Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

Establishment and Validation of a Transdermal Drug Delivery System for the Anti-Depressant Drug Citalopram Hydrobromide.

To enhance the bioavailability and antihypertensive effect of the anti-depressant drug citalopram hydrobromide (CTH) we developed a sustained-release transdermal delivery system containing CTH. A transdermal diffusion meter was first used to determine the optimal formulation of the CTH transdermal drug delivery system (TDDS). Then, based on the determined formulation, a sustained-release patch was prepared; its physical characteristics, including quality, stickiness, and appearance, were evaluated, and its pharmacokinetics and irritation to the skin were evaluated by applying it to rabbits and rats. The optimal formulation of the CTH TDDS was 49.2% hydroxypropyl methyl cellulose K100M, 32.8% polyvinylpyrrolidone K30, 16% oleic acid-azone, and 2% polyacrylic acid resin II. The system continuously released an effective dose of CTH for 24 h and significantly enhanced its bioavailability, with a higher area under the curve, good stability, and no skin irritation. The developed CTH TDDS possessed a sustained-release effect and good characteristics and pharmacokinetics; therefore, it has the potential for clinical application as an antidepressant.

Pharmacokinetics and Brain Delivery of Citalopram Hydrobromide Thermosensitive Nasal Gel in Rats / 中国药学杂志

OBJECTIVE: To investigate the pharmacokinetics of citalopram hydrobromide(CTH)thermosensitive nasal gel and further evaluate its brain delivery in rats. METHODS: The concentrations of CTH in rat plasma and brain tissue were determined by HPLC method. With intragastric administration (ig) of CTH solution as control, CTH thermosensitive nasal gel was intranasally given to rats and the concentrations of CTH in plasma and brain tissues were then determined. Moreover, the main pharmacokinetic parameters of CTH in plasma and brain tissues such as tmax, ρmax,relative bioavailability (Fr) and drug targeting efficiency (DTE) were estimated. RESULTS: Main pharmacokinetic parameters of CTH following nasal and ig administration to rats such as tmax and ρmax were 5 and 45 min, 2 152.86 and 589.68 ng•mL-1 in plasma, and 5 and 45 min, 17 660.56 and 1 171.68 ng•g-1 in brain tissue, respectively. Finally, the Fr and DTE of CTH thermosensitive nasal gel were found to be 184.91% and 250.03%, respectively. CONCLUSION: CTH thermosensitive nasal gel may be an ideal non-oral new dosage form with many advantages such as rapid in vivo absorption, high bioavailability and obvious brain delivery characteristics.

Formulation Optimization of Citalopram Hydrobromide Thermosensitive Nasal Gel and Its In Vitro Properties / 中国药学杂志

OBJECTIVE: To optimize the formulation of citalopram hydrobromide (CTH ) thermosensitive nasal gel and further evaluate its in vitro properties. METHODS: With gelling temperature and gelling time as evaluating indexes, central composite design-response surface and single factor experimental design method were used to optimize the formulation of CTH thermosensitive nasal gel by using poloxamer 407(F127) and carbomer 940 (CP940) as gel materials. Meanwhile, nasal mucosa permeation enhancer for CTH was then sieved by using Franz diffusion cell and ex vivo sheep nasal mucosa as experimental model. Finally, CTH thermosensitive nasal gel was prepared with cold method and then its in vitro properties was evaluated. In vitro cumulative erosion and cumulative release rate of the drug thermosensitive nasal gel were investigated by membrane-free dissolution method and dialysis membrane method, respectively. Moreover, the effect of temperature and pH on the viscosity of the drug nasal gel formulation was also evaluated. RESULTS: The optimal formulation of the thermosensitive nasal gel consisted of CTH 8.0%, F127 20.27%, CP940 0.17%, DM-β-CD 3.0%, ethylparaben 0.05% and distilled water. The gelling temperature, gelling time and pH of the drug thermosensitive nasal gel were found to be about 32.5 ℃,42 s and 5.0, respectively. The in vitro cumulative erosion and cumulative release percentage were both greater than 90% in 55 min and furthermore there was good linear correlation between these two parameters (r=0.998 6). Additionally, in vitro cumulative release of the drug from the gel formulation was determined to be 92% within 8 h, which conformed to Higuchi kinetic equation. Furthermore, the viscosity of the drug nasal gel was influenced by temperature as well as pH in different extent. CONCLUSION: The optimized formulation of the CTH thermosensitive nasal gel with central composite design-response surface method and single factor design method shows suitable gelling temperature, gelling time, pH value for nasal preparation and obvious in vitro drug sustained release characteristics.

Development of bioanalytical HPLC method for simultaneous determination of the antialzhiemer, donepezil hydrochloride and the antidepressant, citalopram hydrobromide in raw materials, spiked human plasma and tablets dosage form.

OBJECTIVES: A novel, fast and sensitive HPLC method has been developed for the simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and Citalopram hydrobromide (CTP) in raw materials, spiked human plasma and tablets. MATERIALS AND METHODS: Elution of both drugs was achieved with very good resolution using a RP-C18 chromatographic column, samples were analyzed using Hypersil Gold (100mm×4.6mm), 5µm particle size column and an isocratic binary mobile phase consists of phosphate buffer (0.05 M): acetonitrile (65:35). A Diode array detector at wavelength 232nm was used. Chromatographic separation was within a short run time (less than 7minutes) for both drugs. RESULTS: Retention times for DON and CTP were 4.5 and 5.8min, respectively. Linear calibration curves were obtained for DON and CTP over the concentration ranges of 0.1-10 and 0.1-50µg/mL. The mean extraction recoveries from spiked plasma were 93.22 and 92.64 for DON and CTP, respectively. The limits of detection and quantification were 0.017, 0.035µg/mL and 0.052, 0.106µg/mL for DON and CTP, respectively. CONCLUSION: The proposed method was successfully applied to the analysis of the cited drugs in raw materials, spiked human plasma and tablets with excellent accuracy and precision.

Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain.

Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2-adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2-adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2-adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax = -44 ± 4%; p < 0.001) and in PFC (Emax = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax = -36 ± 4%). Clonidine administration (0.625-20 µg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50 = 3.2 ± 0.4 µg/kg) and saline-treated groups (ED50 = 2.6 ± 0.5 µg/kg). No significant differences between groups were found in ED50 values. The α2-adrenoceptor agonist UK14304 stimulated specific [35S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2-adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2-adrenoceptor sensitivity.

Effect of citalopram hydrobromide tablets on cognitive function and inflammatory factors in patients with recurrent bipolar disorder / 药物评价研究

Objective To investigate the effect of citalopram hydrobromide tablets on cognitive function and inflammatory factors in patients with recurrent bipolar disorder (BPD),and to analyze its possible mechanism of action.Methods 104 patients with recurrent BPD in our hospital from July 2014 to December 2015 were selected,and they were divided into observation group and control group by random number table,52 cases in each group.Control group was given sodium valproate,while observation group was given citalopram hydrobromide tablets and sodium valproate.After 8-week treatment,the emotional state,cognitive function,inflammatory factors were compared between the two groups.Results Before treatment,HAMD score,BPMS score of two groups were not statistically significant.After 8 weeks of treatment,HAMD score and BPMS score of two groups were significantly lower than those in the same group before treatment (P ＜ 0.01);and the observation group HAMD score and BPMS score were significantly lower than the control group (P ＜ 0.01).Before treatment,TMT-A,TMT-B time of two groups were not statistically significant.After 8 weeks of treatment,TMT-A and TMT-B time of two groups were significantly shorter than the same group before treatment (P ＜ 0.05).TMT-A TMT-B in the observation group were significantly shorter than the control group (P ＜ 0.05).The content of serum MIF,IL-1 beta and IL-6 in two groups before treatment were not statistically significant.After 8 weeks of treatment,the contents ofMIF,IL-1 beta,IL-6 in two groups were significantly lower than the same group before treatment (P ＜ 0.05).And the levels of serum MIF,IL-1 beta,IL-6 in observation group were significantly lower than the control group (P ＜ 0.05).Conclusion Citalopram hydrobromide tablets can relieve clinical symptoms,improve cognitive function,and it possibly has relations with inhibiting the expression of inflammatory factors.

Clinical observation on efficacy of Modified Chaihu Shugan Granule for treating post ischemic stroke depression / 中草药

Objective: To observe the efficacy of Modified Chaihu Shugan Granule on post ischemic stroke depression (PSD) patients, and to explore its effect on serum brain-derived neurotrophic factor (BDNF). Methods: Totally 100 patients with PSD were randomly devided into treatment group (50 cases) and control group (50 cases). Both groups were given the conventional treatment of ischemic cerebrovascular disease, while the control group also took citalopram hydrobromide, once a day, 20 mg each time. Additionally, the treatment group was given Modified Chaihu Shugan Granule. The therapeutic course for all was 8 weeks. Before treatment and 4, 8 weeks after treatment, scores of Hamilton depression rating scale (HAMD) and Barthel Index of both groups were observed to evaluate clinical effects. Serum levels of BDNF were detected at the same time. Results: Total effective rate of clinical effects in the treatment group (94.00%) was better than that of the control group (72.00%) (P<0.05). Compared with before treatment in the same group, HAMD scores all obviously decreased but the scores of Barthel Index and serum levels of BDNF increased (P<0.01), while those after the treatment for 8 weeks showed greater improvements (P<0.01). Separately, HAMD scores of the treatment group were lower than those of the control group at 4 and 8 weeks after the treatment (P<0.01), while the scores of Barthel Index increased all along (P<0.01). Serum levels of BDNF in the treatment group were obviously higher than those in the control group at 4 weeks after the treatment (P<0.05), while it was a significant difference at 8 weeks (P<0.01). Conclusion: Modified Chaihu Shugan Granule used for treating the patients with PSD could improve the clinical efficacy, activities of daily living, and depressive state. Its mechanism might be associated with inhibiting serum levels of BDNF.

Utility of eosin Y as a complexing reagent for the determination of citalopram hydrobromide in commercial dosage forms by fluorescence spectrophotometry.

An accurate, selective and sensitive spectrofluorimetric method was developed for the determination of citalopram hydrobromide in commercial dosage forms. The method was based on the formation of a fluorescent ion-pair complex between citalopram hydrobromide and eosin Y in the presence of a disodium hydrogen phosphate/citric acid buffer solution of pH 3.4 that was extractable in dichloromethane. The extracted complex showed fluorescence intensity at λem = 554 nm after excitation at 259 nm. The calibration curve was linear over at concentrations of 2.0-26.0 µg/mL. Under optimized experimental conditions, the proposed method was validated as per ICH guidelines. The effect of common excipients used as additives was tested and the tolerance limit calculated. The limit of detection for the proposed method was 0.121 µg/mL. The proposed method was successfully applied to the determination of citalopram hydrobromide in commercial dosage forms. The results were compared with the reference RP-HPLC method.

QbD approach to investigate product and process variabilities for brain targeting liposomes.

Efficacy of central nervous system-acting medications is limited by its localization and ability to cross the blood-brain barrier (BBB); therefore, the crux is in designing delivery systems targeted to cross the BBB. Toward this objective, this study proposed pegylated and glycosylated citalopram hydrobromide (Cit-HBr) liposomes as a delivery approach for brain targeting. The multicomponent liposomes were evaluated for drug encapsulation, vesicular size, size distribution, conductivity and drug release characteristics. Moreover, the interaction among the employed components was evaluated by Fourier transform infrared, differential scanning calorimetric and X-ray diffraction analysis. Through a systematic screening design of formulation and process variables in the optimization phase, an improvement of Cit-HBr loading, fine vesicular size with narrow size distribution, greater stability and sustained release features were achieved. The compatibility studies unveiled a significant interaction between Cit-HBr and dicetyl phosphate to control drug encapsulation and release properties. The optimization process showed a minimal range of design space to achieve the preset desirability; more precisely dicetyl phosphate, polyethylene glycol, N-acetyl glucosamine and freeze-thaw cycles of 3%, 5%, 4% and 2 cycles, respectively, were used. Using brain endothelial cell models, the optimized formulations showed an acceptable cell viability with preserved monolayer integrity and an enhanced flux and permeability. Thus, this study has proposed an optimized pegylated and glycosylated vector that is a promising step for brain targeting.

Penicillin G as a novel chiral selector in capillary electrophoresis.

The penicillin sub-class of ß-lactam antibiotics has not been examined for its enantiodiscriminating abilities in capillary electrophoresis (CE) until date. The present work was therefore designed to evaluate penicillin G potassium salt (PenG) as an ion-pair chiral selector (CS) using CE for its several attributes, namely, high solubility in water and lower alcohols, structure allowing multiple interactions with analytes and cost-effectiveness. Systematic experiments were performed to investigate the effect of composition of background electrolyte, applied voltage and capillary temperature on chiral separation. Baseline resolutions of enantiomers of five basic chiral drugs (namely, darifenacin, citalopram, sertraline, propranolol and metoprolol) were attained using a background electrolyte composed of water:methanol (90:10, v/v) and consisting of 10.7 or 16.1mM CS at 20°C using an applied voltage of 5kV.

Pharmacokinetics and Bioequivalence of Domestic Citalopram Hydrobromide Tablet in Healthy Volunteers / 中国药房

OBJECTIVE:To compare the pharmacokinetics and bioavailability between domestic(test)and imported(reference)citalopram hydrobromide tablets and to evaluate the bioequivalence of the two preparations.METHODS:A single dose of 40 mg test tablet or reference tablet of citalopram hydrobromide was administered by randomized crossover way in 20 healthy male volunteers and the plasma concentrations of the citalopram hydrobromide were determined by HPLC.The pharmacokinetic parameters were calculated with 3p97 pharmacokinetic program and the bioavailability was evaluated.RESULTS:The concentration-time curves of two preparations fitted two compartment mode1.The pharmacokinetic parameters of the test preparation versus the reference preparation were as follows,Cmax:(147.00?86.04)ng?mL-1 vs.(154.13?87.57)ng?mL-1;tmax:(4.55?1.35)h vs(4.75?1.65)h;AUC0～196:(6 590.69 ? 1 866.00)ng?h?mL-1 vs.(7 156.26?2 181.18)ng?h?mL-1;AUC0～∞:(7 767.56?2 193.92)ng?h?mL-1 vs.(8 433.45?2 631.88)ng?h?mL-1.The relative bioavailability of the test citalopram hydrobromide tablet was(92.10?18.68)%.CONCLUSION:The domestic and the reference citalopram hydrobromide tablet are bioequivalent.