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Sai V. Nudurupati is assistant director at AbbVie Inc. (North Chicago, IL)
Michael J. Kukulka is senior manager, Global Labeling, Regulatory Affairs, PRA Health Sciences (Deerfield, IL)
Takako Ono is principal scientist, Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Co. Ltd. (Osaka, Japan)
Haiyan Grady is associate scientific director CMCC, Takeda Development Center Americas, 300 Massachusetts Ave (4274), Cambridge, MA 02139, Tel: 1-224-554-2067, firstname.lastname@example.org
This article describes the approaches used during the development of a dexlansoprazole delayed-release orally disintegrating tablet (ODT) to evaluate tablet size and texture as they relate to disintegration rate and patient experience; in addition, the resistance to alcohol was also characterized.
Dexlansoprazole orally disintegrating tablet (ODT) is a proton-pump inhibitor (PPI) in a delayed-release formulation. The ODT presentation facilitates medication intake for patients with swallowing issues, whereas the delayed-release formulation enables intragastric acidity control for 24 hours. The microgranules used to prevent immediate drug release, however, could confer an unpleasant, gritty texture in the mouth. This article describes the approaches used during the development of a dexlansoprazole delayed-release ODT to evaluate tablet size and texture as they relate to disintegration rate and patient experience; in addition, the resistance to alcohol was also characterized. In-vitro and in-vivo disintegration studies, dissolution studies, and bioavailability studies were conducted. The experimental data presented in this article demonstrate the acceptable product physical characteristics of an ODT with a dual delayed-release mechanism.
Orally disintegrating tablets (ODTs) have been widely accepted as a convenient dosage form, especially for geriatric and pediatric patient populations, because they can be taken easily without the need to swallow a whole tablet (1–3). FDA’s Guidance for Industry: Orally Disintegrating Tablets has provided basic requirements for the characteristics of an ODT product (4).
Most ODT products on the market are immediate-release tablets (5, 6). Formulation development for these immediate-release ODT products is commonly focused on achieving rapid oral disintegration in the mouth. After this disintegration, the residuals are either dissolved in the oral cavity or become a wet mixture of fine particles that is easy to swallow without water (7).
Dexlansoprazole ODT is a proton-pump inhibitor (PPI) in a delayed-release ODT formulation. Dexlansoprazole ODT contains two types of active microgranules that do not disintegrate or dissolve in the mouth. These microgranules are coated with different enteric-coated polymers to protect acid-unstable dexlansoprazole from stomach fluid and to release the drug in different intestinal regions via dissolution at different pH levels.
The microgranule size is significantly less than 500 μm to avoid a gritty feeling in the mouth after the ODT disintegrates into microgranules. Sucralose is used as a sweetener (8) and strawberry Durarome as a flavoring agent to create an acceptable taste.
Although the tablet disintegrates quickly in the mouth without water, the microgranules are protected by the enteric coating and remain intact until they enter the intestine and begin dissolving and releasing the drug. As a result, the pulsatile (or dual-delayed) drug-release profile provides prolonged plasma exposure.
The physical integrity of the enteric coating for the two types of microgranules must be preserved throughout the tablet compression process. An appropriate combination of inactive excipients is required to provide sufficient protection from the mechanical compression applied to the microgranules. The excipients must be highly water soluble and the quantity minimized to meet the requirements for a rapidly disintegrating tablet. After incorporation of these elements, the final form of dexlansoprazole ODT was a 700-mg round tablet.
PPIs are the first recommended therapy for patients with gastroesophageal reflux disease, one of the most common ailments treated by gastroenterologists (9); however, swallowing a capsule or a conventional tablet can be challenging for some patients, such as children, and this can impact adherence to medication regimens. Gastroesophageal reflux disease is common among people with difficulty swallowing, and dysphagic patients have reported a preference for ODT preparations over conventional tablets because of the reduced effort required to swallow them (10).
To the best of the authors’ knowledge, there are only two approved ODT PPIs: lansoprazole ODT (Prevacid SoluTab; Takeda Pharmaceuticals America, Inc.; Deerfield, IL) and dexlansoprazole ODT. Prevacid SoluTab is a conventional delayed-release ODT product, whereas dexlansoprazole ODT is the only ODT product with a formulation that has a dual delayed-release mechanism. This formulation is efficacious regardless of food intake and time of administration and enables control of intragastric acidity for 24 hours (11–13). Therefore, the development of this product has widened the field of ODT technology (11, 14).
Several challenges arose in designing a dual delayed-release formulation ODT, including controlling tablet size, disintegration rate, and resistance to alcohol. Tablet size must be balanced with ease of administration and a disintegration rate rapid enough for patients to take it without water. Although tablet weight is not a direct measure of ODT product performance in patients, generally a large tablet (by size or weight) cannot be ingested easily without biting, chewing, or taking with water. Because many factors can affect ease of ingestion, tablet weight must be evaluated within the context of overall product performance (4). Finally, because enteric-coated polymers are soluble in common solvents (15), it is important to ensure that drug release is not significantly affected by alcohol in gastric fluid (16). This is necessary to avoid faster (or earlier) release of excessive drug levels (“dose dumping”) mediated by ethanol.
This article describes the approaches used to address these challenges in the development of dexlansoprazole ODT. The authors focus on the process of evaluating product acceptability and the integrated approaches used, which incorporated in-vitro testing and clinical study data.
Materials. The drug product (dexlansoprazole ODT 30 mg) was manufactured by Takeda Pharmaceutical Company, Osaka, Japan. Common pharmaceutical manufacturing technologies, such as wet granulation, fluid bed enteric coating, and tablet compression, were used. The tablet consists of dexlansoprazole (active ingredient) and the following inactive ingredients: lactose monohydrate-microcrystalline cellulose spheres, magnesium carbonate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hypromellose, talc, titanium dioxide, mannitol, methacrylic acid copolymer, ethyl acrylate–methyl methacrylate copolymer, polysorbate 80, glyceryl monostearate, triethyl citrate, anhydrous citric acid, ferric oxide (red), ferric oxide (yellow), polyethylene glycol 8000, methylacrylate methylmethacrylate methacrylic acid copolymer, microcrystalline cellulose, crospovidone, sucralose, strawberry Durarome, and magnesium stearate.
Enteric polymers were purchased from Evonik Industries (Essen, Germany). The other excipients used are commonly used in pharmaceutical products and were purchased from commercial sources.
In-vitro disintegration test. The disintegration test was performed per the procedure outlined in United States Pharmacopeia (USP) <701>, using a USP standard disintegration apparatus (17). Briefly, a basket rack assembly was used with 1000-mL low-form beakers (138–160 mm in height; inside diameter of 97–115 mm). This assembly contained six baskets, and each test tablet was placed in each basket. The baskets were lowered and raised in water as medium (37 â°C) at a consistent speed. Tablet disintegration was observed and recorded.
In-vivo disintegration study. The in-vivo disintegration of dexlansoprazole ODT was evaluated in a Phase I study conducted at Senopsys LLC (Woburn, MA). In this open-label study, eight healthy subjects (25–80 years of age) performed an oral disintegration test in triplicates. These men and women were trained to detect, identify, recognize, and describe different taste elements and flavor combinations and to measure oral disintegration times.
Each subject sipped and swallowed 20 mL of water. The time recording started. After 30 seconds, each subject placed a single 30-mg dexlansoprazole ODT on the tongue and gently rolled it against the roof of the mouth until it disintegrated into small granules. At the point when they would normally swallow the granules, the subjects recorded the time to disintegration and then expectorated the disintegrated tablet mass. Disintegration time was reported as the total elapsed time minus 30 seconds. This process was repeated on three separate days.
Subjects were contacted by phone one week after the testing to inquire about any adverse events.
Relative bioavailability study 1. The methodology for the clinical study to assess the effect of concomitant administration of a high-fat meal on the bioavailability of dexlansoprazole from the ODT has been reported previously (1). As an exploratory assessment, a taste questionnaire was given to subjects after dosing to assess reactions to the taste of the ODT. Participants evaluated the flavor, texture, and overall taste on a scale of 1–5 (from 1 = “disliked it very much” to 5 =“liked it very much”) and rated the ease with which this formulation can be taken once daily without water for four to eight weeks on a scale of 1–5 (with 5 being the easiest). The results of the taste questionnaire were tabulated and descriptive statistics computed.
Relative bioavailability study 2. The methodology for the clinical study to assess the effect of mixing the ODT with water and administering the mixture via an oral syringe or nasogastric tube on the bioavailability of dexlansoprazole from the ODT has been reported previously (1). A questionnaire assessing the subject’s reaction to the tablet residue and the need for a water rinse was used as an exploratory assessment. The questionnaire was administered after the delayed-release ODT had been placed in the subject’s mouth, allowed to disintegrate on the tongue, and swallowed without water. The following questions were posed:
Following administration of the ODT without water, did you feel that there was tablet residue remaining in your mouth? (Yes or No)
If yes, please estimate the amount of water you think would be needed to clear the residue from your mouth by selecting 1 of the 3 choices below:
a) No water rinse would be needed.
b) A sip of water would be needed.
c) Would need one-half of a glass of water or more.
The results of the questionnaire were tabulated and descriptive statistics computed.
Dissolution test. The dissolution test was performed per the procedure for delayed-release product in USP <711> (18), using USP basket apparatus 1. In-vitro dissolution was performed in two stages (acid and buffer stages). Tablets were first exposed to 0.1 N hydrochloric acid (HCl) for 120 minutes. After acid-stage testing, the resulting granule sample was transferred to the corresponding buffer-stage medium. Buffer-stage testing was continued per the procedure, and the assay was conducted by UV spectrometry.
For evaluation of dexlansoprazole ODT resistance to alcohol, ethanol concentrations of 0, 5, 10, 20, and 40% (vol/vol) were mixed in acid- and buffer-stage dissolution media. The pH of the buffer media was adjusted after ethanol was added.
Disintegration by in-vitro and in-vivo methods. In-vitro disintegration data from three lots in a long-term and accelerated stability study are summarized in Table I. Disintegration time ranged from 29–37 seconds for tablets stored at 25 °C/60% relative humidity between 0 and 24 months and from 29–36 seconds for samples stored at 40 °C/75% relative humidity for six months.
To determine whether dexlansoprazole ODT exhibited the same properties in a more physiological environment, a human in-vivo disintegration study was conducted with four men and four women. Disintegration time is inherently variable because of differences in salivation rate and oral cavity size geometry between subjects. Individual disintegration times for each trial ranged from 29–43 seconds. The mean and median in-vivo disintegration time was 36 seconds.
Dexlansoprazole ODT disintegrates in less than one minute in both in-vitro and in-vivo tests. Similar to what was described in other studies, there was good correlation between the in-vivo human oral disintegration test data and the compendia in-vitro disintegration data for dexlansoprazole ODT (19, 20).
Tablet weight. To assess the size acceptability of dexlansoprazole ODT, a survey was conducted in conjunction with a Phase I food effect study. Responses are summarized in Table II.
Overall, healthy subjects in this study found the product flavor, texture, and overall taste agreeable, with the highest mean scores for flavor and overall taste. Subjects also indicated that dexlansoprazole ODT could be easily taken daily without water for four to eight weeks.
Another survey was conducted during a different Phase I study to assess reaction to tablet residue and the need for a water rinse after administration of dexlansoprazole ODT. After allowing oral disintegration and then swallowing, 60% of subjects reported tablet residue; most (73%) could use a sip of water to clear the residue (Table III).
The active enteric-coated microgranules are designed to remain intact in the mouth, but optimal design should prevent them from imparting a gritty feeling in the mouth. The authors found that 40% of subjects did not sense any residue, whereas of the remaining 60% who felt some residue, 93% thought no water was needed or a sip of water was sufficient to rinse the residue.
Effect of alcohol on dexlansoprazole ODT drug release. Dissolution experiments were performed to evaluate the effect of alcohol on dexlansoprazole ODT drug release. The mean dissolution results of the acid and buffer stages in the presence of ethanol are shown in Figures 1Aand 1B, respectively.
During the acid-stage dissolution test, if the ethanol content was not more than 10%, the prespecified acid resistance criteria were met, with no more than 10% dissolution occurring during a maximum of 120 minutes, and the enteric coating left intact. At 20% ethanol content, the enteric coating was dissolved gradually and reached 28% release by 120 minutes. When 40% ethanol was used, the enteric coating was entirely dissolved within 60 minutes.
At alcohol contents up to 10%, the drug-release profiles in the buffer stage were similar to those seen without alcohol. In 20% alcohol medium, drug release was less than 70% of the starting amount because 28% of the drug had already been released in the acid stage. The buffer-stage medium containing 40% ethanol was not tested because all of the drug was released in the acid-stage medium containing 40% ethanol (18). At 40% alcohol concentration in acid-stage medium, drug release was quite high because of the solubility of the enteric-coated polymer under these conditions. However, alcohol concentrations of 20% to 40% in gastric fluid are much higher than those likely to be present under physiological conditions.
The ODT formulation of dexlansoprazole 30 mg was developed to address challenges in patients who have difficulty swallowing. The FDA Guidance for Industry on ODTs considers the following characteristics in defining an ODT: rapid disintegration time and tablet size and weight in relation to the intended use for the drug. The integrated in-vitro and clinical approach presented here demonstrates how the authors evaluated three key parameters crucial to an effective ODT design: tablet size, disintegration rate, and resistance to ethanol.
FDA recommends that products labeled as ODTs have an in-vitrodisintegration time of approximately 30 seconds or less, based on the USPdisintegration test method (4). Using the USP<701> disintegration test, the disintegration time of dexlansoprazole ODT was shown to be consistent in a range from 29–37 seconds, regardless of product storage conditions and length of time stored.
USP test conditions do not necessarily resemble actual conditions in the human mouth. For example, the testing medium volume significantly exceeds the saliva volume in the human mouth. The testing agitation pattern (i.e., baskets moving in and out of medium) is also different from the motion in a human mouth (19, 21).
To better assess disintegration under physiological conditions, the authors also conducted a human in-vivo disintegration study. The mean in-vivo disintegration time, 36 seconds, was consistent with the results from the in-vitro study. Although FDA guidance recommends less than 30 seconds for disintegration for ODT products, they also acknowledge that 30 seconds is a general time period associated with drugs that match the characteristics of ODTs (4). For this reason, agreement between in-vitro and in-vivo disintegration rates at close to 30 seconds, without water or chewing in the in-vivo test, is acceptable for an ODT formulation.
FDA guidance further states that ODTs should not weigh more than 500 mg, unless the product’s performance and ability to act as an effective ODT justify the extra weight (4). Because of formulation and manufacturing necessities, each dexlansoprazole ODT weighs approximately 700 mg. The surveys reported here showed that volunteers considered the tablet to be easily taken daily with water from four to eight weeks. The authors also found that 40% of all volunteers taking dexlansoprazole ODT without water did not note any tablet residue remaining in their mouth. Almost all the volunteers (93%) who did note residue found that it could be rinsed away with no more than a sip of water. These results together support the acceptance of a 700-mg tablet in this formulation. The results are consistent with the presence of other ODTs on the market that weigh more than 500 mg that have generally been well accepted (14).
Because patients might consume alcoholic beverages while on medication, the risk of dose dumping caused by an alcohol-induced drug-release rate change has generated several discussions between regulatory agencies and the pharmaceutical industry (16, 22, 23). The results of the in-vitro dissolution studies showed that administration of dexlansoprazole ODT with a moderate amount of ethanol did not result in premature or excessive release of the drug (i.e., dose dumping). The enteric coating of the granules maintained its integrity at ethanol concentrations up to 10% for 120 minutes. This concentration of ethanol could be expected in the gastrointestinal tract for patients who consume alcohol immediately before taking the medication. Complete release of the drug in the stomach can only occur at ethanol concentrations of 40% for 60 minutes. This concentration is not likely to occur in vivo for a 60-minute period. For example, a 1.5-ounce (approximately 50 mL) shot would be diluted in the gastric fluid (approximately 240 mL) in the stomach, and the alcohol concentration would be reduced to less than 10% (24,25). Only the rapid intake of a substantial volume of alcohol would increase the concentration over 10%, but it would be very unlikely to reach 40%, which is the ethanol concentration at which the most rapid dissolution occurred in the acid-stage medium.
Dexlansoprazole ODT is a unique ODT product containing two types of enteric-coated microgranules for a delayed-release formulation and extended control of intragastric pH over 4.0. Design of such a tablet presents certain inherent challenges with regard to allowing oral disintegration and a delayed-release pharmacokinetic profile while maintaining convenience and palatability for patients. The authors have described an effective method that combined in-vitro and in-vivo approaches to evaluate the tablet’s weight, disintegration time, mouth feel, and resistance to alcohol. The experimental data presented here demonstrate the acceptable product physical characteristics of an ODT with a dual delayed-release mechanism.
Haiyan Grady is an employee of Takeda Development Center Americas, Inc., Deerfield, IL. Takako Ono is an employee of Takeda Pharmaceutical Company, Japan. Michael Kukulka and Sai Nudurupati were employees of Takeda Development Center Americas, Inc., Deerfield, IL, at the time of this study.
This work was supported by Takeda Development Center Americas, Inc. Medical writing assistance was provided by Nicola Reading Mans, PhD, and Jake Edelstein, PhD, of inVentiv Medical Communications and supported by Takeda Development Center Americas, Inc.
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Submitted: April 30, 2018
Accepted: May 11, 2018
Vol. 43, No. 8
When referring to this article, please cite it as H. Grady et al., "Evaluation of Physical Characteristics of Dexlansoprazole Orally Disintegrating Tablets," Pharmaceutical Technology 43 (8) 2018.
Haiyan Grady* is associate scientific director CMCC, Takeda Development Center Americas, 300 Massachusetts Ave (4274), Cambridge, MA 02139, Tel: 1.224.554.2067, email@example.com; Michael J. Kukulka is senior manager, Global Labeling, Regulatory Affairs, PRA Health Sciences (Deerfield, IL); Takako Ono is principal scientist, Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Co. Ltd. (Osaka, Japan); and Sai V. Nudurupati is assistant director at AbbVie Inc. (North Chicago, IL).
*To whom all correspondence should be addressed.