JP3047948B2 - Composition for nasal administration of peptides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for nasal administration of a peptide having a medically effective effect by absorbing the peptide from the nasal mucosa.

[0002]

2. Description of the Related Art Conventionally, most pharmaceuticals containing a peptide as an active ingredient have been administered in the form of injection preparations and oral administration. However, administration by injectable formulation requires a visit to the patient, is painful and is not an easily implemented form. Oral administration has a low absorption rate from the gastrointestinal tract, and is subject to degradation by proteolytic enzymes, first-pass effects, etc., so that an extremely large amount of peptide must be administered to absorb an effective amount from the gastrointestinal tract. No.

[0003] In order to solve these problems, a method by nasal administration has been studied. However, the nasal absorption of peptides is not sufficient, and they are also degraded by proteolytic enzymes present in mucous membranes. You.

[0004] In order to enhance the absorption in the nasal mucosa, a method of adding a bile salt or a synthetic surfactant to enhance the absorption is known, but continuous use causes mucosal irritation, mucosal damage and other side effects. It is impossible to actually use it.

[0005] On the other hand, a method of promoting absorption by adding proteolytic enzyme inhibitors such as aprotinin and camostat mesylate (described in the program of the 111th Annual Meeting of the Pharmaceutical Society of Japan) is known. Sometimes there is a problem in terms of safety, and it has not been put to practical use. Therefore, development of a more effective formulation has been desired.

[0006]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies to develop a composition for nasal administration of peptides having excellent absorbability and safety, and having few side effects. A composition for nasal administration of peptides containing epsilon aminocaproic acid or tranexamic acid and a composition for nasal administration of peptides obtained by dissolving epsilon aminocaproic acid or tranexamic acid in an acidic citrate buffer; It has been found that the absorbency is significantly improved, and the present invention has been completed.

That is, the present invention provides (1) a composition for nasal administration containing a peptide and epsilon aminocaproic acid or tranexamic acid, and (2) a solution of the peptide and epsilon aminocaproic acid or tranexamic acid in an acidic aqueous solution or an acidic buffer. A composition for nasal administration comprising
(3) The acidic buffer is an acidic citrate buffer (2)
2. A composition for nasal administration according to item 1.

Hereinafter, the compositions for nasal administration of (1), (2) and (3) are referred to as the composition for nasal administration of the present invention.

Specific examples of the peptides used in the present invention include the following, but the present invention is not limited thereto.

[0010] Calcitonin, insulin, proinsulin, epidermal growth factor, growth hormone, somatomedin C, somatostatin, granulocyte / macrophage colony stimulating factor, colony stimulating factor, erythropoietin, interferon, interleukin, atrial natriuretic peptide, parasite Lloyd hormone, superoxide dismutase, tissue plasminogen activator, antithrombin, blood coagulation factor 、, blood coagulation factor 、, protein C, hirudin, hepatitis vaccine, endorphin, ACTH releasing hormone, neurotensin, angiotensin, transferrin, Endothelin, vasopressin, desmopressin, luteinizing hormone, luteinizing hormone-releasing hormone, prolactin, glucagon, gas Phosphorus, secretin, urokinase, Batho Aku Dave Intel Constitution null polypeptide, hepatitis vaccine, influenza vaccine, pertussis vaccine, diphtheria vaccine, tetanus vaccine.

[0011] Of the above peptides, particularly calcitonin is the most preferred peptide used in the present invention. Furthermore, any peptide other than the above and having a serum calcium lowering effect can be used in the present invention.

If the content of epsilon aminocaproic acid and tranexamic acid in the present invention is more than 50% by weight, the osmotic pressure is increased and the mucous membrane is dried.
It is preferably from 1 to 50% by weight, more preferably from 0.1 to 20% by weight.

Further, the composition for nasal administration of the present invention has a pH of 2.
It is preferable that the pH is in the range of pH 2 to 7, since the following acidic or alkaline having a pH of 7 or more increases irritation to the mucous membrane.

Next, the formulation of the composition for nasal administration of the peptide of the present invention will be described.

The composition for nasal administration of the present invention can be used as sprays, nasal drops and aerosols, which are dissolved in an acidic aqueous solution or acidic buffer, and which can be used for polymer compounds such as natural polysaccharides. Can be prepared using a water-soluble gel base of It can also be used in the form of a so-called lipo preparation such as an oil-in-water emulsion, a water-in-oil emulsion, and a liposome. Preservatives, antioxidants, thickeners, tonicity agents and fragrances can be added as additives. Specific examples of the base and the additive are shown below, but the invention is not limited thereto.

(Base) Dilute hydrochloric acid, maleic acid, fumaric acid,
Acetic acid, citric acid, malic acid, phosphate buffer, citrate buffer, acetate buffer, tartrate buffer, natural rubber, methylcellulose, acrylic acid polymer, vinyl polymer, hyaluronic acid and the like.

(Preservatives) Benzalkonium chloride, benzethonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben and the like.

(Antioxidants) Vitamin E, butylhydroxytoluene, butylhydroxyanisole, edetates and the like.

(Thickener) Polysaccharides, gelatin, hydroxypropylcellulose, polyacrylic acids, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyethylene glycol, poloxamer, polyvinylpyrrolidone and the like.

(Isotonicity agents) Sugars such as mannitol, glycerin, sodium chloride and the like.

(Fragrance) Mentha oil, orange oil, lemon oil, menthol, limonene, vanillin and the like.

Among the above-mentioned bases, citrate buffer, in particular, has the effect of expanding the gap by the chelating effect of metal ions in the intercellular space. Therefore, when used in combination with epsilon aminocaproic acid, further absorption is promoted. Immediately lowers blood calcium levels.

Next, examples of formulation will be described in more detail, but these examples are merely for explanation, and the present invention is not limited to these examples.

The compositions for nasal administration of the present invention described in the following Examples 1 to 12 are produced by dissolving or dispersing peptides and additional additives in water.

Example 1 Salmon Calcitonin 0.026% w / v Epsilon aminocaproic acid 2.000% w / v (hereinafter referred to as EACA) Mannit 5.000% w / v Gelatin 1.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100ml

Example 2 Salmon calcitonin 0.026% w / v EACA 3.000% w / v Gelatin 1.000% w / v Methyl paraben 0.020% w / v Purified water qs 100ml

Example 3 Peptide-25 0.026% w / v (Peptide obtained in Example 25 of WO 90/12809; hereinafter referred to as Peptide-25) EACA 2.000% w / v Benza chloride Ruconium 0.010% w / v purified water qs 100ml

Example 4 Peptide-25 0.026% w / v EACA 5.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

Example 5 Peptide-25 0.026% w / v EACA 10.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

Example 6 Peptide-25 0.026% w / v EACA 20.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

Example 7 Peptide-25 0.026% w / v citric acid monohydrate 1.237% w / v sodium citrate dihydrate 1.219% w / v EACA 000% w / v benzalkonium chloride 0.010% w / v purified water qs 100ml

Example 8 Peptide-25 0.026% w / v citric acid monohydrate 1.237% w / v sodium citrate dihydrate 1.219% w / v tranexamic acid 5 0.000% w / v benzalkonium chloride 0.010% w / v purified water qs 100ml

Example 9 Peptide-25 0.026% w / v EACA 10.000% w / v Poloxamer 188 1.000% w / v Benzalkonium chloride 0.020% w / v Mineral oil suitable amount purification 100 ml of water

Example 10 Peptide-25 0.026% w / v Tranexamic acid 1.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

Example 11 Peptide-25 0.026% w / v Tranexamic acid 5.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

Example 12 Peptide-25 0.026% w / v Tranexamic acid 10.000% w / v Benzalkonium chloride 0.010% w / v Purified water qs 100 ml

[Example 13] EACA 1.000% w / v soybean oil 10.000% w / v purified egg yolk lecithin 1.200% w / v glycerin 2.500% w / v purified water qs 100ml The emulsion is emulsified in accordance with a usual method for producing a fat emulsion for intravenous injection to obtain an emulsion having an average particle size of 100 nm to 3000 nm. To this peptide 0.025% w / v was added.
In addition, it was dissolved to give a composition for nasal administration.

Next, the effects of the composition for nasal administration of the present invention will be described with reference to experimental examples.

Experimental Example 1 In this experiment, the concentration of epsilon aminocaproic acid was 2, 5,
Nasal administration of 3.0 μg / kg of the composition for nasal administration of the present invention obtained in Examples 3, 4 and 6 prepared to 20% to 5 rabbits [white male rabbits (New Zealand)] I went.

The following experiment was performed as a control experiment of this experiment.

In Control Experiment 1, the composition of Example 3 except for the peptide was administered nasally.

In Control Experiment 2, 3.0 μg / kg of the composition of Example 3 except for EACA was intranasally administered.

In control experiment 3, a composition obtained by diluting the composition obtained in Example 3 except for the EACA was 80 ng / kg (400 μm).
l) was injected intramuscularly.

Since peptide-25 in the above experiment has calcitonin activity, the absorption rate can be evaluated using the rate of decrease in calcium concentration as an index.

Immediately before administration and 0.5, 1, 2, 3 and 5 hours after administration, 500 to 1000 μl of blood was collected, and the collected blood was left at room temperature for 1 hour or more after blood collection. Thereafter, the blood was centrifuged at 3000 rpm for 20 minutes, and the calcium concentration in the supernatant obtained was measured using an atomic absorption spectrophotometer, and the decrease rate was evaluated based on the calcium concentration immediately before administration. FIG. 1 shows this calcium concentration reduction rate.

When the concentration of epsilon aminocaproic acid is 2,
Area (AUC) of the area surrounded by the serum calcium reduction rate curve of each drug administration group at 5 and 20% and the serum calcium reduction rate curve up to 5 hours before administration of the placebo administration group
And bioavailability was determined relative to that of the intramuscular injection. This is shown in Table 1. (Indicated by the average value of n = 5.)

FIG. 1

Bioavailability up to 5 hours after administration (%) = AUC (nasal) / AUC (im) × Dose (im) /
Dose (nasal) x 100 Table 1 Bioavailability (%)

Experimental Example 2 The test was carried out in the same manner as in Experimental Example 1 except that the test drug was changed to the compositions of Examples 11 and 12. FIG. 2 and FIG.
It is shown in the table.

FIG. 2

Table 2 Bioavailability (%)

EXPERIMENTAL EXAMPLE 3 The test was conducted in the same manner as in Experimental Example 1 except that the test drug was changed to the composition of Example 7. The results are shown in FIG. 3 and Table 3.

FIG. 3

Table 3 Bioavailability (%)

From the above experimental results, it can be seen that the composition for nasal administration of a peptide of the present invention significantly improves the absorption of a peptide having low mucosal absorption.

Continuation of the front page (56) References WO 92/14479 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 38/00 A61K 47/16 CA (STN) MEDLINE (STN )

Claims (3)

(57) [Claims] (1) a bioactive peptide , water and an additive;
0.01-50% by weight of epsilon aminocaproic acid
Or 0.01 to 50% by weight of tranexamic acid ,
A composition for nasal administration having a pH of 2 to 7 . 2. Dissolving in an acidic aqueous solution or acidic buffer.
2. The composition for nasal administration according to claim 1. 3. The composition for nasal administration according to claim 2, wherein the acidic buffer is an acidic citrate buffer.