JPS6310735A - Calcitonin pernasal agent - Google Patents

Abstract

PURPOSE:A practically usable calcitonin pernasal agent, containing an O- acylcarnitine or salt thereof as absorption accelerator and capable of improving the absorption efficiency from mucous membranes in the nasal cavity without tissue inuring property. CONSTITUTION:A calcitonin pernasal agent obtained by containing calcitonin and an O-acylcarnitine or salt thereof, preferably a compound having 6-18C acyl group, particularly O-octanoylcarnitine, O-lauroylcarnitine or O- palmitoylcarnitine or salt thereof used for treating osteoprosis, hypercalcemia, Behcet diseases, etc., in a liquid diluent or carrier suitable for application to nasal musous membranes. The amount of the O-acylcarinitine blended is preferably within the range of 2-10%(wt./vol.) for a liquid or semisolid composition and 1-30%(wt./wt.) for a solid composition.

Description

[Detailed Description of the Invention] (Industrial Application Field) This invention relates to a pharmaceutical composition for intra-door administration containing calcitonin as an active ingredient, and relates to an excellent intranasal calcitonin preparation containing a specific absorption enhancer. .

(Conventional technology and its problems) Calcitonin is used for osteoporosis and hypercalcemia.

It is a polypeptide hormone that has various medicinal activities and is used to treat diseases such as Beget's disease.

Calcitonin, like other bioactive peptides, cannot be administered orally because it is degraded by digestive fluids in the gastrointestinal tract.
In addition, since it is poorly absorbed, it is usually administered by injection, but this causes great pain to the patient, is inconvenient as self-administration is not possible, and is expensive.

Recently, it has been discovered that the use of calcitonin via the nasal route produces the same effects as when intramuscular injection is used, and various nasal calcitonin compositions have been proposed. However, since polypeptides with large molecular weights such as calcitonin are difficult to be absorbed through the nose as they are, nine proposals have been made to include surfactants as absorption enhancers (Japanese Patent Laid-Open No. 59-8
9fi19.

Publication No. 59-130820). At this time, amphoteric and cationic surfactants are also used, but nonionic surfactants, especially ether type surfactants such as polyoxyethylene lauryl ether, are said to have particularly excellent absorption promoting properties. ing.

However, this ether-type surfactant destroys the nasal mucosa and thereby exerts a drug permeation function into the interior, making it very strong! lJ1 It has a woven N-toxicity, and there is a problem in putting it into practical use as it is.

(Means for Solving the Problems) As a result of extensive research into a nasal administration form that promotes the absorption of calcitonin and can be put to practical use, the present inventors have discovered that a certain type of absorption enhancer has been added to calcitonin. It is. That is, the present invention relates to a pharmaceutical composition for intravenous administration comprising calcitonin and O-acylcarnitine or a salt thereof in a liquid diluent or carrier suitable for application to the rc nasal mucosa.

Calcitonin used in the present invention is salmon; lilcitonin, human calcitonin, elcatonin.

Various substances are used, such as porcine calcitonin.

Further, 0-acylcarnitine is a compound represented by the following formula in which the hydroxyl group of carnitine (γ-trimethylβ-hydroxyaminoacetic acid) is acylated.

(CHs)　xN”c　11zCHCHtCOO-old.

(In the formula, R means an acyl group having 2 to 20 carbon atoms.) The 0-acylcarnitine used in the present invention may be any linear or branched lower to higher O-acylcarnitine. but preferably O having 8 to 18 carbon atoms.
-Acylcarnitines should be used. Particularly preferred are O-octanoylcarnitine, O-lauroylcarnitine and O-palmitoylcarnitine. These may be used alone or in a mixture of two or more, and may be used in the form of salts such as 0-7 silcarnitine. Examples of the salts include hydrochloride, bromide, etc. Hydrogen salts [acid salts, inorganic acid salts such as phosphates, acetates. Oxalate. Examples include organic acid salts such as citrate.

The pharmaceutical composition for intradoor administration of the present invention is an aqueous solution. It can be in the form of a hydrogel or a solid powder.

The aqueous solution is prepared by dissolving calcitonin and O-acylcarnitine or a salt thereof in water or a buffer solution by a conventional method, and at this time, additives may be added and dissolved as necessary. The pH of the aqueous solution is preferably 3 to 5 from the viewpoint of stability.

Citrate is used as a buffer. Tartrate. Malate or the like is used, and pH 3 to 5 is preferred.

Additives include sterilizers, preservatives, and thickeners commonly used for nasal preparations. Surfactant. Stabilizers etc. can be added.

The sterilizer and preservative may be those commonly used in intranasal compositions, and examples include paraoxine benzoate, propylene glycol, benzethonium chloride, and sorbic acid (Na).

As the thickener, polyvinyl alcohol, polyvinylpyrrolidone, dextran, etc. can be used.

As surfactants, polyoxyethylene monostearate, polyoxyethylene sorbita monooleate, polyoxyethylene hydrogenated castor oil, etc. are used as surfactants and emulsifiers for various additives.

Stabilizers include gelatin and albumin.

The dosage form is a dropper for intranasal administration.

Drop or atomization methods are used, such as using a spray container or exposed aerosol applicator.

In the case of a powder, mannitol, inositol, gougecose, etc. are further added, dissolved, and freeze-dried, and the resulting solid is administered as a fine powder in the same manner as in the case of a normal powder. Such a powder is filled into a capsule, and the capsule is
One method is to set the capsule in a spray device equipped with a needle, pass the needle through the capsule, make small holes at the top and bottom of the capsule, and blow air into the capsule using a rubber ball or the like to squirt out the powder.

In the case of aqueous gels, commonly used gel bases such as natural gums, methylcelluloses, acrylic acid polymers,
It is made into an aqueous gel using a vinyl polymer or polysaccharide.

The proportions of the active ingredients calcitonin, 0-acylcarnitine or its salts, and various additives used in the pharmaceutical composition of the present invention are not particularly limited, and can be appropriately determined depending on the form of solution, gel, powder, etc. When the calcitonin nasal spray composition is in the form of an aqueous solution, the amount of calcitonin is 200 to 60,001 U/mj! A concentration of 4°C is common, and preferably a concentration of 500 to 2000 IU/mJ.

Throw No. 4 is 2- when the heavy duty composition is solid or semi-solid.
200 mg/time, preferably 10 to 100 mg/time, and when liquid, 9.02 to 0.2 m 12 /time,
Preferably it is 0.05 to 0.15 mj2/time. The appropriate frequency of administration is 1 to 5 times a day. Further, the amount of O-acylcarnitine or its salt varies depending on the type. If the heavy use composition is liquid or semi-solid, usually 0.1 to 30%.
(j/V), preferably 2 to 10% (w/V).
v) is also usually 0.1 to 90% (W/W) in the case of a solid
, preferably 1 to 30% (w/w).

(Function) By using 0-acylcarnitine as an absorption enhancer in the calcitonin nasal preparation, absorption efficiency from the nasal mucosa is increased, and it can be said to be an excellent calcitonin nasal preparation.

(Examples and Effects) The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to this.

Examples 1 to 5 Salmon calcitonin 3501U citric acid elongate 12.2mg sodium citrate in 1ml
12.4 m go-acylcarnitine
(Refer to Table 1) (N-chloride form) Table 1 Narmon calcitonin and absorption enhancer were dissolved in citric acid hydrate and sodium citrate solution at the indicated concentrations, respectively, to a concentration twice the indicated concentration. Then, adjust the pH to 4.0 overnight with a 1N aqueous hydrochloric acid solution or a 1N aqueous solution of caustic soda, add water to make 12 lm, and mix the two in equal volumes.

Example 6 A composition was obtained by carrying out the same procedure as in Example 1, using 35 QIU of pork calcitonin instead of the salmon calcitonin used in Example 1, and using 30 mg of lauroylcarnitine (N-chloride form) as an absorption enhancer. Ta.

Example 7 Mannitol 928 mg, dextran 200 mg
% Benzethonium chloride 0.4 mg, crystalline citric acid 34.8 mg, sodium citrate 35.4
mg and lauroylcarnitine (N-chloride form)
600 mg was dissolved in 50 ml of distilled water with stirring.

12,000 IU of salmon calcitonin was added and dissolved in the resulting solution, filtered through a 220 nm membrane filter, and the filtrate was freeze-dried. The obtained solid was pulverized to obtain a composition.

Experimental Example 1 SD male and female rats 115-145 fed for 18 hours
g) was anesthetized with pendoparbital (50 av/kg, intraperitoneal injection), and the aqueous calcitonin preparations prepared in Examples 1 to 5 and the preparation prepared as a control were administered at 51 U/kg g.
administered.

The administration method is a polyethylene tube (PEIO, clay).
Adams) serially numbered microsyringe (10μl)
Approximately 2 μm depending on body weight at 5-5 mm of nasal septum.
I injected 1. The absorbability of the calcitonin preparation through the nasal mucosa was evaluated by measuring the serum calcium concentration, and the calcium concentration was quantified using a calcium meter (CA-30, Joko). Before administration and after a certain period of time, rats were sacrificed and blood was collected from the descending vena cava. Second result
The values shown in Table 2 are the average values of 4 or more rats.

Table 2 Blood calcium concentration 2 and 4 hours after intranasal administration of calcitonin (51 U/kg) Serum calcium concentration before administration 10.67 wag % From Table 2 Addition of 0-acylcarnitine or its salt Serum C
It can be seen that the a concentration is significantly reduced compared to the control even at low concentrations.

Claims (3)

[Claims] (1) A pharmaceutical composition for intradoor administration of calcitonin, comprising calcitonin and O-acylcarnitine or a salt thereof in a liquid diluent or carrier suitable for application to the nasal mucosa. (2) The pharmaceutical composition for intradoor administration of calcitonin according to claim (1), wherein the O-acylcarnitine is O-acylcarnitine having an acyl group having 6 to 18 carbon atoms or a salt thereof. (3) The pharmaceutical composition for intranasal administration of calcitonin according to claim (1), wherein the O-acylcarnitine is O-octanoylcarnitine, O-lauroylcarnitine, O-palmitoylcarnitine, or a salt thereof. .