JPS63115822A - Powdery composition for nasotracheal administration of physiological active polypeptide - Google Patents

Abstract

PURPOSE:To obtain the titled composition consisting of a polypeptide, a specific absorption promoter and a water-absorbing solid base. CONSTITUTION:A powdery composition for nasotracheal administration containing a physiologically active polypeptide (e.g. peptide hormone such as calcitonin, physiologically active protein, enzyme protein, vaccine, etc.), an ascorbic acid (e.g. ascorbic acid, erysorbic acid, etc.) and a basic amino acid (e.g. arginine, histidine, lysine, etc.) and/or a salt thereof as an absorption promoter and a water-absorbing solid base (e.g. water-absorbing and slightly water- soluble cellulose, starch, crosslinked vinyl polymer or gum) suitable for application to nasal mucosa. The preferable concentrations of the ascorbic acid and the amino acid are 0.1-20wt% and 0.1-20wt% based on sum of the composition, respectively. The composition can be directly made into powder in unit administration form.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a powdered polypeptide composition useful for oral administration. More specifically, the present invention provides bioactive polypeptides such as calcitonin and insulin;
A powder composition consisting of a water-absorbing solid base and a combination of ascorbic acids such as ascorbic acid and a basic amino acid salt such as arginine hydrochloride as absorption enhancers, which can be sprayed into the nasal cavity. The present invention relates to a polypeptide composition useful for oral administration, in which the polypeptide is absorbed extremely efficiently through the nasal mucosa when administered.

<Problems to be solved by the prior art and the invention> Peptide hormones such as insulin and calcitonin have large molecules and are easily degraded by proteolytic enzymes such as pepsin, trypsin, or chymotrypsin, so they are difficult to absorb when administered orally, making them ineffective. 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 salicyl'FIi derivatives such as sodium salicylate, sodium 3-methoxysalicylate, and 5-methoxysalicylic acid as an absorption enhancer [Journal of Pharmacy and Pharmacology] L.J.

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

Eye drop administration (Diabetic Society Abstracts, 237. (197
4) ) method is 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 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.
, Acad, Sci, U.

S, A, > 82. pp7419-7423
(1985)]. Alternatively, an aqueous solution of insulin, glucagon, etc., using fucidin 1ltls such as sodium-tauro-24,25-dihydroxyfucidate as an absorption enhancer (Japanese Unexamined Patent Publication No. 61-33
No. 126) is known.

However, these methods are highly irritating to the mucous membranes during administration, and since all dosage forms are liquid, when administered orally, the liquid tends to leak out of the perineum, and the drug is not fully absorbed by the nasal mucosa. It is difficult to say that it is absorbed efficiently.

Furthermore, a formulation for nasal administration of insulin containing cyclodextrin (Japanese Unexamined Patent Publication No. 189118/1989).

Calcitonin intranasal preparations containing basic and/or neutral amino acids (JP-A-61-118325), intranasal calcitonin preparations containing aldose (JP-A-61-1
26034) is known. In these methods, the irritation to the nasal mucosa during administration is considerably reduced, and in this respect, the methods are satisfactory to some extent. However, even with these methods, it is still 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-60-224-616 disclose a powdered preparation for nasal administration consisting of a water-absorbing base and peptide hormones, and JP-A-61-194034 discloses a The present inventors have disclosed a powder formulation for nasal administration comprising a grade ammonium compound and a cellulose lower alkyl ether.

These preparations cause almost no irritation to the mucous membranes upon administration, and relatively efficiently absorb 1q of high-molecular Q peptide hormones through the nasal mucosa. Furthermore, as a powdered preparation for nasal administration, US Pat. No. 4,294,829 discloses a preparation comprising cellulose lower alkyl ether and a drug. This preparation is characterized in that cellulose lower alkyl ether absorbs water on the 0 mucous membrane, becomes a viscous liquid, flows on the 1 mucous membrane, and gradually releases the drug. However, even with these methods, it is difficult to say that the drug is absorbed from the θ mucosa with sufficient efficiency, and there is still room for improvement.

Therefore, there is a need for a formulation for nasal administration in which drugs are efficiently absorbed through the nasal mucosa and irritation to the nasal mucosa is reduced.

<Means for solving the problem> The present inventors have developed a polypeptide that can efficiently absorb physiologically active polypeptides such as calcitonin through the nasal mucosa and is suitable for administration into the nasal cavity. With the aim of obtaining a preparation for oral administration that causes almost no irritation to the nasal mucosa, we have conducted extensive research and have developed an absorption enhancer consisting of a combination of polypeptides, two specific absorption enhancers, and a water-absorbing formulation. The present invention was achieved by discovering that a powder composition comprising a solid base can surprisingly achieve the above-mentioned objects.

That is, the present invention provides (polypeptides having ω physiological activity, (b) (1) ascorbic acids and I++ as absorption enhancers) basic amino acids and/or pharmaceutically acceptable salts thereof, and (c ) A powder composition for administration to minor injuries, comprising a water-absorbing solid base suitable for application to f4 mucous membranes.

Specific examples of preferable ascorbic acids of the present invention include:
Examples include ascorbic acid and erythorbic acid.

Further, specific examples of the basic amino acids preferred in the present invention include arginine, histidine, lysine, orthinine, ergothioneine, and the like. Among these basic amino acids, arginine, histidine, and lysine are particularly preferred.

These basic amino acids may be in the L-form, D-form, or racemic form.

Pharmaceutically acceptable salts of these basic amino acids are any salts that maintain enhanced absorption of physiologically active polypeptides through mucous membranes and are not harmful. Specific examples include salts of paid acids such as citric acid, tartaric acid, malic acid, and fumaric acid, and mineral acids such as hydrochloric acid.

Among these salts, Salt M salt is particularly preferred.

Preferred concentrations of ascorbic acids in powdered compositions useful for intravenous administration of the present invention range from about 0.1 to 20 E
Ii 1%, more preferably 1 to 15% by weight, still more preferably 5 to 10% by weight.

Further, the preferred concentration of the basic amino acid and/or its pharmaceutically acceptable salt in the powdered composition useful for intravenous administration of the present invention is about 0.1 to 20% by weight based on the total composition. It is more preferably 1 to 15% by weight, and still more preferably 5 to 10% by 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 preferable because they are more easily absorbed than the nasal mucosa.

The molecular weight is particularly preferably in the range of 300 to 150,000. 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, ribomodulin,
Atrial natriuretic peptide [alpha human atrial natriuretic voribeptide (α-hA
N P ), etc.], growth hormone-releasing hormone, growth hormone, erythroboetin, urogastrone, renin,
Paratylin (PTH) and its antagonists, peptide hormones such as corticothrobin-releasing factor, its precursors, its inhibitors or derivatives; interferon, interleukin, tumor necrosis factor (TNF), 1-
Lanceferrin, histaglobulin, macrocortin,
Physiologically active proteins such as blood coagulation factors: Enzyme proteins such as lysozyme and urokinase, pertussis vaccine, diphtheria vaccine.

Vaccines such as tetanus vaccine, influenza vaccine, lymphocytosis factor, fibrillar hemagglutination factor, and vaccine components 1 to 1 can be mentioned. Among these, peptide hormones are particularly preferred, and among peptide hormones, calcitonin, insulin,
α-hANP, luteinizing hormone-releasing hormone;
Corticothrobin.

Desmobrecin, vasopressin, glucagon, oxytocin, PTH or growth hormone are preferred.

More preferred are calcitonin, insulin, and 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 amine acetic 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.

The powder compositions of the present invention useful for oral administration use a water-absorbing solid base as the base. Preferred examples of the water-absorbing solid base include a base that is water-absorbent and poorly water-soluble, and a base that is water-absorbent and water-repellent and easily soluble. The darning base 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 on the human θ 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 poorly water-soluble base of the present invention include the following.

For example, water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, and cross-linked carboxymethylcellulose sodium; water-absorbing and water-resistant celluloses such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, and pectin. 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 poorly water-soluble celluloses are preferred, with crystalline cellulose, α-cellulose, or crosslinked sodium carboxymethylcellulose 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 times or more by weight, more preferably 20 times or more by 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 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, human [1-xypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose <β-, dimethyl β- or dimethyl α-), Chitin, chitosan, lactose, sodium polyacrylate.

Polyethylene glycol, polyvinylpyrrolidone are preferred, especially hydroxypropylcellulose.

β-cyclodextrin, dimethyl β-cyclodextrin, dimethyl α-cyclodextrin.

Lactose is more preferred, and hydroxypropylcellulose, β-cyclodextrin, and lactose are even more 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, 0
When administered intracavitally, it is widely distributed on the mucous membrane and stays well in the adhering area, and when sprayed as a powder into the cavity through the nostrils, it can be efficiently administered into the cavity. .

If particles with an effective particle diameter of less than 10 microns account for more than 1oii% of the dose, when administered by a method such as spraying, many particles reach the lungs or escape outside the membrane when sprayed.

Furthermore, it is difficult to maintain a high drug concentration at the attachment site. On the other hand, 10 particles with an effective particle diameter exceeding 250 microns
If the drug occupies more than % by weight of the mouth, it is not preferred because when administered into the 0 cavity, even if it adheres to the nasal mucosa, it tends to separate from the mucous membrane and the local retention of the drug becomes low. Especially that 90
Preferably, the effective particle size of at least % by weight of the particles is between 20 and 150 microns.

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

That is, physiologically active polypeptides, ascorbic acids, basic amino acids and/or pharmaceutically acceptable salts thereof, and a water-absorbing solid base are mixed mechanically, and then sieved. It can be produced by obtaining a composition in which preferably 90% by weight or more of particles have an effective particle diameter of 10 to 250 microns.

Alternatively, physiologically active polypeptides, ascorbic acids, basic amino acids, and/or pharmaceutically acceptable salts thereof are uniformly dissolved or suspended in an appropriate amount of purified water, and then added to the mucous membranes of the body. A water-absorbing solid base suitable for application, that is, a water-absorbing and poorly water-soluble base and/or a water-absorbing and easily water-soluble base is added to the base and/or After uniformly containing and/or adsorbing polypeptides, ascorbic acids, basic amino acids and/or pharmaceutically acceptable salts thereof on the surface of the base, or A water-absorbing solid base is uniformly dissolved, suspended or kneaded together with a basic amino acid and/or its pharmaceutically acceptable salt in an appropriate amount of purified water, 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. Particles with weight R% or more have an effective particle size of 1
It can be manufactured by obtaining a composition consisting of 0 to 250 microns.

Or polypeptides and ascorbic acids.

Basic amino acids and/or their I! A pharmaceutically acceptable salt is mechanically mixed with a water-absorbing solid base, i.e., a water-absorbing and sparingly water-soluble base or a water-absorbing and easily water-soluble base; The resulting mixture is compressed under pressure, and the resulting compressed product is crushed and sieved to obtain a composition in which preferably 90% or more of particles have an effective particle size of 10 to 250 microns. be done. Or polypeptides, ascorbic acids, basic amino acids and/or pharmaceutically acceptable salts thereof, and water-absorbing solid bases, i.e., water-absorbing and poorly water-soluble bases, or water-absorbing and poorly water-soluble bases; Add the easily water-soluble base to an appropriate amount of purified water and dissolve uniformly! It can also be obtained by making it cloudy or kneading it well, 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, known lubricants, colorants, preservatives, preservatives, flavoring agents, 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, paraoxybenzoic acid esters, buenol, 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 powder into the cavity is to set a capsule filled with the powder in a special spray device equipped with a needle and pass the needle through it, thereby making minute 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/I
Itg) 0.1Rg, 29.8μ of mono-ascorbic acid and 35.61119μ of mono-arginine hydrochloride were placed in a test tube, and 250μ of purified water was added to dissolve them uniformly.
500 IItg of microcrystalline cellulose was added thereto, and the mixture was thoroughly sprinkled and freeze-dried to obtain a uniform composition. This composition is then sieved to obtain 9
A uniform powder composition was obtained in which 0% 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 0.0527! in 1 #IiJ! ng
of L-ascorbic acid, 0.0630 μ of L-arginine hydrochloride and 0.707 M RC units of salmon calcitonin.

+b+ Hydroxypropyl cellulose 500I! t
g, L-ascorbine 1129.8 #19 and L-arginine hydrochloride 35.6η were placed in a mortar, and salmon calcitonin (4,000 M RC units/Irt
g) By adding 0.IItg 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 powdered composition obtained in this way has 0.0% in 1Rg.
0527 IItg Noshiichi Ascorbic Acid and 0.063
0 IItg Noshiichi Arginine Hydrochloride and 0.707M
Contains RC units of salmon calcitonin.

(c) Salmon calcitonin (4,000M RC units imy>0.061!tg and L-ascorbine [17,
8 mg of L-arginine hydrochloride and 21.3 μl of L-arginine hydrochloride were uniformly dissolved in 150 μl of purified water, and then 300 mg of lactose 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 powder composition was obtained in which 90% by weight or more of the particles had a particle size of 46 to 149 microns.

The powder composition thus obtained has a concentration of 0.05 in lq.
Contains 251,119 ml of ascorbic acid, 0.0628 ml of arginine hydrochloride, and 0.708 M RC units of salmon calcitonin.

(Small) Powdered composition containing salmon calcitonin shown in (a), (b), tC) is placed in a prescribed capsule.
A salmon calcitonin preparation for human administration was obtained by filling 0 to 50 IItg.

(It) In order to compare with the composition of the present invention, the following comparative composition containing no absorption enhancer was obtained.

(Small salmon calcitonin (4,000M RC units/R
g) Take 0.11Itg in a test tube and add 250tl of purified water.
, Q were added and dissolved uniformly, 500 ffig of microcrystalline cellulose was added thereto, and the mixture was thoroughly sprinkled and freeze-dried to obtain a uniform composition.

This 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 of salmon calcitonin in 1 mg.

(H) Hydroxypropyl cellulose 500 mg
To'yhJLtcytonin (4,OOOMRC units/m
g>0.11119 in a mortar and thoroughly mixed to obtain 1 q of a uniform powder composition. The powdered composition thus obtained contains 0.800 M in 1 m5.
Contains RC units of salmon calcitonin.

(('l Salmon calcitonin (4,000M RC units/Rg) 0.06μ was uniformly dissolved in 150μ of purified water, then 300mg of milk rIs was added and sprinkled well. (At this time, some of the lactose was This was then freeze-dried to obtain a uniform composition. This composition was sieved to obtain a uniform composition in which 90% by weight or more of the particles had a particle size of 46 to 149 microns. A powder composition was obtained. The powder composition thus obtained contained 0.800M salmon calcitonin of RCE No. 1 in 1 volume.

Example 2 (Nasal administration experiment of powdered salmon calcitonin preparation in domestic rabbits) The (ω, (b ), (c1, (me,
(b), the salmon calcitonin preparation prepared in +C),
Each drug was administered at 1.4 MRC units/Kfl, and blood was collected from the ear vein of the rabbit before and 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after administration. After blood collection, the blood was centrifuged for 10 minutes at 2,800 r, D, m, using a centrifuge to obtain plasma. The powder was administered without anesthesia using a sprayer modified for animals. Specifically, it was performed as follows. That is, first, one of the six types of salmon calcitonin preparations prepared in Example 1 was placed in a predetermined capsule.
．． Fill 9 dosing ports per 4M RC unit.

The capsule is then placed in a sprayer and fitted with a nozzle modified for wJ products. 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 rabbit's cavity, and administration into the rabbit's cavity was carried out by spraying with air pressure. Plasma lucium concentrations were measured before and after administration, and the absorbability of salmon 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, 1y,s m containing 0.16% gelatin and 0.7% sodium chloride
A 1.4M salmon calcitonin aqueous solution dissolved in M citrate buffer (pH about 6) 150 μm/Kg of RC units,
Changes in plasma lucium levels upon intravenous injection are also shown by broken lines in each figure.

Figure 1 shows the case where microcrystalline cellulose is used as a base, and (1) is a preparation containing a combination of ascorbic acid and L-arginine hydrochloride of the present invention ((a
J), (a shows the case where the formulation (heart) of Example 1 was administered without using any of these absorption enhancers.

FIG. 2 shows the case where hydroxypropylcellulose is used as the base, and (1) shows a preparation ((b) of Example 1) in which L-ascorbic acid and L-arginine hydrochloride are added in combination. (2) shows the case where a formulation (ri+ of Example 1) using no absorption enhancer was administered.

Figure 3 shows the case where lactose is used as the base; (1) is a preparation containing L-ascorbic acid in combination with monoarginine hydrochloride ((c) of Example 1); shows the case where a formulation ((c') of Example 1) was administered without using any of these absorption enhancers.

As is clear from FIGS. 1, 2, and 3, the powder composition of the present invention containing L-ascorbic acid and L-arginine hydrochloride has excellent absorption of salmon calcitonin, and It was also shown that strong physiological activity almost equivalent to intravenous injection can be obtained.

Example 3 (I) Dissolve porcine insulin 100119 in 2.5 m of 0.1N hydrochloric acid, add 37.5 m of water, and then
0. By adding about 3.2 volumes of IN-sodium hydroxide aqueous solution to adjust the pi to -17.4, and then freeze-drying it, water-soluble insulin powder (23.5 units/η
) was obtained. Using this insulin powder, 1 q of the composition of the present invention shown below was prepared.

(a Water-soluble insulin powder (23,5 units/mg
) 10#+9 and erythorbine 1lff120η and L-
Take 20Iftg of histidine hydrochloride in a mortar, add 300ffi9 of microcrystalline cellulose, and mix the three components well to make 1q of a uniform powder composition.
is. The powdered composition thus obtained was 11It
Each g contains 0.057 units of erythorbic acid and L-histidine hydrochloride 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/
! ng>10■ and microcrystalline cellulose 340η were placed in a mortar and mixed well to obtain a uniform powder composition. The powdered composition thus obtained is 1R
Contains 0.67 units of insulin per g.

Example 4 (Administration experiment of insulin preparation in domestic rabbits) Injected into the cavity of a white native male domestic rabbit (weight 2.5-3.5 and 5F) with (and the mountain) of Example 3. Each of the prepared powdered insulin preparations was administered at 1.21 units/Kg at 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 1 hour 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 insulin from the mucosa was investigated. Insulin concentration in plasma was measured by radioimmunoassay. The results are shown in Figure 4. Plasma glucose concentration is measured by a method using orthotoluidine.
Mistry) 8, 215 (1962)). The results are shown in Figure 5 as blood sugar lowering rate (%).

The values shown in Figures 4 and 5 are the average values of five domestic rabbits.

As shown in Figure 4, plasma insulin after administration of the powder prepared in Example 3 (a) to which the combination of erythorbic acid and L-histidine hydrochloride of the present invention was added. The level is administration v! It reached its highest level after <10 minutes and increased to more than 50 times the basal value. On the other hand, as shown in +b+, in the case of administering the powder prepared as a comparative example in Example 3 (b), the highest level was reached 30 minutes after administration; The level was slightly lower than in the case of

The above facts indicate that insulin is particularly efficiently absorbed from mucous membranes by administration of the powder of the present invention, and that absorption is efficiently sustained.

In FIG. 5, +b+ represents the case in which the powder containing erythorbic acid and monohistidine hydrochloride of the present invention prepared in Example 3 was administered as an absorption enhancer;
The lowering rate of blood I14 when a powder containing no powder was administered as a comparative example is shown. 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, and the blood sugar lowering rate also indicates that the powder of the present invention is particularly effective. I understand.

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

(1) α-hA N P 0.51rrg, one ascorbic acid 29.81 weight g, one arginine 29.8
#+9 was uniformly dissolved in 250 μm of purified water, and 500 Ing of microcrystalline cellulose was added thereto and sprinkled well. This was then freeze-dried to obtain a uniform 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 a +2-
hANP each contains 0.0532 rng of L-ascorbic acid and L-arginine.

(500 mg of 2-hydroxypropylcellulose and L-
Ascorbic acid 29.8 mg and L-lysine hydrochloride 29.
8η in a mortar, and in this, α-hA N
By adding 5 mg of P 2 O and thoroughly mixing, a homogeneous powder composition was obtained in which particles with a particle diameter of 46 to 149 microns had a particle diameter of 90% or more.

The powdered composition thus mixed has 0.893μ of α-hANP and 0.053μ of α-hANP in lmy.
2 #19 Contains ascorbic acid and L-lysine hydrochloride.

(3) Hydroxypropyl cellulose 500 mg
0.893 μ9 of α-
A homogeneous powder composition was obtained containing hANP and 0.0532 μm each of mono-ascorbic acid and mono-lysine hydrochloride.

(4) Fill a prescribed capsule with the powdered composition containing L-ascorbic acid, L-arginine or di-lysine hydrochloride, and α-hA N P shown in (11, [2) and (3). By doing so, a preparation for human oral administration was obtained.

Example 6 Take 470 #l of β-cyclodextrin in a mortar and add 930 #l of erythorbine! J and histidine hydrochloride 30
~ and lyophilized vasopressin (70-100 units/
ITtg) 10Rg was added and mixed well to obtain a uniform powder composition. The powdered composition thus obtained contained o and ose# in 1rrPg, respectively.
I! Erythorbic acid and histidine hydrochloride of J and 1.3
Contains 0-1.85 units of vasopressin.

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

Example 7 870 mg of dimethyl-β-cyclodextrin was placed in a mortar, and erythorbic acid 60Irrg, histidine hydrochloride 601119, and lyophilized luteinizing hormone-releasing hormone 1101rt were added thereto and mixed well to obtain a uniform powder composition. I got something. The powdered composition thus obtained has a density of 0.06 in 1 Rg.
llll! A formulation for human nasal administration was obtained by filling a prescribed capsule with erythorbic acid and histidine hydrochloride of F and luteinizing hormone-releasing hormone of 0.01 Rg.

Example 8 879 η of dimethyl-α-cyclodextrin was placed in a mortar and mixed with 60 Rg of ascorbic acid, 60 Rg of histidine hydrochloride, and 1 μg of lyophilized desmopressin acetate.
was added and mixed thoroughly to obtain a uniform powder composition. The powdered composition obtained in this way is 1η
The solution contained L-ascorbic acid and histidine hydrochloride of 0.06 J19, and desmobrecin acetate of o, ooiη, respectively, and was filled into a predetermined capsule to obtain a preparation for nasal administration to humans.

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

(1) Take 850 IItg of microcrystalline cellulose in a mortar, add 50Rg of L-ascorbic acid, 501fQ of arginine hydrochloride, and human serum albumin, and freeze-dry the mixture to obtain 50IIt of interferon (100,000 units/■).
g and mixed well to obtain a uniform powder composition. The powdered composition thus obtained is
1#l! 0.05 each during J #I! Contains ascorbic acid, arginine hydrochloride and 5000 units of interferon.

((1) except that hydroxypropyl cellulose 850IItg is used instead of 2 microcrystalline cellulose 850■
In exactly the same way as 1111! 0 each in J.
05■ L-ascorbic acid and arginine hydrochloride and 50
A homogeneous powder composition containing 00 units of interferon was obtained.

(3) A cellulose containing 0.05 Ing of L-ascorbic acid, arginine hydrochloride, and 5000 units of interferon in 1η was prepared in exactly the same manner as in (1) except that lactose 850μ was used instead of microcrystalline cellulose 8501119. A uniform powder composition was obtained.

+4] [11, (By filling the powdered composition containing [-ascorbic acid, arginine hydrochloride, and interferon] shown in 21 and (3) into a predetermined capsule, a preparation for human θ administration can be prepared. Obtained.

Example 10 879 rng of hydroxypropyl cellulose was placed in a mortar, and 60 mg of L-ascorbic acid, 6011 Ig of arginine hydrochloride, and P T HI IQ were added thereto and thoroughly mixed to obtain a uniform powder composition. The powdered composition thus obtained contains 0.06 μ of L-ascorbic acid, arginine hydrochloride, and 0,0011 rtg of PTH in 1 mg, and by filling it into a predetermined capsule, A formulation for human administration was obtained.

Example 11 Hemagglutinin IRg, a component of Bordetella pertussis, and detoxified pertussis toxin 1 to erythorubin 38
II#g, 38 mg of histidine hydrochloride, and 922 Rg of hydroxypropyl cellulose were placed in a mortar and mixed well to obtain a uniform powder composition. The powdered composition thus obtained contained 0.0.
038 ■ Erythorbic acid and arginine hydrochloride and 0.0
A formulation for human nasal administration was obtained by filling a predetermined capsule with a component of Bordetella pertussis of 02■.

Practical examples 12-17. Comparative Examples 1-2 <Examples 12-17> Powder composition useful for nasal administration of the present invention ((of Example 1)
For comparison with b)), exactly as in Example 1 (b), 0.707 M RC units of salmon calcitonin and 0.0527 mg in a hydroxypropylcellulose-based powdered composition lRg were added. L-ascorbic acid and various basic amino acids shown in Table 1 MO10630
A powder composition containing Irtg was created (Example 12)
~17).

Comparative Examples 1 to 2 in Table 1> Furthermore, for comparison with the formulation of the present invention, in <b) of Example 1, ascorbic acid was used instead of ascorbic acid and arginine hydrochloride as absorption enhancers. A powder composition containing only arginine hydrochloride (Comparative Example 1) and a powder composition containing only arginine hydrochloride (Comparative Example 2) were prepared. In these cases, the amount of hydroxypropyl cellulose used as the base was adjusted so that the doses of salmon calcitonin and each absorption enhancer were the same as above.

<Control example> As a control example, 11I! 0.707M in g
A powdered composition containing RC units of salmon calcitonin and based on hydroxypropylcellulose was prepared.

Comparative administration experiments were conducted on white native male domestic rabbits (body weight 3-3, 8
The test was carried out in exactly the same manner as in Example 2 using 4 to 5 kg of birds (group 4 to 5). Dose is 1.4M RC units/9
The results are shown in Table 2 in terms of plasma calcium reduction rate.

Plasma calcium fall rate 2 hours after administration shown in Table 2 (
%) and the total plasma calcium withdrawal rate (%/hr) up to 4 hours after administration. Powders of the present invention used in combination (Example 12 to
17) is better than L-ascorgonic acid alone (Comparative Example 1) or arginine hydrochloride alone (Comparative Example 2) prepared for comparison.
It can be seen that the mucosal absorption of salmon calcitonin is superior to that of the powder used in ) and the control powder that does not contain either of them.

Table 2 Changes in plasma calcium levels after intracavitary administration of hydroxypropylcellulose-based salmon calcitonin powder composition (salmon calcitonin dose: 1.4 MRC/9") (Note)*; L- used in combination
Administration of ascorbic acid ffi: 104μ'J/Kg*
*: Use monoascorbic acid alone and @arginine alone, respectively.

[Brief explanation of the drawing]

Figures 1, 2, and 3 show the absorption of salmon calcitonin in terms of plasma calcium lowering rate (%) when the composition of the present invention using salmon calcitonin as a polypeptide was administered orally. It is something. 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 orally. It is. In FIGS. 1, 2, and 3, (1) shows the case in which an absorption enhancer is used in combination, and (2) shows the case in which no absorption enhancer is included. The wavy line indicates the case where the same dose of calcitonin as in the intravenous administration was administered intravenously. In FIG. 4 and FIG. 5, (a) shows the case where an absorption enhancer was used in combination, and the mountain) shows the case where they were not included. Patent Applicant Teijin Ltd. Ceremony
Former Patent Attorney 1) Jun Hiroshi Administration f
tginri4 (hsu 51st n O1 brother 3 4 5 6 mosquito relief: t'!r 岨にr)

Claims (1)

[Claims] 1. (a) polypeptides having physiological activity (b) (i) ascorbic acids and (ii) basic amino acids and/or pharmaceutically acceptable salts thereof as absorption enhancers and (c) a water-absorbing solid base suitable for application to the nasal mucosa. A powder composition for nasal administration. 2. The composition according to claim 1, wherein the ascorbic acid is ascorbic acid or erythorbic acid. 3. The composition according to claim 1, wherein the basic amino acid is arginine, histidine or lysine. 4. The composition according to claim 1 or 3, wherein the pharmaceutically acceptable salt of the basic amino acid is a hydrochloride. 5. The composition according to claim 1 or 2, wherein the ascorbic acids are present in a concentration of 0.1 to 20% by weight based on the total weight. 6. Claims 1 and 3, wherein the basic amino acid and/or its pharmaceutically acceptable salt is present in a concentration of 0.1 to 20% by weight of the total weight. Or the composition according to item 4. 7. The composition according to claim 1, wherein the water-absorbing solid base is a water-absorbing and poorly water-soluble cellulose, starch, protein, crosslinked vinyl polymer, or gum. . 8. The composition according to claim 7, wherein the water-absorbing and poorly water-soluble cellulose is crystalline cellulose, α-cellulose, or crosslinked carboxymethylcellulose sodium. 9. Water-absorbing and poorly water-soluble crosslinked vinyl polymers,
The composition according to claim 7, which is a crosslinked polyvinylpyrrolidone or a crosslinked carboxyvinyl polymer. 10. The water-absorbing solid base is water-absorbing and easily water-soluble cellulose lower alkyl ethers, sugars, starches,
The composition according to claim 1, which is a vinyl polymer, a polyacrylate, or a protein. 11. The composition according to claim 10, wherein the water-absorbing and easily water-soluble cellulose lower alkyl ether is hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, or hydroxypropylmethylcellulose. 12. The composition according to claim 10, wherein the water-absorbing and easily water-soluble saccharide is lactose. 13. The composition according to claim 10, wherein the water-absorbing and easily water-soluble starch is β-cyclodextrin, dimethyl-β-cyclodextrin, and/or dimethyl-α-cyclodextrin. 14. Claims 1 and 7 using one type of water-absorbing solid base or an appropriate combination of two or more types
The composition according to any one of Items 1 to 13. 15. Polypeptides with physiological activity have a molecular weight of 30
2. The composition of claim 1, wherein the composition is 0 to 300,000 polypeptides. 16. Claim 1 or 15, 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. Compositions as described. 17. Claims in which the peptide hormone is calcitonin, insulin, alpha hANP, luteinizing hormone-releasing hormone, desmopressin, growth hormone, parathyrin (PTH), vasopressin, or oxytocin. The composition according to item 16. 18. The composition according to claim 16, wherein the physiologically active protein is interferon. 19. The composition according to claim 16, wherein the enzyme protein is lysozyme, urokinase, or a precursor or inhibitor thereof. 20. The composition according to claim 16, wherein the vaccine is an influenza vaccine or a pertussis vaccine. 21. 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.