A Pilot Study of Ketotifen in Patients Aged 8-17 Years with Functional Dyspepsia Associated with Mucosal Eosinophilia.

BACKGROUND AND OBJECTIVE: Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia. METHODS: We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis. RESULTS: Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h. CONCLUSIONS: While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov: NCT02484248.

Pharmacokinetic/pulmokinetic analysis of optimized lung targeted spray dried ketotifen-dextran core shell nanocomplexes-in-microparticles.

A passive lung targeted system for controlled lung delivery of ketotifen (KT) was developed based on the green complexation of dextran sulphate (DS) and KT. Achieving deep lung deposition of high drug fraction, while evading lung defense mechanisms were set as goals. Optimized uniform negatively charged nanocomplexes (NC), <80 nm, were obtained at KT/DS weight ratio of 1:0.66 to 1:0.5 and 1% surfactant concentration with 90% drug complexation efficiency. The interaction between KT and DS and matrix formation were evidenced by Fourier-transform infrared (FT-IR) spectra and differential scanning calorimetry (DSC) studies. A respirable particle percent reaching 67.41 ±â€¯2.6% was obtained following co-spray drying NC containing poloxamer with leucine. A higher lung/plasma partitioning was obtained following pulmonary administration of selected nanocomplexes in microparticles (NCEMP) to rats compared to oral and intravenous (iv) routes. A new core shell nanocomplex formed of DS and KT as main substrates exhibited a potential for lung targeting of the anti-asthmatic drug.

Extended release of ketotifen from silica shell nanoparticle-laden hydrogel contact lenses: in vitro and in vivo evaluation.

Ketotifen an anti-allergic drug delivered via eye drops has major limitations, including poor ocular bioavailability and poor patient compliance. The objective of the research work was to fabricate ketotifen loaded microemulsion laden hydrogels and silica shell nanoparticle-laden (prepared from microemulsion using octyltrimethoxysilane) hydrogels to achieve extended ocular drug delivery. The porous silica shell membrane was synthesized at the liquid interface of microemulsion, which facilitates the prolongation of drug release duration from hydrogels. Drug encapsulated microemulsion and silica shell nanoparticles were dispersed separately in pre-monomer mixture, and fabricated to hydrogel. For comparison, hydrogel with direct drug entrapment was also fabricated. Significant loss in transmittance and physical properties was observed in hydrogels with direct drug entrapment. While, microemulsion and silica shell nanoparticle-laden hydrogels did not show significant effect on transmittance and physical properties. The in vitro drug release data showed extended release of ketotifen from hydrogels in following order: direct loading

Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3² experimental design: in vitro/in vivo evaluation.

Orally dissolving films (dissofilms) have gained increasing popularity and attention due to their ease of administration and avoidance of first pass metabolism. Ketotifen fumarate (KF) bioavailability is reported to be only ~ 50% due to hepatic first-pass metabolism. Aiming to surmount this drawback and improve patients' compliance, a 3(2) full factorial design was applied to formulate KF Orodispersible films, and to investigate the effects and interactions of the concentrations of the novel film former; Lycoat NG73® and the film modifier; maltodextrin (MDX) on the characteristics of the films prepared using solvent casting technique. The dissofilms were thoroughly evaluated regarding their weight uniformity, content uniformity, moisture uptake, in vivo mouth dissolving time (MDT) and their thermal behavior via differential scanning calorimetry. Statistical analysis revealed the significant influence of Lycoat NG73® concentration on percent elongation, percent KF dissolved after 5 min, and in vivo MDT, while MDX concentration had significant effect only on percent elongation. Further, storage of the optimal selected formula (15% Lycoat NG73 and 0% MDX) at 40 °C/75% relative humidity for 12 weeks caused no significant change in appearance, KF content or drug dissolution profile. Pharmacokinetic study revealed that the orally dissolving films showed significantly higher absorption extent than the reference marketed product, while no significant difference was observed for Cmax.

Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies.

Delivery of ketotifen fumarate by commercial contact lens materials.

PURPOSE: To investigate the uptake and delivery of the anti-allergy drug ketotifen fumarate (KF) by commercially available contact lenses. METHODS: A total of 14 different commercially available contact lenses were investigated, including five frequent-replacement silicone hydrogels, three conventional hydrogels, and six daily disposable lenses. Lenses were soaked in a 0.025% KF loading solution for 24 h, and the concentration of KF in solution over time was determined by ultraviolet absorbance at 297 nm. After the 24-h loading period, lenses were placed in fresh vials containing borate buffered saline, and the release of drug into solution at 34°C was monitored for 24 h. RESULTS: All the lenses studied demonstrated significant uptake and release of KF into the borate buffered saline (p < 0.05 compared with initial time point). Lenses with charged surfaces [balafilcon A, etafilcon A, and etafilcon A (daily disposable)] demonstrated the greatest uptake and release of KF. Etafilcon A released 284.5 ± 29.8 µg/lens, whereas balafilcon A released 227.6 ± 14.7 µg/lens, which was substantially more (p < 0.05) than the lowest releasing lenses [nelfilcon A (40.4 ± 4.1 µg/lens) and comfilcon A (110.4 ± 8.9 µg/lens)]. The majority of lenses were able to match or exceed the total amount of KF commonly administered to the eye using twice-daily dosing of commercially available (0.025%) eye drop formulations. Most of the lenses surveyed reached a plateau concentration of KF relatively quickly, and no lens was able to release KF for longer than 4 h. CONCLUSIONS: Commercially available lenses demonstrated the ability to release a clinically relevant amount of KF compared with conventional eye drops. The use of commercially available contact lenses as a KF delivery system in a daily wear scenario may be feasible.

In vivo enhancement of transdermal absorption of ketotifen by supersaturation generated by amorphous form of the drug.

The enhancing effect of supersaturation generated by amorphous ketotifen in silicone pressure-sensitive adhesive matrices (PSA) on the transdermal absorption was evaluated in vivo using hairless rats, and it was compared with the increase of drug amount in skin tissues. The duration of the enhancing effect was also investigated in relation to the time how long supersaturation was maintained in PSA. PSA containing crystalline ketotifen (PSA-Crystalline) and that containing amorphous ketotifen (PSA-Amorphous) were prepared by the solvent casting method using n-hexane and dichloromethane, respectively. In vivo transdermal absorption was evaluated by measuring the amount of ketotifen in PSAs, the stratum corneum, and viable skin tissues after administration of PSAs on abdominal sites of hairless rats. The amount of ketotifen absorbed into the systemic circulation was calculated by subtracting the drug amount in whole skin tissues from the amount of the drug released from PSAs, then it was monitored for up to 23 h. In both types of PSA, a constant absorption rate was maintained for up to 23 h after 7-h lag time. The enhancement factor of PSA-Amorphous against PSA-Crystalline was approximately 7, which was in good agreement with the difference of drug amount in viable skin tissues. Time course of the drug amount in PSA-Amorphous suggested that the supersaturated level was gradually decreased after 10h, but the decline of the driving force from PSAs was supplemented by the drug release from the skin depot resulting in the constant absorption rate up to 23 h. These results suggest the usefulness of amorphous ketotifen to obtain enhanced transdermal absorption.

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy.

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

Synergistic interaction between TS-polysaccharide and hyaluronic acid: implications in the formulation of eye drops.

An interaction between tamarind seed polysaccharide (TSP) and hyaluronic acid (HA) in aqueous solution has been ascertained. Various TSP/HA mixtures have been studied as the basis for the development of a potential excipient for eye drops synergistically improved over those of the separate polymers. Information about the nature of interpolymer interactions, and their dependence on TSP/HA ratios were obtained by NMR spectroscopy in solution. Superior mucin affinity of TSP/HA mixtures with respect to the single polysaccharides was assessed by NMR proton selective relaxation rate measurements. The mucoadhesivity of the TSP/HA (3/2) mixture, evaluated in vitro by NMR or viscometry, and in vivo by its mean and maximum residence time in rabbit precorneal area, is stronger than that of the component polysaccharides or the TSP/HA mixtures of different composition. TSP/HA (3/2) is little viscous and well tolerated by rabbit eyes. It stabilizes the tear film, thereby prolonging the residence of ketotifen fumarate and diclofenac sodium in tear fluid, but is unable to permeabilize the cornea. In conclusion, mucoadhesivity is responsible for the TSP/HA (3/2) synergistic enhancement of either extra- or intra-ocular drug bioavailability.

Formulation of ketotifen fumarate fast-melt granulation sublingual tablet.

The purpose of this study was to prepare sublingual tablets, containing the antiasthmatic drug ketotifen fumarate which suffers an extensive first-pass effect, using the fast-melt granulation technique. The powder mixtures containing the drug were agglomerated using a blend of polyethylene glycol 400 and 6000 as meltable hydrophilic binders. Granular mannitol or granular mannitol/sucrose mixture were used as fillers. A mechanical mixer was used to prepare the granules at 40 degrees C. The method involved no water or organic solvents, which are used in conventional granulation, and hence no drying step was included, which saved time. Twelve formulations were prepared and characterized using official and non official tests. Three formulations showed the best results and were subjected to an ex vivo permeation study using excised chicken cheek pouches. The formulation F4I possessed the highest permeation coefficient due to the presence of the permeation enhancer (polyethylene glycol) in an amount which allowed maximum drug permeation, and was subjected to a pharmacokinetic study using rabbits as an animal model. The bioavailability of F4I was significantly higher than that of a commercially available dosage form (Zaditen solution-Novartis Pharma-Egypt) (p > 0.05). Thus, fast-melt granulation allowed for rapid tablet disintegration and an enhanced permeation of the drug through the sublingual mucosa, resulting in increased bioavailabililty.

Selected polysaccharides at comparison for their mucoadhesiveness and effect on precorneal residence of different drugs in the rabbit model.

Mucoadhesive polysaccharides may prolong the residence of ophthalmic drugs in precorneal area. In this article, the mucoadhesiveness of arabinogalactan, tamarind seed polysaccharide, hyaluronan, hydroxyethylcellulose is compared in vivo, by the polymer residence time in rabbit tear fluid, and in vitro, by the polymer-induced increase of viscosity of a mucin dispersion. Polymer residence is prolonged by increased viscosity but shortened by reflex tearing caused by excessive viscosity. Tamarind seed polysaccharide is the most effective in prolonging the residence of ketotifen and diclofenac in precorneal area; hence, it is the optimal eyedrop additive as it is mucoadhesive while not increasing viscosity excessively.

Bioequivalence of two formulations of ketotifen fumarate ophthalmic solution: a single-center, randomized, double-masked conjunctival allergen challenge investigation in allergic conjunctivitis.

BACKGROUND: Ketotifen fumarate ophthalmic solution 0.025% (reference formulation), a topical mast cell stabilizer/antihistamine combination, has been found to be effective and well tolerated in the prevention of ocular itching associated with allergic conjunctivitis (AC). A recently developed formulation of ketotifen fumarate ophthalmic solution 0.025% (test formulation) contains the same active ingredient in the same concentration as the reference formulation, is intended for twice-daily dosing, and may provide a treatment option in patients with AC. OBJECTIVE: The aim of this study was to determine the clinical bioequivalence of the test and reference formulations using a conjunctival allergen challenge (CAC) model. METHODS: This prospective, randomized, double-masked, active- and placebo-controlled CAC study was conducted in a clinical setting (ORA Clinical Research and Development, North Andover, Massachusetts). Patients aged <18 years who had AC, a successful allergen challenge during screening and allergen confirmation visits, a history of ocular allergies, and positive skin-test reactivity were enrolled. Patients' eyes were randomized to receive the test or reference formulation or inactive vehicle (1 drop of 1 study medication per eye per visit). The primary efficacy end point was ocular itching, and the secondary end points were ocular redness, chemosis, lid swelling, tearing, and mucous discharge. Efficacy was assessed following challenge at 8 hours and 15 minutes after instillation. The test and reference formulations were considered bioequivalent if the 95% CIs for the differences in mean ocular itching scores between the 2 groups were within the range of 0.40 to 0.40. RESULTS: There were 108 patients enrolled (61 men, 47 women; mean age, 42 years; 91.7% white). The test and reference formulations both yielded clinically significant results compared with placebo in the prevention of ocular itching at CACs performed 8 hours and 15 minutes after instillation. At the 8-hour posttreatment CAC, the mean ocular itching scores for test formulation-treated eyes were 1.158, 1.265, and 1.305 units lower, respectively, than for eyes at 3, 5, and 7 minutes that were administered placebo. At 15-minute posttreatment CAC, the mean ocular itching scores for reference formulation-treated eyes at 3, 5, and 7 minutes were 1.481, 1.622, and 1.565 units lower, respectively, than for eyes that were administered placebo. With regard to the primary and secondary efficacy variables, no statistically significant differences were observed between test and reference formulations at any post-CAC time point. CONCLUSIONS: In this population of patients with AC, the test formulation of ketotifen fumarate ophthalmic solution 0.025% met criteria for bioequivalence to the reference formulation, as established by the protocol. The test and reference formulations were well tolerated in the population studied.

The sorption of ketotifen fumarate by chitosan.

The purpose of this investigation was to determine the mechanism of interaction between ketotifen fumarate and chitosan at different pH values. The specific surface area of chitosan was determined using gas sorption analyzer. The sorption experiments were conducted at pH 7 and 10 using two different particle size ranges of chitosan. The solutions were prepared at constant ionic strength and buffer concentration, with only varying the pH. The rotating bottle method was used for measuring the sorption. The average specific surface areas for the two different particle size ranges of chitosan were found to be 4.56 and 0.74 m(2)/g. The Langmuir-like equation and a model independent equation were both applied to the sorption experimental data. The extent of ketotifen uptake at pH 7 for small and large particles of chitosan was found to be 1,073 and 2,204 mg/g respectively. While the extent of ketotifen uptake at pH 10 for small and large particles of chitosan was found to be 4 and 11 mg/g respectively. The aforementioned results indicated that sorption of ketotifen fumarate at pH 7 is extremely high compared to pH 10 and that the sorption increases by decreasing the specific surface area of chitosan. Based on the results obtained, the following conclusions were reached. Ketotifen might be absorbed into the bulk structure of chitosan in addition to being adsorbed on the surface and the ability of chitosan to swell at pH 7 has a significant role in increasing its uptake.

Ketotifen-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers: characterization and in vivo evaluation.

Ketotifen (KT) was encapsulated into poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA 50/50) by spray-drying to investigate the use of biodegradable drug-loaded microspheres as delivery systems in the intraperitoneal cavity. Ketotifen stability was evaluated by HPLC, and degradation was not observed. Drug entrapment efficiency was 74 +/- 7% (82 +/- 8 microg KT/mg for PLA) and 81 +/- 6% (90 +/- 7 microg KT/mg for PLGA 50/50). PLA microspheres released ketotifen (57% of encapsulated KT) in 350 h at two release rates (221 microg/h, 15 min to 2 h; 1.13 microg/h, 5-350 h). A quicker release of ketotifen took place from PLGA 50/50 microspheres (67.4% of encapsulated KT) in 50 h (322 microg/h, 15 min to 2 h; 16.18 microg/h, 5-50 h). After intraperitoneal administration (10 mg KT/kg b.w.), microsphere aggregations were detected in adipose tissue. Ketotifen concentration was determined in plasma by HPLC. The drug released from PLA and PLGA 50/50 microspheres was detected at 384 and 336 h, respectively. Noncompartmental analysis was performed to determine pharmacokinetic parameters. The inclusion of ketotifen in PLGA and PLA microspheres resulted in significant changes in the plasma disposition of the drug. Overall, these ketotifen-loaded microspheres yielded an intraperitoneal drug release that may be suitable for use as delivery systems in the treatment of inflammatory response in portal hypertension.

Duration of action of topical antiallergy drugs in a Guinea pig model of histamine-induced conjunctival vascular permeability.

The topical application of 0.1% olopatadine has been shown to provide significant attenuation of histamine-induced conjunctival vascular permeability (CVP) within 5 min and for as long as 24 h following a topical administration. The duration of the action of olopatadine was compared to that of epinastine, azelastine, and ketotifen. Male Hartley outbred guinea pigs (weighing 250-300 g) were administered a drug or vehicle as single O.D. topical drops, at times ranging from 4 to 24 h prior to histamine challenge. One (1) h prior to histamine challenge, the animals were administered 1 mL of Evans blue dye (1 mg/mL) through the marginal ear vein. Histamine (300 ng) was administered by a subconjunctival injection, and the guinea pigs were sacrificed 30 min later. CVP was assessed as the area and color intensity stained with Evans blue dye. The potencies of each drug were determined by calculating a 50% effective dose (ED(50)) for the inhibition of vascular leakage, compared to vehicle treatment, at each time point. Olopatadine was the only compound tested that was significantly effective 16 h following a single topical application. The ED(50) for olopatadine at 16 h was 0.031%. Epinastine, azelastine, and ketotifen were only significantly effective for up to 4 h. Olopatadine exhibited the longest duration of action for inhibition of histamine-induced vascular permeability in guinea pigs of any topical antiallergic drug tested. Concentrations of olopatadine, which provided a greater than 50% inhibition of the histamine-induced vascular response, were consistently less than 0.1% over a 16-h pretreatment interval.

Development of a stick-type transdermal eyelid delivery system of ketotifen fumarate for ophthalmic diseases.

A transdermal eyelid delivery system for treating ocular diseases (eye-stick) has been developed. Ketotifen fumarate (KT) was used as a model drug. An in vivo study using rabbits showed that the eye-stick device maintained a constant conjunctival concentration of the drug for an extended period of time, which was equivalent or higher than the therapeutic level following eye drop administration. Moreover, the conjunctival concentration after eye-stick application was well predicted using the physicochemical parameters, diffusion coefficient and partition coefficient, obtained from in vitro hairless mouse skin permeation experiments.

Skin permeation of ketotifen applied from stick-type formulation.

A stick-typed long lasting device for both transdermal and topical drug delivery has been developed. Ketotifen fumarate (KT) was used as a model drug. The effect of a variety of permeation enhancers was investigated using hairless mouse skin in vitro. Polyoxyethylene oleyl ether (POE), among the enhancers used, most enhanced the skin permeation of KT. The permeation enhancement was mainly due to the increase in the drug solubility in the stratum corneum and the resulting increase in the partition coefficient. The rate of skin permeation of KT was approximately proportional to the loading dose of the drug.

Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen.

Deformable liposomes and ethosomes were investigated as carriers for skin delivery of ketotifen (KT) in terms of vesicle size, entrapment efficiency, stability, in vitro permeation and skin deposition properties. Phosphatidylcholine (PC) from soybean lecithin was used in the preparation of all vesicles. Sodium cholate, sodium deoxycholate and Tween 80 were investigated as edge activators in preparation of KT deformable liposomes. KT ethosomes were prepared in two PC concentrations, 2% and 4.25% w/v, in 30% v/v ethanol. KT deformable liposomes showed improved entrapment efficiency over KT ethosomes. KT deformable liposomes with Tween 80 as an edge activator were more stable upon storage at 5 +/- 1 degree C than those prepared using sodium cholate or sodium deoxycholate and were more stable than KT ethosomes. In vitro permeation and skin deposition studies employed only deformable liposomes with Tween 80 as an edge activator and ethosomes with 4.25% w/v PC concentration. Both of them improved skin delivery of KT over controls and over traditional liposomes, with greater improvement of KT skin deposition than KT skin permeation, hence are more useful for dermal than for transdermal delivery of KT.

Enhancement of skin permeation of ketotifen by supersaturation generated by amorphous form of the drug.

Pressure sensitive adhesive (PSA) matrices containing amorphous ketotifen were prepared and evaluated for enhanced skin permeability of the drug. A solvent casting method using silicone-typed PSA was employed, and n-hexane, an original solvent for the PSA and one more solvent, dichloromethane, tetrahydrofuran, acetone, ethyl acetate or toluene, were used for complete dissolution of ketotifen and high dispersion in an amorphous state of the drug. Presence of the amorphous form was judged based on the in vitro drug release rate from the matrix. As a result, dichloromethane and tetrahudrofuran were selected as appropriate dilution solvents. In vitro permeation experiments through excised hairless mouse skin revealed that the steady-state flux from the amorphous ketotifen-dispersed matrices was about five times greater than that of the crystalline ketotifen-dispersed matrices, and that the enhancement ratio was in good agreement with the solubility ratio of the amorphous to crystalline form of the drug. Comparison of the skin permeation profiles of amorphous ketotifen-dispersed matrices between two different drug contents suggested that the steady-state flux was not influenced by the drug content. In addition, at both drug contents, the period of the steady-state permeation coincided with the time until the amorphous drug was depleted from the matrix. These results suggest that the increase in skin permeation of ketotifen from PSA matrix was due to the supersaturation generated by amorphous form, and that the amorphous form was stable during the application period.