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Orally disintegrating tablets (ODTs) can be easily swallowed without drinking water and are a convenient dosage form for the elderly and infirmed patients, as well as other patients, such as businesspeople. A major challenge in the development of ODTs is masking the unpleasant taste of the drug, which can make ODTs palatable. Flavors are often used for taste-masking. A few comprehensive studies have been conducted on the selection of suitable flavors for ODTs. This study aimed to evaluate the effects of different flavors on the taste sensation of ODTs using a visual analog scale (VAS). Sixteen flavors were studied for their effects on the taste sensation of pioglitazone ODTs in a randomized single-blind study involving the gustatory sensation testing of ODTs. Healthy volunteers were enrolled and asked to periodically evaluate the bitterness, sweetness, astringency, sourness, and overall palatability of ODTs, both during and after disintegration in the oral cavity, using the VAS. Most flavors improved the sweetness of ODTs without the addition of a sweetener, and some suppressed bitterness, astringency, and sourness. In particular, blueberry, and yoghurt flavors significantly improved sweetness and overall palatability during disintegration of the pioglitazone ODT. The approach of using VAS score analysis was effective in selecting the most suitable flavor for improving the overall palatability of ODT. Furthermore, the addition of a suitable flavor can successfully mask the unpleasant taste of the drug and effectively improve the overall palatability of ODT.

Good adherence to medication is critical for successfully treating psychiatric disorders. Tailor-made pharmaceutical formulations can provide a suitable dosage form to meet the specific needs of individual patients who exhibit poor adherence to industrially manufactured products. Herein, we prepared aripiprazole (ARP) gummies (ARP-Gs) using a commercially available ARP formulation. We aimed to clarify the palatability of ARP-Gs by performing a gustatory sensation test in healthy volunteers. We performed two types of organoleptic masking of ARP-Gs, cocoa- and fruit-flavoured gummies (6.0 mg of ARP/3.5 g of gummy), and conducted two different gustatory sensation tests for each ARP-G. Ten young, healthy volunteers (mean ± standard deviation, 23.7 ± 1.2 years) were enrolled in each trial. The overall palatability of ARP-Gs was evaluated using the 100-mm visual analogue scale (VAS). Receiver operating characteristic (ROC) curve analysis was performed between VAS scores of total ARP-G palatability and acceptability assessed using a 5-point rating scale. Among cocoa-flavoured ARP-Gs, those combining aspartame, cocoa powder, and banana flavour (ABC-ARP-G) exhibited the highest VAS scores for total palatability. Similarly, the VAS scores of grapefruit-flavoured ARP-Gs (GF-ARP-G) showed the highest values considering all fruit-flavoured ARP-Gs. The VAS scores for ABC-ARP-G and GF-ARP-G greatly exceeded the cut-off values of acceptability calculated using the ROC curve. We developed two types of ARP-Gs with organoleptic masking as tailor-made pharmaceutical formulations. ABC-ARP-Gs and GF-ARP-Gs could be acceptable in patients. ARP-Gs could be an alternative to currently available pharmaceutical formulations to enhance their adherence and meet the specific needs of individual patients.

Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5-12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.

Oral mucositis is one of the most common adverse effects of radiation and chemotherapy in treatments of cancers. Some clinical guidelines have focused on the prevention and treatment of oral mucositis, and thus, a mouthwash containing drugs is often recommended. In this study, we aimed to evaluate the disappearance time and palatability in the oral cavities of healthy volunteers in foams prepared from different concentrations of the three viscosity grades of methylcellulose (SM-4, -100, -400). In addition, we prepared foam formulations of drugs (benzydamine, dexamethasone, allopurinol and rebamipide) for use as a prevention and treatment of oral mucositis. There was a significant relationship between the foam drainage ratios at 5-15 min and the disappearance time in the oral cavities. The significant relationship of foam densities to the foam disappearance time and overall palatability in a clinical study were observed. Thus, the foam density is considered an important parameter and reflects these clinically important properties. The foam from SM-4 has the longest disappearance time and the best palatability followed by foams from the 4 and 1% SM-4. Drug contents in drug-containing foam formulations which were prepared with 1-4% SM-4 represented 101-112% of the loaded drug contents, and the relative standard deviations of drug contents were <2.2%, which suggests that these formulations had pharmaceutically acceptable properties. This is the first report in regard to foam formulations containing drugs for the prevention and treatment of oral mucositis, and these formulations could be potentially useful for the prevention and treatment of oral mucositis.

The aim of the present study was to determine whether solid dispersions (SDs) are applicable to gummi formulations. Amenamevir was selected as a model of a poorly water-soluble drug, and polyvinyl alcohols (PVAs) with various degrees of hydrolysis (PVA 66, PVA 80, PVA 88, and PVA 66/88) were used as SD carriers. Design of experiments (DOE) was used to develop a gummi formulation that was suitable for an amenamevir SD using SD with PVA 66. Dissolution studies and clinical sensory tests on 11 formulations calculated by DOE revealed that a gummi formulation comprising 10.5% gelatin and 22.8% water was suitable for SD of the drug. Gummi formulations comprising amenamevir SDs with various PVAs were prepared using the determined gummi formulation, and their ability to dissolve amenamevir, their stability, and their oral absorption in dogs were evaluated. The results suggested that PVA 66, PVA 66/88, and PVA 80 were appropriate in terms of dissolution, stability, and in vivo absorption, respectively. Considering these results comprehensively, it was concluded that PVA 80, which enabled the highest degree of absorption, was the most suitable SD carrier for gummi formulations. Thus, it was possible to apply a PVA SD of amenamevir to gummi formulations.

Recently, owing to their pharmaceutical and clinical utility, mini-tablets have been well studied by researchers. Mini-tablets are usually manufactured by compression molding using a multiple-tip tool in a rotary tableting machine. Owing to their special structure, ensuring uniformity is a very important challenge in the manufacturability of mini-tablets using the multiple-tip tool. In this study, we aimed to evaluate the weight variation in mini-tablets produced by a multiple-tip tool, which is considered to be the root cause affecting the uniformity, and to investigate the physical properties of drug granules and tableting conditions in a rotary tableting machine that could reduce this weight variation. In addition, the relationship between these factors and response was visualized using response surface analysis. It was shown that the weight variation in mini-tablets produced by a multiple-tip tool was reduced when using a forced feeder compared with an open feeder. Furthermore, in the case of an open feeder, the optimal range of the average particle size diameter of drug granules and the rotational speed of the rotating disc in the rotary tableting machine were determined from response surface analysis. It was suggested that it is possible to reduce the weight variation in the mini-tablets by selecting drug granules with an average particle size diameter of 100-150 µm and using tableting conditions with a rotational speed of 40-60 rpm. This study elucidated the factors that affect uniformity and determined their optimal range for the manufacture of mini-tablets.

Fixed-dose combination (FDC) medicines containing two or more active pharmaceutical ingredients (APIs) in a single dosage form have been reported to improve patient adherence to a greater extent than single dosages of individual components (ICs). Orally disintegrating tablets (ODTs) are easier to swallow than conventional tablets. The aim of this study was to elucidate the clinical pharmaceutical characteristics of taking a FDC-ODT and two IC-ODTs. We prepared three ODTs containing mitiglinide, voglibose, and mitiglinide/voglibose and three corresponding placebo ODTs and performed 2 independent clinical trials with 13 healthy subjects (mean age, 23.4 ± 1.6 years). One trial evaluated the ease of taking tablets and the amount of water required for taking the tablets; placebo ODTs were used in order to avoid administering APIs. The other trial evaluated the bitterness, sweetness and overall palatability of ODTs containing APIs during disintegration and after spitting out. Ease and taste were evaluated using both a visual analog scale (VAS) and a verbal rating scale (VRS). The results of the VAS and VRS evaluation indicated that FDC-ODT could ease tablet intake unlike IC-ODTs. In addition, FDC-ODT reduced the amount of water required for tablet intake in contrast to IC-ODTs. Taste evaluation results did not reveal any difference between FDC-ODT and IC-ODTs, except for the sweetness score after spitting out. In conclusion, FDC-ODT is easy to take and can help improve patient adherence.

Solifenacin (Sol), an antimuscarinic agent has been widely used for the treatment of overactive bladder. Transdermal formulations can be administered without water as well as absorbed slowly into the blood over a long period of time. The aim of this study was to develop cream and tape formulations of Sol, and evaluate the transdermal permeation and absorption of the drug from the two formulations in vitro and in vivo, respectively. In the preparation of cream formulation, Sol succinate was dissolved in purified water, and the mixture was added to the hydrophilic cream. Then, aqueous sodium hydroxide was added to the cream. In the tape formulation, Sol succinate was dissolved in a solvent with propylene glycol, diisopropanolamine, triethyl citrate, and EUDRAGIT E100. The dissolved solvent was poured onto a polyethylene film. Cream (5%) and tape (15%) formulations demonstrated high skin permeability. Addition of an adsorption enhancer (N-methyl-2-pyrrolidone) did not further increase the level of skin permeability. In subsequent in vivo experiments in rats, both the cream and tape formulations led to slow absorption of Sol into plasma, with increased t 1/2 compared with oral administration. Plasma Sol concentrations peaked 24 h after transdermal application and the drug was still detectable in plasma 72 h after application. Additionally, the cream (5%) and tape (15%) formulations resulted in a higher area under the plasma concentration vs. time curve from 0 to 72 h (AUC 0-72 ) compared with oral formulation (30 mg/kg). In conclusion, significant in vitro permeability and in vivo absorption of Sol from the transdermal formulations were observed.

Orally disintegrating tablets (ODTs), which are administered without water, are beneficial for elderly patients and patients with dysphagia. Masking the unpleasant taste of a drug is an important factor associated with adherence of patients consuming ODTs. We prepared cocoa powder-containing ODTs of bitter-tasting rebamipide (rebamipide chocolet) and evaluated their clinical palatability. We prepared rebamipide ODTs by adding a sweetener and 0, 2.5, 5, and 10% cocoa powder (Ch0-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs, respectively). Rebamipide ODTs without cocoa powder and sweetener were used as controls (Cont-ODTs). We performed a gustatory sensation test in 30 healthy adult volunteers. We used the 100-mm visual analog scale (VAS) to evaluate bitterness, sweetness, scent, and overall palatability of the ODTs. The acceptability of each ODT was evaluated on a 5-point scale. Compared to Cont-ODTs, Ch0-ODTs showed no significant improvement in the VAS score for bitterness, scent, and overall palatability during disintegration. However, compared to Cont-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs showed an improvement in all items evaluated using the VAS. In particular, Ch2.5-ODTs showed a significant improvement compared to the Cont-ODTs in the VAS score of all items. Evaluation on a 5-point scale indicated that Ch2.5-ODTs and Ch10-ODTs had the highest acceptability. We prepared rebamipide chocolet with excellent palatability properties, which could not be achieved using a sweetener alone, by using the combination of a sweetener and cocoa powder as a new agent for masking bitterness. Our results indicate that cocoa powder may be used as a taste-masking agent in ODTs.

We examined the amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity. Additionally, 5 different in vitro short dissolution test methods (Tricorptester, magnetic stirrer, rotating injection syringe, paddle apparatus, shaking) were used to evaluate dissolution and the results were compared to those obtained with the human volunteers. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured using the RACTAB ® technique. Quantitative findings showed that amlodipine dissolution from ODT was dependent on time in the oral cavity and the amount of coating applied for physical masking. We also found that dissolution in the oral cavity was best correlated to that in in vitro short dissolution tests with a time period of 30 s. For more detailed evaluations, mean prediction error, mean absolute error, and root mean square error values were calculated, each of which was lowest with the Tricorptester method among all of the investigated test methods. Our results indicate that mimicking of the inside of the human oral cavity is accurate with a testing time of 30 s, while the Tricorptester method was the most preferable of all in vitro tests investigated in this study.

This study aimed to elucidate the appropriate physical characteristics that are clinically acceptable for gummi formulations. We prepared 11 placebo gummi formulations containing different amounts of gelatin and water and evaluated their penetration and restitution using a penetrometer and rheometer, respectively. Clinical sensory tests in 16 healthy volunteers (age, 23.4±0.9 years, mean±standard deviation) were conducted on the placebo gummi formulations using the visual analog scale (VAS) score to evaluate elasticity, hardness, and overall palatability, with a 5-point rating scale of preference. The penetration increased with decreasing amounts of gelatin or increasing amounts of water in the gummi formulations. Similarly, the VAS score of elasticity and hardness from the clinical sensory tests increased with increasing amounts of gelatin but decreased with increasing amounts of water. The relationship between the penetration and VAS scores of elasticity and hardness revealed good linear correlations. This suggests that the penetration was well reflected by the hardness results of the clinical VAS scores. The overall palatability evaluated using the VAS score increased until the penetration was 10 mm and then plateaued at >10 mm penetration. The 5-point rating score for preference revealed that >50% of volunteers "prefer" the gummi formulations with penetration values of 9.8 to 13.5 mm. These results suggest that gummi formulations likely have an appropriate window of hardness. Furthermore, appropriate gummi formulations with clinically preferred physical characteristics could be prepared by adjusting the amount of gelatin and water and measuring their penetration.

The objective of this study was to establish the key factor of the lauryl sulfate (LS) salt/complex for sustained release of a hydrophilic drug at various physiological pH levels. Mirabegron is a hydrophilic drug that exhibits pH-dependent solubility. Sodium lauryl sulfate (SLS) bound to mirabegron in a stoichiometric manner. The formation of the LS salt/complex significantly reduced mirabegron solubility and helped achieve sustained release of mirabegron over a wide range of pH levels. In addition to SLS, other additives containing a sulfate group formed salts/complexes with mirabegron and reduced its solubility at different pH levels. Furthermore, octyl sulfate (OS), myristyl sulfate (MS), and cetyl sulfate (CS) salts/complexes, which contain alkyl chains of different lengths, showed a lower solubility than mirabegron and promoted sustained release of mirabegron. The rank order of solubility and dissolution rate were as follows: OS salt/complex>LS salt/complex>MS salt/complex>CS salt/complex, which corresponded to the rank of alkyl chain lengths. We conclude that the presence of a sulfate group and the length of the alkyl chain are key factors of the LS salt/complex for sustained release of a hydrophilic drug at various physiological pH levels.

The manufacture of highly drug-loaded fine globular granules eventually applied for orally disintegrating tablets has been investigated using a unique multi-functional rotor processor with acetaminophen, which was used as a model drug substance. Experimental design and statistical analysis were used to evaluate potential relationships between three key operating parameters (i.e., the binder flow rate, atomization pressure and rotating speed) and a series of associated micromeritics (i.e., granule mean size, proportion of fine particles (106-212 µm), flowability, roundness and water content). The results of multiple linear regression analysis revealed several trends, including (1) the binder flow rate and atomization pressure had significant positive and negative effects on the granule mean size value, Carr's flowability index, granular roundness and water content, respectively; (2) the proportion of fine particles was positively affected by the product of interaction between the binder flow rate and atomization pressure; and (3) the granular roundness was negatively and positively affected by the product of interactions between the binder flow rate and the atomization pressure, and the binder flow rate and rotating speed, respectively. The results of this study led to the identification of optimal operating conditions for the preparation of granules, and could therefore be used to provide important information for the development of processes for the manufacture of highly drug-loaded fine globular granules.

The purpose of the present study was to develop orally disintegrating tablets (ODTs) containing fat-soluble drugs that disintegrate rapidly while having appropriate tablet strength. We chose vitamin E (VE) as a model drug; d-α-tocopheryl acetate, as the oily VE (VE-OI), and d-α-tocopheryl acid succinate, as the powder VE (VE-PO), were used. The oily VE was added directly to ODTs (VE-OI ODTs) and also used for the preparation of two types of VE granule, i.e., granules prepared using adsorption to calcium silicate (VE-FL granules) and granules prepared using spray-drying with gelatin (VE-SD granules); each type of granule was added to ODTs (VE-FL ODTs and VE-SD ODTs). Powder VE was added directly to ODTs (VE-PO ODTs). Various VE ODTs were prepared using these four additional methods with varying amounts of VE per tablet and were evaluated with respect to their manufacturability, physicochemical characteristics, and stability. It was demonstrated that a tablet porosity of 30% to 35% and tensile strength of 7 kg/cm(2) or greater are required to provide VE ODTs with rapid disintegration and appropriate tablet strength, and that VE-SD granules and powder VE are suitable forms of VE to be added. When stability tests of VE-SD ODTs and VE-PO ODTs were performed, VE-PO ODTs exhibited prolongation of disintegration time and increased tensile strength, whereas VE-SD ODTs showed none of these changes. These changes were thought to be attributable to a decrease in the pore size of VE-PO ODTs resulting from the softening and migration of powder VE under hot storage conditions.

About half of patients with schizophrenia have poor adherence to taking medication, so many have recurrence, therefore, providing formulations that enable patients to continue their medication without interruption is important. We aimed to develop a gummi drug that contains aripiprazole (which can reduce schizophrenia and manic symptoms in bipolar disorder). We were able to develop gummi drugs (OD-G, PW-G and OS-G) using three commercially available aripiprazole products (Abilify® orally disintegrating tablets, powder formulation, and oral solutions, respectively) as hospital formulations. Furthermore, we developed improved OD-G (iOD-G), which contained high aripiprazole content. Pharmaceutical characteristics of iOD-G were demonstrated to be suitable for hospital formulations, and iOD-G could be stored for ≤1 month. No significant differences in the dissolution and pharmacokinetics of divided portions of iOD-G were observed when compared with commercially available aripiprazole products. This study confirmed that new dosage forms of aripiprazole in gummi drugs can be developed as hospital formulations, which will contribute to improve medication adherence of patients.

The aim of this study was to obtain injectable high-drug-loading core-shell structure microspheres that release aripiprazole over 2 months. The microparticles were prepared by the oil-in-water emulsion solvent evaporation method and characterized. The microparticles were prepared with aripiprazole and 3 types of poly(lactic acid) (PLA) (DL-PLA: molecular weight (MW), ca. 20000; DL-PLA: MW, ca. 95000; or L-PLA: MW, ca. 110000), which were dissolved within the organic phase, and prepared in 3 temperature conditions for the external aqueous phase (two fixed temperature conditions and a gradually increased temperature condition). The theoretical drug loading in the particles was set to 80%. When prepared at fixed temperature conditions, all of the microparticles that were prepared with the 3 types of PLA were not spherical or smooth-surfaced. These microparticles released 100% of the drug within 1 week in the in vitro study. However, the microparticles that were prepared with DL-PLA (MW, 95000) in the gradually increased temperature condition were spherical with a smooth surface. The dissolution profile of the microparticles showed a long release over 7 weeks in vitro. The actual drug loading in the microspheres was 73-80%. A core-shell structure was observed in the inner structure of the microspheres. The core-shell microspheres were injected subcutaneously into rabbits. Aripiprazole was detected in the serum over 12 weeks. Production of high-drug-loading core-shell structure microspheres was successfully achieved by using high molecular weight of PLA and specific temperature condition at preparation. It showed long release profile in vitro and in vivo.

Multiple regression analysis (MRA) and principal component analysis (PCA) have been used in the present study to examine the relationships between the operational conditions of a unique multi-functional rotor processor, material attributes such as water content during granulation, and a series of associated micromeritics, including the flowability, granule mean size and granule density values. A variety of different operational conditions were tested, including the binder flow rate, atomization pressure, slit air flow rate, rotating speed and temperature of the inlet air. The results of MRA revealed several trends, including (1) the granule mean size was negatively affected by the atomization pressure, and positively affected by the binder flow rate; (2) the granule flow property, Carr's index was positively affected by the atomization pressure, and negatively affected by the slit air flow rate; and (3) the granule density was positively affected by the rotating speed. Taken together, these results suggested that the binder flow rate, atomization pressure and slit airflow rate were critical process parameters for the preparation of fine globular granules. Using PCA, it was possible to examine each relationship of all 19 batches and 10 variables, as well as determine which process parameters or material attributes impacted on the quality of the final product. The PCA results revealed that the roundness was positively correlated with the water content. Therefore, we believe this fundamental information will be important for the development of processes for the facile manufacture of fine globular granules.

Orally disintegrating tablets (ODTs) are useful for improving benefits for patients of various ages. Masking the unpleasant taste of a drug is an important factor in the compliance of patients who take ODTs. We evaluated the taste acceptability effects of various taste-masking methods on bitter famotidine ODTs as a clinical pharmacological study. The following methods were tested to compare taste-masking effects: physical masking by spray-coating famotidine with ethyl cellulose versus organoleptic masking with added sweetener and flavor. The ODT samples were prepared as single or combinations of each taste-masking method using a novel suspension spray-coating method including a placebo. A total of 31 healthy volunteers were enrolled in this randomized, double-blind study and asked to score their bitterness, sweetness and total palate impressions by 100 mm visual analogue scale (VAS). VAS scores were significantly improved by the physical and organoleptic methods as compared to without taste-masked ODTs. Furthermore, the combination of both taste-masking methods was most effective for improving palatability and VAS scores were similar to those of placebo ODTs. The results of this study suggest that different taste-masking mechanisms function cooperatively.

In this study, we aimed to design orally disintegrating tablets by employing a formulation design approach that enables the production of such tablets in the same facilities used for the production of solid dosage forms on an industrial scale. First, we examined the relationships between the types of binders used in the tablets and the properties of orally disintegrating tablets prepared by the wet granulation method. Results revealed that partly pregelatinized starch is a relatively suitable binder for orally disintegrating tablets as it also serves as a disintegrant. Next, we employed a central composite design for 2 factors, namely, corn starch and partly pregelatinized starch, in order to design granules suited for orally disintegrating tablets composed of D-mannitol, corn starch or partly pregelatinized starch. The effects of these 2 factors on 3 types of responses, namely, 50% granule size, compressing index and disintegrating index, were analyzed with a software package, and responses to changes in the factors were predicted. This study investigated the effects of binder type and binder content in orally disintegrating tablets, and provided evidence that the binder exerts a strong influence on tablet properties, and is therefore an important component of orally disintegrating tablets.