Development of Bitter-Taste Masked Instant Jelly Formulations of Diphenhydramine Hydrochloride with Easy-to-Consume Granules

Abstract

This study developed easy-to-consume bitter taste-masking granules for the preparation of instant jelly formulations. Composite granules containing diphenhydramine hydrochloride (DPH) and polymers were prepared via spray drying. The taste-masking effect on DPH was evaluated with acceptable linearity between DPH concentration and intensity of bitterness using an electronic tongue sensor. The results indicated that ι-carrageenan could provide the greatest suppression effect on the DPH bitterness among the polymers selected for preparing spray-dried particles (SDPs). The thixotropic index (TI) of ι-carrageenan was higher than that of the other polymers. In addition, two sulfate groups per two galactose molecules in one unit of ι-carrageenan improved interaction with DPH. Compared to κ-carrageenan, the electrostatic interaction with DPH may be stronger. Easy-to-consume SDPs with ι-carrageenan were used to prepare instant jelly formulations. The instant jelly formulation containing DPH with ι-carrageenan (3.0%) met the criteria for texture properties (hardness, adhesiveness, and cohesiveness) for patients with difficulty swallowing, as specified by the Consumer Affairs Agency. Furthermore, instant jelly enhanced the bitter taste suppression of DPH. Overall, using spray-dried granules with ι-carrageenan, this technique for preparing instant jelly formulations is simple and inhibits the bitter taste of drugs, contributing to the development of oral dosage forms suitable for patients of all ages.

Introduction

Oral jelly formulations, orally disintegrating tablets (ODTs), and mini tablets that are easily ingested have been designed.^1–5) These dosage forms are expected to improve geriatric and pediatric patients’ compliance with treatments. Palatability and taste of these dosage forms are important quality requirements. Especially, bitter taste derived from active pharmaceutical ingredients (APIs) is a major concern.⁶⁾ Taste-masking for APIs with unfavorable bitterness or astringency was conducted using various techniques.⁷⁾ ODTs and sprinkle-capsules have been designed as palatable dosage forms for geriatric and pediatric patients using taste-masking polymer-coated granules that were prepared by spray-drying.^8,9) Particularly, flexible dosage forms would be preferable if a dosage adjustment is needed for pediatric patients. In such cases, age-appropriate sprinkles were dispersed onto foods because they were easier to ingest than tablets; however, these sprinkles were unfavorable for pediatric patients because of the alterations in taste.¹⁰⁾ Jelly formulations have attracted much attention because they are highly palatable and acceptable to both pediatric and geriatric patients as easier-to-swallow and bitter taste-masked medicines.^11,12) Several jelly formulations with immediate drug release have been launched on the market.¹³⁾ Drugs with these formulations are difficult to stock and transport; therefore, they have not been in circulation. Additionally, conventional jelly formulations require preservatives because they contain a large amount of water. The safety of excipients in pediatric patients is a critical concern for the design of alternative dosage forms. Therefore, easy-to-use jelly preparations using granules have been developed.^14–17)

This study aimed to design easy-to-use, bitter taste-masking granules for the preparation of instant jelly formulations. Composite granules containing diphenhydramine hydrochloride (DPH) were prepared with polymers using spray-drying as a model bitter taste-masking drug.^18,19) The successful formulation of taste-masking polymer granules with DPH was investigated using an electronic tongue.^20,21) Taste-masking polymer granules containing DPH were employed to prepare instant jelly formulations. The texture profiles of the prepared instant jelly formulations were also assessed. The appropriate concentration of gelling agents in water was determined by evaluating the criteria of texture properties for patients with difficulty swallowing, as specified by the Consumer Affairs Agency.

Results and Discussion

Taste Masking Effect of Polymers on DPH

For a precise API evaluation of the sensitive response to the electronic sensor, the ability to differentiate the bitter intensity of DPH depending on the dissolved concentration is essential.²¹⁾ The calibration curve was constructed by plotting the correlation between DPH concentrations and change in membrane potential caused by adsorption (CPA) values obtained using a BT0 sensor (Supplementary Fig. S1). The correlation between DPH concentration and CPA value was linear in the range of 0.02–10.0 mM (correlation coefficient exceeding 0.98). The CPA values of DPH was evaluated by the addition of each polymer (hydroxypropyl methylcellulose (HPMC), gelatin, κ-carrageenan, and ι-carrageenan). The concentrations of DPH and each polymer were adjusted to 1.0 and 10.0 mM, respectively. The CPA value of DPH without polymers was almost 100 mV, whereas the addition of polymers to the DPH solutions decreased the CPA values of DPH (Supplementary Fig. S2). Among these, the addition of ι-carrageenan reduced the CPA value of DPH the most effectively. This result indicates that the selected polymers have inhibitory effects on the bitterness of DPH.

The polymer coating technique for granules containing APIs is useful for preparing taste-masked formulations. The spray-drying technique is the most popular for microencapsulation to mask the bitter taste.^6,22) HPMC, gelatin, κ-carrageenan, and ι-carrageenan that could decrease the CPA values of DPH were selected as wall materials for DPH encapsulation via spray-drying. The efficiency of the spray-drying technique in attenuating the bitter taste of DPH was evaluated using an electronic tongue. Figure 1 shows a comparison of the CPA values of the DPH spray-dried particles (SDPs) among the polymers. The SDPs with the polymer showed reduced CPA values. The polymer for SDPs appeared to have a stronger suppressive effect than PMs on the bitterness intensity of DPH. In particular, SDPs and PMs with ι-carrageenan had the strongest suppression effect on the bitter taste of DPH. The thixotropic index (TI) was calculated as the ratio of viscosity at rotation speeds of 6 and 60 rpm (Table 1). Generally, TI is a simple and intuitive method for describing fluid thixotropy.²³⁾ The TI of ι-carrageenan was the highest among all the polymers. Additionally, two sulfate groups per two galactose molecules in a unit of ι-carrageenan improve interactions with DPH.²⁴⁾ Compared to κ-carrageenan, the electrostatic interaction with DPH may be stronger. These two factors could be due to ι-carrageenan attenuating the strongest CPA values. When the solvent evaporation from the droplets occurs, SDPs with ι-carrageenan showing the highest TI may form homogeneous encapsulations.

Fig. 1. Comparison of the Taste-Masking Effect of Polymers on the Change in Membrane Potential Caused by DPH Adsorption

* p < 0.05 Compared with untreated DPH.

Table 1. Comparative Thixotropic Index among Polymers Used in Spray-Drying

Polymers	Viscosity (mPa·s)		Thixotropic index (−)
	6 rpm	60 rpm
ι-Carrageenan	3.27	2.23	1.47
Gelatin	1.28	0.97	1.32
HPMC	1.23	0.88	1.40
κ-Carrageenan	4.65	4.48	1.04

The release profiles of untreated DPH and DPH from the four SDPs in a phosphate buffer solution (pH 6.8) are illustrated in Fig. 2. Untreated DPH immediately dissolved in buffers of pH 6.8, and DPH dissolution rates were almost 100% within 2 min. In contrast, DPH dissolution rates from SDPs with any polymer were delayed compared to those of untreated DPH. As previously reported, delayed dissolution rates of API within 5 min could induce bitter taste suppression in the oral cavity.^2,3) The DPH dissolution rate from SDPs with ι-carrageenan was the slowest, at 44.8% after 5 min. The SDPs of DPH with ι-carrageenan were used to prepare easy-to-use jelly formulations.

Fig. 2. Release Profiles of Untreated DPH and DPH from Four Spray-Dried Particles in Phosphate Buffer Solution (pH 6.8)

Evaluation of Easy-to-Use Instant Jelly Formulation Preparation

Instant jelly formulations were prepared using SDPs of DPH with ι-carrageenan by dispersing the SDPs in distilled water heated at approximately 55 °C to 2, 3, and 4% (w/w). The uniqueness and concept of instant jelly formulations prepared from solid powders were introduced in detail by Patel et al.¹⁴⁾ This preparation of instant jelly using the ι-carrageenan can mitigate drug instability because it is heated up to around 55 °C for 3 min, as opposed to the conventional jelly formulations that involve heating up to approximately 70 °C using κ-carrageenan and gelatin.^25–27) Although it takes several minutes to complete gelation in this formulation at room temperature around 25 °C, we could shorten preparation time for jelly as practical use if this formulation is stored at 5 °C in refrigerator. The design of texture for jelly formulations is critical for patients with difficulty swallowing.²⁸⁾ Texture profile analysis (TPA) can obtain several parameters, like hardness, adhesiveness, and cohesiveness, which can be used to compare the rheological properties and sensory attributes of foods and pharmaceuticals.²⁹⁾ TPA curves were drawn by compressing the hydrogels twice at a constant speed, following a general method (Fig. 3A). The first TPA curve peak of hydrogels prepared with PMs or SDPs was almost identical, while the second TPA curve peak of PM hydrogels was lower than that of SDP hydrogels. Both TPA curve peaks for the hydrogels increased with ι-carrageenan concentration. Three parameters, namely, hardness, adhesiveness, and cohesiveness, against different ι-carrageenan concentrations were estimated³⁰⁾ (Fig. 3B). The hardness of the hydrogels increased with increasing ι-carrageenan concentration, regardless of the preparation method. The adhesiveness of hydrogels prepared from SDP hydrogels was stronger than that of PM hydrogels, indicating that homogeneous interactions in ι-carrageenan in the SDP hydrogels were formed in the state of holding water and DPH. The cohesiveness of SDP hydrogels decreased with increasing ι-carrageenan concentrations. The Consumer Affairs Agency in Japan established the standard criteria for foods authorized for individuals with swallowing difficulty (Supplementary Table S1). The appropriate concentration of ι-carrageenan in the hydrogels was approximately 3% if the present formulations were aimed at meeting the Consumer Affairs Agency’s Standard I. Untreated DPH dissolved faster than DPH from SDPs and hydrogels with ι-carrageenan (Fig. 4). Additionally, the DPH released from the SDPs showed faster kinetics than that of the hydrogels. This may be due to the formation of homogeneous hydrogels with carrageenan. The CPA value of hydrogels was half than that of the SDPs (Fig. 5).

Fig. 3. (A) Texture Profile Curves of ι-Carrageenan-Containing Hydrogels between Physical Mixture and Spray-Dried Particles; (B) Textural Properties of Hydrogels with ι-Carrageenan between Physical Mixture and Spray-Dried Particles; (1) Hardness, (2) Adhesiveness, and (3) Cohesiveness

Fig. 4. Dissolution Profiles of Untreated DPH, Spray-Dried Particles of DPH/ι-Carrageenan, and Hydrogels Prepared with Spray-Dried DPH/ι-Carrageenan Particles in pH 1.2

Fig. 5. Comparison of the Change in Membrane Potential Caused by DPH Adsorption among Hydrogel or Spray-Dried Particle Formulations and Untreated Samples

In conclusion, the findings indicate that hydrogels prepared using SDPs with ι-carrageenan can meet the standard I criteria, allowing geriatric and pediatric patients with swallowing difficulties to consume them easily and without bitter taste. Furthermore, these hydrogels are easy to prepare. These hydrogel formulations have promising dosage forms applicable to patients of all ages, although further study of panel tests using healthy volunteers and more optimal formulation study are required in the future.

Experimental

Materials

HPMC was supplied by Shin-Etsu Chemical Co. Ltd. (Tokyo, Japan). Gelatin (Type B) was a gift from Nitta Gelatin Inc. (Osaka, Japan). Both κ-carrageenan and ι-carrageenan were gifted by Sansho Co., Ltd. (Osaka, Japan). DPH was procured from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). All other chemicals and solvents were of HPLC grade or reagent grade.

Sample Preparations

The components of the solutions were prepared by dissolving DPH (330 mg) and the polymers (3.3 g) in 100 mL of distilled water at a 1/10 loading weight of DPH and each polymer. The solution was transferred to a Mini Spray Dryer (B-290, Buchi K.K., Tokyo, Japan) equipped with a nozzle of 0.7-mm diameter at a rate of 5.5 mL/min, and then the gas flow rate was 473 L/h.

Instant jelly formulations containing 10 mg DPH using ι-carrageenan were prepared. The weight ratio of the DPH/ι-carrageenan jelly formulations prepared using PMs and SDPs was fixed at 1/10. The PMs and SDPs of DPH/ι-carrageenan were dispersed in distilled water at approximately 55 °C to yield 2, 3, and 4% (w/w). The sample solutions were then stirred at 55 °C for 3 min. Next, the samples were left at approximately 25 °C for 60 min.

Taste Evaluation Using an Electric Tongue Sensor

A taste sensing system (SA402B, Intelligent Sensor Technology, Inc., Kanagawa, Japan) was used. The BT0 sensor was used to evaluate the bitterness intensity of the DPH.^20,31) The principle and operating procedure of this equipment were described in detail.³²⁾

Briefly, the difference in the potential values of the reference solutions before and after is represented as V_r′ − V_r. This difference was due to the CPA, which corresponds to the aftertaste.³³⁾

By dissolving 10 mM DPH in phosphate buffer solutions (pH 6.8), a calibration curve of DPH bitterness as a function of concentration was prepared. The range of DPH concentration in phosphate buffer solution (pH 6.8) was 0.005–10.0 mM. In 50 mL of phosphate buffer solution (pH 6.8), the PM samples of DPH (14.591 mg) and each polymer (145.91 mg) were dissolved.

Viscosity Measurement

The viscosity of the dissolved polymer solutions (0.3%) was measured using a rotational cone-plate viscometer (DVNext Rheometer; Brookfield, MA, U.S.A.) equipped with a cone spindle (CP-40). The rotation speed varied from 1 rpm to 100 rpm every 30 s at 25 °C. The TI was determined using the following equation:

  

Release Study

The release of DPH from polymers with SDPs was studied in 50 mL of phosphate buffer solution (pH 6.8) using a small-scale apparatus (ML-10F, Taitec Cooperation, Saitama, Japan) at 37 °C under 100 strokes/min. After definite intervals, 500 µL of each sample was withdrawn and filtered through a 0.45-µm membrane filter. The dissolution study was performed at 37 °C (NTR-8000AC, Toyama Sangyo, Osaka, Japan) employed in 900 mL of a buffer solution (pH 1.2) under constant stirring at 100 rpm. At each point, 3 mL of solution was similarly withdrawn and filtered .

The DPH content in the samples was determined using HPLC (SPD-10A; Shimadzu Co., Ltd., Kyoto, Japan) under the following conditions: column (COSMOSIL 5C18–MS-II (3 µm, 4.6 × 150 mm; Nacalai Tesque, Inc.)) temperature, 40 °C; injection volume, 10 µL; wavelength, 220 nm; and flow rate, 1.0 mL/min. The mobile phase was methanol/20 mM, phosphate buffer (pH 7.0).

Texture Profile Analysis

The EZtest-500 N (Shimadzu Co., Ltd.) was used for hydrogels TPA. The gel samples were stored in 40.0-mm diameter and 15.0-mm height cups.

A compression speed of 10 mm/s was added to the hydrogels twice with an analytical probe (20.0-mm diameter; 8.0-mm height) until a depth of 2/3 of the sample height was reached. Three textural parameters were evaluated.^34,35)

Acknowledgments

We thank Dr. Hidekazu Ikezaki and the members of the Intelligent Sensor Technology Inc. for providing technical suggestions for the electronic tongue.

Funding

This study was partially supported by the Japan Society for the Promotion of Science (JSPS)-Joint Research Project (JPJSBP 12022942).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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