Optimal Administration of Phosphorus Adsorbents When Using Medical Nutritional Supplements for Tube-fed Patients

Summary

All medical enteral nutrition products contain phosphorus and when administered to patients with chronic kidney disease (CKD) and on dialysis, they lead to the risk of elevated serum phosphorus levels. Thus, serum phosphorus levels should be monitored, and phosphorus adsorbents should be used in cases of high serum phosphorus levels. In this study, we investigated the effect of phosphorus adsorbents on enteral nutrition, using Ensure Liquid^®, a medical nutritional formula, for patients with CKD and those on dialysis. Additionally, we compared the effects of the simple suspension method, in which various phosphorus-adsorbing agents are suspended and mixed directly with the nutritional formula for tube administration (hereafter referred to as the “pre-mix method”), and the conventional method, in which only the phosphorus-adsorbing agents are administered separately from the nutritional formula for tube administration (hereafter referred to as the “normal administration method”). The administration of various phosphorus adsorbents using the pre-mix technique resulted in a phosphorus removal rate of 8–15% (approximately 12% on average). Therefore, through the pre-mix method, maintaining the phosphorus content of Ensure Liquid^® below the daily phosphorus intake standard was possible for patients on dialysis. The pre-mix method via the simple suspension method of administering phosphorus adsorbent with Ensure Liquid^® resulted in less drug adsorption to the injector and tube and a higher phosphorus removal rate than the normal administration method.

INTRODUCTION

The life expectancy of patients on dialysis is impaired by poor phosphorus control; hence, the management of serum phosphate levels is important.^1,2) Serum phosphorus homeostasis is maintained by the absorption of dietary phosphorus from the intestinal tract, its translocation into and out of bone and cells, and its excretion in feces and urine.³⁾ Consequent to reduced urinary phosphorus excretion, serum phosphorus levels increase in patients on hemodialysis. Appropriate phosphorus management includes modification of dialysis conditions (increased duration and frequency of hemodialysis and increased dialysate volume and frequency of peritoneal dialysis, diet, and phosphorus adsorbent therapy).³⁾ Patients on dialysis need to maintain good nutritional status with adequate protein intake to prevent frailty and sarcopenia and improve life expectancy. Malnutrition due to renal failure is called protein energy wasting (PEW) due to inflammation and other factors associated with renal failure rather than solely insufficient energy intake.⁴⁾ However, enteral nutrition for patients with renal failure is only used when PEW is present and oral nutritional intake is inadequate or insufficient.⁵⁾

Enteral nutrition is actively administered to patients with chronic kidney disease (CKD) and on dialysis because the risk of infection is higher in these patients than in healthy participants. In this type of feeding, bloodstream infection, a complication of intravenous nutrition, can be avoided, and nutrition can be administered with a relatively small amount of fluid.⁶⁾ However, all medical enteral nutrition products contain phosphorus; thus, a risk of elevated serum phosphorus levels is still present when such products are administered to patients with CKD and on dialysis. Therefore, serum phosphorus levels should still be monitored, and a phosphorus adsorbent should be used if high levels of phosphorus are observed. Enteral feedings are administered as tablets or capsules, either by pulverization or simple suspension. When comparing these two methods of administration, the simple suspension method is often used due to drug stability and efficacy concerns.^7,8)

In this study, we experimentally evaluated the effects of various phosphorus adsorbents on medical enteral nutritional supplements for patients with CKD and on dialysis who require enteral nutritional therapy. Additionally, we assessed the applicability of the simple suspension method in the smallest formulation unit of the phosphorus adsorbent and the formulation unit at the clinical dosage (the usual one-dose package). Furthermore, we compared the use of the simple suspension method, in which various phosphorus adsorbents are mixed directly with nutritional products and administered by gavage (hereafter referred to as the “pre-mix method”), and the conventional method, in which phosphorus adsorbents alone are administered by gavage separately from nutritional products (hereafter referred to as the “normal administration method”).

MATERIALS AND METHODS

1. Medicinal Products

We used phosphorus adsorbents listed in the National Health Insurance drug price standard as of March 2022 (Table 1). Enteral nutrition was supplied by Ensure Liquid^® (Lot No.: 608710; Abbott Japan LLC, Tokyo), and sterile water for injection (Lot No.: K207M; Otsuka Pharmaceutical Co., Ltd., Tokyo) was used for flushing.

Table 1. Usual Dosages and Serial Numbers of Phosphorus Adsorbents Indicated on the Label

Name of phosphorus adsorbent	Serial number	Usual dosage on the package insert (single dosage in mg)
Cartan® fine granules	225KOA	1000
Cartan® Tablets OD	M159AD9	1000
Fosrenol® granules	JPS4409	250
Fosrenol® Tablets OD	JPS4493	250
Kiklin® granules	20005F1	500
P-TOL® granules	ANV0905	250
RENAGEL® Tablets	20J010Z	1000–2000
Riona® Tablets	829DA	500

Ensure Liquid^® was selected because it is the only medical enteral formula that is not contraindicated for patients with severe renal impairment and is covered by insurance. It is also the most commonly used medical enteral formula at Fujioka General Hospital.

2. Apparatus

The following equipment was used: JMS Feeding Bottle (locking type) 600 mL (JF-FP060; JMS Co., Ltd., Tokyo), Jayfeed^® Feeding Catheter 8 Fr. (JF-C08120Q; JMS Co., Ltd., Tokyo), Jayfeed^® Feeding Set (DEHP-free) (JF-YSL35; JMS Co., Ltd., Tokyo), and Jayfeed^® EN Syringe 50 mL (JF-3S50Z; JMS Co., Ltd., Tokyo).

3. Pre-mix and Normal Administration Methods

In the pre-mix method, various phosphorus adsorbents are mixed directly with enteral nutritional supplements (Ensure Liquid^®) via the simple suspension method and allowed to stand at room temperature (20.0±5.0°C) for 10 min. The supernatant is then administered through a tube. In the normal administration method, enteral nutrition is first administered through a tube, followed by various phosphorus adsorbents via the simple suspension method (Fig. 1).

Fig. 1. Pre-mix and Normal Administration Methods

4. Measuring the Phosphorus Removal Rate of Phosphorus Adsorbents in Ensure Liquid^®

In the pre-mix method, the usual single dose of each phosphorus adsorbent was suspended in 20 mL of sterile water for injection heated to 55°C in a syringe and mixed with 500 mL of Ensure Liquid^® by inverting a graduated cylinder 10 times and allowing it to stand for 10 min at 18.2±1.1°C. After incubation at 20.0±5.0°C, 50 mL of the supernatant was used to detect phosphorus levels by inductively coupled plasma emission spectrometry at the Tama Research Institute of the Japan Food Research Laboratories, Tokyo, Japan.

5. Disintegration/suspension and Passability Tests of Phosphorus Adsorbents Via the Simple Suspension Method⁹⁾

5-1. Disintegration/suspension test

The plunger of the Jayfeed^® EN syringe was briefly removed for the placement of various phosphorus adsorbents. The syringe was filled with 20 mL of sterile water for injection heated to 55°C. To determine the status of disintegration and suspension, the syringe was capped, left for 10 min at 20.0±5.0°C, and rotated at a 90° angle.

5-2. Passability test

The disintegrating suspension was injected from the Jayfeed^® Feeding Catheter at a rate of approximately 2–3 mL/s. The catheter was observed for passability, flushed with approximately 20 mL of distilled water, and deemed passable if no phosphorus adsorbent remained. The mass of the syringe and catheter was measured before and after the passability test. After the test, the syringe and catheter were dried to measure the amount of residual phosphorus for each adsorbent.

5-3. Interpretation of the disintegration/suspension and passability test results

Based on the evaluation of a practitioner and an observer, the disintegration/suspension and passability test results were used to determine the suitability of the phosphorus adsorbents. An evaluation was considered discriminant if their judgment was the same. Each phosphorus adsorbent was examined three times and its final evaluation was based on the results of two or three of three examinations. Based on a previously established criteria, the adsorbent was classified as “Suitable 1”¹⁰⁾ if “the tablets were tested without breaking the coating and disintegrated within 10 min, and the tablets were then suspended at 8 Fr.” In contrast, the adsorbent was classified as “Unsuitable” if it could not be administered by the simple suspension method.

6. Passability Test Via the Pre-mix Method

6-1. Passability test of Ensure Liquid^® mixed with phosphorus adsorbents via the pre-mix method

In the pre-mix method, the phosphorus adsorbents were suspended in 20 mL of sterile water for injection at 55°C, mixed with 500 mL of Ensure Liquid^®, and evaluated for passage from the feeding bottle to the catheter. The dosing rate was adjusted to 240 mL/h (60 drops per min) using the Jayfeed^® Feeding Set (creme).

6-2. Influence of phosphorus adsorbents administered via the pre-mix method

The mixture of suspended phosphorus adsorbents and Ensure Liquid^® was incubated at 20.0±5.0°C for 10 min, and the supernatant was used as a sample. The passage of the sample through the feeding tube and catheter was evaluated. The dosing rate was adjusted to 240 mL/h (60 drops per min) using the Jayfeed^® Feeding Set (creme). Afterwards, a graduated cylinder was placed at the end of the feeding catheter, and the sample volume that reached the gastrointestinal tract was measured. The residual rate of the phosphorus adsorbent in the injector and tube and the phosphorus removal rate in the pre-mix method were used to calculate the phosphorus removal rate in the conventional administration method and compare both methods. The control group was administered sterile water for injection.

6-3. Confirming changes in the properties of Ensure Liquid^® mixed with phosphorus adsorbents

The dose rate was adjusted to 240 mL/h (60 drops per min) using the Jayfeed^® Feeding Set (creme). After 130 min, changes in the properties of Ensure Liquid^® in the nutrition bottle were observed visually.

7. Statistical Analysis

Dunnett’s and Student’s t-tests were performed using IBM^® SPSS^® Statistics Version 27 (IBM Japan, Ltd., Tokyo). All significance levels were set at <5%.

8. Ethics Review Committee

This study was approved by the Research Ethics Committee of Takasaki University of Health and Welfare and conducted according to the “Ethical Guidelines for Medical Research Involving Human Subjects (2014)” (Approval No. 3044).

RESULTS

1. Phosphorus Removal Rate in Ensure Liquid^® Mixed with Phosphorus Adsorbents Via the Pre-mix Method

The highest phosphorus removal rate was observed in 1000 mg RENAGEL^® tablets at 14.56%±0.40 (mean±SD). The lowest phosphorus removal rate was observed for 500 mg Riona^® tablets at 8.20%±0.26. The pre-mixed phosphorus adsorbent had a mean phosphorus removal rate of approximately 12%, significantly decreasing the phosphorus content in Ensure Liquid^® (* p<0.05, Dunnett’s test) (Fig. 2).

Fig. 2. Phosphorus Removal Rate (%) of Phosphorus Adsorbents Mixed with Ensure Liquid^® Administered by the Pre-mix Method

n=3, * p<0.05, Dunnett’s test.

2. Disintegration/suspension and Passability Test of Phosphorus Adsorbents

First, the disintegration/suspension and passability tests were conducted at the smallest dosage units of each phosphorus adsorbent, i.e., one tablet and one packet (Table 2). The results demonstrated that the disintegration and suspension of most adsorbents were “acceptable,” except for Fosrenol^® granules 250 mg and P-TOL^® granules 250 mg. Thus, most adsorbents were classified as “Suitable 1” and only Fosrenol^® granules 250 mg and P-TOL^® granules 250 mg were deemed “unfavorable” in the final evaluation.

Table 2. Disintegration/suspension and Passability Tests of Phosphorus Adsorbents at the Smallest Unit of the Formulation

Phosphorus adsorbent/dosage	Test dosage	Disintegration suspension test	Passability test	Final assessment
Cartan® fine granules 500 mg	0.6 g	〇	〇	Suitable
Cartan® Tablet OD 500 mg	1 tablet 500 mg	〇	〇	Suitable
Fosrenol® granules 250 mg	0.7 g	×	×	Unsuitable
Fosrenol® Tablet OD 250 mg	1 tablet 250 mg	〇	〇	Suitable
Kiklin® granules 500 mg	0.58 g	〇	〇	Suitable
P-TOL® granules 250 mg	1 package	×	×	Unsuitable
RENAGEL® Tablets 250 mg	1 tablet 250 mg	〇	〇	Suitable
RENAGEL® Tablets 500 mg	2 tablets (1 tablet 250 mg)	〇	〇	Suitable
RENAGEL® Tablets 750 mg	3 tablets (1 tablet 250 mg)	〇	〇	Suitable
Riona® Tablets 250 mg	1 tablet 250 mg	〇	〇	Suitable

〇: Possible, ×: not possible.

Next, the disintegration/suspension and passability tests were conducted at the clinical dosage, i.e., the single dose indicated on the package insert. In the disintegration/suspension test (Table 3), all adsorbents were successfully disintegrated and suspended, except for Fosrenol^® and P-TOL^® granules. In the passability test, Cartan^® tablets, Fosrenol^® granules, P-TOL^® granules, and RENAGEL^® tablets blocked the tube; meanwhile, the remaining medications passed through without any issues. Based on these results, Cartan^® fine granules 1000 mg, Fosrenol^® tablets 250 mg, Kiklin^® granules 500 mg, and Riona^® tablets 500 mg were classified as “Suitable 1.” Since a single dose of RENAGEL^® tablets 1000 mg caused tube occlusion, additional studies were conducted at doses of 500 mg and 750 mg. The results of the disintegration/suspension and passability tests showed no issues, and the medication was classified as “Suitable 1” in the final evaluation (Table 2). The results of the passability test differed between the smallest dosage units and the single dose indicated on the package insert.

Table 3. Disintegration/suspension and Passage Tests of Phosphorus Adsorbents at the Single Dose Indicated on the Package Insert

Phosphorus adsorbent/dosage	Single dosage	Disintegration suspension test	Passability test	Final assessment
Cartan® fine granules 1000 mg	1.2 g	〇	〇	Suitable
Cartan® tablet OD 1000 mg	2 tablets (1 tablet 500 mg)	〇	×	Unsuitable
Fosrenol® granules 250 mg	0.7 g	×	×	Unsuitable
Fosrenol® tablet OD 250 mg	1 tablet (1 tablet 250 mg)	〇	〇	Suitable
Kiklin® granules 500 mg	0.58 g	〇	〇	Suitable
P-TOL® granules 250 mg	1 package	×	×	Unsuitable
RENAGEL® tablet 1000 mg	4 tablets (1 tablet 250 mg)	〇	×	Unsuitable
RENAGEL® tablet 500 mg	2 tablets (1 tablet 250 mg)	〇	〇	Suitable

〇: Possible, ×: not possible.

Fosrenol^® tablets 250 mg had the highest residual rate in the injector and tube at 9.81%±5.75 (mean±SD), which was approximately 10%. On the other hand, Riona^® tablets 500 mg had the lowest residual rate at 1.96%±1.37 (Table 4).

Table 4. Percentage of Phosphorus Adsorbents Remaining in the Injector and Feeding Tube Following the Simple Suspension Method (n=3)

Phosphorus adsorbent/dosage	Mean (%)	SD
Cartan® fine granules 1000 mg	3.48	3.04
Fosrenol® tablet OD 250 mg	9.81	5.75
Kiklin® granules 500 mg	4.76	4.69
Riona® tablet 500 mg	1.96	1.37

3. Comparing the Phosphorus Removal Rates Following the Administration of Phosphorus Adsorbents Via the Pre-mix and Normal Administration Methods

Compared with that of the control group, the pre-mix method significantly decreased the phosphorus content in Ensure Liquid^® (Fig. 3). Compared with the normal administration method, the pre-mix method had a significantly higher phosphorus removal rate for all drugs except Kiklin^® granules (* p<0.05, Student’s t-test) (Fig. 3).

Fig. 3. Comparing the Phosphorus Removal Rate (%) of Phosphorus Adsorbents Administered by the Pre-mix (with Ensure Liquid^®) and Normal Administration (Immediately Before or After Ensure Liquid^®) Methods Via the Simple Suspension Method

n=3, * p<0.05, Student’s t-test.

4. Passability Test Via the Pre-mix Method and Changes in the Properties of Ensure Liquid^®

First, the phosphorus adsorbents were directly mixed with 500 mL of Ensure Liquid^® and observed for passability from the feeding bottle to the outlet of the feeding tube. Only Cartan^® fine granules and Fosrenol^® granules passed through the tube without any issues (Table 5).

Table 5. Passability Test of Ensure Liquid^® from the Nutrition Bottle to the Catheter Outlet Following the Pre-mix Method

Phosphorus adsorbent/dosage	Single dosage	Passage of Ensure Liquid mixed with phosphorus adsorbent suspension	Passage of Ensure Liquid supernatant after 10 min of incubation	Volume of supernatant passed in Ensure Liquid after 10 min of incubation (mL)	Gastrointestinal reach of Ensure Liquid supernatant (%)	Change in properties
Cartan® fine granules 1000 mg	1.2 g	〇	〇	512	98.5	none
Cartan® tablet OD 1000 mg	2 tablets (1 tablet 250 mg)	×	〇	515	99.0	none
Fosrenol® granules 250 mg	0.7 g	〇	〇	518	99.6	none
Fosrenol® tablet OD 250 mg	1 tablet 250 mg	×	〇	515	99.0	none
Kiklin® granules 500 mg	0.58 g	×	〇	515	99.0	none
P-TOL® granules 250 mg	1 package	×	〇	510	98.1	none
RENAGEL® tablet 1000 mg	4 tablets (1 tablet 250 mg)	×	〇	510	98.1	none
Riona® tablet 500 mg	2 tablets (1 tablet 250 mg)	×	〇	510	98.1	Solid adhesion

Ensure Liquid^® supernatant 520 mL=Ensure Liquid^® 500 mL+20 mL water for injection for suspension. ○: Available, ×: not available.

Next, the phosphorus adsorbents were suspended in 20 mL of sterile water for injection at 55°C, mixed with 500 mL of Ensure Liquid^®, and allowed to stand for 10 min. The precipitate was removed, and the supernatant was used for the passability test.

The supernatant of each phosphorus adsorbent passed through the tube without any issues, and more than 98% of the Ensure Liquid^® supernatant reached the gastrointestinal tract, assuming that the supernatant reached the gastrointestinal tract through the tube in clinical use (Table 5).

When mixed with Riona^® tablets, Ensure Liquid^® left deposits on the wall of the nutrition bottle (Fig. 4). The other phosphorus adsorbents did not change the liquid properties of Ensure Liquid^®.

Fig. 4. Changes in the Properties of the Ensure Liquid^® in the Feeding Bottle Following the Administration of Riona^® Tablets via the Pre-mix Method

DISCUSSION

According to the Japanese Society for Dialysis Therapy,¹¹⁾ the standard upper limit of phosphorus intake for patients on dialysis is (0.9–1.2)×15×standard body weight (kg) in mg, which is approximately 810–1080 mg for a person measuring 165 cm in height and 60 kg in weight. One can (250 mL) of Ensure Liquid^® contains 130 mg of phosphorus. Thus, the standard daily phosphorus intake is 780–1170 mg per day for a patient receiving the standard daily dose of Ensure Liquid^®, which is 1500–2250 mL.¹²⁾ Theoretically, this exceeds the standard daily phosphorus intake for patients on dialysis. Therefore, calculated values may also exceed the standard value.

However, in our study, administering phosphorus adsorbents via the pre-mix method resulted in a phosphorus removal rate of 8–15% (approximately 12% on average). Therefore, the pre-mix method can reduce the phosphorus content in Ensure Liquid^® below the standard daily intake for patients on hemodialysis. Further, the method resulted in less drug adsorption to the infuser and tube and a higher phosphorus removal rate than did the normal administration method, in which the phosphorus adsorbent is administered immediately before or after Ensure Liquid^®. In a previous study, Riona^® tablets, a phosphorus adsorbent containing iron, were administered to improve anemia.¹³⁾ In such cases, performing the pre-mix method is difficult if the iron is in the precipitate because only the supernatant is administered after 10 min of incubation. Therefore, the normal administration method must be considered. However, the amount of iron contained in Riona^® tablets that reached the gastrointestinal tract was not investigated. Thus, further detailed investigation is required.

Disintegration/suspension and passability tests were also conducted to examine the administration of phosphorus adsorbents via the simple suspension method. Our results showed that all phosphorus adsorbents, except Fosrenol^® and P-TOL^® granules, can be administered as a single tablet or packet, which is the minimum dosage unit, via the simple suspension method. Next, the tests were conducted at the single dose indicated on the package insert. In the passability test, Cartan^® and RENAGEL^® tablets occluded the tube. The suitability of the simple suspension method at clinical doses is not discussed in the Handbook of Oral Drugs for Tube Administration,¹⁰⁾ which examines the same method at the smallest dosage unit of one tablet or packet. If the clinical dosage of a phosphorus-adsorbing drug is “not acceptable” and the minimum dosage unit is “acceptable,” as in this study, then the minimum dosage unit should be divided into multiple doses and administered by the simple suspension method. However, in patients with CKD and on dialysis who require fluid restriction and adjustment, administering multiple intravenous doses of the smallest formulation unit is not practical because of the individualized adjustment of fluid intake¹⁴⁾ and the complicated clinical work involved. Therefore, drugs that are “suitable” for simple suspension at clinical doses must be selected instead. Overall, our study findings, which include the final evaluation of the simple suspension method at clinical doses, can guide appropriate tube administration.

As previously mentioned, administering phosphorus adsorbents via the pre-mix method can reduce the phosphorus content in Ensure Liquid^®. We mixed Ensure Liquid^® with various phosphorus adsorbents at clinical doses and directly placed the mixture into a feeding bottle without separating the supernatant and sediment. The result showed that the mixture of Cartan^® fine granules and Fosrenol^® granules passed through the tube without any issues (normal tube dosing rate: 240 mL/h); meanwhile, the other phosphorus adsorbents blocked the tube. Next, we mixed 500 mL of Ensure Liquid^® with 520 mL of various phosphorus adsorbents suspended in 20 mL of sterile water for injection, allowed the mixture to stand for 10 min, and placed the supernatant into a feeding bottle. The result indicated that more than 98% off the mixture passed through the feeding tube and catheter, reaching a graduated cylinder in place of the gastrointestinal tract. Thus, administering only the supernatant may prevent hypercalcemia, a common side effect of drugs such as Cartan^®.¹⁵⁾ Conversely, administering iron-containing phosphorus adsorbents, such as Riona^® tablets, via the pre-mix method cannot be used to treat anemia if most of the iron is in the precipitate.

In addition, when Riona^® tablets were administered via the pre-mix method, deposits were found inside the feeding bottle (Fig. 4). Under acidic pH conditions, Ensure Liquid^® causes curding due to a change in the charged polar group of protein.¹⁶⁾ Thus, the adherent material may be protein; however, further investigation is required.

The results of the passability test showed a difference between the smallest unit of the formulation (one tablet or one packet) and the single dose indicated on the package insert. Therefore, the possibility of tube occlusion must be considered when a phosphorus adsorbent is administered at a clinical dose via enteral feeding.

The pre-mix method may be useful in administering phosphorus adsorbents to patients with CKD and on hemodialysis who require enteral feeding. However, this study had notable limitations. As this was an in vitro study, we measured only the phosphorus concentration in Ensure Liquid^®, and in vivo changes in the serum inorganic phosphorus concentration of patients were not examined. Therefore, we intend to evaluate the usefulness of the pre-mix method in vivo and perform clinical measurements of serum inorganic phosphorus levels in patients in future studies. Additionally, apart from that of Cartan^®, the clinical dose of the drugs used in this study was the starting dose and not the maintenance or maximum dose; thus, further investigation of this aspect is required.

Acknowledgements

This study was partially supported by a research grant from the Gunma Pharmaceutical Network of Health Sciences.

Conflict of Interest

The authors declare no conflict of interest.

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