JP3009911B2 - Novel formulation of peptide or protein for internal use - Google Patents

Description

The present invention relates to a novel preparation for internal use of a peptide or protein,
Specifically, when administered orally, the bioavailability is reduced by degradation in the digestive tract or in the digestive tract wall, thereby improving the bioavailability of peptide or protein drugs that cannot exert sufficient pharmacological action. Formulation.

[Problems to be solved by conventional technology and invention]

Many peptide or protein drugs have been developed and provided for medical treatment, but when administered orally, they are degraded in the gastrointestinal tract, so their bioavailability is very low and effective pharmacological effects may not be exhibited . For this reason, many inventions have hitherto been made to increase the bioavailability at the time of oral administration. For example, JP-A-60-215633 discloses that the absorption from the intestinal tract can be enhanced by adding a polyalkylene glycol, calcium and a higher fatty acid to a urokinase liposome.
No. 5324 discloses a technique for enhancing absorption from the intestinal tract by coating a capsule containing an absorption promoter, which is an organic aromatic carboxylic acid ester, amide or a salt thereof, with a film that is insoluble at pH 7 or less, further,
JP-A-53-50316 discloses that mixed micelles obtained by mixing a bile salt with a fatty acid monoglyceride or a higher fatty acid salt enhance intestinal absorption of the peptide.

However, liposomes or mixed micelles are expected to be difficult to commercialize due to their stability and other factors.In addition, the technology of coating capsules containing an absorption promoter with an insoluble film at pH 7 or lower is the most effective in the digestive tract. It is thought that it passes through the duodenum to the upper part of the small intestine with good absorbability.

Further, in JP-A-62-33128, an unsaturated fatty acid, a polyoxyethylene fatty acid ester,
Alkylpolyoxyethylene ether or sucrose fatty acid ester is added to the capsule and tablets to give enteric properties and administered orally. When administered orally, it is less inactivated and is absorbed from the gastrointestinal tract. However, this is not always an efficient method for oral absorption of peptides or proteins.

Therefore, at present, it is difficult to say that a technique for efficiently absorbing a peptide or protein drug by oral absorption and that can be easily industrialized is sufficient.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve the above problems,
The present inventors have found a preparation for internal use of a peptide or protein that has good oral absorption and is easy to industrialize, and has completed the present invention.

That is, the present invention relates to an oral preparation containing a peptide or protein-containing core, wherein the core contains citric acid, tartaric acid, fumaric acid, maleic acid, succinic acid, malic acid, malonic acid, sorbic acid, ascorbic acid, and gluconic acid. A peptide or protein, wherein one or more acids selected from sodium dihydrogen phosphate are blended in an amount of 5% by weight or more based on the peptide or protein, and the core is coated with an enteric coating. The present invention provides a new formulation for internal use.

The reason why the preparation of the present invention enhances the oral absorption of peptides or proteins is considered as follows.

That is, by mixing the acid in the core, as the core is dissolved, the pH in the gastrointestinal tract, particularly the highest in the duodenum to the upper small intestine, decreases, and the proteases contained in the pancreatic juice and the gastrointestinal tract membrane are reduced. It is thought that work is suppressed.
Furthermore, by coating this core with an enteric coating, not only stabilization of peptides or proteins unstable to pepsin, which is active at low pH or in the stomach, but also stable in the stomach. It is considered that the dissolution of the enteric coating in the duodenum to the upper part of the small intestine increases the concentration of the peptide or protein in the gastrointestinal tract, which is considered to have the best absorbability, and promotes the absorption of the peptide or protein. It is considered that the acid incorporated in the nucleus is also coated with the enteric coating to increase its concentration in the digestive tract and effectively inhibit digestive enzymes.

The two effects mentioned above, namely, suppression of gastrointestinal enzymes by acid, and rapid release of peptide or protein and acid at the most efficient site in the gastrointestinal tract due to coating with enteric coating, It is believed that the formulations of the invention significantly increase the gastrointestinal absorption of peptides or proteins.

In the present invention, the drug is a peptide or protein having a physiological activity. Preferred specific examples of the peptide or protein having a physiological activity include the following.

For example, there is neurotensin and its derivatives. Although neurotensin is an antipsychotic drug with few extrapyramidal side effects, it has the drawback that it is inactive in vivo and does not show an effect by systemic administration such as oral administration. The applicant of the present invention has studied the derivatives thereof, found a novel polypeptide useful as a medicament, and has already filed a patent application (Japanese Patent Application No. Hei.
No. 55941). Some of these novel polypeptides have the following structural formula:

(Me) Arg-Lys-Pro-Trp-Tle-Leu-OEt.3HCl (hereinafter abbreviated as peptide 1) (Me) Arg-Lys-Pro-Trp-Tle-Leu-OH.3HCl (hereinafter abbreviated as peptide 2) D-Lys-Arg-Pro-Trp-Tle-Leu-OH.3HCl (hereinafter abbreviated as peptide 3) Here, the amino acid is an L-form unless otherwise specified.

Other preferred specific examples include dynorphin and its derivatives. An example of the structural formula is as follows.

_{CH 3 -Tyr-Gly-Gly-} Phe-Leu-Arg-CH 3 Arg-D-Leu
-NHC ₂ H ₅ (hereinafter abbreviated as peptide 4) Other peptides or proteins used in the present invention include elastase, secretin, lysozyme, insulin, proinsulin, desmopressin, vasopressin, angiotensin, protirelin, human growth hormone, luteinization Hormones, luteinizing hormone-releasing hormone, adrenocorticotropic hormone, somatotropin, somatostatin, corticotropin, prolactin, thyrotropin, calcitonin, kallikrein, glucagon, oxytocin, gastrin, ventgastrin, renin, paratilin, erythropoietin, enkephalin, oxycotin, parathyroid gland , Thyrotropin-releasing hormone, interferon, interleukin, tissue plasminogen activator (TPA), modified form Woven plasminogen activator (modified forms PTA), transferrin, tumor necrosis factor (TNF), urokinase, serratiopeptidase, tetanus vaccine, influenza vaccine, and the like.

Among these peptides or proteins, particularly preferred are bioactive peptides or proteins having a molecular weight of tens of thousands or less, insulin, secretin, elastase, lysozyme, neurotensin, derivatives of neurotensin, dynorphin, dynorphin derivatives, vasopressin, calcitonin, glucagon. , Gastrin and pentagastrin are preferred.

Acids incorporated into the core of the formulation of the present invention are citric acid,
Tartaric acid, fumaric acid, maleic acid, succinic acid, malic acid,
Malonic acid, sorbic acid, ascorbic acid, gluconic acid,
One or more selected from sodium dihydrogen phosphate may be mentioned, and more preferred are citric acid, tartaric acid, malic acid, succinic acid and sodium dihydrogen phosphate.

The mixing ratio of the acid in the present invention is preferably 5% by weight or more, more preferably 10% by weight, based on the peptide or protein.
That is all. The upper limit of the mixing ratio of the acid is not particularly limited and is not limited by the moldability of the nucleus and irritation to the digestive tract.

In the present invention, the core portion of the preparation is a tablet, a granule,
It means a dosage form usually used for humans, such as fine granules and capsules. The core can be manufactured according to a normal manufacturing method. For example, if the core is a tablet, besides a peptide or protein drug and an acid, if necessary, an excipient such as mannitol and a binder such as polyvinylpyrrolidone are mixed and granulated by a method such as fluidized bed granulation or tumbling granulation. Then, it may be compressed into tablets. If the peptide or protein drug is destabilized by contact with acids or other components, it can be granulated separately to make a tablet.

In addition, the formulation of the present invention is a small amount of a pH adjuster, an additive, a coloring agent, a fragrance, in the same manner as a usual drug according to a means known per se,
The inclusion of a preservative or the like is not limited at all.

As the base used for the enteric film coating the core part of the preparation of the present invention, one or more selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer are appropriately selected. .

 Specifically, hydroxypropyl methylcellulose
Talate dissolves at pH 5.0 to pH 5.5 or higher depending on the degree of substitution
(For example, HP-50 manufactured by Shin-Etsu Chemical Co., Ltd.) , HP−
55 , HP-55S ). Also, hydroxypropylmethyl
Cellulose acetate succinate also dissolves at pH 5.0 to pH 5.5
And marketed as a base in which water can be used as a solvent.
Yes (for example, Shin-Etsu Chemical AQOAT )
Lylic acid copolymer (for example, Eudragit manufactured by Rohm)
L30D-55 ) Can also be used as a base that dissolves at pH 5.5 and above.
Wear. In addition, cellulose acetate trimellitka
Ruboxymethylethylcellulose is also the base for enteric coatings
Useful as

In the present invention, in order to apply the enteric coating to the core portion, a solvent for dissolving the base of the enteric coating as it is or for dissolving it, for example, ethanol, acetone, dichloromethane,
Dissolve in isopropyl alcohol, water, etc. to make a liquid,
If necessary, a plasticizer, a colorant, or the like may be mixed, and a coating may be applied to the core portion by commonly used means such as spraying or kneading.

In the present invention, if necessary, a readily soluble coating such as hydroxypropylcellulose may be applied between the core and the enteric coating to stabilize the peptide or protein.

In the present invention, the use ratio of the base for the enteric film can be changed depending on the dosage form of the nucleus, but it is better to use a coating as small as possible to the extent that dissolution does not occur during retention in the stomach. Make the invention more effective.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 <Core Composition> (1) Peptide 1 275 mg (2) Citric acid 275 mg (3) Mannitol 1375 mg (4) Microcrystalline cellulose 990 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32-mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 300 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 2 <Composition of core portion> (1) Peptide 1 275 mg (2) Citric acid 1100 mg (3) Mannitol 990 mg (4) Crystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32-mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 300 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 3 <Core composition> (1) Peptide 1 275 mg (2) Tartaric acid 1100 mg (3) Mannitol 990 mg (4) Crystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg ( 1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate. About 40 ℃
After sieving with a 32-mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 300 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 4 <Composition of core portion> (1) Peptide 2 550 mg (2) Citric acid 27.5 mg (3) Microcrystalline cellulose 1567.5 mg (4) Coastal starch 110 mg (5) Polyvinylpyrrolidone 44 mg (6) Magnesium stearate 11 mg (1) to (4) are mixed in a mortar, and (5) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving through a 20-mesh sieve, (6) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 210 mg per tablet. To this tablet, add hydroxypropyl methylcellulose phthalate 30
0g, Titanium oxide 15g, Talc 30g, Myvaset 30g 80
The solution, which was dissolved and suspended in a mixed solvent of ethanol and water, was coated with a fluidized bed apparatus to obtain enteric coated tablets.

Example 5 <Composition of core portion> (1) Peptide 3 110 mg (2) Tartaric acid 1925 mg (3) Mannitol 440 mg (4) Crystalline cellulose 220 mg (5) Polyvinylpyrrolidone 44 mg (6) Magnesium stearate 11 mg (1) to (4) ) Is mixed in a mortar, and (5) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32 mesh sieve, (6) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 250 mg per tablet. In this tablet, 300 g of methacrylic acid copolymer, 15 g of titanium oxide,
A solution obtained by dissolving and suspending 30 g of talc and 30 g of triethyl citrate in ethanol was coated with a fluidized bed apparatus to obtain enteric coated tablets.

Example 6 <Composition of core portion> (1) Porcine insulin 275 mg (2) Tartaric acid 275 mg (3) Mannitol 990 mg (4) Crystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg ( 1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate. About 40 ℃
After sieving with a 32 mesh sieve, (7) was mixed, and the mixture was tableted to obtain 10 tablets of 225 mg / tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 7 <Composition of core portion> (1) Salmon calcitonin 11 mg (2) Succinic acid 550 mg (3) Mannitol 946 mg (4) Crystalline cellulose 440 mg (5) Corn starch 220 mg (6) Polyvinylpyrrolidone 22 mg (7) Magnesium stearate 11 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32 mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 200 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 8 <Core composition> (1) Elastase 275 mg (2) Tartaric acid 330 mg (3) Mannitol 990 mg (4) Crystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg (1) ) To (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32 mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 230 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 9 <Composition of core part> (1) Secretin 55 mg (2) Malic acid 220 mg (3) Mannitol 1210 mg (4) Crystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg ( 1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate. About 40 ℃
After sieving with a 32-mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 220 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 10 <Composition of core portion> (1) Modified tissue plasminogen activator 275 mg (2) Sodium dihydrogen phosphate 330 mg (3) Mannitol 990 mg (4) Microcrystalline cellulose 550 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32 mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 230 mg per tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Example 11 <Composition of core portion> (1) Peptide 4 1250 mg (2) Citric acid 5000 mg (3) Mannitol 5750 mg (4) Crystalline cellulose 3750 mg (5) Corn starch 1500 mg (6) Polyvinylpyrrolidone 200 mg (7) Magnesium stearate 50 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32-mesh sieve, (7) was mixed and the mixture was compressed into tablets to obtain 48 tablets of 350 mg each. To this tablet, a solution obtained by dissolving 50 g of hydroxypropylmethylcellulose in water was subjected to intermediate coating by a fluidized bed apparatus, and further 300 g of hydroxypropylmethylcellulose phthalate,
A solution prepared by dissolving and suspending 15 g of titanium oxide, 30 g of talc, and 30 g of Myvaset in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Reference Example 1 Peptide 1 (25 mg) was dissolved in physiological saline (0.5 ml) and filled into a capsule to obtain a capsule.

Reference Example 2 <Composition of core portion> (1) Peptide 1 275 mg (2) Mannitol 1650 mg (3) Microcrystalline cellulose 990 mg (4) Corn starch 330 mg (5) Polyvinylpyrrolidone 44 mg (6) Magnesium stearate 11 mg (1) to (4) ) Is mixed in a mortar, and (5) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving with a 32-mesh sieve, (6) was mixed, and the mixture was tableted to obtain 10 tablets of 300 mg / tablet. To this tablet, 50 g of hydroxypropylcellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, intermediate coated with a fluidized bed apparatus, and further, 300 g of hydroxypropylmethylcellulose phthalate, 15 g of titanium oxide, and 3 g of talc 3
A solution in which 0 g and 30 g of Myvaset were dissolved and suspended in a mixed solvent of 80% ethanol / water was sprayed with a fluidized bed apparatus to obtain enteric coated tablets.

Reference Example 3 <Composition of core portion> (1) Peptide 1 275 mg (2) Citric acid 275 mg (3) Mannitol 1375 mg (4) Microcrystalline cellulose 990 mg (5) Corn starch 330 mg (6) Polyvinylpyrrolidone 44 mg (7) Magnesium stearate 11 mg (1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added, followed by granulation. About 40 ℃
After sieving through a 20-mesh sieve, (7) was mixed, and the mixture was compressed into tablets to obtain 10 tablets of 300 mg per tablet.

Reference Example 4 <Core composition> (1) Peptide 4 1250 mg (2) Mannitol 2500 mg (3) Microcrystalline cellulose 1750 mg (4) Corn starch 500 mg (5) Polyvinylpyrrolidone 200 mg (6) Magnesium stearate 50 mg (1) to (4) ) Is mixed in a mortar, (5) is dissolved in ethanol, gradually added, and granulated. The granulated product is dried at about 40 ° C., sieved with a 32-mesh sieve, and (6) is mixed. The tablet was compressed to obtain a tablet of 125 mg / tablet.

Reference Example 5 The tablets obtained in Reference Example 4 were subjected to intermediate coating and enteric coating in the same manner as in Example 11 to obtain enteric coated tablets.

〔The invention's effect〕

The following animal experiments were performed to confirm the effects of the preparations for internal use of the peptide or protein of the present invention.

Experimental Example 1 <Sample> The tablets prepared in Examples 1 to 3 were used as a sample. For comparison, a capsule of Reference Example 1 in which a peptide or protein was directly dissolved in physiological saline and filled in capsules, and Reference Example 2 in Example 1, which had a composition containing no acid in the core portion.
And the tablet of Reference Example 3 having no intermediate film or enteric film in Example 1.

<Method> Beagle was used as an animal species. Since the gastric acidity of beagle is often low, the gastric acidity was adjusted by referring to the method of Nakata et al. (Japanese Society of Pharmaceutical Sciences 2nd Annual Meeting, Abstracts, P65).

That is, pentagastrin was injected subcutaneously 30 minutes before administration into a beagle fasted overnight. Example 1 for these beagles
1 to 3 and 1 tablet or 1 capsule each obtained in Reference Examples 1 to 3 were forcibly administered together with 30 ml of water, and the drug concentration in plasma was measured.

Blood collection is 20 minutes, 40 minutes, 1 hour, 1.5 hours,
After 3 hours, 3 hours, 4 hours, 5 hours and 6 hours, blood was collected, and about 1 ml of plasma was separated.

<Results> FIG. 1 shows the time course of the plasma drug concentration in Example 1 and Reference Examples 1 to 3. As compared to Reference Examples 1 to 3, Example 1 showed a higher drug concentration in plasma.

Table 1 shows the area under the plasma drug concentration-time curves of Examples 1 to 3 and Reference Examples 1 to 3. The areas under the plasma drug concentration-time curves of Examples 1 to 3 were significantly higher than those of Reference Examples 1 to 3.

Experimental Example 2 <Sample> The tablets obtained in Example 11 and Reference Examples 4 and 5 were used.

<Method> The test was carried out in the same manner as in Experimental Example 1, using four tablets per beagle.

<Results> FIG. 2 shows the time course of the plasma drug concentration in Example 11 and Reference Examples 4 and 5. Example 11 showed a higher drug concentration in plasma as compared to Reference Examples 4 and 5.

Table 2 shows the drug concentration in plasma of Example 11 and Reference Examples 4 and 5.
The area under the time curve is shown. Plasma drug concentration of Example 11
The area under the time curve was significantly higher than in Reference Examples 4 and 5.

[Brief description of the drawings]

1 is a graph showing the time course of the plasma drug concentration in Example 1 and Reference Examples 1 to 3, and FIG. 2 is Example 11 and Reference Examples.
4 is a graph showing the time course of plasma drug concentrations of Nos. 4 and 5.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 47/32 A61K 47/32 47/38 47/38 (56) References Reference table 1-500589 (JP, A) (58 ) Surveyed fields (Int. Cl. ⁷ , DB name) A61K 37 / 02,47 / 12,47 / 22 A61K 47 / 32,47 / 38,9 / 00 CA (STN)

Claims (2)

(57) [Claims] (1) A preparation for internal use containing a peptide or protein-containing core, wherein the core contains citric acid, tartaric acid, fumaric acid, maleic acid, succinic acid, malic acid, malonic acid, sorbic acid, ascorbic acid, gluconic acid, A peptide characterized in that one or more acids selected from sodium dihydrogen phosphate are blended in an amount of 5% by weight or more with respect to the peptide or protein, and the core is coated with an enteric coating; New formulation for internal use of protein. 2. The preparation according to claim 1, wherein the enteric coating is at least one selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer.