Application of smart chemometric models for spectra resolution and determination of challenging multi-action quaternary mixture: statistical comparison with greenness assessment.

A multivariate spectrophotometric method is a potential approach that enables discrimination of spectra of components in complex matrices (e.g., pharmaceutical formulation) serving as a substitution method for chromatography. Four green smart multivariate spectrophotometric models were proposed and validated, including principal component regression (PCR), partial least-squares (PLS), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural networks (ANN). The developed chemometric models were compared to resolve highly overlapping spectra of Paracetamol (PARA), Chlorpheniramine maleate (CPM), Caffeine (CAF), and Ascorbic acid (ASC). The four multivariate calibration models were assessed via recoveries percent, and root mean square error of prediction. Hence, the proposed models were efficiently applied with no need for any preliminary separation step. The models were utilized to analyze the studied components in their combined pharmaceutical formulation (Grippostad® C capsules). Analytical GREEnness Metric Approach (AGREE) and eco-scale tools were applied to assess the greenness of the established models and found to be 0.77 and 85, respectively. Moreover, the proposed models have been compared to official ones showing no considerable variations in accuracy and precision. Therefore, these models can be highly advantageous for conducting standard pharmaceutical analysis of the substances researched within product testing laboratories.

Novel HPTLC method for simultaneous estimation from ternary mixture of chlorpheniramine maleate, dextromethorphan hydrobromide and phenylephrine hydrochloride in syrup formulations.

OBJECTIVES: A synergic antihistamine, cough suppressant, and decongestant combination of chlorpheniramine, dextromethorphan, and phenylephrine is used to treat acute respiratory infections caused by seasonal viruses. The effective qualitative and quantitative methods require the simultaneous measurement of a ternary combination in the pharmaceutical syrup dosage form. Therefore, a new, simple, fast and robust high performance thin layer chromatographic (HPTLC) method has been developed and validated for chlorpheniramine maleate (CPM), dextromethorphan hydrobromide (DEXO) and phenylephrine hydrochloride (PE). MATERIAL AND METHODS: The chromatographic separation was carried out on precoated aluminium plates with silica gel 60 F254 as the stationary phase. Mobile phase used was chloroform: methanol: ammonia (2.5:7.5:0.3, v/v/v) for proper separation. The detection was carried out at 270nm wavelength in absorbance mode. Developed method was validated as per International Council for Harmonization (ICH) Q2 (R1) guideline. RESULTS: The linearity range is 400 to 1400ng/band for CPM, 3000 to 11500ng/band for DEXO and 1000 to 3500ng/band for PE with correlation coefficient ≥ 0.995. The consistent lower values of relative standard deviation (RSD, %) for precision and robustness study indicate the method reliability. The percent recovery ranged from 97.82 to 102.03% indicates the good accuracy of the method. CONCLUSION: The proposed method was complying for the analytical method validation parameters suggested by the ICH Q2 (R1) guideline. The method was found to be simple, rapid and reliable for the simultaneous estimation of CPM, DEXO and PE from its pharmaceutical syrup dosage form. The method was successfully applied to quantify these analytes from the several pharmaceutical syrup dosage form.

The Rise of SARS-CoV-2 (COVID-19) Omicron Subvariant Pathogenicity.

During the COVID-19 pandemic, variants of the Betacoronavirus SARS-CoV-2, the etiologic agent of COVID-19 disease, progressively decreased in pathogenicity up to the Omicron strain. However, the case fatality rate has increased from Omicron through each major Omicron subvariant (BA.2/BA.4, BA.5, XBB.1.5) in the United States of America. World data also mirror this trend. We show that the rise of Omicron pathogenicity is exponential, and we have modeled the case fatality rate of the next major subvariant as 0.0413, 2.5 times that of the Alpha strain and 60% of the original Wuhan strain which caused the greatest morbidity and mortality during the pandemic. Small-molecule therapeutics have been developed, and some of these, such as chlorpheniramine maleate, may be useful in the event of an Omicron subvariant of higher risk.

Chlorpheniramine Maleate Throat Spray for the Treatment of COVID-19-Induced Acute Viral Pharyngitis: Case Series.

Acute viral pharyngitis (AVP) is a common respiratory illness affecting many individuals. Despite symptomatic treatment management of AVP, therapies are lacking to target a broad spectrum of viruses and the inflammatory nature of the disease. Available for many years, Chlorpheniramine Maleate (CPM), is considered a low-cost and safe first-generation antihistamine displaying antiallergic, anti-inflammatory, and as of recently, identified as a broad-spectrum antiviral agent with activity against influenzas A/B viruses and SARS-CoV-2. Efforts have been made to identify repurposed drugs with favorable safety profiles that could significantly benefit the treatment of COVID-19-induced symptoms. The present case series highlights three patients in which a CPM-based throat spray was used to alleviate the symptoms of COVID-19-induced AVP. The CPM throat spray was associated with significant improvements in patient symptoms after approximately three days of use as opposed to the typical five to seven days reported elsewhere. While AVP is a self-limited syndrome and usually improves without pharmaceutical therapy, CPM throat spray may significantly reduce the overall time that the patient has symptoms. Additional clinical studies to evaluate the efficacy of CPM for the treatment of COVID-19-induced AVP are warranted.

Molecular Modeling and Preliminary Clinical Data Suggesting Antiviral Activity for Chlorpheniramine (Chlorphenamine) Against COVID-19.

Chlorpheniramine maleate, a widely used over-the-counter antihistamine, has been identified as a structural analog of aminoquinolines known to possess antiviral activity against the Betacoronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Structural similarities include the chlorophenyl group, pyridine ring, alkyl sidechain, and terminal tertiary amine; the comparison of aqueous energy-minimized structures indicates significant three-dimensional similarity as well. Preliminary clinical evidence supports these conclusions. The present study suggests that chlorpheniramine possesses antiviral activity against COVID-19.

Utilising Co-Axial Electrospinning as a Taste-Masking Technology for Paediatric Drug Delivery.

The present study describes the use of two taste-masking polymers to fabricate a formulation of chlorpheniramine maleate for paediatric administration. Co-axial electrospinning was utilized to create layered nanofibres; the two polymers, Eudragit® E PO and Kollicoat® Smartseal, were alternated between the core and the shell of the system in order to identify the optimum taste-masked formulation. The drug was loaded in the core on all occasions. It was found that the formulation with Kollicoat® Smartseal in the core with the drug, and Eudragit® E PO in the shell showed the most effective taste-masking compared to the other formulations. These fibres were in the nano-range and had smooth morphology as verified by scanning electron microscopy. Solid-state characterization and thermal analysis confirmed that amorphous solid dispersions were formed upon electrospinning. The Insent E-tongue was used to assess the taste-masking efficiency of the samples, and it was found that this formulation was undetectable by the bitter sensor, indicating successful taste-masking compared to the raw version of the drug. The E-tongue also confirmed the drug's bitterness threshold as compared to quinine HCl dihydrate, a parameter that is useful for formulation design and taste-masking planning.

Eco-friendly synthesis of the Li/Al in nonionic surfactant-based vesicles (niosomes) modified with graphene oxide quantum dot nanostructures for controlled released of chlorpheniramine maleate.

The aim of the present work was the preparation of Li/Al nanoparticles (NPs) functionalized with graphene oxide quantum dots (GOQDs) for the controlled release of chlorpheniramine maleate (CPAM). The role of lemon and egg white extracts as oxidation agents were investigated for the morphology and particle size of the products. GOQDs were synthesized using green, environmentally friendly, and cost-effective precursors. This work demonstrates that Li/Al NPs functionalized with graphene oxide as a nanolayer structure can be used as efficient nanocarriers for loading and delivery of CPAM as water-insoluble aromatic drugs The final products were identified with X-ray diffraction, scanning electron microscopy, atomic force microscopy, ultraviolet-visible spectroscopy, dynamic light scattering, thermogravimetric analysis, and transmission electron microscopy nitrogen adsorption [i.e. Brunauer-Emmett-Teller (BET) surface area analysis] techniques. The calibration curve for Li/Al nanoparticles functionalized with GOQDs for controlled released of CPAM was calculated as y = 0.0137x + 0.0103 with R2  = 0.9995. The data found through BET and Barrett-Joyner-Halenda analysis using the adsorption/desorption isotherm method demonstrated by total pore volumes and dead volume were calculated respectively as 0.162 nm2 , 0.0439 cm3 g-1 . The mean pore diameter was calculated as 20.33 nm using BET isotherm data.

A Randomized Controlled Pilot Trial to Test the Efficacy of Intranasal Chlorpheniramine Maleate With Xylitol for the Treatment of Allergic Rhinitis.

The prevalence of allergic rhinitis (AR), including symptoms of sneezing, nasal itching, airflow obstruction, and nasal discharge caused by histamine and immunoglobulin E (IgE)-mediated reactions, is ~30% in the U.S. Recent studies seem to suggest that the allergic inflammatory processes in AR may be induced by the interaction between an allergen (trigger) and the nasal microbiome (substrate). In this study, we have identified two agents with antihistaminic and microbiome-modulating characteristics that can be administered intranasally, namely, chlorpheniramine maleate (CPM) and xylitol (X). This study aimed to test the efficacy of intranasal CPM plus xylitol (CPM+X) nasal for the treatment of AR in an outpatient setting. A multicenter, randomized, double-blind, 30-day pilot study was conducted during the spring of 2019. After starting five days of placebo therapy (run-in period), patients with moderate-to-severe AR nasal symptoms were randomized to treatment with CPM+X (n=16) spray and nasal saline placebo (PLB; n=13). Both treatments were administered in the form of one spray dose (~100 µL of the solution containing 1.25 mg CPM) per nostril twice a day. Outcome variables were the changes in visual analog scale (VAS) and daily symptoms score (DSS) at days 1, 5, 10, 15, 25, and 30 after the initiation of the treatment. ANOVA (analysis of variance) with repeated revealed a significant treatment-by-time interaction such that the CPM+X group had a significant decrease (p < 0.05) in both DSS (∆-3.0 ± 2.7) and VAS (∆-3.8 ± 2.0) scores compared to PLB after 30 days. The difference in DSS and VAS scores between the groups was evident just after five days (day 10) of using CPM+X. The CPM+X scores were significantly lower (p < 0.008) starting from day 10 compared with day 1, whereas there were no statistically significant (p > 0.008) changes in the PLB during the 30-day treatment window. The present data suggest that nasal CPM+X use effectively improves AR symptoms. A large-scale study of the long-term effects of CPM+X for the treatment of other chronic respiratory disorders and the potential microbiome-modulating effects warrants further investigation.

Effects of Chlorpheniramine Maleate on Catheter-Related Bladder Discomfort in Patients Undergoing Ureteroscopic Stone Removal: A Randomized Double-Blind Study.

Catheter-related bladder discomfort (CRBD) associated with intraoperative urinary catheterization is a distressing symptom during recovery from anesthesia. Anticholinergics have been used to manage CRBD. Chlorpheniramine maleate (CPM) is a first-generation antihistamine, which also has anticholinergic effects. This study was undertaken to evaluate the efficacy of CPM in preventing CRBD. Seventy-six adults (19-65 years old) with American Society of Anesthesiologists physical status I, II, or III of either sex, undergoing elective ureteroscopic stone removal under general anesthesia were randomized into one of two groups (each n = 38). Group C (control) received a placebo, and group CPM received 8 mg of intravenous CPM before the induction of anesthesia. CRBD was assessed upon arrival in the post-anesthetic care unit at 0, 1, 2, and 6 h. The severity of CRBD was graded as none, mild, moderate, and severe. Tramadol was administered when the severity of CRBD was more than moderate. The incidence rate and overall severity of CRBD did not differ between the groups at any of the time points (р > 0.05). The incidence of moderate CRBD was higher in group C than in group CPM only at 0 h (26.3% vs. 5.3%, р = 0.025). However, fewer patients in the CPM group required rescue tramadol to relieve CRBD after surgery (31.6% vs. 60.5%, р = 0.011). CPM administration before the induction of anesthesia had little effect on the incidence and severity of CRBD after surgery, but it reduced the administration of tramadol required to control CRBD postoperatively.

Protocol development, validation, and troubleshooting of in-situ fiber optic bathless dissolution system (FODS) for a pharmaceutical drug testing.

Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.

In Vitro Virucidal Effect of Intranasally Delivered Chlorpheniramine Maleate Compound Against Severe Acute Respiratory Syndrome Coronavirus 2.

Background The initial global outbreak of the novel coronavirus disease 2019 (COVID-2019) pandemic, which is responsible for the severe acute respiratory syndrome 2 (SARS-CoV-2), shares similarities with the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) and behaves similarly to influenza with a high intranasal viral load. The genome sequence of COVID-19 opened the opportunity for multiple in vitro and clinical trials, but we still do not have a clear path to treatment. Chlorpheniramine maleate (CPM) is a safe and effective antihistamine with potent antiviral activity against various strains of influenza A/B, thus suggesting that CPM has broad antiviral activity. We tested the virucidal potential of CPM in a nasal spray composition currently in development as an anti-allergy medication. Methods The virucidal activity of CPM was tested using viral stock of SARS-CoV-2, USA-WA1/2020 strain in Vero 76 infected cells. The endpoint titer 50% cell culture infection dose (CCID50) values were calculated using the Reed-Muench (1948) equation. Three independent replicates of each sample were tested, and the average and standard deviation were calculated. Results were compared with untreated controls using one-way ANOVA (analysis of variance) with Dunnett's multiple comparison test in GraphPad Prism (version 8) software. Results After 25 minutes of contact time, the nasal spray reduced the levels of the virus from 4.2 to 1.7 log10 CCID50 per 0.1 mL, a statistically significant 2.5 log reduction value or 99.7% reduction in the viral load. Conclusions This study demonstrates the strong virucidal effect against SARS-CoV-2 of a nasal spray containing CPM. Given that CPM has broad antiviral effects against influenza and virucidal effect against SARS-CoV-2, we propose two further studies: a randomized placebo-controlled study of intranasally delivered chlorpheniramine in patients with mild-to-moderate SARS-CoV-2 and a second study aiming to determine the potential antiviral and adjuvant effects of CPM plus hydroxychloroquine, versus hydroxychloroquine alone, in hospitalized patients with SARS-CoV-2.

Method development for simultaneous determination of active ingredients in cough and cold pharmaceuticals by high performance liquid chromatography.

A rapid, simple and efficient liquid chromatographic method was developed for simultaneous determination of three active ingredients namely, chlorpheniramine maleate, phenylephrine hydrochloride and guaifenesin along with sodium benzoate preservative common cold medications (syrups) and the method was validated based on the International Conference on Harmonization (ICH) and United State Pharmacopeia (USP) guidelines. Separation of the analytes was achieved within 15 min on a nucleosil gravity phenyl column in a single run with a mobile phase consisting of methanol: buffer mixture (15:85 v/v) at room temperature, in isocratic mode with flow rate of 0.8 mL min-1. A comprehensive study on specificity, range, accuracy (recovery), intraday and interday precisions, limit of detection, limit of quantitation, robustness, ruggedness, system suitability and specification was performed as a part of method validation. The linearity was obtained in the range of 7.1-12.2 µg mL-1 (r2 = 0.9984), 17.6-30.1 µg mL-1 (r2 = 0.9995), 39.6-67.8 µg mL-1 (r2 = 0.9995) and 351.1-601.8 µg mL-1 (r2 = 0.9996) for chlorpheniramine maleate, phenylephrine hydrochloride, sodium benzoate and guaifenesin, respectively. The proposed liquid chromatographic method was successfully applied for the routine analysis of these compounds in different commercial cough and cold pharmaceutical preparations including syrups with no interference from the excipients.

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) characterized by severe central nervous system (CNS) degeneration. The disease is caused by mutations in the SGSH gene coding for the lysosomal enzyme sulfamidase. Sulfamidase deficiency leads to accumulation of heparan sulfate (HS), which triggers aberrant cellular function, inflammation and eventually cell death. There is currently no available treatment against MPS IIIA. In the present study, a chemically modified recombinant human sulfamidase (CM-rhSulfamidase) with disrupted glycans showed reduced glycan receptor mediated endocytosis, indicating a non-receptor mediated uptake in MPS IIIA patient fibroblasts. Intracellular enzymatic activity and stability was not affected by chemical modification. After intravenous (i.v.) administration in mice, CM-rhSulfamidase showed a prolonged exposure in plasma and distributed to the brain, present both in vascular profiles and in brain parenchyma. Repeated weekly i.v. administration resulted in a dose- and time-dependent reduction of HS in CNS compartments in a mouse model of MPS IIIA. The reduction in HS was paralleled by improvements in lysosomal pathology and neuroinflammation. Behavioral deficits in the MPS IIIA mouse model were apparent in the domains of exploratory behavior, neuromuscular function, social- and learning abilities. CM-rhSulfamidase treatment improved activity in the open field test, endurance in the wire hanging test, sociability in the three-chamber test, whereas other test parameters trended towards improvements. The unique properties of CM-rhSulfamidase described here strongly support the normalization of clinical symptoms, and this candidate drug is therefore currently undergoing clinical studies evaluating safety and efficacy in patients with MPS IIIA.

Chlorpheniramine maleate containing chitosan-based nanoparticle-loaded thermosensitive in situ gel for management in allergic rhinitis.

The aim of the present study was to fabricate a thermosensitive gel containing chlorpheniramine maleate (CPM)-loaded nanoparticles following intranasal administration for effective treatment of allergic rhinitis. Chitosan-based nanoparticles were prepared by a precipitation method followed by the addition of developed NPs within the poloxamer 407- and carbopol 934P-based mucoadhesive thermoreversible gel. Developed formulations were evaluated for particle size, PDI, % entrapment efficiency, and % cumulative drug permeation. NP3 formulation was found to be optimized on the basis of minimum particle size (143.9 nm), maximum entrapment efficiency (80.10 ± 0.414%), and highest drug permeation (90.92 ± 0.531%). The optimized formulation NP3 was then formulated into thermoreversible in situ gel. This intensifies the contact between the nasal mucosa and the drug and increases and facilitates the drug absorption which results in increased bioavailability. G4 formulation was selected as the optimized formulation on the basis of gelation ability and mucoadhesive strength. Histology was carried out to examine the damage caused by the optimized G4 formulation. Results revealed no visual signs of tissue damage thus indicated safe nasal delivery of nanoparticulate in situ gel formulation G4. Thus, intranasal CPM NP-loaded in situ gel was found to be a promising formulation for the management of allergic rhinitis.

Electrospinning Optimization of Eudragit E PO with and without Chlorpheniramine Maleate Using a Design of Experiment Approach.

Electrospinning is increasingly becoming a viable means of producing drug delivery vehicles for oral delivery, particularly as issues of manufacturing scalability are being addressed. In this study, electrospinning is explored as a taste-masking manufacturing technology for bitter drugs. The taste-masking polymer Eudragit E PO (E-EPO) was electrospun, guided by a quality by design approach. Using a design of experiment, factors influencing the production of smooth fibers were investigated. Polymer concentration, solvent composition, applied voltage, flow rate, and gap distance were the parameters examined. Of these, polymer concentration was shown to be the only statistically significant factor within the ranges studied ( p-value = 0.0042). As the concentration increased, smoother fibers were formed, coupled with an increase in fiber diameter. E-EPO (35% w/v) was identified as the optimum concentration for smooth fiber production. The optimized processing conditions identified were a gap distance of 175 mm, an applied voltage of between 15 and 20 kV, and a flow rate of 1 mL/h. Using this knowledge, the production optimization of electrospun E-EPO with chlorpheniramine maleate (CPM), a bitter antihistamine drug, was explored. The addition of CPM in drug loads of 1:6 up to 1:10 CPM/E-EPO yielded smooth fibers that were electrospun under conditions similar to placebo fibers. Solid-state characterization showed CPM to be molecularly dispersed in E-EPO. An electronic tasting system, or E-tongue, indicated good taste-masking performance as compared to the equivalent physical mixtures. This study therefore describes a means of producing, optimizing, and assessing the performance of electrospun taste-masked fibers as a novel approach to the formulation of CPM and potentially other bitter drug substances.

Involvement of histamine H1 and H2 receptor inverse agonists in receptor's crossregulation.

Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H1 and H2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H1 and H2 receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to histamine H1 and H2 receptor inverse agonists and how histamine H1 and H2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H1 and H2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H1 receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H2 receptor agonist. In turn, histamine H2 receptor inverse agonists interfere with histamine H1 receptor signaling. We also determine that the crossdesensitization induced by histamine H1 or H2 receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H1 receptor affects cAMP response induced by histamine H2 receptor inverse agonists, whereas histamine H2 receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H1 receptor inverse agonists. Binding studies revealed that histamine H1 and H2 receptors cointernalize after stimulus with histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of histamine H1 and H2 receptors that explain the effect of histamine H1 and H2 receptor inverse agonists and opens up new venues for novel therapeutic applications.

Investigation of the distributional homogeneity on chlorpheniramine maleate tablets using NIR-CI.

Homogeneity is the basic element of pharmaceutical analysis. Distributional Homogeneity Index (DHI) was proposed to assess the distributional homogeneity of commercial chlorpheniramine maleate (CPM) tablets. Furthermore, the divergence value of DHI value from expectation DHI (value = 1) was calculated to obtain the CPM distributional homogeneity. The distribution of commercial CPM tablets from six brands was successfully visualized using near infrared chemical imaging (NIR-CI) coupled with characteristic wavenumber method and binary image. Besides, content homogeneity of CPM was obtained through calculating the proportion of white region in the binary image. The result demonstrated that the distributional homogeneity of brand 4 was to be the best among all the brands, following by brand 2, brand 3, brand 5, brand 6 and brand 1. Furthermore, the sequence of the content uniformity was different from the distributional homogeneity, which demonstrated that content uniformity could not represent the distributional homogeneity. This work was a significant method guideline to assess the distributional homogeneity in pharmaceutical field.

Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats.

It seems that histamine release in the site of neuronal injury could contribute to the neuropathic pain mechanism. In the present study, we investigated the anti-allodynic effects of chronic administration of different classes of histamine H1 and H2 receptor antagonists on neuropathic nociceptive behavior following tibial nerve transection (TNT) in rats. Peripheral neuropathy was induced by TNT surgery. We performed acetone tests (AT) to record cold allodynia, Von Frey tests (VFT) to measure mechanical allodynia, double plate test (DPT) to evaluate thermal place preference/avoidance and open field test (OFT) for evaluation of animal activity. TNT rats showed a significant mechanical and cold allodynia compared to the sham group. Chlorpheniramine (5 and 15 mg/kg, i.p) significantly attenuated cold allodynia and prevented cold plate avoidance behavior and at the dose of 15 mg/kg remarkably decreased mechanical allodynia. Fexofenadine (10 and 30 mg/kg, p.o) significantly attenuated the mechanical allodynia and prevented cold plate avoidance. Ranitidine (5 and 15 mg/kg, i.p) significantly prevented cold plate avoidance behavior and at the dose of 15 mg/kg notably improved mechanical and cold allodynia. Famotidine (1 and 3 mg/kg, p.o) was ineffective on all nociceptive tests. Gabapantin (100 mg/kg, p.o) significantly improved all types of nociceptive behaviors. These results indicate that both blood brain barrier penetrating (chlorpheniramine) and poorly penetrating (fexofenadine) histamine H1 receptor antagonists could improve the neuropathic pain sign, but only the blood brain barrier penetrating histamine H2 receptor antagonist (ranitidine) could produce anti-allodynic effects in the TNT model of neuropathic pain in rats.

Stability indicating HPLC-DAD method for analysis of Ketorolac binary and ternary mixtures in eye drops: Quantitative analysis in rabbit aqueous humor.

Ketorolac tromethamine (KTC) with phenylephrine hydrochloride (PHE) binary mixture (mixture 1) and their ternary mixture with chlorpheniramine maleate (CPM) (mixture 2) were analyzed using a validated HPLC-DAD method. The developed method was suitable for the in vitro as well as quantitative analysis of the targeted mixtures in rabbit aqueous humor. The analysis in dosage form (eye drops) was a stability indicating one at which drugs were separated from possible degradation products arising from different stress conditions (in vitro analysis). For analysis in aqueous humor, Guaifenesin (GUF) was used as internal standard and the method was validated according to FDA regulation for analysis in biological fluids. Agilent 5 HC-C18(2) 150×4.6mm was used as stationary phase with a gradient eluting solvent of 20mM phosphate buffer pH 4.6 containing 0.2% triethylamine and acetonitrile. The drugs were resolved with retention times of 2.41, 5.26, 7.92 and 9.64min for PHE, GUF, KTC and CPM, respectively. The method was sensitive and selective to analyze simultaneously the three drugs in presence of possible forced degradation products and dosage form excipients (in vitro analysis) and also with the internal standard, in presence of aqueous humor interferences (analysis in biological fluid), at a single wavelength (261nm). No extraction procedure was required for analysis in aqueous humor. The simplicity of the method emphasizes its capability to analyze the drugs in vivo (in rabbit aqueous humor) and in vitro (in pharmaceutical formulations).

Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology.

The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.