JPS63303931A - Drug preparation for transnasal administration having growth hormone releasing activity - Google Patents

Abstract

PURPOSE:To obtain the titled drug preparation having remarkably improved absorptivity of an active substance through nasal mucosa into blood, exhibiting low local toxicity and stimulation and resistant to decomposition of the active component, by suppressing the osmotic pressure ratio of the aqueous solution of the active substance below a specific level. CONSTITUTION:The titled drug preparation having improved absorptivity of an active substance through the nasal mucosa into blood, exhibiting effective activity to release growth hormone at a low rate of administration without accompanying harmful reaction and able to be easily administered can be produced by suppressing the osmotic pressure ratio of an aqueous solution of the active substance to <=1 (preferably 0.3-0.1). The osmotic pressure ratio is a relative ratio to physiological osmotic pressure and the content of the active substance in the drug preparation is preferably 0.01-10W/V% in aqueous solution. The above drug preparation can be prepared by mixing and dissolving necessary components in distilled water and adjusting to a prescribed osmotic pressure ratio. It can be converted to a powdery preparation to be dissolved before using e.g. by freeze-drying.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field] The present invention relates to a formulation for nasal administration containing a growth hormone-releasing active substance.

[Conventional technology and its problems]

G RF (Growth Hormone Rele)
Growth hormone-releasing active substances, typified by growth factor (G H:
rowth IIor+5one) release activity, and temporary or long-term administration has been attempted for diagnostic or therapeutic purposes in clinical medicine (human medicine, veterinary medicine, and animal husbandry).

GRF has been shown to have activity with several types of peptides each consisting of 44, 40, 37, or 29 amino acids.

Growth hormone-releasing active substances such as GRF, like general physiologically active peptides, cannot be administered orally because they are degraded and inactivated by enzymes in the gastrointestinal tract, and their absorption is also low, so conventionally they have been mainly administered as injections. It is being said. However, since administration by injection is painful and inconvenient, there is a desire to develop a simpler administration method.

Recently, it has been discovered that GRF is absorbed by nasal administration, and various studies are being conducted.

However, in the case of nasal administration, the absorption rate is not high, so there is a problem that an increase in blood GH cannot be achieved unless a large amount of GRF is used, and it has not been put into practical use. On the other hand, poorly absorbed drugs such as peptides are used as absorption enhancers.
For example, it is common practice to include a surfactant. However, these absorption enhancers have considerable local toxicity and irritation effects on biological membranes. Therefore, for example, when using GRF to treat patients with dwarfism, it is necessary to repeat administration over a long period of time, and there are concerns about adverse reactions due to these effects.
The reality is that it is considered difficult to put it into practical use as is.

[Means for solving problems]

From this point of view, the present inventors have conducted extensive research into practical nasal preparations that can promote the absorption of GRF, etc. and allow for safe and frequent administration, and have discovered something completely different. It has been found that when a growth hormone-releasing active substance is nasally administered in the form of a solution with an osmotic pressure ratio of 1 or less, the growth hormone-releasing active substance is quickly and efficiently absorbed into the bloodstream through the nasal mucosa. This phenomenon was confirmed by the fact that the concentration of plasma growth hormone increased significantly immediately after intranasal administration of GRF.

By the way, regarding nasal administration of secretin, which is a vepquid with 27 amino acids, it has been shown that absorption is high when the osmotic pressure ratio of the administered aqueous solution is between 1 and 5 (Japanese Patent Application Laid-open No. 6O-123426). It is completely unexpected that GRF, etc., which have a similar number of amino acids, can be absorbed quickly and efficiently through the nose in a solution state with an osmotic pressure ratio of 1 or less.

The present invention has been completed based on the above-mentioned new findings, and relates to a growth hormone-releasing active substance preparation for nasal administration, which is characterized in that the osmotic pressure ratio is 1 or less when it is made into an aqueous solution.

In the present invention, the growth hormone-releasing active substance is not particularly limited as long as it is a peptide that exhibits GH-releasing activity, and examples thereof include GRF and its derivatives. GRF may be of natural origin or synthetic origin, specifically a peptide consisting of 44 amino acids (GRFI-44), a peptide consisting of 40 amino acids (GRFI-40),
A peptide consisting of 37 amino acids (GRF l-3,
7), a peptide consisting of 29 amino acids (GRFI-
29) is exemplified. GRF derivatives include those in which some of the amino acids constituting the natural or synthetic GRF are replaced with other amino acids, those in which some of the amino acids constituting GRF are deleted, and those in which GRF is modified with other amino acids or peptides, etc. means.

Nasal administration is a form of administration in which the drug is absorbed through the nasal mucosa, and specifically, it is mainly carried out by spraying or dropping an aqueous solution onto the nasal mucosa. Therefore, it is convenient for the formulation of the present invention to be in the form of a liquid so that it can be sprayed or dropped into the nasal cavity, but from the viewpoint of storage stability of the growth hormone-releasing active substance, it is preferable to form it into a lyophilized powder and dissolve it in a liquid before use. Any preparation may be selected as long as it can be used as a preparation dissolved in a water solution, that is, it can be used as an aqueous solution upon final administration, and is not limited to the above examples.

The solvent used in the formulation of the final dosage form of the invention is an aqueous solvent, such as distilled water (especially distilled water for injection),
Examples include buffers (phosphate buffer, glycine buffer, acetic acid-sodium acetate buffer, citric acid-phosphate buffer, etc.).

It is an essential condition that the osmotic pressure ratio of the formulation of the present invention is 1 or less, more preferably 0.5 or less, and even more preferably 0.3 to 0.1. As shown in the experimental examples below, by setting the osmotic pressure ratio to 1 or less, GRF
Nasal absorption of growth hormone-releasing active substances, typified by , is promoted and the amount of OH released increases.

The osmotic pressure ratio in the present invention is expressed as a relative ratio to physiological osmotic pressure. That is, it means the osmotic pressure ratio determined by converting the concentration of sodium chloride, assuming that the osmotic pressure ratio of an aqueous solution of 0.9% sodium chloride is 1. for example,
The osmolality ratio of the solution corresponding to an aqueous solution of 0.45% sodium chloride is 0.5.

The content of the growth hormone-releasing active substance in the preparation is usually 0.001 to LOW/V%, particularly 0.01 to I
Although the OW/V% is preferred, the present invention is not particularly limited by the content of the growth hormone-releasing active substance.

The pH of the formulation of the present invention is usually 2.
As above, from the viewpoint of stability, 2 to 7 are preferable.

Pharmaceutically acceptable buffers, stabilizers, preservatives, solubilizing agents, pH adjusters, osmotic pressure adjusters, and the like can be added to the preparations of the present invention, if necessary.

The formulation of the present invention is manufactured by known means or similar means. For example, it is manufactured by mixing and dissolving the required components in any order to achieve a predetermined osmotic pressure ratio. It is most simply produced by dissolving the growth hormone releasing active substance in distilled water.

Furthermore, it is also possible to prepare a powder preparation that can be dissolved at the time of use by freeze-drying the aqueous solution obtained above.

The dosage of the preparation of the present invention may be appropriately selected depending on symptoms, body weight, age, etc. For example, for the treatment of dwarfism,
GRF may be administered nasally at a dose of 100/1) to 50 ml, usually 1 to 6 times a day.

[Action/Effect]

In the formulation of the present invention, by setting the osmotic pressure ratio to 1 or less, the absorption of the growth hormone-releasing active substance into the blood through the nasal mucosa is significantly improved. Moreover, this preparation has low local toxicity and irritation, and because it is administered nasally, the active ingredient is not degraded by enzymes in the gastrointestinal tract.

Therefore, the preparation of the present invention has the effect of effectively exhibiting growth hormone-releasing activity with substantially no adverse reactions at a small dose, and also has the effect of being easy to administer.

[Example/Experiment example]

Examples and experimental examples are shown below, but the present invention is not limited thereto.

Example 1 30 μg of GRF (1-44) was added to glycine buffer (pH 3
) to obtain a GRF preparation for nasal administration with an osmotic pressure ratio of 0.1.

Example 2 GRF in acetic acid-sodium acetate buffer 10-pH 4
(1-44) 5■ was dissolved to obtain an aqueous solution with an osmotic pressure ratio of 0.4. This lxnl was dispensed into 2TIIl vials and lyophilized, and an ampoule filled with 1IR1 of distilled water for injection was attached to obtain a GRF formulation for nasal administration that dissolves at the time of use.

Example 3 10 μg of GRF (1-29) was dissolved in a physiological isotonic solution of citric acid-phosphate buffer (pl+3.5) 100 to prepare an aqueous solution for nasal administration. This is a formulation with an osmotic pressure ratio of 1.

Example 4 20 μ of GRF (1-29) was dissolved in 10 wJ of a 0.27% aqueous sodium chloride solution to obtain a GRF preparation for nasal administration with an osmotic pressure ratio of 0.3.

Experimental Example I By dissolving GRF (1-29) in PUS phosphate buffer and further dissolving an appropriate amount of sodium chloride, GRF preparations for nasal administration A, B, C, D, and E with different osmotic pressure ratios were prepared.
was prepared. In both cases, the concentration of GRFCl-29> is 1/-, Wistar male rats (body weight 20
(0-240 g) were anesthetized by intraperitoneal injection of pendoparbital. Formulation ANE was administered intranasally with a micropipette at a volume of 0.1 m/kg. Thereafter, blood was collected over time from a cannula previously inserted into the jugular vein, and the concentration of rat growth hormone (rGH) in the plasma was determined by the RIA method.

The results are shown in Table 1. In addition, each value was shown as the average value of 4-5 rats.

(Margin below)

Claims (3)

[Claims] (1) A growth hormone-releasing active substance preparation for nasal administration, which has an osmotic pressure ratio of 1 or less when made into an aqueous solution. (2) The growth hormone-releasing active substance preparation for nasal administration according to claim (1), which is an aqueous solution preparation. (3) The growth hormone-releasing active substance preparation for nasal administration according to claim (1), which is a powder preparation and is used after being dissolved in a solution before use.