JPH03120229A - Calcitonin intranasal preparation - Google Patents

Abstract

PURPOSE:To obtain an intranasal administration agent of calcitonin, capable of improving pernasal absorption rate of the calcitonin and enabling pernasal administration by blending the calcitonin with carbenoxolone. CONSTITUTION:An intranasal administration agent of calcitonin, obtained by blending (A) the calcitonin used as the first aid for a danger caused in the heart if hypercalcemia suddenly occurs due to bone metastatis of hyperthyroidism or malignant tumor with (B) carbenoxolone as essential ingredients, enabling at-home treatment of patients due to the aforementioned effects thereof and capable of avoiding complicatedness in attending hospitals and pains in injection. The above-mentioned ingredients are preferably blended in the following amounts. The ingredient (A) in an amount of 20-7000IU/ml for the form of an aqueous solution, 2-200mg/time for the form of a solid or semisolid and 0.02-0.2ml/time for the form of a solution and the ingredient (B) in an amount of 0.01-10wt.% for the form of a liquid or semisolid and 0.05-20wt.% for the form of solid powder at 1:(0.05-2500) weight ratio of the ingredients (A):(B).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel composition for intranasal administration of calcitonin.

[Prior art] Intranasal administration of drugs was only used as nasal drops for local effects in the field of otorhinolaryngology, etc., but in recent years, it has become clear that drugs can be well absorbed through the nasal mucosa. has become known, and many attempts have been made in anticipation of systemic effects [Problems to be solved by the invention] It is known that the absorption rate of peptides through nasal absorption is very low. In particular, the molecular weight is t, oo.

The nasal absorption of the above drugs is extremely low, on the order of a few percent, so absorption enhancers must be used to increase the absorption rate.

Substances currently being investigated as nasal mucosal absorption enhancers include ionic and nonionic synthetic surfactants, bile salts, and saponins.

Calcitonin is used as an emergency treatment because hypercalcemia that suddenly occurs due to hyperparathyroidism or bone metastasis of a malignant tumor poses a risk to the heart. The main formulation is an injection, but recently attempts have been made to develop an intranasal formulation. However, no absorption enhancer is known that provides sufficient blood concentration when administered intranasally.

[Means for Solving the Problems] The present inventors investigated medium-chain fatty acids, glycyrrhizin, glycyrrhetinic acid, and their derivatives as absorption enhancers for intranasal administration of calcitonin, and found that calcitonin The present invention was completed by discovering that nasal absorption was significantly increased when carbenoxolone was added.

The present invention is an intranasal preparation characterized by containing calcitonin and carbenoxolone.

The intranasal preparation of the present invention can be in the form of an aqueous solution, a hydrogel, or a solid powder.

The calcitonin of the present invention includes not only naturally occurring calcitonin such as salmon calcitonin, human calcitonin, pig calcitonin, eel calcitonin 1, and chicken calcitonin, but also various calcitonins having pharmaceutical activity such as derivatives and analogs of elcatonin. Salmon calcitonin is the most preferred, and the common name rubenoxolone can also be used as an alkali addition salt, such as is commercially available as the disodium salt of glycyrrhetinic acid-3-hemisuccinate.

When the calcitonin nasal spray composition is in the form of an aqueous solution, the blending amount of calcitonin is preferably 20 to 7000 IU/m, more preferably 250 to 2000 IU/m.
When the nasal composition is solid or semi-solid, it is preferably 2 to 200 μ/ml, more preferably 10
~100 ■/time. Moreover, when the composition for nasal spray is a solution, the amount is preferably 0.02 to 0.2 td/time, more preferably 0.04 to 0.1 d/time.

In addition, when the intranasal preparation of the present invention is a liquid or semi-solid, the amount of carbenoxolone to be blended is usually 0.01 to 10.
% (W/W) (7) range, preferably 0.1 to 5
% (W/W).

Carbenoxolone in the solid powder composition useful for nasal administration of the present invention can be incorporated in a pharmaceutically acceptable amount, usually in the range of 0.05 to 20% (W/W). , more preferably in the range of 0.1 to 10% (w/w).

The blending ratio of calcitonin and carbenoxolone is an aqueous solution,
Although it can be appropriately selected depending on the form of the hydrogel or solid powder, it is preferably used in the range of 2500 parts by weight, more preferably 10 parts by weight to 500 parts by weight of carbenoxolone per 1 part by weight of calcitonin. .

The appropriate frequency of administration of the intranasal preparation of the present invention is 1 to 3 times a day.

In the case of an aqueous solution, the method for producing the intranasal preparation of the present invention includes:
It is produced by dissolving calcitonin and carbenoxolone in water or a buffer solution by a conventional method, and at this time, additives can be added if necessary. The pH of the aqueous solution can be adjusted between 2 and 10, but from the viewpoint of stability it is preferably between 3 and 8.Buffers include phosphate, tartrate, malate, citrate, and tris-hydrochloride. etc. can be used.

As additives, bactericides, preservatives, thickeners, surfactants, stabilizers, etc. commonly used for nasal preparations can be added. Examples of disinfectants and FJJlf agents include paraoxybenzoic acid ester, propion glycol, benzalkonium chloride, benzethonium chloride, butanol, and sodium sorbin. As a thickener,
These include polyvinyl alcohol, polyacrylic acid, polyvinylpyrrolidone, and dextran. Surfactants are added as dispersants and emulsifiers for various additives, and surfactants with low mucosal irritation are preferred. Among these surfactants, nonionic surfactants include polyoxyethylene sorbitan fatty acid esters and sorbitan fatty acids. Examples include esters, propylene glycol fatty acid esters, pentaerythritol fatty acid esters, sucrose fatty acid esters, polyethylene glyfur fatty acid esters, polyoxyethylene castor oil, hydrogenated castor oils, and the like.

Furthermore, lecithin or a mildly amphoteric surfactant can be used, or a combination of these surfactants can be used. As a stabilizer, proteins such as gelatin, albumin, and casein can be added. Furthermore, an aqueous solution of acidic, neutral, and basic amino acids or saccharides such as trehalose can be added as a diluent if necessary. These amino acids include arginine, lysine, citrulline, ornithine, histidine,
tryptophan, threonine, alanine, cysteine,
Cystine, leucine, isoleucine, methionine, phenylalanine, proline, serine, glycine, valine,
Glutamic acid, alginic acid, etc. can be used. The amino acid may be in the L-form, 0-form, or racemic form.The administration form includes a dropper for intranasal administration;
A method of administering by dropping or spraying using a spray container or an aerosol applicator is used.

In the case of powder form, mannitol, inositol, glucose, lactose, hydroxypropyl cellulose, crystalline cellulose, polyacrylates, etc. are further added and mixed, and the resulting solid is finely powdered and administered nasally. do.

A method of filling such a powder into a sprayer and blowing it out by sending air with an elastic rubber ball or the like through an installed nozzle hole is used.

In the case of an aqueous gel, commonly used gel bases, methylcelluloses, natural gums, acrylic acid polymers, vinyl polymers, polysaccharides, and even pluronic gels are used to form an aqueous gel.

[Effects of the Invention] According to the present invention, the nasal absorption rate of calcitonin has been improved, nasal administration has become possible, and home treatment of patients has become possible.

This makes it possible to avoid complicated hospital visits and pain during injections.

[Example] Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples.

Example 1 Salmon calcitonin 100 in pH 7.4 isotonic phosphate buffer
．． 000 IU (25 mg) and 1 g of carbenoxolone disodium salt were added and dissolved, and a pH 7.4 isotonic phosphate buffer was further added thereto to make up the volume to 100 ml.

Example 4 1 g of carbenoxolone disodium salt and 100 g of salmon calcitonin. OOOIU (25mg) Gelatin 1g
was dissolved in 90ml of distilled water, and further added 0.0ml of distilled water. IN sodium hydroxide was added to adjust the pH to 7.0, and distilled water was further added to make the total amount 100 d.

Example 2 0.5 g of carbenoxolone disodium salt and 100.000 IU (25 mg) of salmon calcitonin were dissolved in distilled water. Add 3g of glycerin to this and dissolve. Add IN sodium hydroxide to adjust pH to 5,
Distilled water was further added to make the total volume 100ml.

Example 3 1.5 g of carbenoxolone disodium salt and 100,000 IU (25 mg) of salmon calcitonin were dissolved in distilled water. Add to this sodium acetate 3H*01.36
g and 0.6 g of acetic acid were added and dissolved, and distilled water was further added to make the total amount 100 TIIQ.

Example 5 Mannitol 900ff1g, trehalose 200m
g, glycine 10■, benzethonium chloride 0.4mg,
') Citric acid 34.8 mg, sodium citrate 35.
4 mg and 500 mg of sucrose fatty ester were dissolved in 50 mQ of distilled water. 0.2 g of carbenoxolone disodium salt and 5.0 OO of salmon calcitonin were added to the resulting solution.
IU was added and dissolved, filtered through a 0.22JJ11 membrane filter, and the filtrate was freeze-dried. The obtained solid was pulverized to obtain a composition.

Test Example 1 (Sample) Sample 1; Salmon Calcito: 100 OIU/ml (
25 hg/mQ) and carbenoxolone disodium salt 10a+g/ml in isotonic phosphate buffer (pH 7,4).

Control sample 1; Salmon calcitonin 100OIυ/mQ (
The preparation was dissolved in isotonic phosphate buffer (pH 7.4) to a concentration of 1.5 m/ml).

Control sample 2: salmon calcitonin 1000IU/ml! (
250 fish/TIIQ) and sodium caprate 10
Isotonic phosphate buffer (
Formulation dissolved at pH 7.4).

After securing the test sample and inserting a cannula from the esophagus into the nasal cavity to prevent leakage of the administered solution, test sample 0.1ml/1l/
Kg (salmon calcitonin 100 I (J/Kg)) was administered intranasally, and blood was collected from the femoral vein over time.

Measurement of blood calcitonin concentration associated with absorption of salmon calcitonin is carried out using the Salmon Calcitonin RIA Measurement Kit (P
en1nsula Lab, Inc.) and 0CPC method (
It was measured using Calcium C-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).

The pharmacological effects were confirmed from the salmon lucitonin blood concentration and Ca blood concentration.

(result) The results are shown in Tables 1 and 2.

Table 1 Bioavailability after nasal administration of salmon calcitonin (test method) Rats (body weight: 200-250 g) were placed under anesthesia,
The method of sain et al. [J, Pharm, Sci.
69, p. 1411, (1980)], a cannula was inserted into the trachea and breathing was performed. The group treated with Sample 1 showed higher bioavailability than the group to which no absorption enhancer was added (Control 1) or the group to which sodium caprate was added to the formulation (Control 2), and furthermore, blood Ca
The concentration reduction effect was also found to be higher than the control group.

Claims (1)

[Claims] 1) An intranasal agent comprising calcitonin and carbenoxolone.