Patent Description:
Pentosan polysulfate sodium is a semisynthetic compound obtained by chemically modifying polysaccharides extracted from European beeches, and was initially developed as an anticoagulant in Germany. Currently, a liquid injection (SP54 (registered trademark)) and an encapsulated oral preparation (Elmiron (registered trademark)) are marketed as therapeutic agents for interstitial cystitis. Moreover, pentosan polysulfate sodium has been known to have an effect of treating arthritis in animals (Non-Patent Document <NUM>). A lyophilized pentosan polysulfate preparation has not been known in the past.

<CIT> relates to pentosan polysulfate having a uronic acid content of <NUM>% by mass to <NUM>% by mass.

<CIT> relates to physically and chemically stabilized polyatomic clusters for magnetic resonance image and spectral enhancement.

<CIT> relates to conjugate compounds of hyalauronic acid bonded to pentosan polysulfate which are shown to induce chondrogenic differentiation of a population of mesenchymal stem cells.

<CIT> relates to stabilized pentosan polysulfate formulations and methods of analyzing them.

While developing a therapeutic agent for human arthritis by using a pentosan polysulfate injection, the inventors of the present invention found that minute particles were generated due to delamination in an ampule of a pentosan polysulfate injection for treatment of human arthritis. Although a pentosan polysulfate injection has been used over the past <NUM> or more years, such findings had not been obtained. Accordingly, the present invention was achieved in order to prevent the occurrence of delamination in a pentosan polysulfate injection.

Based on the thought that using a lyophilized pentosan polysulfate sodium preparation makes it possible to prevent delamination in a pentosan polysulfate injection, the inventors of the present invention investigated various lyophilized preparations and various methods for manufacturing the lyophilized preparations. As a result, the inventors of the present invention succeeded in producing a lyophilized pentosan polysulfate preparation for the first time and found that delamination did not occur when the lyophilized preparation was reconstituted, and thus the present invention was completed.

The present invention relates to a lyophilized preparation for injection of pentosan polysulfate or a salt thereof, comprising pentosan polysulfate or a salt thereof, a buffer, and no cryoprotectants,.

In this specification, "pentosan polysulfate" is a polysaccharide that includes <NUM>-<NUM> linked β-D-xylanopyranose units as a basic skeleton and has a weight average molecular weight of <NUM> to <NUM> daltons or <NUM> to <NUM> daltons. For example, the pentosan polysulfate is represented by the formula below. <CHM>
(In this formula, R<NUM> and R<NUM> represent SOsH.

It is known that, in the pentosan polysulfate, one R<NUM> per n of about <NUM> to <NUM> may be a <NUM>-<NUM> linked acetyl-substituted β-D-xylanopyranose group represented by the formula below. Accordingly, the pentosan polysulfate sodium in this specification may include a polysaccharide represented by the formula above in which one R<NUM> per n of <NUM> to <NUM> (preferably <NUM> to <NUM> or <NUM> to <NUM>) on average is a <NUM>-<NUM> linked acetyl-substituted β-D-xylanopyranose group represented by the formula below.

Pentosan polysulfate is described in <NPL>; <CIT> and <CIT>; and <CIT>.

The pentosan polysulfate of the present invention includes sulfate groups and thus forms a salt with a base. Accordingly, the pentosan polysulfate salt of the present invention is the sodium salt of pentosan polysulfate. The term "pharmacologically acceptable salt" refers to a salt that is formed by the pentosan polysulfate of the present invention binding to an inorganic or organic base and is acceptable as a medicine to be administered to the body. Such salts are, for example, described in<NPL>) and so on. Examples of further salts include salts formed with alkali metals and alkali earth metals such as zinc, lithium, sodium, potassium, magnesium, calcium, silver, lead, copper, gold, palladium, and barium; salts formed with amines such as ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, <NUM>-amino-<NUM>-methyl-<NUM>-propanol, ethanolamine, N-methylglucamine, and L-glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine, and arginine. Specific examples thereof include pentosan polysulfate sodium, pentosan polysulfate calcium, and pentosan polysulfate potassium, wherein pentosan polysulfate sodium is the salt according to the invention.

The lyophilized preparation of the present invention contains pentosan polysulfate sodium (R<NUM> and R<NUM> represent SOsNa in Formula (I)) such that its concentration after reconstitution is <NUM> to <NUM>/mL, and preferably <NUM> to <NUM>/mL, <NUM> to <NUM>/mL, or <NUM>/mL.

The lyophilized preparation of the present invention contains a phosphate buffer comprising disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate. In this specification, the "buffer" means a substance that serves to adjust a pH to be within a target value range when the lyophilized preparation of the present invention is reconstituted and that can be administered as a medicine to mammals. Examples of buffers include, but are not limited to, a borate buffer (containing sodium borate and sodium hydroxide), a phosphate buffer (containing sodium dihydrogen phosphate and disodium hydrogen phosphate), a carbonate-bicarbonate buffer (containing sodium carbonate and sodium hydrogen carbonate), a citrate buffer (containing sodium citrate and citric acid), an acetate buffer (containing acetic acid and sodium acetate), a succinate buffer, a histidine buffer, a tartrate buffer, HBSS, tris(hydroxymethyl)aminomethane (THAM), a citrate/phosphate buffer, a barbital buffer, a Britton-Robinson buffer, a cacodylate buffer, a collidine buffer, a formate buffer, a maleate buffer, a Mcllvaine buffer, a Prideaux-Ward buffer, a citratephosphate-borate buffer (Teorell-Stanhagen buffer), a veronal acetate buffer, a MES (<NUM>-(N-morpholino)ethanesulfonic acid) buffer, a BIS-TRIS (bis(<NUM>-hydroxyethyl)iminotris(hydroxymethyl)methane) buffer, an ADA (N-(<NUM>-acetamido)-<NUM>-iminodiacetic acid) buffer, an ACES (N-(carbamoylmethyl)-<NUM>-aminoethanesulfonic acid (sulfonaic acid)) buffer, a PIPES (piperazine-N, N'-bis(<NUM>-ethanesulfonic acid)) buffer, a MOPSO (<NUM>-(N-morpholino)-<NUM>-hydroxypropanesulfonic acid) buffer, a BIS-TRIS PROPANE (<NUM>,<NUM>-bis(tris(hydroxymethyl)methylamino) propane) buffer, a BES (N,N-bis(<NUM>-hydroxyethyl)-<NUM>-aminoethanesulfonic acid (sulfonaic acid)) buffer, a MOPS (<NUM>-(N-morpholino)propanesulfonic acid) buffer, a TES (N-tris(hydroxymethyl)methyl-<NUM>-aminoethanesulfonic acid) buffer, a HEPES (N-(<NUM>-hydroxyethyl)piperazine-N'-<NUM>-ethanesulfonic acid) buffer, a DIPSO (<NUM>-(N,N-bis(<NUM>-hydroxyethyl)amino)-<NUM>-hydroxypropanesulfonic acid) buffer, a MOBS (<NUM>-(N-morpholino)butanesulfonic acid) buffer, a TAPSO (<NUM>-(N-tris(hydroxymethyl)methylamino)-<NUM>-hydroxypropanesulfonic acid) buffer, a tris(hydroxymethylaminomethane) buffer, a HEPPSO (N-(<NUM>-hydroxyethyl)piperazine-N'-<NUM>-hydroxypropanesulfonic acid) buffer, a POPSO (piperazine-N,N'-bis(<NUM>-hydroxypropanesulfonic acid)) buffer, a TEA (triethanolamine) buffer, an EPPS (N-(<NUM>-hydroxyethyl)piperazine-N'-<NUM>-propanesulfonic acid) buffer, a TRICINE (N-tris(hydroxymethyl)methylglycine) buffer, a GLY-GLY (glycylglycine) buffer, a BICINE (N,N-bis(<NUM>-hydroxyethyl)glycine) buffer, a HEPBS (N-(<NUM>-hydroxyethyl)piperazine-N'-(<NUM>-butanesulfonic acid)) buffer, a TAPS (N-tris(hydroxymethyl)methyl-<NUM>-aminopropanesulfonic acid) buffer, and an AMPD (<NUM>-amino-<NUM>-methyl-<NUM>,<NUM>-propanediol) buffer. In the present invention the buffer is a phosphate buffer.

The lyophilized preparation of the present invention may contain a buffer such that the pH after reconstitution is <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>.

The lyophilized preparation of this specification contains a pH adjuster as needed. Examples of the pH adjuster include potassium hydroxide, sodium hydroxide, lactic acid, hydrochloric acid, adipic acid, aqueous ammonia, dry sodium carbonate, diluted hydrochloric acid, a citric acid hydrate, a sodium citrate hydrate, sodium dihydrogen citrate, glycine, glucono-δ-lactone, gluconic acid, crystalline sodium dihydrogen phosphate, succinic acid, acetic acid, ammonium acetate, a sodium acetate hydrate, diisopropanolamine, tartaric acid, D-tartaric acid, L-sodium tartrate, calcium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, a sodium carbonate hydrate, triisopropanolamine, triethanolamine, carbon dioxide, a calcium lactate hydrate, sodium lactate, glacial acetic acid, monosodium fumarate, sodium propionate, boric acid, ammonium borate, borax, maleic acid, anhydrous citric acid, anhydrous sodium acetate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, meglumine, methanesulfonic acid, monoethanolamine, sulfuric acid, a potassium aluminum sulfate hydrate, DL-malic acid, phosphoric acid, trisodium phosphate, a sodium hydrogen phosphate hydrate, dipotassium phosphate, potassium dihydrogen phosphate, and sodium dihydrogen phosphate.

The lyophilized preparation of the present invention does not contain a saccharide cryoprotectant. In particular, common lyophilized preparations require a cryoprotectant such as a saccharide (e.g., maltose or mannitol) to maintain the stability, whereas the lyophilized preparation of this specification contains no cyroprotectants but can be provided as a stable preparation. Accordingly, the present invention includes a lyophilized preparation containing no saccharide cryoprotectants.

The lyophilized preparation of the present invention contains pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate such that their concentrations after reconstitution are <NUM> to <NUM>/mL (preferably <NUM> to <NUM>/mL, <NUM> to <NUM>/mL, or <NUM>/mL), <NUM> to <NUM>/mL, and <NUM> to <NUM>/mL, respectively. More preferably, the lyophilized preparation of the present invention contains pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate such that their concentrations after reconstitution are <NUM>/mL, <NUM>/mL, and <NUM>/mL, respectively. The lyophilized preparation of the present invention may contain pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate at a mass ratio of <NUM> to <NUM> : <NUM> to <NUM> : <NUM> to <NUM>, or at a mass ratio of <NUM>:<NUM>:<NUM>. Alternatively, the lyophilized preparation of the present invention may contain pentosan polysulfate sodium, disodium hydrogen phosphate, and sodium dihydrogen phosphate at a mass ratio of <NUM> to <NUM> : <NUM> to <NUM> : <NUM> to <NUM>, or at a mass ratio of <NUM>:<NUM>:<NUM>.

The lyophilized preparation of the present invention can be manufactured by lyophilizing an aqueous solution containing pentosan polysulfate sodium and additives such as a buffer according to claim <NUM>.

Pentosan polysulfate sodium can be obtained by reacting xylan extracted from bark of a plant such as beech with a sulfating agent such as chlorosulfonic acid or chlorosulfuric acid to form a sulfate and treating the resultant sulfate using sodium hydroxide. Also, pentosan polysulfate sodium can be manufactured in consideration of <CIT>, <CIT>, and <CIT>. Moreover, novel methods for manufacturing pentosan polysulfate sodium (<CIT>; <CIT>; <CIT>; <CIT>) are also reported, and pentosan polysulfate sodium may be manufactured in consideration of these methods.

For example, the lyophilized preparation of the present invention can be manufactured as a preparation that is stabler or is easy to reconstitute by lyophilizing an aqueous solution containing pentosan polysulfate sodium and a buffer at concentrations that are <NUM> to <NUM> times (preferably <NUM> times) as high as those after reconstitution. For example, the lyophilized preparation of the present invention can be manufactured by lyophilizing an aqueous solution containing pentosan polysulfate sodium at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL), disodium hydrogen phosphate dodecahydrate at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL), and sodium dihydrogen phosphate dihydrate at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL).

Acording to claim <NUM>, the present invention encompasses such an aqueous solution to be used to manufacture a lyophilized preparation. Preferably, the aqueous solution to be used to manufacture the lyophilized preparation of the present invention is an aqueous solution containing pentosan polysulfate sodium and a buffer at concentrations that are <NUM> to <NUM> times (preferably <NUM> times) as high as those after reconstitution. The aqueous solution of the invention, which may be used to manufacture the lyophilized preparation of the present invention contains pentosan polysulfate sodium at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL), disodium hydrogen phosphate dodecahydrate at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL), and sodium dihydrogen phosphate dihydrate at a concentration of <NUM> to <NUM>/mL (preferably <NUM> to <NUM>, <NUM> to <NUM>, or <NUM>/mL).

Lyophilization can commonly include a preliminary freezing step, a primary drying step, and a secondary drying step. In the preliminary freezing step, freezing is commonly performed at a temperature that is lower than or equal to the eutectic point. For example, the preliminary freezing step can be performed at a constant temperature, but the temperature can also be changed as appropriate. In this specification, the preliminary freezing step can preferably include a step performed at -<NUM> to -<NUM> for <NUM> minutes to <NUM> hours, a step performed at -<NUM> to -<NUM> for <NUM> to <NUM> hours, and a step performed at -<NUM> to -<NUM> for <NUM> minutes to <NUM> hours in the stated order.

The primary drying step is a step of sublimating frozen water under reduced pressure. It is known that water boils at <NUM> under a pressure of <NUM> Pa, and a sublimation temperature decreases as the atmospheric pressure decreases. According to the present invention, the primary drying step is performed at -<NUM> to -<NUM>. In this specification, the primary drying step is preferably performed at <NUM> to <NUM> Pa and -<NUM> to -<NUM>, more preferably at <NUM> to <NUM> Pa and -<NUM> to -<NUM>, and most preferably at <NUM> Pa and -<NUM>. There is no particular limitation on the period of the primary drying step as long as all of the contained water can be sublimated, and the period can be set to <NUM> to <NUM> hours or <NUM> to <NUM> hours, for example. This may also be applied to a case of ten thousand <NUM>-mL ampules.

The secondary drying step is a dehumidifying step for removing remaining water by increasing the temperature at lower pressure. In this specification, the secondary drying step is preferably performed by gradually increasing the temperature under a full vacuum environment. For example, the secondary drying step may be performed by increasing the temperature to <NUM> to <NUM> under a full vacuum environment and then keeping the temperature at <NUM> to <NUM> for <NUM> hours.

The sterilization degree or stability of the obtained lyophilized preparation can be maintained through capping, aluminum cap sealing, or the like, as needed.

This lyophilized preparation is excellent in stability required to supply the lyophilized preparation as a medicine. Specifically, the lyophilized preparation of this specification is stable at <NUM>±<NUM> and <NUM>%RH, which are known as the conditions of an acceleration test, for at least <NUM> months. In the medicine stability test, one month in an acceleration test is considered to correspond to <NUM> months of storage at ordinary temperatures and pressures, and therefore, this lyophilized preparation is stable at ordinary temperatures and pressures for <NUM> months. It is possible to confirm whether or not a lyophilized preparation to be tested is stable as described above by storing the lyophilized preparation at <NUM>±<NUM> and <NUM>% RH for <NUM> months and then analyzing whether or not the lyophilized preparation itself and a solution obtained by reconstituting the lyophilized preparation satisfy the specifications set for the preparation. When the preparation satisfies the specifications after the storage, it is determined that the preparation is stable under such storage conditions. Examples of the items of such specifications include the external appearance, the clarity and color, the average mass, the uniformity of mass, the uniformity of an administration unit, the mixing of minute particles (into the reconstituted solution): invisible minute particles, the mixing of minute particles (into the reconstituted solution): visible minute particles, the pH value (of the reconstituted solution), the drying loss, the transparency, the identification of a phosphate, the identification of pentosan polysulfate sodium (PPS) by gel permeation chromatography (GPC) and wet chemical analysis, the purity of sodium sulfate (IC), the purity (GPC), the purity of calcium, the PPS assay (GPC), the sterility, and the bacterial endotoxin. The following describes specific examples of the standards of these items: the external appearance: a white to bright yellow lyophilized product; the clarity and color: colorless to light yellow clear solution; the uniformity of mass: up to ±<NUM>% for <NUM> ampules, and up to ±<NUM>% for <NUM> ampules (average mass deviation); the acceptable value (AV) of the uniformity of an administration unit (Ph. <NUM>): based on Ph. ; the mixing of minute particles (into the reconstituted solution) (invisible minute particles) (Ph. <NUM>): up to <NUM> minute particles with a diameter of <NUM> pm or more per ampule, and up to <NUM> minute particles with a diameter of <NUM> pm or more per ampule; the mixing of minute particles (into the reconstituted solution) (visible minute particles) (Ph. <NUM>): no minute particles contained; the pH value (of the reconstituted solution) (Ph. <NUM>): <NUM> to <NUM>; the identification of a phosphate (Ph. <NUM>): Yes; the identification of PPS (GPC): retention time of a main peak in a chromatogram of a sample solution corresponds to retention time of a standard solution; the identification of PPS (wet chemical analysis): red to purple; the purity of sodium sulfate (IC): less than <NUM>% when calculated from the applied PPS content; the purity (GPC): no additional peaks; the PPS assay (GPC): <NUM> to <NUM>% when calculated from the applied PPS content; the sterility (Ph. <NUM>): based on Ph. ; and the bacterial endotoxin (Ph. <NUM>): less than <NUM> IU/ml.

The lyophilized preparation of the present invention can be reconstituted by adding a sterile aqueous diluent, preferably sterile water, thereto and mixing them. The present invention includes a method for preparing a liquid pharmaceutical composition containing pentosan polysulfate sodium, the method including reconstituting the above-mentioned lyophilized preparation in a sterile aqueous diluent according to claim <NUM>. The method for preparing a liquid pharmaceutical composition containing pentosan polysulfate sodium of the present invention includes adding a sterile aqueous diluent to a lyophilized preparation such that the concentration of pentosan polysulfate sodium is <NUM> to <NUM>/mL, and preferably <NUM> to <NUM>/mL, <NUM> to <NUM>/mL, or <NUM>/mL.

Also, the present invention encompasses a liquid pharmaceutical composition obtained through the reconstitution. In this specification, the terms "reconstituted solution", "reconstituted liquid pharmaceutical composition", and "liquid pharmaceutical composition obtained through reconstitution" are the same in meaning. It is more preferable that the liquid pharmaceutical composition contains pentosan polysulfate sodium, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate such that their concentrations after reconstitution are <NUM>/mL, <NUM>/mL, and <NUM>/mL, respectively. Also, the pH of the liquid pharmaceutical composition is preferably <NUM> to <NUM>.

The lyophilized preparation or reconstituted liquid pharmaceutical composition of the present invention can be used for humans and mammals such as oxen, deer, horses, donkeys, wild boars, pigs, sheep, goats, dogs, cats, raccoon dogs, foxes, rabbits, mice, and squirrels for medical purposes (treatment purposes or prevention purposes). For example, the lyophilized preparation of the present invention is for use as a therapeutic agent or preventive agent in the treatment or prevention of interstitial cystitis, osteoarthritis, lysosomal disease, and human lymphotropic virus type <NUM> (HTLV-<NUM>) associated myelopathy (HAM); or for use as an anticoagulant in a human or mammal. For example, <CIT> discloses that pentosan polysulfate sodium has anti-TNFα activity and is effective at treating lysosomal disease. Lysosomal disease refers to a disease or disorder caused by the accumulation or presence of lysosomal enzymes due to abnormality in lysosomal enzymes. Examples of lysosomal disease include type-II glycogenosis, Pompe disease, α-glucosidase (acid maltase) deficiency, sphingolipidosis, GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease), metachromatic leukodystrophy (MLD), Fabry disease, Farber disease, Gaucher disease, Niemann-Pick disease (A, B, C types), Krabbe disease, mucopolysaccharidosis, mucolipidosis, multiple sulfatase deficiency (MSD), sialidosis, galactosialidosis, I-cell disease, α-mannosidosis, β-mannosidosis, fucosidosis, aspartylglucosaminuria, Schindler disease, Wolman disease, Danon disease, free sialic acid storage disease, and ceroid lipofuscinosis.

Also described herein is composition for use in a method of treating or preventing interstitial cystitis, osteoarthritis, lysosomal disease, or HAM, the method including administering an effective amount of a liquid pharmaceutical composition obtained by reconstituting the lyophilized preparation of the present invention to patients in need thereof. The term "patients in need thereof' means patients who are affected with or are likely to be affected with these diseases. Patients who are affected with these diseases and need to be treated are preferable. For example, when the above-mentioned liquid pharmaceutical composition is for use in therapeutic purposes or preventive purposes, the liquid pharmaceutical composition can be administered in the parenteral administration form such as an injection or infusion. The dose varies depending on the symptom, age, sex, weight, administration form, and the like, and when the composition is orally administered, for example, the daily dose per adult is commonly <NUM> to <NUM>.

Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to these examples.

First, <NUM> of disodium hydrogen phosphate dodecahydrate was added to <NUM> of water for injection, and then <NUM> of sodium dihydrogen phosphate dihydrate was added thereto. Next, <NUM> of pentosan polysulfate sodium was added to the resultant phosphate buffer and dissolved. Water for injection was added thereto, and then the pH was adjusted to <NUM> to <NUM> using <NUM> mol/L hydrochloric acid and <NUM> mol/L sodium hydroxide. Water for injection was added such that the total quantity was <NUM> and the resultant solution was stirred. The solution was sterilized using a <NUM>-pm filter and was then filled into vials such that each vial contained <NUM> of the solution.

The vials were half-capped with rubber stoppers, and then lyophilization was performed using a K1 lyophilizer (DFB-60R-07ASC) under the following conditions.

Preliminary freezing: reducing the temperature from room temperature to -<NUM> or lower (about -<NUM>); keeping the temperature at -<NUM> or lower (about -<NUM>) for <NUM> hour; increasing the temperature to -<NUM>; keeping the temperature at -<NUM> for <NUM> hours; reducing the temperature from -<NUM> to -<NUM> or lower (about -<NUM>); keeping the temperature at -<NUM> (about -<NUM>) for <NUM> hour.

Primary drying: performed at a pressure of <NUM> Pa throughout, increasing the temperature from -<NUM> or lower (about -<NUM>) to -<NUM> over <NUM> hours; keeping the temperature at -<NUM> for <NUM> hours.

Secondary drying: performed under reduced pressure (full vacuum condition) throughout, increasing the temperature from -<NUM> to <NUM>; keeping the temperature at <NUM> for <NUM> hours.

After recovery of the pressure through N2 substitution, the vials were taken out and sealed with aluminum caps. Thus, the lyophilized pentosan polysulfate sodium preparation was obtained.

The lyophilized pentosan polysulfate sodium preparation manufactured using the method of Example <NUM> was stored at <NUM> and <NUM>%RH for <NUM> months, and then the stability thereof was evaluated (acceleration test).

Table <NUM> shows the results. It was shown that the lyophilized preparation met the standards of all of the evaluation items after <NUM>-month storage. In particular, mixing of minute particles (visible minute particles) was never observed during the <NUM>-month storage period, and thus it was also found that delamination did not occur.

Claim 1:
A lyophilized preparation for injection of pentosan polysulfate or a salt thereof, comprising pentosan polysulfate or a salt thereof, a buffer, and no cryoprotectants,
wherein the buffer is a phosphate buffer and comprises disodium hydrogen phosphate dodecahydrate in an amount such that the concentration is <NUM> to <NUM>/mL after reconstitution, and sodium dihydrogen phosphate dihydrate in an amount such that the concentration is <NUM> to <NUM>/mL after reconstitution, and
wherein the cryoprotectant is saccharide, and
wherein the salt of pentosan polysulfate is pentosan polysulfate sodium that is present in an amount such that the concentration is <NUM> to <NUM>/mL after reconstitution.