Studies on orally disintegrating tablet of diphenhydramine hydrochloride and caffeine / 药学实践杂志

Objective To optimize the formulation and preparation of diphenhydramine hydrochloride and caffeine orally disintegrating tablet. Methods Melt granulation technology of steric acid and API was used to mask the unpleasant tasting of diphenhydramine hydrochloride. The tablets were prepared by direct pressing the dry powder with CCMC-Na as disintegrating agent. The formulation was optimized by orthogonal experiments to achieve the shortest disintegration time and the best taste correction. Results The optimized formula of orally disintegrating tablet was as follows： diphenhydramine hydrochloride 25 mg, caffeine 60 mg, stearic acid 25 mg, aspatan 40 mg, blueberry essence 7 mg, mannitol 45 mg, MCC 210 mg, CCMC-NA 25 mg, SDS 8 mg and magnesium stearate 5 mg. Conclusion This preparation method for orally disintegrating tablet of diphenhydramine hydrochloride and caffeine is practical and easy for quality control.

Uso de emulsiones lipídicas en el tratamiento exitoso de un caso de intoxicación por difenhidramina / Use of lipid emulsions in the successful treatment of a case of diphenhydramine poisoning / Uso de emulsões lipídicas no sucesso do tratamento de um caso de intoxicação por difenidramina

La difenhidramina tiene efectos antihistamínico anti-H1 específico y antimuscarínico que pueden ocasionar un desenlace fatal según la dosis total ingerida. Se reporta un caso de intoxicación por difenhidramina tratado de forma exitosa con emulsiones lipídicas a pesar de ingesta de dosis letal. Se presenta el caso de un paciente de 19 años que ingresó por intoxicación por difenhidramina a dosis de 25 mg/kg (1.5 g) después del tiempo de descontaminación, con toxidrome anticolinérgico, con neurotoxicidad, cardiotoxicidad (QRS y QT prolongados) y sin respuesta al enfoque inicial, se iniciaron emulsiones lipídicas y, a su vez, se logró alta temprana por evolución clínica favorable y resolución de la prolongación del intervalo QTc y del cuadro anticolinérgico. La emulsión lipídica es una opción terapéutica para disminuir la morbimortalidad y la estancia hospitalaria por contrarrestar la cardiotoxicidad y neurotoxicidad producidas por moléculas lipofílicas como la difenhidramina.

Diphenhydramine has specific anti-H1 antihistamine and antimuscarinic effects that can be fatal depending on the total dose ingested. A case of diphenhydramine poisoning successfully treated with lipid emulsions despite ingesting a lethal dose is presented. We present the case of a 19-year-old patient who was admitted for diphenhydramine intoxication at a dose of 25 mg/kg (1.5 g) after the decontamination time, with anticholinergic toxidrome, with neurotoxicity, cardiotoxicity (prolonged QRS and QT) and without response to initial approach. Lipid emulsions were started and, in turn, early discharge was achieved due to favorable clinical evolution and resolution of the prolongation of the QTc interval and the anticholinergic symptoms. Lipid emulsion is a therapeutic option to reduce morbidity and mortality and hospital stay by counteracting cardiotoxicity and neurotoxicity produced by lipophilic molecules such as diphenhydramine.

A difenidramina tem efeitos anti-histamínicos e antimuscarínicos anti-H1 específicos que podem ser fatais dependendo da dose total ingerida. Relata-se um caso de intoxicação por difenidramina tratada com sucesso com emulsões lipídicas apesar da ingestão de uma dose letal. Apresentamos o caso de uma paciente de 19 anos que foi internada por intoxicação por difenidramina na dose de 25 mg/kg (1,5 g) após o tempo de des-contaminação, com toxina anticolinérgica, neurotoxicidade, cardiotoxicidade (QS e QT prolongados) e sem resposta na abordagem inicial, iniciaram-se emulsões lipídicas e, por sua vez, obteve-se alta precoce devido à evolução clínica favorável e resolução do prolongamento do intervalo QTc e dos sintomas anticolinérgicos. A emulsão lipídica é uma opção terapêutica para reduzir a morbimortalidade e o tempo de internação por neutralizar a cardiotoxicidade e a neurotoxicidade produzidas por moléculas lipofílicas como a difenidramina.

Diphenhydramine hydrochloride asaay in compound diphenhydramine cream by HPLC / 药学实践杂志

Objective To establish the HPLC method of assay for diphenhydramine hydrochloride in compound diphenhydramine cream. Method HPLC analysis was carried on ACE5C18S/N-A66766 column (150 mm×4.6 mm, 5 µm) with the mobile phase of methanol-water-triethylamine (70:30:0.67, adjusting pH to 6.50 with phosphoric acid) at room temperature. The detection wavelength was set at 230 nm and the flow rate was 1.0 ml/min. The analyte was extracted from the cream and 20 μl of sample was injected. Results The calibration curve of diphenhydramine hydrochloride was linear in the range of 39.52-197.6 µg/ml (r=0.999 7). The average recovery of diphenhydramine hydrochloride was 100.5% (RSD=1.25%, n=9). The repeatability of the method was expressed using RSD with 0.78% (n=6). The results of assay were 101.3%, 99.83% and 99.62%. Conclusion The method is accurate, sensitive, selective and repeatable, which can be applied for improving the quality standard of compound diphenhydramine cream.

Safety pharmacological study of the compound of diphenhydramine hydrochloride and caffeine / 药学实践杂志

Objective To provide the reference resource for the safe clinical use of the compound of diphenhydramine hydrochloride and caffeine by observing its effects on the nervous system, cardiovascular system and respiratory system in experimental animals. Methods Single dose of the compound of diphenhydramine hydrochloride and caffeine was given to animals orally. The effects on climbing ability of mice and blood pressure, electrocardiogram, respiration rate and amplitude in beagle dogs were observed and recorded. Results With the dosage of the compound of diphenhydramine hydrochloride and caffeine (diphenhydramine hydrochloride / caffeine ratio is 1/2.4) at 51, 102, 204 mg/kg, there was no significant effect on the climbing ability in mice. With the dosages of 14.2, 28.3, 56.6 mg/kg for male Beagle dogs and 5.66, 14.2, 28.3 mg/kg for female Beagle dogs, no significant effects were observed in systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, ECG（P wave, R wave , T wave, QRS time, PR interval, QT interval）, respiratory rate and amplitude. Conclusion Under the experimental conditions, single oral dose of the compound of diphenhydramine hydrochloride and caffeine has no significant effect on the nervous system, cardiovascular system and respiratory system in experimental animals. Those results suggest that the compound of diphenhydramine hydrochloride and caffeine is a safe agent for clinical use.

The pharmacokinetic study on compound diphenhydramine hydrochloride and caffeine in rats / 药学实践杂志

Objective To establish an assay method for diphenhydramine hydrochloride and caffeine in rat plasma by UPLC-MS/MS for pharmacokinetic study. Methods The chromatographic separation was performed on an ACE 3 C18-PFP (3.0 mm×150 mm, 3 μm) by isocratic elution with the mobile phase of water containing 0.1% formic acid and acetonitrile (62:38, V/V). MS condition was optimized in the positive ion detection mode by multiple reaction monitoring (MRM), along with the Agilent JetStream electrospray source interface (AJS-ESI). The precursors to the product ion transitions were 256.2→167.0 (m/z) for diphenhydramine hydrochloride, 262.0→167.0 (m/z) for the internal standard (IS) diphenhydramine-D6, 195.0→138.0 (m/z) for caffeine and 204.0→116.2 (m/z) for the IS caffeine-D9. Results The calibration curve was linear in the range of 1-1×103 ng/ml for diphenhydramine hydrochloride in rat plasma (r=0.999 6), and in the range of 15-1.5×105 ng/ml for caffeine in rat plasma, (r=0.999 9). The intra-day and inter-day precision and accuracy were good (RSD<10%, RE<±10%). Pharmacokinetic studies showed that metabolic characteristics of diphenhydramine hydrochloride 10-30 mg/kg and caffeine 24-72 mg/kg were linear after intragastric administration. The two components were metabolized in rats with gender difference, the cmax and the AUC of diphenhydramine hydrochloride and caffeine were greater in female than those in males. Conclusion This method is accurate, rapid and sensitive. It can be used for the determination of diphenhydramine hydrochloride and caffeine in rat plasma collected for pharmacokinetic study. The results of pharmacokinetic studies in rats provide reliable data support for the clinical application of the compound preparation.

Simultaneous Determination of 3 Components in Compound Diphenhydramine Nasal Drop by RP-HPLC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of ephedrine hydrochloride,nitrofural and di-phenhydramine hydrochloride in Compound diphenhydramine nasal drop. METHODS:RP-HPLC method was adopted. The determi-nation was performed on Inertsil ODS-3 C18 column with mobile phase consisted of 0.05 mol/L potassium dihydrogen phosphate buf-fer(pH 7.0)-acetonitrile(gradient elution)with flow rate of 1.0 mL/min. The detection wavelength was set at 256 nm,and the col-umn temperature was 35 ℃. The sample size was 20 μL. RESULTS:The concentrations of phedrine hydrochloride,nitrofural and diphenhydramine hydrochloride ranged 122.1-366.3 μg/mL(r=0.9999),5.2-15.5 μg/mL(r=0.9998)and 31.5-94.5 μg/mL(r=0.9994),respectively. The limits of quantitation were 2.442,0.010,2.520 μg/mL,and the limits of detection were 0.810,0.003, 0.830 μg/mL,respectively. RSDs of precision,stability and reproducibility tests were lower than 1.0%. The recoveries of them were 99.2%-101.7%(RSD=0.9%,n=9),96.4%-102.0%%(RSD=1.7%,n=9),100.2%-101.9%(RSD=0.4%,n=9),respec-tively. CONCLUSIONS:The method is simple,accurate and reproducible,and can be used for simultaneous determination of ephedrine hydrochloride,nitrofural and diphenhydramine hydrochloride in Compound diphenhydramine nasal drop.

Preparation and Quality Control of Thermosensitive Nasal Gel of Ephedrine Hydrochloride and Diphen-hydramine Hydrochloride / 中国药师

Objective:To prepare the thermosensitive nasal gel of ephedrine hydrochloride and diphenhydramine hydrochloride and establish its quality control method. Methods:The amounts of P407, P188 and PEG 6000 were optimized by an orthogonal test with the gelling temperature as the index. An HPLC method was established to determine the contents of ephedrine hydrochloride and di-phenhydramine hydrochloride. Results:The optimum amount of P407, P188 and PEG 6 000 was 19%, 2% and 1%, respectively. The linear range of ephedrine hydrochloride was 1.600 0-2.400 0 mg·ml-1(r=0.999 6), and the average recovery was 99.76%with RSD of 1. 02%(n=9). The linear range of diphenhydramine hydrochloride was 0. 160 0-0. 240 0 mg·ml-1(r=0. 999 7), and the average recovery was 101. 27% with RSD of 1. 10%(n=9). Conclusion:The formula design and preparation technology of the gel are feasible. The HPLC method is suitable for the quality control of the preparation.

Research progress of pyrilamine-sensitive H+/OC antiporter / 药学学报

In recent years, a new type of organic cation transporter has been found to transport organic cation drugs like pyrilamine, diphenhydramine and oxycodone in brain capillary endothelial cells, Caco-2 cells and other cells. Its transport activity can not be inhibited by typical organic cation transporter substrates or inhibitors, and its transport characteristics are different from those reported for the organic cation transporters, such as organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), multidrug and toxin extrusion transporters (MATE) and the plasma membrane monoamine transporter (PMAT). It is a novel organic cation transporter, called pyrilamine-sensitive H+/OC antiporter. This review will present a comprehensive summary to elaborate the transport characteristics, structure of the substrates, tissue expression and the differences with other organic cation transporters.

Determination of Ethanol and Toluene Residual Solvent in Diphenhydramine Hydrochloride Raw Materia by Headspace Capillary Gas Chromatography / 中国药房

OBJECTIVE:To establish a method for the determination of residual solvent of ethanol and toluene in diphenhydr-amine hydrochloride raw material. METHODS:Headspace capillary gas charmatography and butanone as internal standard were used. The column was Agilent DB-624 capillary column,inlet temperature was 200 ℃,hydrogen flame ionization detector was 250 ℃,the carried gas was high purity nitrogen,flow rate was 3.0 ml/min with temperature programmed,the splitting-ratio was 20∶1,the containers of headspace injector were in equilibrium at 80 ℃ for 30 min,and the injection time was 1 min. RESULTS:With this chromatographic condition,ethanol,toluene and internal standard peak were well separated;there was a good linear rela-tionship of ethanol and toluene in the range of 0.02-0.8 mg/ml (r=0.999 8 and r=0.999 4);RSDs of precision and stability test were lower than 3%;recoveries were 95.50%-103.50%(RSD=2.6%,n=9) and 96.91%-103.74%(RSD=2.2%,n=9). CON-CLUSIONS:The method is simple,sensitive and accurate,and can be used for the determination of residual solvent of ethanol and toluene in diphenhydramine hydrochloride raw material.

Clinical Observation of Diphenhydramine Combined with Prednisone in the Prevention of Iodine-containing Contrast Agent Allergic Reactions / 中国药房

OBJECTIVE:To observe the success rate and safety of diphenhydramine combined with prednisone in the preven-tion of iodine-containing contrast agent allergic reactions. METHODS:1 day before surgery,42 patients with positive iodine aller-gy test was given 40 mg Prednisone tablet,orally,3 times a day,50 mg diphenhydramine was given by intramuscular injection and 1 ml iodine contrast by intravenous injection(allergy test performed again)1 h before surgery. After all patients used iodine con-trast in 15 min,vascular interventional treatment was conducted if there was no bronchospasm,angioedema,leather ball sample itchy rash,hypotension,itching and other allergic reactions. Prevention success rate were observed,and the incidence of adverse re-actions was recorded. RESULTS:Prevention success rate was 90.48%,the incidence of adverse reactions was 7.14%,and it self-improved after stopping drugs. CONCLUSIONS:Diphenhydramine combined with prednisone has high success rate in the pre-vention of iodine-containing contrast agent allergic reactions,with good safety.

Simultaneous Contents Determination of Chloramphenicol and Diphenhydramine Hydrochloride in Chloro-benzene Alcohol Solution by HPLC / 中国药房

OBJECTIVE:To establish a method for the simultaneous contents determination of chloramphenicol and diphenhydr-amine hydrochloride in Chlorobenzene alcohol solution. METHODS:HPLC was performed on the column of Diamonsil C with mo-bile phase of phosphate buffer-acetonitrile(66.5∶33.5,V/V)containing 0.01 mol/L sodium heptane,column temperature was 35 ℃, flow rate was 1 ml/min,detection wavelength was 258 nm for diphenhydramine hydrochloride and 277 nm for chloramphenicol, the injection volume was 10μl. RESULTS:The linear range was 34.8-139.4μg/ml for chloramphenicol(r=0.999 8)and 93.0-930.5μg/ml for diphenhydramine hydrochloride (r=0.999 8);RSDs of precision,stability and reproducibility tests were lower than 2.0%;recoveries were 97.70%-104.02%(RSD=2.2%,n=9)and 96.72%-101.72%(RSD=1.6%,n=9). CONCLUSIONS:The method is specific,accurate with good precision,and suitable for the quality control of Chlorobenzene alcohol solution.

Simultaneous Determination of Camphor and Menthol in Compound Diphenhydramine Liniment by GC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of camphor and menthol in Compound diphen-hydramine liniment. METHODS:GC was performed on the column of Agilent 19095N-123 INNOWAX capillary column,column temperature was 120 ℃,injection volume temperature was 220 ℃,FID detector was used with the temperature of 260 ℃,carrier gas was nitrogen gas,flow of column was 6.0 ml/min,air was 450 ml/min,hydrogen gas was 40 ml/min,split ratio was 20∶1 and injection volume was 1 μl. RESULTS:The linear range of mass concentration was 0.612-6.12 mg/ml(r=0.999 9)for camphor and 0.593-5.93 mg/ml(r=0.999 9)for menthol;RSDs of precision,stability and reproducibility tests were lower than 2%;the recov-eries were respectively 98.0%-100.7%(RSD=1.0%,n=6)and 98.7%-100.7%(RSD=0.7%,n=6). CONCLUSIONS:The meth-od is simple,accurate and reproducible,and can be used for the contents determination of camphor and menthol in Compound di-phenhydramine liniment.

New Coumarinic Azo-Derivatives of Metoclopramide and Diphenhydramine: Synthesis and In Vitro Testing for Cholinesterase Inhibitory Effect and Protection Ability Against Chlorpyrifos

This study aims to synthesize new coumarin azo compounds of metoclopramide and diphenhydramine and to evaluate their in vitro cholinesterase inhibitory effects and protection abilities against chlorpyrifos. Methods: Two series of azo coumarin compounds were synthesized. Series I compound resulted from the diazotization of metoclopramide and then coupling with coumarin and 4-methyl coumarin to give compounds 1 and 2 respectively. Series II compound resulted from the diazotization of 7-aminocoumarin and 7-amino 4-methyl coumarin and then coupling with diphenhydramine to give compounds 3 and 4 respectively. The new compounds were tested for their in vitro cholinesterase inhibitory effect and protection ability against chlorpyrifos using the modified Elman electrometric method. Results: Metoclopramide derivatives with coumarin show selectivity protection for ChE against chlorpyriphos inhibitory effect as protect BChE and increase the inhibition of the AChE, or the opposite. Conclusion: Diphenhydramine derivatives with coumarin show more protective ability for both BChE and AChE as one of them shows the maximum protection for all concentration. However, the other derivative shows different manner as the low concentrations act as metoclopramide derivatives while the high concentration act as first diphenhydramine derivative (protect both AChE and BChE).

Formulation and evaluation of Diphenhydramine hydrochloride and Ibuprofen soft gelatin capsules.

The present invention provides a new composition for treating pain-associated sleep disturbances, especially shortened sleep duration, comprising ibuprofen and diphenhydramine hydrochloride. In the present work the soft gelatin capsules were formulated comprising 25 mg diphenhydramine hydrochloride and 200 mg ibuprofen using polyethylene glycol 400, propylene glycol, potassium hydroxide and purified water. The prepared soft gelatin capsules were evaluated for weight variation test, assay, dissolution and disintegration. The capsules had a fill weight of 550 ± 5%, Disintegration time of 5-6 minutes and showed 97.00% to 99.50% of labeled amount of ibuprofen and diphenhydramine hydrochloride indicating uniformity in drug contents. The capsules containing 75 mg/capsule of propylene glycol released 99.40% of diphenhydramine hydrochloride and 99.70% of ibuprofen at the end of 60 minutes. Thus, it may be concluded that soft gelatin capsules of diphenhydramine hydrochloride and ibuprofen could be successfully prepared with existing technology and machinery which have a commercial viability and enhance patient compliance with improved bioavailability.

Cardiac Toxicity Following a Diphenhydramine Overdose

PURPOSE: This study was designed to analyze the contributing factors, as well as the incidence and nature of the cardiac toxicity, in patients presenting with diphenhydramine overdose. METHODS: We retrospectively reviewed the medical records of the intoxicated patients who presented to the ED of Korea University Anam Hospital from January 2008 to December 2010. Those patients who visited due to a diphenhydramine overdose were selected and the following features were recorded for analysis: the general characteristics, vital signs, the amount of ingested diphenhydramine, the time interval from ingestion to presentation, the coingested drugs (if any), the toxicities and the ECG findings. Cardiac toxicity, while defined mainly in terms of the temporary ECG changes such as QTc prolongation, right axis deviation, QRS widening, high degree AV block and ischemic changes, also encompassed cardiogenic shock, which is a clinical finding. RESULTS: A total of eighteen patients were enrolled. Of the eighteen patients, eight had ingested diphenhydramine only, while ten had ingested other drugs in addition to diphenhydramine. The most commonly observed toxicity following diphenhydramine overdose included cardiac toxicity (78%). Cardiac toxicity was observed in all the patients who presented to the emergency department 2 hours after ingestion. The patients with QTc prolongation turned out to have ingested significantly larger amounts of diphenhydramine. CONCLUSION: QTc prolongation and right axis deviation were common findings for the patients with a diphenhydramine overdose. QTc prolongation was more likely to occur with ingesting larger amounts of diphenhydramine. Close monitoring is mandatory for patients who have ingested large amounts of diphenhydramine to prevent such potentially lethal cardiac toxicity.

Comparative Analysis of Overdose with Common Sleep-aid Medications: Doxylamine vs Diphenhydramine

PURPOSE: The previous studies on H1 antihistamine overdose have generally been limited to cases of acute doxylamine succinate (DS) poisoning, yet there have been some studies on diphenhydramine (DPH) overdosing. But many clinicians consider the two drugs to be very similar and to have similar ingredients. The purpose of this study was to clarify the toxicologic characteristics and clinical outcomes between DS and DPH poisoning/overdose. METHODS: We reviewed the medical and intensive care records of the patients with acute DS or DPH poisoning and who admitted to our emergency department from January 2008 and April 2010. We collected patient information regarding the features of the poisoning and the clinical and demographic characteristics. The patients were assessed for the clinical outcomes, the GCS, the PSS (Poisoning Severity Score) and the SOFA (Sequential Organ Failure Assessment). RESULTS: Fifty seven patients (45 cases of DS poisoning and 12 cases of DPH poisoning) were enrolled. Compared with the DS group, the DPH group had higher incidences of intubation, serious mental change, QTc prolongation and ECG conduction abnormality (p=0.041, <0.001, 0.014 and 0.044, respectively). The DPH group had a higher PSS and a longer ICU stay. The peak CPK time and the CPK normalization time were longer for the patients with rhabdomyolysis due to DS poisoning. CONCLUSION: Two common H1 antihistamines, doxylamine and diphenhydramine, are in the same ethanolaminestructural class, but the toxico-clinical outcomes are different according to many aspects. Therefore, clinicians could take a careful approach for the differential diagnosis and management between DS and DPH poisoning.

A Case of Electrocardiographic and Mental Change in a Patient with a Diphenhydramine Overdose

The antihistaminic drug diphenhydramine is mainly used as a sedative, hypnotic and antiemetic. In many countries it is available over-the-counter, very common, and generally regarded as a harmless drug. However, diphenhydramine overdose can result in cardiotoxicity due to its ability to block fast sodium channels in a manner analogous to classic Vaughan-Williams type IA antidysrhythmic agents. As such, cardiotoxicity from diphenhydramine resembles that of the tricyclic antidepressant agents. Here we report a case of a 52 year old man who ingested 2,000 mg of diphenhydramine and presented with an altered mental state and an electrocardiographic change. His electrocardiogram showed sinus tachycardia with a rate 145 beat/min, a QRS interval of 88 ms, and a QTc of 556 ms. He had a wide anion gap metabolic acidosis. He was treated with intravenous sodium bicarbonate and supportive therapy. His clinical manifestations waned and he was transferred to another hospital nearby his hometown.

A Case of Seizure in Diphenhydramine Overdose

A 21-year-old woman ingested 1,250 mg of diphenhydramine in a single overdose. Diphenhydramine, a rare ingredient in over-the-counter medication, is used to treat insomnia in Korea. Toxicity is usually limited to anticholinergic symptoms. The standard approach to therapy for the treatment of diphenhydramine overdose is supportive care, including physostigmines and sodium bicarbonates. Here, we review the literature and for the first time report a case of acute diphenhydramine overdosage in Korea, complicated with seizures.

Effect of Four Penetration Enhancers on Percutaneous Absorption of Diphenhydramine Hydrochloride / 中国药房

glycerol,and the best penetrable concentrations for it were 0.5%,0.5% and 0.2%,respectively.No obvious penetration efficacy was noted for glycerol.CONCLUSIONS: 4 kinds of penetrations enhances can increase the percutaneous absorption of DH under the certain concentration.

Preparation and Quality Control of Diphenhydramine Hydrochloride Gel / 中国药房

OBJECTIVE:To prepare diphenhydramine hydrochloride gel and establish its quality control.METHODS:The best formula was optimized by orthogonal design with sodium carboxymethyl cellulose and so on as the base materials,the content of diphenhydramine hydrochloride was determined by UV-spectrophotometry at the wavelength of258nm.RE?SULTS:The diphenhydramine hydrochloride gel was even,fine and which has a good dispersivity;In the concentration range of100～400?g/ml,the diphenhydramine hydrochloride had a linear relationship(r=0.9999,n=6),the average recovery was99.95%,RSD=0.95%(n=9).CONCLUSION:The preparation was stable in quality and reliable in quality control method.