JPH05148154A - Pharmaceutical containing physiologically active polypeptide - Google Patents

Abstract

PURPOSE:To obtain a pharmaceutical containing a physiologically active polypeptide for oral administration or administration into the oral cavity by blending a polypeptide with an absorbefacient composed of a combination of an organic acid with a sucrose ester of a fatty acid. CONSTITUTION:A pharmaceutical is obtained by blending a physiologically active polypeptide (e.g. calcitonin) with an organic acid (e.g. malic acid or succinic acid) and a sucrose ester of a fatty acid (e.g. sucrose stearate) in combination as an absorbefacient. In a pharmaceutical for oral administration, 0.1-70wt.% organic acid and 0.1-50wt.% sucrose ester of the fatty acid are blended. In a pharmaceutical for administration into the oral cavity (a sublingual tablet), 0.1-30wt.% organic acid and 0.1-20wt.% sucrose ester of the fatty acid are blended. Since polypeptide hormones undergo hydrolysis by a proteolytic enzyme and not sufficiently absorbed and desired pharmacological action is not exhibited, high absorption of the hardly absorbable polypeptide hormones from intestinal tracts or mucous membranes in the oral cavity is obtained by blending the absorbefacient.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a physiologically active polypeptide-containing preparation containing an absorption enhancer comprising a combination of an organic acid and sucrose fatty acid ester. The present invention relates to a preparation for oral administration or buccal administration containing a physiologically active polypeptide that promotes absorption from the intestinal tract.

[0002]

2. Description of the Related Art Polypeptide hormones such as insulin and calcitonin are
It is a water-soluble polymer compound that is easily decomposed by gastric juice and intestinal proteases such as pepsin and trypsin.
Therefore, when these polypeptides are orally administered, they are hardly absorbed and cannot exhibit an effective pharmacological action.
In order to obtain the desired physiological activity, these polypeptides are currently usually formulated in injectable dosage forms. However, such routes of administration are inconvenient and painful to the patient, especially when these polypeptides must be administered regularly and frequently.

Therefore, various methods for effectively administering such a polypeptide by methods other than injection have been studied, and the applicants have already proposed a vaginal preparation.
(JP-A-1-294632). Oral administration has also been studied, and an orally administered preparation containing sucrose fatty acid ester and the like has been proposed (JP-A-62-1002).
No. 0 and JP-A-62-33128) are still not sufficient in terms of absorbability.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that by using a combination of an organic acid and a sucrose fatty acid ester as an absorption enhancer, a physiologically active substance can be obtained. It was found that the above-mentioned polypeptide is efficiently absorbed from the intestinal tract or the oral mucosa, and thus can be orally or bucally administered, and the present invention has been completed. That is, the present invention provides a physiologically active polypeptide-containing preparation for oral administration or buccal administration, in which a physiologically active polypeptide is mixed with an absorption enhancer comprising a combination of an organic acid and a sucrose fatty acid ester. ..

Organic acids used as the absorption enhancer of the present invention include acetic acid, butyric acid, fumaric acid, malonic acid, phthalic acid, propionic acid, glutaric acid, adipic acid, valeric acid,
Selected from the group consisting of caproic acid, maleic acid, ascorbic acid, isoascorbic acid, malic acid, succinic acid, lactic acid, tartaric acid, citric acid, and benzoic acid, especially tartaric acid, citric acid, malic acid, lactic acid, benzoic acid and Succinic acid is preferred. These are used alone or in combination of two or more. Although the blending amount varies slightly depending on the type of preparation, in the preparation for oral administration, it is 0.1 to 70% by weight, preferably 1 to 50% by weight, based on the total weight of the preparation. Sublingual tablet) is 0.1 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the preparation. In the preparation for oral administration, in the case of the fast-dissolving preparation, it is 30 to 90% by weight, preferably 50 to 80% by weight, based on the total weight of the preparation (weight after lyophilization).

Examples of the sucrose fatty acid ester include sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate,
It is selected from the group consisting of sucrose behenate and sucrose erucate, with sucrose stearate, sucrose palmitate, sucrose oleate and sucrose laurate being particularly preferred. These are used alone or in combination of two or more. The blending amount varies slightly depending on the type of formulation, but in the formulation for oral administration,
0.1 to 50% by weight, preferably 0.5 to 30% by weight, based on the total weight of the preparation, and 0.1 to 20% by weight based on the total weight of the preparation in the preparation for buccal administration (sublingual tablet). weight%,
It is preferably 1 to 10% by weight. Further, among the preparations for oral administration, in the case of the fast-dissolving preparation, it is 5 to 50% by weight, preferably 15 to 3% with respect to the total weight of the preparation (weight after lyophilization).
It is 5% by weight.

The physiologically active polypeptide used in the present invention refers to a polypeptide having a relatively low molecular weight. Preferred examples of biologically active polypeptides that can be used in the present invention include insulin, angiotensin, vasopressin, desmopressin, LH-RH (luteinizing hormone releasing hormone), somatostatin, calcitonin,
Glucagon, oxytocin, gastrin, somatomedin, secretin, h-ANP (human natriuretic polypeptide), ACTH (adrenocorticotropic hormone), MSH
(Melanophore-stimulating hormone), β-endorphin, muramyl dipeptide, enkephalin, neurotensin (neu
rotensin), bombesin, VIP (vasoactive intestinal peptide), CCK-8 (cholecystokin-8), PT
H (parathyroid hormone), CGRP (calcitonin inheritance related peptide), TRH (thyrothrombin releasing hormone),
Endothelin, TSH (thyroid stimulating hormone) and their derivatives are mentioned.

The various polypeptides used in the present invention include not only the naturally occurring polypeptides themselves, but also pharmacologically active derivatives and analogs thereof. For example, calcitonin to be used in the present invention includes salmon calcitonin, human calcitonin, porcine calcitonin,
Not only natural products such as eel calcitonin, chicken calcitonin, rat calcitonin, bovine calcitonin and sheep calcitonin but also analogs such as [ASU1,7] -eel calcitonin or elcatonin are included.

The content of the physiologically active peptide in the preparation of the present invention depends on the type of polypeptide used, but it is an amount sufficient to exhibit the desired pharmacological action. For example, when calcitonin is selected, it is in an amount sufficient to treat a pathological condition such as Behcet's disease, hypercalcemia or osteoporosis.

Among the preparations of the present invention, the preparations for oral administration include
Animal proteins and / or vegetable proteins can be optionally incorporated in order to avoid enzymatic degradation of the polypeptide that occurs during the process of oral administration of the polypeptide. Such animal protein and vegetable protein are preferably those used for food or medicine.

Preferred examples of animal protein include:
Examples thereof include albumin (eg, bovine serum albumin, human serum albumin, etc.), casein, gelatin and the like. Examples of vegetable proteins include gluten, zein, soybean protein and the like. These animal proteins or plant proteins may be used alone, or the animal protein and the plant protein may be used in combination at an appropriate ratio. The amount of animal and / or vegetable protein used in the oral preparation of the present invention depends on the polypeptide to be stabilized, but generally 0.001 to 25% by weight based on the total weight of the preparation.
The range is.

The dosage form of the preparation of the present invention includes preparations for oral administration such as tablets, capsules and granules, and preparations for oral administration such as sublingual tablets. These formulations consist of conventional excipients,
It is prepared by a conventional method using a binder, a lubricant and the like. Excipients used for tablets include lactose, sucrose, glucose, starch, crystalline cellulose and the like, and the compounding amount thereof is in the range of 50 to 90% by weight based on the total weight of the preparation. As the binder, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, gum arabic, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, tragacanth,
Examples include sodium alginate and the like, and the amount thereof is 1 to 25% by weight based on the total weight of the preparation. Examples of the lubricant include magnesium stearate, calcium stearate, talc and the like, and the compounding amount thereof is 0.5 to 3% by weight based on the total weight of the preparation. Examples of enteric coating agents include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylic acid copolymer. Excipients used for sublingual tablets include lactose, sucrose, mannitol, sorbit, starch and the like, and their compounding amount is in the range of 50 to 90% by weight relative to the total amount of the preparation. Examples of the binder include crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose Na, hydroxypropyl methyl cellulose, methyl cellulose, dextrin and the like, and the compounding amount thereof is in the range of 1 to 25% by weight based on the total weight of the preparation. Examples of the disintegrating agent include carboxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose, starch and the like, and the compounding amount thereof is in the range of 1 to 15% by weight based on the total weight of the preparation. Examples of the lubricant include talc and magnesium stearate, and the compounding amount thereof is in the range of 0.5 to 3% by weight based on the total weight of the preparation. Further, in the preparation for oral administration of the present invention, particularly the sublingual tablet, a fast-dissolving preparation is also included for the purpose of rapid dissolution in the oral cavity. Such a fast-dissolving preparation contains one or more kinds of natural gums such as gelatin, agar, polyvinylpyrrolidone or guar gum, and locust bean gum in place of the above-mentioned excipients, binders, disintegrants and lubricants. Used as a base component, add active ingredient and absorption promoter to these base components, and after homogeneous mixing,
It is prepared by freeze-drying by a conventional method.

[0013]

EXAMPLES The present invention will be described in more detail below with reference to experimental examples and examples, but the present invention is not limited thereto. As the sucrose fatty acid ester, ryote sugar ester manufactured by Mitsubishi Kasei Foods was used.

Experimental Example 1 (Calcitonin absorption promoting effect by combination of various organic acids and sucrose fatty acid ester) Bovine serum albumin (BSA) 0.3 w / v%, absorption promoter
(0.5 and 1.0 w / v% of each organic acid and 0.5 w / v%
Sucrose lauric acid ester combination) and human calcitonin (h-CT) 5 μg / ml were prepared. A Wistar male rat weighing about 250 g was anesthetized with Nembutal, and a required amount of blood was collected from the right external jugular vein before administration. The rat was laparotomized, and 0.1 ml of each calcitonin solution was administered to the lower small intestine by the closed loop method per 100 g of body weight. Blood was collected over time (5, 15, 30, and 60 minutes after administration). After separation of the serum, the serum calcium concentration was measured using a calcium C kit "registered trademark" (Wako Pure Chemical Industries, Ltd.). (n = 3) The results are shown in Table 1.

[0015]

[Table 1] Table 1 Reduction rate of serum Ca value (%) Time after administration of organic acid concentration (min) (%) 5 15 30 60 Malic acid 0.5 1.5 1.5 5.0 8.8 4.8 Amber Acid 0.5 2.6 4.7 3.9 -2.5 Lactic acid 0.5 1.9 7.6 9.0 9.0 4.4 Tartaric acid 0.5 3.9 5.3 5.3 5.2 -2.8 Tartaric acid 1.0 0.4 8.2 9.9 10.1 Citric acid 1.0 0.1 4.1 4.1 6.1 -2.8 Benzoic acid 1.0 2.9 10.8 10.1 8.1 . Three

As shown in Table 1, a decrease in serum calcium level was observed in each test solution.

Experimental Example 2 (Absorption promoting effect of sucrose fatty acid esters having different HLB values) BSA 0.3 w / v%, absorption promoter (1.0 w / v% tartaric acid and 0.5 w / v% of the following sucrose) A solution containing a fatty acid ester combination) and h-CT 10 μg / ml was prepared. Sucrose fatty acid ester HLB value 1. Sucrose stearate (S-270) 2 2. 〃 (S-970) 9 3. 〃 (S-1670) 16 4. Sucrose lauric acid ester (L-1695) 16

As a control, BSA 0.3 w / v%, 1.0 w
0.1M containing / v% tartaric acid, h-CT 10 μg / ml
Acetate buffer was used. Administration in the same manner as in Experimental Example 1,
Blood was collected over time (after 5, 15, 30 and 60 minutes). After separating the serum, the h-CT concentration in blood was measured by the RIA method. The results are shown in Figure 1. The graph shows the difference value from the initial value. As shown in FIG. 1, the blood h-CT concentration reached the maximum value 5 minutes after the administration, and the blood h-CT concentration was higher than that of the control (tartrate alone).

Experimental Example 3 (Absorption promoting effect of sucrose fatty acid ester having different bound fatty acids) BSA 0.3 w / v% absorption promoting agent (tartaric acid 1.0 w /
v% and the following sucrose fatty acid ester 0.5 w / v% combination), and a solution containing 5 μg / ml of h-CT was prepared. Sucrose fatty acid ester- bonded fatty acid 1. S-1670 Sucrose stearate stearic acid 2. P-1670 Sucrose palmitate palmitate 3. L-1695 Sucrose lauric acid ester Lauric acid

Each solution was administered to rats in the same manner as in Experimental Example 1, blood was collected over time, and the serum calcium concentration was measured. The results are shown in Figure 2. As shown in FIG. 2, a decrease in serum calcium concentration was observed regardless of the difference in bound fatty acids.

Experimental Example 4 (Comparison of absorption promoting effect between tartaric acid and sucrose fatty acid ester alone and in combination) BSA 0.3 w / v% absorption promoting agent (tartaric acid 1.0 w / v% and sucrose lauric acid ester 0.5 w / V% combination)
And hSA containing 5 μg / ml and BSA
A solution containing 5 μg / ml of h-CT containing 0.3 w / v% and tartaric acid or sucrose laurate alone as an absorption promoter was prepared.

It was administered to rats in the same manner as in Experimental Example 1, blood was sampled over time, and after serum separation, calcium concentration and h-CT concentration in serum were measured. The results are shown in FIGS. 3 and 4. As shown in FIG. 3 and FIG. 4, the decrease in serum calcium level and the change in blood h-CT level were observed. As compared with the use of tartaric acid or sucrose laurate alone as an absorption enhancer, both were combined. It is recognized that the h-CT excels in the absorption promoting effect.

Experimental Example 5 (Thyroid stimulating hormone (TSH)
Absorption-promoting effect) BSA 0.3 w / v%, absorption promoter (tartaric acid 1.0 w / v%
And sucrose stearate (S-1670) 0.5w
/ V% combination) and TSH 500 μg / ml. As a control, a solution containing 0.3 w / v% of BSA and 500 μg / ml of TSH was used. By the same procedure as in Experimental Example 1, TSH 100 μg per rat
Was administered. Blood is collected over time, serum is separated, and T
The SH concentration was measured by the RIA method. Results are shown in FIG. As shown in FIG. 5, the increase in blood TSH concentration was far superior to that of the control containing no absorption enhancer.

Experimental Example 6 (Adrenocorticotropic hormone (ACT
H) absorption promoting effect) BSA 0.3 w / v%, absorption promoter (tartaric acid 1.0 w / v%
And sucrose palmitate (P-1670) 0.5w
/ V% combination) and ACTH 500 μg / ml. As a control, a solution containing 0.3 w / v% BSA and 500 μg / ml ACTH was used. By the same procedure as in Experimental Example 1, ACTH10 per rat was obtained.
0 μg was administered. Blood is collected over time, plasma is separated and RI
The ACTH concentration was measured by Method A. Results are shown in FIG. As shown in FIG. 6, the blood concentration of ACTH was much higher when the absorption enhancer was added, as compared with the control containing no absorption enhancer.

Example 1 Tablets: According to the tablet composition shown in Table 2, lactose, corn starch, tartaric acid, sucrose fatty acid ester (ryoto sugar ester L1695), h-CT and BSA were mixed to prepare an aqueous solution of hydroxypropyl cellulose (HPC). Is added and kneaded, and this is extruded and granulated to give granules. The mixture obtained by adding magnesium stearate to the granules is tableted using a tableting machine to obtain plain tablets having a diameter of 8 mm and a weight of 250 mg.

[0026]

Table 2 Tablet composition Formulation amount Lactose 22.8 g Corn starch 21.0 g Sucrose fatty acid ester 1.5 g Tartaric acid 3.0 g Human calcitonin (h-CT) 0.1 g Bovine serum albumin (BSA) 0.3 g Hydroxypropyl Cellulose (HPC) 1.2g Magnesium stearate 0.1g

Using the uncoated tablets thus obtained, a coating liquid prepared according to the coating composition shown in Table 3 is coated using a high coater to obtain the tablets of the present invention.

[0028]

[Table 3] Table 3 Formulation of coating composition Hydroxypropyl methylcellulose acetate succinate 10 g Triethyl citrate 2 g Ethanol 80 g Water 8 g

Example 2 Capsules: According to the composition shown in Table 4, malic acid, sucrose fatty acid ester (ryo-sugar ester L-1)
695), salmon calcitonin and BSA are mixed, and 100 mg of the mixture is filled into a JP No. 4 capsule to give a capsule.

[0030]

[Table 4] Table 4 Capsule composition Compounding amount Malic acid 12.4 g Sucrose fatty acid ester 6.0 g Salmon calcitonin 0.4 g Bovine serum albumin (BSA) 1.2 g

The coating liquid prepared according to the composition shown in Table 5 using the above-mentioned capsules is coated with a fluidized bed granulator to obtain the capsules of the present invention.

[0032]

[Table 5] Table 5 Coating composition blending amount Methacrylic acid copolymer S 20 g Castor oil 3 g Ethanol 377 g

Example 3 Granules: Lactose, cornstarch, human calcitonin, BSA, citric acid and sucrose fatty acid ester were mixed according to the composition shown in Table 6, and an HPC aqueous solution was added to form a kneaded product, which was extruded and granulated. Use as an agent.

[0034]

[Table 6] Table 6 Granule composition blending amount Lactose 7.2 g Corn starch 12.3 g Human calcitonin 0.2 g Bovine serum albumin (BSA) 0.6 g Citric acid 6.2 g Sucrose fatty acid ester 3.0 g Hydroxypropyl cellulose (HPC) ) 0.5g

The above granules are film-coated with a suspension prepared according to the composition shown in Table 7 by a fluidized bed granulator to obtain the granules of the present invention.

[0036]

[Table 7] Table 7 Coating composition blending amount Methacrylic acid copolymer S 30 g Castor oil 1.5 g Talc 15 g Ethanol 498 g Purified water 55.5 g

Example 4 Sublingual tablet: Lactose, corn starch, hydroxypropyl cellulose, sucrose stearate, tartaric acid and human calcitonin were added according to the composition shown in Table 8 and mixed, and the mixture was tableted using a tableting machine. Then, the sublingual tablet of the present invention is obtained.

[0038]

[Table 8] Table 8 Sublingual tablet composition blending amount Lactose 75.6 g Corn starch 13 g Hydroxypropyl cellulose 1 g Sucrose stearate 3 g Tartaric acid 7 g Human calcitonin (h-CT) 0.4 g

Example 5 Sublingual tablet: According to the composition shown in Table 9, the same treatment as in Example 4 was carried out to obtain a sublingual tablet of the present invention.

[0040]

[Table 9] Table 9 Sublingual tablet composition blending amount Lactose 58.8 g Crystalline cellulose 24 g Polyvinylpyrrolidone 3 g Sucrose palmitate 4 g Malic acid 10 g Human calcitonin (h-CT) 0.2 g

Example 6 Sublingual tablet: According to the composition shown in Table 10, the same treatment as in Example 4 was carried out to obtain a sublingual tablet of the present invention.

[0042]

[Table 10] Table 10 Sublingual tablet composition blending amount Lactose 67 g Sorbitol 4 g Mannitol 8.4 g Carboxymethyl cellulose Na 2.6 g Sucrose oleate 5 g Citric acid 12 g Salmon calcitonin 1 g

Experiment 7 (Calcitonin absorption promoting effect in sublingual tablets) Sublingual tablets obtained in the same manner as in Examples 4 and 5 were used as test samples. (Calcitonin content in one tablet: 250 mg) One of each of these samples was sublingually administered to a beagle dog (male) that had been fasted overnight. After administration, over time (5, 10, 15, 20,
Blood was collected after 30, 45, 60, and 120 minutes), and after serum separation, the human calcitonin concentration in blood was measured by the RIA method. The result is shown in FIG. 7.

Example 7 Fast-dissolving formulation: Gelatin solution according to the composition shown in Table 11
To 10 ml of (1 w / v%), 10 mg of salmon calcitonin, 2 g of tartaric acid and 1 g of sucrose stearate were added and dissolved. 1 ml of this liquid is dispensed into a container and freeze-dried to obtain the fast-dissolving preparation (sublingual tablet) of the present invention.

[0045]

[Table 11] Table 11 Formulation amount of rapidly dissolving formulation Gelatin solution 1w / v% 10ml Tartaric acid 2g Sucrose stearate 1g Salmon calcitonin 10mg

Example 8 Fast-dissolving formulation: According to the composition shown in Table 12, a fast-dissolving formulation (sublingual tablet) was obtained in the same manner as in Example 7.

[0047]

[Table 12] Table 12 Formulation amount of fast-dissolving drug formulation Gelatin solution 1w / v% 10ml Citric acid 1g Sucrose oleate 0.2g Human calcitonin 10mg

Experimental Example 8 (Effect of promoting absorption of calcitonin by combination of various organic acids and sucrose fatty acid ester in fast-dissolving preparation) 1 w / v% gelatin aqueous solution 3 ml, salmon calcitonin 3 m
g, organic acid 20w / v%, sucrose stearate (S
-970) 10 w / v% was dissolved. Each 1 ml was dispensed into a container and freeze-dried to prepare a test sample. One of this sample was sublingually administered to a beagle dog (male) that had been fasted overnight.
After administration, blood was collected over time (10, 20, 30, 45, 60 minutes later), serum was separated, and serum calcium concentration was measured using a calcium C kit (Wako Pure Chemical Industries, Ltd.). The results are shown in Table 1.
As shown in 3, the serum calcium level was decreased in each organic acid, but the serum calcium level was not decreased in the preparation containing no organic acid. The results are shown in Table 13. (Average of 3 measurements)

[0049]

[Table 13] Table 13 Reduction rate of serum Ca value (%) Time after administration (min) Organic acid 10 20 30 45 60 Tartaric acid 3.0 2.9 5.1 8.3 7.8 Citric acid 4.5 2.3 3.0 1.6 2.2 Malic acid 4.5 2.7 3.7 3.3 1.4 1.5 (-) -2.2 -1.5 -3.6 -3.1 -4 .1

Experimental Example 9 (Absorption-promoting effect of sucrose fatty acid esters having different HLB values in fast-dissolving preparations) 1 w / v% gelatin aqueous solution 3 ml, salmon calcitonin 3 m
g, tartaric acid 20w / v%, sucrose fatty acid ester 10w /
v% dissolved. Each 1 ml was dispensed into a container and freeze-dried to prepare a test sample. Hereinafter, similar to Experimental Example 8,
After administration, blood was collected over time and the serum calcium concentration was measured. The results are shown in Table 14. As shown in Table 14, a decrease in serum calcium level was observed in each HLB sucrose fatty acid ester.

[0051]

[Table 14] Table 14 Serum Ca level decrease rate (%) Time after administration (min) HLB value 10 20 30 45 60 9 3.0 3.0 2.9 5.1 8.3 7.8 5 3.0 7 .5 4.1 8.6 6.1 6.1 3 4.7 3.3 3.2 2.8 3.6

Experimental Example 10 (Effect of Concentration of Organic Acid and Sucrose Fatty Acid Ester in Fast-Dissolving Formulation) 1 w / v% gelatin aqueous solution 3 ml, human calcitonin 3 mg
And citric acid and sucrose stearate (S-9
70) was added and dissolved to a concentration shown in Table 15 below. Each 1 ml was dispensed into a container and freeze-dried to obtain a test sample. Thereafter, administration and blood collection were performed in the same manner as in Experimental Example 8,
After serum separation, the human calcitonin concentration in blood was measured by the RIA method. The results are shown in Table 15. As shown in Table 15, absorption of human calcitonin was observed at all concentrations, but when the concentration of the absorption enhancer was low, the absorption enhancing effect was weak.

[0053]

[Table 15] Table 15 Absorption enhancer concentration (%) Average human calcitonin S-970 Citric acid Maximum blood concentration (pg / ml) 10.0 20.0 1652 5.0 10.0 10.0 1116 2.5 5.0 191 1.0 2.0 86

Experimental Example 11 (Calcitonin Absorption-Promoting Effect of Combination of Organic Acid and Sucrose Fatty Acid Ester in Fast-Dissolving Formulation) Human calcitonin (h- was added to 3 ml of 1 w / v% gelatin aqueous solution.
CT) 3 mg, tartaric acid 10 w / v%, and sucrose stearate (S-570) 2 w / v% were dissolved. Each 1 ml of this was dispensed into the solution and freeze-dried to prepare a test sample. Thereafter, administration was carried out in the same manner as in Experimental Example 8, and blood was collected over time, and the calcium concentration in serum was determined by the calcium C kit (Wako Pure Chemical Industries), the phosphorus concentration by Phosphor C test (Wako Pure Chemical Industries, Ltd.), and the human calcitonin concentration by RIA. It was measured by the method. The result is shown in FIG. As shown in FIG. 8, a decrease in serum Ca concentration and a decrease in P concentration were observed with an increase in human calcitonin concentration in serum.

[0055]

[Effects of the Invention] When orally administered, the polypeptide hormone is degraded by proteolytic enzymes and is not sufficiently absorbed,
Since it does not exert the desired pharmacological action, it is administered exclusively by injection.However, according to the formulation containing the absorption enhancer of the present invention, high absorption of the poorly absorbable polypeptide hormone from the intestinal tract or the oral mucosa is achieved. As a result, the desired effect can be achieved by oral administration or buccal administration.

[0056]

[Brief description of drawings]

FIG. 1 is a graph showing a human calcitonin (h-CT) absorption promoting effect by a combination of various sucrose fatty acid esters and tartaric acid.

FIG. 2 is a graph showing the serum Ca level lowering effect associated with the promotion of h-CT absorption by the combination of various sucrose fatty acid esters and tartaric acid.

FIG. 3 is a graph showing a comparison of a serum Ca level-lowering effect of a combination of sucrose lauric acid ester and tartaric acid and their individual use.

FIG. 4 is a graph showing a comparison of h-CT absorption-promoting effects of a combination of sucrose lauric acid ester and tartaric acid and their individual use.

FIG. 5 is a graph showing the effect of promoting the absorption of thyroid stimulating hormone by the combination of sucrose stearate and tartaric acid.

FIG. 6 is a graph showing the effect of promoting the absorption of adrenocortical hormone by the combination of sucrose palmitate and tartaric acid.

FIG. 7 is a graph showing the absorption promoting effect of calcitonin in sublingual tablets.

FIG. 8 is a graph showing the absorption promoting effect of calcitonin by the combination of an organic acid and a sucrose fatty acid ester in a fast-dissolving preparation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 37/26 8314-4C 37/28 8314-4C 37/30 8314-4C 37/32 8314-4C 37/34 8314-4C 37/36 8314-4C 37/38 8314-4C 37/43 8314-4C 47/12 E 7329-4C 47/26 E 7329-4C (72) Inventor Naoki Uchida Okawa-gun, Kagawa Prefecture Uchimachi Sanbonmatsu 1278-1 (72) Inventor Susumu Misuzu 1041-5 Sanbonmatsu, Ouchi Town, Okawa District, Kagawa Prefecture

Claims (6)

[Claims] 1. A physiologically active polypeptide-containing preparation comprising a physiologically active polypeptide and an absorption enhancer comprising a combination of an organic acid and a sucrose fatty acid ester. 2. The organic acid is malic acid, succinic acid, lactic acid, tartaric acid, citric acid, benzoic acid, acetic acid, butyric acid, fumaric acid, malonic acid, phthalic acid, propionic acid, glutaric acid, adipic acid, valeric acid, capron. The preparation according to claim 1, which is one or more selected from the group consisting of acids, maleic acid, ascorbic acid, isoascorbic acid or pharmaceutically acceptable salts thereof. 3. A sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate, sucrose behenate and sucrose erucate. 1 type or 2 or more types which are
The preparation according to. 4. The physiologically active polypeptide is insulin, angiotensin, vasopressin, desmopressin, LH-RH, somatostatin, calcitonin, glucagon, oxytocin, gastrin, somatomedin, secretin, h-ANP, ACTH, MSH, β-endorphin. , Muramyl dipeptide, enkephalin, neurotensin, bombesin, VIP, CCK-8, PT
The preparation according to claim 1, which is a hormone selected from the group consisting of H, CGRP, TRH, TSH, endothelin and derivatives thereof. 5. The preparation according to claim 4, wherein the calcitonin is selected from the group consisting of salmon calcitonin, human calcitonin, pig calcitonin, eel calcitonin, chicken calcitonin, rat calcitonin, bovine calcitonin, and sheep calcitonin. 6. The preparation according to claim 5, wherein the eel calcitonin is (ASU1,7) eel calcitonin (elcatonin).