JPS60224616A - Composition for administration through nose - Google Patents

Abstract

PURPOSE:The titled composition consisting of a polypeptide having physiologically activity and a slightly water-soluble base having water absorption properties, dispersible properly into the mucosa of the nose, capable of retaining in the attached affected part, absorbing efficiently the polypeptide when it is sprayed and administered to the nasal cavity. CONSTITUTION:A granular composition comprising a polypeptide having physiological activity, preferably a peptide hormone (e.g., calcitonin, insulin, or leuteinizing hormone) having 1,000-300,000, especially 1,000-150,000mol.wt. and 15 times as much a water-absorbing and slightly water-soluble base such as a cellulose (e.g., crystalline cellulose, crosslinked Na-CMC), or crosslinked vinyl polymer (e.g., crosslinked polyvinyl pyrrolidone) as the polypeptide by weight, wherein >=90wt% particles have 10-250mu effective particle diameters. When the base is used with 1-50wt% water-absorbing and easily water-soluble base, the base is provided to some extent with viscosity and fluidity, and sustained-release effect is produced.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a powdered polypeptide composition for nasal administration. More specifically, the present invention provides a powder composition comprising physiologically active polypeptides such as calcitonin and insulin, and a water-absorbing and poorly water-soluble base, which is administered by spray into the nasal cavity. The present invention relates to a polypeptide composition for oral administration that is efficiently absorbed through the mucous membrane of the polypeptide.

PRIOR ART Peptide hormones such as insulin and calcitonin have large molecular weights and are easily degraded by proteolytic enzymes such as pepsin, trypsin, or chymotrypsin, so they are difficult to absorb when administered orally and cannot exert effective pharmacological effects. Currently, administration is being carried out.

However, since administration by injection is painful, various other administration methods have been attempted.

For example, rectal administration using a layer agent using salicylic acid derivatives such as storium salicylate, sodium 3-methoxysalicylate, and 5-methoxysalicylic acid as an absorption enhancer (J, Pharm, Pharmacol,
33.334 (1981). Another method is intratracheal administration (D 1abetes, 20,552
．． (1971) ), ophthalmic administration (Abstracts of the Diabetes Society, 2
37. (1974) ) and other methods are being considered.

However, since all of these methods require a higher dose than injection and have the disadvantage that absorption tends to fluctuate, very few methods have yet reached practical use.

On the other hand, as an attempt at nasal administration, a method of nasal administration of an acidic aqueous solution of insulin using a surfactant such as λ sodium glycolate as an absorption enhancer is known (Q 1abetes, 27.296, (1978)
).

However, in this method, since the dosage form is liquid, when administered intravenously, the liquid drug tends to flow out of the 0 cavity.
Furthermore, since it uses a surfactant, it is difficult to say that it is a safe administration method.

In addition, U and S are used as powdered preparations for nasal administration.

P, No. 4.294.829 discloses a formulation consisting of a cellulose lower alkyl ether and a drug. This formulation is characterized in that cellulose lower alkyl ether absorbs water on the nasal mucosa, becomes a viscous liquid, flows on the nasal mucosa, and gradually releases the drug. Such preparations become a viscous liquid state in the nasal cavity, so in the case of a drug with a large molecular weight, the drug tends to remain in the cellulose lower alkyl ether, making it difficult to release the drug. Therefore, there is still room for improvement in this formulation when a high molecular weight drug such as calcitonin or insulin is used as the drug.

OBJECTS OF THE INVENTION An object of the present invention is to provide a powdered composition for nasal administration.

An object of the present invention is to provide a powdered composition for nasal administration for physiologically active polypeptides.

An object of the present invention is to provide a powdered composition for nasal administration in which physiologically active polypeptides are efficiently absorbed through the nasal mucosa without using an absorption enhancer.

The purpose of the present invention is to absorb polypeptides such as insulin and calcitonin without using absorption enhancers.
An object of the present invention is to provide a powdered composition for nasal administration that is efficiently absorbed through mucous membranes.

The purpose of the present invention is to provide biologically active polypeptides that
The object of the present invention is to provide a powdered composition for nasal administration that is efficiently absorbed through the nasal mucosa and also has a sustained release effect.

An object of the present invention is to provide a powdered composition for nasal administration that has an appropriate particle size and can be efficiently administered into the nasal cavity when sprayed into the nasal cavity.

Other objects and advantages of the invention will become apparent from the description below.

Structure and Effects of the Invention According to the present invention, these objects and advantages are achieved by a powdered composition for nasal administration comprising physiologically active polypeptides and a water-absorbing and poorly water-soluble base. be done.

In the present invention, drugs are polypeptides that exhibit physiological activity. Polypeptides have a molecular weight of 1,000
Polypeptides in the range of 300,000 to 300,000 are preferable because they are easily absorbed through mucous membranes.

The molecular weight is particularly preferably in the range of 1,000 to 150,000.

Preferred specific examples of physiologically active polypeptides include the following. For example, insulin, angiotensin, pap pressin, and desmoresin. Felipresin, protirelin, luteinizing hormone-releasing hormone, corticotropin.

Prolactin, somatovin, thyrotropin.

Luteinizing hormone, calcitonin, kallikrein.

Balacylin, glucagon, oxytocin, gastrin, secretin, serum gonadotropin.

growth hormone, erythroboetin, angi A-tensin,
Peptide hormones such as gastron and renin; interferon and interleukin.

Physiologically active proteins such as transferrin, histaglobulin, macrocortin, and blood coagulation factor; enzyme proteins such as lysozyme and urokinase; pertussis vaccine, diphtheria vaccine, tetanus vaccine, influenza vaccine or lymphocytosis factor, fibrillar hemagglutination factor Vaccine components such as

Among these, peptide hormones are particularly preferred, and among the peptide hormones, calcitonin, insulin, luteinizing hormone-releasing hormone, and desmoresin are particularly preferred. Pappressin or oxytocin are preferred. More preferred are calcitonin and insulin.

In the composition for nasal administration of the present invention, physiologically active polypeptides in powder form are preferably used. Furthermore, in consideration of absorption through the nasal mucosa, the physiologically active polypeptides are preferably water-soluble. Here, water-soluble means that polypeptides are soluble on human nasal mucosa or in an environment similar to this, i.e., in an aqueous solution with a H of about 7.4 and a temperature of about 36°C to 37°C. It is the meaning.

Therefore, polypeptides that are not water-soluble or that do not exhibit water-soluble properties should be dissolved in water by adjusting the pH value, and then freeze-dried to make them water-soluble and powder-like before use. It is preferable to do so.

Furthermore, polypeptides that are not in powder form are preferably lyophilized before use.

Of course, water-soluble polypeptides in powder form can be used without lyophilization. In this case, there is an advantage that the formulation can be prepared by a simple method since freeze-drying is not required.

The above polypeptides include human serum albumin, mannitol, sorbitol, and aminoacetic acid for stabilization or as a bulking agent along with stabilization.

Amino acids, sodium chloride, phospholipids, etc. may be used in combination.

The composition for nasal administration of the present invention uses a water-absorbing and poorly water-soluble base as a base. Here, "water-absorbing and poorly water-soluble" means that it is water-absorbing on human mucous membranes or in an environment similar to this, that is, water with a pH of about 7.4 and a temperature of about 36°C to about 37°C. This means that it has the property of being large and poorly soluble in water.

By using a water-absorbing and poorly water-soluble base,
When the composition of the present invention is administered into the nasal cavity, it first absorbs the moisture on the nasal mucosa, and the particles become a viscous liquid and are appropriately dispersed without flowing. It is believed that high molecular weight polypeptides remain in the adhesion site and come into good contact with the nasal mucosa, which is why the polypeptides exhibit high absorption. In the present invention, by selecting such a base as the base of a polypeptide formulation for nasal administration. Polypeptides are absorbed to a sufficient extent to exert their pharmacological effects without the use of absorption enhancers.

The water-absorbing and poorly water-soluble base of the present invention is distinguished from cellulose lower alkyl ethers, such as cellulose lower alkyl ethers, such as hydroxypropylcellulose, which forms a viscous liquid on the nasal mucosa. . Preferred specific examples of the water-absorbing and slightly water-soluble base of the present invention include the following.

For example, water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, and cross-linked carboxymethylcellulose sodium; hydroxypropyne starch, carboxymethyl starch, cross-linked starch, amylose, aminovecdine, pectin, etc. Starches that are water-absorbing and poorly soluble; gelatin.

Water-absorbing and poorly water-soluble proteins such as casein and sodium caseinate: gum arabic, gum tragacanth,
Water-absorbing and poorly water-soluble gums such as glucomannan; polyvinylpolypyrrolidone.

Examples include crosslinked polyacrylic acid and its salts, crosslinked polyvinyl alcohol, and crosslinked vinyl polymers such as polyhydroxyethyl methacrylate. Among these, water-absorbing and poorly water-soluble celluloses are preferred;
Especially preferred is crystalline cellulose.

The use ω of a water-absorbing and poorly water-soluble base varies depending on the type of polypeptide used, etc. - Although it cannot be generalized, it is usually in the range of 1 times or more by weight, especially 151111 times the weight of the polypeptide. A range of 20 times or more by weight or more is preferable.

In the composition of the present invention, a water-absorbing and slightly water-soluble base may be used together with a water-absorbing and easily water-soluble base. By using a water-absorbing and easily water-soluble base together, some solubility is imparted to the water-absorbing and slightly water-soluble base, resulting in the following effects. That is, when administered intranasally, particles consisting of a water-absorbing and poorly water-soluble base and polypeptides are dispersed, and at the same time, the water-absorbing and easily water-soluble base is dissolved, resulting in a viscous liquid state. Then,
The base of the present invention is imparted with some viscosity and fluidity, allowing the polypeptide to be gradually absorbed, resulting in a so-called sustained release effect.

A water-absorbing and easily water-soluble base may be used simply by mixing with a water-absorbing and poorly water-soluble base, or it may be added to and lyophilized together with the water-absorbing and poorly water-soluble base when freeze-drying polypeptides. You may. When freeze-dried together with polypeptides, the polypeptides are dispersed in particles of a water-absorbing and easily water-soluble base material, and the final composition has better sustained release properties. Become what you have.

Examples of the water-absorbing and easily water-soluble base used here include sodium polyacrylate.

Polyacrylates such as potassium polyacrylate and ammonium polyacrylate; methylcellulose, human O
Examples include cellulose lower alkyl ethers such as xyethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose; polyethylene glycol polyvinylpyrrolidone, amylose, pullulan, and the like.

Among these, sodium polyacrylate, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone are particularly preferred. Particularly preferred is hydroxypropyl cellulose. The amount of the water-absorbing and easily water-soluble base used is preferably 0.1 to 60% by weight, particularly preferably 1 to 50% by weight, based on the water-absorbing and poorly water-soluble base.

In the powder composition of the present invention, 90% by weight or more of the particles preferably have an effective particle size of 10 to 250 microns. By making the particles have a particle size within this range, when administered into the nasal cavity, they are widely distributed on the nasal mucosa and remain well at the adhesion site, and when sprayed as a powder into the nasal cavity through the nostrils, It can be efficiently administered intranasally.

If particles with an effective particle diameter of less than 10 microns account for more than 10% by weight, when administered by a method such as spraying, many particles will reach the lungs or will dissipate out of the nostrils when sprayed.

Furthermore, it is difficult to maintain a high drug concentration at the attachment site.

On the other hand, if particles with an effective particle size exceeding 250 microns account for more than 10% by weight, when administered into the nasal cavity, even if they adhere to the nasal mucosa, they tend to separate from the mucous membrane, resulting in a decrease in local retention of the drug. Undesirable. Particularly preferred is one in which 90% by weight or more of the particles have an effective particle diameter of between 20 and 150 microns.

In the composition of the present invention, the water-absorbing and poorly water-soluble base and the polypeptide may form independent particles, and the polypeptide may be formed on the surface of the water-absorbing and poorly water-soluble base. The polypeptides may be attached to a base material that is water-absorbing and poorly water-soluble, or the polypeptides may be dispersed by forming a distinct phase within the particles of a water-absorbing and poorly water-soluble base material; The polypeptides may be tightly dispersed in a well-dispersed state within the particles of the base material.

The composition of the present invention, in which the water-absorbing and poorly water-soluble base and the polypeptide form independent particles, or the polypeptide is attached to the surface of the water-absorbing and poorly water-soluble base. The product is prepared by adding polypeptides to a water-absorbing and poorly water-soluble base, mechanically mixing, and then sieving, preferably at a 90% concentration. It can be produced by obtaining a composition in which % or more of the particles have an effective particle diameter of 10 to 250 microns.

When a water-absorbing and easily water-soluble base is used in combination, the water-absorbing and poorly water-soluble base may be mixed simultaneously with the mechanical mixing.

Either polypeptides form distinct phases and are dispersed within the particles of a water-absorbing and poorly water-soluble base, or polypeptides are dispersed within the particles of a water-absorbing and poorly water-soluble base. The composition of the present invention which is tightly dispersed in a dispersed state can be obtained as follows. Mechanically mixing polypeptides with a water-absorbing and sparingly water-soluble base, then compressing the resulting mixture under pressure, crushing the resulting compressed product, and sieving. Preferably, it is produced by obtaining a composition in which 90% by weight or more of the particles have an effective particle size of 10 to 250 microns. Alternatively, it can be obtained by adding a water-absorbing and poorly water-soluble base and polypeptides to water, kneading well, drying by a conventional method, and then sieving.

When using a water-absorbing and easily water-soluble base together, when mechanically mixing the polypeptide and the water-absorbing but slightly water-soluble base, The base may be added, and the mixture may then be subjected to a step of compressing as described above. Alternatively, a water-absorbing and easily water-soluble base can be added when adding the water-absorbing and poorly water-soluble base and the polypeptide to water and kneading them.

On the other hand, as mentioned above, when polypeptides are freeze-dried, a water-absorbing and easily water-soluble base is added and freeze-dried at the same time. You can also take the method of

The powder composition of the present invention has physical properties as a preparation.

In order to improve the appearance or odor, known coloring agents, preservatives, preservatives, flavoring agents, etc. may be added as necessary. Coloring agents include copper chlorophyll, β-carodin, Red No. 2, Blue No. 1, etc.; preservatives include stearic acid, ascorbic acid stearate, ascorbic acid, etc.; preservatives include rose oxybenzoin, etc. IJ stell, phenol, butanol, etc.: Examples of flavoring agents include menthol, citrus paint, etc.

The composition of the present invention can be made into a unit dosage form of a powder.

Such powders can be filled into capsules, such as hard gelatin capsules, as a preferred form for administration.

For example, a method for spraying a powder into a cavity involves setting a capsule filled with the powder in a special spray device equipped with a needle and passing the needle through it, thereby making a minute hole at the top and bottom of the capsule. Next, there is a method of blowing out the powder by blowing air in with a rubber ball or the like.

The present invention will be described in detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 (1) A powdered composition for nasal administration of the present invention was obtained as follows.

(a) 0.0 for insulin. Water-soluble insulin powder (25,5
Unit/IR (J) 400II1g 3,600IIF
A uniform powder composition in which 90% or more of the particles had a particle size of 75 to 149 microns was obtained by taking the powder and crystalline cellulose (I) into a mixer and mixing them well. The powdered composition thus obtained has an insulin activity of 2.55 units/RI.

Mountain) Insulin 10■ (25,5 units/Rg) 0
．． IN hydrochloric acid 0.2I! 1! Add 40% of Carbobol 934 to an aqueous insulin solution prepared by dissolving it in water and adding 200% of water.
■Add and dissolve. About 30 ste of 0.01 N aqueous sodium hydroxide solution was added to this solution to adjust the temperature to I) 87.4, and then lyophilized, the insulin and Carbobol 934 having an insulin activity of 5.1 units/WJ were combined. A neutral and uniform powder composition (I>) was obtained.

Next, the powdered composition 501IIy and 50 cm of crystalline cellulose were placed in a mortar and mixed well to form 9
A uniform powder composition (n) in which 0% by weight or more of the particles had a particle size of 75 to 149 microns was obtained. The powder composition (n) thus obtained was 2.55 units/Ill.
It has insulin activity.

(C) Insulin preparations for intravenous administration to humans were obtained by filling capsules with the powdered compositions containing insulin shown in (ω, mountain).

(m) In order to compare with the composition of the present invention, the following comparative composition was obtained.

+d+ Water-soluble insulin powder obtained by dissolving insulin once and then freeze-drying it (25
, 5 units/#J) and 6,300 IFl of lactose are placed in a mixer and mixed well to form a uniform powder composition in which 90% by weight or more of the particles have a particle size of 75 to 149 microns. Obtained. The powdered composition thus obtained has an insulin activity of 2.55 units/IIg.

+01 Water-soluble insulin powder obtained by dissolving insulin once and then freeze-drying it (25
, 5 units/I1g) 400j19 and 3,600PF hydroxypropyl cellulose are placed in a mixer and mixed well, so that 90% by weight or more of the particles are 75-1
A uniform powder composition with a particle size of 49 microns was obtained. The powdered composition thus obtained has an insulin activity of 2.55 units/m9.

Example 2 (Nasal administration experiment of powdered insulin preparation in dogs) Nembutal injection solution (bentoparbital sodium 5
Male peagle dogs (body weight 9.4-12.
(1Jg), (Ten, Yama) and (Small) in Example 1.

3 ml of each of the powdered insulin preparations prepared in (e)
Units/units were administered. The powdered insulin preparation was administered by inserting a polyethylene tube (approximately 2 in diameter) into the external orifice and spraying in duplicate, and blood was collected from the forearm vein over time after administration.

Glyose concentration in plasma was measured by a method using orthotoluidine (Clinical Chemistry (C1i)).
nical Chemistry) 8.215 (1
962) ).

Figure 1 shows changes in plasma glucose in terms of blood sugar effect rate (%). The values shown in Fig. 1 are the average values of four large peagles. For comparison, the insulin bulk powder itself was suspended in water and used with a micropipette for 5 units/10μ polishing/K.
The results of changes in plasma glucose concentration upon nasal administration are also shown in FIG. 1 with a broken line.

In Figure 1, (1) is crystalline cellulose (
(ω), +21 in Examples indicates the case where a freeze-dried product of insulin and sodium polyacrylate and crystalline cellulose were used (Example 10), and (3) indicates the case where lactose was used as the base (Example 10)). +cb of 1) and +41 indicate the case where hydroxypropyl cellulose ((e) of Example 1) was used.

As is clear from Figure 1, the composition using crystalline cellulose has excellent insulin absorption, and the composition using crystalline cellulose and sodium polyacrylate has excellent insulin absorption and sustained release effect. show.

Example 3 (1) An insulin solution was prepared by dissolving Insulin 1100II1 in 0.1N hydrochloric acid 111e and then adding 40% of water, and freeze-drying this to obtain water-soluble insulin powder (26.3 units/WJ). ) was obtained. Using this insulin powder, the following composition of the present invention was obtained.

(a) Water-soluble insulin powder (26,3 units/L
IIg) 1 g of 20I and 140WI of crystalline cellulose were placed in a mortar and mixed well to obtain a uniform powder composition. The powdered composition thus obtained is about 3
．． It has an insulin activity of 3 units/Rg.

oi) Using the above insulin powder, the following comparative composition was obtained for comparison with the composition of the present invention.

Mountain) Water-soluble insulin powder (26,3 units/II
A uniform powdery composition was obtained by taking F>1 and 105 IIy of lactose in a mortar and mixing well.

The powder composition thus obtained was approximately 3.3 units/
It has an insulin activity of ~.

(C) Water-soluble insulin powder (26,3 units/1
119) 20IIg and hydroxypropyl cellulose 1
A homogeneous powdery composition was obtained by taking 40 ml of the mixture in a mortar and mixing well. The powdered composition thus obtained has an insulin activity of approximately 3.3 units/I1g.

Example 4 (Intranasal administration experiment of powdered insulin preparation at the apex) Injected into the 8 cavities of a white native male domestic rabbit (body weight 3.0-3.5 Ky) was prepared from Example 3 (ω~tC+). Each powdered insulin preparation was administered at 10 units/head, and blood was collected from the ear vein of the rabbit at 10, 20, 30, and 60 minutes after administration, and before administration.The powder was administered using a nebulizer modified for animals. The test was carried out under light anesthesia with ether or under normal conditions.The serum insulin concentration was measured by radioimmunoassay.The results are shown in Figure 2. This is the average value for 3 domestic rabbits.For comparison, suspend the insulin bulk powder itself in water and use a micropipette to collect 10 units at 150μl/h.
The results when ead was administered nasally are also shown by the broken line in FIG.

In Figure 2, (1) shows crystalline cellulose (
+, v) and (2) in Example 2 are lactose (+b) in Example 3).

(3) is hydroxypropylcellulose ((of Example 3)
A case using C)) is shown.

As is clear from FIG. 1, the composition of the present invention has high insulin absorption.

Example 5 Freeze-dried [ASU] with 2,000 μm of crystalline cellulose
1,7]-eel calcitonin (4,OOOMRC units/JIFF) and 0,5III were placed in a mixer and thoroughly mixed to obtain a uniform powdery composition.

The powdered composition thus obtained contains approximately IMRC units/jIy of [ASU 1.7]-eel calcitonin. A preparation for human nasal administration was obtained by filling a predetermined capsule with 10 to 50#F wA1' of the composition using a capsule filler.

The following (ω, (b)) shows an example of preparing a calcitonin powder composition for animal experiments.

(ω) Take 200 mg of crystalline cellulose in a mortar, add freeze-dried [ASU 1,7]-eel calcitonin (4,000 M RC units/η) 0.319, and mix well to obtain a uniform powder composition. The powder composition thus obtained had a mass of 5,99 MR.
Contains C units/lg of [ASU 1.7]-eel calcitonin.

+b> Take crystalline cellulose 100j119 in a mortar and add freeze-dried salmon calcitonin (2,000M
A uniform powder composition was obtained by adding 0.3 μm (RC unit/I1g) and mixing well.

The powder composition thus obtained had a MRC of 5.98 MRC.
Contains units/η of salmon calcitonin.

Example 6 (Nasal administration experiment of powdered calcitonin preparation at the tip) Injected into the nasal cavity of a white native male rabbit (body weight 2.5-3.ONg) was prepared using (ω, (b)) of Example 5. The powdered calcitonin preparation was administered 9 times per 6MRC units, and blood was collected from the ear vein of the rabbit before administration and at 1, 2, 4, and 6 hours after administration.Administration of the powder was the same as in Example 2. The serum calcium concentration before and after administration was measured to examine the absorbability of calcitonin through the nasal mucosa.Serum calcium was measured using a calcium measurement kit manufactured by Yatron.Results Table 1 shows the degree of decrease (%) in calcium value relative to the serum calcium value before administration of calcitonin powder.The values shown in the table are the average values of 3 rabbits.

As a control, Table 1 also shows the results of nasal administration of a nearly neutral [ASU 1.7]-eel calcitonin aqueous solution of 6 MRC units/15 μg/~.

Table 1 Degree of decrease in serum calcium level (blank below) Example 7 490 μm of crystalline cellulose was placed in a mortar, and 10 I of freeze-dried pap pressin (70-100 units/ay) was added to the mortar.
A uniform powder composition was obtained by adding Ilj and mixing well. The powder composition thus obtained was 1
．． Contains 4 to 2.0 units/η of papresin.

A preparation for human administration was obtained by filling the powdered composition into a predetermined capsule.

Example 8 Ma Micellulose 990 was placed in a mortar, 10 μm of freeze-dried luteinizing hormone-releasing hormone was added thereto, and the mixture was thoroughly mixed to obtain a uniform powder composition. The powdered composition thus obtained contained 10 μN/η of luteinizing hormone-releasing hormone, and was filled into a predetermined capsule to obtain a formulation for human nasal administration.

Example 9 950 μm of crystalline cellulose was placed in a mortar, human serum albumin was added thereto, and interferon (1 μm) was freeze-dried.
A homogeneous powdery composition was obtained by adding 50 cm (0,000 units/■) and mixing well. The powder composition thus obtained contained 5,000 units/cm of interfine, and was filled into a predetermined capsule to obtain a preparation for nasal administration to humans.

Example 10 2,000 #j of crystalline cellulose was placed in a mortar, and 1 g of freeze-dried desmopressin acetate/I was added thereto and thoroughly mixed to obtain a uniform powder composition. The powder composition thus obtained contained 0.5 μg/4 desmopressin acetate, and was filled into a predetermined capsule to obtain a formulation for human nasal administration.

Example 11 (1) Porcine insulin powder (26,3 units/IIg
) and 90 cm of crystalline cellulose were placed in a mortar and mixed thoroughly to obtain a uniform powder composition.

The powder composition thus obtained was 2.63 units/
It has insulin activity of η.

(2) The following comparative compositions were obtained for comparison with the compositions of the present invention.

(ω Porcine insulin powder (26,3 units/η) 20
A uniform powdery composition was obtained by taking ~ and 180 ml of lactose in a mortar and mixing well.

The powder composition thus obtained was 2.63 units/
It has insulin activity of η.

(b) Porcine insulin powder (26,311/my)
A homogeneous powdery composition was obtained by placing 20 μm and 180 μm of hasidroxypropyl cellulose in a mortar and mixing well. The powdered composition thus obtained has an insulin activity of 2.63 units/η.

Example 12 (Administration experiment of powdered insulin preparation at tip) Example 11 (1) and ■ (ω , 5 units/dose of each of the powdered insulin preparations prepared in (b) were administered, and blood was collected from the ear vein of the rabbit at 30 minutes, 1 hour, 2 hours, 4 hours after administration, and before administration. Blood after blood collection. Serum was obtained by centrifugation for 10 minutes at 2,800 r, p, ■, in a centrifuge.The powder was administered to animals under light anesthesia with ether or under normal conditions using a nebulizer modified for animals. The serum glucose concentration was measured by a method using orthotoluidine (Clinical Chemistry+, 8. 215 (1962)). Table 2 shows the changes in serum glucose as blood glucose lowering rate (%). ).The values shown in the table are the average values of 5 domestic rabbits.As a control, the insulin bulk powder itself was suspended in water and administered nasally at 5 units/15 μm/9 times using a micropipette. The results are also shown in Table 2.

Table 2 Changes in serum glucose (blank below) Example 13 ■ Crystalline gululose 99.9 JIy and salmon calcitonin (approximately 3,000 M RC units/IIIg > 0.1 ■) were taken in a mortar and mixed well. A homogeneous powder composition was obtained. The powder composition thus obtained contains about 3 MRC units/Rg of salmon calcitonin.

0) Hydroxib Ovir cellulose 19.9#J and salmon calcitonin (approximately 3,000M RC units/Rg)
A uniform powder composition (I) was obtained by taking 0.1 WJ in a mortar and mixing well. The powdered composition (
I[) is about 15M RC! Contains salmon calcitonin at position 1/R9.

Next, 10 parts of powdered composition (I) and 40 parts of crystalline cellulose were added.
A uniform powdery composition (n) was obtained by taking η in a mortar and mixing well. The powdered composition (II) thus obtained contains about 3 MRC units/Ilg of salmon calcitonin.

Example 14 (l!14 administration experiment of powdered calcinin-1-nin preparation in domestic rabbits) Example 13 (1) and The powdered calcitonin preparation prepared in α) was administered at 5 MRC units/KfJ, and blood was frequently collected from the ear vein of the rabbit before administration and at 1 hour, 2 hours, 4 hours, and 6 hours after administration. The powder was administered in the same manner as in Example 12. The serum calcium concentration was measured before and after administration, and the absorbability of calcitonin from the nasal mucosa was investigated.

Serum calcium was measured using a calcium measurement kit manufactured by Yatron. Changes in serum calcium are shown in Table 3 as calcium fall rate (%). The values shown in the table are the average values of four domestic rabbits.

As a control, an almost neutral salmon calcitonin aqueous solution 5 was used as a control.
Table 3 also shows the results when 9 was administered nasally to MRC unit/15 μm/.

Table 3 Changes in serum calcium (below 1/margin) Example 15 Crystal cell loaf! , 2.000419 and [AStJ
1.7] -'7 Nagicalcitonin (4,OOOMRC
unit/III) 0.5 ■ or salmon calcitonin (2,
OOOMRC units/III) 1.0 .mu. were taken in a mortar and mixed thoroughly to obtain a uniform powder composition. The powdered composition thus obtained contains approximately IMRC units/■ of [ASU 1.7]-eel calcitonin or salmon calcitonin.

The composition is filled into a predetermined capsule by a capsule filler.
A preparation for human nasal administration was obtained by filling 0 to 50 ml.

Example 16 Hydroxypropyl cellulose 199IIy and salmon calcitonin (2,000M RC units/19) were dissolved in 1q to 50d of water. By freeze-drying this solution, a homogeneous powder composition (I) of salmon calcitonin and hasidroxypropyl cellulose having an activity of 10 M RC units/III was obtained. Then the powdered composition (I
>10,011 g and 900 μg of crystalline cellulose are taken in a mortar and mixed well, so that more than 90% of the particles are 10
A homogeneous powdered composition (n) with a particle size of ~250 microns was obtained. The powdered composition thus obtained (
n) contains 1 MRC unit/R9 of salmon calcitonin.

A preparation for human nasal administration was obtained by filling 10 to 50 I1 g of the composition (II) into a predetermined capsule using a capsule filler.

Example 17 Hydroxypropylcellulose 499Rg and [ASI
J 1.7]-eel calcitonin (4,OOOMRC
Unit/IfJ) 11Ig was taken in a mortar and mixed well to obtain a uniform powdery composition (I). The powdered composition (I) has 8 MRC units/Rg of [ASU 1
．． 7] - Contains eel calcitonin.

Next, the powdered composition (I>200II1g and the crystal cell [
]-S 8001FJ in a mortar and thoroughly mixed to obtain a uniform powder composition (If) in which 90% or more of the particles have a particle size of 10 to 250 microns.

The powdered composition (II) thus obtained consists of 1.
6M RC units/1111 [ASU 1. Contains eel calcitonin.

A preparation for human nasal administration was obtained by filling 10 to 50 cubic centimeters of the composition (II) into a predetermined capsule using a capsule filler.

Example 18 Blush method agglutinin 1#19, a component of Bordetella pertussis
and detoxified white day cough toxin 11Fl and crystalline cellulose 1
A homogeneous powdery composition was obtained by taking and mixing well in a mortar. The powdered composition thus obtained contains approximately 2 μg/η of B. pertussis components.

The composition is filled into a predetermined capsule by a capsule filler.
A formulation for human nasal administration was obtained by filling 1 g of 0-25I.

Example 19 Powder 200μ obtained by freeze-drying influenza HA vaccine and hydroxypropylcellulose 800I
I! A uniform powdery composition (I) was obtained by taking the ingredients and mixing them well in a mortar. The powdered composition (I>
contains approximately 200 μg/■ of lyophilized powder of influenza HA vaccine.

Next, 50 µm of powdered composition (I) and 950#iF of crystalline cellulose were placed in a mortar and mixed thoroughly to form a uniform powdered composition (II) in which 90% or more of the particles had a particle size of 10 to 150 microns. ) was obtained. The powdered composition (II) thus obtained contains 10 μ9/■ of lyophilized powder of influenza 1-(A vaccine.

A preparation for human nasal administration was obtained by filling 10 to 30 IIg of the composition (H) into a predetermined capsule using a capsule filler.

[Brief explanation of the drawing]

FIG. 1 shows the absorption of insulin in terms of blood sugar lowering rate when the composition of the present invention using insulin as a polypeptide was administered to a minor injury. FIG. 2 shows the insulin absorption in serum insulin concentration 1 when the composition of the present invention using insulin is administered nasally. In FIG. 1, (1) shows the case where crystalline cellulose is used as the base ((b) of Example 1), and (3)
is lactose (+d+ in Example 1) as the base, (4)
is hydroxypropyl cellulose ((e) of Example 1)
This shows the case where . Dashed lines indicate controls. In Figure 2, (1) shows crystalline cellulose (
(a) of Example 2), (21 is lactose (Example 31)
7)(b)). (3) is hydroxypropylcellulose ((of Example 3)
A case using C)) is shown. Dashed lines indicate controls. Arithmetic 10 Get off at Hoshijin (Continuation of Kari 1st page ■Int, C1,' Identification code Office serial number

Claims (1)

[Scope of Claims] 1. A powdered composition for nasal administration comprising a physiologically active polypeptide and a water-absorbing and poorly water-soluble base. 2. Powder for nasal administration according to claim 1, wherein the base is a water-absorbing and poorly water-soluble cellulose, starch, protein, crosslinked vinyl polymer, or gum. Composition. 3. The powdered composition for nasal administration according to claim 1, wherein the base is a water-absorbing and poorly water-soluble cellulose. 4. The powdered composition for nasal administration according to claim 3, wherein the water-absorbing and poorly water-soluble cellulose is crystalline cellulose, α-cellulose, or crosslinked sodium carboxymethyl cellulose. 5. The powdered composition for nasal administration according to claim 3, wherein the water-absorbing and poorly water-soluble cellulose is crystalline cellulose. 6. The powdered composition for nasal administration according to claim 1, wherein the base is a water-absorbing and poorly water-soluble crosslinked vinyl polymer. 7. Water-absorbing and poorly water-soluble crosslinked vinyl polymers,
7. The powdered composition for nasal administration according to claim 6, which is a crosslinked polyvinylpyrrolidone or a crosslinked carboxyvinyl polymer. 8. Claims 1 to 3 that use a water-absorbing and easily water-soluble base together with a water-absorbing and poorly water-soluble base
The powdered composition for nasal administration according to any one of Item 7. 9. The powdered composition for nasal administration according to claim 8, wherein the water-absorbing and easily water-soluble base is cellulose lower alkyl ether or polyacrylates. 10. The powdered composition for nasal administration according to claim 8, wherein the water-absorbing and easily water-soluble base is human oxypropyl cellulose. 11. Physiologically active polypeptides have a molecular weight of 1,
The powdered composition for nasal administration according to any one of claims 1 to 10, which is a polypeptide of 000 to 300,000. 12. The powdered composition for nasal administration according to any one of claims 1 to 11, wherein the physiologically active polypeptide is a water-soluble polypeptide. 13. The powdered composition for nasal administration according to any one of claims 1 to 12, wherein the physiologically active polypeptide is a powdered polypeptide. 14. The powdered drug according to any one of claims 1 to 13, wherein the physiologically active polypeptides are water-soluble, powdered, and non-lyophilized polypeptides. Composition for nasal administration. 15. The powdered composition for nasal administration according to any one of claims 1 to 14, wherein the physiologically active polypeptide is a peptide hormone, a physiologically active protein, an enzyme protein, or a vaccine. . 16. The powdered composition for nasal administration according to any one of claims 1 to 15, wherein the physiologically active polypeptide is a peptide hormone. 17. The powdered composition for nasal administration according to claim 16, wherein the peptide hormone is calcitonin, insulin, luteinizing hormone, releasing hormone, desmobrecin, pappressin, or oxytocin. 18. The powdered composition for nasal administration according to any one of claims 1 to 17, wherein the physiologically active polypeptide is a vaccine. 19. The powdered composition for nasal administration according to claim 18, wherein the vaccine is an influenza vaccine or a pertussis vaccine. 20. Any one of claims 1 to 19, wherein the physiologically active polypeptide is a physiologically active protein.
The powdered composition for nasal administration as described in 2. 21. The powdered composition for nasal administration according to claim 20, wherein the physiologically active protein is interferon. 22. More than 90% by weight of particles have an effective particle size of 10 to 250
22. The powdered composition for nasal administration according to any one of claims 1 to 21, which is between microns.