JPS63115820A - Powdery composition for nasotracheal administration containing ascorbic acids - Google Patents

Abstract

PURPOSE:To obtain the titled composition consisting of a polypeptide, an ascorbic acid as an absorption promoter and a water-absorbing solid base suitable for nasal mucosa. CONSTITUTION:A powdery composition for nasotracheal administration containing a physiologically active polypeptide (e.g. peptide hormone such as calcitonin, physiologically active protein such as interferon; enzyme protein such as lysozyme, etc., vaccine such as influenza vaccine, etc.), an ascorbic acid (e.g. ascorbic acid, erysorbic acid, etc.) as an absorption promoter and a water-absorbing solid base (e.g. water-absorbing and slightly water-soluble cellulose, starch, protein, crosslinked vinyl polymer or gum) suitable for application to nasal mucosa. The concentration of the ascorbic acid is preferably 0.1-30wt% based on sum of the composition. The composition can be made into powder in unit administration form and can be packed into capsules as preferable form.

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 provides a powder composition comprising physiologically active polypeptides such as calcitonin and insulin, ascorbic acids as an absorption enhancer, and a water-absorbing solid base. The present invention relates to a polypeptide composition useful for intranasal administration, in which the polypeptide is absorbed extremely efficiently through the external mucosa when administered by spraying into the nose.

<Problems to be solved by the prior art and the invention> Peptide hormones such as insulin and calcitonin have large molecular weights and are easily degraded by proteins such as pepsin, trypsin, or chymotrypsin, so they are difficult to absorb when administered orally, so they are not effective. Currently, it is unable to exhibit pharmacological effects, and therefore is administered as an injection.

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

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

Pharm, Pharmacol, ), 33.
334 (1981)]. Other methods include intratracheal administration [Diabetes,
20. 552. (1971)].

Eye drop administration (Diabetic Society Abstracts, 237. (197
4) Methods such as ) are being considered.

However, since both methods require a higher dose R than injection and have the drawbacks of variable absorption, very few methods have yet been put into practical use.

On the other hand, as an attempt at intracavitary administration, a method of nasally administering an aqueous solution of insulin using a surfactant such as sodium glycodeoxycholate as an absorption enhancer is known [Proceedings of the National・Academy of Science (proc, Natl, A
cad, sci, ll.

S, A, ) 82. pp7419-7423 (
1985)]. Alternatively, a method of administering insulin, glucagon, etc. in an aqueous solution using a fusidic acid derivative such as sodium-tauro-24,25-dihydroxyfusidate as an absorption enhancer is known (Japanese Patent Application Laid-open No. 33126/1983). There is. Furthermore, a liquid preparation for nasal administration of insulin containing cyclodextrin is also known (Japanese Unexamined Patent Publication No. 58-189118@).

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

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

This preparation allows high molecular weight peptide hormones to be absorbed relatively efficiently through mucous membranes. Furthermore, as a powdered preparation for nasal administration, US Pat. No. 4,294,829
In JP-A No. 61-194034, there is a preparation consisting of cellulose lower alkyl ether and a drug.
Formulations consisting of cellulose lower alkyl ethers, quaternary ammonium compounds, and polypeptides are disclosed. These preparations have the characteristic that cellulose lower alkyl ether absorbs water on the mucous membrane, becomes a viscous liquid, flows on the mucous membrane, and gradually releases the drug. . However, even with these methods,
However, it cannot be said that drugs are absorbed efficiently through the mucous membranes, and there is still room for improvement.

On the other hand, ascorbic acid and/or its salts or esters have conventionally been used as antioxidants in foods or medicines, and JP-A-60-161924 discloses that ascorbic acid and/or its salts or esters are included as antioxidants in compositions for pulmonary absorption. Moreover, JP-A-61-194034 discloses that it may be included as an antioxidant in a powdered composition for nasal administration.

As described above, the use of ascorbic acids and/or their salts or esters as antioxidants is known.

However, it has hardly been reported that these compounds have the effect of promoting the absorption of drugs, especially polypeptides, when administered through the nasal mucosa, and only a few have been reported in JP-A-56.
Publication No. 138112 only discloses that ascorbic acids and/or sodium ascorbate have the effect of promoting rectal absorption of drugs in suppository administration by the present inventors; There has been no report on what kind of action acids have.

Means for Solving the Problems> The present inventors have discovered that ascorbic acids, as well as their salts and/or
We also thought that these esters could serve as absorption enhancers, and we conducted extensive studies on this possibility.

As a result, it was surprisingly found that nasal mucosal absorption of polypeptides was significantly promoted only when a powdered nasal preparation containing ascorbic acid or erythorbic acid was produced and administered. When producing and administering powdered nasal preparations containing salts and/or their esters, such as sodium ascorbate, ascorbic acid stearate, etc., nasal mucosal absorption of polypeptides is hardly or only slightly promoted. The present invention was finally completed based on the discovery that, among ascorbic MM, their salts and/or their esters, which are generally used as antioxidants, ascorbic acids are the only polypeptides. It could not have been predicted from the prior art that it would have the effect of significantly promoting mucosal absorption.

That is, the present invention provides (a) polypeptides having physiological activity, (b) ascorgotic acid as an absorption enhancer,
and (c) a water-absorbing solid base material suitable for application to mucous membranes.

Specific examples of ascorbic acids preferable as the absorption enhancer of the present invention include ascorbic acid,
■An example is resorpic acid. It does not contain salts of ascorbic acids and/or their salts.

Preferred concentrations of the particular ascorbic acids in the powdered compositions useful for nasal administration of the present invention are about 0.1 to 3% of the total composition width.
It is 0 weight %, more preferably 0.5 to 20 weight %, and still more preferably 1 to 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. 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, vasopressin,
Desmobrecin, ferribrecin, protirelin, luteinizing hormone-releasing hormone, corticosteroids, prolactin, somatotropin, thyrotropin, luteinizing hormone, calcitonin.

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

Lipomodulin, atrial natriuretic peptide [alphahuman atrial natriuretic polybebutide (α-hANP), etc.], growth hormone-releasing hormone, growth hormone, erythroboetin, urogastrone, renin, parathylin (PTH) and their antagonists peptide hormones such as corticotropin-releasing factors, precursors thereof, inhibitors thereof or derivatives thereof;
interferon, interleukin, tumor necrosis factor (
TNF), transferrin, histaglobulin.

Physiologically active proteins such as macrocortin and superficial fluid coagulation factor;
Enzyme proteins such as lysodeme and O-kinase; vaccines or vaccine components such as pertussis vaccine, diphtheria vaccine, tetanus vaccine, influenza vaccine, lymphocytosis factor, hemagglutinating factor 111, etc. may be mentioned.

Among these, peptide hormones are particularly preferred, and among the peptide hormones, calcitonin, insulin, α-hANP, luteinizing hormone-releasing hormone, corticosteroid, desmobrecin, vasopressin,
Glucagon, oxytocin, PTH or growth hormone are preferred. Furthermore, calcitonin, insulin, α-h
ANP is preferred.

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 money used for the above-mentioned polypeptides 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 other than basic, sodium chloride, phospholipids, etc. may be used in combination.

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 mucous membrane 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 about 36°C to about 37°C. Furthermore, water-absorbing and water-soluble means that it is on the human mucous membrane or in an environment similar to this, that is, at a pH of about 7.4.
This means that it has the property of being water-absorbing and easily soluble in water at a temperature of about 36°C 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, water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, and cross-linked sodium carboxymethylcellulose; and poorly water-soluble starches;
Water-absorbing and poorly water-soluble proteins such as gelatin, casein, and sodium caseinate; Water-absorbing and poorly water-soluble gums such as gum arabic, gum tragacanth, and glucomannan; polyvinyl polypyrrolidone, crosslinked polyacrylic acid, and its salts. , crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate, and other water-absorbing and poorly water-soluble crosslinked vinyl polymers. Among these, water-absorbing and slightly water-soluble celluloses are preferred, with crystalline cellulose, α-cellulose, or crosslinked carboxymethyl cellulose sodium being particularly preferred, and crystalline cellulose being even more preferred.

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 the weight or more of the polypeptide.
Particularly preferred is a range of 15 weight or more, more preferably 200 weight or more.

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 methyl cellulose and cellulose sodium; dextrin, cyclodextrin (α-, β-, γ- or dimethyl α- −
or dimethyl β-), water-absorbing and easily water-soluble starches such as pullulan; water-absorbing and easily water-soluble vinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and sodium salts of carboxyvinyl polymers; Water-absorbing and easily water-soluble polyacrylates such as sodium acrylate, potassium polyacrylate, and ammonium polyacrylate; Water-absorbing and easily water-soluble proteins such as chitin and chitosan; Lactose, glucose, maltose,
Examples include water-absorbing and easily water-soluble sugars such as sucrose. Among these water-absorbing and easily water-soluble bases, in particular, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (β-.dimethylβ- or dimethylα-), chitin,
Chitosan, lactose, sodium polyacrylate, polyethylene glycol, polyvinylpyrrolidone are preferred, especially hydroxypropylcellulose, β-cyclodextrin, 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 used varies depending on the type of polypeptide used, etc. - Although it cannot be generalized, it is usually in the range of 1 times the weight or more of the polypeptide.
Particularly preferred is a range of 15 times by weight or more, more preferably 20 times by weight or more.

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 cavity, they are widely distributed on the mucous membrane and remain well at the adhesion site, and are also sprayed into the cavity through the pores as a powder. When administered, it can be efficiently administered intracavitally.

Particles smaller than 10 microns in effective particle size are 10ffl
If the amount is greater than fa%, when administered by a method such as spraying, a large amount will reach the lungs or dissipate outside the membrane when sprayed.

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

On the other hand, when particles with an effective particle size exceeding 250 microns account for more than 10% by weight, when administered into the necrotic cavity, they tend to separate from the mucous membrane even if they adhere to the mucous membrane, resulting in low local retention of the drug. Therefore, it is undesirable. Particularly preferred are particles whose effective particle diameter is between 20 and 150 microns and whose weight is 900 or more.

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

That is, physiologically active polypeptides, ascorbic acids, and a water-absorbing solid base are mechanically mixed and then sieved so that preferably 90% by weight or more of the particles have an effective particle size of 10 to 250 microns. It can be manufactured by preparing 1 q of the composition.

Alternatively, polypeptides having physiological activity.

After homogeneously dissolving or suspending ascorbic acids in an appropriate amount of purified water, a water-absorbing solid base suitable for application to the nasal mucosa, that is, a water-absorbing and sparingly water-soluble base, and/or Alternatively, add a water-absorbing and easily water-soluble base to uniformly contain and/or adsorb polypeptides and ascorbic acids in the base and/or on the base surface, or add polypeptides and A water-absorbing solid base is uniformly dissolved, suspended or kneaded together with ascorbic acids in an appropriate amount of purified water, then frozen, and then the frozen composition is freeze-dried and then ground by a conventional method. , by further sieving, or by pulverizing and further homogeneously mixing with a desired water-absorbing solid base, preferably 90% by weight or more of the particles have an effective particle size of 10 to 250 microns. It can be manufactured by obtaining a composition.

Alternatively, polypeptides and ascorbic acids are mechanically mixed with a water-absorbing solid base, that is, a water-absorbing and poorly water-soluble base and/or a water-absorbing and easily water-soluble base. , the resulting mixture is then compressed under pressure, and the resulting compressed product is ground and sieved to preferably 90%
It is 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, ascorbic acids, and a water-absorbing solid base, i.e., a water-absorbing and poorly water-soluble base and/or a water-absorbing and easily water-soluble base, are added to the purified water. It can also be obtained by uniformly dissolving or suspending the mixture or kneading it thoroughly, drying it by a conventional method, and then passing it through a sieve.

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

In order to improve the appearance or odor, a known lubricant 1, coloring agent, preservative, preservative, flavoring agent, etc. may be added as necessary. Examples of lubricants include talc, stearic acid and its salts; colorants include copper chlorophyll, β-carotene, Red No. 2, and Blue No. 1; examples of preservatives include stearic acid, ascorbic acid stearate, etc. Preservatives include, for example, quaternary ammonium compounds such as benzalkonium chloride, roseoxybenzoic acid esters, phenol, chlorobutanol, etc.; Examples of flavoring agents include menthol, 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 spraying and administering powder into the cavity is to set a capsule filled with powder in a special spray device equipped with a needle and pass 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.

<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 oral administration of the present invention was obtained as follows.

(Salmon calcitonin (4,000M RC units/R
g) Take Q, iq and 29.8η of ascorbic acid 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. Next, this composition was sieved to obtain a uniform powder composition in which 90% by weight or more of particles had a particle size of 46 to 149 microns. The powdered composition thus obtained contains 0.0562 Rg of L-ascorbic acid and 0.755 M RC units of S-calcitonin in 1 mg.

(b) Hydroxypropyl cellulose-500■ and L-ascorbine'R29,861 tg were placed in a mortar, and salmon calcitonin (4,0OOMR) was placed in a mortar.
C units/mg) was added and mixed thoroughly to obtain a uniform powder composition in which more than 90% of the particles had a particle size of 46 to 149 microns. The powder composition thus obtained contained 0.0% in 11Itg.
0563η L-ascorbic acid and 0.755M RC
Contains units of salmon calcitonin.

(c) Salmon calcitonin (4,000 M RC units/ing) 0.06111! F and L-ascorbic acid 1
7.801119 was uniformly dissolved in 150 μm of purified water, and 300 μm of lactose was added and sprinkled well (some of the lactose was dissolved at this time). This was then freeze-dried to obtain a homogeneous composition.

This composition was sieved to obtain a uniform powder composition in which 90% or more of the particles had a particle size of 46 to 149 microns.

The powder composition obtained in this way has a concentration of 0.0 in 1 q.
560 Rg of ascorbic acid and 0.755M R
Contains C units of salmon calcitonin.

(d) (Ta, +b+, +c+) 10 times the powdered composition containing the salmon calcitonin shown in the capsules.
By filling ~50 IItg, a salmon calcitonin preparation for human oral administration was obtained.

(II) In order to compare with the composition of the present invention, a comparative composition shown below and containing no monoascorbic acid was obtained.

(ω salmon calcitonin (4,000 MRC units/m3)
Take 0.IRg in a test tube, add 250μ of purified water to dissolve it uniformly, and add microcrystalline cellulose sooI to this.
A uniform composition was obtained by adding Rg, thoroughly sprinkling, and freeze-drying.

This composition is then sieved to remove 90%
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 of salmon calcitonin in 1 Rg.

+b+ Hydroxypropyl cellulose 500rng
and salmon calcitonin (4,000 M RC units/■) 0
．． 11119 in a mortar and thoroughly mixed to obtain a uniform powder composition. The powdered composition thus obtained contains 0,800 MRC units of salmon calcitonin in 1η.

(6 salmon calcitonin (4,OOOMRC units/η)0
．． After 06 Rg was uniformly dissolved in 150 μm of purified water, lactose 3001+19 was added and sprinkled well (at this time, some of the lactose was dissolved). This was then freeze-dried to obtain a homogeneous composition. By sieving this composition, a uniform powdery composition in which 90% by weight or more of particles had a particle size of 46 to 149 microns was obtained. The powder composition obtained in this way has 0.0.
Contains 800M RC units of salmon calcitonin.

Example 2 (Nasal administration experiment of powdered salmon calcitonin preparation in domestic rabbits) , mountain), (c1, (me, t
Salmon calcitonin preparations prepared with ti+ and +c+ were each administered 9 times at 1.4 M RC units/dose, and blood was collected from the ear vein of rabbits before administration and at 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after administration. did. After blood collection, the blood was centrifuged for 10 minutes at 2,800 r, p, m, using a centrifuge to obtain blood. The powder was administered without anesthesia using a sprayer modified for animals. Specifically, it was performed as follows. That is, first, 6 created in Example 1
1,4 kinds of salmon calcitonin preparations in the prescribed capsules.
Fill so that the dosage ω is M RC units/Kg. The capsule is then placed in a nebulizer and fitted with a nozzle modified for use on animals. Furthermore, by putting the cap on, 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 8th cavity of the rabbit, and administration into the 0th cavity was carried out by spraying with air pressure. Plasma calcium concentrations were measured before and after administration, and the absorbability of salmon calcitonin from the mucous membrane was investigated. Plasma lucium was measured using a calcium measurement kit manufactured by Yatron. Figure 1,
Figures 2 and 3 show changes in plasma lucium in terms of plasma calcium fall rate (%). The values shown in each figure are the average value ± standard error of 4 to 5 domestic rabbits.

For comparison, 17.5 mM citric acid containing 0.16% gelatin and 0.7% sodium chloride was used.
The change in plasma lucium when 9 was intravenously injected into 150 μl/1.4 MRC units of a salmon calcitonin aqueous solution dissolved in a buffer solution (pH approximately 6) is also shown by a broken line in each figure.

FIG. 1 shows the case where microcrystalline cellulose is used as a base, and (1) is the preparation containing L-ascorbic acid of the present invention ((a+) of Example 1, and (2) is the preparation containing L-ascorbic acid. The figure shows the case where a formulation (Kuno of Example 1) was administered that did not use any of the above.

Figure 2 shows the case where hydroxypropylcellulose is used as the base, and (1) is a formulation containing L-ascorbic acid (Ichi in Example 1)), and (2J is a formulation that does not use L-ascorbic acid at all). The case where the formulation ((c) of Example 1) was administered is shown.

Figure 3 shows the case where lactose is used as the base, and (1) is the preparation containing L-ascorbic acid ((c) of Example 1).
), (a) shows the case where a formulation ((d) of Example 1) containing no ascorbic acid was administered.

As is clear from FIGS. 1, 2, and 3, the powdered composition of the present invention to which L-ascorbic acid has been added has excellent absorption of salmon calcitonin.
It was shown that a strong physiological activity of 80% was obtained.

Example 3 (I) Porcine insulin 110OR was mixed with 0.1N hydrochloric acid 2
．． After dissolving in 0.5-ml of water, add 37.5ml of water, then 0.5-ml of water.
Add about 3.2 ml of 1N-sodium hydroxide aqueous solution and
Water-soluble insulin powder (23.5 units/η) was obtained by adjusting the concentration to l-17.4 and freeze-drying. Using this insulin powder, the following composition of the present invention was obtained.

(ω Water-soluble insulin powder (23,5 units/mg
10 μm and 20 μm of erythorbic acid were placed in a mortar, 320 μm of microcrystalline cellulose was added thereto, and the three components were thoroughly mixed to obtain a uniform powder composition. The powdered composition obtained in this way has 0.0
Contains 57 units of erythorbic acid and 0.67 units of insulin.

(If> Using the above insulin powder, the following comparative composition was obtained for comparison with the composition of the present invention.

<b) Water-soluble insulin powder (23,5 units/
(2) A uniform powder composition was obtained by taking 10 Ing and 340 rIt9 of microcrystalline cellulose in a mortar and mixing well. The powdered composition thus obtained is
Contains 0.67 units of insulin in 111PI.

Example 4 (Dooral administration experiment of insulin preparation in domestic rabbits) The powdered insulin preparation prepared in Example 3 (ω) was administered into the cavity of white native male domestic rabbits (body weight 2.5 to 3.589). were administered at 1.21 units/dose for 9 doses, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours before and after administration.

Blood was drawn orally for 6 hours. The powder was administered in the same manner as in Example 2. Plasma glucose concentrations were measured before and after administration, and the absorbability of insulin through the nasal mucosa was investigated. Plasma glucose concentration was measured by a method using orthotoluidine (Clinical Chemistry (cl1ni)).
cal (:, hemistry)8, 215(
1962) ). The results are shown in Figure 4 as blood sugar lowering rate (%).

The values shown in Figure 4 are the average values of five domestic rabbits.

For comparison, 1.21 units/9 of the powdered insulin preparation containing no absorption enhancer prepared in Example 3
The results when administered orally are also shown by the broken line in Figure 4.

As shown in Figure 4 (a), the blood sugar lowering rate after administering the powder containing erythorbic acid of the present invention was higher than the blood sugar lowering rate after administering the powder prepared in the comparative example as shown in (b). The above facts indicate that administration of the powder of the present invention allows insulin to be absorbed particularly efficiently through the mucous membranes of the body.

Example 5 A powdered composition useful for oral administration of the present invention was obtained as follows.

(1) After 5 Itg of α-hANPo and 29.8 Iftg of L-ascorbic acid were uniformly dissolved in 250μ of purified water, 500~ of microcrystalline cellulose was added thereto and sprinkled well. This was then freeze-dried to obtain a homogeneous composition. By sieving this composition, a uniform powder composition was obtained in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. The composition thus obtained has 0.943μSF in 1rItg.
of α-hANP and 56μ9 of L-ascorbic acid.

(21 hydroxypropyl cellulose 500R1J and L
- Take 29.8Rg of ascorbic acid in a mortar, add 005mg of α-hA NP to this, and mix well, so that the particles with 90 or more bases are 4.
A homogeneous powder composition with a particle size of 6 to 149 microns was obtained. The powdered composition thus obtained was 11
rtFl contains 0.943μ9 α-hANP and 56μL L-ascorbic acid.

(3) Same as (2) except that 500 η of lactose was used instead of 500 mg of hydroxypropylcellulose.
A uniform powder composition containing P and 56μ of L-ascorbic acid was obtained.

[41fi+,' By filling the powdered composition containing L-ascorbic acid and α-hANP shown in (2] and (3) into a predetermined capsule, a preparation for human intravenous administration was obtained. .

Example 6 500111 il of β-cyclodextrin was placed in a mortar, and erythorbine M3Q mg and 10 Ing of freeze-dried vasopressin (70-100 units/Rg) were added thereto and mixed well to obtain a uniform powder composition.

The powdered composition thus obtained has a content of 0.0% in 1η.
056#+9 erythorbic acid and 1.30-1.85
Contains units of vasopressin.

By filling the obtained powder composition into a predetermined capsule, a formulation for light human administration was obtained.

Example 7 930η of dimethyl-β-cyclodextrin was placed in a mortar, and L-ascorbine 160#19 and lyophilized luteinizing hormone-releasing hormone 10IItg were added thereto and mixed well to obtain a uniform powder composition. Ta. The powder composition thus obtained was 11Itg.
0.06ff9 L-ascorbic acid and o, oi
A preparation containing mg of luteinizing hormone-releasing hormone was filled into a predetermined capsule to obtain a preparation for intravenous administration to humans.

Example 8 Dimethyl-α-cyclodextrin 939 m9 was placed in a mortar, L-ascorbine M 30#+9, erythorbine M30rItg, and lyophilized desmobrecin acetate 119 were added thereto and mixed well to form a uniform powder composition. I got it. The powdered composition thus obtained (q) contains 0.06η of ascorbic acids and 0°OOIIrrg of desmobrecin acetate in 1Rg,
By filling this into a predetermined capsule, a formulation for human nasal administration was obtained.

Example 9 A powdered composition useful for oral administration of the present invention was obtained as follows.

(1) Take 900 mg of microcrystalline cellulose in a mortar,
To this, 50Rg of L-ascorbic acid and human serum albumin were added and freeze-dried interferon (100,000 units/
rIt9) 50rlt9 was added and mixed well to obtain a uniform powder composition. The powdered composition thus obtained contains 0.05 rrtg of L-ascorbic acid and 5000 units of interferon in 1 mg.

(2 Except using 900 mg of hydroxypropyl cellulose instead of 900 IItg of microcrystalline cellulose (
0.05 Itg in lRg in exactly the same manner as in 1)
A homogeneous powder composition containing 500 units of L-ascorbic acid and 500 units of interferon was obtained.

(3) In exactly the same manner as in (1) except that 900 mg of microcrystalline cellulose was replaced by 900 μg of lactose, L-ascorbic acid of o, os Rg and 5
A homogeneous powder composition containing 1,000 units of interferon was obtained.

+4) [11, +21, and the powdered composition containing L-ascorbic acid and interferon shown in (3) were filled into predetermined capsules to obtain a preparation for human oral O administration.

Example 10 939 µm of hydroxypropyl cellulose was placed in a mortar, 60 µm of L-ascorbic acid and PTHL my were added thereto, and the mixture was thoroughly mixed to obtain a uniform powder composition. The powdered composition thus obtained was 11t
0.06■ ascorbic acid and 0.001η in g
A formulation for human nasal administration was obtained by filling a predetermined capsule with PTH.

Example 11 Hemagglutinin 1 which is a component of Bordetella pertussis and detoxified pertussis toxin 1 and 38 mg of erythorubin M
and 960 ml of hydroxypropyl cellulose were placed in a mortar and mixed well to obtain a uniform powder composition. The powdered composition thus obtained was 11r
0.038 mg of erythorbic acid and 0.002 mg in tg
A formulation for human classical administration was obtained by filling a predetermined capsule with components of Bordetella pertussis #.

Example 12 [ASU 1.7] - A homogeneous composition was prepared by uniformly dissolving 1 my of eel calcitonin, 0.2 g of ascorbic acid, and 0.8 g of hydroxypropyl cellulose in 10 ml of purified water and then freeze-drying. I got it.

By sieving this composition, a uniform powdery composition (I) in which particles of 90% by weight or more had a particle size of 10 to 250 microns was obtained. [ASU in this powder composition
1.7]-Eel calcitonin, ascorbic acid and hydroxypropylcellulose ffl competitive ratio is:
The ratio is 1:200:800.

Then, (J powder composition (I) 100.11I
tg and hydroxypropylcellulose 399.1#+9
A uniform powder composition (II>) in which 90% or more of the particles have a particle size of 10 to 250 microns was obtained by taking and mixing well in a mortar.Powder composition (I) 100 .1 ■ and microcrystalline cellulose 399.1 #1
9 was taken in a mortar and mixed thoroughly to obtain a uniform powder composition (n[) in which 90% or more of the particles had a particle size of 10 to 250 microns. The powder compositions (It) and (I[[) thus obtained are each 11
0.041ftg of L-ascorbic acid and 0.041ftg of L-ascorbic acid in Itg.
．． Contains 8M RC units of [ASU 1.7]-eel calcitonin. A formulation for human nasal administration was obtained by appropriately combining compositions (I) and (III) and filling them into predetermined capsules for a total of 10 to 50 ay using a capsule filler.

Example 13. Comparative Examples 1 to 2 The powder composition useful for administering the sutra of the present invention was prepared from the + of Example 1.
b+ was prepared in exactly the same manner as Example 13. For comparison, the following powdered composition was prepared.

That is, ascorbic acid 29. of Example 1(b).
90 wt.
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 0.05621 ng of sodium ascorbate or 0.755 MRC of mono-ascorbic acid stearate in 1 mg.
Containing units of salmon calcitonin (Comparative Examples 1-2)
.

In addition, as a control example, 0.755M RC in 1mg
A hydroxypropylcellulose-based powder composition was prepared containing a unit of salmon calcitonin.

Comparative administration experiments were conducted on white native male domestic rabbits (body weight 3-3.8K).
g) in exactly the same manner as in Example 2.

The results when the dose was 1.4 M RC units/Kg are shown in Table 1 in terms of plasma calcium lowering rate. As is clear from the comparison of the plasma calcium lowering rate (%) 2 hours after administration and the total plasma calcium lowering rate (%・hr) up to 4 hours after administration shown in Table 1, it was found that The absorption efficiency of salmon calcitonin was higher in the powder formulation of the present invention (Example 13) than in the comparative formulations using monosodium ascorbate or L-ascorbic acid stearate (Comparative Examples 1 to 2), and It can be seen that the comparative formulation exhibits almost the same absorption effect as the control example that does not use ascorbic acids as an absorption enhancer.

Table 1 Changes in blood calcium level after intranasal administration of hydroxypropylcellulose-based salmon calcitonin powder composition (salmon calcitonin dose: 1.4 MRC position/3)

[Brief explanation of the drawing]

Figures 1, 2, and 3 show the absorption of salmon calcitonin when the composition of the present invention using salmon calcitonin as a polypeptide is administered nasally, and the blood calcium lowering rate (
%). FIG. 4 shows the absorption of insulin in terms of blood sugar lowering rate when the composition of the present invention using insulin was administered nasally. In Figures 1, 2, and 3, (1) indicates the case in which the absorption enhancer of the present invention is included, and (a indicates the case in which it is not included. The wavy line indicates the administration of calcitonin in nasal administration as a control. The figure shows the case where the same dose as the above amount is administered intravenously. In Figure 4, (the box indicates the case where an absorption enhancer is included), and the case where it is not included. Patent applicant: Teijin Co., Ltd. Person Patent Attorney Former 1) Jun Fu
Recommended after 1 kidney (hr) fi'J? rlls(hr)

Claims (1)

[Claims] 1. (a) polypeptides having physiological activity, (b) ascorbic acids as an absorption enhancer, and (c) a water-absorbing solid base suitable for application to the nasal mucosa. A powder composition for nasal administration consisting of: 2. The composition according to claim 1, wherein the ascorbic acid is ascorbic acid or erythorbic acid. 3. Ascorbic acids are 0.1 to 30% by weight of the total weight
A composition according to claim 1 or 2, wherein the composition is present in a concentration of . 4. The water-absorbing solid base is a water-absorbing and poorly water-soluble cellulose, starch, protein, crosslinked vinyl polymer,
The composition according to claim 1, which is a gum or a gum. 5. The composition according to claim 4, wherein the water-absorbing and poorly water-soluble cellulose is crystalline cellulose, α-cellulose, or crosslinked carboxymethylcellulose sodium. 6. Water-absorbing and poorly water-soluble crosslinked vinyl polymers,
The composition according to claim 4, which is a crosslinked polyvinylpyrrolidone or a crosslinked carboxyvinyl polymer. 7. A patent claim in which the water-absorbing solid base is water-absorbing and easily water-soluble cellulose lower alkyl ethers, starches, vinyl polymers, polyacrylates, proteins, or saccharides. A composition according to scope 1. 8. The composition according to claim 7, wherein the water-absorbing and easily water-soluble cellulose lower alkyl ether is hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or hydroxypropylmethylcellulose. 9. The composition according to claim 7, wherein the water-absorbing and easily water-soluble saccharide is lactose. 10. The composition according to claim 7, wherein the water-absorbing and easily water-soluble starch is β-cyclodextrin, dimethyl-β-cyclodextrin, or dimethyl-α-cyclodextrin. 11. The composition according to any one of claims 1 and 4 to 10, which uses at least one type of water-absorbing solid base or an appropriate combination of two or more types. . 12. The physiologically active polypeptides have a molecular weight of 30
2. The composition of claim 1, wherein the composition is 0 to 300,000 polypeptides. 13. Claim 1 or 12, wherein the physiologically active polypeptide is a peptide hormone, a precursor thereof, an inhibitor thereof, or a derivative thereof, a physiologically active protein, an enzyme protein, or a vaccine or vaccine component. Compositions as described. 14. A patent claim in which the peptide hormone is calcitonin, insulin, alpha human laboratory polypeptide (α-hANP), luteinizing hormone-releasing hormone, desmopressin, growth hormone, parathyrin (PTH), vasopressin, or oxytocin The composition according to item 13. 15. The composition according to claim 13, wherein the physiologically active protein is interferon. 16. The composition according to claim 13, wherein the enzyme protein is lysozyme, urokinase, or a precursor or inhibitor thereof. 17. The composition according to claim 13, wherein the vaccine is an influenza vaccine or a pertussis vaccine. 18. 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.
Compositions as described in Section.