JPS632932A - Powdery composition for nasal administration - Google Patents

Abstract

PURPOSE:To provide the titled composition composed of a physiologically active polypeptide, a specific natural bile acid and a water-absorbing solid base and effective in efficiently absorbing the polypeptide through nasal mucosa. CONSTITUTION:The objective composition contains (I) a physiologically active polypeptide (e.g. calcitonin), (II) a natural bile acid of formula (D is OH, -NHCH2COOH, etc.; V is H or beta-OH; W is H, alpha-or beta-OH; X, Y and Z are H, alpha-or beta-OH or =O; when all X, Y and Z are OH and both V and W are H, then D is OH or -NHCH2CH2SO3H) and/or its salt as an absorbefacient and (III) a water-absorbing solid base suitable for the application to nasal mucosa. Preferably, >=90wt% of the particles of the composition has an effective diameter of 10-250mu to enable uniform distribution over nasal mucosa and stable retention to the attached part when administered to nasal cavity and to enable the administration to nasal cavity in high efficiency when sprayed into nasal cavity through nare in the form of powdery drug.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a powdered polypeptide composition useful for nasal administration. More specifically, the present invention comprises bioactive polypeptides such as calcitonin and insulin, specific natural bile acids such as sodium urtudesoxycholate as an absorption enhancer, and a water-absorbing solid base. The present invention relates to a polypeptide composition useful for nasal administration, which is a powder composition, and when administered by spray into the nasal cavity, the polypeptide is absorbed extremely efficiently through the nasal mucosa.

<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, it is administered as a drug.

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

For example, intrarectal administration through a half-open method using salicylic acid derivatives such as sodium salicylate, sodium 3-methoxysalicylate, and 5-methoxysalicylic acid as an absorption enhancer [Journal of Pharmacy and Pharmacy] Rosie (J.

Pharm, Pharmacol, ), 33.
334 (1981)]. Another method is intratracheal administration [diabetes].
, 20. 552. (1971)].

Eye drop administration (Diabetic Society Abstracts, 237. (197
4) Methods such as ) 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 intranasal administration, a method of intranasal administration of an aqueous solution of insulin using a surfactant such as sodium glycodeoxycholate as an absorption enhancer is known [Procedure Ingestion of the National Academy of Science (Proc. Natl.
, Acad, Sci, U.

S, A, ) 82. l1p7419-742
3 (1985)]. Alternatively, a nasal administration method using an aqueous solution of insulin, glucagon, etc. using fusidic acid derivatives such as sodium-tauro-24,25-dihydroxyfusidate as an absorption enhancer (Japanese Patent Application Laid-Open No. 61-3312
6) is known. Furthermore, a liquid formulation of insulin for nasal administration that uses cyclodextrin is also known (Japanese Patent Application Laid-open No. 189118/1983).

However, in these methods, the dosage form is all liquid, so when administered nasally, the liquid tends to flow out of the nasal cavity, and it is difficult to say that the drug is absorbed efficiently through the nasal mucosa. .

- On the other hand, as a powdered preparation for nasal administration, JP-A-59-1
No. 63313 and JP-A No. 60-224616 disclose powdered nasal preparations comprising a water-absorbing base and peptide hormones.

This preparation allows high molecular weight peptide hormones to be absorbed relatively efficiently through the nasal mucosa. Furthermore, as powdered preparations for nasal administration, u, s, and p.

No. 4, 294. No. 829 discloses a formulation consisting of a cellulose lower alkyl ether and a drug. In this formulation, cellulose lower alkyl ether absorbs water on the nasal mucosa, making it sticky! It has the characteristic that it becomes a liquid and flows over the nasal mucosa, gradually releasing the drug. However, even with these methods, it is difficult to say that the drug is absorbed through the nasal mucosa with sufficient efficiency, and there is still room for improvement.

<Object of the Invention> The object of the present invention is to provide a powder form useful for nasal administration, in which physiologically active polypeptides are absorbed extremely efficiently through the nasal mucosa by using a specific absorption enhancer. An object of the present invention is to provide a composition.

Another object of the present invention is that polypeptides such as calcitonin, insulin, etc. can be absorbed into the nasal mucosa by using certain natural bile acids and/or their pharmaceutically acceptable salts as suitable absorption enhancers. The object of the present invention is to provide a powder composition useful for nasal administration that is absorbed more efficiently.

Still another object of the present invention is to provide a powder composition useful for nasal administration, in which physiologically active polypeptides are absorbed extremely efficiently through the nasal mucosa and also have a sustained release effect. Furthermore, other objects and advantages of the invention will become apparent from the description below.

<Disclosure of the Invention> The present inventors have developed a nasally administered polypeptide that can efficiently absorb physiologically active polypeptides such as calcitonin through the nasal mucosa and is suitable for intracavitary administration. As a result of extensive research with the aim of obtaining a formulation, a powder form consisting of polypeptides, a specific natural bile acid and/or its pharmaceutically acceptable salt, and a water-absorbing solid base was developed. The present invention has been achieved by discovering that a composition can surprisingly achieve the above-mentioned objects.

That is, the present invention provides physiologically active polypeptides, a natural bile acid represented by the following formula as an absorption enhancer and/or a pharmaceutically acceptable salt thereof, and a water-absorbing solid base. This is a powdered composition useful for nasal administration.

(In the formula, OH, NHCH2COOH or i; t-NHC
H2CH2SOa H represents H, and the pharmaceutically acceptable salt of bile acid represents one in which the above H is replaced with a salt. Further, in the formula, V represents H or β-HO, and W represents H, α or β
-OH, X represents H9C- or β-OH or =O, Y represents H2C- or β-OH or =O, Z represents H
Indicates 2C- or β-OH or =O. However, when all of X, Y and Z are OH and both G and W are H, D represents OH or -NHCH2CH2SO3H. ) Among such natural bile acids, natural bile acids having at least two hydroxyl groups in their molecules are preferred.

Specific examples of preferred natural bile acids include cholic acid, ursodesoxycholic acid, taurocholic acid, chenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycoursodesoxycholic acid, and tauroursodesoxycholic acid. Oxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, hyocholic acid, glycohyocholic acid, taurohyocholic acid, 3α,7α-dihydroxy-12-keto-cholic acid, 3,6,7.12-tetrahydroxycholic acid.

3α, 6α, 12α-trihydroxycholic acid.

Examples include 1β, 3α, 12α-trihydroxycholic acid.

Among these natural bile acids, especially cholic acid.

Ursodesoxycholic acid, taurocholic acid, chenodeoxycholic acid, deoxycholic acid 9 glycodeoxycholic acid, taurodeoxycholic acid, biocholic acid. Glycochenodeoxycholic acid, Taurochenodeoxycholic acid,
Glycoursodesoxycholic acid, Tauroursodesoxycholic acid.

Glycohyocholic acid and taurohyocholic acid are preferred;
Among them, cholic acid, ursodesoxycholic acid,
Glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycourtucholic acid, and taurourtucholic acid are preferred.

Pharmaceutically acceptable salts of natural bile acids are any salts that maintain enhanced absorption of bioactive polypeptides through the nasal mucosa and are not harmful; examples of such salts include: Examples include alkali salts. Preferred alkali salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, and ferric.

Salts derived from inorganic bases such as manganese can be mentioned. Among these alkali salts, sodium, potassium, ammonium, calcium and magnesium salts are particularly preferred, and among these, alkali metal salts such as sodium salts are particularly preferred.

The preferred concentration of the particular natural bile acid and/or its pharmaceutically acceptable salt in the powdered composition useful for nasal administration of the present invention is about 0.1-30% by weight of the total composition; More preferably 0.5 to 20% by weight, still more preferably 1
~10 weight%.

In the present invention, the target drug is polypeptides having physiological activity. Polypeptides have a molecular weight of 300 to 3
Polypeptides in the range of 0,000,000 are preferred because they are more easily absorbed than the nasal mucosa. The molecular weight is especially 300-15
A range of 10,000 is preferred. Preferred specific examples of physiologically active polypeptides include the following. For example, insulin.

proinsulin, angiotensin, pap pressin,
Desmopressin, Felipressin, Protirelin, Luteinizing Hormone Releasing Hormone, Corticosteroids, Prolactin, Tumor 1 to Mouth Pins, Thyrotropin, Luteinizing Hormone, Calcitonin.

kallikrein, valathyrin, glucagon, oxytocin, gastrin, secretin, serum gonadotropin, lipomodulin, atrial natriuretic peptide [alpha human atrial natriuretic volupeptide (α-hANP), etc.], growth hormone-releasing volmon, growth Hormones, erythropoietin, angiotensin, urogastrone, renin, parathyroid hormones and their antagonists, peptide hormones such as cortutropin release factor, precursors thereof, inhibitors thereof or derivatives thereof: interferons, interleukins,
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, lymphocytosis factor, and fibrillar hemagglutination factor Vaccines such as vaccines or vaccine components can be mentioned. Among these, peptide hormones are particularly preferred, and among the peptide hormones, calcitonin and insulin are particularly preferred.

Alpha human atrial natriuredic polypeptide (α-hANP), luteinizing hormone releasing hormone, corticotropin, desmobrecin, pap pressin, glucagon, Axidocin or growth hormone are preferred. More preferred are calcitonin, insulin, and alpha hikoman atrial natriuretic polypeptide (α-hANP).

In the composition for nasal administration of the present invention, physiologically active polypeptides in powder form are preferably used.

Polypeptides that are not in powder form are preferably lyophilized before use.

The amount of the above-mentioned polypeptides to be used is appropriately determined depending on the strength of the medicinal efficacy of each polypeptide.

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 also be used.

Powdered compositions useful for nasal administration of the present invention use a water-absorbing solid base as the base. Examples of the water-absorbing solid base include a base that is water-absorbent and has poorly water-soluble properties;
Preferred examples include bases that are water-absorbent and easily water-soluble. Such bases may be used alone or in combination of two or more depending on the purpose.

Here, "water-absorbing and poorly water-soluble" means on the human nasal mucosa or in an environment similar to this, that is, at a pH of about 7.
．． 4 means that it has the property of being water absorbent and poorly soluble in water at a temperature of 36°C to about 37°C. Furthermore, "water-absorbing and water-soluble" means that on the human nasal mucosa or in an environment similar to this, that is, at a pH of about 7.4.
This means that it is water-absorbent and easily soluble in water at a temperature of about 36 to about 37°C.

Preferred specific examples of the water-absorbing and slightly water-soluble base of the present invention include the following.

For example, crystalline cellulose, α-cellulose, cross-linked carboxymethylcellulose sodium, water-absorbing and poorly water-soluble cellulose; hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin, etc. Starch that is poorly soluble in water; 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 polyhuman O-oxyethyl methacrylate.

Among these, water-absorbing and water-soluble celluloses are preferred, particularly crystalline cellulose, α-cellulose, or crosslinked sodium carboxymethylcellulose, and even more preferably crystalline cellulose.

The amount of the water-absorbing and poorly water-soluble base to be used 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 the weight of the polypeptide, especially 15 times the weight of the polypeptide. It is preferably at least 20 times the weight, more preferably at least 20 times the weight.

Preferred specific examples of the water-absorbing and easily water-soluble base of the present invention include the following. For example, water-absorbable and easily water-soluble cellulose lower alkyl ethers such as hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sodium carboxymethyl cellulose; dextrin, cyclodextrin (α, β, γ
or dimethyl α or dimethyl β), amylose.

Water-absorbing and easily water-soluble starches such as pullulan: polyvinyl alcohol, polyvinylpyrrolidone.

Water-absorbing and easily water-soluble vinyl polymers such as sodium salts of carboxyvinyl polymers; sodium polyacrylate, potassium polyacrylate.

Water-absorbing and easily water-soluble polyacrylates such as ammonium polyacrylate; Water-absorbing and easily water-soluble proteins such as chitin and chitosan; Water-absorbing proteins such as lactose, glucose, maltose, and sucrose. Examples include sugars that are large and easily water-soluble. Among these water-absorbing and easily water-soluble bases, hydroxypropylcellulose,
Methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, dextrin, cyclodextrin (β-, dimethyl β- or dimethyl α-), chitin,
Chitosan, lactose, sodium polyacrylate, polyethylene glycol, and polydonylpyrrolidone are preferred, particularly hydroxypropylcellulose, β-cyclodex [
・Phosphorus, dimethyl β cyclodextrin, dimethyl α-
Cyclodextrin and lactose are more preferred, and hydroxypropyl cellulose, β-cyclodextrin,
Lactose is preferred.

The amount of the water-absorbing and easily water-soluble base to be used varies depending on the type of polypeptide used, etc. - Although it is difficult to generalize, it is usually in the range of 1 times the weight of the polypeptide or more, especially 15 The range is preferably at least 20 times the weight, more preferably at least 20 times the weight.

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.

When 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 reach the lungs or escape outside the nasal cavity when sprayed.

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

- If particles with an effective particle diameter 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 will easily separate from the mucous membrane, resulting in a low local retention of the drug. Therefore, it is 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.

The powder composition of the present invention can be produced, for example, as follows.

That is, a physiologically active polypeptide, a natural bile acid and/or a pharmaceutically acceptable salt, and a water-absorbing solid base are mechanically mixed and then sieved, preferably at least 90% by weight. It can be produced by obtaining a composition in which the particles have an effective particle diameter of 10 to 250 microns.

Alternatively, polypeptides having physiological activity.

Natural bile acids and/or their pharmaceutically acceptable salts,
A water-absorbing solid base suitable for application to the nasal mucosa after uniformly dissolving or suspending in an appropriate amount of purified water; After adding a readily soluble base and uniformly adsorbing and/or containing the polypeptides and natural bile acids and/or their pharmaceutically acceptable salts in and/or on the base, Alternatively, a water-absorbing solid base is uniformly dissolved, suspended or kneaded together with polypeptides and natural bile acids and/or their pharmaceutically acceptable salts, and then frozen. The composition is preferably lyophilized and then milled by conventional methods and further sieved, or by milling and further homogeneous mixing with the desired water-absorbing solid base. It can be produced by obtaining a composition in which more than % by weight of the particles have an effective particle size of 10 to 250 microns.

Alternatively, polypeptides and natural bile acids and/or pharmaceutically acceptable salts thereof may be mixed into a water-absorbing solid base, that is, a water-absorbing and poorly water-soluble base, or a water-absorbing and water-insoluble base. mechanically mixing with a readily soluble base, then compressing the resulting mixture under pressure, and crushing the resulting compressed product;
It is produced by sieving to obtain a composition in which preferably 90% by weight or more of the particles have an effective particle size of 10 to 250 microns. Or polypeptides and natural bile acids and/or their pharmaceutically acceptable salts and a water-absorbing solid base, i.e., a water-absorbing and poorly water-soluble base, or a water-absorbing and easily water-soluble base. It is also possible to add the base material to water and homogeneously dissolve or suspend it, or knead it well, then dry it by a conventional method, and then sieve it.

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

In order to improve the appearance or depth, if necessary, known lubricants 1, coloring agents, preservatives, antiseptics, flavoring agents, etc. may be added. Examples of lubricants include talc, stearic acid and its salts; coloring agents include copper chlorophyll, β-carotene, Red No. 2, Blue No. 1; and preservatives such as stearic acid, ascorbic acid stearate, Ascorbic acid, etc.; Examples of preservatives include quaternary ammonium compounds such as benzalkonium chloride, paraoxybenzoic acid esters, phenol, chlorobutanol, etc.;
Examples of the flavoring agent include men's alcohol, citrus flavor, and the like.

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 administering a powder by spraying it into the nasal cavity involves placing a capsule filled with the powder in a special spray device equipped with a needle, passing the needle through it, and making tiny holes 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.

<Examples> Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

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

(ω salmon calcitonin (4,000M RC units/R
g) Take 0.1■ and 1g of sodium cholate 29.8II in a test tube, add 250μ of purified water to dissolve it uniformly, add 500μ of microcrystalline cellulose, sprinkle well, and freeze-dry. A homogeneous composition was obtained by doing this. The composition is then sieved to obtain 9
A uniform powder composition was obtained in which 0% by weight or more of the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0,755 M RC units/IFI of salmon calcitonin.

Mountain> Salmon calcitonin (4, OOOMr (C units/I
Take Rg) o, iRg and 29.8μ of sodium cholate in a test tube, add 250 μl of purified water and dissolve uniformly, then add 500 IItg of microcrystalline cellulose, sprinkle well, and vacuum dry. A homogeneous composition was obtained by this. Next, the composition was sieved to obtain a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained had a density of 0.755 M RC units/Irt.
Contains 1.5 g of salmon calcitonin.

(C) Microcrystalline cellulose 500I! g in a mortar and add salmon calcitonin (4, OOOMRC units/
I1g) 0.1#l! and]-sodium chlorate29.
A uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns was obtained by adding 8.8 cm and mixing thoroughly. The powder composition thus obtained has 0.755 M RC units/#! Contains 1 of salmon calcitonin. A salmon calcitonin preparation for nasal administration to humans was obtained by filling 10 to 50 IIg of the powdered composition containing salmon calcitonin shown in (C) into a predetermined capsule.

(I) For comparison with the composition of the present invention, the following comparative composition containing no natural bile acid was obtained.

(Small salmon calcitonin (4,000M RC units/I
#g) 0.119 in a test tube, add 250 μm of purified water to dissolve it uniformly, and then add 5 μm of microcrystalline cellulose to this.
A homogeneous composition was obtained by adding 00IItg, thoroughly sprinkling, and freeze-drying.

The composition is then sieved to obtain 90% by weight
A uniform powder composition was obtained in which the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0,800 M RC units/Ing of salmon calcitonin.

+b+ Salmon calcitonin (4,000M RC units/Rg) 0.
After adding micro-polishing to uniformly dissolve the mixture, 500 wJ of microcrystalline cellulose was added thereto, and the mixture was thoroughly sprinkled and vacuum-dried to obtain a uniform composition.

Next, the composition was sieved to obtain a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0.800 M RC units/IIH of salmon calcitonin.

(C') Microcrystalline cellulose 500R9 was placed in a mortar, and salmon calcitonin (4, OOOMRC units/
By adding η)0.1 column and mixing thoroughly, a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns was obtained.

The powder composition thus obtained was 0.800M
Contains RC units/seasonal salmon calcitonin.

Example 2 (Nasal Administration Experiment of Powdered Calcitonin Preparation in Domestic Rabbits) Injected into the cavity of white native male domestic rabbits (body weight 2.5-3.Jg), c), (za), (b'
1.4 M RC units/Ky of each of the calcitonin preparations prepared in +, tC) were administered, and specimens were taken from the ear veins of rabbits at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration, and before administration. . The white liquid after the bare surface is centrifuged at 2 and 8.
00r.

Plasma was obtained by centrifugation for 10 minutes. The powder was administered without anesthesia using a sprayer modified for animals. Specifically, it was performed as follows. That is, first, six types of calcitonin preparations prepared in Example 1 are filled into predetermined capsules at a dosage of 1.4 MRC units/Kg. The capsule is then placed in a nebulizer and fitted with a modified animal nozzle. Furthermore, by putting on the cap, a hole was made in the capsule using the needle attached to the inside of the cap, and the nozzle was immediately inserted into the nasal cavity of the rabbit, and nasal administration was performed by spraying with air pressure. Plasma lucium concentrations were measured before and after administration, and the absorbability of calcitonin through the nasal mucosa was investigated.

Plasma lucium was measured using a calcium measurement kit manufactured by Yatron.

The results are shown in Table 1 as the degree of decrease (%) in calcium value relative to the plasma calcium value before calcitonin powder administration. The values shown in the table are the average values of 5 rabbits. As shown in Table 1, the degree of decrease in plasma calcium 2 hours after intranasal administration of the six types of powders prepared by the method shown in Example 1 was approximately three times lower than that of the comparative example. In addition, the degree of total plasma calcium reduction (%/hr) increased by about 1.7 times or more compared to the comparative example. This shows that the formulation of the present invention, that is, the addition of sodium cholate, greatly increases the absorption of salmon calcitonin from the nasal mucosa, and that its absorption promoting effect is not significantly affected by the preparation method of the formulation. .

Example 3 Powder compositions (4 types in total) useful for nasal administration of the present invention were obtained as follows.

(1) Salmon calcitonin (4,000M RC units/Rg) 0, IRg and sodium hyocholate 29.7
#Il! After uniformly dissolving F in 250 μρ of purified water, 1 g of microcrystalline cellulose 500I was added thereto and sprinkled well.

Next! A uniform composition was obtained by freeze-drying this. The composition was further sieved to obtain a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0.0561 η of sodium hyocholic acid and 0.755 M RC units of salmon calcitonin in 1 Fjg.

0) A uniform powder composition was obtained in exactly the same manner as in (1) except that 29.55 WJ of sodium chenodeoxycholate was used instead of 29.7 IItg of sodium hyocholate. The powder composition obtained in this way has 1Fj
Contains 0.0558 μl of U-thorium chenodeoxycholate and 0.755 M RC units of salmon calcitonin per g.

(To) A uniform powder composition was obtained in exactly the same manner as in (1) except that 29.75 Rg of sodium taurocholate was used in place of 29.71119 of sodium hyocholate.

The powdered composition obtained in this way has 0.0% in 1Fjg.
0561 Itg Sodium Taurocholate and 0.7
Contains 55M RC units of salmon calcitonin.

(f) Sodium glycochenodeoxycholate 29,751F instead of sodium hyocholate 29.7Rg
A uniform powdery composition was obtained in exactly the same manner as in 0) except that j was used. The powdered composition thus obtained is 1
Contains 0.0558 Rg of sodium glycochenodeoxycholate and 0.755M RC units of salmon calcitonin.

Example 4 (Nasal Administration Experiment of Powdered Calcitonin Preparation in Domestic Rabbits) The (+), (i), b) and (f)
1.4M RC
The drug was administered 9 times to i11/, and blood was collected from the ear vein of the rabbit before and 30 minutes, 1 hour, 2 hours, and 4 hours after administration. The powder was administered in the same manner as in Example 2. Plasma lucium concentrations were measured before and after administration, and the absorbability of calcitonin through the nasal mucosa was investigated. Plasma lucium was measured using a calcium measurement kit manufactured by Yatron.

Table 2 shows the changes in plasma lucium and the calcium fall rate (
%). The values shown in the table are the average values of four domestic rabbits.

As a contrast, the powdered calcitonin preparation prepared in Example 1, which does not contain bile salts, was prepared at 1.4 MRC units/
Table 2 also shows the results when Ky was administered nasally.

33-Example 5 (I) A powdered composition useful for nasal administration of the present invention was obtained as follows.

(1) Salmon calcitonin (4, OOOMRC units/
Rg) o, oe #iF and sodium ursodesoxycholate 17.73 WJ were added with 150 μl of purified water and dissolved uniformly, then microcrystalline cellulose 300 erg
Added and sprinkled well. This was then freeze-dried to obtain a homogeneous composition. By sieving the composition, a uniform powder composition in which 90% by weight or more of particles had a particle size of 46 to 149 microns was obtained. The powdered composition obtained in this way has 0.055 in 119
8 mg of sodium ursodesoxycholate and 0,
Contains 755M RC units of salmon calcitonin.

Oi) Hydroxypropylcellulose 500IIt
g and sodium ursodesoxycholate 29.861
9 in a mortar, and add salmon calcitonin (4, OOOMRC units/Ill!J) 0.11f into the mortar.
90% by weight by adding tg and mixing well.
A uniform powder composition was obtained in which the particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0.0563 #j of sodium ursodesoxycholate and 0.755 M RC units of salmon calcitonin per volume.

(b) Salmon calcitonin (4,000M RC units/
■) 0.06■ and sodium ursodesoxycholate 17.804 were uniformly dissolved in 150μ of purified water, and then 300μ of lactose was added and sprinkled well. ). This was then freeze-dried to obtain a homogeneous composition. By further sieving the composition, 90% by weight or more of particles are 46-149
A uniform powder composition with a particle size of microns was obtained.

The powder composition thus obtained contained 0.0 in 1jIy.
560 η of sodium ursodesoxycholate and 0.
Contains 755M RC units of salmon calcitonin.

(to) By filling the powdered compositions containing salmon calcitonin and sodium ursodesoxycholate shown in (+), (i) and (to) into respective prescribed capsules, human nasal administration is possible. A calcitonin preparation for use was obtained.

(n) For comparison with the composition of the present invention, the following comparative composition containing no natural bile acid was obtained.

(V) Hydroxypropylcellulose 5001ft
g and salmon calcitonin (4, OOOMRC units/my)
0.1* in a mortar and thoroughly mixed to obtain a uniform powder composition. The powdered composition thus obtained contains 0.800 M RC units/IFJ of salmon calcitonin.

Salmon calcitonin (4,OOOMRC units/If
g) Dissolve 0.061jJ uniformly in 150μ of purified water, then add 300Rg of lactose and sprinkle well (at this time, part of the lactose has been dissolved). This was then freeze-dried to obtain a homogeneous composition.

The composition was further sieved to obtain a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. The powder composition thus obtained contains 0,800 M RC units/Rg of salmon calcitonin.

Example 6 (Nasal administration experiment of powdered calcitonin preparation in domestic rabbits) (1), Qi), and Ixl of Example 5 were administered into the nasal cavity of white native male domestic rabbits (weight 2.5 to 3.5 kg). , (v)
, &D and Example 1 (1.4 MRC units/Ky of the powdered calcitonin preparation was administered before and 30 minutes after administration.

Blood was collected from the ear vein of the rabbit at 1 hour, 2 hours, 4 hours, and 6 hours. The powder was administered in the same manner as in Example 2.

Plasma lucium concentrations were measured before and after administration, and the absorbability of calcitonin through the nasal mucosa was investigated. Plasma lucium was measured using a calcium measurement kit manufactured by Yatron. Figures 1, 2, and 3 show changes in plasma lucium in terms of plasma calcium lowering rate (%). The values shown in each figure are the standard error of the average value of 4 to 5 domestic rabbits. For comparison, 17.51 containing 0.16% gelatin and 0.7% sodium chloride.
The change in plasma lucium when 9 was intravenously injected into 150 μρ/1.4 M RC units of a salmon calcitonin aqueous solution dissolved in 1 IM citrate buffer (approximately 6 vomit) is also shown in each figure by a dashed line.

Figure 1 shows the case where microcrystalline cellulose is used as the base; (1) shows the preparation containing ursodesoxycholic acid of the present invention ((1) of Example 5), and (2) shows the case of bile salts. The figure shows the case where a formulation (the crystal of Example 1) that does not contain any of the following is administered.

Figure 2 shows the case where hydroxypropyl cellulose was used as the base; (1) is the formulation containing ursodesoxycholic acid ((g) of Example 5); ('2I is the formulation in which no bile salts are used); The figure shows the case where a formulation ((V) of Example 5) was administered.

Figure 3 shows the case where lactose is used as the base; (1) is the formulation containing ursodesoxycholic acid (@ in Example 5), and (2) is the formulation containing no bile salts (@). This shows the case where ψ) of Example 5 was administered.

As is clear from Figures 1, 2, and 3, the powdered compositions containing sodium ursodesoxycholate have excellent absorption of salmon calcitonin, and both have strong physiological activity almost equivalent to intravenous injection. We showed that it can be obtained.

Example 7 (I) B') Insi:x ri>100#Jwo0.1
Dissolve in 2.5d of 112M N and add 37.57ml of water, then add about 3.7ml of 0.1N aqueous sodium hydroxide solution.
Water-soluble insulin powder (23.5 units/I
Ig) was obtained. Using this insulin powder, the following composition of the present invention was obtained.

(ω Water-soluble insulin powder (23,5 units/■)
Take 10Rg and 20μ of sodium glycodeoxycholate in a mortar, and add 320μ of microcrystalline cellulose to this.
IfJ was added and the three components were thoroughly mixed to obtain a homogeneous powder composition.

The powdered composition thus obtained contained 0% in 111g.
．． 057 ■ sodium glycodeoxyfurate and 0.
Contains 67 units of insulin.

(I) Using the above insulin powder, the following comparative compositions were obtained for comparison with the compositions of the present invention.

(b) Water-soluble insulin powder (23,5 units/
■) 10I! g and 340 Rg of microcrystalline cellulose were placed in a mortar and mixed well to obtain a uniform powder composition. The powder composition thus obtained was 0.6
It has an insulin activity of 7 units/■.

(C) Water-soluble insulin powder (23,5 units/
I#g) 7.11Pj and sodium glycodeoxycholate 20.7IRg are made isotonic with a chloric acid W solution (pH 7,
4) By dissolving in 2.07 yd, a solution composition having a final concentration of 81 to 80.6 units/Id insulin and 1% (w/v) sodium glycodeoxycholate was obtained.

Example 8 (Nasal Administration Experiment of Insulin Preparation in Domestic Rabbits) Intranasal injections were prepared as described in Example 7 (J and mountain) in the nasal cavity of white native male domestic rabbits (weight 2.5-3.5, 5F). Each powdered insulin preparation was administered at 1.21 units/Kg, 5 minutes, 10 minutes, 2C) minutes, 30 minutes, 1 minute before and after administration.
Blood was collected at 2 hours, 4 hours, and 6 hours. The powder was administered in the same manner as in Example 2. Plasma glucose concentrations and plasma insulin concentrations were measured before and after administration, and the absorbability of calcitonin from the nasal mucosa was investigated. Insulin concentration in plasma was measured by radioimmunoassay. The results are shown in Figure 4. Plasma glucose concentration was measured by a method using orthotoluidine (Clinical Chemistry (Gl1nical Ch.
emistry) 8, 215 (1962)). The results are shown in Figure 5 as blood sugar lowering rate (%).

The values shown in FIGS. 4 and 5 are the average values of five domestic rabbits. For comparison, the results were also obtained when the insulin solution prepared in (C) of Example 7 was administered nasally at 1.21 units/15μd/9 times using a microsyringe with a tip for nasal administration attached to the tip. This is shown in broken lines in FIGS. 4 and 5.

As shown in Figure 4 (a), the plasma insulin level after administration of the powder supplemented with sodium glycodeoxycholate of the present invention reached its highest level 10 minutes after administration, increasing more than 50 times the basal level. In the case of the powder administration prepared in Comparative Example as shown in 2003-12-12, the highest level was reached 30 minutes after administration, and the value was almost the same as in the case of the powder administration of the present invention. Furthermore, as shown by the dotted line, in the case of administration of the liquid formulation prepared in the comparative example to which sodium glycodeoxycholate was added, the highest level was reached 5 minutes after administration, but this value was lower than in the case of administration of the powder formulation of the present invention. In this case, the level returned to almost the basal value 60 minutes after administration. The above facts indicate that administration of the powder of the present invention allows insulin to be absorbed particularly efficiently from the nasal mucosa and that absorption is efficiently sustained. As shown in Figure 5, the fluctuation pattern of the blood sugar lowering rate correlates well with the fluctuation pattern of the insulin level after administration of each preparation, indicating that the powder of the present invention is particularly superior in terms of blood sugar lowering rate. I understand.

Example 9 (1) Take the water-soluble insulin powder prepared in Example 7 (I) (23.5 units/IIg) and 20 μl of IFI sodium tursotes oxycholate in a mortar.
Furthermore, microcrystalline cellulose 320 (j is added to this,
A homogeneous powder composition was obtained by thoroughly mixing the three components. The powdered composition thus obtained contains 0.057 I1 g of sodium ursodesoxycholate and 0.67 units of insulin activity per volume.

(2) A homogeneous product containing 0.057Rg of sodium cholate and 0.67 units of insulin activity in 11Ig was prepared in exactly the same manner as in (1) except that sodium cholate was used instead of sodium ursodesoxycholate. A powdered composition was obtained.

(3) Contains 0.057IItg of sodium taurocholate and 0.67 units of insulin activity in 1r#g in exactly the same manner as in (1) except that sodium taurocholate is used instead of sodium ursodesoxycholate. A uniform powder composition was obtained.

Example 10 (Administration experiment of powdered insulin preparation in dogs) m, (2+, +3 of Example 9) was administered into the nasal cavity of a male peagle dog (weight 9.0 to 11.0 kg) without anesthesia.
1 and 4 types of preparations prepared in Example 7 (b) for comparison were each administered 9 times per unit, 5 minutes before and 5 minutes after administration.

Blood was drawn orally at 10 minutes, 20 minutes, 30 minutes, 1 hour and 2 hours. The powder was administered in the same manner as in the case of domestic rabbits in Example 2.
The liquid preparation was administered in the same manner as in Example 8 for domestic rabbits. Absorption of insulin from the nasal mucosa was investigated by measuring insulin levels in the plasma before and after administration by radioimmunoassay. The plasma insulin level measurement results are shown in Table 3. The values shown in the table are the average values of 4 peagle dogs. As a control, Example 7 (
1 unit/1 insulin aqueous solution containing 1% (W/V) of the bile salts described in Example 9 prepared in the same manner as C)
Table 3 also shows the results when 5 μU//(g) was administered nasally.

Example 11 A powdered composition useful for nasal administration of the present invention was obtained as follows.

(1) Alpha Human Atrial Nutrition Polypeptide (α-hANP) 0.5
Itg and sodium ursodesoxycholate 29.8
After uniformly dissolving (2) in 250 μρ of purified water, 50011 g of microcrystalline cellulose was added thereto and sprinkled well. This was then freeze-dried to obtain a homogeneous composition. 90% by further sieving the composition.
A uniform powder composition was obtained in which the largest percent by weight of particles had a particle size of 46 to 149 microns. The composition thus obtained contained 0.943 μ9 of alpha human atrial natriuretate polypeptide (α-h
ANP) and 56 μ3 of sodium ursodesoxycholate.

(2) Hydroxypropylcellulose 500115
1 and sodium ursodesoxycholate 29.8Rg
in a mortar, and in this mortar add alpha human atrial uretic polypeptide (α-hA).
By adding N P ) 0.5~ and mixing well, a uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns was obtained. The composition thus obtained contains 0.943 .mu.9 of alphahuman atrial natriuretic polypeptide (.alpha.-hANP) and 56 .mu.9 of sodium ursodesoxycholate per volume.

(3) In exactly the same manner as in (2) except that 500 IItg of lactose was used instead of 500μ of hydroxypropyl cellulose, 0.943μg of alpha human atrial natriuretic polypeptide (α-hANP) and 11Ig were added. A homogeneous powder composition containing 56μ of sodium ursodesoxycholate was obtained.

(41 [11, (2) and (3)) and alpha human atrial natriuretic polypeptide (α-hA N
A preparation for human nasal administration was obtained by filling a powdered composition containing P ) into a predetermined capsule.

Example 12 Take 500 q of microcrystalline cellulose in a mortar, add 30 q of sodium glycodeoxycholate and 10 q of freeze-dried papresin (70 to 100 units/■), and mix well to obtain a uniform powder composition. I got something. The powdered composition thus obtained contained 0.0% in 1aiF.
056■ Sodium glycodeoxycholate and 1.3
Contains 0-1.85 units of pap pressin.

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

Example 13 1 g of microcrystalline cellulose 930I was placed in a mortar, and 60 kg of sodium glycodeoxycholate and 10 #iF of lyophilized luteinizing hormone-releasing hormone were added thereto and mixed well to obtain a uniform powder composition. Ta. The powdered composition obtained in this way has 0.06
1 rtg of sodium glycodeoxycholate and 0.0
A preparation for human nasal administration was obtained by filling a predetermined capsule with the luteinizing hormone-releasing hormone #1 #j.

Example 14 Microcrystalline cellulose 939Fl was placed in a mortar, and sodium glycodeoxycholate 60Wj and freeze-dried desmopressin acetate 1#i+ were added thereto and mixed well to obtain a uniform powder composition. The powder composition thus obtained contains 0.06 μ sodium glycodeoxycholate and 0.001 J115 F desmopressin acetate in 1 IPJ, and can be administered nasally to humans by filling it into a prescribed capsule. A formulation was obtained.

Example 15 A powdered composition useful for nasal administration of the present invention was obtained as follows.

(1) Take 900WJ of microcrystalline cellulose in a mortar, add 50μ of sodium taurodeoxycholate and 5Qq of interferon (100,000 units/+y) freeze-dried with human face albumin and mix well. A homogeneous powder composition was obtained. The powdered composition thus obtained contains 0.05 μ of sodium taurodeoxycholate and 5000 units of interferon per 1 μ.

(2) 0.05w in 11Itg in exactly the same manner as in (1) except that hydroxypropyl cellulose 900Rg was used instead of microcrystalline cellulose 900I#g.
A homogeneous powder composition containing sodium taurodeoxycholate of J and 5000 units of interferon was obtained.

(3) A homogeneous powder containing 0.05 μ of sodium taurodeoxycholate and 5000 units of interferon in 1R9 was prepared in exactly the same manner as in (1) except that lactose 900 μ was used instead of microcrystalline cellulose 900115F. A composition was obtained.

(41 [11, (21 and (3)) A preparation for human nasal administration was obtained by filling a powdered composition containing sodium taurodeoxycholate and interferon into a predetermined capsule.

Example 16 Hydroxypropylcellulose 499WJ and [ASIJ
1.7]-eel calcitonin (4000 M RC units/IfI) 1.5 mm was taken in a mortar and mixed thoroughly to obtain a uniform powder composition (I). The powdered composition (I) has 8 MRC units/m9 of [ASUl, 7]
- Contains eel calcitonin.

Next, powder composition (I) 70#+51 and sodium glycochenodeoxycholate (30 IItg) were placed in a mortar, and 400 mg of microcrystalline cellulose was added thereto and mixed well, so that 90% or more of the particles were 10 to 25 g.
A homogeneous powder composition with a particle size of 0 microns (If
) was obtained. Powdered composition (I) thus obtained
is sodium glycogutthioxycholate of 0.06 Irg in 11Ig and [ of 1.12 M RCt+i position]
ASU 1.7] - Contains eel calcitonin.

A preparation for human nasal administration was obtained by filling 10 to 50I1g of the composition (I[) into a predetermined capsule using a capsule filler.

Example 17 [ASU 1,7]-Eel calcitonin 1 and 0.2 g of sodium glycochenodeoxycholate were uniformly dissolved in 10 d of purified water and then freeze-dried to obtain a uniform powder composition (I). Obtained.

The weight ratio of [ASU 1.7]-eel calcitonin and sodium glycocholate in the powdered composition is i
: 200. Then, (ω powder composition (I
>20.1q and hydroxypropyl cellulose 479
．． 9 by taking 1 #j in a mortar and mixing well.
A uniform powder composition (I) in which 0% or more of the particles had a particle size of 10 to 250 microns was obtained. Furthermore, +b+ powder composition (I) 20.1q and microcrystalline cellulose 47
By taking 9.1■ in a mortar and mixing well,
19. A homogeneous powder composition (I[I) in which more than 0% of the particles have a particle size of 10 to 250 microns. The powdered compositions ([) and (I[[) thus obtained are composed of 0.04 IRg of sodium glycochenodeoxycholate and 0.8 M RC units of [ASU] in 1Rg, respectively.
1.7]-contains eel calcitonin.

The composition (n) and (I[[)
In total, combine 10 to 50 ■ into the designated capsule.
A preparation for human nasal administration was obtained by filling.

Example 18 Hemagglutinin IRg, a component of Bordetella pertussis, detoxified white pertussis toxin IRg, sodium ursodesoxycholate 38#llj and crystalline cellulose 960
IItg in a mortar and thoroughly mixed to obtain a uniform powder composition. The powder composition thus obtained contains 0.038#+ in 1rRg! Contains 7 parts of sodium ursodesoxycholate and 0,002 IIrg of Bordetella pertussis components.

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

Example 19 Powder 200Rg obtained by freeze-drying influenza HA vaccine and hydroxypropylcellulose 800R
A uniform powdery composition (I) was obtained by taking the ingredients and mixing them well in a mortar. The powdered composition (I) contains about 200 μ'j/Rfl of a lyophilized powder of influenza HA vaccine. Then the powdered composition (I
) 50■ and sodium ursodesoxycholate 5
By taking 0#19 and crystalline cellulose 900η in a mortar and mixing well, 90% or more of the particles are 10 to 15
A homogeneous powder composition with a particle size of 0 microns (II
) was obtained. Powdered composition (n) thus obtained
contains 50 microns of sodium ursodesoxycholate and 10 microns of lyophilized powder of influenza 1-(A vaccine in 11 tg. Fill 10 to 50 microns of the composition (II) into a given capsule using a capsule filler. By doing so, a formulation for human nasal administration was obtained.

Example 20 (I) A powdered composition useful for nasal administration of the present invention was obtained as follows.

(J glucagon 0,511 Ig and sodium ursodesoxycholate 5IItg and microcrystalline cellulose 10
0 ■ in a mortar and mix well to make 90%
A uniform powder composition was obtained in which the particles had a particle size of 25 to 149 microns.

The powdered composition thus obtained contained 47
．． 4 μq of sodium ursodesoxycholate and 4.
Contains 74μ7 glucagon.

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

(b) Glucagon 0.511PI and microcrystalline cellulose io.

(2) were taken in a mortar and mixed thoroughly to obtain a uniform powder composition in which more than 90% of the particles had a particle size of 25 to 149 microns. The powdered composition thus obtained contains 4.98 μg/■ of glucagon.

(C) 0.5 mg of glucagon and 15 Itg of sodium ursodesoxycholate were mixed in isotonic phosphate buffer (
pH7.4) It was uniformly dissolved in 1.5m. The solution thus obtained contains 1% (W/V) of sodium ursodesoxycholate and 333.3 μg/d of glucagon.

Example 21 (Administration experiment of glucagon preparation in dogs) The (ω, (b) and (C)) of Example 20 was administered into the nasal cavity of a male peagle (body weight 9.0 to 11,0K9) without anesthesia. 5μ9 each of the two types of powder and one type of liquid that were created
'j administered to /, 5 minutes, 10 minutes, 20 minutes before and after administration.
Blood was collected at 30 minutes, 1 hour and 2 hours. The powder formulation was administered in the same manner as in Example 2 for rabbits, and the liquid formulation was administered in the same manner as in Example 8 for rabbits. Table 4 shows the results of examining the absorption of glucagon from the nasal mucosa by measuring plasma glucagon levels before and after administration using radioimmunoassay (Glucagon RIA kit manufactured by Dynabot). It is shown as the average value.

In the case of the formulation of the present invention containing sodium ursodes oxycholate, the plasma glucagon level reached its maximum 10 minutes after intracavitary administration, and the value was approximately 40 times the basal value, but compared to ursodes oxycholate. In the case of the comparative preparation that did not contain sodium desoxycholate, the maximum value was reached 20 minutes after administration, and the value was about 18 times the basal value. In addition, in the case of powder administration, plasma glucagon levels above the basal value were observed even 2 hours after administration.

On the other hand, when a control solution containing 1% (w/v) sodium ursodesoxycholate was administered, the plasma glucagon level reached its maximum level 5 minutes after administration; It was lower than in the previous case, and completely returned to the basal level 2 hours after administration. These results indicate that glucagon in the formulation of the present invention was most efficiently absorbed through the nasal mucosa.

Example 22 A powdered composition useful for nasal administration of the present invention was obtained as follows.

Q) Corticothrobin 0.5II! g, sodium deoxycholate 19.5 μg and microcrystalline cellulose 4
80#l! ? A uniform powder composition in which 90% by weight or more of the particles had a particle size of 10 to 250 microns was obtained by taking the ingredients in a mortar and mixing them well. The powder composition thus obtained contains 0.03911 g of sodium deoxycholate and 1 μm of corticothrobin in 11 Rg.

0) A uniform powder composition was obtained in exactly the same manner as in (1) except that 19.51 Rg of sodium glycodeoxycholate was used instead of sodium deoxycholate. The powdered composition obtained in this way is 1q.
Contains 0.039 IPJ of sodium glycodeoxycholate and 1 μ9 of cordicotropin per g.

(A) A uniform powder composition was obtained in exactly the same manner as in (+) except that 19.5 μg of sodium taurodeoxycholate was used instead of sodium deoxycholate. The powdered composition thus obtained contains 0.039 Rg of sodium taurodeoxycholate and 1 μg of corticothrobin in 11 Rg.

(f) A uniform powder composition was obtained in exactly the same manner as in (1) except that 19.51 ftg of sodium glycochenodeoxycholate was used instead of sodium deoxycholate. The powder composition thus obtained was 1
1 Ig contains 0.03911 Ig of sodium glycochenodeoxycholate and 1μ of corticothrobin.

(V) A uniform powder composition was obtained in exactly the same manner as in (1) except that 19.511 tg of sodium taurochenodeoxycholate was used instead of sodium deoxycholate. The powdered composition thus obtained contains 0.039 R9 of sodium taurochenodeoxycholate and 1 μ9 of corticothrobin in 111 g.

(A uniform powder composition was obtained in exactly the same manner as in (1) except that 19.5 μl of glycoursodesoxycol Mputrium was used instead of sodium deoxycholate. The powder thus obtained The composition is 11It
Contains 0.0391 ng of sodium glycoursodesoxycholate and 1 μ9 of corticothrobin per g.

A uniform powder composition was obtained in exactly the same manner as (D) except that 19.5 Ing of sodium tauroursodesoxycholate was used instead of sodium deoxycholate. The material is 1N
! Contains 0.0391 ftg of sodium tauroursodesoxycholate and 1 μq of corticotropin per g.

(1) except that sodium glycohyocholate 19.5η is used instead of sodium deoxycholate.
A uniform powder composition was obtained in exactly the same manner as above. The powdered composition thus obtained contained 0.0 tg in 11 tg.
391119 sodium glycohyocholate and 1 μ3
Contains fluticothrobin.

OX) Except for using sodium taurohyocholate 19.5■ instead of sodium deoxycholate (
A uniform powdery composition was obtained in exactly the same manner as in +).

The powdered composition thus obtained contains 0.0391 rtg of sodium taurohyocholic acid and 1 μ3 of corticothrobin in 111 Pg.

(X) Filling a prescribed capsule with 10 to 50 WJ of nine types of powdered compositions containing bile salts and corticothrobin prepared in (1) to 0, either alone or in combination of two or more types. A formulation for human nasal administration was obtained.

Example 23 Powder composition useful for nasal administration of the present invention ((of Example 5))
For comparison with 1)), the following powdered composition was prepared. Namely, sodium ursodesoxycholate17.
73 Rg instead of nonionic surfactant polyoxyethylene (10) cetyl ether 17.73 tRg
A uniform powder composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns was obtained in exactly the same manner as in Example 5 (1), except that .

-b, 3- Powdered composition 11IF thus obtained! Contains 0.0558 IPJ of polyoxyethylene (10) cetyl ether and 0.755 M RC units of saccharitonin.

Comparative administration experiments were conducted on white native male domestic rabbits (body weight 3-3.8/cm).
(9) in exactly the same manner as in Example 2. The results when the dose was 1.4M RC units/9 were shown in the fifth column.
The table shows the plasma calcium lowering rate. Plasma calcium fall rate (%) 2 hours after administration and 4 hours after administration shown in Table 5
As is clear from the comparison of the total plasma calcium lowering rate (%/hr) up to 1 hour, the powder of the present invention using sodium ursodesoxycholate is better than the powder using polyoxyethylene (10) cetyl ether. It can be seen that the absorption efficiency of salmon calcitonin is higher than that of the formulation.

-b 4- Example 24 ■8 Composition (I) for comparison with the powdered composition useful for nasal administration of the present invention and powdered composition (I[ , I[[and TV] were created as follows.

(1) Water-soluble insulin powder (23.5 units/■) prepared in the same manner as in Example 7 by dissolving 50 #19 and 100 q of sodium taurocholate in 30 - of purified water, and then freeze-drying. A homogeneous composition was obtained. A powdered composition (I) was obtained by passing the composition through a 100 mesh (149 micron) sieve. The water-absorbing solid base-free powder composition (I) thus obtained contains 667 .mu.q of sodium taurocholate and 333 .mu.9 (7,83 units) of insulin per volume.

([i) (+) Powdered composition (I >
30Rg and 160μ of microcrystalline cellulose were placed in a mortar, thoroughly mixed, and then sieved to obtain a uniform powder composition (n) in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. . The powdered composition thus obtained (I [>) contains 105 μl of sodium taurocholate and 1.24 units of insulin in 11 Irg.

(b) Except for replacing microcrystalline cellulose 1601rtg with hydroxypropyl cellulose 160Itg (i
) to obtain a homogeneous powder composition (I[[) containing 105 μl of sodium taurocholate and 1.24 units of insulin in 11 Itg.

(g) Microcrystalline cellulose 160Ifj to lactose 160q
In 1g8, do exactly the same as O) except for replacing with
Homogeneous powder composition (IV) containing 105 μ9 of sodium taurocholate and 1.24 units of insulin
I got it.

■Comparative administration experiments were conducted on male Peagle dogs (body weight 9-11N).
g) was used. Nasal administration was performed in the same manner as in Example 8 for domestic rabbits. Each preparation was filled into capsules with a weight such that the dose of insulin was 1 unit/dose of 9. Changes in plasma glucose concentration after administration are shown in Table 6 as blood glucose lowering rate (%). Especially the 6th
Blood glucose lowering rate (%) 1 and 2 hours after administration as shown in the table
As is clear from the comparison of the total blood glucose lowering degree (% hr) up to 6 hours after administration, the present invention using a water-absorbing solid base such as microcrystalline cellulose, hydroxypropyl cellulose, or lactose. It was inferred that the powder formulation had higher absorption of insulin from the nasal mucosa than the comparative formulation that did not use a water-absorbing solid base.

[Brief explanation of drawings]

Figures 1, 2, and 3 show the absorption of salmon calcitonin when the composition of the present invention using salmon calcitonin as a polypeptide was administered nasally, and the plasma calcium lowering rate (
%). Figures 4 and 5 show the absorption of insulin in terms of insulin concentration (Figure 4) and blood sugar lowering rate (Figure 5), respectively, when the composition of the present invention using insulin was administered nasally. be. In FIGS. 1, 2, and 3, (1) is based on microcrystalline cellulose (FIG. 1, (+) in Example 5), hydroxypropylcellulose (FIG. 2, (+) in Example 5), 5)) and lactose (Figure 3, Example 5)
), each containing sodium ursodesoxycholate as an absorption enhancer, [2
1 have the same base material (Fig. 1: (a) of Example 1, Fig. 2: (b) of Example 5, Fig. 3: Example 5).
(v)), which does not contain sodium ursodesoxycholate. The wavy line indicates a platform where the same dose of calcitonin as the intranasal administration was administered intravenously as a control. In FIGS. 4 and 5, (a and mountains) indicate the case where microcrystalline cellulose is used as the base, and J indicates the case where sodium glycodeoxycholate is included as the absorption enhancer (Example 7). In (a)), +b+ indicates the case where it is not included (the hoe of Example 7). The wavy line indicates 1 (w/
Figure 3 shows the case where an insulin liquid preparation ((C) of Example 7) containing %v)% of sodium glycodeoxycholate was administered nasally at the same dose as the powder preparation.

Claims (1)

[Scope of Claims] 1. (a) Polypeptides having physiological activity (b) Natural bile acid represented by the following formula and/or a pharmaceutically acceptable salt thereof as an absorption enhancer; and (c) A powder composition for nasal administration, comprising a water-absorbing solid base suitable for application to the nasal mucosa. (In the formula, D is OH, -NHCH_2COOH or -NHC
H_2CH_2SO_3H, V is H or β-HO
, W represents H, α or βOH, and X, Y and Z each represent H, α- or β-OH or =O. however,
When X, Y and Z are all OH and both V and W are H, D is OH or -NHCH_2CH_
Indicates 2SO_3H. 2. The composition according to claim 1, wherein the natural bile acid has at least two hydroxyl groups in its molecule. 3. Natural bile acids include cholic acid, ursodesoxycholic acid, taurocholic acid, chenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycodesoxycholic acid, tauroursodesoxycholic acid, glycosyl Chenodeoxycholic acid, taurochenodeoxycholic acid, hyocholic acid, glycohyocholic acid, taurohyocholic acid, 3α,7α-dihydroxy-12-ketocholic acid, 3,6,7,12-tetrahydroxycholic acid, 3α,6α,12α-trihydroxy The composition according to claim 1 or 2, which is cholic acid or 1β,3α,12α-trihydroxycholic acid. 4. The composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of the natural bile acid is an alkali metal salt. 5. According to any one of claims 1 to 4, wherein the natural bile acid and/or its pharmaceutically acceptable salt is present in a concentration of 0.1 to 30% by weight of the total weight. Composition of. 6. The water-absorbing solid base is water-absorbing and poorly water-soluble celluloses, starches, proteins, crosslinked vinyl polymers,
The composition according to any one of claims 1 to 5, which is a gum or a gum. 7. The composition according to any one of claims 1 to 6, wherein the water-absorbing solid base is a water-absorbing and easily water-soluble base. 8. Polypeptides with physiological activity have a molecular weight of 300
8. A composition according to any one of claims 1 to 7, which is a polypeptide of ~300,000. 9. Claims 1 to 8, wherein the physiologically active polypeptide is a peptide hormone, its precursor, its inhibitor, or its derivative, a physiologically active protein, an enzyme protein, or a vaccine or vaccine component. The composition according to any one of the items. 10. Claim 1 in which 90% by weight or more of the particles of the powder composition have an effective particle size of between 10 and 250 microns.
The composition according to any one of Items 1 to 9.