A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects.

Purpose: The aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects. Methods: A total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72 h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations. Results: For the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all <0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%-111.74%), 98.80% (94.47%-103.33%), and 98.63% (94.42%-103.03%), respectively. The two-sided 90% CI of the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient. Conclusion: The test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status. Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217.

Green micellar stability-indicating high-performance liquid chromatography method for determination of rupatadine fumarate in the presence of its main impurity desloratadine: Oxidative degradation kinetics study.

A green micellar stability-indicating high-performance liquid chromatography method was developed for rupatadine fumarate determination in existence with its main impurity desloratadine. Separation was attained using Hypersil ODS column (150 × 4.6 mm, 5 µm), the micellar mobile phase consisted of 0.13 M sodium dodecyl sulfate, 0.1 M disodium hydrogen phosphate adjusted by phosphoric acid to pH 2.8 and 10% n-butanol. The column was maintained at 45◦ C and detection was carried out at 267 nm. A linear response was achieved over the range of 2-160 µg/ml for rupatadine and 0.4-8 µg/ml for desloratadine. The method was applied for rupatadine determination in alergoliber tablets and alergoliber syrup without the interference of methyl paraben and propyl paraben present as main excipients. Rupatadine fumarate revealed pronounced susceptibility to oxidation; further study of oxidative degradation kinetics was carried out. Rupatadine was found to follow pseudo-first-order kinetics when exposed to 10% H2 O2 at 60 and 80°C and the activation energy was found to be 15.69 Kcal/mol. At a lower temperature (40°C), degradation kinetics regression was best fitted as a polynomial quadratic relationship, thus rupatadine oxidation at a lower temperature tends to adopt a second-order kinetics rate. Oxidative degradation product structure was revealed using infrared and found to be rupatadine N-oxide at all temperature values.

Incorporation of Ethylcellulose Microparticles Containing a Model Drug with a Bitter Taste into Nanofibrous Mats by the Electrospinning Technique-Preliminary Studies.

Electrospinning is considered a simple and comprehensive technique to formulate ultrafine fibres by using an electric field. Polymeric nanofibers constitute promising materials in biomedical applications as drug delivery systems. For their preparation, both natural and synthetic polymers are utilised. Owing to the potential use of electrospun nanofibers as an orodispersible drug dosage form, ethylcellulose microparticles containing the antihistamine drug rupatadine fumarate, prepared by the spray drying technique to conceal the drug's bitter taste, were incorporated into nanofibers. The obtained nanofibrous mats were evaluated for morphology, mechanical strength, disintegration time, the drug solid state and acceptability in terms of taste masking efficiency. Preliminary studies showed that hypromellose used as a single polymer was not a suitable substance for the manufacturing of nanofibers. Therefore, in order to facilitate the obtention of homogeneous nonwovens, different grades of polyethylene oxide (2,000,000-2M-Da and 4,000,000-4M-Da) were added, which improved the quality of the prepared mats. Nanofibers of the most satisfactory quality were obtained from hypromellose (6.5% w/v) and PEO (2M, 0.5% w/v). SEM image analysis has shown that the nanofibers were homogeneous and smooth and possessed a fast disintegration time (below 30 s) and an adequate drug content with a simultaneous taste-masking effect (as indicated by the in vivo and in vitro methods). However, further studies are necessary to refine their mechanical characteristics.

Orodispersible Films with Rupatadine Fumarate Enclosed in Ethylcellulose Microparticles as Drug Delivery Platform with Taste-Masking Effect.

Orally disintegrating (orodispersible) films provide a versatile tool for drug administration, especially in the pediatric and geriatric population, since they reduce the risk of choking and do not necessitate drinking water during application. By considering their direct contact with the taste buds, palatability is an influential aspect related to patient compliance. The microparticles based on taste-masking polymers containing drugs enclosed inside effectively mask the unpleasant taste of medicines. Ethylcellulose is a hydrophobic polymer widely used as a taste-masking material. Rupatadine fumarate, a second-generation antihistamine drug, is characterised by an intense bitter taste; therefore, it is crucial to achieve a tolerable taste whilst developing orodispersible formulations with its content. The objective of this study was to develop orally disintegrating films with rupatadine fumarate in the form of ethylcellulose-based microparticles obtained from aqueous dispersions of ethylcellulose-Surelease® or Aquacoat® ECD. It was a technological challenge to achieve homogenous drug content per dosage unit and sufficient mechanical properties for film operating due to the necessity to suspend the microparticles in the casting solution. Although the process of obtaining films consisted of several steps (mixing, pouring, drying), the particles were homogeneously dispersed, and each film of the desired size contained the proper dose of the drug. The taste-masking effect was also maintained. This parameter was confirmed by three independent methods: in vivo by healthy volunteers, an electronic tongue and a dissolution test. The applied taste-evaluation techniques showed that the films containing Aquacoat® ECD microparticles have the highest degree of bitter taste reduction, which confirms the results obtained in our previous studies.

Utilization of Ethylcellulose Microparticles with Rupatadine Fumarate in Designing Orodispersible Minitablets with Taste Masking Effect.

Minitablets in orodispersible form constitute a flexible drug delivery tool for paediatric and geriatric population as they eliminate the risk of chocking and do not require drinking water in the application. Due to their direct contact with taste buds, taste sensation is an important factor. Preparing microparticles with taste masking polymers utilizing spray drying is an efficient technique for reducing the bitterness of drugs. Ethylcellulose is a hydrophobic polymer widely used as a taste masking material. Rupatadine fumarate, one of the newest antihistamines, features an intensive bitter taste, hence in designing orodispersible formulations, achieving an acceptable taste is a crucial issue. The main objective of this work was to formulate orodispersible minitablets containing taste masked ethylcellulose-based microparticles with rupatadine fumarate and evaluation of their quality, especially in terms of taste masking efficacy. The accessed data indicated that all obtained minitablets were characterized by beneficial pharmaceutical properties. Three independent methods: in vivo with healthy volunteers, in vitro drug dissolution, and "electronic tongue" confirmed that all designed formulations provided satisfactory taste masking rate and that formulation F15 (prepared with Pearlitol® Flash and Surelease® microparticles with rupatadine fumarate) was characterized by the lowest bitterness score.

Development of immediate release Rupatadine fumarate 10 mg tablets: A Quality by Design (QbD) approach.

Objective: The main objective of this research is to develop an immediate release Rupatadine fumarate 10 mg tablets formulation by direct compression, through a Quality by Design approach in Costa Rica. Methods: According to a Quality by Design approach; Target Product Profile, Quality Target Product Profile, and the Critical Quality Attributes were defined. In the preformulation study, compatibility tests were carried out between the raw materials. The Critical Material Attributes were established using Quality Risk Management. Three formulation prototypes were prepared by direct compression and its Critical Process Parameters were defined. The analysis of the prototypes was realized in terms of organoleptic properties, identification, potency, content uniformity, dissolution, disintegration, friability and loss by drying. Results: All the prototypes showed a white or slightly pink surface, potency between 90.0 -110.0 % of the labeling, an acceptance value for the content uniformity lower than the specification (AV < 15), the dissolved amount of active pharmaceutical ingredient was greater than 85.0 % at 30 minutes, friability less than 1.0 %, a disintegration time less than 15 minutes and moisture content less than 2.0 %. Conclusions: The approaching of a Quality by Design model to the current development allowed to obtain satisfactory results in the three formulation prototypes. The excipients to be used can be lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, stearic acid, and PVP K-30.

Ethylcellulose in Organic Solution or Aqueous Dispersion Form in Designing Taste-Masked Microparticles by the Spray Drying Technique with a Model Bitter Drug: Rupatadine Fumarate.

The taste of drugs is an important factor affecting pharmacotherapy effectiveness, and obtaining formulations with acceptable organoleptic properties is still an ongoing issue in pharmaceutical technology. One of the innovative methods of taste masking is preparation of microparticles by the spray drying technique, utilizing polymers with different physicochemical properties. Rupatadine fumarate (RUP) is one of the newest antihistamines, with an innovative and multidirectional mechanism of action, and an extremely bitter taste. The aim of this work was to investigate the feasibility of utilizing organic or aqueous forms of ethylcellulose (EC) for the preparation of microparticles with RUP by the spray drying technique. Spray dried samples at different drug:polymer ratios were prepared using organic solution (Ethocel®) or aqueous dispersions of EC (Surelease®, Aquacoat® ECD). Evaluation of the taste masking efficacy was performed in vivo in human taste panel, in vitro based on dissolution test, and by self-constructed electronic tongue. It was shown that microparticles obtained from aqueous dispersions of EC have superior pharmaceutical properties in terms of both morphology and taste masking efficacy in comparison to those obtained from organic solution.

Determination of Residual Solvents in Rupatadine Fumarate by Headspace Gas Chromatography / 中国药师

Objective:To determine the content of cyclohexane, ethyl acetate, methanol, methylene chloride and trichloromethane in rupatadine fumarate by headspace gaschromatography. Methods:A DB-WAXETRR capillary column(30 m × 0. 32 mm,0. 25 μm)was used and the carrier gas was nitrogen. The detector was an FID and the inlet temperature was 200℃ . The column temperature program was with the initial temperature of 35℃,maintained 10 min,and then risen to 220℃ with the rate of 20℃·min -1 ,and maintained 5 min. Results:Cyclohexane,ethyl acetate,methanol,methylene chloride and trichloromethane showed a good linear relationship within the range of 77. 590 1- 698. 310 9 μg·ml -1(r = 0. 999 7),102. 166 6- 919. 499 4 μg· ml -1(r = 0. 999 8),62. 744 7- 564. 703 2μg·ml -1(r = 0. 999 9),12. 011 2- 108. 101 1 μg·ml-1(r = 0. 999 6)and 1. 262 8-11. 365 6 μg·ml -1(r = 0. 999 6). The average recovery was 103. 9% ,103. 5% ,104. 9% ,107. 1% and 103. 4% and RSD was 2. 3% ,2. 6% ,3. 1% ,2. 8% and 4. 5%(n = 9),respectively. The five residual solvents were not detected out in rupatadine fumarate. Conclusion:The method is stable,simple,sensitive and accurate,and can be used for the determination of residual solvents in rupatadine fumarate.