 0.6–18 µg/band for the densitometric method, 0.4–24 & 2–24 µg/band for ImageJ built method and 0.8–20 & 5–20 µg/band for Color Picker built method for NAL and BUP, respectively. The methods were found to be appropriate for assaying both active drug substances in pure forms and combined in marketed pharmaceutical formulations. The excellent sustainability of densitometric and ImageJ-based methods enabled also the assessment of their dosage form content uniformity. The greenness and sustainability of the methods were assessed by three metric tools, namely Green Analytical Procedure Index (GAPI), Analytical GREEnness Metric Approach (AGREE), and White Analytical Chemistry (WAC). The assessments results confirmed the sustainability and superiority of the proposed methods in terms of sample treatment, waste mount, energy consumption, cost, and number of analyzed samples per an hour.

Gambaran Peresepan Obat Untuk Pasien Asma Rawat Jalan di Klinik X Dumai

Asthma is a heterogeneous disease with chronic inflammation of the airways involving inflammatory cells in them, which will respond excessively to a trigger, causing episodic symptoms such as wheezing, shortness of breath, a feeling of pressure in the chest, and coughing (especially in the morning and evening). The aim of this research is to determine the description of drug prescribing for asthma patients at the X Dumai Clinic. This research method was carried out using a retrospective method at the X Dumai Clinic Outpatient Pharmacy during the period July to December 2022. The instruments used were asthma patient prescription sheets and patient prescription data collection sheets. Sampling was carried out using the random sampling method. The number of samples that met the inclusion criteria for this study was 222 patients. Based on gender and age, from the results of research that has been carried out, it is found that the percentage (%) of drug use in asthma patients based on female gender is as high as 122 patients (54.95%) and 100 patients (45.05%) were male. Based on age, it showed that most patients were aged 56-65 years with 59 patients (26.58%). Based on the therapeutic pattern of drug classes, the active drug substance in the drug dosage form showed the highest percentage of 31.98%. Namely Salbutamol. Meanwhile, combination asthma drug prescriptions were 20.27%. Namely Salbutamol and Methylprednisolone.

How Should Regulators and Manufacturers Prevent Avoidable Deaths of Children From Contaminated Cough Syrup?

This commentary responds to a case about diethylene glycol-contaminated glycerin in cough syrup. Glycerin is a commonly used excipient in medicines to improve texture and taste. Excipients are typically pharmacologically inactive ingredients contained in prescription and over-the-counter drugs that play a critical role in the delivery, effectiveness, and stability of active drug substances. The commentary first canvasses how contaminants enter the excipient supply chains. One way is by misleading labeling or intentional adulteration by manufacturers or suppliers. Another way is by human or systemic error. This commentary then discusses quality control testing and suggests the ethical and clinical importance of increased transparency in excipient supply chains.

Development and Evaluation of Pullulan Based Mouth Dissolving Film of Furosemide

Mouth dissolving oral film is an innovative approach as Oromucosal route for systemic delivery of therapeutically/medicinally active drug substance. As we know Furosemide belongs class IV in BCS classification of drug, having low solubility and permeability due to the presence of strong inter and intramolecular bond. Due to low aqeous solubility, it exhibits low oral bioavailability. Here we are preparing mouth dissolving film of furosemide to increase its solubility, which ultimately will enhance its bioavailability. By this way, we will achieve more rapid drug absorption, desired pharmacological effect with quick onset of action by avoiding degradation in GIT and first pass metabolism. This system will provide maximum therapeutic efficacy and maximum stability by reducing the frequency of dosage and as well as improve patient compliance. The present research aimed to prepare pullulan based mouth dissolving oral films of furosemide used in treatment and control of hypertension. Pullulan was selected as film former exhibit better moisture retention, oxygen barrier and uniform film forming properties. Due to the hydrophilic nature of pullulan, it provides quick dissolution. By considering above points, the film was prepared through solvent casting method by pullulan as film-forming polymer, glycerol as plasticizer and lepidium sativum mucilage as a natural disintegrant known as Asaliyo. Disintegration time, drug release, moisture loss and folding endurance of film were evaluated. Promising batch F6 exhibited better drug dissolution 98.75±0.09% within 8±0.4 minutes than the other films. The disintegration time for batch F6 was 23±5 sec. It is evident from the above results that it is an innovative dosage form to improve the drug delivery, onset of action as well as improve patient compliance.

Potential for Incompatibility, Instability, and Prescription Drug Interactions in Pulveres Prescription Pediatric Patients at RSI (Islamic Hospital) Sultan Hadlirin, Jepara, Indonesia

In Indonesia, there are still many doctors who prescribe compounded medicines for pediatrics, including pulveres. Compounding is an alternative for pediatrics who cannot swallow tablets, but compounding medicines is a concern because it can cause incompatibility and instability during storage and cause side effects. drug interactions. This study aimed to determine the potential for incompatibility, instability, and drug interactions on pediatric patient prescription sheets. This research is descriptive observational, and data collection is carried outretrospective, data taken from prescription sheets for pediatric patients at RSI Sultan Hadlirin Jepara. The total sample in this study was 247 prescriptions that met the inclusion criteria. The results of the study showed that the age classification of patients 0-5 years who received pulveres prescriptions was 175 (71.8%), while for those aged 6-11 years, it was 72 (29.1%). %). Based on the number of medications, 197 (80.1%) patients received 4-6 medications, while 50 (20.3%) pediatric patients received 2-3 medications. There is no potential for 0% incompatibility. There is the potential for instability in the pediatric prescription sheets. As many as 62 (25.1%) of the active drug substance preparations that experience instability include CTM, paracetamol, and vitamin B complex. There were 126 (51.0%) potential drug interactions based on the pharmacodynamic mechanism of action and 126 (51.0%) based on moderate severity in the salbutamol tablet preparation with pseudoephedrine. It can be concluded that on the prescription sheet, there is no potential for 0% incompatibility, there is a potential for instability of 62 (25.1%), and there is moderate interaction, and pharmacodynamic mechanisms were 126 (51.0%).

Antioxidant and Antiangiogenic Effect of Homoleptic Palladium (II) Carboxamide Complex Loaded Chitosan Modified PLGA Nanoparticles: In vitro Evaluation and In vivo Chick Embryo Chorioallantoic Membrane (CAM) Assay

Background: Angiogenesis is a natural and complex mechanism that is regulated by biomolecules formed by the body. Medicinal inorganic chemistry is increasing in popularity due to metal-based compounds, offering significant chances and possibilities for building novel anti-cancer medicines with promising anti-angiogenic effects. Objective: This study aimed to examine the successful results obtained from treatments with nanoparticle formulations of active drug substances. Methods: The nanoprecipitation/solvent displacement approach, with some changes, was used to make PLGA-based NPs. Results: The particle size obtained in the blank formulation was 82.4–473.9 nm, while the particle size in the API-loaded NPs was 193.2–678.0 nm. Among the formulations, NP-950-P, NP-390-P, and NP-350-CSP2 were found to have significant antioxidant potentials with IC50 values of 3.025, 5.198, and 7.4242 µg.mL-1, respectively, when compared to Vit C. According to the microscopic evaluations, NP-950-P (including Pd(PyCrbx)2Cl2 as 50 µg.pellet-1) and NP-950-CSP2 (including Pd(PyCrbx)2Cl2 as 50 µg.pellet-1) showed strong anti-angiogenic effect whereas the other NP formulations showed weak anti-angiogenic effect when compared with the positive control (±)-Thalidomide at the concentration of 50 µg.pellet-1. Conclusion: When the results were examined, it was found that nanoscale drug carrier systems were prepared, and high antioxidant activity and anti-angiogenesis activity were detected, especially in nanoparticles prepared with 950. As per our knowledge, it is the first study in this field that will bring a new perspective to cancer treatment.

Development of Different Separation Techniques for Impurity Profiling of Neostigmine Methylsulfate: A Comparative Study.

Different separation techniques have been employed to resolve mixtures of multicomponent preparations over the last few decades. They could be efficiently applied for impurity profiling of active drug substances. Impurity profiling has become a critical procedure in pharmaceutical companies to comply with numerous regulatory standards. Isolation and characterization of impurities are crucial for obtaining data that proves biological safety and efficacy. In this contribution, different HPLC, capillary electrophoresis (CE) and TLC-densitometric methods were developed for the determination of neostigmine methylsulfate (NEO) along with 3-hydroxyphenyltrimethyl ammonium methylsulfate (3-HPA) and 3-dimethylaminophenol (DAP) as its impurities in the presence of citric acid. The linearity for NEO was attained in the range of 5-120μg/mL and 10-60μg/mL for the HPLC and CE methods, respectively. Regarding the impurities, linearity was obtained over the range of 10-30μg/mL for 3-HPA and 5-30μg/mL for DAP in the two proposed methods. For the TLC method, NEO and DAP were determined within the range of 1-11μg/band, whereas 3-HPA was assayed over the range of 2-12μg/band. The suggested methods can be securely utilized for routine analysis of the cited components in quality control laboratories.

Impact of Rapid Environmental Changes on Stress Distribution in Tablet Coatings: Simulations

Immediate-release film coatings, also known as "non-functional" film coating, are applied to core tablets to improve product appearance and swallowability, impart taste-masking properties, improve handling and stability of the dosage form, and reduce exposure to active drug substance for caregivers. The coatings have no measurable impact on bio-performance of the drug product but they protect tablets from negative effects of environment such as humidity, oxidation, and light. The mechanical stability and integrity of tablet coatings are therefore important to maintain drug product quality attributes such as appearance and stability. Therefore, environmental conditions under which these coatings may crack are important to understand so as to prevent their occurrence. In this work, we present a novel computational framework to assess the mechanical integrity of tablet coatings exposed to rapid variations in environmental conditions. We perform detailed stress and strain analysis of tablet coatings on tablet surfaces with debossed regions and identify conditions for cracking. Coatings with both elastic and viscoelastic properties are considered. Rapid changes in environmental temperature and humidity can cause differential expansion/contraction of coating and tablet core resulting in stresses that are higher than those experienced during the drying process in a coater. Debossed regions on the tablet surface with sharp surface curvatures act as stress concentrators that nucleate cracks. Small changes in the design of the debossed regions lead to modest reductions in the peak stress. Stress calculations show that coatings that are well bonded to tablet surface can crack only under very extreme conditions.

Comedication of Proton Pump Inhibitors and Dasatinib Is Common in CML but XS004, a Novel Amorphous Solid Dispersion Formulation of Dasatinib, Provides Improved Uptake and Low pH-Dependency, Minimizing Unwanted Drug-Drug Interactions

Dasatinib (Sprycel®), together with other tyrosine kinase inhibitors (TKI), has profoundly improved the prognosis of patients with chronic myeloid leukemia (CML). However, as a lipophilic, poorly soluble, weakly basic, orally applied drug, the bioavailability of dasatinib is highly pH-dependent, with significantly reduced plasma concentrations at higher gastric pH. Comedication with proton pump inhibitors (PPI) such as omeprazole, thus provides a clinical challenge, decreasing dasatinib plasma exposure by more than 40%. Consequently, dasatinib and PPI comedication is cautioned against by the FDA (US). Here we studied TKI-PPI comedication by investigating the prevalence and outcome of such treatments in CML patients in a real-world setting and by assessing the influence of PPI-comedication on the plasma pharmacokinetics of XS004-dasatinib (XS004, Xspray Pharma, Solna, Sweden), a novel immediate release and amorphous solid dispersion (ASD) formulation of dasatinib. Using the Swedish CML- and Prescribed Drug-Registries we identified 722 chronic phase CML-patients, of which 676 (93.6%) had received TKI treatment. We observed that 302 (45%) of these had also been prescribed PPI at some point after CML diagnosis. Among patients given dasatinib, the two-year cumulative prescribed comedication with PPI was 24%. With longer follow-up and given the fact that unprescribed but difficult to quantify over-the-counter usage of PPI is common in Sweden, the proportion of patients with such comedication is likely to be considerably larger. Interestingly, the estimated 5-year survival was lower for TKI-treated CML patients with vs. without PPI comedication (79% vs. 94%; total 5-years survival of TKI-treated CML patients: 88%). This corresponds to a significantly increased crude hazard ratio (HR) of death of 3.5 (95% CI, 2.1-5.3, p<0.0001) and a HR of 3.1 (95% CI, 2.0-4.7, p<0.0001) after adjusting for age, sex, year of diagnosis, and comorbidity index. Further, we assessed the pharmacokinetics of XS004, given alone or together with omeprazole, to sixteen healthy volunteers in a cross-over study design. XS004 is produced with the NyNap™ technology allowing for an ASD-formulation of dasatinib and is designed to increase solubility of the active drug substance in slightly acidic to neutral gastrointestinal pH conditions, thereby reducing gastric pH dependency and promoting optimized absorption and bioavailability of the drug. XS004 has demonstrated improved bioavailability and reduced intra- and inter-individual variability when compared to the original, non-ASD formulated dasatinib (Sprycel®). As shown in Table 1, describing plasma pharmacokinetics of XS004 administered as a single drug or together with omeprazole, neither Cmax nor plasma AUC values of XS004 were significantly altered by the PPI comedication. This contrasts with previous studies describing clear reductions of non-ASD formulated dasatinib plasma AUC after comedication with PPI. We conclude that, despite warnings, co-medication with PPI is common among dasatinib-treated CML patients in a real-world setting. Our data suggest that PPI-comedication to TKI can negatively influence the survival of CML patients, although covariant factors may be present. The plasma pharmacokinetics of XS004 dasatinib was, in contrast to the original non-ASD, pH-sensitive dasatinib formulation, not significantly affected by comedication with omeprazole. In the clinic, with its low pH-dependency and augmented intestinal absorption, XS004 dasatinib can provide an improved option for safely administering the often-needed comedication with PPIs, potentially improving long-term efficacy and tolerability of dasatinib in CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Simultaneous estimation of crotamiton and hydrocortisone by RP-UPLC using green analytical principles embedded analytical quality by design (AQbD) method

Analyzing varied concentrations of pharmaceutical active drug substances in dosage forms without any interferences using eco-friendly principles is more challenging. Hence, the aim of the present study is used to estimate Crotamiton (CTM) and Hydrocortisone (HCS) simultaneously by applying green analytical principles together with Analytical Quality by Design (AQbD)- rotatable central composite based approach using RP-UPLC based method development and validation. The study was intended to enhance efficiency and reduce environmental consequences, by reducing the toxic solvents/chemicals usage and waste emission. The separation was carried out through the aid of a Waters X-Bridge (C18 50 × 2.5 mm i.d, 1.7 µm) column with an optimized mobile phase for the determination of two drugs were ethanol:0.01 M ammonium acetatebuffer (pH 3.0) 30:70v/v at a flow rate of 0.3 ml/min. The measurement was made at aconcentration of 70–130 µg/ml for CTMand 1.75–3.75 µg/ml for HCS(R2 = 0.9998–0.9995). The results of the degradation study revealed that the drugs degraded under stressed conditions and the degradation products were identified using MS, and the proposed structures were depicted. The suggested methodology’s linearity, accuracy, and precision have been verified using ICHcriteria and green assessment tools, with environmentally acceptable results. This novel eco-friendly AQbD-based analytical approach could be readily adaptable by chemical and pharmaceutical industries for regular analysis without any regulatory barriers.

3D Molecular Imaging of Stratum Corneum by Mass Spectrometry Suggests Distinct Distribution of Cholesteryl Esters Compared to Other Skin Lipids.

The crucial barrier properties of the stratum corneum (SC) depend critically on the design and integrity of its layered molecular structure. However, analysis methods capable of spatially resolved molecular characterization of the SC are scarce and fraught with severe limitations, e.g., regarding molecular specificity or spatial resolution. Here, we used 3D time-of-flight secondary ion mass spectrometry to characterize the spatial distribution of skin lipids in corneocyte multilayer squams obtained by tape stripping. Depth profiles of specific skin lipids display an oscillatory behavior that is consistent with successive monitoring of individual lipid and corneocyte layers of the SC structure. Whereas the most common skin lipids, i.e., ceramides, C24:0 and C26:0 fatty acids and cholesteryl sulfate, are similarly organized, a distinct 3D distribution was observed for cholesteryl oleate, suggesting a different localization of cholesteryl esters compared to the lipid matrix separating the corneocyte layers. The possibility to monitor the composition and spatial distribution of endogenous lipids as well as active drug and cosmetic substances in individual lipid and corneocyte layers has the potential to provide important contributions to the basic understanding of barrier function and penetration in the SC.

GC-FID Quantification of N, N-Dimethyl Aminopropyl Chloride, a Genotoxic Impurity, in Imipramine Hydrochloride and Clomipramine Hydrochloride

Background: Early antidepressant Active Pharmaceutical Ingredients (API) like Imipramine hydrochloride and Clomipramine hydrochloride have not been assessed for Genotoxic Impurities (GTI) as per ICHM7. Objective: The main aim of the study was to develop a new simple and sensitive method for the determination of genotoxic impurities in Imipramine hydrochloride and Clomipramine hydrochloride active pharmaceuticals ingrediens. Methods: A simple, selective, and sensitive gas chromatography (GC) liquid injector method was developed for the quantitative determination of N, N-Dimethyl amino propyl chloride (DAPC) in API s. This method provided an excellent sensitivity and a typical target analyte level of 4.0 ppm. The DPAC content in the sample was analyzed on ZB-624, 30m x 0.53mm x 3.0μm column interfaced with a flame ionization detector (FID). The developed method was validated as per ICH guidelines. Results: The validated method showed good linearity over the concentration range of LOQ to 120% (1.18ppm to 4.8ppm) with a correlation coefficient of 0.9986. Limit of detection (LOD) and limit of quantitation (LOQ) were found to be 0.36 ppm and 1.18 ppm, respectively. This method showed high sample recovery (&gt;90.0%). Conclusion: The developed method was a simple and sensitive gas chromatography liquid injector method. This method was validated as per ICH guidelines and could be very useful for the determination of a potential genotoxic impurity (DAPC) in imipramine hydrochloride and clomipramine hydrochloride active drug substance quality checking and ensuring safety of the patients.

Investigational Study of DASATINIB N-Oxide Impurity in Different Diluents.

Dasatinib is an aminopyrimidine used as an inhibitor of multiple tyrosine kinases in two different formulations an immediate-release tablet and a powder for oral suspension. It shows a very low pH-dependent solubility in aqueous solutions and higher solubility in organic solvents. The solubility plays an essential role in analytical methodology to establish the purity, potency, safety and efficacy of any drug product as a diluent. Also, extraction of active drug substance with a suitable diluent from matrix composition is crucial for any analytical method development. However, a diluent optimization study during the method development of related substances for the drug product reveals that the Piperazine ring presented in Dasatinib is susceptible to oxidation and forms an N-oxide impurity. The impurity formation is due to the micro oxidic properties of the solvent used as a diluent which is inducing an oxidation reaction. Therefore, a comprehensive investigative study was conducted to optimize the diluent by limiting N-Oxide generation.

Therapeutic Importance of Biological Half-Life of Antineoplastic Agents- A Review

Lung, prostate, and stomach cancer are the most prevalent cancers among males. Breast, colon, and cervical cancer are the most prevalent cancers among women. The literature also shows that patients suffering from cancer are increasing constantly, and hence the number of different chemotherapy treatments administered is increasing. The main objective of this review article is to summarize the effect of age on the half-life of some antineoplastic drugs belonging to the category of Topoisomerase inhibitors, alkylating agents, anthracyclines, purine analogs, antimetabolites, and N-nitrosoureas along with their pharmacokinetic properties. Literature indicates that highly bound antineoplastic drugs have higher differences in unbound drug concentrations among patients, and in some cases, the amount of concentration is not reflective of the unbound drug level and has an impact on pharmacokinetic parameters, including absorption, the volume of distribution, drug metabolism, and excretion. Protein binding affects the distribution and bioavailability of active drug substances.

Coating of Primary Powder Particles Improves the Quality of Binder Jetting 3D Printed Oral Solid Products

Binder jetting (BJ) 3D printing is especially suitable for the fabrication of an orodispersible solid dosage form, as it is an efficient way to avoid the use of mechanical forces typical for compaction-based processes. However, one of the existing challenges related to pharmaceutical applications of BJ is the relatively high amount of binder needed in the primary powder to ensure the sufficient mechanical strength of printed products. In this study, a strategy based on pre-processing with a thin layer coating was explored. With this strategy, the matrix particles (lactose monohydrate) of the primary powder for BJ 3D printing were coated with the binder (polyvinylpyrrolidone, PVP). The investigated compositions of the primary powder contained PVP at three levels, namely, 10 %, 15% and 20% (w/w). The primary powder compositions were prepared with or without the coated lactose powder, and they were subsequently 3D BJ printed into oral solid products with paracetamol as a model active drug substance. The presence of coated lactose in the primary powder increased the interparticulate interactions in the BJ 3D printed products. Especially for the composition with a relatively small amount of binder (i.e., 10% and 15% w/w PVP in the primary powder), the use of coated particles significantly improved the resistance to crushing and decreased the disintegration time of printed products. In conclusion, thin layer coating is an effective way to pre-process primary powder particles for BJ 3D printing of oral solid products.

Current Perspectives on Biosimilars and Impact of Biosimilars in Supportive Care in Breast Cancer

Biopharmaceuticals are medicines whose active drug substance is made by living cells. Copies of these drugs, called Biosimilars are not identical to their reference drug and therefore specific regulatory requirements for registration apply. Whereas pharmaceutical quality evaluation requires a full dossier and a detailed comparative analysis to the reference drug, non-clinical and clinical requirements are much less extensive compared to the requirements for an innovator. Limited clinical experience and their complex nature exclude biosimilars from being considered interchangeable with the reference drug. The utilization of trastuzumab biosimilar medications is of particular interest in HER2-positive breast cancer as these drugs have the potential for cost savings and increased utilization/access to HER2 targeted therapy in both early stage and metastatic HER2-positive breast cancers. Five trastuzumab biosimilars: MYL-1401O (Ogivri), CT-P6 (Herzuma), SB3 (Ontruzant), PF-05280014 (Trazimera), and ABP980 (Kanjinti), have now been approved by the US Food and Drug Administration (FDA) for use in HER2-positive breast cancers. This review provides an overview of these agents with special consideration of the development and approval process, including available clinical data results for these trastuzumab biosimilars.

On the possibility of therapeutic action after transdermal patch application

Background. As scientific knowledge about the peculiarities of the structure and functional properties of the skin increased, it became clearer that during transdermal administration, drug may accumulate in the deep layers of the dermis and subsequently get diffused into the bloodstream even after the transdermal therapeutic system (TTS), also called transdermal patch, had been removed. Objective: to quantify active drug substances remaining in an animal skin after TTS application. Materials and methods. Two previously developed transdermal patches containing Russian-made drug substances were chosen for the study: aminodihydrophthalazinedione sodium (immunomodulator) and bis(1-vinylimidazole-N) zinc diacetate (antidote for carbon monoxide). The study was performed on male Chinchilla rabbits weighing 2.5–3 kg. Five series of experiments were performed for each substance: immediately after removal of the patch, 4 hours later, at week 1, 2 and 3 after removal. High-performance liquid chromatography and atomic absorption spectroscopy methods were used to quantify residual drug substances left in the skin. Results. In the skin flap that was in contact with the aminodihydrophthalazinedione sodium TTS for 24 hours, 0.516 mg of the drug was detected immediately after removal of the patch. Over the next two weeks, the drug substance in the skin decreased with the immunomodulator significantly reducing to 0.41 mg in the first 4 hours. In the skin flap that had been in contact with zinc bis(1-vinylimidazole-N) diacetate for 24 hours, about 1 mg of the drug was present immediately after patch removal. Four hours after removal of the transdermal patch, the quantity of active substance in the skin remained practically unchanged. At week 1 and 2, the quantity of the antidote decreased slightly to ~0.7 mg and ~0.25 mg, respectively. Conclusion. For transdermal application of aminodihydrophthalazinedione sodium, the skin can act as a drug depot and prolong the effect of this drug even after the transdermal patch had been removed. No such effect was found in the case of bis(1-vinylimidazole-N) zinc diacetate, which is apparently due to the different solubility of the drugs in the biotissue.

Impurities Present in Cardiovascular Active Substances and Medicinal Products: A Pharmacopoeial Perspective

Abstract: The quality of drugs is a major concern for drug regulatory authorities and other stake-holders across the globe. Recently, drug regulatory authorities across the globe are facing a chal-lenge in controlling the purity of cardiovascular (CVS) drugs for human use, especially drugs from the Angiotensin Receptor Blocker family, such as Valsartan. The present article aims to provide comprehensive knowledge on how pharmacopeias worldwide play a key role in ensuring the quality of active pharmaceutical ingredients (API) and finished pharmaceutical products (FPPs). In this ar-ticle, the focus is on comprehensive information regarding pharmaceutical impurities, separation strategies, relevant regulatory guidelines to control impurities, and their acceptable limits, particu-larly with respect to cardiovascular active drug substances and drug formulations for human use.

A Scientific Approach and Perception for Clinical Practice in India

The rate and extent of absorption of a drug from its dosage form is referred to as bioavailability. While bioequivalence between two drug products is attained if their extent and rate of absorption do not relatively differ when administered at the same dose. A bioequivalence study comprises of two or more bioavailability studies which are performed by i) Measurement of active drug substance or its metabolites in the biological fluid; ii) Comparative pharmacodynamic studies in humans; iii) Comparative clinical trials; iv) Comparative in-vitro dissolution studies. The rationale of the study is the monitoring of the pharmacokinetic-pharmacodynamic parameters (AUC, Cmax) after administration of the tested drug. This study is not an experimental study but a form of data analysis and reporting of comparative bioavailability studies. The study data obtained is required to be equipped with applications of new drug products as notified in Schedule Y. Cumulatively, it aids in the development of pharmaceutical preparations in the pharmaceutical industry. This review article aims to illustrate the systematic overview of BA/BE study with an emphasis on its experimental aspects like study design, volunteer selection, dosing regimen, sample collection procedures along with a detailed insight on Informed Consent Document, Case Report Form, Trial Master file and the Protocol which collectively form the backbone of the clinical study.