Formulation and optimization of dimenhydrinate emulgels for topical delivery using response surface methodology.

Development of dimenhydrinate (DMN) emulgel formulation has been described in this work with enhanced permeation for transdermal delivery of DMN for effective management of motion sickness. Various DMN emulgel formulations were prepared using central composite design in response surface methodology. Propylene glycol and olive oil were used in varying ratios as permeation enhancers along-with carbopol-934 as gelling agent. Prepared formulations were evaluated by physico-chemical properties, stability and Fourier transform infrared spectroscopy (FTIR) studies. In-vitro drug release was studied using cellophane membrane. Formulation F2 showed maximum drug permeation following diffusion-based release mechanism and was used in further studies. Rat skin was used in Franz cell for ex-vivo studies to determine various permeation kinetic parameters. FTIR studies provided no evidence of chemical interaction between DMN and polymers used, whereas molecular docking revealed formation of a stable complex in the presence of aqueous environment with stable intermolecular binding and the complex was well hydrated. No evidence of skin irritation was observed in human volunteers following application of the optimized formulation. Histopathology data of the rat skin showed a decreased proliferation of the lymphocytes whereas monocytes were induced. In conclusion, combination of propylene glycol and olive oil was successfully employed for delivery of DMN through transdermal route with good permeability and prolonged release time that can be highly beneficial in treating motion sickness in unusual circumstances.

Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine-induced wheal formation: a pilot study.

BACKGROUND: Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine. HYPOTHESIS/OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (≈5 mg/kg diphenhydramine). ANIMALS: Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design. METHODS AND MATERIALS: Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation. RESULTS: There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (± 20) and 124 (± 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (± 7.1) and 11.6 (± 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs. CONCLUSION: Oral absorption of diphenhydramine was approximately three times greater with a longer half-life when it was administered as the combination product dimenhydrinate.

Intranasally administered in situ gelling nanocomposite system of dimenhydrinate: preparation, characterization and pharmacodynamic applicability in chemotherapy induced emesis model.

The aim of the current manuscript was to test the applicability of a nanocomposite system of penetration enhancer vesicles (PEVs) within polymeric in situ forming gel network composed of poloxamer and hyaluronic acid for the intranasal delivery of the antiemetic dimenhydrinate (DMH). PEVs were prepared using phospholipids and labrasol/transcutol/PEG 400 as penetration enhancers, and characterized for entrapment efficiency (EE%), particle size, zeta potential and morphology. The nanocomposite in situ forming gel system was characterized for its sol-gel temperature, viscosity and mucoadhesiveness, and was pharmacodynamically tested on a cisplatin induced emesis model in rats in terms of food, water, kaolin intake and stomach weight content. The selected PEVs formula displayed EE% of 83% for DMH, particle size of 121 nm and a surface charge of 0.83 mV. The selected nanocomposite in situ gelling formula showed a viscosity of 2.13 Pa.S, mucoadhesive force of 0.62 N and DMH controlled release over 6 hours. The pharmacodynamic study showed the superiority of the nanocomposite in situ gelling formula; being administered at a lower dose than the oral marketed formula. The described nanocomposite system proved to be successful for the intranasal delivery of DMH, thus presenting a promising delivery modality for similar antiemetics.

Preparation and in-vivo evaluation of dimenhydrinate buccal mucoadhesive films with enhanced bioavailability.

Dimenhydrinate (DMH)-loaded buccal bioadhesive films for the prevention and treatment of motion sickness were prepared and optimized. This study examines the rate of drug release from the films for prolonged periods of time to reduce or limit the frequency of DMH administration. Based on preliminary studies using various polymers and concentrations, hydroxyethylcellulose (2.5, 3.0, and 3.2%), and xanthan gum (2.8%) were chosen as matrix polymers. The films were analyzed with respect to their mechanical, physicochemical, bioadhesive, swelling, and in-vitro release properties. In in-vivo pharmacokinetic studies, xanthan gum-based DMH buccal film was associated with significantly increased DMH plasma levels between 1 h and 5 h after DMH dosing when compared with an oral drug solution. The area under the curve AUC0-7 h value of the mucoadhesive buccal film was two-fold higher than the oral DMH solution. Histological analysis revealed that DMH films cause mild morphological and inflammatory changes in rabbit buccal mucosa. The DMH buccal film is effective for approximately 7 h, thus representing an option for single-dose antiemetic therapy. This dosage regimen could be particularly beneficial for chain travelers who travel for long periods of time.

Formulation and evaluation of in situ gelling system of dimenhydrinate for nasal administration.

Nasal drug delivery has a variety of advantages. Drugs can be rapidly absorbed through the nasal mucosa, giving rapid onset of action, and avoiding presystemic metabolism. In present study; the nasal mucoadhesive in situ gels of anti-emetic drug Dimenhydrinate were formulated using Gellan gum and Carbopol 934P. The in situ gels so prepared were characterized for gelation, viscosity, gel strength, mucoadhesion, drug content, drug diffusion, ex vivo permeation and histopathological studies. The optimized formulation passing from above tests was further subjected to accelerated stability study. It retained the good stability over the period of 90 days. From the overall performance this in situ gel seems to be an effective delivery system for the nasal route.

Determination of dimenhydrinate in human plasma by liquid chromatography-electrospray tandem mass spectrometry: application to a relative bioavailability study.

Here we present a sensitive and specific liquid chromatography-tandem mass spectrometric method for the quantification of dimenhydrinate (I) in human plasma. Sample preparation is conducted using citalopram (II) addition as an internal standard (IS), liquid-liquid extraction with basified plasma using a mixture hexane/acetate (1:1, v/v) as the extracting solvent, and the final extract reconstituted in the mobile phase. I and II (IS) were injected in a C8 column with the mobile phase composed of methanol:isopropanol:water:formic acid (78.00:19.92:2.00:0.08, v/v/v/v) and monitored using a positive electrospray source with tandem mass spectrometry analyses. The selected reaction monitoring (SRM) was set using precursor ion and product ion combinations of m/z 256.0>167.0 and m/z 325.0>109.0 for I and II, respectively. The limit of quantification (LOQ) was 0.4 ng/mL, the dynamic range being 0.4-200 ng/mL. Validation results on linearity, specificity, accuracy, precision and stability, as well as on application to the analysis of plasma samples taken up to 24 h after oral administration of 100 mg of dimenhydrinate in healthy volunteers demonstrated its applicability to bioavailability studies.

Release characterization of dimenhydrinate from an eroding and swelling matrix: selection of appropriate dissolution apparatus.

The objective of this study was to evaluate the effect of various hydrodynamic conditions on drug release from an eroding and gel forming matrix. For this purpose, dimenhydrinate was formulated with hydroxypropyl methyl cellulose and polyethylene oxide into matrix tablets and the drug release in deionized water was evaluated spectrophotometrically, using multiple dissolution methods, namely, compendial USP 27-apparatus I-III, and a modified apparatus II (paddle over mesh). Various hydrodynamic conditions were examined at the agitation rates of 50 and 100 rpm for apparatus I and II, and 5 and 8 dpm for apparatus III. Similarity and difference factors were calculated using compendial apparatus II release data as reference. Among the methods, apparatus I showed the slowest initial release, while the release from apparatus III at 8 dpm was the highest among the methods. This was further compared via the dissolution half-times and calculation of the average release rate for each method. Based on the analysis of difference and similarity factors (f(1) and f(2)), the study clearly demonstrates the significance of hydrodynamics and the choice of a dissolution method and their respective effect on overall release profiles when erodible and swellable matrix systems are involved. Full surface exposure with insertion of mesh device in apparatus II may provide more realistic conditions especially when release data are to be used in developing IVIVCs.

Pharmacokinetics of diphenhydramine in healthy volunteers with a dimenhydrinate 25 mg chewing gum formulation.

This pharmacokinetic study evaluated diphenhydramine in the plasma of healthy volunteers after a single 25 mg oral dose of dimenhydrinate (diphenhydramine theophyllinate), corresponding to 12.7 mg diphenhydramine, in a chewing gum formulation. Seven volunteers (4 men, 3 women; age: 26.3 +/- 1.2 years; body weight: 63.1 +/- 4.1 kg; height: 172.4 +/- 4.6 cm) chewed the gum for 1 h. Blood samples (10 ml) were collected at different time intervals up to 24 h. Blood plasma was subsequently processed and analyzed for diphenhydramine content using a GLC method and an NPD detector. Analytical data revealed the following kinetic parameters: AUC(0-24h): 155.2h x ng x ml(-1); AUC(0-infinity): 195.3 h x ng x ml(-1); Mean resident time: 16 h; t(1/2): 10 h; C(max): 14.5 ng x ml(-1); t(max): 2.6 h; and plasma clearance: 9.0 ml x min(-1) x kg(-1). This study indicates that the pharmaceutical formulation employed provided sustained plasma concentrations of diphenhydramine, presumably sufficient to support its clinical efficacy towards motion sickness owing to the almost complete (> 95%) release by the formulation of the active principle. Moreover, the maximal concentrations of diphenhydramine attained in plasma were much lower than the concentration threshold needed to produce drowsiness.

Effect of propylene glycol on the disposition of Dramamine in the rabbit.

Dimenhydrinate (Dramamine) is the 8-chlorotheophylline salt of diphenhydramine. Dramamine is commercially available as a solution containing 50 mg dimenhydrinate per ml in 50% propylene glycol/5% benzyl alcohol. Studies in which New Zealand albino female rabbits received dimenhydrinate, i.v. and/or im, revealed evidence of inhibition of drug clearance apparently due to exposure to vehicle. Following im administration of 8-chlorotheophylline to naive rabbits, peak drug levels of 420 ng/ml were attained in 60 min which declined exponentially to near baseline levels within 7 hr. Animals treated with an additional im dose 2 days later achieved blood drug levels of > 2000 ng/ml which were sustained for the duration of the experimental period. Initial i.v. administration of 8-chlorotheophylline resulted in peak concentration of about 5000 ng/ml which declined to near baseline levels within 90 min, while 8-chlorotheophylline (i.v.) blood levels in rabbits exposed to im vehicle (2 days prior) appeared to plateau around 250 ng/ml after 60 min. Acute, short-term exposure to im vehicle did not appear to elicit the altered elimination profiles. An investigation of the influence of the recommended vehicle on the bioavailability and clearance of dimenhydrinate in isolated rabbit liver microsomes revealed that vehicle at concentrations > 0.68 mg/ml significantly decreased the percent of drug metabolized. This effect was directly proportional to the concentration of vehicle added. Studies showed this effect to be due to the propylene glycol component of the vehicle.

Method for the determination of diphenhydramine in rabbit whole blood by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection in conjunction with gas chromatography (GC) with mass selective detection (MSD).

An HPLC/GC-MSD method for the determination of diphenhydramine in rabbit whole blood has been developed and validated. This method is based on a liquid-liquid extraction and reversed-phase chromatography with ultraviolet absorbance detection monitored at 258 nm. HPLC eluant fractions containing diphenhydramine and the internal standard, orphenadrine, were collected, reextracted, then subjected to GC-MSD analysis. Whole blood was utilized, thereby decreasing the required sample volume and increasing the sensitivity of the assay. Diphenhydramine concentrations can be quantitated over a range of 1 to 1000 ng/ml whole blood.

Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration.

Eight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas-liquid chromatography with nitrogen-phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38.3 vs 47.8 ng ml-1), and the time of peak concentration was similar (2.6 vs 2.3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration-time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml-1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0.58 vs 0.69, NS), and both were significantly less than 1.0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.