HK40113604A - Pharmaceutical composition - Google Patents

Description

Pharmaceutical Composition

This application is a divisional application of the original patent application filed on September 18, 2020 (priority date September 20, 2019), with original application number 202080064874.7 (international application number PCT/JP2020/035438) and entitled "Pharmaceutical Composition".

Technical Field

This invention relates to pharmaceutical compositions comprising a specified polysaccharide used as a nasal polyp shrinking agent, or methods for treating nasal polyps using a specified polysaccharide, etc.

Background Technology

Nasal polyps, also known as nasal polyposis, are fleshy growths of the nasal mucosa that form at sites of dependent edema (usually around the opening of the maxillary sinuses) in the lamina propria. This condition often co-occurs with chronic sinusitis, exacerbating the nasal congestion symptoms of chronic sinusitis, and is one of the major nasal diseases (MSD manual professional version, https://www.msdmanuals.com/ja-jp).

Regarding the causes of nasal polyps, various factors are considered, including edema caused by increased vascular permeability, prolapse of the lamina propria of the mucosa, and accumulation of extracellular matrix. Furthermore, associations with various cytokines or growth factors have been reported. As growth factors, the association between vascular endothelial growth factor or platelet-derived growth factor and nasal polyps has been reported (Non-patent literature 1: Kawasaki Medical Association Journal 35(1):39-50, 2009).

Chronic sinusitis can cause respiratory symptoms such as nasal congestion, nasal discharge, postnasal discharge, and cough for more than 3 months. Its causes include viral or bacterial, fungal, allergic, or eosinophilic sinusitis of unknown cause. In addition, it can also be caused by different nasal cavity morphology or the influence of living environment, genetics and other factors, resulting in a complex condition including the formation of nasal polyps (Non-Patent Literature 2: Journal of the Japanese Society of Otorhinolaryngology 2018, 121, 1118-1120).

Chronic sinusitis can be accompanied by nasal polyps in both eosinophilic and non-eosinophilic sinusitis. Eosinophilic sinusitis is a designated intractable condition, characterized by severe nasal congestion and olfactory dysfunction due to multiple bilateral nasal polyps and thick nasal discharge; it is a refractory sinusitis affecting adults. Antibiotics are ineffective in treating this condition; only oral steroids provide a response. Because the nasal cavity is filled with polyps, surgical removal of the polyps is performed, but immediate recurrence is a concern.

As a drug therapy for nasal polyps, the use of topical steroids, systemic steroids, monoclonal antibodies or antagonists against interleukin-4 (Patent Document 1: Japanese Patent 6463351), interferon (Patent Document 2: Japanese Patent Application Publication No. 09-104636), aspirin powder (Patent Document 3: Japanese Patent Application Publication No. 10-203988) and/or hyaluronic acid (Non-Patent Document 3: Indian Journal of Otolaryngology and Head & Neck Surgery 67(3):299-307, September 2015) has been reported.

On the other hand, it has been reported that heparin, which has anticoagulant effects, significantly inhibits mucus production or neutrophil infiltration in a rat nasal mucosal inflammation model (Non-Patent Literature 4: Otorhinolaryngology 29(3):221-227,2011), but it did not show a shrinkage effect on nasal polyps collected from patients with eosinophilic sinusitis (Non-Patent Literature 5: Allergology International 66(2017)594-602).

Existing technical documents

Patent documents

Patent document 1: Japanese Patent 6463351;

Patent Document 2: Japanese Patent Application Publication No. 09-104636;

Patent Document 3: Japanese Patent Application Publication No. 10-203988;

Non-patent literature

Non-patent literature 1: Kawasaki Medical Association Journal 35(1): 39-50, 2009;

Non-patent literature 2: Journal of the Japanese Society of Otorhinolaryngology 2018, 121, 1118-1120;

Non-patent literature 3: Indian Journal of Otolaryngology and Head & Neck Surgery 67(3):299-307, September 2015;

Non-patent document 4: Otolaryngology Immunology 29(3):221-227, 2011;

Non-patent literature 5: Allergology International 66(2017)594-602.

Summary of the Invention

The problem that the invention aims to solve

This invention provides a nasal polyp shrinking agent or a method for treating nasal polyps that exhibits excellent shrinkage effects and is safe.

Methods for solving problems

Through in-depth research, the inventors discovered that specified polysaccharides, particularly heparinoids or polysulfated pentosans (PPS), which are sulfated polysaccharides, significantly reduce nasal polyps, thus completing this invention.

That is, the present invention is as follows.

(1) Nasal polyp shrinking agent, the active ingredient of which is a polysaccharide or its salt selected from polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan, inulin and xylooligosaccharide.

(1a)(1) The nasal polyp shrinking agent, wherein the polysaccharide or its salt is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan and inulin.

(1b) Nasal polyp shrinking agent, which uses sulfated polysaccharide or its salt as active ingredient.

(1c)(1b) The nasal polyp shrinking agent, wherein the sulfated polysaccharide or its salt is selected from chondroitin sulfate polysulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate and pentosan sulfate.

(2)(1b) The nasal polyp shrinking agent, wherein the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose and L-arabinose, and the monosaccharide may be partially acetylated.

(3)(1b) or (2) the nasal polyp shrinking agent, wherein the sulfated polysaccharide is chondroitin sulfate polysulfate, dermatin sulfate polysulfate or pentosan polysulfate.

The nasal polyp shrinking agent described in any one of (4), (1) to (3) is administered intranasally.

(5) A pharmaceutical composition for reducing nasal polyps in patients with chronic sinusitis, comprising a polysaccharide selected from chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sulfate, dextran sulfate, pentosan sulfate, chondroitin, glucomannan, inulin and xylooligosaccharides or their salts.

The pharmaceutical composition of (5a)(5) wherein the polysaccharide is selected from chondroitin sulfate polysulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, pentosan polysulfate, chondroitin, glucomannan and inulin.

(5b) A pharmaceutical composition comprising a sulfated polysaccharide or a salt thereof for reducing nasal polyps in patients with chronic sinusitis.

(6)(5b) The pharmaceutical composition thereof, wherein the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose and L-arabinose, wherein the monosaccharide may be partially acetylated.

The pharmaceutical composition of (7)(5b) or (6), wherein the sulfated polysaccharide is chondroitin sulfate polysulfate, dermatin sulfate polysulfate, or pentosan polysulfate.

The pharmaceutical composition of any one of (8), (5) to (7), wherein the patient with chronic sinusitis is an eosinophilic sinusitis patient or a non-eosinophilic sinusitis patient.

The pharmaceutical composition of any one of (9)(5) to (8), wherein the patient with chronic sinusitis is an eosinophilic sinusitis patient.

(10) An intranasal administration preparation comprising any one of (5) to (9) a pharmaceutical composition.

(11) A method for treating nasal polyps, which involves administering to a patient in need of treatment an effective amount of a polysaccharide or salt thereof selected from polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan, inulin and xylooligosaccharide.

(12)(11) The method wherein the polysaccharide or its salt is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan and inulin.

(13) A method for reducing nasal polyps, which includes administering an effective amount of sulfated polysaccharide or its salt to a patient who needs treatment for nasal polyps.

(14)(13) The method wherein the sulfated polysaccharide or its salt is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate and polysulfated pentosan.

(15)(13) The method wherein the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose and L-arabinose, wherein the monosaccharide is partially acetylated.

(16)(13) The method wherein the sulfated polysaccharide is chondroitin sulfate polysulfate, dermatan sulfate polysulfate, or pentosan polysulfate.

(17)(11) The method described above, wherein the patient suffers from sinusitis.

(18)(11) The method wherein the above-mentioned patient has chronic sinusitis with eosinophilic sinusitis or non-eosinophilic sinusitis.

The method described in (19)(11) wherein the patient has eosinophilic sinusitis.

(20)(11) The method of administration is to administer the drug via the nasal cavity.

Invention Effects

Specified polysaccharides, especially sulfated polysaccharides such as heparin-like substances or polysulfated pentosans, can be used as effective and safe nasal polyp shrinking agents at low doses.

Attached Figure Description

[Figure 1] Shows the changes in nasal polyp weight at different doses of heparin (0.3, 30 and 3000 μg/mL).

[Figure 2] Shows the changes in nasal polyp weight at various doses of heparin (0.003, 0.03, 0.3 and 30 μg/mL).

[Figure 3] Shows the change in nasal polyp weight under 0.003 μg/mL polysulfated pentosan (PPS).

Detailed Implementation

The present invention will now be described in detail.

The polysaccharides used in this invention are: sulfated mucopolysaccharides selected from polysulfated mucopolysaccharides such as chondroitin sulfate, chondroitin, dermatan sulfate, keratin sulfate, heparan sulfate, and polysulfated chondroitin sulfate; sulfated mucopolysaccharides further comprising dextran sulfate and polysulfated pentosans; and polysaccharides selected from glucomannan, inulin, and xylooligosaccharides. Preferably, the polysaccharides are selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosans, chondroitin, glucomannan, and inulin.

The sulfated polysaccharides of this invention are composed of monosaccharides selected from D-glucosamine, D-galactosamine, D-glucuronic acid, L-iduronic acid, D-galacturonic acid, D-glucose, D-galactose, D-xylose, and L-arabinose. These monosaccharides can be partially acetylated, and the polysaccharides, which are repeating units of one or more of these monosaccharides, contain sulfate groups. The sulfated polysaccharides used in this invention have an average of 0.55 to 4 sulfate groups per molecule of monosaccharide, preferably an average of 0.6 to 2.9 molecules, and more preferably an average of 0.7 to 2 molecules.

Furthermore, the sulfate content of the sulfated polysaccharide used in this invention is preferably 10 to 70 w/w, as determined by the quantitative method specified in the "heparinoid" section of the Japanese Pharmacopoeia Standard for Non-Pharmacopoeia 2002, and more preferably a sulfated polysaccharide with an organic sulfate content of 10 to 65 w/w.

Preferably, the main monosaccharide is selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose, and L-arabinose, and this monosaccharide is a sulfated polysaccharide that can be partially acetylated. More preferably, it is a sulfated polysaccharide composed of monosaccharides selected from D-galactosamine, D-glucuronic acid, D-glucose, D-galactose, D-xylose, and L-arabinose.

It should be noted that, as partially acetylated monosaccharides, such as naturally occurring monosaccharides, examples include: acetylglucosamine, N-acetylglucosamine, acetylglucose, N-acetylglucosamine, acetylxose, etc.

The sulfated polysaccharide or its salt used in this invention has a weight-average molecular weight of about 1,000 to 10,000,000, preferably about 4,000 to 1,000,000.

The weight-average molecular weight used in this specification, in the case of Ni polymers with a molecular weight of Mi, refers to the value expressed by the following formula:

Weight average molecular weight (Mw)=Σ(Ni·Mi ² )/Σ(Ni·Mi).

Weight-average molecular weight (MAM) refers to the value obtained by gel permeation chromatography (GPC). For example, MAM is the MA converted from pullulan or polyethylene glycol as a standard obtained by GPC determination using pullulan or polyethylene glycol as a standard. MAM determination can be performed, for example, by high-performance liquid chromatography (HPLC) (Waters or Shimadzu Corporation), using Ohpak SB-804 and SB-803 columns (both manufactured by Showa Denko Corporation). As the mobile phase, an aqueous solvent such as ammonium acetate aqueous solution or sodium chloride aqueous solution can be used, with a flow rate set to 1.0 mL/min. Differential refractive index can be used in the detection method.

The various sulfated polysaccharides used in this invention are obtained by the following methods.

Sulfated polysaccharides are obtained by sulfation of polysaccharides composed of partially acetylated monosaccharides and the introduction of sulfate groups.

The sulfation reaction is carried out as follows: Prepare 10–30 mL of ice-cold solvent relative to 1 g of the raw polysaccharide. Add 2–6 times the amount of sulfating agent relative to 1 g of the raw polysaccharide to this solvent. Add 1 g of the raw polysaccharide to this solution and allow it to react at 0°C–100°C for 1–10 hours to carry out sulfation. Pyridine, N,N-dimethylformamide, N,N-dialkylacrylamide, etc., can be used as the solvent, and chlorosulfonic acid, triethylamine-sulfur trioxide complex salt, etc., can be used as the sulfating agent.

The sulfated polysaccharide used in this invention, which is composed of partially acetylated monosaccharides, preferably has 0% to 60% (molar ratio) of its constituent sugars N-acetylated or O-acetylated.

In this invention, sulfated polysaccharides can be used in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include: alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts; and magnesium salts, as well as a variety of their salts.

Examples of sulfated polysaccharides in this invention include: sulfated mucopolysaccharides, sulfated dextran, and polysulfated pentosans. Preferred alternatives include polysulfated chondroitin sulfate, chondroitin sulfate, chondroitin, dermatan sulfate, keratin sulfate, heparan sulfate, sulfated dextran, and polysulfated pentosans.

In this application specification, chondroitin sulfate, chondroitin, dermatan sulfate, keratin sulfate, heparan sulfate, and polysulfated chondroitin sulfate, etc., are classified as sulfated mucopolysaccharides.

In addition, glucomannan, inulin, and xylooligosaccharides are classified as polysaccharides that do not meet the above criteria.

"Mucopolysaccharide" refers to a long-chain amino sugar with a basic structure consisting of repeating disaccharide units composed of hexosamine and uronic acid or galactose.

"Sulfated mucopolysaccharide" refers to a mucopolysaccharide containing a sulfate group. The sulfated mucopolysaccharide of the present invention also includes: a naturally occurring mucopolysaccharide with a sulfate group in its sugar chain, and a substance obtained by further chemically modifying the mucopolysaccharide or the naturally occurring sulfated mucopolysaccharide.

"Polysulfated mucopolysaccharides" are sulfated mucopolysaccharides that have more sulfate groups in their sugar chains. In addition to naturally occurring polysulfated mucopolysaccharides, they also include substances obtained by further chemically sulfating mucopolysaccharides or naturally occurring sulfated mucopolysaccharides.

The following describes examples of sulfated mucopolysaccharides, whose overall structure exhibits polymorphism depending on the type of proteoglycan formed from these sulfated mucopolysaccharides, the animal species, tissue, and developmental stage in which they are present. That is, naturally occurring mucopolysaccharides or sulfated mucopolysaccharides are sometimes further modified in the structures described below, which form the basic structure of these sulfated mucopolysaccharides, or a portion thereof may have structures or sugars other than the basic structure. The sulfated mucopolysaccharides used in this invention also include such variants.

In a broad sense, "hexosamine" refers to compounds obtained by replacing the hydroxyl group of a hexose with an amino group. Specifically, examples include D-glucosamine and D-galactosamine.

In addition, "uronic acid" in a broad sense refers to substances obtained by oxidizing the primary alcohol of aldose to a carboxyl group. Specifically, examples include D-glucuronic acid, L-iduronic acid, D-galacturonic acid, and other naturally occurring uronic acids.

"Chondroitin sulfate" is a substance isolated from the viscous secretions or cartilage tissue of animals. Based on the bonding positions of the sugar and sulfate groups, it is classified as chondroitin sulfate A, C, D, E, etc. However, in this application, chondroitin sulfate A and C are classified as sulfated mucopolysaccharides, while chondroitin sulfate D and E are sulfated mucopolysaccharides that are also classified as polysulfated mucopolysaccharides.

Chondroitin sulfate A (4-chondroitin sulfate) has a basic structure consisting of a repeating disaccharide of N-acetyl-D-galactosamine (GalNAc) and D-glucuronic acid (GlcA) with a sulfate group at the 4 position.

Chondroitin sulfate C (6-chondroitin sulfate) has a repeating structure of disaccharides GalNAc and GlcA with sulfate groups at the 6-position as its basic structure.

Chondroitin sulfate A and C are preferred.

Alternatively, low-molecular-weight chondroitin sulfate, obtained by reducing the weight average molecular weight of chondroitin sulfate to below 100,000, preferably between 10,000 and 50,000, can also be used. Low-molecular-weight chondroitin sulfate is obtained by degrading natural chondroitin sulfate using enzymes such as chondroitinase or chondroitin sulfate lyase.

"Dermatan sulfate" is composed of a repeating disaccharide of iduronic acid (IdoUA) and GalNAc, with a basic structure having a sulfate group at the 4 position of GalNAc. It is sometimes also called chondroitin sulfate B.

"Keratin sulfate" is composed of repeating disaccharides formed by alternating β(1→4) and β(1→3) bonds of galactose (Gal) and N-acetyl-D-glucosamine (GlcNAc), respectively. The 6-position of GlcNAc always uses the structure obtained by sulfate as the basic structure.

"Heparan sulfate" is an N-acetyl, N-sulfuric acid, and O-sulfuric acid-substituted polysaccharide composed of D-glucosamine, D-glucuronic acid, and L-iduronic acid.

Chondroitin sulfate has a basic structure of repeating disaccharides GalNAc and GlcA and is a mucopolysaccharide with very few sulfate groups (typically, each disaccharide unit is less than 0.7 molecules). In addition to natural sources such as bovine cornea, it can also be obtained by chemically desulfating chondroitin sulfate.

The sulfated mucopolysaccharides used in this invention are preferably sulfated mucopolysaccharides having repeating units of disaccharides composed of N-acetyl-D-galactosamine or N-acetyl-D-glucosamine and uronic acid or galactose, and more preferably chondroitin sulfate, dermatan sulfate, keratin sulfate and heparan sulfate.

In addition, the sulfated mucopolysaccharides used in this invention also include polysulfated mucopolysaccharides obtained by further sulfated chondroitin sulfate, dermatan sulfate, keratin sulfate, etc.

The number of sulfate groups in the sulfated mucopolysaccharides of the present invention is not particularly limited. Each monosaccharide typically has sulfate groups in an average of 0.55 to 4 molecules, preferably an average of 0.6 to 2.9 molecules, and more preferably an average of 0.7 to 2 molecules.

The molecular weight of the sulfated mucopolysaccharide or its salt used in this invention varies depending on the type of polysaccharide and is not limited. Its average molecular weight, calculated as weight average molecular weight, is approximately 10,000 to 1,000,000, and preferably approximately 10,000 to 50,000.

The sulfated mucopolysaccharide of the present invention is not particularly limited in its source. As a more suitable sulfated mucopolysaccharide, examples include sulfated mucopolysaccharides formed by artificially sulfating the above-mentioned natural mucopolysaccharides.

"Polysulfated mucopolysaccharides" refer to mucopolysaccharides obtained by replacing more sulfate groups in the aforementioned sulfated mucopolysaccharides. Specifically, examples include polysulfated chondroitin sulfate and polysulfated dermatin sulfate. Polysulfated chondroitin sulfate is preferred.

Methods for further introducing sulfate groups into sulfated mucopolysaccharides such as chondroitin sulfate A or C to obtain polysulfated mucopolysaccharides include known methods, such as heating the reaction in a suitable solvent in the presence of a sulfating agent. The sulfating agent can be any substance that achieves polysulfation and is not particularly limited; a complex of sulfuric anhydride with pyridine or triethylamine is preferred. The proportion of the sulfating agent can be arbitrarily selected based on the desired sulfation rate (or sulfur content) of the sulfated mucopolysaccharide and the reaction conditions, typically used at a ratio of 2 to 10 parts by weight relative to 1 part by weight of polysulfated sulfated mucopolysaccharide. Examples of solvents include protophilic solvents such as dimethylformamide. There are no particular limitations on the reaction temperature or time, as long as the desired sulfation rate is achieved; for example, a reaction at 40–90°C for approximately 30 minutes to 20 days is acceptable.

The polysulfated mucopolysaccharides generated by the above operations can be purified using various purification techniques commonly used in modified polysaccharides. Examples include: neutralization, dialysis-based desalting, recovery of precipitates generated by adding organic solvents, and freeze-drying-based recovery.

In this invention, polysulfated mucopolysaccharides can be used in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include: alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts; and magnesium salts, as well as various salts thereof.

"Chondroitin sulfate polysulfate" refers to a polymer in which each disaccharide unit composed of D-acetylgalactosamine and D-glucuronic acid contains about 2 to 4 molecules, preferably about 2 to 3 molecules, of sulfate groups.

Examples of polysulfated chondroitin sulfate include chondroitin D, chondroitin E, and heparin-like substances listed in the Japanese Pharmacopoeia. Heparin-like substances listed in the Japanese Pharmacopoeia are preferred.

In addition to naturally occurring substances such as chondroitin sulfate D and chondroitin sulfate E, polysulfated chondroitin sulfate can also be readily manufactured by known methods, for example, by reacting chondroitin components such as chondroitin, chondroitin sulfate (A, C, D, E) with sulfating agents such as chlorosulfuric acid, concentrated sulfuric acid, and sulfur trioxide-pyridine complexes.

As a preferred polysulfated chondroitin sulfate, an example is heparin-like substances listed in the Japanese Pharmacopoeia's Standard for Drug Ingredients.

Specifically, it is chondroitin sulfate polysulfated, which exhibits the following physicochemical properties:

a) Sulfate content: 25.8–37.3%;

b) Limiting viscosity: 0.09～0.18.

Chondroitin sulfate polysulfated can be used as a free acid derived from sulfuric acid residues, but it is usually used as an alkaline salt.

Examples of such alkali salts include: alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; and magnesium salts, etc.

Chondroitin D sulfate is isolated from shark cartilage and has a structure similar to chondroitin C sulfate. Its basic structure has a sulfate group at the 6 position of GalNAc and at the 2 or 3 position of GlcA.

Chondroitin E (4,6-chondroitin sulfate) was isolated from squid cartilage and has a structure similar to chondroitin C. Its basic structure has sulfate groups at positions 4 and 6 of GalNAc.

"Polysulfated dermatan sulfate" refers to substances synthesized by chemically introducing sulfate groups into dermatan sulfate, a natural sulfated mucopolysaccharide having repeating sugar units composed of N-acetylgalactosamine and L-iduronic acid, as well as naturally occurring polysulfated dermatan sulfate, or substances synthesized by chemically introducing sulfate groups into it.

There is no particular limitation on the number of sulfate groups introduced; for example, more than one per repeating sugar unit, up to four, preferably 1.3 to 4, and more preferably 2 to 4. Furthermore, the weight-average molecular weight of the polysulfated dermatin sulfate of the present invention is, for example, around 1000 to tens of thousands.

Hereinafter, sulfated polysaccharides other than those described above will be described for use in this invention.

"Sulfated dextran" is a polysaccharide, i.e., a polyanionic derivative of dextran, which is composed of glucose units. The glucose units are composed of straight chains obtained by α(1→6) bonding of glucose and branches starting from α(1→3) bonds, typically ranging in length from 1,000 to several thousand Da to hundreds of thousands of Da. Part of the C2 to C4 positions and the C1 and C6 positions of the terminal groups are sulfated.

"Polysulfated pentosans" are semi-synthetic sulfated polysaccharides, comprising a mixture of polyvalent anionic polysaccharides with D-xylose and/or L-arabinose as monosaccharides. Polysulfated pentosans are produced by the chemical sulfation of polysaccharides (e.g., xylan) obtained from woody plants, such as beech trees. They are generally considered to be polysulfates of substances with O-methylglucuronic acid bonded as side chains to the xylan chain.

Polysulfated pentosans can be used in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include: alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts; and magnesium salts. A particularly preferred salt is sodium polysulfated pentosan.

There are no particular limitations on the polysulfated pentosan, but it is preferred to use polysulfated pentosan with a weight average molecular weight of 1,000 to 30,000, more preferably 2,000 to 10,000, and even more preferably 4,000 to 6,500.

The following provides specific examples of polysaccharides other than sulfated polysaccharides.

"Glucomannan" is mainly composed of glucose and mannose, which are bonded together by β(1→4) bonds to form the main chain. Some of them have branched structures formed by β(1→3) bonds or β(1→6) bonds.

Inulin is a substance obtained by β(2→1) bonding of 2 to 140 molecules of fructose with terminal glucose.

"Xylo-oligosaccharides" are hydrolysates of xylan, which are oligosaccharides with a structure consisting of about 2 to 7 xylose groups linked by β(1→4) bonds. They also include xylo-oligosaccharides derived from xylan used as a raw material and having 4-O-methylglucuronic acid side chains, arabinofuranyl side chains, etc.

The polysaccharides mentioned above can be used in the form of physiologically acceptable salts. Physiologically acceptable salts include: alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts; and magnesium salts, as well as various salts thereof.

The aforementioned polysaccharides can be extracted and recovered from animal or plant tissues, microorganisms such as Streptococcus, or cultures of animal or plant cells. Alternatively, commercially available products can also be used.

According to the present invention, a medicament effective in reducing nasal polyps can be provided, the medicament comprising the polysaccharides specified above, preferably sulfated polysaccharides, as the active ingredient.

Furthermore, since the drug of the present invention has the effect of shrinking nasal polyps, it is also expected to improve the symptoms of diseases presenting with nasal polyps, specifically including eosinophilic sinusitis or non-eosinophilic sinusitis, chronic sinusitis, or allergic rhinitis.

In addition, another aspect of the present invention provides a method for treating nasal polyps, a method for shrinking nasal polyps, or a method for preventing or treating nasal polyps, which is carried out by administering the prescribed polysaccharide used in the present invention to a patient who needs treatment for nasal polyps.

Nasal polyps, also known as nasal polyposis, are fleshy growths of the nasal mucosa that form at sites of drooping edema in the lamina propria (usually around the openings of the maxillary sinuses). Patients requiring treatment for nasal polyps are those with accompanying conditions, specifically sinusitis, preferably chronic sinusitis. Chronic sinusitis includes eosinophilic sinusitis and non-eosinophilic sinusitis.

Treatment of nasal polyps includes: improving symptoms such as nasal congestion caused by nasal polyps, shrinking nasal polyps, or treating nasal polyps, namely shrinking nasal polyps and improving symptoms such as nasal congestion.

Improving symptoms such as nasal congestion caused by nasal polyps means that, although there is no reduction in the number or size of nasal polyps, clinical symptoms such as nasal congestion are improved compared with the non-drug group of the polysaccharide used in this invention.

The reduction of nasal polyps refers to at least one of the following: a decrease in the number of nasal polyps or a reduction in the size (area or weight of each nasal polyp).

In the case of liquid formulations, the concentration of the polysaccharide used in this invention is preferably about 3× ^10⁻⁷ to 30 w/v%, more preferably about 0.003 to 10 w/v%.

The polysaccharide used in this invention is used as an intranasal administration formulation, which is delivered to the nasal cavity containing nasal polyps via intranasal administration.

Intranasal drug delivery systems are drug formulations intended for administration via the nasal cavity. Specifically, they include liquid formulations, suspensions, powders, solid formulations, and semi-solid formulations. Suspensions are liquid formulations containing solid particles dispersed in a liquid medium.

Preferred dosage forms for intranasal drug delivery include: nasal drops.

Nasal drops are preparations administered to the nasal cavity or nasal mucosa, and are divided into liquid nasal drops and powder nasal drops. Nasal drops can be inhaled as needed using a spray device with an appropriate spray volume and uniformity, such as a spray pump. The dosage of nasal drops can be adjusted by using a spray device with an adjustable spray volume.

Nasal liquid preparations are liquid nasal drops, or solid nasal drops that are dissolved or suspended during use for administration into the nasal cavity. They are typically manufactured by dissolving or suspending the active ingredient directly or with the addition of a solvent or other suitable additives, followed by filtration as needed. Alternatively, suitable dissolving or suspending solutions can be used to dissolve or suspend the active ingredient during use. Solubilizers, isotonic agents, buffers, or pH adjusters may be added to nasal liquid preparations as needed. Furthermore, in the case of suspensions, dispersants or stabilizers may be added as needed to achieve a uniform state of the active ingredient.

Examples of nasal liquid preparations administration methods include: nasal sprays, nasal aerosols, or nasal nebulizers. Nasal sprays typically contain polysaccharides dissolved or suspended in a solution or mixture in an unpressurized dispenser. Nasal sprays offer advantages such as small, convenient delivery devices, ease of use, and accurate dispensing of 25–200 μL. Liquids or suspensions containing polysaccharides can be used in nasal sprays. Another intranasal method is nasal aerosols. Nasal aerosols dispense medication due to excess pressure and release it through a valve. In nasal sprays, the medication is forcibly dispensed using a micropump bucket, but the pressure in the vial is the same as atmospheric pressure. Nasal aerosols offer the same advantages as sprays.

Nasal nebulizers are a method of drug delivery that uses ultrasound to create a fine mist of medication.

When filling nasal liquid preparations into multiple-use containers, an appropriate amount of preservative (antiseptic) is added, as needed, to inhibit microbial growth. Containers for nasal liquid preparations are typically airtight.

Nasal powder drops are micronized nasal drops administered into the nasal cavity. They are typically manufactured by forming the active ingredient into moderately fine particles, and if necessary, by mixing with appropriate additives and homogenizing. Containers for nasal powder drops are usually airtight. Moisture resistance is provided as needed.

In addition to nasal drops, the drugs of the present invention can also be formulated into ointments, plasters, creams, gels, or other solid or semi-solid preparations, or highly viscous liquid preparations or suspensions for application to the nasal mucosa, thereby administering the drugs by applying them into the nasal cavity.

These nasal drops, ointments, plasters, creams, gels, and other dosage forms are formulated by combining the polysaccharides used in this invention with pharmaceutically acceptable additives.

Pharmaceutically acceptable additives for the medicaments used in this invention include: additives commonly used in the field, such as pharmaceutical excipients or pharmaceutical carriers as shown below. With appropriate use of these additives, pharmaceutical compositions suitable for their respective forms of administration can be formulated by commonly employed methods.

As pharmaceutically acceptable additives for the medicaments used in this invention, any additive commonly used in the field is acceptable and is not particularly limited. Examples include: matrix, solubilizer, excipient, dispersant, emulsifier, thickener, isotonic agent, buffer, pH adjuster, stabilizer, chelating agent, preservative, antioxidant, absorption enhancer, humectant, filler, crosslinking agent, cooling agent, and coating agent. With appropriate use of these additives, pharmaceutical compositions suitable for their respective forms of administration can be formulated by commonly employed methods.

Examples of matrices used in the present invention include hydrophobic matrices, hydrophilic matrices, and water.

There are no particular limitations on the hydrophobic matrix; higher hydrocarbons, oils, waxes, fatty acids, higher alcohols, and fatty acid esters can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, and microcrystalline wax. Examples of oils include sesame oil, corn oil, olive oil, and cocoa butter. Examples of waxes include beeswax, white beeswax, lanolin, reduced lanolin, and ceresin. Examples of fatty acids include stearic acid and oleic acid. Examples of higher alcohols include lanolin alcohol, myristol, cetyl alcohol, stearyl alcohol, cetearyl alcohol, and cholesterol. Examples of fatty acid esters include isopropyl myristate, stearyl myristate, and medium-chain triglycerides.

Examples of hydrophilic matrices include ethanol, propanol, isopropanol, butanol, isobutanol, propylene glycol, polyethylene glycol, and macrogol.

There are no particular limitations on the cosolvents, but examples include: propylene glycol, D-mannitol, benzyl benzoate, ethanol, isopropanol, triethanolamine, sodium carbonate, and sodium citrate.

In the case where the drug of the present invention is a nasal powder, excipients are used as additives as needed.

There are no particular limitations on excipients, but examples include: sugar alcohols such as erythritol, maltitol, mannitol, sorbitol, xylitol, and lactitol; sugars such as refined sugar, lactose, reduced maltose syrup, powdered reduced maltose syrup, glucose, and maltose; and corn starch, crystalline cellulose, dicalcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, light silicic anhydride, hydrated silica, and silicon dioxide.

In the case where the drug of the present invention is a suspension, a dispersant may be used as an additive as needed.

There are no particular limitations on dispersants, but examples include: cellulose-based compounds such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose; synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers; nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene polyalkyl ethers, sorbitol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyethylene glycerol fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene polymers; amphoteric surfactants such as alkyl betaine, alkylamide betaine, alkyl sulfobetaine, and imidazoline; and anionic surfactants such as saturated higher fatty acid salts, alkyl sulfonates, alkyl ether sulfonates, and polyoxyethylene alkyl ether phosphates.

Examples of emulsifiers include: cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.

There are no particular limitations on cationic surfactants; examples include: hexadecyltrimethylammonium chloride, dodecyldimethylbenzylammonium chloride, tetrabutylammonium chloride, and dioctadecyldimethylammonium chloride.

There are no particular limitations on anionic surfactants; examples include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium cocoyl ethoxysulfate, sodium α-olefin sulfonate, and emulsified cetearyl alcohol.

There are no particular limitations on nonionic surfactants, but examples include: polyoxyethylene alkyl ethers, polyoxyethylene alkylphenol ethers, polyoxyethylene dehydrated sorbitol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, glycerol fatty acid esters, and diglycerol fatty acid esters.

There are no particular limitations on amphoteric surfactants; examples include N-alkyl-N,N-dimethylammonium betaine and imidazoline-type amphoteric surfactants.

The surfactants mentioned above can be used alone or in combination.

There are no particular restrictions on thickeners; examples include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymers, carboxymethylcellulose, and sodium polyacrylate.

There are no particular limitations on isotonic agents, and examples include: sugars such as sorbitol, glucose and mannitol; polyols such as glycerol, polyethylene glycol and propylene glycol; and inorganic salts such as sodium chloride and potassium chloride.

There are no particular limitations on the buffer, but examples include: boric acid, borax, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, sodium dihydrogen citrate, and disodium citrate.

There are no particular limitations on pH adjusters; examples include: diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, and glacial acetic acid.

There are no particular limitations on stabilizers; examples include sodium edetate, sodium oleate, casein, and sodium casein salt.

There are no particular limitations on chelating agents; examples include edema, oxalic acid, citric acid, pyrophosphate, hexametaphosphate, gluconic acid, and their salts.

There are no particular limitations on preservatives, but examples include: quaternary ammonium salts such as benzalkonium chloride, benzoxonium chloride, benzododecinium bromide, benzyl chloride, cetylpyridinium chloride, and cetrimide; _C1 - _C7 alkyl esters of 4-hydroxybenzoic acid and their salts, such as methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate; chlorhexidine and its intranasal acceptable salts, such as chlorhexidine digluconate, chlorhexidine acetate, and chlorhexidine chloride; 2-phenylethanol, 2-phenoxyethanol, chlorobutanol, and sorbic acid.

As a preservative, an intranasal preservative is preferred.

There are no particular limitations on antioxidants, but examples include: polyphenols, ascorbic acid, tert-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, L-cysteine hydrochloride, sodium bisulfite, and α-tocopherol and its derivatives.

There are no particular limitations on absorption enhancers, but examples include: diisopropyl adipate, lecithin, squalane, squalene, l-menthol, polyethylene glycol, isopropyl myristate, dimethyl sulfoxide, peppermint oil, eucalyptus oil, d-limonene, and dl-limonene.

There are no particular restrictions on moisturizers; for example, glycerin, propylene glycol, and 1,3-butanediol can be listed.

There are no particular restrictions on fillers; for example, kaolin, titanium dioxide, and zinc oxide are all acceptable.

There are no particular limitations on crosslinking agents; examples include acetaldehyde, dimethyl ketone, and aluminum sulfate.

There are no specific limitations on cooling agents; examples include: L-menthol, dL-camphor, d-borneol, fennel oil, peppermint oil, and peppermint water.

Nasal drop liquid formulations containing the drugs of the present invention may include an intranasal, acceptable coating agent. The addition of a coating agent enhances the moisturizing and pain-relieving effects of the compositions of the present invention by inhibiting moisture loss and maintaining good hydration levels of the nasal mucosa for a longer period.

There are no particular limitations on the coating agent. Examples include: cellulose materials that are soluble or swollen in water, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, and sodium carboxymethyl cellulose; polyvinylpyrrolidone (Povidone); and cross-linked polyvinylpyrrolidone (CLOPS).

The medication of this invention varies depending on the patient's age, weight, gender, and the degree (amount, extent) of nasal polyps, and is not particularly limited. The dosage varies depending on the degree of nasal polyps.

Apply 5× ^10⁻¹¹ to 1g into the nasal cavity once or several times a day.

It should be noted that, since chronic sinusitis, especially eosinophilic sinusitis, is closely related to asthma, the drug of this invention can be administered in combination with asthma treatment drugs for patients with chronic sinusitis complicated by asthma.

As a treatment for asthma, the following medications can be listed as examples.

Inhaled steroid medications or nasal spray steroid medications: beclomethasone propionate, fluticasone propionate, budesonide, ciclesonide, mometasone furan carboxylate, etc.;

Combination therapy of inhaled steroids and long-acting β2 agonists: combination therapy with salmeterol xinafoate, combination therapy with formoterol fumarate hydrate;

Theophylline sustained-release preparations: Theodur (theophylline sustained-release tablets), Theolong, Slo-bid (anhydrous theophylline long-acting preparation), Uniphyl, Unicon, Neophyllin, Theodrip, etc.

Short-acting theophylline drugs: Neophyllin, Theocolin, Monophylline, Asthmolysin-D/M, Asthphyllin, Albina suppositories, etc.

Long-acting β2 agonists: inhaled (LABA)/Serevent, patch/Hokunalin band, oral medication/Meptin, Spiropent, Hokunalin, Berachin, Atock, Broncholin, etc.;

Short-acting β2 agonists (SABA): Inhalers/Airomir, Sultanol, Medpin Air, Berotec aerosol, etc., Oral medications/Venetlin, Alotec, Inolin, LEANOL, ephedrine, Isopal P, etc.

Leukotriene antagonists (receptor antagonists): Onon, Accolade, Singulair, Kipres, etc.;

Th2 cytokine inhibitors: IPD, etc.;

Histamine H1 receptor antagonists: Zesulan, Nipolazin, Zaditen, Celtect, Alesion, etc.

Mediator release inhibitors: Intal, Rizaben, Solfa, Romet, Ketas, Alegysal, Pemilaston, Tazanol, Tazalest, etc.

Thromboamyl A2 inhibitors: Vega, Domenan, etc.;

Thromboyl thromboxane A2 antagonists: Bronica, Baynas, etc.;

Oral steroid medications: prednisone, prednisolone, Medrol (methylprednisolone), rinderon, ledercort, decadron, Corson, dexamethasone, peramisone, etc.

Immunosuppressive drugs: cyclosporine, etc.;

Interleukin-4R (IL-4R) inhibitors: dupilumab, etc.;

Iodine preparations: Jolethin, etc.

Alternatively, the drug of the present invention can be administered in combination with a vasoconstrictor. Examples of vasoconstrictors include: naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate, and epinephrine.

Example

The present invention will now be described in further detail with reference to embodiments. It should be noted that the present invention is not limited to the embodiments described below.

[Example 1] Heparin-induced nasal polyp reduction in patients with eosinophilic sinusitis. Heparin-derived heparin (organosulfate group 25.8–37.3% w/w, D-glucuronic acid 19.0–24.0% w/w, Maruho Co., Ltd.) was dissolved in physiological saline to prepare heparin solutions (0.3, 30, and 3000 μg/mL). Nasal polyp samples from patients with eosinophilic sinusitis were finely cut into approximately 5 mm squares, wiped dry, and weighed. Each sample was transferred to a 12-well plate, and 1 mL of physiological saline or heparin solution of each concentration was added. The plates were incubated at 37°C for approximately 24 hours. Samples were removed from the plates, wiped dry, and weighed. The difference in sample weight before and after incubation was used as an indicator of nasal polyp reduction. The number of cases in the physiological saline group and the heparin solution groups of each concentration in Figure 1 was 6.

The changes in sample weight before and after culture are shown in Figure 1. * and ** in Figure 1 indicate significant differences in nasal polyp weight before and after culture according to paired t-tests (*p < 0.05, **p < 0.01). No significant change in nasal polyp weight was observed after culture with saline solution; in contrast, a significant reduction in nasal polyp weight was observed after culture with heparin-like solutions (0.3, 30, and 3000 μg/mL), suggesting that heparin-like solutions have a polyp-shrinking effect.

[Example 2] The effect of heparin on nasal polyp reduction in patients with eosinophilic sinusitis: The polyp reduction effect of 0.003, 0.03, 0.3, and 30 μg/mL heparin solutions was evaluated using the same method as in Example 1. Additionally, the number of cases in the saline group and each concentration of heparin solution group in Figure 2 was 6.

The changes in sample weight before and after culture are shown in Figure 2. ** in Figure 2 indicate a significant difference in nasal polyp weight before and after culture, as determined by a paired t-test (**p < 0.01). No significant change in nasal polyp weight was observed after culture with saline solution; in contrast, a significant reduction in nasal polyp weight was observed after culture with heparin-like solutions (0.003, 0.03, 0.3, and 30 μg/mL), suggesting that heparin-like solutions have a polyp-shrinking effect.

[Example 3] Polyp-reducing effect of polysulfated pentosan (PPS) on nasal polyps in patients with eosinophilic sinusitis. The polyp-reducing effect was evaluated using a PPS solution (0.003 μg/mL) prepared using the same method as in Example 1. Sodium polysulfated pentosan (weight-average molecular weight 4000–6500, sulfur content 13.0–20.0% w/w, glucuronic acid content 2.5–4.0% w/w) manufactured by Molclone Labs was used as the PPS. The number of cases in the saline group and the PPS solution group in Figure 3 were 6.

The changes in sample weight before and after culture are shown in Figure 3. Culture with physiological saline resulted in almost no reduction in nasal polyp weight, while culture with PPS solution (0.003 μg/mL) resulted in a significant reduction in nasal polyp weight, suggesting that PPS has a polyp-shrinking effect in patients with eosinophilic sinusitis.

[Example 4] The effect of various polysaccharides on nasal polyp reduction in patients with eosinophilic sinusitis: Using the same method as in Example 1, 11 polysaccharide solutions were prepared (300 μg/mL for all polysaccharides except glucomannan, and 30 μg/mL for glucomannan), and the polyp reduction effect was evaluated. Additionally, the number of cases in the saline group and each polysaccharide solution group listed in Tables 1-4 was 1.

• Chondroitin (sodium chondroitin, weight average molecular weight 42,351, sulfate content 2.6%, manufactured by Maruho Co., Ltd.);

• Low molecular weight chondroitin sulfate (low molecular weight chondroitin sulfate sodium, weight average molecular weight of 11,500, sulfate content of 8.9%, manufactured by Maruho Co., Ltd.);

• Chondroitin A sulfate (sodium chondroitin A sulfate, manufactured by PG Research, Inc.);

• Dermatin sulfate (sodium dermatin sulfate, manufactured by Tokyo Chemical Industry Co., Ltd.);

• Chondroitin C sulfate (sodium chondroitin C sulfate, manufactured by PG Research, Inc.);

• Glucomannan (Propol A, manufactured by Shimizu Chemical Co., Ltd.);

• Dextran sulfate (sodium dextran sulfate 500,000, manufactured by Fujifilm and Kohden Chemical Co., Ltd.);

• Keratin sulfate (sodium keratin sulfate, manufactured by PG Research, Inc.);

• Inulin (manufactured by Tokyo Chemical Industry Co., Ltd.);

• Heparan sulfate (manufactured by Toronto Research Chemicals, Inc.);

• Xylo-oligosaccharides (made from xylo-hexane and Megazyme).

Chondroitin was synthesized by desulfation of sodium chondroitin sulfate (manufactured by Bioiberica) using the same method as described in Japanese Patent Application Publication No. 07-062001. Low molecular weight chondroitin sulfate was synthesized by hydrolyzing sodium chondroitin sulfate (manufactured by Bioiberica) under acidic conditions. Other polysaccharides were commercially available as described.

The changes in sample weight before and after culture are shown in Tables 1-4. Culture with physiological saline showed almost no reduction in nasal polyp weight. In contrast, culture with 11 polysaccharide solutions (300 μg/mL for all polysaccharides except glucomannan, and 30 μg/mL for glucomannan) resulted in a significant reduction in nasal polyp weight, suggesting that the 11 polysaccharides have a polyp-shrinking effect in patients with eosinophilic sinusitis.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Example 5] Reduction of Nasal Polyps in Patients with Non-Eosinophilic Sinusitis: Heparin and PPS solutions (0.03, 0.3, 30, and 300 μg/mL, respectively) were prepared using the same method as in Example 1 to evaluate their reduction effect on nasal polyp samples extracted from patients with non-eosinophilic sinusitis. It should be noted that the same substances as those used in Examples 1 and 3 were used for heparin and PPS. Additionally, the number of cases in the saline group, heparin solution group, and PPS solution group in Table 5 was 1.

The changes in sample weight before and after culture are shown in Table 5. No reduction in nasal polyp weight was observed when cultured with physiological saline. In contrast, a significant reduction in nasal polyp weight was observed when cultured with heparin-like solutions and PPS solutions (0.03, 0.3, 30, and 300 μg/mL, respectively), suggesting that heparin-like solutions and PPS also have a shrinking effect on nasal polyps in patients with non-eosinophilic sinusitis.

[Table 5]

Industrial practicality

A certain polysaccharide containing heparin-like substances as sulfated polysaccharides has shown significant effects on nasal polyps at low doses. Therefore, a specified polysaccharide containing sulfated polysaccharides can be used as a nasal polyp shrinking agent for the treatment or prevention of chronic sinusitis patients with nasal polyps.

Claims (8)

1. A nasal polyp shrinking agent, wherein the active ingredient is a polysaccharide or its salt selected from polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan, inulin and xylooligosaccharide. 2. The nasal polyp shrinking agent according to claim 1, wherein the polysaccharide is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, polysulfated pentosan, chondroitin, glucomannan and inulin. 3. The nasal polyp shrinking agent according to claim 1 or 2, wherein the nasal polyp shrinking agent is administered intranasally. 4. A pharmaceutical composition for reducing nasal polyps in patients with chronic sinusitis, comprising a polysaccharide selected from chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan sulfate, dextran sulfate, pentosan sulfate, chondroitin, glucomannan, inulin, and xylooligosaccharides, or a salt thereof. 5. The pharmaceutical composition of claim 4, wherein the polysaccharide is selected from chondroitin sulfate polysulfate, chondroitin sulfate, keratin sulfate, heparan sulfate, dextran sulfate, pentosan polysulfate, chondroitin, glucomannan and inulin. 6. The pharmaceutical composition of claim 4 or 5, wherein the aforementioned chronic sinusitis patient is an eosinophilic sinusitis patient or a non-eosinophilic sinusitis patient. 7. The pharmaceutical composition according to any one of claims 4 to 6, wherein the aforementioned chronic sinusitis patient is an eosinophilic sinusitis patient. 8. A nasal administration formulation comprising the pharmaceutical composition according to any one of claims 4 to 7.