JPH01230530A - Liquid agent composition for nasal administration of calcitonin - Google Patents

Abstract

PURPOSE:To obtain the stable title composition obtained by blending an organic acid as an absorption accelerator, being free from disorder of nasal mucosa and having good absorption. CONSTITUTION:A liquid agent composition for nasal administration being a peptide having serum calcium lowering action, containing various kind of natural calcitonins or peptide analogue thereof as active ingredients, containing 0.05-60% (w/v), preferably 0.1-50% (w/v) of organic acid (especially preferably citric acids, tartaric acid, cinnamic acid or L-aspartic acid), preferably selected from dicarboxylic acids, tricarboxylic acids and hydroxycarboxylic acids in the composition as an absorption accelerator. Calcitonin is used in the concentration in the composition of 1-10000unit/ml, preferably 5-5000unit/ml and administered at an amount of preferably 0.05-0.5ml/time, properly once-three times daily.

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] (Industrial Field of Application) The present invention relates to a liquid pharmaceutical composition for nasal administration containing calcitonins having a serum calcium-lowering effect as an active ingredient.

(Prior art) Calcitonins are peptides that have a serum calcium-lowering effect, and are associated with hypercalcemia, vitamin D toxicity,
It is used as a therapeutic agent for metabolic bone diseases, etc.

Natural calcitonin or its analogs are known as calcitonins, and examples of natural calcitonin include:
Examples include eel calcitonin, salmon calcitonin, pig calcitonin, human calcitonin, chicken calcitonin, and analogues include elcatonin ((ASU
1-7) Eel calcitonin), [:ASUl-7]
Human calcitonin and the like are known.

These calcitonins are hydrolyzed by enzymes in the gastrointestinal tract or on the wall of the gastrointestinal tract, so absorption from the gastrointestinal tract is extremely difficult. Therefore, conventional administration has been limited to injections.

However, injection administration is generally not preferred as it is painful and patients cannot administer it themselves.
Continuous administration is inconvenient, and a simpler and more easily applied formulation was desired.

Therefore, preparations for intranasal administration have been considered, and liquid preparations for intranasal administration of insulin and calcitonins using surfactants and the like as absorption enhancers have been reported.

[1nt, J, Pharm,, Skin 165-172 (19
81); Int, J.

Pharm, 9. 173-184 (1981);
Diabetes, 27.296-299 (1978
); J, Japan Oiab, Sac,, 2
0(2), 146-152 (1977); N, E
ngl, J. Med, 312.1078-10
84 (1985); D+abetes, 20.55
2-556 (1971); Diabetes.

32, 1040-1047 (1983); Proc.
Natl, Acad, Sci.

U, S, A,, board, Nα21.7419-7423
．． (1985); JP-A-59-89619;
JP-A-59-130820. ] (Problems to be Solved by the Invention) However, the above-mentioned nasally administered preparation does not contain the nonionic ether type surfactant and bile acid contained in the preparation as an absorption enhancer. Since it has strong tissue-damaging properties, it is impossible to actually apply it, and to date there are almost no products that have been put into practical use.

The present invention has been made in response to the above-mentioned problems, and solves the problems in the prior art by providing a liquid preparation for intranasal administration containing calcitonins as an active ingredient that does not cause any damage to the nasal mucosa. It is.

[Structure of the invention]

(Means and effects for solving the problem) The present inventors have investigated various formulations that do not cause any damage to the nasal mucosa regarding liquid preparations for intranasal administration of calcitonins, and have found that organic acids are added as absorption enhancers. The inventors have discovered that a formulation suitable for this purpose can be obtained by doing so, leading to the present invention.

That is, the present invention is a liquid pharmaceutical composition for nasal administration containing calcitonins as an active ingredient, which is characterized by containing an organic acid as an absorption enhancer.

Calcitonin, which is an active ingredient of the present invention, may be any peptide that has a serum calcium lowering effect, and refers to various natural calcitonins or peptide analogs thereof.

Examples of natural calcitonin include eel calcitonin, human calcitonin, salmon calcitonin, pig calcitonin, and chicken calcitonin.

Further, as an example of the peptide analogue, (ASUl-7
] Eel calcitonin (lIIH〇-ship name: Elcatonin), [^5tll-7) salmon calcitonin, [ASI
ll-7] human calcitonin mari lt (AS[11-
7] Chicken calcitonin and the like.

These substances and synthetic methods are described, for example, in British Patent No. 15169.
No. 47, the 50th Spring Annual Meeting of the Chemical Society of Japan, 1985 Lecture Proceedings ■, page 947, etc. Furthermore, calcitonin-like peptides other than those mentioned above that have a serum calcium-lowering effect can be used in the present invention, and are widely involved in bone diseases, endocrine metabolic diseases, gastrointestinal diseases, etc., and are associated with hypercalcemia and osteoporosis. It is used to treat pain in dementia, Behcet's disease of bones, etc.

The concentration of calcitonin in the composition of the invention is generally between 1 unit/ml and 10.000 units/rd, preferably between 5 units/ml and 5.000 units/rnI! It is.

During administration, the dose is preferably 0.05 to 0.51 nl/time, and the appropriate number of doses is 1 to 3 times a day.

The organic acids used in the present invention include water-soluble organic acids.

The water-soluble organic acids are preferably dicarboxylic acids, tricarboxylic acids, and hydroxycarboxylic acids, such as maleic acid, malonic acid, fumaric acid, tartaric acid, citric acid, succinic acid, and L-ascorbic acid. , tartaric acid, citric acid, succinic acid, and L-aspartic acid are preferred.

The concentration of organic acid in the composition of the present invention is from 0.05 to
60% (W/V), preferably 0.1-50% (W/V)
V).

The nasal preparation of the present invention can be manufactured according to methods known per se.

The form of the present invention can also be made into an aqueous solution that can be dropped or sprayed in a certain amount into the nasal cavity.

The aqueous solution of the present invention can be produced by dissolving, suspending, or emulsifying it in water. At this time, pharmaceutically acceptable stabilizers, thickeners, solubilizing agents, surfactants, preservatives, fillers, tonicity agents, etc. can be added as necessary.

The thickener may be any water-soluble viscous substance, such as methylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, propylene glyconopeglycerin, polyethylene glycol, polyglycerin, polyvinyl alcohol, polyvinylpyrrolidone, polylactic acid,
Examples include gelatin, hydroxypropylmethylcellulose, hydroxypropylstarch, pullulan, carboxymethylcellulose, hyaluronic acid, chitosan, chondroitin sulfate, polyamino acids, and the like.

Preservatives include parabens such as paraoxybenzoate, propyloxybenzoate, ethyl paraoxybenzoate, 2-phenylethanonohethyl alcohol, chlorobutanol, benzalkonium chloride, benzethonium chloride, and cetyl chloride. Cationic surfactants such as pyridinium may also be used.

As the surfactant, nonionic surfactants are preferred, and for example, the following can be used.

Examples of polyoxyethylene sorbitan fatty acid esters include E! manufactured by Kao Atlas Co., Ltd. JASOL 1130
(POE sorbitan monolaure):HLB16.3)
, EMASOL 3130 (POE sorbitan monostearate: HLB 14.9),
TWEEN 20 (POE (20) Sorbitan Monolaure): HLB 16.7).

TWEIEN 40 (POE (20) Sorbitan Monopalmitate: HLB 15.6), TW
IJN 60 (POE (20) sorbitan monostearer): HLB 14.9), TlsEEN80 (
POE (20) Sorbitan monooleate: HLB15.
0), NIKKOL TL-1 manufactured by Nikko Chemicals
010゜TP-10, TS-10, To-10M, manufactured by NOF Corporation Nonion 0T-221, Nonion 5T-2
21, Nonion PT-221, Nonion LT-221, and the like.

Examples of polyoxyethylene hydrogenated castor oil include NIKKOL lIc0-40 (P
OE (40) Hydrogenated Castor Oil: HL B12.5)
, NIKKOL HCD-50 (POE (50) hydrogenated castor oil: HL B13.5), NIKKOLH
CO-60 (P OE (60) hydrogenated castor oil: HLB
14. O).

Examples include Uniox HC-40, Uniox HC-50, and Uniox HC-60 manufactured by NOF Corporation.

Examples of polyoxyethylene sorbitol fatty acid esters include NIKKOLGO-4 manufactured by Nikko Chemicals Co., Ltd.
30 (POE (30) Sorbittetraoleate: HLB 11.5), NIKKOL GO
-440 (POE(40) Sorbittetraoleate)
HLB 12.5).

NIKKOL GO-460 (POE (60) Sorbittetraoleate): HLB 14.0),
NIKKOL GL-1 (POE(6) Sorbitlaurate: HLB 15.5).

Manufactured by Kao Atlas ^tlox 1045A (P
OE solpitol oleitol laure): HLB
13.2).

At1ox 1196 (P OE 7 rubitol oleate: HLB 11.4), G-1045 (P
OE Sorbitol Laurate: HLBll. 5),
G-1441 (POE sorbitol lanolin derivative:
HLB 14.0), etc.

Examples of polyoxyethylene glycerin fatty acid esters include NIKKOL TMGS-15 (POE
(15) Glycerin monostearate): HLB 13
．． 5).

NIKKOL TLlG5-5 (P OE (5)
Glyceryl monostearate: HLB 9.5)
Examples include.

Examples of polyethylene glycol fatty acid esters include NIKKOL MYL-11 manufactured by Nikko Chemical Co., Ltd.
0 (POE (10) monolaure): HLB 12
．． 5).

NIKKOL MMS-10 (P OE (10) monostearate: HLB 11.0), NIKKO
Examples include L MYS-40 (POE (40) monostearate: HLB 17.5).

Examples of polyoxyethylene alkyl phenyl ethers include NIKKOLNP-10 manufactured by Nikko Chemical Co., Ltd.
(POE(10) nonylphenyl ether: HLB
16.5), NIKKOL UP-10 (POE
(10) Octylphenyl ether: HLB 11.
5), EλIULGEN 810 manufactured by Kao Atlas (
P OE octyl phenyl ether: HL 8 1
3.1), EMULG [EN 911 (POE nonylphenyl ether: HLB 13.7).

EMULGEN 930 (P OE / Nilfz
Nyl x-fur: HLB 15.1), Emulg
en 95Q (POE nonylphenyl ether: H
LB 18.2) etc.

The HLB value of these nonionic surfactants is 8-18, preferably 10-17.

The bulking agent may be any general pharmaceutically acceptable excipient, such as saccharides, polysaccharides, dexl-IJ syns, celluloses, and water-soluble polymers.

Examples of saccharides (monosaccharides and oligosaccharides) include D-mannitol, glucose, lactose, fructose, inositol, and sucrose, and examples of polysaccharides include dextran and pullulan. Dextrins include α-cyclodextrin, β-cyclodextrin, T-cyclodextrin, dextrin hydroxypropyl starch, hydroxyethyl starch, and the like.

Further, water-soluble celluloses include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and the like.

Examples of water-soluble synthetic polymers include polyvinyl alcohol, carboxyvinyl polymer, polyethylene gelcol, polyvinylpyrrolidone (PVP), and sodium polyacrylate.

Among these water-soluble bulking agents, α-cyclodextrin, β-cyclodextrin, pullulan, D-
Mannitol, inositol, lactose, dextran, methylcellulose, hydroxypropylcellulose, and polyvinyl alcohol are preferred.

The liquid composition for nasal administration of the present invention reduces side effects on the nasal mucosa and has extremely good absorbability from the nasal mucosa in the order of calcitonin, compared to conventional nasal administration formulations.

(Example) The present invention will be explained in more detail with reference to Examples and Experimental Examples below, but the present invention is not limited thereto.

Example l Take 1.000 units of elcatonin ((AS[J+・7] eel calcitonin 6,000 units/mg) and
Physiological saline containing the organic acid shown in 10rnI! dissolved in

Each of the preparations thus obtained contained 100% of Elcatone.
Unit/mj! Contained.

Table 1 Experimental Example 1 Effects of various organic acids and additive amounts on absorption promotion Experimental animals and administration method Wistar male rats weighing 200 to 250 g, fasted for 16 to 18 hours, were used in experiments with a group of 4 rats. provided. Twenty minutes before the experimental administration, pentoharbital (50 mg/kg) was administered intraperitoneally for anesthesia, and then the method of Hirai et al. (Int. J. Pharm.

Skin 165-172 (1981)], we first made an incision in the neck, inserted a polyethylene tube into the trachea, then made a partial incision in the esophagus, inserted a tube with the tip of the same diameter sealed, and glued the incision with adhesive (Aron). Using a microsyringe, the calcitonin intranasal administration solution prepared in Example 1, which was kept closed with a tube (alpha), was administered through the external nostril.
U/0.1 mf/kg was administered, and the external nostrils were immediately closed with Aron Alpha.

Measurement of blood calcium concentration Blood was collected 5 minutes before administration and 1 hour, 2 hours, 3 hours, and 4 hours after administration.
0.25 m from the femoral vein over time and every 6 hours
Blood was collected from each patient and centrifuged for 5 minutes at 15.00 Or, p, m, and then the calcium concentration in plasma was measured using an atomic absorption spectrometer using 10.1 mf of the blood.

The results are shown in Table 2 below.

As is clear from Table 2 of the results, it can be seen that the addition of various organic acids significantly lowers the blood calcium concentration compared to the control test results.

Example 2 (1) L-glutamic acid 10 mg (2
) Sodium chloride 9 mg (3) Methyl paraoxybenzoate 1.36 mg (4) Propyl paraoxybenzoate 0.16 mg (5) Elcatonin 500 units Dilute the total amount to 1 with distilled water
ml.

According to the above formulation, components (1) to (5) were dissolved together with distilled water to prepare an aqueous solution for nasal administration of the present invention.

This aqueous solution for nasal administration also showed the same decrease in blood calcium concentration as in Experimental Example 1.

Example 3 (1) Adipic acid 10mg (2)
D-Mannitol 50mg (3) Elcatonin 500 units Dilute the total amount to 1 with distilled water
−.

According to the above prescription, components (11 to (3)) were dissolved with distilled water, and 1 d of the solution was dispensed into a 2 mI nasal vial. It showed a decrease in concentration.

In addition, all of the organic acids mentioned in the present invention were calcitonin-containing liquid preparations for nasal administration that had equivalent good absorption properties.

Example 4 1,000 units of 1-fold flaming elcatonin were taken and dissolved in 10 ml of physiological saline containing the organic acids shown in Table 3.

The formulations thus obtained were prepared fresh prior to animal experiments.

Table 3 fruit.

A111 Using the same method as in Experimental Example 1, the effect of an organic acid on the nasal absorption of elcatonin was investigated. The results are shown in Table 4.

Table 4 [Effects of the Invention] The composition for intranasal administration of calcitonin of the present invention can efficiently absorb calcitonin from the nasal mucosa by adding an organic acid as an absorption enhancer. As described above, according to the present invention, it is possible to provide a stable and well-absorbable preparation for intranasal administration of calcitonins, and it has become possible to put it into practical use.

Claims (3)

[Claims] (1) A liquid composition for nasal administration, which contains calcitonins as an active ingredient and an organic acid as an absorption enhancer. (2) The liquid composition for nasal administration according to claim 1, wherein the organic acid is one or more selected from the group consisting of dicarboxylic acids, tricarboxylic acids, and hydroxycarboxylic acids. . (3) The organic acid is maleic acid, malonic acid, fumaric acid,
One or more selected from the group consisting of tartaric acid, citric acid, succinic acid, L-ascorbic acid, malic acid, L-glutamic acid, L-aspartic acid, glutaric acid, adipic acid, D-glucuronic acid, etc. 2. A liquid composition for nasal administration according to claim 2.