DRUG THAT PREVENTS DIALYSIS SHIFT OR RENAL DEATH

Abstract

A method of preventing dialysis shift or renal death includes administering to a primary glomerular disease or nephrosclerosis patient with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl a sustained-release preparation including, as an active ingredient, a compound represented by formula (I):

##STR00001##

wherein R represents hydrogen or a pharmacologically acceptable cation, such that the compound represented by formula (I) is administered at 220 to 260 μg per day.

Claims

1-12. (canceled)

13. A method of preventing dialysis shift or renal death, comprising administering to a primary glomerular disease or nephrosclerosis patient with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl a sustained-release preparation comprising, as an active ingredient, a compound represented by formula (I): ##STR00009## wherein R represents hydrogen or a pharmacologically acceptable cation, such that the compound represented by formula (I) is administered at 220 to 260 μg per day.

14. The method according to claim 13, wherein the compound represented by formula (I) is beraprost sodium.

15. The method according to claim 13, wherein the primary glomerular disease or nephrosclerosis patient has an estimated glomerular filtration rate (eGFR), as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2.

16. The method according to claim 13, wherein the primary glomerular disease or nephrosclerosis patient has a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration of the sustained-release preparation comprising the compound represented by formula (I) as an active ingredient once after a meal at 120 μg as the compound represented by formula (I).

17. The method according to claim 13, wherein the preparation is combined with an angiotensin-converting enzyme inhibitor as an active ingredient.

18. The method according to claim 13, wherein the preparation is administered simultaneously, separately, or sequentially with a different preparation comprising an angiotensin-converting enzyme inhibitor as an active ingredient.

19. The method according to claim 13, wherein the preparation is combined preparations to be administered simultaneously, separately, or sequentially in treatment or prophylaxis of preventing dialysis shift or renal death, the drug separately comprising preparations (a) and (b): (a) an oral sustained-release preparation comprising the compound represented by formula (I) as an active ingredient; and (b) a preparation comprising an angiotensin-converting enzyme inhibitor as an active ingredient.

20. The method according to claim 13, wherein the preparation is used in combination with an angiotensin-converting enzyme inhibitor.

21. A method of preventing dialysis shift or renal death, comprising administering to a primary glomerular disease or nephrosclerosis patient with a nutritional disorder a sustained-release preparation comprising, as an active ingredient, a compound represented by formula (I): ##STR00010## wherein R represents hydrogen or a pharmacologically acceptable cation, such that the compound represented by formula (I) is administered at 220 to 260 μg per day.

22. The method according to claim 21, wherein the nutritional disorder is protein energy wasting (PEW) or a preliminary disease thereof.

23. The method according to claim 21, wherein the nutritional disorder satisfies at least one of four constituent elements of PEW.

24. The method according to claim 21, wherein the nutritional disorder is cachexia, sarcopenia, or frailty.

25. The method according to claim 14, wherein the primary glomerular disease or nephrosclerosis patient has an estimated glomerular filtration rate (eGFR), as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2.

26. The method according to claim 22, wherein the nutritional disorder satisfies at least one of four constituent elements of PEW.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 is a view showing the transition of event-free survival after administration of BPS or placebo to a Japanese patient group with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl before the start of administration. The event was dialysis shift.

[0045] FIG. 2 is a view showing the results of a group administered with BPS at 240 μg per day in a Japanese patient group with a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration of BPS sustained-release tablets after a meal at 120 μg per dose when the event was dialysis shift.

[0046] FIG. 3 is a view showing the results of, among a 240-μg BPS-administered Japanese group and a 240-μg BPS-administered Asian group other than Japanese, a patient group combined with ACEI and a patient group not combined with ACEI when dialysis shift was set as an event.

[0047] FIG. 4 is a view showing the transition of event-free survival when 240 μg BPS or placebo was administered to Japanese chronic renal failure patients and Asian chronic renal failure patients other than Japanese with a body mass index (hereinafter, abbreviated as BMI) of less than 23 before the start of administration. The event was dialysis shift.

[0048] FIG. 5 is a view showing the transition of event-free survival when 240 μg BPS or placebo was administered to Japanese chronic renal failure patients with a BMI of less than 23 before the start of administration. The event was dialysis shift.

[0049] FIG. 6 is a view showing the transition of event-free survival after 240 μg BPS or placebo was administered to Japanese chronic renal failure patients with a serum albumin level of less than 3.8 g/dl before the start of administration. The event was dialysis shift.

[0050] FIG. 7 is a view showing the transition of event-free survival when 240 μg BPS or placebo was administered to Japanese chronic renal failure patients with a total lymphocyte count of less than 1500/mm.sup.3 before the start of administration. The event was dialysis shift.

DETAILED DESCRIPTION

[0051] The sustained-release preparation that can be used comprises a compound represented by formula (I):

##STR00008##

wherein R represents hydrogen or a pharmacologically acceptable cation.

[0052] Examples of the pharmacologically acceptable cation include alkali metals and alkaline earth metals such as sodium, potassium, and calcium; amines typified by mono-, di-, or trimethylamine, methyl piperidine, mono-, di-, or triethanolamine, and lysine; basic amino acids; and the like. Of these, sodium and potassium are particularly preferably used.

[0053] Further, among the compounds represented by formula (I), beraprost or pharmacologically acceptable salts thereof are preferably used. Of these, in addition to beraprost, BPS, which is a sodium salt of beraprost, or a potassium salt of beraprost is particularly preferably used.

[0054] BPS is composed of four stereoisomers, and its medicinal effect is mainly responsible for BPS-314d (sodium (+)-(1R,2R,3aS,8b S)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate) (Kajikawa et al., Arzneimittelforschung (1989) 39, 495-9). Therefore, preparations containing only BPS-314d, which is an active ingredient of BPS, are also preferably used. Regarding the plasma concentration of BPS-314d when BPS is administered, both AUC (area under the blood concentration time curve; the area of the part surrounded by the curve (blood drug concentration-time curve) showing the time course of blood concentration and the horizontal axis (time axis)) and Cmax (maximum drug concentration) are known to be almost ¼ (Shimamura et al., J Clin Pharmacol (2017 57, 524-535). Therefore, when a preparation containing an active body of BPS (e.g., BPS-314d) alone is administered, the effective dose per day of BPS-314d is 55 to 65 which is ¼ the dose of BPS. Further, an active body of beraprost potassium (potassium (+)(1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octen-6-nyl]-1H-cyclopenta[b]benzofuran-5-butyrate) is also particularly preferably used. The daily dose in this example is 57 to 67 μg.

[0055] As BPS preparations, immediate-release tablets are commercially available. However, the half-life in blood of BPS is as short as about 1 hour, and it is thus necessary to take them three or four times a day. Moreover, due to the rapid increase in plasma concentration, the frequency of side effects such as flushing and headache increases so that the dose that can be administered has been limited. For this reason, as the drug of this disclosure, beraprost or a pharmacologically acceptable salt thereof, preferably a BPS sustained-release preparation, particularly an oral sustained-release preparation, is used.

[0056] Sustained-release preparations are those that delay the release of active ingredients from preparations to reduce the number of doses, and keep the active ingredient concentration in the blood constant for a long period of time to avoid side effects, as described in the Pharmaceutical Glossary of the Pharmaceutical Society of Japan.

[0057] The sustained-release preparation is defined as satisfying the dissolution behavior of the following dissolution test. That is, when a test is carried out at 100 rpm by the paddle method (however, using a sinker) while taking one tablet of this preparation and using 50 ml of water containing 0.5 ml of Polysorbate 80 as a test liquid, the preparation has a 3-hour dissolution rate of 25±10%, a 6-hour dissolution rate of 50±10%, and a 10-hour dissolution rate of 70% or more; and the preparation preferably satisfies these dissolution rates within a pH range of 1.2 to 7.5.

[0058] By satisfying such conditions, preparations that show effectiveness by oral administration once or twice a day due to the sustainability of the effective plasma concentration of BPS can be obtained.

[0059] The sustained-release preparation is not particularly limited as long as it satisfies the above dissolution characteristics. For example, WO98/41210 and WO2004/103350 disclose BPS sustained-release preparations comprising a hydrogel base as a release control component of BPS. The BPS sustained-release preparations produced by these methods have already received manufacturing and marketing approval as therapeutic agents for pulmonary arterial hypertension, and have been widely clinically applied.

[0060] The BPS sustained-release preparation comprising a hydrogel base will be described in detail below. That is, the release control component refers to a substance that has the function of changing the release rate of BPS when being mixed in the preparation, and the mixing method are not particularly limited. Examples of such release control components include so-called sustained-release bases that delay the release rate, buffers that suppress pH changes during release such as pH changes in the gastrointestinal tract, to avoid the pH dependency of the release rate, solubilizing agents that improve the solubility of medicinal substances to stabilize the release rate with diffusion rate control, release promoters, and the like.

[0061] As the release control component, a hydrogel base is used, in terms of stably releasing a slight amount of BPS. When a hydrogel base is used as the release control component, even with a slight amount (about 0.1 to 10000 μg) of BPS, so-called zero-order release with very little variation over time in the release rate is possible.

[0062] As such hydrogel bases, known hydrogel bases can be used. The term “hydrogel” means a water-swellable polymer or a combination of two or more of such polymers. Such a suitable hydrogel is composed of a polymer substance that absorbs, when being brought into contact with water or another aqueous medium, water or the other medium and swells to some extent. Such absorption is reversible or irreversible, both of which are included in the scope of this disclosure. As hydrogel bases, various polymer substances of natural and synthetic origin are known. Desirable hydrogel bases are substantially linear polymers that are easy to control preparation production and the ability to control release by the molecular weight, that do not have a crosslinked structure as a covalent bond, and that do not have drug interaction and adsorption. Examples of such hydrogel bases include methylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (hereinafter, abbreviated as HPMC), polyethylene oxide (PEO), sodium carboxymethylcellulose, sodium alginate, sodium hyaluronate and like water-soluble polymers, or mixtures of two or more of these.

[0063] As a preferred hydrogel base, HPC, HPMC, PEO, or a mixture of two or more of these is used. There are various types of hydrogel bases depending on the degree of viscosity, which are selected as appropriate depending on the intended purpose.

[0064] The content of the hydrogel base in the preparation is preferably 10 wt. % to the balance of BPS (when a buffer is contained, then the balance of BPS and the buffer), and more preferably 40 to 95 wt. %, based on the weight of the preparation.

[0065] Buffers refer to substances that suppress pH changes during release such as pH changes in the gastrointestinal tract, to avoid the pH dependency of the release rate, as described above. Examples thereof include those having a buffering action in the acidic region, those having a buffering action in the neutral region, and those having a buffering action in the basic region. It is preferable to suitably select one from these buffers depending on the physical properties of BPS. BPS has a weakly acidic carboxyl group. Thus, it is desirable to control disassociation of the carboxyl group of BPS to keep solubility in the aqueous solvent constant in the hydrogel. Organic acids, amino acids, and inorganic salts are preferred. Examples of organic acids include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, or salts thereof; examples of amino acids include glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, or salts thereof; and examples of inorganic salts include magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, or salts thereof; and mixtures of one or two or more of these. In particular, in expectation of a long-term buffering effect, the buffer of the sustained-release preparation is preferably a poorly soluble buffer with a solubility in water of 15 wt. % or less. Examples thereof include succinic acid, fumaric acid, ascorbic acid, glutamine, glutamic acid, arginine, magnesium oxide, zinc oxide, magnesium hydroxide, boric acid, or salts thereof, and mixtures of two or more of these. Acidic buffers are more preferable because they reduce the dissolution rate and sustain the release by suppressing dissociation of the carboxyl group of BPS. Examples thereof include succinic acid, fumaric acid, ascorbic acid, glutamic acid, boric acid, or salts thereof, and mixtures of two or more of these. Such poorly soluble and acidic buffers are particularly preferable as the buffer of the sustained-release preparation because they suppress drug-releasing pH changes and also suppress changes in the release rate over time so that a constant release rate can be maintained for a long period of time.

[0066] The buffer is used in an amount, for example, of 0.1 to 30 wt. % of the weight per preparation. The preferred amount is 1 to 20 wt. %, and particularly preferably 1 to 10 wt. %.

[0067] The sustained-release preparation may contain, if necessary, available additives such as excipients, lubricants, binders, stabilizers, and solubilizing agents. The additives are not particularly limited as long as they are pharmacologically acceptable. Examples of excipients include lactose, saccharose, sucrose, D-mannitol, sorbitol, xylitol, crystalline cellulose, corn starch, gelatin, polyvinyl pyrrolidone, dextran, polyethylene glycol (PEG) 1500, PEG 4000, PEG 6000, PEG 20000, polyoxyethylene polyoxypropylene glycol (PEP 101 (trademark) and Pluronic (trademark)) and the like. Further, examples of lubricants include magnesium stearate, calcium stearate, talc and the like; examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, stearic acid, propylene glycol and the like; examples of stabilizers include butylhydroxytoluene, butylhydroxyanisole, ascorbic acid, propyl gallate, dibutylmethylphenol, sodium thiosulfate and the like; and examples of solubilizing agents include cyclodextrin, polyethylene hydrogenated castor oil, polyethyleneglycol monostearate and the like. The amounts of these additive mixed are selected as appropriate depending on the type and purpose thereof.

[0068] The additive content is not particularly limited, but is generally 0 wt. % to about the balance of BPS and the hydrogel base (when a buffer is contained, then the balance of BPS, the hydrogel base, and the buffer), and preferably 5 wt. % to about the balance of BPS and the hydrogel base (when a buffer is contained, then the balance of BPS, the hydrogel base, and the buffer), based on the weight per preparation.

[0069] The combination of BPS, the release control component, and the buffer in the sustained-release preparation is not particularly limited, and is, for example, a combination of BPS, polyethylene oxide, and a poorly soluble and acidic buffer such as fumaric acid or glutamic acid.

[0070] The form of the BPS sustained-release preparation containing the hydrogel base is not particularly limited. However, tablets are preferably used.

[0071] Moreover, the BPS sustained-release preparation that satisfies the dissolution characteristics described above can also be produced in the following manner. Specifically, WO2004/103350 discloses an oral sustained-release pharmaceutical composition comprising a plurality of granules having a particle size of 1000 μm or less, wherein the granules each comprise a BPS-containing nuclear granule and a coating agent, the coating agent is composed of at least two film layers including (1) a film layer containing a poorly water-soluble polymer substance and (2) a film layer containing a heat-meltable low-melting-point substance, and the nucleus granule is coated with the coating agent.

[0072] The amount of BPS mixed in the oral sustained-release pharmaceutical composition comprising the plurality of granules is not particularly limited as long as it is a therapeutically effective amount, and is, for example, 20 to 250 μg/preparation, and preferably 115 to 250 μg/preparation. The term “per preparation” as used herein means an amount of preparation orally administered at a time. The weight per preparation is not particularly limited, but is generally about 20 mg to 1000 mg.

[0073] The poorly water-soluble polymer substance that constitutes the film layer refers to a water-insoluble polymer substance that has film-forming ability and drug release control ability. The coating method or additives to be mixed are not particularly limited. Examples of such poorly water-soluble polymer substances include water-insoluble alkyl cellulose ether derivatives (e.g., ethyl cellulose and butyl cellulose), water-insoluble vinyl derivatives (e.g., polyvinyl acetate and polyvinyl butyrate), and water-insoluble acrylic polymer derivatives (e.g., acrylic acid-methacrylic acid copolymers), and mixtures of two or more of these. Examples of preferred poorly water-soluble polymer substances include acrylic acid-methacrylic acid copolymers.

[0074] The heat-meltable low-melting-point substance that constitutes the film layer refers to a heat-meltable substance that has a relatively low melting point, preferably 70° C. or lower, and more preferably from room temperature to 70° C., and that has release control ability. The coating method and the additives to be mixed are not particularly limited. Examples of such heat-meltable low-melting-point substances include higher fatty acids (e.g., stearic acid, capric acid, lauric acid, myristic acid, and palmitic acid), higher alcohols (e.g., stearyl alcohol, myristyl alcohol, lauryl alcohol, and cetyl alcohol), higher fatty acid glycerol esters (e.g., glycerol palmitate oleate, glycerol monooleate, glycerol monostearate, glycerol monomyristate, glycerol monobehenate, glycerol trimyristate, and glycerol tribehenate), waxes (e.g., carnauba wax), saturated hydrocarbons (e.g., paraffin), and mixtures of two or more of these. Examples of preferred heat-meltable low-melting-point substances include cetyl alcohol, stearic acid, glycerol palmitate oleate, glycerol monooleate, glycerol monostearate, glycerol monomyristate, glycerol monobehenate, glycerol tristearate, glycerol trimyristate, and glycerol tribehenate.

[0075] The weight ratio of (1) the film layer containing a poorly water-soluble polymer substance and (2) the film layer containing a heat-meltable low-melting-point substance in the film layer, and the coverage of the film layer in the granule are not particularly limited, and are determined as appropriate depending on the drug used, the effective dosage and the like. In general, the ratio thereof may be 1:9 to 9:1, and preferably 3:7 to 7:3.

[0076] The film layer may contain pharmacologically acceptable additives. Examples of additives include propylene glycol, polyethylene glycol (PEG) 1500, PEG 4000, PEG 6000, PEG 20000, polyoxyethylene polyoxypropylene glycol (PEP 101 (trademark) and Pluronic (trademark)), glycerol, triethyl citrate, tributyl citrate, triacetin, sodium lauryl sulfate, sorbitol, polyvinylpyrrolidone, Polysorbate 80 and like plasticizers. The effective amount of pharmaceutical plasticizer currently available on the market varies between 1 to 30% of the total dry weight of the coating material.

[0077] Examples of brittleness inducers, which are additives that reduce the elasticity of films forming the coatings, include talc, magnesium stearate, calcium stearate, Aerosil, and titanium oxide. The effective amount of brittleness inducer varies depending on the type of brittleness inducer used. For example, when talc is used, the effective amount is 10 to 70%, when Aerosil, 1 to 40%, and when magnesium stearate, 1 to 70%. All percentages are based on the total dry weight of the coating material.

[0078] Additives that can be mixed into the BPS-containing nuclear granules are not particularly limited as long as they are pharmacologically acceptable.

[0079] Examples of preferred additives include binders, excipients, stabilizers, solubilizing agents, and buffers.

[0080] Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, stearic acid, and propylene glycol. Examples of excipients include lactose, saccharose, sucrose, D-mannitol, sorbitol, xylitol, crystalline cellulose, corn starch, gelatin, polyvinylpyrrolidone, dextran, PEG 1500, PEG 4000, PEG 6000, PEG 20000, and polyoxyethylene polyoxypropylene glycol (PEP 101 (trademark) and Pluronic (trademark)). BPS-containing nuclear granules can be prepared by coating existing spherical granules such as Nonpareil (trademark) (saccharose), Suglets (trademark) (saccharose), or Ethispheres (trademark) (crystalline cellulose), with a pharmaceutically active substance together with a binder. Alternatively, BPS-containing nuclear granules can be produced by mixing BPS with an excipient, and granulating the mixture into spherical granules. Examples of stabilizers include butylhydroxytoluene, butylhydroxyanisole, ascorbic acid, propyl gallate, dibutylmethylphenol, sodium thiosulfate, and titanium oxide. The effective compounding amount varies depending on the pharmaceutically active substance. Examples of solubilizing agents include cyclodextrin, polyethylene hydrogenated castor oil, polyethylene glycol monostearate, poloxamer, and Polysorbate 80. Examples of buffers include alkaline reactants such as MgO, and acidic reactants such as organic acids (e.g., citric acid and tartaric acid).

[0081] The particle size of the granules is 1000 μm or less, preferably 100 to 850 μm, and more preferably 300 to 750 μm.

[0082] The oral sustained-release pharmaceutical composition comprising the plurality of granules is composed of a plurality of granular particles having a particle size of 1000 μm or less, each of which has a sustained-release function. By controlling the particle size within the above-mentioned range, it is possible to maintain stable release in the lower part of the gastrointestinal tract. The final form thereof is not particularly limited, but may be a form that can be orally administrated. Examples thereof include tablets, granules, fine granules, capsules, suspensions and the like.

[0083] Since the drug is a pharmaceutically stable preparation with excellent sustainability, oral administration once or twice a day results in stable medicinal properties for a long period of time and excellent bioavailability, and it is easy to take.

[0084] Examples of sustained-release preparations for oral administration include single-unit and multiple-unit sustained-release preparations. Many of single-unit preparations gradually release drugs while the dosage form is maintained in the gastrointestinal tract. Examples of single-unit preparations include wax matrix, gradumet, repetab, lontab, spantab and the like. As for multiple-unit preparations, administered tablets or capsules are rapidly distinguished to release granules, and the released granules show sustained-release properties. Examples of multiple-unit preparations include spacetab, spansule, granule and the like. Further, in terms of release control mechanism, they are divided into reservoir preparations and matrix preparations. Reservoir preparations are obtained by coating drug-containing tablets or granules with polymer coatings, and the drug release rate is determined by the properties and thickness of the coating. Repetab, spacetab, spansule, and granule belong to reservoir preparations. Matrix preparations are obtained by dispersing drugs in bases such as polymers or waxes, and the release rate is determined by the diffusion rate of drug molecules in the matrix. Wax matrix, gradumet, lontab, spantab or the like belong to matrix preparations. Various sustained-release preparations can be used, regardless of the method of sustained-release, as long as they have the release characteristics described above.

[0085] The sustained-release preparation comprising a compound represented by formula (I) as an active ingredient is administered once or twice so that the dose of the compound represented by formula (I) is 220 to 260 μg per day.

[0086] The sustained-release preparations comprising the compound represented by formula (I) as an active ingredient are commercially available as Careload (trademark) LA Tablets 60 μg (Toray Industries, Inc.) and Berasus (trademark) LA Tablets 60 μg (Kaken Pharmaceutical Co., Ltd.) as BPS-containing sustained-release preparations. Therefore, when 2 tablets of Careload (trademark) LA Tablets 60 μg (Toray Industries, Inc.) or Berasus (trademark) LA Tablets 60 μg (Kaken Pharmaceutical Co., Ltd.) are administered per dose twice a day (4 tablets in total), 240 μg BPS per day is supposed to be administered.

[0087] Further, as sustained-release preparations that can be used, compared to sustained-release preparations that have been approved for manufacturing and marketing in Japan as Careload (trademark) LA Tablets 60 μg (Toray Industries, Inc.) or Berasus (trademark) LA Tablets 60 μg (Kaken Pharmaceutical Co., Ltd.), preparations for which bioequivalence is shown by dissolution behavior, clinical pharmacokinetic studies and the like, according to the “Guideline for Bioequivalence Studies of Generic Products,” SUPAC-MR (Modified Release Solid Oral Dosage Forms) or the like are particularly preferably used.

[0088] The drug can be administered to a primary glomerular disease or nephrosclerosis patient with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl before the start of treatment and/or an estimated glomerular filtration rate (eGFR), as calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2 before the start of treatment, thereby preventing dialysis shift or renal death.

[0089] Fujita et al., Vascular Biology & Medicine has reported that as a result of long-term follow-up when 20 μg BPS immediate-release tablets were administered three times a day to chronic renal failure patients, a patient group with a serum creatinine level of 2.8 mg/dl or more before the start of BPS administration shifted to dialysis within 24 months, and that the effect of BPS was not observed when the serum creatinine level was 2.2 mg/dl or more. However, the application target can be limited to primary glomerular disease or nephrosclerosis patients, thereby preventing dialysis shift or renal death. Further, dialysis shift or renal death can also be prevented in patients with a serum creatinine level of 2.2 mg/dl or more, for which no effect has been confirmed in Fujita et al., Vascular Biology & Medicine.

[0090] Dialysis includes peritoneal dialysis, in addition to blood dialysis.

[0091] The drug shows practically excellent effects for, among the primary glomerular disease or nephrosclerosis patients mentioned above, patients with a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration of a BPS sustained-release preparation at 120 μg as BPS once after a meal.

[0092] Since the pharmacological action of BPS is observed depending on the concentration of BPS, it is estimated that a higher effect will be obtained as the plasma concentration at the time of administration of BPS is higher. From the relationship between Cmax and AUC (when Cmax is 214.7±89.1 pg/ml, AUC is 1225±343 pg.Math.hr/ml, which is about 5.7 times) at the time of administration of 240 μg BPS sustained-release tablets, AUC estimated when Cmax of the sustained-release tablets is 50 pg/ml is 286 pg.Math.hr/ml, and due to administration twice a day, AUC per day is 572 pg.Math.hr/ml.

[0093] On the other hand, regarding Cmax and AUC when 20 μg immediate-release tablets, for which no sufficient dialysis delay effect has been confirmed, are administered to a healthy subject, 1) when 40 μg BPS immediate-release tablets are orally administered daily to a human twice a day after a meal, Cmax on day 7 at the time of final administration is 242.2±81.4 pg/ml, and AUC is 550±148 pg.Math.hr/ml (interview form of Careload Tablets), and 2) linearity is observed between the dosage of BPS immediate-release tablets, Cmax, and AUC (Non-Patent Literature 12). Thus, Cmax is 121 pg/ml and AUC is about 275 pg.Math.hr/ml. Since immediate-release tablets are generally administered three times a day, AUC per day is assumed to be about 825 pg.Math.hr/ml. Further, it has been reported that both Cmax and AUC are elevated in renal damage patients compared to healthy subjects (Shimamura et al., J Clin Pharmacol). Therefore, Cmax and AUC were considered to be even higher when 20 μg immediate-release tablets were administered to a chronic renal damage patient.

[0094] In light of the above, it could not be predicted from the conventional finding that the significant effect of beraprost sustained-release tablets on prevention of dialysis shift or renal death in patients with a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration (AUC per day is 570 pg.Math.hr/ml or more), which was around Cmax at the time of administration of BPS sustained-release tablets, was observed in Cmax and AUC lower than those in administration of 20 μg immediate-release tablets three times a day.

[0095] Regarding the phrase “a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration of a BPS sustained-release preparation at a dose of 120 μg as BPS once after a meal,” the plasma concentration may be measured once or more times 2 to 6 hours after administration, and the average of the measured values may be 50 pg/ml or more; or “administration at 120 μg once after a meal” may be performed once or more times, and the average of the measured values may be 50 pg/ml or more. These may also be combined.

[0096] Moreover, it is known that when BPS is administered to a human, the Cmax of BPS-314d, which is the essence of the activity of BPS, is ¼ that of BPS (Shimamura et al., J Clin Pharmacol). Therefore, it is possible to replace the particularly effective plasma concentration of BPS, i.e., 50 pg/ml or more, by the plasma concentration of BPS-314d, i.e., 12.5 pg/ml or more. In particular, when a preparation containing BPS-314d alone is administered, it is necessary to define it by the plasma concentration of BPS-314d.

[0097] The drug exhibits particularly excellent effects for, among primary glomerular disease or nephrosclerosis patients, patients who take ACEI. Further, the drug is particularly effectively used for patients with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl before administration, or patients with an eGFR, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2.

[0098] Examples of the ACEI include captopril, enalapril, benazepril, imidapril, lisinopril, perindopril, ramipril, moexipril, fosinopril, and quinapril. The usage and dosage of these ACEIs may follow the usage and dosage of each ACEI approved as an antihypertensive agent. Moreover, when ACEI is contained as an active ingredient, compound drugs of ARB, a calcium antagonist, a beta blocker, and various diuretics may be used.

[0099] We provide a drug that is combined preparations used to be administered simultaneously, separately, or sequentially in treatment or prevention dialysis shift or renal death, the drug separately comprising the following two preparations (a) and (b):

[0100] (a) an oral sustained-release preparation comprising a compound represented by formula (I) as an active ingredient, for administering the compound represented by formula (I) at 220 to 260 μg per day; and

[0101] (b) a preparation comprising ACEI as an active ingredient.

[0102] The drug, which separately comprises two preparations, can be administered to chronic renal failure patients, thereby preventing dialysis shift or renal death.

[0103] The drug is particularly effectively used for primary glomerular disease or nephrosclerosis patients with nutritional disorders.

[0104] The drug is particularly effective for malnutrition among nutritional disorders. Malnutrition is generally defined by the serum protein mass, body size, muscle mass, nutritional intake and the like. However, various standards have been proposed, and it is thus not always limited to one standard.

[0105] The drug is particularly effective in satisfying the criteria of PEW as a nutritional disorder, which are characteristic indicators of renal damage patients, and satisfying the elements constituting PEW. Specifically, any one of the four elements constituting PEW, i.e., “serum chemistry,” “body mass,” “muscle mass” and “dietary intake,” may be satisfied, and further one parameter in each element may be satisfied. Needless to say, some of the elements may be satisfied. Rather, the effect of BPS is more clearly observed in typical patients having some of the elements.

[0106] Further, the drug is particularly effective for patients with nutritional disorders who have a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl, and patients with nutritional disorders who have an estimated glomerular filtration rate, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2.

[0107] In addition, the drug is also effectively used for chronic renal failure patients with a complication of pre-cachexia or cachexia, both of which are more serious PEW. Further, the drug is extremely useful for chronic renal failure patients with a complication of sarcopenia or frailty, both of which occur as a result of the progress of nutritional disorder.

[0108] The treatment using the drug does not result in a decrease in the body weight or muscle mass during treatment with SGLT2 inhibitors, and can therefore be effectively used for chronic renal failure patients with PEW or cachexia, further with a complication of sarcopenia or frailty.

[0109] In the primary glomerular disease or nephrosclerosis, there is no particular problem even if there is a complication of diabetes.

Method of Calculating eGFR

[0110] The eGFR values are calculated by the CKD-EPI equation and described in Levey et al., Ann Intern Med, 150 (2009), 604-612. Specifically, the eGFR values are expressed as follows. That is, when [Cr] ml/dl represents serum creatinine, and [Age] represents age, eGFR is calculated by Equation (1) for males, and Equation (2) for females:

[00001]$\begin{array}{cc}\mathrm{eGFR}\left(\mathrm{ml}/\min /1.73m^2\right)=141\times {\left(\left[\mathrm{Cr}\right]/0.9\right)}^{-1.209}\times {0.993}^{\left[\mathrm{Age}\right]}& \mathrm{Equation}\left(1\right)\end{array}$$\begin{array}{cc}\mathrm{eGFR}\left(\mathrm{ml}/\min /1.73m^2\right)=144\times {\left(\left[\mathrm{Cr}\right]/0.9\right)}^{-1.209}\times {0.993}^{\left[\mathrm{Age}\right]}.& \mathrm{Equation}\left(2\right)\end{array}$

[0111] In the CKD-EPI equation, separately, correction coefficients are applied to match the measured values using iothalamate and inulin in various countries including Japan. It is expected that it will be proposed in the future. However, it is preferable to use the above estimate equations based on the original document. For serum creatine used in the calculation of the CKD-EPI equation, values measured by the enzymatic method are used in principle. Values measured by the Jaffe method need to be corrected.

Method of Measuring Serum Creatinine Levels

[0112] Serum creatinine levels are measured by the enzymatic method. Specifically, in addition to Cygnus Auto CRE (Shino-Test Corporation), L-type Wako CREM (FUJIFILM Wako Pure Chemical Corporation), Pureauto S CRE-N(Sekisui Medical Co., Ltd.), Serotec CRE-N(Serotec Co., Ltd.), Aqua-auto Kainos CRE-III plus (Kainos Laboratories, Inc.), and Shikarikid-N CRE (Kanto Chemical Co., Inc.), all of which are sold as clinical test drugs, are used; however, any clinical test drugs that use the enzymatic method can be used without any particular limitation.

[0113] When the enzymatic method is compared to the conventionally used Jaffe method, it is cautioned that the Jaffe method, which has lower specificity, results in 0.2 mg/ml higher values (Japanese Society of Nephrology, Evidence-based Practice Guideline for the Treatment of CKD (2009), p. 3). Therefore, when creatinine levels measured by the Jaffe method are used, 0.2 mg/ml is subtracted to convert them to values measured by the enzymatic method.

Method of Measuring Plasma BPS Concentration

[0114] The plasma BPS concentration is quantified by the GC-MS method, LC-MS method, LC-MS-MS method or the like. However, any validated method can be used.

[0115] For the analysis, the full analysis set and Intention-To-Treat (ITT) defined in Nakamoto et al., BMC Nephrology were used, and the hazard ratio (HR) of the drug and placebo was calculated by the Cox proportional hazard model. A lower HR value indicates a higher effectiveness of the drug.

EXAMPLES

[0116] Next, our drugs and methods will be described in more detail while showing Examples and Comparative Examples. However, this disclosure is not limited by these examples. The measurement methods performed in the following Examples and Comparative Examples are shown below.

Method of Calculating eGFR

[0117] eGFR was calculated using Equations (1) and (2) described above.

Method of Measuring Serum Creatinine Levels

[0118] Serum creatinine levels were measured by the enzymatic method in SRL, Inc.

Method of Measuring Plasma BPS Concentration

[0119] The plasma BPS concentration was quantified by the LC-MS/MS method in Toray Research Center, Inc.

Example 1

[0120] A BPS sustained-release tablet, TRK-100STP (the same preparation as Careload (trademark) LA Tablets 60 μg (Toray Industries, Inc.)), which is a gel-matrix sustained-release preparation containing 60 μg BPS and, as additives, polyethylene oxide 5000K, Macrogol 6000, L-glutamic acid, and magnesium stearate, was produced together with placebo tablets at Mishima Plant of Toray Industries, Inc. The in vitro dissolution behavior from TRK-100STP was measured in the following manner. Specifically, a test was carried out at 100 rpm by the paddle method (however, using a sinker) while taking one tablet of this preparation and using 50 ml of distilled water containing 0.5 ml of Polysorbate 80 as a test liquid. At this time, the 3-hour dissolution rate of BPS was 25%, the 6-hour dissolution rate was 50%, and the 10-hour dissolution rate was 83%. Further, when a dissolution test was carried out by the same protocol using Japanese Pharmacopoeia 1st liquid (pH: 1.2) and Japanese Pharmacopoeia 2nd liquid (pH: 6.8) in place of water, equivalent dissolution rates were obtained.

[0121] A data set obtained in the CASSIOPEIR trial according to the protocol described in Nakamoto et al., BMC Nephrology was used. Summarizing the protocol of the CASSIOPEIR trial, the targets are chronic renal failure patients with primary glomerular disease and nephrosclerosis as primary diseases, and a BPS sustained-release tablet, TRK-100STP (the same preparation as Careload (trademark) LA Tablets 60 μg (Toray Industries, Inc.)), is administered at 120 μg or 240 μg as BPS per day in two divided doses, morning and evening. Further, this trial was a multicenter, randomized, placebo-controlled, double-blind comparative trial, and carried out in Japan, China, South Korea, Taiwan, Hong Kong, Malaysia, and Thailand.

[0122] The duration of drug administration was 2 to 4 years, and the number of patients underwent randomization was 892, and the trial was conducted in 160 sites. Further, the ITT population was the primary analysis target population. The primary endpoint was the time to occurrence of the renal composite endpoint defined by doubling of serum creatinine or end-stage renal disease. The guidelines (2013) of the Japanese Society for Dialysis Therapy were used as a reference to determine the time to shift to dialysis. Specifically, according to the policy that “even with adequate conservative treatment, progressive deterioration of renal function is observed, and the need arises when GFR<15 ml/min/1.73 m.sup.2. However, the introduction of actual blood dialysis is determined by comprehensively judging the symptoms of renal failure, activity in daily life, and nutritional status, and a decision is made when these cannot be avoided except by dialysis therapy,” and finally based on the judgment of the investigator, the time to shift to dialysis and the time to reach renal death were determined. The term “dialysis” as used herein includes peritoneal dialysis, in addition to blood dialysis.

[0123] Furthermore, in the CASSIOPEIR trial, in the Japanese population who had been confirmed to have a high drug compliance rate from the description of the example report form and the measurement results of plasma concentrations, a patient group with a serum creatinine level of 2.0 mg/dl or more and less than 3.0 mg/dl before the start of administration showed an HR of 0.51 and a P value of 0.0429, thus confirming the effect of preventing dialysis shift (FIG. 1). Moreover, when the event was the time to renal death defined by dialysis shift or transplantation, the HR was 0.54 and the P value was 0.0624, which was below 0.1. A strong tendency similar to the dialysis shift was observed. Further, patients with a serum creatinine level of more than 2.2 mg/dl and less than 3.0 mg/dl before the start of administration showed an HR of 0.51 and a P value of 0.0495 when dialysis shift was set as an event. A significant effect of prolonging the time to dialysis shift was observed. In addition, in the Japanese population in the CASSIOPEIR trial, a patient group with an eGFR, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2 before the start of administration showed an HR of 0.64 and a P value of 0.0691 when dialysis shift was set as an event. A tendency of prolonging the time to dialysis shift was observed.

Comparative Example 1

[0124] In the CASSIOPEIR trial, Japanese patients with a serum creatinine level of 3.0 mg/dl or more before the start of treatment showed an HR of 0.91 and a P value of 0.7219 when dialysis shift was set as an event. No effect of TRK-100STP administration was observed. Similarly, Japanese patients with an eGFR, as calculated by the CKD-EPI equation, of less than 15 ml/min/1.73 m.sup.2 before the start of treatment showed an HR of 1.05 when dialysis shift was set as an event. No effect of TRK-100STP administration was observed at all.

Example 2

[0125] Of all the Japanese patients participating the CASSIOPEIR trial, in patients who were confirmed to have a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration of BPS sustained-release tablets at 120 μg as BPS per dose after a meal, the effect of administration at 240 μg per day was examined while setting the time to dialysis shift as an event. As a result, HR=0.63 and P value=0.0315, indicating that dialysis shift was delayed by administration of 240 μg BPS (FIG. 2). A similar tendency was also observed when the event was renal death. In Example 1 and this Example, the data of the Japanese population with a high drug compliance rate were used for analysis. However, the application target is not limited to Japanese patients as long as drug compliance is maintained. Similar effects will be obtained from patients of China, South Korea, Taiwan, Hong Kong, Malaysia, Thailand, and other Asian countries, as well as other countries. For example, for Chinese and Thailand cases in the CASSIOPEIR trial, in patients with a plasma concentration of 50 pg/ml or more on average 2 to 6 hours after administration, who were assumed to take medication more reliably, the HR was 0.74 when dialysis shift was set as an event, thus indicating effectiveness almost equal to that of the Japanese partial population.

[0126] Further, in patient groups for which the above BPS concentration was confirmed, a patient group with an eGFR, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2, who corresponded to CKD stages 3b and 4 as CKD stages before the start of treatment, showed HR=0.59 and P value=0.0368. The effect of minimizing the time to dialysis shift was more significant. Moreover, a patient group with a serum creatinine level of less than 3 mg/dl showed HR=0.46 and P value=0.0251. The effect of minimizing the time to dialysis shift was further significant. A similar tendency was also observed when renal death was set as an event.

Comparative Example 2

[0127] In Example 2, in patients who did not show a plasma concentration of 50 pg/ml or more after administration of BPS, the time to dialysis shift was not prolonged by the administration of BPS sustained-release tablets at 240 μg per day in the Chinese case and further in the Thailand case, in addition to the Japanese case. The prolongation of the time to renal death was also the same.

Example 3

[0128] In the CASSIOPEIR trial, when the time to dialysis shift or renal death was set as an event in all of the subjects who used BPS sustained-release tablets in combination with ACEI (lisinopril, temocapril, delapril, perindopril, benazepril, enalapril, captopril, quinapril, fosinopril, imidapril, or a hydrochloride thereof, cilazapril, trandolapril, quinapril, ramipril, temocapril, or a hydrochloride thereof, or trandolapril), the HR and P value of groups administered with BPS at 240 μg per day were analyzed by the Cox Hazard model.

[0129] Among the groups administered with BPS at 240 μg per day, a patient group who used ACEI in combination (except for patients who further used ARB in combination) showed HR=0.60 and P value=0.0994 (FIG. 3). The P value was below 0.1, strongly suggesting that the combined use of 240 μg BPS and ACEI prolonged the time to dialysis shift.

[0130] Further, when the patient group was limited to Japanese patients, HR=0.49 and P value=0.0882, suggesting a further significant effect of prolonging the time to dialysis shift by the combined use.

Comparative Example 3

[0131] In the CASSIOPEIR trial, in the patient groups who used ARB (telmisartan, valsartan, losartan, irbesartan, candesartan, olmesartan, or eprosartan) in combination, but did not use ACEI in combination, the hazard ratio and P value of the 240 μg BPS administration group when the time to dialysis shift was set as an event were HR=0.88 and P value=0.5401. The Japanese partial population showed HR=0.79 and P value=0.3597. In the ARB combined use group, no effect of prolonging the time to dialysis shift by the administration of BPS at 240 per day was observed.

Comparative Example 4

[0132] Further, in using, in combination, a calcium antagonist (amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, nitrepin, pranidipine, fendiline, gallopamil, verapamil, diltiazem, Micamlo Combination, Sevikar, ecroforge, or amlodipine) widely used as an antihypertensive agent, when BPS sustained-release tablets were administered at 240 μg per day, HR=0.85 and P value=0.3718 when the time to dialysis shift was set as an event. No effect of prolonging the time to dialysis shift was observed.

Example 4

[0133] As an indicator of patients with malnutrition, a BMI of less than 23 (see Table 2 below), which is one of the diagnostic criteria for PEW, was used. In the CASSIOPEIR trial, a patient group with a BMI of less than 23 showed HR=0.66 and P value=0.0411 when dialysis shift was set as an event. A significant effect of preventing dialysis shift by 240-μg administration was confirmed (FIG. 4).

TABLE-US-00002 TABLE 2 Diagnostic criteria Serum Serum albumin < 3.8 g/dl chemistry Serum prealbumin (transthyretin) < 30 mg/dl Serum cholesterol < 100 mg/dl Body mass BMI < 23 Unintended loss of body weight: 5%/3 months or 10%/ 6 months Body-fat percentage < 10% Muscle mass Muscle wasting: loss of muscle mass: 5%/3 months or 10%/6 months 10% or more decrease in arm muscle circumference Dietary intake Dietary protein intake < 0.6 g/kg/day continues for at least 2 months Dietary energy intake < 25 kcal/kg/day continues for at least 2 months

[0134] Further, Japanese patients with a BMI of less than 23 showed HR=0.38 and P value=0.0048, thus confirming a further significant effect of preventing dialysis shift (FIG. 5). Moreover, in the BPS sustained-release tablet administration group and the placebo group, no significant change in BMI was observed before and after administration. We confirmed that the above dialysis shift prevention effect was not caused by the change in BMI during the trial period. This finding was also observed when the event was renal death defined by dialysis shift or transplantation.

Comparative Example 5

[0135] Of all of the patients participating the CASSIOPEIR trial, patients with a BMI of 23 or more showed HR=1.38 and P value=0.0754 when dialysis shift was set as an event. The time to dialysis shift was not prolonged by the BPS sustained-release tablets. Even in the Japanese population, HR=1.06 and P value=0.8266; no effect of the BPS sustained-release tablets was observed.

Example 5

[0136] As an indicator of patients with malnutrition, a serum albumin level of less than 3.8 g/dl (Table 2), which is one of the diagnostic criteria for PEW, was used. Among the Japanese patients participating the CASSIOPEIR trial, patients with a serum albumin level of less than 3.8 g/dl showed HR=0.50 and P value=0.1567 when dialysis shift was set as an event. There was a tendency of preventing dialysis shift by 240-μg administration (FIG. 6). Further, in the BPS sustained-release tablet administration group and the placebo group, no change in serum albumin levels was observed before and after administration. We confirmed that the above dialysis shift prevention effect was not caused by the change in serum albumin levels.

[0137] Among the above patients, a patient group with an eGFR, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2, who corresponded to CKD stages 3b and 4 as CKD stages before the start of treatment, showed HR=0.43 and P=0.0273 when dialysis shift was set as an event, indicating further significant effectiveness of this drug. This finding was also observed when the event was renal death defined by dialysis shift or transplantation.

Comparative Example 6

[0138] Among the Japanese patients participating the CASSIOPEIR trial, patients with a serum albumin level of 3.8 g/dl or more showed HR=0.78 and P value=0.2656 when dialysis shift was set as an event. The HR was close to 1, and the time to dialysis shift was not prolonged at all by the BPS sustained-release tablets.

Example 6

[0139] Among the Japanese patients participating the CASSIOPEIR trial, patients with a total lymphocyte count of less than 1500/mm.sup.3 showed HR=0.62 and P value=0.0689 when dialysis shift was set as an event. There was a tendency of preventing dialysis shift by 240-μg administration (FIG. 7). Further, in the BPS sustained-release tablet administration group and the placebo group, no change in the lymphocyte count was observed before and after administration. We confirmed that the above dialysis shift prevention effect was not caused by the change in the lymphocyte count itself.

[0140] Among the above patients, a patient group with an eGFR, as calculated by the CKD-EPI equation, of 15 ml/min/1.73 m.sup.2 or more and less than 45 ml/min/1.73 m.sup.2, who corresponded to CKD stages 3b and 4 as CKD stages before the start of treatment, showed HR=0.52 and P value=0.0383. The effect of prolonging the time to dialysis shift was further significant. This finding was also observed when the event was renal death defined by dialysis shift or transplantation.

Comparative Example 7

[0141] Among the Japanese patients participating the CASSIOPEIR trial, patients with a total lymphocyte count of 1500/mm.sup.3 or more showed HR=0.83 and P value=0.5822 when dialysis shift was set as an event. The HR was close to 1, and the time to dialysis shift was not prolonged at all by the BPS sustained-release tablets.

Example 7

[0142] Among the Japanese patients participating the CASSIOPEIR trial, patients with a BMI of less than 23 and a serum albumin level of less than 3.8 g/dl showed HR=0.29 when dialysis shift was set as an event. As described in Examples 4 and 5, the Japanese patient group with a BMI of less than 23 showed HR=0.38, and the Japanese patient group with a serum albumin level of less than 3.8 g/dl showed HR=0.50. Thus, the effect of BPS was observed more significantly with some of the constituent elements of PEW, rather than with one of the constituent elements of PEW. This finding was also observed when the event was renal death defined by dialysis shift or transplantation.

Example 8

[0143] Among the Japanese patients participating the CASSIOPEIR trial, a patient group with a total lymphocyte count of less than 1500/mm.sup.3 and a serum albumin level of less than 3.8 g/dl showed HR=0.23 and P value=0.0404 when dialysis shift was set as an event. Compared to patients who satisfied only one criterion, i.e., a BMI of less than 23, a serum albumin level of less than 3.8 g/dl, or a total lymphocyte count of less than 1500/mm.sup.3, as the elements constituting nutritional disorders described in Examples 4, 5, and 6, in patients with more significant nutritional disorders having some of these constituent elements, a significant effect was observed in the group administered with BPS sustained-release tablets at 240 μg per day.