JPS63243033A - Nasal administration composition - Google Patents

Abstract

PURPOSE:To obtain the titled composition having excellent absorption free from side effects to nasal mucosa, containing an absorption promoter selected from alkyl beta-D-glucosides and a polypeptide selected from carcitonins as active ingredient. CONSTITUTION:A composition containing one or more absorption promoters selected from a group consisting of alkyl-beta-D-glucosides and alkyl-N- methylglucamides (e.g. n-heptyl beta-D-glucopyranoside and heptanoyl-N- methylglucamide) and a polypeptide selected from calcitonins (e.g. rabbit cacitonin) and parathyroid hormones as active ingredients. The composition is efficiently absorbed in administration in nasal cavity and shows temperature bioavailability.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to calcitonin and parathyroid hormones.
The present invention relates to a nasal calcitonin composition comprising a polypeptide selected from the group consisting of 1 (ormone; hereinafter also referred to as PTH) which is effectively absorbed by nasal mucosal administration. The purpose is to increase the effect of promoting absorption of calcitonins or PTHs during nasal administration.

Jubei Keio Insulin, calcitonin, thyroid stimulating hormone (
TSH), gastrin, somatosfutin, secretin,
Physiologically active polypeptides such as luteinizing hormone-releasing hormone (LHRH), adrenocorticotropic hormone (ACTH), vasopressin, oxytocin, glucagon, and PTH@ are generally hydrolyzed by enzymes in the gastrointestinal tract or on the wall of the gastrointestinal tract. , absorption from the gastrointestinal tract is extremely difficult.

Therefore, in order to expect sufficient medicinal efficacy, administration of these physiologically active polypeptides has been limited to injection administration.

However, administration by injection is painful, and furthermore, a simpler and easier to apply formulation is desired during continuous administration.

As a report regarding intranasal administration, there are known liquid preparations for intranasal administration of insulin or calcitonins using surfactants as absorption enhancers.

(Int, J, Pharm,, 9. I 6
5-172 (1981); Int, J, Phar
m,, 9. 173-184 (19B]);D
iabetes, 27. 296 299 ;J
, Japan Diab, Soc,, 20 (
2), 146-152° (1977); N,
Engl, J. Med, 312. 1078-
1084 (1985); Diabetes,
20, 552-556 (1971);Dia
betes, 32. 1040-1047 (1
983) ;Proc, Natl, Acad,
Sci.

U, S, A,, ■, 隘21, 7419-7423゜19
85; JP-A-59-89619; JP-A-59-1
No. 30820,] Nonionic ether type surfactants or sodium salts of bile acids that have an absorption-promoting effect have strong tissue damage to the nasal mucosa, and to date, none have been put into practical use. rare.

As a result of various studies on calcitonins and compositions for nasal administration of PTH, the inventors unexpectedly discovered that alkyl glucosides and alkyl-N-methylglucamides are absorption enhancers. The conventional techniques and their problems were solved by adding them to a nasally administered composition containing calcitonin and PTH.

In addition, alkyl glucosides and alkyl-N-methylglucamides were administered to rabbits for 24 hours and 4 hours after intranasal administration.
Dissections were performed every 8 hours and the nasal mucosa was histologically observed using a microscope. As a result, it was found that the degree of damage was lower and the safety was higher than that of conventional surfactants.

The present invention is directed to a composition suitable for intranasal administration of calcitonins and PTHs, that is, a group consisting of alkyl β-D-glucosides and alkyl-N-methylglucamides. The present invention relates to a nasally administered composition containing, as an active ingredient, one or more absorption enhancers selected from the group consisting of calcitonins and PTHs.

When administered intranasally, these compositions release calcitonins,
PTHs are efficiently absorbed through the nasal mucosa and do not cause side effects such as irritation or discomfort even when used for a long period of time.

Calcitonins in the present invention may be any peptides having a serum calcium lowering effect, and include various natural calcitonins or peptide analogs thereof.

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

Further, as an example of the peptide analogue, (ASUl-7
) Rabbit calcitonin (WHO-ship name: Elcatonin)
, (ASUI-7) salmon calcitonin, (ASUI-7
) human calcitonin or (ASUI-7) chicken calcitonin.

These substances and synthetic methods are described, for example, in British Patent No. 15169.
It is described in the specification of No. 47, Proceedings of the 50th Spring Annual Meeting of the Chemical Society of Japan, 1985 ■, page 947, etc. moreover,
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 patients, Behcet's disease, etc.

In the case of an aqueous solution, the concentration of calcitonin in the composition of the present invention is generally 5 MRC units/m7! ~10. OO
At a concentration of OMRC units/ml, preferably 50MR
C units/mA~2. OOOMRC units/ml.

The dosage is preferably 0.05 to 0.2 ml/time, and the appropriate number of administrations is 1 to 3 times a day.

On the other hand, PTHs are peptides that have an effect of increasing serum calcium, and have a sequence of 34 to 84 amino acids.
Natural PTH or its analogs are known.

For example, human-PTH (h-PTH) (184)CB
iochemis try 7.5723 (197
8)), h-PTH (1-38) (JP-A-57-814
No. 48), h-PTH (1-34) (Hop
pe-3eyler's Z, Physiol, C
hem,, 355. 415 (1974)), h-P
TH (1-34) NHK (Japanese Unexamined Patent Publication No. 58-96052), [NIea″8]b, -PTH (1-34)
, (Nle818.Tyr”)h-PTH(
1-34) C JP-A-55-113753 Koyuki U],
(Nle””] h PTH(13
4) NHZ [Unexamined Japanese Patent Publication No. 61-24598], (
Nle""+Tyr34'J h-PTH(134)
Nl2C JP-A No. 60-34996], Rat-PTH (1-84), [J, Biol
, Chem, 259 (5).

3320 (1984), rat-PTH (1-34
) (Endocrinol,, 117 (3)
, 1230 (1985)), bovine-PTH (1-8
4) (Am, J, Med, 50.639 (19
71,)), bovine PTH(1-34), bovine-PT
H(1-34)NH2 etc. rPthobiology a
nual 11, 53 (1981)).

These PTHs cause an increase in blood calcium and a decrease in phosphorus, and are currently used clinically primarily for testing purposes.

However, it is currently being developed as a therapeutic drug, and if it is put into practical use, the single dose will be extremely small, just like calcitonin, considering its medicinal efficacy, and the concentration of PTH in the composition of the present invention will be in an aqueous solution. In the case of agents, generally 1
Preferably 10-50 at a concentration of ~1000 μg/ml
It is 0 μg/ml.

The dosage is preferably 0.05 to 0.2 12 times, and the appropriate number of administrations is 1 to 3 times a day.

Also, the absorption enhancer used in the present invention, alkyl-β
-D-glucosides may be glucosides having an alkyl group having 6 to 16 carbon atoms, such as n-heptyl β-D-glucopyranoside, n-octyl β-D-glucopyranoside, n-decyl β-D -glucopyranoside, n-dodecyl β-D-glucopyranoside,
Examples include n-dodecyl maltoside.

Further, the alkyl-N-methylglucamides may be methylglucamides having an alkyl group having 6 to 16 carbon atoms, such as heptanoyl-N-methylglucamide, octanoyl-
Examples include N-methylglucamide, nonanoyl-N-methylglucamide, and decanoyl-N-methylglucamide.

Alkyl-β-D-glucosides and alkyl-N-
In the case of an aqueous solution, the concentration of methyl glucamide used is 0.1% to 20% (W/V), preferably 0.1% to 20% (W/V).
5%~10% (W/V)? It is a1 degree.

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

In addition, the above-mentioned nasal preparations may be used as aqueous solutions for calculation or spraying, or freeze-dried preparations for dissolution before use, and can also be used as semi-solid or solid preparations for insertion into the nostrils. In the case of an aqueous solution, various additives such as buffers, stabilizers, thickeners, etc. can be further added. Furthermore, if necessary, various preservatives can be added. When used as an aqueous solution, it is convenient to use distilled water as a medium, and this distilled water can be used with the addition of an acid such as hydrochloric acid, acetic acid, citric acid, or tartaric acid, or its acidic buffer solution. By setting p), it is preferable to set it to 12 to 6, and the absorbency becomes better due to this liquid property.

Examples of buffer solutions include organic acids such as acetic acid, citric acid, and tartaric acid; diphosphoric acid; inorganic acids such as carbonic acid; aspartic acid;
Preferably, amino acids such as glutamic acid, glycine, histidine, and arginine hydrochloride are used.

Stabilizers include gelatin, albumin, and lecithin.

Thickeners include methylcellulose, hydroxypropylcellulose, propylene glycol, glycerin, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, and the like.

Examples of preservatives include 2-phenylethanol, chlorobutanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, and phenol.

Implementation Example Next, an in vivo nasal mucosal absorption experiment was conducted in rats, but the present invention is not limited thereto.

Example 1 Seiton 1Ω familiarity I- per ml of preparation, Elcatonin 100 MRC units, Sodium citrate 4.63■, Anhydrous citric acid 0,37■, Sodium chloride 7.00mg.

Absorption enhancers (see Table 1) The total volume is made up to 1 mβ with distilled water.

Dissolve each component in distilled water to a concentration having the above composition,
The pH was adjusted to 6.0, and Formulation 1 was prepared.

1. Four Wistar type A rats weighing 200 to 250 g that had been fasted for 16 to 18 hours were used in the experiment. After administering bendoparbital (50 μ/kff) intraperitoneally 20 minutes before experimental administration, the animals were anesthetized.
The method of Hirai et al. (Int, J, Pharm, 9 +
165-172 (1981)), first make an incision in the neck, insert a polyethylene tube into the trachea, then make a partial incision in the esophagus, insert a tube with the tip of the same diameter sealed, and seal the incision with adhesive (Aron Alpha). ), then administer calcitonin (10 Ul) through the external nostril using a microsyringe using a microsyringe to administer the intranasal solution of calcitonin prepared in Formulation 1.
1 tall/kg was administered, and the external nostrils were immediately closed with Aron Alpha.

Calcium Agency's SI Blood sampling is done 5 minutes before administration and 1, 2, 3, and 4 hours after administration.
0.25 m from the femoral vein over time and every 6 hours
jl! 15. Collect blood one by one. After centrifugation at 000 r, p, m for 5 minutes, 0.1 ml of the plasma was used to measure the calcium concentration in the plasma using an atomic absorption spectrometer.

boar fruit The results are shown in Table 2.

Table 2 shows that the addition of the absorption enhancer according to the present invention significantly lowers the blood calcium concentration compared to the control test results.

Example 2 1ton 1■Kunritsu preparation 1 ml Buffer Sodium acetate 1.91mg
Glacial acetic acid 0.36+++g,〃
Propylene glycol 10.0■, absorption enhancer n-octyl β-D 50.0■, -glycopyranoside first part preservative 2-phenylethanol 4.0■, elcatonin 200 MRC units, total volume with distilled water 1 Let it be mjl.

Dissolve each component in distilled water to a concentration that provides the above composition, and
It was adjusted to H5.0 and designated as Formulation 2.

The obtained formulation 2 was filled into a commercially available nasal mechanical spray. New sealant male rabbit (weight 2.5~
3.0 kg, 4 animals per group), 100μ of the calcitonin intranasal administration composition (formulation 2) prepared as above was placed in the nasal cavity.
I! (one intranasal injection N) was administered. Before administration and every 1 hour, 2 hours, 3 hours, and 6 hours after administration, 2.5 mp of blood was collected from the rabbit ear artery. 15000r after blood collection
, p, m, , Plasma was obtained by centrifugation for 5 minutes.

Calcium concentration in plasma was measured using an atomic absorption spectrophotometer.

In addition, the standard for blood calcium concentration (+! (100%)
indicates the value of blood collected 15 minutes before administration.

Figure 1 shows the change in blood calcium concentration over time after calcitonin (IU/kg) was administered to the nasal mucosa (-X-) or intramuscularly (-○-).

From the figure, it can be seen that the effect on blood calcium concentration is equal to or higher than that of intramuscular administration.

Example 3 Elcatonin 500 MRC units Sodium acetate 2.0 mg Glacial acetic acid per mβ formulation
2.0■Methylcellulose 5.0■n-dodecylmaltoside 20.0mg Benzalconium chloride
Adjust the total volume to 1 mA with 0.1■ distilled water.

Dissolve each component in distilled water to a concentration having the above composition and pH 3
, 0 and used as a formulation.

Example 4 Elcatonin 500 MRC units Gelatin 20.0 octanoyl per ml of formulation
N-Methylglucamide 10.0 ■ Methyl paraoxybenzoate 0.26 + ng Propyl paraoxybenzoate 0.14 ■ Add the total amount to 1 me with distilled water
shall be.

Dissolve each component in distilled water to a concentration having the above composition and pl(
6.0 and used as a preparation.

Example 5 Preparation 1m7! per elcatonin 500 MRC units glycine 1. O, O ■ Sodium hydrogen phosphate 2.0 ■ Citric acid
1.3 ■ Sodium chloride
5.0mg decanoyl-N-methylglucamide 10. Onw chlorobutanol
1.0 ■I n+11 the total amount with distilled water!
shall be.

Dissolve each component in distilled water to a concentration having the above composition and pH 6.
, 0 and used as a formulation.

Example 6 Per 1 ml of preparation, h-PTH(1-34) 307μg Sodium acetate 1.91mg Glacial acetic acid 0.36■ Propylene glycol 10.0■ n-octyl β-D -50,0■ Glucopyranoside 2-phenylethanol 4.0■ Make the total volume to 1 iff with distilled water.

Dissolve each component in distilled water to a concentration having the above composition and pH 5.
, 0 and used as a formulation.

The intranasal administration composition of calcitonin, PTH@, of the present invention had few side effects on the nasal mucosa, improved absorption through the nasal mucosa, and showed good bioavailability. Furthermore, the composition of the present invention also exhibits the effect of promoting absorption from the oral mucosa.

[Brief explanation of drawings]

FIG. 1 shows the change in blood calcium concentration over time after administration to rabbit nasal mucosa. --X- shows the results of the composition of Example 2, and 10- shows the results when calcitonin (IU/kg) was administered intramuscularly. Agent Masao Miyake and 1 other person (hours)
Hr)

Claims (1)

[Claims] One or two selected from the group consisting of alkyl β-D-glucosides and alkyl-N-methylglucamides
1. A composition for nasal administration containing as active ingredients at least one absorption enhancer and a polypeptide selected from the group consisting of calcitonins and parathyroid hormones.