JP3386348B2 - Aqueous suspension formulation for intranasal administration - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous suspension preparation for nasal administration, which has excellent drug retention on the nasal mucosa. More specifically, the retention of the drug in the nasal mucosa is better than that of a conventional formulation prepared by adding a specific type of gel-forming suspending agent to an aqueous solution of a specific amount of gel-forming nonionic cellulose ethers. Relates to an aqueous suspension preparation excellent in nasal administration. The present invention also relates to an aqueous suspension preparation for nasal administration, which is excellent in drug retention in the nasal mucosa and excellent in nasal mucosal permeability. More specifically, conventional preparations produced by adding a specific type of gel-forming suspending agent and a specific type of water-insoluble polysaccharide to an aqueous solution of a specific amount of gel-forming nonionic cellulose ethers. The present invention relates to an aqueous suspension preparation for nasal administration, which has excellent drug retention on the nasal mucosa and excellent nasal mucosal permeability.

[0002]

2. Description of the Related Art The intranasal administration of drugs is as follows. For local nasal mucosal diseases such as nasal allergy, it is possible to directly administer to the diseased site.2. It is recognized as one of the useful administration methods for systemic diseases because of the fact that the drug can be rapidly absorbed from the nasal mucosa into the blood vessels and thus a rapid effect can be expected. However, it is known that the drug deposited on the mucous membrane due to the cilia of the nasal mucosa exhibits a local action or is rapidly excreted in the throat direction before being absorbed through the nasal mucosa. Therefore, conventional preparations for nasal administration are often required to be administered twice a day, and in many cases, irritating additives have to be used in order to promote absorption. Therefore, a method of retaining the drug in the nasal cavity has been devised. For example, a method of using a mucoadhesive gel such as carboxyvinyl polymer, a method of administering a liquid that gels depending on the temperature in the nasal cavity, or a method of administering a powdery composition comprising gel-forming cellulose ethers (Suzuki et al .:
Japanese Patent Publication No. 60-34925) is known.

[0003]

As a result of the present inventors' comparative examination of these methods, it was found that the method of administering a powdery composition comprising gel-forming cellulose ethers is different from other liquids in terms of drug retention. It was confirmed to be superior to the composition. However, the method of administering the powdery composition requires the use of a somewhat special administration device, and that the operation is not always easy, and that some people complain of a foreign body sensation after spraying into the nasal cavity, Etc. These facts indicate that a liquid composition having a nasal mucosal retention property comparable to that of a powdered composition is desired in consideration of a preparation that can be used for a wider range of patients or a preparation that requires administration for a longer period of time. It indicates that

[0004]

In view of the effect of a powdery composition comprising gel-forming cellulose ethers, the present inventors have dissolved and suspended a drug in a solution of gel-forming cellulose ether in water. The thus prepared aqueous liquid preparation was prepared and the retention property in the nasal cavity of the liquid preparation was examined (in the examples described below, Comparative Example 1-
3). The solution became more viscous as the amount of gel-forming cellulose ethers added increased, but the drug could not show the retention property of nasal mucosa. Therefore,
The inventors of the present invention further studied, produced a composite gel preparation comprising the gel-forming cellulose ethers and a second gelling agent, and examined its effect. That is, carboxyvinyl polymer used as a gelling agent for pharmaceuticals, carrageenan, alginic acid, gums such as pectin, bentonite, colloidal magnesium aluminium silicate,
Clays such as colloidal magnesium silicate, gelatin, crystalline cellulose / carmellose sodium (Avicel RC), etc. were added to the gel-forming cellulose ether aqueous solution to prepare an aqueous solution, and the retention of the drug in the nasal cavity was compared. As a result, when the second gelling agent was added, the retention was often shortened instead of being prolonged, which was surprisingly surprising.
The present invention was achieved by recognizing the prolongation of drug retention in the nasal cavity only when carmellose sodium (Avicel RC) was added. Among the second gelling agents examined, bentonite, clays such as colloidal magnesium aluminium silicate, colloidal magnesium silicate, gelatin, crystalline cellulose / carmellose sodium (Avicel RC) were not dissolved, and the aqueous liquid preparation was not dissolved. Was used as an aqueous suspension, but it was found that the retention of the drug in the nasal cavity was prolonged. Crystalline cellulose / carmellose sodium (Avicel
RC) alone, and the effect of the second gelling agent, which brings about the effect of the complex gel system of the present invention, is presumed to be specific to crystalline cellulose-carmellose sodium (Avicel RC).

Although an aqueous suspension for nasal administration using a crystalline cellulose / carmellose sodium (Avicel RC) having a gelling function as a suspending agent is already known, it is intranasal when coexisting with cellulose ethers. Up to now, it has not been known that the drug retention property of is increased. Furthermore, coexistence of other ingredients including cellulose ethers with gel-forming suspending agents other than crystalline cellulose-carmellose sodium (Avicel RC) does not increase drug retention in the nasal cavity. It has been previously known that the retention of drugs in the nasal cavity does not increase even if components other than cellulose ethers are added to an aqueous suspension for nasal administration, which uses sodium lactose (Avicel RC) as a gel-forming suspension agent. It wasn't done. That is, an aqueous suspension for nasal administration in which drug retention in the nasal cavity is increased only when crystalline cellulose / carmellose sodium (Avicel RC) is used as a gel-forming suspension agent and gel-forming cellulose ethers are allowed to coexist. It is obvious that the novelty and inventive step of the present invention are obtained.
In other words, it is a novel finding that addition of water-insoluble polysaccharides to the aqueous suspension for nasal administration of the above composition increases not only drug retention in the nasal cavity but also nasal mucosal permeability, and novelty and progress thereof. The sex is clear.

[0006]

Thus, the present invention provides an effective amount of drug, about 0.05 to about 5% w / w crystalline cellulose-carmellose sodium (Avicel RC), about 0.05 to about 5% w / w non-dose. An aqueous suspension for nasal administration, which contains ionic cellulose ethers and has excellent retention in the nasal cavity. Further, the present invention provides an effective amount of drug, about 0.05 to about 5% w / w crystalline cellulose carmellose sodium (Avicel RC), about 0.05 to about 5% w / w nonionic cellulose ethers, about 0.05. -An aqueous suspension for nasal administration, which comprises about 5% w / w of a water-insoluble polysaccharide and has excellent retention in the nasal cavity and excellent permeability to the nasal mucosa.

The drug of the present invention is not particularly limited, but those having a relatively high lipophilicity can be mentioned as preferable ones. Among them, vitamin D3s, prostaglandins and steroid hormones are preferable. Specifically, vitamin D3s include cholecalciferol, ergocalciferol, 1α-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol, 1,24-dihydroxycholecalciferol, 25-hydroxycholecalciferol and the like. Can be mentioned. Prostaglandins include prostaglandin E ₁ and its analogs such as alprostadil,
Examples include prostaglandin E ₂ and its analogs such as dinoprostone, prostaglandin I _{1 and} its analogs, prostaglandin I ₂ and its analogs such as clinprost, and prostacyclinic acid. Examples of sex hormones include testosterone, drostanolone, fosfestrol, estradiol, estriol, progesterone and the like. Examples of corticosteroids include beclomethasone dipropionate, triamcinolone acetonide, flunisolide, fluticasone dipropionate, dexamethasone, budesonide, hydrocortisone, halopredone, betamethasone and prednisolone. Further, the drug of the present invention is used in such an amount that an effective amount is contained in a single use of the aqueous suspension for intranasal administration of the present invention. Although the amount to be blended varies depending on the activity of the drug, for example, the amount is usually 20 to 20 times, more preferably 10 to 10 times the amount used for injection administration of each drug. More specifically, about 0.0
1% w / w to about 1% w / w is preferred, and about 0.05% w / w to about 0.5% w / w is particularly preferred.

The particle size of the drug of the present invention is 10 μm.
The following is preferable, and when it is larger than this, pulverization by pulverization is required. Examples of such pulverization methods include dry pulverization using a high-speed rotary impact shear pulverizer, ball mill, jet pulverizer, etc., and wet or submerged pulverization using a rotary cylinder mill, vibrating ball mill, centrifugal ball mill, medium stirring mill, colloid mill, etc. There is a method and the like, and among them, a medium stirring mill such as an attrition mill is preferable because it can be pulverized into a uniform particle size in a short time.

The crystalline cellulose-carmellose sodium (Avicel RC) of the present invention is a crystalline cellulose whose surface is coated with carmellose sodium and is sold by Asahi Kasei Corporation as the Avicel RC series. As these, Avicel RC-591, RC-591N
F and CL-611 are mentioned, but among them RC-59
1, RC-591NF is desirable. "Avicel"
Is a registered trademark. Further, the crystalline cellulose of the present invention
The concentration of carmellose sodium (Avicel RC) is about 0.05% w / w to about 5% w / w.

Examples of the nonionic cellulose ethers of the present invention include hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hydroxyethyl cellulose.

The grade of hydroxypropyl cellulose of the present invention is H (the viscosity of a 2% aqueous solution is 1000 to
4000 cps), M (viscosity of 2% aqueous solution is 150 to 4)
00 cps), L (viscosity of 2% aqueous solution is 6 to 10 cp)
s), SL (the viscosity of a 2% aqueous solution is 3 to 5.9 cps), or one or more selected from the group consisting of: Among these, as the hydroxypropyl cellulose in the present invention, those having grades S and SL are preferable, and among them, SL is particularly preferable. The term "viscosity" as used herein means a kinematic viscosity, and is measured by a viscometer such as Canon-Fenske, Canon-Fenske opaque liquid, Ubbelohde, Ostwald. Above all, measurement with an Ubbelohde viscometer is preferable because of its high accuracy. The viscosity values described herein are 3
It is obtained by an Ubbelohde viscometer manufactured by Shibata Scientific Mechanical Engineering Co., Ltd. under an environment of 7 ° C.

The concentration of hydroxypropyl cellulose of the present invention is about 0.05% w / w to about 5% w / w. Hydroxypropyl methylcellulose 2208 and hydroxypropyl methylcellulose 290 depend on the substitution ratio of methoxy groups and the like.
6, hydroxypropylmethylcellulose 2910, and like the above-mentioned hydroxypropylcellulose, there are many grades with different molecular weights, and in the case of Shin-Etsu Chemical's Metroses 90SH, Metroses 65SH, Metroses 60SH, TC-5 (TM), 9 each
0SH-100, 90SH-4000, 90SH-15
000, 90 SH-30000, 65 SH-50, 65
SH-400, 65SH-1500, 65SH-400
0, 60SH-50, 60SH-4000, TC-5
E, TC-5EW, TC-5MW, TC-5R, TC-
It is classified into 5RW and TC5S. The hydroxypropylmethyl cellulose of the present invention is one or more selected from the group consisting of the above grades. Among these, as the hydroxypropylmethyl cellulose in the present invention, those of TC-5 series are preferable, and among them, grades thereof are TC-5R and TC5R.
W and TC5SG can be mentioned as preferable ones.

Like the above-mentioned hydroxypropyl cellulose, there are many grades of hydroxyethyl cellulose having different molecular weights, and NATORO made by Aqualon Co.
In the case of SOL (TM), it is classified into four grades of HHX, HX, M and G. The hydroxyethyl cellulose of the present invention is one kind or two or more kinds selected from the group consisting of respective grades (HHX, HX, M, G).
Among these, as the hydroxyethyl cellulose in the present invention, those having grades M and G are preferable, and G is particularly preferable.

Examples of the water-insoluble polysaccharide of the present invention include crystalline cellulose, potato starch, starch such as corn starch, chitin and chitosan. The concentration of the water-insoluble polysaccharide of the present invention is about 0.05 to about 5% w / w.

The composition of the present invention may further contain known buffers, colorants, preservatives, preservatives, flavoring agents, if necessary, in order to improve the physical properties, appearance, odor and the like of the preparation.
An osmotic pressure adjusting agent and the like may be added. Examples of buffering agents include phosphoric acid and salts thereof; examples of coloring agents include red No. 2 and the like; examples of preservatives such as ascorbic acid;
Examples of preservatives include paraoxybenzoic acid esters, etc .; examples of fragrances include menthol; and examples of osmotic pressure regulators include sodium chloride.

As a preparation method for obtaining the composition of the present invention, a method for preparing a suspension preparation is generally applicable, and the nonionic cellulose ethers as the component are crystals before addition of the medicine. It may be added to the cellulose / carmellose suspension or may be added after suspending the drug. Alternatively, an aqueous solution of nonionic cellulose ethers is prepared in advance, and crystalline cellulose / carmellose powder is dissolved or added thereto. May be. When adding the water-insoluble polysaccharide, it may be added to any step, but a high-concentration suspension of the drug and the water-insoluble polysaccharide is prepared in advance, and this high-concentration drug suspension is added to crystalline cellulose. By adding to the carmellose suspension or the crystalline cellulose-carmellose suspension to which the nonionic cellulose ethers have been added, the effect of the present invention becomes more remarkable, which is preferable. In these cases, uniform suspension after addition is important for obtaining a stable composition of the present invention, but a high-speed shearing stirrer such as a homomixer or polytron or an ultrasonic stirrer. Is preferably used. For example, the following preparation method is preferable.
A high-concentration crystalline cellulose-carmellose suspension of 2-10% w / w was prepared in advance using a homomixer as a master. Separately, an aqueous solution of nonionic cellulose ethers of 1-10% w / w was separately prepared. Prepare a drug powder or a drug suspension containing a surfactant such as Tween 80, and stir with a homomixer to prepare a drug / nonionic cellulose ether suspension. . The composition of the present invention is prepared by stirring approximately equal amounts of the above-mentioned master and this drug / nonionic cellulose ether suspension using a homomixer or the like. When adding the water-insoluble polysaccharide, a crystalline cellulose-carmellose suspension having a high concentration of 2-10% w / w is prepared as a master using a homomixer in advance.
Separately, a suspension of the water-insoluble polysaccharide and the drug is prepared with a homomixer. Further, an aqueous solution of 1-10% w / w nonionic cellulose ethers is prepared, and the water-insoluble polysaccharide is added to the master. The composition of the present invention is prepared by adding a suspension of the drug and the mixture, stirring the mixture with a homomixer, etc., and further stirring approximately the same amount of the nonionic cellulose ether suspension with a homomixer.

The composition of the present invention is in a dosage form suitable for administration as a preparation. As such a form, there is a spray type container in which the present invention is filled for each dosage unit, and this is sprayed into the nasal cavity. Further, the composition of the present invention in a dosage unit amount or the composition of the present invention in a plurality of dosage unit amounts is housed in a suitable spray type container, and the composition of the present invention in a dosage unit amount at the time of administration operation, It may be administered in a single dose or in divided doses.

[0018]

INDUSTRIAL APPLICABILITY Thus, the present invention provides a suspension preparation for nasal administration which is excellent in retention of the drug on the nasal mucosa. The present invention also provides an aqueous suspension preparation for nasal administration, which has excellent drug retention on the nasal mucosa and excellent nasal mucosal permeability. With such an aqueous suspension preparation for nasal administration of the present invention, the effect of the drug can be more efficiently exhibited even with the same usage amount as conventional. This can also lead to a reduction in drug usage.

Therefore, it can be said that the present invention has extremely high significance not only in terms of therapeutic effect but also in economic effect, for drug therapy by intranasal administration.

[0020]

The present invention will be described in detail below with reference to examples and comparative examples, but these do not limit the present invention. In the following examples and the like, hydroxypropyl cellulose may be abbreviated as HPC. A nasal suspension having the following formulation was prepared with a homomixer.

[Example 1] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 2] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl methylcellulose 0.1% w / w TWEEN80 0.01% w / w Purified water 100%

[Embodiment 3] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxyethyl cellulose 0.1% w / w Purified water 100%

[Embodiment 4] Beclomethasone dipropionate 0.01% w / w Avicel RC591 2.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 5] Beclomethasone dipropionate 0.01% w / w Avicel RC591 0.5% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Sixth Embodiment] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.5% w / w Purified water 100%

[Embodiment 7] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 1.0% w / w Purified water 100%

[Embodiment 8] Beclomethasone dipropionate 0.01% w / w Avicel CL611 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 9] Beclomethasone dipropionate 0.01% w / w Avicel CL611 0.5% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Example 10] Beclomethasone dipropionate 0.01% w / w Avicel CL611 1.0% w / w Hydroxypropyl methylcellulose 0.1% w /
w Purified water 100%

[Embodiment 11] Beclomethasone dipropionate 0.01% w / w Avicel CL611 1.0% w / w Hydroxyethyl cellulose 0.1% w / w Purified water 100%

[Embodiment 12] Estradiol benzoate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[0033]     [Example 13] 1,24-dihydroxycholecalciferol 0.001% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 14] Klinprost 0.1% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 15] Testosterone 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 16] Triamcinolone acetonide 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 17] Dexamethasone 0.01% w / w Avicel RC591 0.5% w / w Hydroxypropyl cellulose 0.1% w / w Purified water 100%

[Embodiment 18] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Crystalline cellulose 0.1% Purified water 100%

[0039]     [Example 19] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl methylcellulose 0.1% w / w Potato starch 0.1% Purified water 100%

[Embodiment 20] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxyethyl cellulose 0.1% w / w Corn starch 0.1% Purified water 100%

[Embodiment 21] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Chitin 0.1% Purified water 100%

[Embodiment 22] Beclomethasone dipropionate 0.01% w / w Avicel RC591 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Chitosan 0.1% Purified water 100%

[Embodiment 23] Beclomethasone dipropionate 0.01% w / w Avicel CL611 1.0% w / w Hydroxypropyl cellulose 0.1% w / w Crystalline cellulose 0.1% Purified water 100%

[Test Example] The retention effect in the nasal cavity of the present invention was examined in rabbits using the outflow amount of the drug into the esophagus and the absorption amount in the blood after intranasal administration of the suspension as indexes. . As a test animal, a 13-week-old male Japanese white rabbit (Kitayama Labes)
In order to measure the amount of outflow to the esophagus, an esophagus near the pharynx was surgically attached with a cannula for collecting the esophageal effluent and a cannula for securing the esophagus.

Test method : Examples 1-11 and 18-2
Suspension of beclomethasone dipropionate prepared according to Example 3 and Control Examples 1-15 and 17, 1 shown in Table 1 below.
The nasal suspension prepared as No. 8 (all containing 0.01% beclomethasone dipropionate) was administered into the right nasal cavity of the above-mentioned test animal using a metered-dose nebulizer, 100 μL each, and 15 , 30, 60, 90, 120 minutes later, blood was collected from the ear vein and esophageal effluent was collected to measure the amount of beclomethasone dipropionate absorbed from the nasal mucosa and the amount of beclomethasone dipropionate that had flowed into the esophagus. . In addition, 240 minutes after administration, 100 mL of PBS buffer was injected from the right nasal cavity, and beclomethasone dipropionate retained in the nasal cavity was forcibly poured into the esophagus, and retained in the nasal cavity from the collected esophageal effluent. The amount of beclomethasone dipropionate used was measured. The amount of beclomethasone dipropionate in blood was measured by the RIA method, and the amount of beclomethasone dipropionate in the esophageal effluent was measured by the HPLC method. The results are shown in Tables 2 and 3.

[0046]

[Table 1]

[0047]

[Table 2]

[0048]

[Table 3]

[0049]

[Table 4]

[0050]

[Table 5]

Test Results: As shown in Table 2, beclomethasone dipropionate from the nasal cavity was tested in Examples 1-11,
In addition, it was revealed that 18-23 was more sustained than that of the control example in the examples, which are a part of the present invention, although the amount of 18-23 was small in both control examples. In addition, it was also clarified that the blood levels in Examples 18-23, which could be an index of tissue permeability, were higher than those in other examples. Than this. It was suggested that the suspensions of Examples stayed in the nasal cavity for a longer period of time than the Control Examples, and that Examples 18-23 had excellent tissue permeability.

Further, as shown in Table 3, the outflow to the esophagus was significantly significant in Examples 1-11 and 18-2.
3 was slower than the control example, suggesting that the suspension of the Example stayed in the nasal cavity for a longer time than the control example.

As described above, the suspension of the present invention allows the drug to be retained more in the nasal cavity, which leads to effective use of the drug when administered to the nasal cavity.

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Claims (11)

(57) [Claims] 1. A nasal retention comprising an effective amount of drug, 0.05% -5% w / w crystalline cellulose carmellose sodium, 0.05% -5% w / w nonionic cellulose ethers. Aqueous suspension formulation for nasal administration with excellent properties. 2. An effective amount of drug, 0.05% -5% w / w crystalline cellulose carmellose sodium, 0.05% -5% w / w nonionic cellulose ethers, 0.05% -5% w / w An aqueous suspension preparation for nasal administration, which comprises the water-insoluble polysaccharide described above and is excellent in retention and nasal mucosal permeability in the nasal cavity. 3. A drug according to claim 1, wherein the drug is poorly soluble in water.
The aqueous suspension preparation for nasal administration according to item 2. 4. The aqueous suspension preparation for nasal administration according to claim 3, wherein the poorly water-soluble drug is selected from the group consisting of vitamin D3s, prostaglandins, sex hormones, and corticosteroids. 5. Vitamin D3s are cholecalciferol, ergocalciferol, 1α-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol, 1,24-dihydroxycholecalciferol, 25-hydroxycholecalciferol. The aqueous suspension preparation for nasal administration according to claim 4. 6. The prostaglandins are prostaglandin E ₁ and its analogs such as alprostadil, prostaglandin E ₂ and its analogs such as dinoprostone, prostaglandin I _{1 and} its analogs, prostaglandins. The aqueous suspension preparation for nasal administration according to claim 4, which is I ₂ and its analog such as clinprost and prostacyclic acid. 7. The sex hormones include testosterone, drostanolone, fosfestrol, estradiol,
Claim 4 which is estriol and progesterone
The aqueous suspension preparation for nasal administration according to the above item. 8. The nasal administration according to claim 4, wherein the adrenocortical hormones are beclomethasone dipropionate, triamcinolone acetonide, flunisolide, fluticasone dipropionate, dexamethasone, budesonide, hydrocortisone, halopredone, betamethasone, prednisolone. Aqueous suspension formulation. 9. Crystalline cellulose-carmellose sodium is Avicel (registered trademark) RC-591 or Avicel (registered).
An aqueous suspension preparation for nasal administration according to claims 1 and 2, which is either or both of ( registered trademark) CL-611. 10. The aqueous solution for nasal administration according to claim 1, wherein the nonionic cellulose ether is one kind or two or more kinds selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hydroxyethyl cellulose. Suspension formulation. 11. The retention property in the nasal cavity and the nasal mucosa according to claim 2, wherein the water-insoluble polysaccharide is one or more selected from the group consisting of crystalline cellulose, starches, chitin and chitosan. Aqueous suspension formulation for nasal administration with excellent penetrability.