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About DailyMed DailyMed provides stworthy information about marketed gs in the United States. DailyMed is the official provider of FDA label information (package inserts). This Web site provides a standard, prehensive, up-to-date, look-up and download resource of medication content and labeling found in medication package inserts. The National Library of Medicine (NLM) provides this as a public service and does not accept advertisements. The g labeling information on this Web site is the most recent submitted to the Food and g Administration (FDA) and currently in use it may include, for example, strengthened warnings undergoing FDA review or minor editorial changes. These labels have been reformatted to make them easier to read. In the sublingual (SL) cavity, pared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution.
None of the officialpendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was conscted, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40x000a0mg SL tablet formulations under development and twomercial SL tablets, isosorbide dinitrate 5x000a0mg and nitroglycerin 0.6x000a0mg, were studied. The dissolution medium was 2x000a0mL of distilled water at 25x000b0C. Dissolution was measured at 60 and 120x000a0s.
The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and waspared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different ( p x02009x0003cx020090.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method. Key words: custom-made dissolution apparatus, development and validation, dissolution testing, novel in vitro dissolution method, sublingual tablets INTRODUCTION Dissolution testing is a critical and mandatory in vitro quality control procedure for solid dosage forms such as tablets. Such testing confirms that a tablet has released the labeled quantity of active pharmaceutical ingredient (API) into solution within a designated time interval. It demonstrates that the API will be readily available for absorption after oral administration.
Ideally, sublingual (SL) tablets such as nitroglycerin should release the total quantity of API within seconds, for maximum absorption via the SL veins into the systemic circulation. The SL route is highly useful for an API, such as epinephrine, that is inactivated in the gastrointestinal tract (GIT) due to extensive metabolism (1 ). Conversely, buccal formulations are intended to release their APIs over an extended time period. Although buccal and SL delivery both take place within the oral cavity, they differ in aspects such as specific location, mucosa permeability, and intended duration of release of medication (2 x020134 ). The SL route of administration has not been extensively studied because relatively few SLmercial products are currently available.
The SL cavity is characterized by unique anatomical and physiological conditionspared with other segments of the GIT such as the stomach and small intestine. A tablet that is swallowed will be subjected to GIT peristalsis in the presence of relatively large volumes of digestive fluids secreted throughout the GIT, facilitating tablet disintegration and g dissolution. In the SL cavity, tablets are exposed to minimal physiological agitation moreover, a limited volume of saliva, 0.3x000a0mL/min resting flow rate up to 1x000a0mL/min stimulated flow rate (5 ), is available to facilitate tablet disintegration and g dissolution. Currently, the available pharmacopeiasx02019 dissolution apparatuses and methods (6 x020139 ) do not simulate these unique characteristics for testing rapidly disintegrating SL tablets. For example, the US Pharmacopeia (USP) dissolution method rmended for isosorbide dinitrate SL tablets uses apparatus 2 (Paddle), 900x000a0mL of water, and 50 rotations per minute (rpm) to achieve not less than 80 of the labeled amount dissolved in 20x000a0min (10 ). Upon reviewing other pharmacopeia such as the European Pharmacopeia (8 ) and Japanese Pharmacopeia (9 ), it is readily apparent that none of the officialpendia dissolution apparatuses or methods are designed to evaluate the release of API from a rapidly disintegrating SL tablet dosage form under simulated SL conditions. The few new nonpendial in vitro methods cited for dissolution testing of SL tablets, utilize similarpendial apparatuses under modified conditions (11 ,12 ). Smaller volumes of dissolution medium have been proposed, but they are still larger than the volume of saliva secreted in the SL cavity within 2x000a0min. For example, a mini-paddle apparatus, which can amodate a minimum operational volume of approximately 30x000a0mL of dissolution medium, has been introduced (13 x0201315 ).
However, the fluid hydrodynamics of these apparatuses are still not appropriate for modeling dissolution within the SL cavity. Custom-made dissolution apparatuses and more bio-relevant methods are needed to evaluate rapidly disintegrating tablets intended for SL administration. In addition, an in vitro dissolution method should be capable of detecting and discriminating among minor changes in SL tablet formulations (16 ). Due to the short residence time within the SL cavity, we propose that the minor changes in formulations might have major effects on the rate and the extent of SL absorption (17 ,18 ). It is therefore mandatory to develop a dissolution method that meets these requirements. We designed and conscted a custom-made apparatus suitable for measuring the dissolution of rapidly disintegrating SL tablets under simulated SL conditions. This novel in vitro method was evaluated for accuracy, reproducibility, and discrimination capability, and waspared with an official USP dissolution method.
MATERIALS AND METHODS Parts of the Custom-Made Apparatus Unit Parts purchased included Nalgene 180 vacuum tubing and automatic shut-off, quick-disconnect coupling inserts (Sigma-Aldrich Inc. Oakville, ON, Canada) and Millipore 25x000a0mm glass microanalysis vacuum filter holders and supports, Whatman 0.45x000a0x003bcm nylon filter membranes, and 4x000a0mL polystyrene disposable plastic tubes (Fisher Scientific Co. Nepean, ON, Canada). APIs Used Throughout the Study Epinephrine bitartrate (EB) (Sigma-Aldrich Inc. St. Louis, MO, USA) was used in the preparation of standard epinephrine (E) solutions and E SL tablets formulated in the tablet manufacturing laboratory of the Faculty of Pharmacy (19 ,20 ). Diluted isosorbide dinitrate and diluted nitroglycerin were purchased as standards from the US Pharmacopeia (Rockville, MD, USA) and used to consct their corresponding calibration curves. Themercial generic isosorbide dinitrate 5x000a0mg (Apo-ISDN) and brand nitroglycerin 0.6x000a0mg (Nitrostat x000ae ) were purchased from the University Centre Pharmacy (Winnipeg, MB, Canada). Components of E SL Tablets Under Development All epinephrine SL tablet formulations (E ax02013g ) evaluated were formulated in our laboratory. Non-medicinal ingredients (NMIs) incorporated into the E SL tablets included microcrystalline cellulose (Asahi Kasei Chemicals Corp, Tokyo, Japan), mannitol (Roquette America Inc. Keokuk, IA, USA), citric acid (Fisher Scientific Co. Fair Lawn, NJ, USA), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co. Tokyo, Japan), and magnesium stearate (Mallinckrodt Baker, Phillipsburg, NJ, USA). Consction of One-Unit and Six-Unit Custom-Made Apparatus Schematic diagram showing the a one-unit and b six-unit custom-made apparatus with brief description of the novel in vitro dissolution method A six-unit custom-made apparatus was created by joining six individual assemblies to amon vacuum line. The vacuum for each individual unit was controlled by its own on/off switch (Fig. x000a0 1b ). The Novel In Vitro Dissolution Method A volume of 2x000a0mL of distilled water, as the dissolution medium, was measured into the 15x000a0mL glass funnel at 25x000b0C. The tablet was placed into the dissolution medium undisturbed for each specified time.
The time-points, ranging from 15 to 120x000a0s (stopwatch), were used initially to assess the dissolution profile of a representative formulation of E 40x000a0mg SL tablets. Based on these results, the 60 and 120x000a0s time-points were selected for subsequent experiments. At each appropriate time-point, the full vacuum was applied by opening the on/off switch causing the total volume of dissolution medium to be withdrawn instantly through a 0.45-x003bcm filter membrane into the collection tube and terminating any further dissolution. The membrane prevented the passage of any undissolved particles and was replaced by a new membrane for each dissolution analysis. The API content in each sample was measured by HPLC with UV detection (Waters Corp) according to the official USP assays for epinephrine injection (21 ,22 ), nitroglycerin sublingual tablets (23 ), and isosorbide dinitrate sublingual tablets (10 ). To obtain the percent of g released (DR), the API content (mg) in the filtrate waspared with the mean content uniformity of ten individual dosage forms of the SL tablets being tested. Assessment of E Adsorption to Apparatusponents Using EB, the standard solutions equivalent to E 5, 10, 20, and 40x000a0mg/mL (E 5. E 10. E 20. and E 40. respectively) were prepared and 10x000a0mL of each was filtered through the apparatus corresponding to 50, 100, 200, and 400x000a0mg of E passing through the filter membrane and the fritted glass base to evaluate any loss of E through adsorption to apparatusponents. The E content in the four standard solutions before and after filtration was measured. The 0.45-x003bcm filter membrane was soaked in 10x000a0mL distilled water to extract any E residues retained in the membrane for quantification. In addition, the fritted glass base was washed with five 10x000a0mL aliquots of distilled water to detect any E residue remaining from the E 5 and E 40 solutions after filtration.
Formulation of E SL Tablets and Evaluation of All Tablets The representative first and second generations of E SL tablet formulations (E ax02013g ) under development using directpression (19 ) were available for dissolution testing. In all E formulations, EB was used to prepare SL tablets equivalent to E 40x000a0mg. NMIs incorporated into these formulations included several grades of microcrystalline cellulose (MCC, diluent), mannitol (powder flow enhancer), citric acid (flavor) (24 ), low-substituted hydroxypropyl cellulose (disintegrant), and magnesium stearate (lubricant). These formulations differed by grade and proportion of MCC, by proportion of mannitol, and by thepression forces used to maintain uniform hardness (H) and disintegration times (DTs) (19 ,20 ). All the representative E SL tablet formulations, as well as themercial Apo-ISDN and Nitrostat x000ae.
were evaluated for weight variation (WV) and content uniformity (CU) according to USP specifications (25 ). Assessment of Dissolution Profile Using Representative E 40x000a0mg SL Tablets The dissolution testing of a representative formulation of E 40x000a0mg SL tablets was evaluated at 15, 30, 45, 60, 75, 90, 105, and 120x000a0s. The minimum time evaluated was 15x000a0s, the time required forplete disintegration of the E SL tablets irrespective of E dose (17 ) the maximum time evaluated was 120x000a0s, the time rmended for patients to retain themercially available SL tablets under the tongue (26 ). Appropriate time-points were selected accordingly for subsequent experiments. Assessment of Reproducibility To assess day-to-day variability, dissolution testing at 60 and 120x000a0s was performed andpared between dayx000a01 and dayx000a02 using onemercial SL tablet, Nitrostat x000ae. and three representative E SL tablet formulations, E a. E b. and E c . Assessment of the Discrimination Ability To assess the ability to discriminate among SL tablet formulations, dissolution testing at 60 and 120x000a0s was performed using twomercial SL tablets, Nitrostat x000ae and Apo-ISDN, and one representative E 40x000a0mg SL tablet formulation, E d. The dissolution testing of Apo-ISDN was also evaluated in 10x000a0mL of dissolution medium due to the limited solubility of ISDN.
The dissolution testing at 60x000a0s of ten representative E 40x000a0mg SL tablet formulations with DT of x0226415x000a0s was also evaluated. Dissolution Testing Using the Six-Unit Apparatus The six-unit apparatus (Fig. x000a0 1b ) was conscted and used to test the dissolution of six tablets simultaneously, using three E SL tablet formulations, E e. E f. and E g. Results werepared with previous dissolution data collected using the one-unit apparatus. Dissolution Testing Using the Official USP Apparatus and Method Data Analysis Results were presented as meansx02009x000b1x02009standard errors of means (SEM) of at least three replicate experiments and statistically analyzed by one-way ANOVA using Microsoft Excel software. The differences were considered significant at p x02009x0003cx020090.05. Assessment of E Adsorption to Apparatusponents Epinephrine (E) Retention (mg) in the Custom-Made Apparatus Following the Filtration of 10x000a0mL of Standard E 5, 10, 20, and 40x000a0mg/mL Solutions (E 5. E 10. E 20. and E 40. Respectively) After filtration of E 5. x0003e88 of the retained E residue in the fritted glass base was washed out after the first wash. The following washes removed x0003e97 of the E residue in the fritted glass base.
When filtering standard E solution with higher concentration (E 40 ), x0003e94 of the E residue was removed from the fritted glass base after the first wash and x0003e99 after the fourth wash. Evaluation of All SL Tablets Used in This Study Thepression forces applied in the manufacturing of representative first and second generation E SL tablet formulations resulted in a uniform H of 1.31x02009x000b1x020090.04x000a0kg (meanx02009x000b1x02009SEM). All SL tablets, including themercial Apo-ISDN and Nitrostatx000ae SL tablets, resulted in a DT of x0226415x000a0s and were within USP limits of WV and CU. Assessment of Dissolution Profile Using Representative E 40x000a0mg SL TabletsAtomic Tabs are great tasting chewable energy tablets that pack the power of a single energy shot into one small chewable tablet to help you feel sharp and alert for hours, with no crash. dagger In addition to caffeine, Atomic Tabs contains a blend of B-Vitamins, Amino Acids, and essential nutrients. Atomic Tabs contains zero sugar, zero herbal stimulants, and zero calories. And we still managed to make them taste amazing Just the right amount of sweet and tart, and never bitter.
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