Drug-Tea Polyphenol Interaction (III) Incompatibility between Aripiprazole Oral Solution and Green Tea

Abstract

The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the residual rate of ARIP in the mixed solution decreased to 15.7–17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (−)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.

Introduction

Aripiprazole (ARIP; Fig. 1) is an antipsychotic that was developed in 1987 by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). ARIP shows dopamine D₂ receptor partial agonist action. Therefore, depending on the state of dopaminergic neurotransmission, ARIP acts as an antagonist or acts as an agonist for the dopamine D₂ receptor.^1,2) ARIP is used worldwide for medical treatment. ARIP is one of the most frequently prescribed drugs for schizophrenia in Japan.

Fig. 1. Chemical Structure of Aripiprazole (ARIP)

According to the website of Ministry of Health, Labour and Welfare in Japan (MHLW), the morbidity rate of schizophrenia is approximately 1%. It is known that the morbidity rate does not depend on the country, area or race. Since the main treatments for schizophrenia are medications, it is important that the patient continues taking a drug to control symptoms of schizophrenia.

The statistics of MHLW show that the average life span of Japanese has exceeded 80 years for both men and women since 2014. It is thought that the long life span of Japanese is mainly due to eating habits. Therefore, Japanese food has become a global boom in recent years. Since Japanese food has a low calorie content, Japanese food is considered to be good for health. Green tea has also attracted attention because many Japanese people have a custom of drinking green tea with a meal. It is well known that green tea contains many bioactive components.^3–5) In particular, the effect of green tea polyphenols (GTPs; Fig. 2) is in the limelight. GTPs having high bioactivity may interact with a drug taken at the same time. If the effect of a drug is decreased by an interaction with GTPs, it will be a serious problem in medication.

Fig. 2. Chemical Structures of Green Tea Polyphenols

It is well known that drug incompatibilities are mainly caused by mixing injections and infusions.^6–8) Many studies have been pointed out that the drug efficacy is reduced because the solubility of a drug decreases due to incompatibilities of injections and infusions. However, there are few research papers on drug incompatibilities of oral solutions such as ARIP oral solution.

Previously, the interaction of green tea with iron preparations was a problem in the treatment of iron deficiency anemia. However, in the 1980 s, it was reported that even if patients with iron deficiency anemia took iron preparations with green tea, iron preparations was sufficiently absorbed from the digestive tract.^9,10) Since then, taking the drug with green tea has become less of a problem in the medical field. On the other hands, because GTP has many bioactive effects, many reports on the interaction of GTP are mainly on the interaction between GTP and protein.^11–13) Furthermore, studies on the interaction of small molecules such as drugs with GTP have reported the interaction of caffeine with GTP in green tea. It has been pointed out that intermolecular hydrogen bonds and π–π interactions are formed between GTP and caffeine.^14,15)

We have already found that risperidone (RISP; Fig. 3) and propericiazine (PCZ; Fig. 3), which are used as schizophrenia therapeutic agents like ARIP, interact with GTPs.^16–19) It was pointed out that this interaction may reduce the water solubility of RISP or PCZ and may also reduce their efficacy. Furthermore, it was clarified that the intermolecular hydrogen bond involving the nitrogen atom of the piperidine ring of RISP or PCZ and the galloyl group of gallate-type GTPs greatly affects the water solubility of RISP or PCZ. As shown in Fig. 1, ARIP has a piperazine ring. The structure of the piperazine ring is similar to that of the piperidine ring. Therefore, ARIP and GTPs are expected to interact by forming intermolecular hydrogen bonds as do RISP and PCZ. In fact, in the package insert of ARIP oral solution, it is stated that the content of ARIP may decrease when ARIP oral solution is diluted with green tea. However, the cause of this decrease in content has not been clarified. This study focuses on the physicochemical interaction in which the solubility of ARIP decreases due to the incompatibility between ARIP oral solution and green tea. The results of an investigations conducted to find the main factor of this incompatibility are presented in this paper.

Fig. 3. Chemical Structures of Risperidone (RISP) and Propericiazine (PCZ)

Beverages and supplements containing a large amount of GTPs are commercially available for the purpose of reducing body fat mass. Patients taking ARIP may gain weight,^20,21) so those beverages and supplements may be taken with ARIP. When ARIP is taken with large amounts of GTPs, the solubility of ARIP is reduced, which may reduce its gastrointestinal absorption and reduce the efficacy of ARIP.

Experimental

Materials

PET bottled green tea beverages (A and B) used for this study were purchased from neighboring retail stores. Aripiprazole (ARIP) oral solution, which contains 0.100% (w/v) (=2.33 mM) ARIP, was purchased from Otsuka Pharmaceutical Co., Ltd. ARIP was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). (−)-Epigallocatechin gallate (EGCg), (−)-epicatechin gallate (ECg), (−)-epigallocatechin (EGC), and (−)-epicatechin (EC) were purchased from Nacalai Tesque Inc. (Kyoto, Japan). Lactic acid, sodium lactate solution, Na₂SO₄, CH₃CN, CH₃OH, and CH₃COOH were purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). All reagents were analytical grade or guaranteed. All ARIP and GTP solutions used for this study were prepared with pH 3.0 lactate buffer solution. The measured values of the concentration of each GTP contained in the PET bottled green tea beverages (A and B) used in this study were as follows; A (EGCg 0.162 mM, ECg 0.0184 mM, EGC 0.354 mM, and EC 0.0653 mM), B (EGCg 0.438 mM, ECg 0.0653 mM, EGC 0.351 mM, and EC 0.0716 mM).

HPLC Measurement for ARIP

The HPLC apparatus used for measurement of ARIP consisted of a pump (LC-10AD, Shimadzu Corporation, Japan) and a UV detector (UV-1570, Jasco, Japan). A C₁₈ reversed phase column (250 × 4.60 mm, particle size of 5.00 µm, Mightysil RP-18, Kanto Chemical Industry Co., Ltd., Japan) was used, and the column temperature was set at 308.15 K. A mixed solution of 0.254% (w/v) Na₂SO₄ solution, CH₃CN, CH₃OH, and CH₃COOH was used as the mobile phase. The volume ratio (0.254% (w/v) Na₂SO₄ solution : CH₃CN : CH₃OH : CH₃COOH) was 55 : 33 : 11 : 1. The flow rate of the mobile phase was set at 1.00 mL/min, and the eluate was detected at 254 nm. Measurement using HPLC was performed three times for each solution.

HPLC Measurement for GTP

For the determination of GTP, the HPLC apparatus consisted of a pump (PU-2080 plus, Jasco) and a UV detector (UV-2075 plus, Jasco). A C₁₈ reversed phase column (250 × 4.60 mm, particle size of 5.00 µm, Mightysil RP-18, Kanto Chemical Industry Co., Ltd.) was used and the column temperature was set at 313.15 K. A mixed solution of 0.500% (v/v) H₃PO₄ solution, and CH₃OH was used as the mobile phase. The volume ratios (0.500% (v/v) H₃PO₄ solution : CH₃OH) were 75 : 25 for PET bottled green tea beverages, EGCg, and EC, 70 : 30 for ECg, and 82 : 18 for EGC. The flow rate of the mobile phase was set at 1.00 mL/min, and the eluate was detected at 280 nm. Quantitation of GTP in each solution by HPLC was performed in triplicate.

Mixing of ARIP Oral Solution and Green Tea Beverage

After 0.600 mL of 0.100% (w/v) ARIP oral solution and 5.00 mL of PET bottled green tea beverage had been mixed, the mixed solution was stirred and the mixture was filtered through a membrane filter (pore size: 0.450 µm). The peak areas of ARIP and GTP remaining in the filtrate were measured by HPLC. As controls, the following mixed solutions were prepared using pH 3.0 lactate buffer solution: a mixture of 0.600 mL of 0.100% (w/v) ARIP oral solution and 5.00 mL of pH 3.0 lactate buffer solution and a mixture of 0.600 mL of pH 3.0 lactate buffer solution and 5.00 mL of PET bottled green tea beverage. Then ARIP and GTP in the filtrate of the control mixed solution were measured in the same manner. Residual rate (%) was calculated as follows:

  

where AREA_mixture represents the molarity of ARIP or GTP in the filtrate of the mixed solution and AREA_control represents the molarity of ARIP or GTP in the filtrate of the control mixed solution.

Mixing of ARIP Solution and GTP Solution

EGCg, ECg, EGC, and EC were used as GTPs, and four 2.23 mM GTP solutions were prepared using each GTP. After 2.23 mM ARIP solution and 2.23 mM GTP solution had been prepared using pH 3.0 lactate buffer solution, 1.00 mL of 2.23 mM ARIP solution and 1.00 mL of 2.23 mM GTP solution were mixed and filtered through a membrane filter (0.450 µm). The concentrations of ARIP and GTP remaining in the filtrate were measured by HPLC. The residual rate of ARIP or GTP in the filtrate was calculated by the method shown in the section above.

Determination of Stoichiometry of Interaction between ARIP and EGCg by the Continuous Variation Method

After 3.00 mM ARIP solution and 3.00 mM EGCg solution had been prepared using pH 3.0 lactate buffer solution, eight mixed solutions with different mole fractions of ARIP were prepared using 3.00 mM ARIP solution and 3.00 mM EGCg solution (Table 1). The total volume of the mixed solution was set to 5.00 mL. After the mixed solution had been centrifuged at 4000 rpm for 10.0 min, 4.50 mL of the supernatant was removed from the mixed solution. Then the mixed solution was lyophilized. The mass of the residue was determined. In a similar manner, a blank test without ARIP and EGCg was performed to determine the mass of the residue. The difference between the mass of the residue of the mixed solution and the mass of the residue of the blank test was determined, and it was regarded as the mass of the insoluble substance by ARIP and EGCg.

Table 1. Mole Fraction of ARIP and Concentrations of ARIP and EGCg in the Mixture

Mole fraction of ARIP	0.2	0.3	0.4	0.5	0.6	0.7	0.8	0.9
ARIP (mM)	0.6	0.9	1.2	1.5	1.8	2.1	2.4	2.7
EGCg (mM)	2.4	2.1	1.8	1.5	1.2	0.9	0.6	0.3

Results and Discussion

Mixing of ARIP Oral Solution and Green Tea Beverage

In the package insert of 1.00 mg/mL ARIP oral solution, it is stated that 6.00 to 12.0 mg of ARIP as the starting dose and 6.00 to 24.0 mg of ARIP as the maintenance dose should be administered orally once or twice per day. It is also stated that the ARIP oral solution should be taken directly or after diluting with a cup of hot water, cooled boiled water or juice. An investigation was conducted on mixing 0.600 mL ARIP oral solution with 5.00 mL of commercial PET bottled green tea beverage (A or B). The mixed solution immediately became cloudy, and the insoluble substances formed in the solution was precipitated (Fig. 4). The residual rates of ARIP and each GTP dissolved in the mixed solution are shown in Table 2. The residual rate of ARIP in the mixed solution decreased from 15.7 to 17.6% by mixing with PET bottled green tea beverage. Also, the residual rates of the gallate-type GTPs (EGCg and ECg) in the mixed solution were decreased, but there was little decrease in the residual rates of the non-gallate-type GTPs (EGC and EC). From the above experimental results, it is considered that the main factor causing the decrease in the content of ARIP in an oral solution diluted with green tea beverage is the interaction between ARIP and gallate-type GTPs.

Fig. 4. Mixed Solution of ARIP Oral Solution and Green Tea Beverage A

Table 2. Average Residual Rates ± Standard Error (%) of ARIP and Each GTP in the Filtrate of the Mixed Solution of ARIP Oral Solution and Green Tea Beverage (n = 3)

PET bottled green tea beverage	ARIP	EGCg	ECg	EGC	EC
A	17.6 ± 3.05	81.9 ± 0.280	66.7 ± 0.699	96.8 ± 0.894	96.9 ± 0.408
B	15.7 ± 1.35	89.0 ± 1.43	80.8 ± 2.51	98.4 ± 0.863	97.4 ± 0.0160

Mixing of ARIP Solution and GTP Solution

From the results shown in the previous section, it was found that the decrease in the content of ARIP in the mixed solution of ARIP oral solution and green tea beverage was mainly caused by gallate-type GTPs. However, the ARIP oral solution contains various additives (glycerin, propylene glycol, lactic acid, sodium hydroxide, sodium edetate hydrate, methyl paraoxybenzoate, propyl paraoxybenzoate, sucralose, stevia extract, fragrance, and purified water). Glycerin and propylene glycol are presumed to be solubilizers for ARIP. Therefore, it is assumed that the decrease in ARIP content caused by mixing with green tea beverages is due to the interaction between the solubilizers for ARIP and gallate-type GTPs. As shown in Fig. 1, ARIP is a basic drug. Therefore, if the pH of the mixed solution of ARIP oral solution and the green tea beverage increases, the water solubility of ARIP may decrease and the residual rate of ARIP in the filtrate may decrease.

To rule out the effects of additives in ARIP oral solution or pH change of solution after mixing on ARIP content, 1.00 mL of 2.23 mM ARIP solution prepared by dissolving the pure ARIP reagent in a pH 3.0 buffer solution was mixed with 1.00 mL of 2.23 mM GTP solution prepared by dissolving the pure GTP reagent in a pH 3.0 buffer solution. The reason why ARIP solution and GTP solution were prepared with pH 3.0 lactic acid buffer solution that the pH value of the commercially available ARIP oral solution is approximately 3, and according to the interview form of ARIP oral solution, it is considered that the oral solution is prepared with lactic acid buffer. The residual rates of ARIP and GTPs in the filtrate after the mixed solution had been filtered through a membrane filter are shown in Table 3.

Table 3. Average Residual Rates ± Standard Error (%) of ARIP and Each GTP in the Filtrate of the Mixed Solution of ARIP Solution and GTP Solution (n = 3)

	ARIP-EGCg	ARIP-ECg	ARIP-EGC	ARIP-EC
ARIP	31.7 ± 1.44	31.8 ± 1.49	97.2 ± 0.773	98.5 ± 0.419
GTP	52.7 ± 1.11	58.4 ± 1.94	102.3 ± 2.96	97.8 ± 1.44

Like RISP and PCZ, ARIP was found to form an insoluble substances with gallate-type GTPs as shown in Tables 2 and 3. On the other hand, non-gallate-type GTPs did not reduce the content of ARIP in the mixed solution. Therefore, it is thought that the galloyl group of gallate-type GTPs mainly contributes to the decrease in the content of ARIP due to the mixture of ARIP and green tea described in the package insert of ARIP. According to Table 3, 68.3% of ARIP and 47.3% of EGCg form a precipitation when equal amounts of ARIP and EGCg are mixed. It is speculated that ARIP and EGCg interact at a molar ratio of 3 : 2. Similarly, ARIP and ECg are presumed to form a precipitation with a molar ratio of 3 : 2.

Piperidine derivatives such as RISP and PCZ shown in Fig. 3 have been reported to interact with gallate-type catechins at a molar ratio of 1 : 1.^19,22) On the other hand, piperazine derivatives such as lomerizine (LMZ) and cetirizine (CTZ) have been found to interact with EGCg at a molar ratio of 2 : 1.²³⁾ From the results of this experiment, it is speculated that the interaction mechanism between ARIP and gallate-type GTP is different from the interaction mechanism reported for the above-mentioned drugs.^19,22,23)

Determination of Stoichiometry of Interaction between ARIP and EGCg by the Continuous Variation Method

As described above, when the ARIP solution mixed with gallate-type GTPs, the mixed solution immediately becomes cloudy and an insoluble substances is formed. In this experiment, EGCg was used as a typical gallate-type GTPs.

The continuous variation method is widely used for determining stoichiometry in complex formation. For example, it is often used to determine stoichiometric ratios in the formation of an inclusion complex by cyclodextrin and a guest molecule.^24–26)

As shown in Table 1, the sum of the molar concentrations of the ARIP solution and the EGCg solution to be mixed was maintained at 3.00 mM, and eight mixed samples having different molar fractions of ARIP were prepared. The mass of the cloudy precipitate formed in each sample was measured. The results of plotting the mass of the precipitate against the mole fraction of ARIP in the mixed solution are shown in Fig. 5. The maximum value of the Job plot shown in Fig. 5 is approximately 0.6. Therefore, it was found that the stoichiometric ratio of the interaction between ARIP and EGCg is 3 : 2.

Fig. 5. Continuous Variation Plot of ARIP-EGCg System

Each measured value shown in the figure is mean ± standard error (mg) (n = 3).

Conclusion

The content decrease of ARIP caused by the mixing of ARIP oral solution and the tea leaf extract beverage is due to the formation of an insoluble substances between ARIP and gallate-type GTPs. ARIP interacts with EGCg, the main component of GTP in green tea, at a molar ratio of 3 : 2. These findings obtained in this study are considered to be important in the treatment of diseases using ARIP. In the future, it is necessary to further investigate the details of the interaction mechanism between ARIP and gallate-type GTPs.

Conflict of Interest

The authors declare no conflict of interest.

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