Evaluation of the Simple Suspension Method for Oral Anticancer Drugs

Summary

The simple suspension method (SSM) involves administering tablets or capsules using a tube after disintegration and suspension in hot water without crushing or opening the capsule. Particularly, for anticancer drugs, it is an excellent method of administration that reduces the risk of exposure during dispensing. In contrast, information on SSM for individual drugs is insufficient. Anticancer drugs present a therapeutic challenge because their information is limited. We investigated whether SSM is possible with 36 anticancer drugs. Furthermore, we examined the pH of the suspension of these drugs, for which no information on SSM is available. We found that suspension was possible for 24 of the 36 drugs. Furthermore, the pH of the suspension was measured, which provided important information when considering dissolution solutions other than hot water. Little changes in the pH were observed before or after passing through the tube. The results of this study may improve medication adherence in patients with cancer experiencing dysphagia.

INTRODUCTION

The simple suspension method (SSM) is a method for administering tablets or capsules using a tube after disintegration and suspension in hot water without crushing or opening the capsule.¹⁾ The SSM has several advantages over crushing or opening; it can be applied to several products; it has no influence on physicochemical stability and drug losses,²⁾ and it can prevent exposure to anticancer drugs.³⁾ The SSM, developed by Kurata in 1997, has gradually spread in Japanese clinical settings, leading to the publication of the tube administration of drug handbook in 2001, which summarizes the indications for the SSM for each drug. The importance of the SSM has been recognized with its approval by the Japanese medical insurance system with the medical fee revisions in 2020, and the 4th edition of the handbook was published in 2020.⁴⁾

Because SSM is used by patients and their families in addition to physicians, nurses, and other medical personnel, pharmacists should be involved. This is because providing support based on the characteristics of the formulation is considered important, such as (1) selection of an appropriate dosage form according to the patient’s situation, (2) guidance on the procedure, and (3) provision of information to the patient. Recently, pharmacists have been required to provide interpersonal services for patients and medical staff, in addition to their traditional physical services. One reason for this is that pharmacists are expected to be involved in ensuring that drug therapy is safe and effective. The SSM is an important method in both objective and interpersonal work and encompasses the knowledge and skills required by pharmacists today. Therefore, it is no exaggeration to say that the dissemination of knowledge and skills related to the SSM affects patient outcomes.

In contrast, information on the SSM for individual drugs is insufficient, and many do not include statements in the package inserts or interview forms regarding the acceptability of the SSM. In particular, anticancer drugs present a therapeutic challenge because their information is limited. The reasons for this may include the fact that anticancer drugs are expensive and many drugs are cytotoxic, making examination difficult. In 2013, Amano et al. and Murakami et al. in 2016 reported the acceptability of the SSM for several anticancer drugs^5,6); however, no new studies have been conducted since then, and further information should be updated.

In this study, we examined the acceptability of the SSM for anticancer drugs available at the Saitama Cancer Center that were not listed in the interview form or in the 4th edition of the handbook. Furthermore, because studies have reported that the pH of suspensions is useful for evaluating the stability of pharmaceuticals,⁷⁾ pH measurements were also performed.

MATERIALS AND METHODS

The test environment was an ISO Class 6 safety cabinet from Baker Company at a room temperature of 22±3°C. The test procedure was based on the 4th edition of the handbook, and a disintegration suspension test was performed first, followed by a tube passage test on drugs evaluated to be acceptable for suspension.⁴⁾ Furthermore, the pH of the suspension was measured for drugs that met the disintegration suspension test.

Of the oral anticancer drugs not listed in the 4th edition of the handbook and for which the availability of the SSM was unknown, 36 drugs available at our hospital were included in the study.

1. Device

Injector: Nipro EN syringe 20 mL (ISO80369-3), Nipro EN syringe cap, tube: Kangaroo New Enteral Feeding Tube 8 Fr, 120 cm (Covidien Japan), water for injection (HIKARI PHARMACEUTICAL CO., LTD., Tokyo), pH meter: LAQUAtwin-pH-33B (HORIBA Scientific, Kyoto).

2. Suspension Test

The piston part of the dispenser was pulled out, the drug product (tablets: 1 tablet, capsules: 1 capsule) was placed in the dispenser, and the piston was returned. The dispenser was aspirated with 20 mL of hot water at approximately 55°C, syringe-capped, and left at room temperature for 5 min. After 5 min, the dispenser was overturned at an angle of 90° for 15 round trips, and a collapse suspension was observed. If no suspension was observed, the mixture was left for another 5 min (for a total of 10 min), and the same procedure was performed. If no suspension was observed after 10 min, a tube passage test was not performed.

3. Tube Passage Test

The tube passage test was performed on drugs that passed the suspension test. The passage of the suspension was observed for approximately 20 s from the injection end of the tube. After the drug was injected, the inside of the tube was rinsed by injecting approximately 20 mL of water and the test was passed if no drug remained in the tube.

4. Evaluation

The suspension and tube passage tests were performed for each part. In the suspension test, tablets or capsules suspended within 5 or 10 min were considered as acceptable. The tube passage test was performed on drugs that were evaluated as acceptable in the suspension test, and drugs that passed without remaining in the injector and tube were evaluated as acceptable in the final evaluation. Because many drugs are cytotoxic, we did not 1) crack the tablets, 2) open the capsules, or 3) crack the coating immediately before administration. Three tests were performed for each drug and the final evaluation was performed when the same result was obtained two or more times (n=3). Both two tests were conducted with one operator and two evaluators.

5. pH Measurement

The pH of the suspension before and after passage through the tube was measured for drugs that passed the suspension test.

RESULTS

Table 1 shows the results of suspension and tube passage tests for the 36 drugs. Thirteen anticancer drugs were suspended within 5 min, 10 were suspended in 10 min, and 13 were not suspended. Of the 24 drugs evaluated as acceptable in the suspension test, 23 were evaluated as acceptable in the tube passage test. Xtandi® Tablets 40 mg and ZYKADIA® Tablets 150 mg were considered acceptable because they clogged the feeding tube once out of three passage tests, though passed twice.

Table 1. Results of Suspension Test and Tube Passage Test

Proprietary name	Suspension test						Final evaluation of suspension test	Tube passage test			Final evaluation of tube passage test	Both disintegrated within 10 min and passed the tube passage test
	5 min			10 min
	1st	2nd	3rd	1st	2nd	3rd		1st	2nd	3rd
ADLUMIZ Tablets 50 mg	○	○	○	no data			○	○	○	○	○	○
ALECENSA Capsules 150 mg	×	×	×	×	×	×	×	no data			no data	×
ANASTROZOLE TABLETS 1 mg “DSEP”	×	×	×	○	○	○	○	○	○	○	○	○
ALUNBRIG Tablets 90 mg	○	○	○	no data			○	○	○	○	○	○
BRAFTOVI Capsules 50 mg	×	×	×	×	×	×	×	no data			no data	×
BRAFTOVI Capsules 75 mg	×	×	×	×	×	×	×	no data			no data	×
CABOMETYX tablets 60 mg	×	×	×	○	○	○	○	○	○	○	○	○
Giotrif Tablets 20 mg	○	○	○	no data			○	○	○	○	○	○
IBRANCE Tablets 125 mg	○	○	○	no data			○	○	○	○	○	○
IBRANCE Capsules 125 mg	×	×	×	○	○	○	○	○	○	○	○	○
IMBRUVICA Capsules 140 mg	×	×	×	○	○	○	○	×	×	×	×	×
LenaDex Tablets 4 mg	○	○	○	no data			○	○	○	○	○	○
Lynparza Tablets 100 mg	×	×	×	×	×	×	×	no data			no data	×
Lynparza Tablets 150 mg	×	×	×	×	×	×	×	no data			no data	×
MEKTOVI Tablets 15 mg	○	○	○	no data			○	○	○	○	○	○
ROZLYTREK Capsules 200 mg	×	×	×	×	×	×	×	no data			no data	×
Stivarga tablets 40 mg	×	×	×	×	×	×	×	no data			no data	×
TAGRISSO Tablets 40 mg	×	×	×	○	○	○	○	○	○	○	○	○
TAGRISSO Tablets 80 mg	×	×	×	○	○	○	○	○	○	○	○	○
TARCEVA Tablets 25 mg	○	○	○	no data			○	○	○	○	○	○
TARCEVA Tablets 150 mg	×	×	×	○	○	○	○	○	○	○	○	○
TEPMETKO Tablets 250 mg	○	○	○	no data			○	○	○	○	○	○
VANFLYTA TABLETS 26.5 mg	×	×	×	×	×	×	×	no data			no data	×
Verzenio Tablets 50 mg	○	○	○	no data			○	○	○	○	○	○
Verzenio Tablets 100 mg	○	○	○	no data			○	○	○	○	○	○
Verzenio Tablets 150 mg	○	○	○	no data			○	○	○	○	○	○
VENCLEXTA Tablets 50 mg	×	×	×	×	×	×	×	no data			no data	×
VENCLEXTA Tablets 100 mg	×	×	×	×	×	×	×	no data			no data	×
VEPESID Capsules 25 mg	×	×	×	○	○	○	○	○	○	○	○	○
VEPESID Capsules 50 mg	×	×	×	×	×	×	×	no data			no data	×
Votrient Tablets 200 mg	○	○	○	no data			○	○	○	○	○	○
XALKORI Capsules 200 mg	×	×	×	○	○	○	○	○	○	○	○	○
Xtandi Tablets 40 mg	×	×	×	○	○	○	○	×	○	○	○	○
Xtandi Tablets 80 mg	×	×	×	○	○	○	○	○	○	○	○	○
ZYKADIA Capsules 150 mg	○	○	○	no data			○	○	×	○	○	○
ZYTIGA Tablets 250 mg	×	×	×	×	×	×	×	no data			no data	×

Table 2 shows the pH values of the suspensions of the 23 drugs that were considered acceptable in the suspension test. The pH of each drug was measured before and after its passage through a tube. The effect of tube passage on pH was small, and there was little change in pH before or after passage through the tube.

Table 2. pH of Suspension Solution before and after Passage through a Tube

Proprietary name	pH (Before tube passage)			pH (After tube passage)
	1st	2nd	3rd	1st	2nd	3rd
ADLUMIZ Tablets 50 mg	5.78	5.50	5.54	5.72	5.72	5.63
ANASTROZOLE TABLETS 1 mg “DSEP”	7.53	8.36	8.39	8.06	8.39	8.40
ALUNBRIG Tablets 90 mg	8.15	8.71	8.56	8.61	8.63	8.65
CABOMETYX tablets 60 mg	4.08	4.00	3.95	4.07	3.97	3.97
Giotrif Tablets 20 mg	4.39	4.29	4.29	4.43	4.36	4.36
IBRANCE Tablets 125 mg	3.84	3.80	3.86	3.88	3.85	3.91
IBRANCE Capsules 125 mg	6.47	6.41	6.35	6.52	6.64	6.39
Xtandi Tablets 40 mg	6.24	6.20	6.17	6.36	6.24	6.31
Xtandi Tablets 80 mg	5.99	5.94	5.98	6.03	5.93	5.93
LenaDex Tablets 4 mg	8.19	8.10	8.09	8.12	8.13	8.12
MEKTOVI Tablets 15 mg	7.26	7.26	7.28	7.58	7.43	7.30
TAGRISSO Tablets 40 mg	6.52	6.61	6.62	6.71	6.76	6.77
TAGRISSO Tablets 80 mg	6.61	6.53	6.54	6.56	6.54	6.58
TARCEVA Tablets 25 mg	3.94	3.86	3.79	3.85	3.80	3.80
TARCEVA Tablets 150 mg	3.40	3.40	3.41	3.39	3.36	3.33
TEPMETKO Tablets 250 mg	7.03	6.94	6.87	7.01	7.01	7.03
Verzenio Tablets 50 mg	8.01	7.94	7.92	8.03	8.03	8.03
Verzenio Tablets 100 mg	8.41	8.88	8.79	8.55	8.98	8.80
Verzenio Tablets 150 mg	8.82	8.35	8.57	9.08	9.15	9.16
VEPESID Capsules 25 mg	5.42	5.29	5.35	5.26	5.30	5.30
Votrient Tablets 200 mg	2.98	2.85	2.84	2.84	2.86	2.84
XALKORI Capsules 200 mg	7.80	7.94	7.99	7.96	7.98	8.01
ZYKADIA Capsules 150 mg	6.70	6.72	6.81	6.84	6.84	6.93

DISCUSSION

The lack of information on the SSM for anticancer drugs may limit patients’ treatment options. Drugs with multiple dosage forms of the same component offer options for administration; however, when only one dosage form of an oral drug is available, the ability or inability to take the drug orally can have a significant impact on treatment. However, the results revealed that 24 drugs are indicated for the SSM, contributing to medication support for patients who receive their medications via a tube or have difficulty swallowing. Of the drugs evaluated as unacceptable in the suspension test, VEPESID® Capsules (50 mg) were evaluated as unacceptable because the capsule contents were suspended; however, the outer skin occluded the tube. We consider this is due to the difference in the size of the residue after disintegration and suspension, as VEPESID® Capsules 25 mg uses No. 4 capsules and VEPESID® Capsules 50 mg uses No. 2 capsules.⁸⁾ Since the contents of both capsules are viscous liquids, there is no problem with passage through the tube after suspension, although, we believe that the capsule’s outer shell has obstructed the tube. Therefore, we suggest using a tube with a larger diameter or using two 25 mg capsules for a 50 mg dose. In contrast, the VENCLEXTA® Tablets (50 and 100 mg) were evaluated as unacceptable because they were not suspended at all, and the reason for the unacceptable rating varied from one individual drug to another. On the other hand, IMBRUVICA® Capsules 140 mg passed the suspension test in 10 min, but not the tube passage test. Because, this is thought to be the relatively large size of the IMBRUVICA® Capsules 140 mg, a No. 0 capsule,⁹⁾ which took longer to disintegrate and suspend. Also, even after the capsule was disintegrated and suspended, it could not pass through the 8Fr tube because of the large amount of residue; it could have passed through a larger diameter tube such as 10Fr or 12Fr. The SSM requires a certain level of proficiency and knowledge of the technique and does not simply clarify the suspension or non-suspension of tablets/capsules. Therefore, without proper techniques, the results may differ, or the risk of exposure may increase. For example, tilting of the syringe during suspension injection or the speed of injection can cause tubing to become blocked. Furthermore, exposure countermeasures such as the use of double gloves and water-absorbent sheets are necessary to prevent suspension exposure. Thus, although SSM is an excellent method, it requires adequate knowledge and skills. Although the test was conducted in a safety cabinet in this case, if it is to be performed in a hospital ward or at home, it should be done in personal protective equipment, a sealable bag with double gloves. The bag should be lined with absorbent paper, syringe caps should be used during suspension to prevent leakage of the suspension, and gauze should be used to cover the connecting portion of the tube when connecting the tube to prevent exposure.¹⁰⁾

Among the results of this study, the results of the suspension study will be useful not only for patients who receive medications via a tube but also for patients who have difficulty swallowing, such as children and the elderly. However, in some cases, a tube is not used when the original dosage form is difficult to administer orally; therefore, suspending the drug in an appropriate container may be possible. Furthermore, the pH of the suspensions of the 23 products evaluated as acceptable in the suspension test was also clarified, which can be used as a reference when selecting dissolution solutions other than hot water. Suspensions are more likely to taste bitter and irritating than the original dosage forms. However, it is envisioned that a dissolution solution other than hot water may be used to mask the taste and irritation to the extent that the stability is unaffected. For example, TEMODAL® Capsules are suspended in acidic solutions, such as apple juice, without loss of stability.¹¹⁾ Although there have been other reports on the stability of individual anticancer drugs with respect to pH, none have yet covered as many drugs as in this study.^12–16) The pH information obtained in this study will be useful for testing the stability of suspensions and for selecting dissolution solutions. Little changes in pH were observed before or after passage through the tube, suggesting that the drugs tested in this study were unaffected by the tube. In particular, younger children may choose the simple suspension method for taste correction purposes or because they have difficulty swallowing the original formulation. In such cases, we hope that the pH information from this study will help in selecting an appropriate suspension.

Recently, the Japan Association for Patient Support on Medication has been steadily accumulating information on individual drugs related to the SSM, although with new and generic drugs coming on the market one after another, regularly updating this information is required. We believe that the results of this study will provide information on >30 new products and contribute to future cancer treatments.

A limitation of this study is that we only examined the acceptability of the SSM for each anticancer drug and were not able to evaluate their stability after suspension. Therefore, it cannot be ruled out that some drugs may be less stable at 5 or 10 min after suspension or may be adsorbed on the tube. However, because drugs are ineffective if not taken, the first step is to evaluate whether they can be taken and administered, and we believe that we have provided important information as a first step in this regard. The strengths of this study are that it clarified the acceptability of the SSM for several oral anticancer drugs and the pH of the suspension. More than three years have passed since the 4th edition of the handbook was published in September 2020, and several anticancer drugs did not exist at that time. We hope that the results of this study will improve medication adherence for as many patients as possible.

Conflicts of Interest

The authors declare no conflict of interest.

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