JPH01308235A - Human growth hormone for transnasal administration - Google Patents

Abstract

PURPOSE:To obtain the subject agent for nasal administration free from action to damage the tissue such as nasal mucosa, by compounding o-acylcarnitine as an absorbefacient. CONSTITUTION:A human growth hormone (somatotropin) and a compound of formula (R is 2-20C acyl) or its salt are included in a liquid diluent or carrier suitable for the application to nasal mucosa. The compound of formula is prefer ably a 8-18C compound, especially o-octanoylcarnitine, o-lauroylcarnitine or o-palmitoylcarnitine and the weight ratio of the compound to the human growth hormone is 1:0.007-2.3, preferably 1:0.07-0.8 when the composition is liquid and is 0.007-150, preferably 1:0.07-50 when the composition is solid or semi-solid.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a pharmaceutical composition for intranasal administration of human growth hormone (somatotropin).

(Prior Art) Human growth hormone is a polypeptide with 191 agennoic acids and a molecular weight of 22,000, which is secreted from the anterior pituitary gland. The characteristics of growth hormone are that it is highly species-specific, and for humans only growth hormone is more effective than for primates. The physiological action of this growth hormone is ■ Promote the production of somatomedin.

Promotes bone and cartilage growth. ■Increases amino acid uptake into cells and protein synthesis, while suppressing amino acid and protein degradation. ■Decomposes neutral fats and releases fatty acids. ■ Mobilizes glucose to supply energy sources. ■Sodium,
It has a wide range of functions, including storing electrolytes such as potassium, and promotes growth in various aspects of substance metabolism.

Conventionally, this growth hormone has been administered by subcutaneous injection or intramuscular injection, but there are drawbacks such as frequent administration and pain during administration.

On the other hand, a method has recently been proposed in which polypeptides that are difficult to absorb are administered orally via the nasal route.5 For example, peptides with a large molecular weight of 2 are difficult to be absorbed through the nose as they are, so absorption enhancers are used. (Japanese Patent Application Laid-Open No. 59-89619, 59-13082)
Publication No. 0).

However, these absorption enhancers do not necessarily enhance the absorption effect for all polypeptides.

In addition, even those known as nasal absorption enhancers exhibit the function of drug permeation into the interior like ether type surfactants, but they destroy the nasal mucosa and have tissue damage at temperatures above 5°C and 7°C. There is also.

(Another Means to Solve the Problem) The present inventors have conducted intensive research into a dosage form that can promote the absorption of growth hormone and can be put to practical use. The present invention has been completed based on the discovery that the absorption of human growth hormone can be significantly increased by adding and administering it nasally.

That is, the present invention relates to a pharmaceutical composition for intranasal administration comprising human growth hormone and o-'-acylcarnitine or a salt thereof in a liquid diluent or carrier suitable for application to the nasal mucosa.

The human growth hormone used in the present invention may be directly extracted from the human pituitary gland or obtained from Escherichia coli by genetic engineering.

Further, o-acylcarnitine is a compound represented by the following formula in which the hydroxyl group of carnitine (γ-trimethyl-β-hydroxyaminobutyric acid) is acylated.

(CH3)3N+CH2CHCT-12COO-R (In the formula, R means an acyl group having 2 to 20 carbon atoms.) The 0-acylcarnitine used in the present invention is a linear or branched lower to higher acyl group. o -Acylcarnitine, preferably 8 to 1 carbon number 0
-Acylcarnitines are used. Particularly preferred are 0-octanoylcarnitine, 0-lauroylcarnitine and 0-valmitoylcarnitine. These may be used alone or in combination of two or more. Moreover, o-acylcarnitines may be used in the form of their salts. Examples of the salt include inorganic acid salts such as hydrochloride dihydrobromide, sulfate, and phosphate, and organic acid salts such as acetate, oxalate, and citrate.

The pharmaceutical composition for intranasal 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 human growth hormone and 0-acylcarnitine or its salt 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 5.5 to 8.5 from the viewpoint of stability.

As an additive, it is commonly used for nasal preparations.

Sterilizers, preservatives, thickeners, surfactants, stabilizers, etc. can be added.

The sterilizer and preservative may be those commonly used in intranasal compositions, such as paraoxine benzoate.

Propylene glycol, [benzethonium].

Examples include sorbic acid (Na).

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

The surfactant is added as a dispersant or emulsifier for various additives, and nonionic surfactants that cause almost no mucosal irritation are preferred. Examples of these nonionic surfactants include polyoxyethylene monostearate 1, polyoxyethylene monostearate 1, polyoxyethylene hydrogenated castor oil, and the like.

Stabilizers include gelatin and albumin.

For intranasal administration, a single drop or spraying method is used using a drop container, a spray container, an aerosol applicator, or the like.

In the case of powder form 2 Same as in the case of normal powder.

Adding ingredients such as saranimannito, inositol, glucose, etc.
After dissolution, it is lyophilized and the resulting solid is administered nasally as a fine powder. A method of filling such a powder into a capsule, inserting the capsule into a spray device equipped with a needle, passing the needle through it, making micro holes at the top and bottom of the capsule, and blowing air through a rubber ball or the like to squirt the powder. etc. are taken.

In the case of aqueous gels, commonly used gel bases 5 such as natural gums, celluloses such as hydroxyglobil cellulose and crystalline cellulose, acrylic acid polymers such as Carbopol, vinyl polymers, or polysaccharides such as hyaluronic acid, etc. may also be used.

The proportions of the active ingredients, human growth hormone, 0-acylcarnitine or a salt thereof, and various additives used in the pharmaceutical composition of the present invention are not particularly limited.

It can be adjusted as appropriate depending on the form of solution, gel, powder, etc. When the human growth hormone nasal spray composition is in the form of an aqueous solution, the blending amount of human growth hormone is 13 to 800 mg/
ml concentration is common, preferably 27-2401
The concentration is 11 g/ml. The dosage is 40-300μ/7 times or 40-30 times when the composition is liquid.
It is 0mg/dose.

The appropriate frequency of administration is 1 to 5 times a day. Also.

The amount of 0-acylcarnitine or its salt varies depending on the type. When the composition is liquid, the weight ratio to human growth hormone is usually in the range of 1:0.007 to 2.3, preferably 1:QO7-08, and when it is solid or semi-solid, it is usually 1:0.007 to 2.3. :0007-150, preferably 1:007-50 is used.

(for production) In the human growth hormone nasal preparation of the present invention.

As shown in the experimental examples below, by using O-acylcarnitine as an absorption enhancer, the efficiency of absorption from the nasal mucosa can be significantly increased, and this can be said to be an excellent method for administering human growth hormone.

(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.

Example 1 NNa citrate 1001TI, glycine 102 mg,
Benzalkonium chloride 0.41T1g, sodium bicarbonate 128mg.

EDTA2Na4IT1g, mannitol 102.4
mg, was dissolved in 3 ml of distilled water. To the resulting solution were added 1500 IU (500,111 g) of human growth hormone and octanoylcarnitine (N-chloride form) in an amount equivalent to 048 weight ratio to the crude drug, and the solution was made into 4 ml and dissolved.

Example 2-5 In Example 1, each absorption enhancer was used in place of octanoylcarnitine (N-chloride) in the following proportions,
A solution composition was obtained.

Table 1 Example 6 Mannitol 100mg, Carbopol 934500m
g.

3Qmg of sodium hydrogen carbonate was dissolved in 200ml of distilled water with stirring. Add human growth hormone 300I to the resulting solution.
U (100 Ing) and valmitoylcarnitine (N-chloride form) in an amount equivalent to 02 weight ratio to the main drug were added and dissolved. After freeze-drying, the obtained solid was crushed and passed through a sieve (3
2Mesh-42Mesh) to obtain a composition.

Example 7 Mannitol 80mg, Carboball 941.350■
.

The solid obtained by mixing 1.001 TIg of human growth hormone and lauroylcarnitine (N-chloride) at a weight ratio of 2 to the main drug was ground. j passed (
32Mesh-42Mesh) to obtain a composition.

Example 8 Weight ratio of human growth hormone 21.0■ to main drug 02
A considerable amount of octanoylcarnitine (N-chloride form) was dissolved in 5 g of glopylene glycol, and added to 5 m7 of a mixture of 7 g of white petrolatum and 1 g of stearyl alcohol, which had been dissolved in advance, and stirred. A hydrophilic ointment was obtained.

Experimental Example 1 (In vivo rat nasal absorption experiment method) Wis-ta was left in agony for 20 hours (water provided ad libitum) before use.
An R-strain male rat (9 weeks old, 260-290 g, Animal Breeding Research Institute, +1-3-4) was administered intraperitoneal anesthesia with pendoparvicunalium (50 mg/kg).
g, 64.8111 g/ml.

0.1 ml/130 g rat, Somnop
Entyl, PITMAN-MOORE). Fix the rat on a dissection plate and insert the nasal operculum into a bamboo tube.
opalatine) to synthetic adhesive (A,] one
Closed with Alpha A, Toa Chemical Industry). After anesthesia 1
．． enopendorf pipeno after C1) (200/411
) by test liquid (2.5mg/kg 6.25mg/m
t.

4, 0 / iL / 1. OOgrat) was injected.

After a certain period of time (0,0,25°0.5.0.75, 1.
2.3.4. , 6 hours), blood was collected (approximately 0.1.3 ml)
L.

0.1 ml of that and 0.1 ml of water. ml was combined to obtain whole blood. Intraperitoneal anesthesia (25mg/k,
g) was performed.

In addition, an intravenous injection was given to recite the Bio-Abe.

The growth hormone concentration at each blood sampling time is shown in Figure 1.

The test solutions used in the above nasal absorption experiment were the control, reference, and Example 3 shown in Table 2. Here, taurocholic acid was used as a control at a temperature of 0.degree. C., and the amount used was 0.08, which is the limit weight ratio for practical use, taking two local irritations into consideration.

As a result, the bioavailability of the control containing no absorption enhancer was 0.5%, meaning that it was hardly absorbed, and Na taurocholate, a known absorption enhancer, is concerned about local irritation (J. Harm, Sci. ,.

-]1- had a pieo-availability of 1''3%, whereas the composition of the present invention (Example 3) showed a high pieo-availability of 192%.

[Brief explanation of the drawing]

FIG. 1 is a diagram that does not show the time change of human growth hormone concentration in rat plasma.

Claims (1)

[Scope of Claims] (1) A pharmaceutical composition for intranasal administration of human growth hormone, comprising human growth hormone and o-acylcarnitine or its salt in a liquid diluent or carrier suitable for application to the nasal mucosa. thing. (2) The pharmaceutical composition for intranasal administration of human growth hormone 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. thing. (3) The pharmaceutical composition for intranasal administration of human growth hormone according to claim (1), wherein the o-acylcarnitine is o-octanoylcarnitine, o-lauroylcarnitine, o-palmitoylcarnitine, or a salt thereof. thing.