JPH0386834A - New pharmaceutical of peptide or protein for oral medicine - Google Patents

Abstract

PURPOSE:To obtain a readily industrialized pharmaceutical for oral administration excellent in oral absorption by coating a peptide- or protein-containing core containing an acid blended therein with an enteric film. CONSTITUTION:A pharmaceutical obtained by blending a peptide- or protein- containing core with an acid (preferably citric, tartaric, malic, succinic acid or sodium dihydrogenphosphate) in an amount of >=5wt.%, preferably >=10wt.% based on an active ingredient and coating the resultant core with an enteric film selected from hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate and methacrylic acid copolymer. A gastric- soluble coating, such as hydroxypropyl cellulose, as necessary, can be applied to a space between the core and the enteric film to stabilize the peptide or protein.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a new preparation for internal use of peptides or proteins. Specifically, when administered orally, it undergoes biological degradation within the gastrointestinal tract or on the wall of the gastrointestinal tract. The present invention relates to a novel formulation that improves the bioavailability of peptide or protein drugs whose availability has been reduced and they are unable to exert sufficient pharmacological action.

[Prior art and problems to be solved by the invention] Many peptide or protein drugs have been developed and used for medical treatment, but when administered orally, they are degraded in the gastrointestinal tract, resulting in poor bioavailability. It may be so low that no effective pharmacological effect can be expressed. For this reason, many inventions have been made to increase the bioavailability during oral administration.

For example, JP-A No. 60-215633 discloses that absorption from the intestinal tract is enhanced by incorporating polyalkylene glycol, calcium, and higher fatty acids into urokinase liposomes;
Publication No. 2-195324 discloses a technology to increase absorption from the intestinal tract by coating a capsule containing an absorption promoter that is an organic aromatic carboxylic acid ester, amide, or a salt thereof with a film that is insoluble at pH 7 or lower. Furthermore, JP-A-53-50316 discloses that mixed micelles in which bile salts are mixed with fatty acid monoglycerides or higher fatty acid salts improve the intestinal absorption of peptides.

However, it is expected that there will be many difficulties in commercializing liposomes or mixed micelles in terms of stability, etc.
In the technique of coating a capsule containing an absorption promoter with a film that is insoluble at pH 7 or lower, it is thought that the capsule passes through the duodenum and upper small intestine, where absorption is the highest among the gastrointestinal tract.

In addition, JP-A-62-33128 discloses that interferon includes unsaturated fatty acids, polyoxyethylene fatty acid esters, alkyl polyoxyethylene ethers, or sig'l.
It has been found that when 11 fatty acid ester is blended into capsules, tablets, etc. and then administered orally, it is absorbed from the gastrointestinal tract with less deactivation, and after absorption, the lymph fluid is transferred to a high concentration. However, it cannot necessarily be said that it is an efficient method for oral absorption of proteins.

Therefore, at present, it is difficult to say that there is a sufficient technology for efficiently absorbing peptide or protein drugs through oral absorption, and also for easy industrialization.

[Means to solve the problem]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found an internal preparation of a peptide or protein that has good oral absorption and is easily industrialized, and has completed the present invention.

That is, the present invention provides a novel peptide or protein preparation for internal use containing a peptide or protein-containing core, which is characterized in that the core contains an acid and the core is coated with an enteric coating. It provides:

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

In other words, by adding acid to the core part, as the core part dissolves, the pH of the digestive tract, especially in the duodenum to the upper part of the small intestine, where the absorption capacity is highest, decreases, and the pH of the proteolytic enzymes contained in pancreatic juice and the gastrointestinal membrane decreases. It is thought that the action is suppressed.

Furthermore, by coating this core part with an enteric coating, it not only stabilizes peptides or proteins that are unstable to the low pH in the stomach or to pepsin, which is active in the stomach, but also stabilizes peptides or proteins that are unstable in the stomach. Even in the case of peptides or proteins, it is thought that the dissolution of the enteric coating in the duodenum to the upper small intestine increases the concentration of the peptide or protein in the gastrointestinal region, where absorption is considered to be the best, and promotes absorption. It is thought that the acid added to the vegetation is also coated with an enteric coating, increasing its concentration in the digestive tract and effectively inhibiting digestive enzymes.

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

In the present invention, the target drug is a physiologically active peptide or protein. Preferred specific examples of physiologically active peptides or proteins include the following.

For example, neurotensin and its derivatives. Neurotensin is an antipsychotic drug with few extrapyramidal side effects, but it has the disadvantage that it is unstable in vivo and does not show any effect when administered systemically, such as by oral administration. The applicant of the present invention investigated derivatives thereof, discovered a new polypeptide useful as a medicine, and has already applied for a patent (Patent Application No. 1-5
5941), some of these novel polypeptides have the following structural formulas.

Here, the main amino acid is L unless it is specifically stated that it is D.
They are one.

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

CH3-Tyr-G 1y-Gly-Phe-Leu
-Arg-CHJrg-D-Leu-NHC1H5 (hereinafter abbreviated as peptide 4) Other peptides or proteins used in the present invention include elastase, secretin, lysozyme, insulin, proinsulin, desmopressin, vasobrescin,
angiotensin, protirelin, human growth hormone,
Luteinizing hormone, luteinizing hormone-releasing hormone, adrenocutaneous M-stimulating hormone, somatotropin, somatostatin, corticothrobin, prolactin, thyrotropin,
Calcitonin, kallikrein, glucagon, oxytocin, gastrin, pentagastrin, renin, parathylin, erythropoietin, enkephalin, oxytocin, parathyroid hormone, thyrotropin-releasing hormone, interferon, interleukin, tissue plus nogen activator (TPA), modification shape structure plus ξ
Examples include nogen activator (modified TPA), transferrin, tumor necrosis factor (TNF), urokinase, seratiopeptidase, tetanus vaccine, influenza vaccine, and the like.

Among these peptides or proteins, biologically active peptides or proteins with a molecular weight of less than 100% are particularly preferred, such as insulin,
Secretin, elastase, lysozyme, neurotensin, derivatives of neurotensin, guinorphine, guinorgui 70) m11 body, vasopressin, calcitonin, glucagon, gastrin, and pentagastrin are preferred.

The acid blended in the core part of the preparation of the present invention may be either an organic acid or an inorganic acid, and organic acids include citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, gluconic acid, sorbic acid, and succinic acid. , malonic acid, ascorbic acid, lactic acid, etc., and examples of inorganic acids include sodium dihydrogen phosphate,
Examples include potassium dihydrogen phosphate, but more preferred are citric acid, tartaric acid, malic acid, and sodium dihydrogen phosphate.

Although the blending ratio of acid in the present invention cannot be defined as one type, it is usually preferably 5% by weight or more based on the peptide or protein.
More preferably, it is 10% or more. The upper limit of the blending ratio of the acid is not particularly limited, except for limitations such as moldability of the core and irritation to the gastrointestinal tract.

In the present invention, the core part of the preparation means a dosage form commonly used by humans, such as tablets, granules, fine granules, and capsules. The core part can be manufactured according to the usual manufacturing method. For example, if the core part is a tablet, in addition to the peptide or protein drug and acid, if necessary, an excipient such as mannitol and a binder such as polyvinylpyrrolidone are mixed. If the peptide or protein drug is destabilized by contact with acid or other ingredients, it may be granulated by a method such as fluidized bed granulation or transfer granulation, and then compressed into a tablet. It can also be granulated into tablets.

Succinic acid, the preparation of the present invention can be prepared in the same manner as ordinary pharmaceuticals by means known per se, including small amounts of pH adjusters, additives, colorants, fragrances,
There are no restrictions on the inclusion of preservatives or the like.

The base material used for the enteric coating coating the core portion of the preparation of the present invention is appropriately selected from one or more selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymer. .

Specifically, hydroxypropyl methyl cellulose phthalate is pos, due to the difference in the degree of substitution.

- You can choose a base that dissolves at pH 5.5 or above (for example, Shin-Etsu Chemical IP-508, IP-558, HP-55S)
@).

Hydroxypropyl methylcellulose acetate succinate is also commercially available as a base that dissolves at pH 5.0 to pH 5.5 and can use water as a solvent (for example, AQOAT @ manufactured by Shin-Etsu Chemical), and methacrylic acid copolymers (for example, , Eudragit L manufactured by Rehm
30D-550) can also be used as a base that dissolves at pH 5.5 or higher. Furthermore, cellulose acetate trimellitate carboxymethylethyl cellulose and the like are also useful as bases for enteric coatings.

In the present invention, in order to apply an enteric coating to the core portion, the base material of the enteric coating may be used as it is or a solvent that dissolves it;
For example, dissolve it in ethanol, acetone, dichloromethane, isopropyl alcohol, water, etc. to form a liquid, mix with a plasticizer, colorant, etc. as necessary, and apply a coating to the core by commonly used means such as spraying or kneading. can be applied.

Furthermore, in the present invention, if necessary, an easily soluble coating such as hydroxypropyl cellulose may be applied between the core and the enteric coating to stabilize the peptide or protein.

In the present invention, the ratio of the base material used in the enteric coating can be changed depending on the dosage form of the core, but it is better to use as little coating as possible to prevent dissolution during gastric retention. Making the invention more effective.

〔Example〕

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to these examples.

Composition of the core part for working examples> (1) Peptide 1275■ (2) Citric acid 275■ (3) Mannitol 1375■ (4) Crystalline cellulose 990■ (5) Corn starch
330 ■ (6) Polyvinylpyrrolidone
44■(7) Magnesium stearate 11■(1
) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate it. 20 The granulated product was dried at about 40°C, passed through a 32-mesh sieve, mixed with (7), and compressed to obtain 10 tablets each weighing 300 cm. 50 g of propyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, followed by 300 g of hydroxypropyl methyl cellulose phthalate and 1 titanium oxide.
A solution prepared by dissolving and suspending 5 g of talc, 30 g of talc, and 30 g of myvaset in a mixed solvent of 80% ethanol and water was sprayed using a fluidized bed apparatus to obtain melted tablets II.

Example 2 <Composition of core portion> (1) Peptide 1275■ (2) Citric acid 1100■ (3) Mannitol 990 mg (4) Crystalline cellulose 550■ (5) Cornstarch 330■ (6) Polyvinylpyrrolidone 44■ (7) ) Magnesium stearate 1
1) Mix (1) to (5) in a mortar, dissolve (6) in ethanol, and gradually add it to granulate. Approximately 4
After drying at 0'C and sieving through a 32-mesh sieve,
) were mixed and compressed to obtain 10 tablets each weighing 300 square meters. To this tablet, 50 g of hydroxypropyl cellulose and IO g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, and then 300 g of hydroxypropyl methylcellulose phthalate, 15 g of titanium oxide, 15 g of talc, 30 g of mybaset were added to 8
A solution suspended in a 0% ethanol/water mixed solvent was sprayed using a fluidized bed apparatus to obtain enteric coated tablets.

Example 3 Composition of core part> (1) Peptide 1275 (2) Tartaric acid 1100 (3) Mannitol 990 (4) Crystalline cellulose 550 (5) Corn starch
330 ■ (6) Polyvinylpyrrolidone
44 ■ (7) Magnesium stearate 11 ■
(1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate it. This granulated material is heated at approximately 40°
After drying at C and sieving through a 32-mesh sieve, (7) was mixed and tableted to obtain 10 tablets each weighing 300 square meters. To these tablets, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus. Furthermore, 300 g of hydroxypropyl methyl cellulose phthalate, 15 g of titanium oxide, 30 g of talc, and 30 g of mybaset were added to 80 g of
% ethanol/water mixed solvent was sprayed using a fluidized bed apparatus to obtain enteric coated tablets.

Example 4 Composition of core part> (1) Peptide 2550 ■ (2) Citric acid 27.5 ■ (
3) Crystalline cellulose 1567.5■ (4)
Cornstarch IIO ■(5)
Polyvinylpyrrolidone 44 ■(6) Magnesium stearate 11 ■(1) to (4)
are mixed in a mortar, and (5) is dissolved in ethanol and gradually added to granulate it. The granulated product was dried at about 40 DEG C-t, passed through a 32-mesh sieve, mixed with (6), and compressed to obtain 10 tablets each weighing 210 square meters. In this pill,
Hydroxypropyl methylcellulose phthalate) 300
g, titanium oxide 15g 1 talc 30g, Mybaset 3
A solution obtained by dissolving and suspending 0 g in a mixed solvent of 80% ethanol and water was coated using a fluidized bed apparatus to obtain enteric-coated tablets.

Example 5 Composition of core portion> (1) Peptide 3110 (2) Tartaric acid 1925 (3) Mannitol 440 (4) Crystalline cellulose 220 (5) Polyvinylpyrrolidone 44 (6) Magnesium stearate
11 mg (1) to (4) are mixed in a mortar, and (5) is dissolved in ethanol and gradually added to granulate. The granules were dried at about 40°C, passed through a 32-mesh sieve, mixed with (6), and compressed into 10 tablets each weighing 250 square meters.
I got the tablet. This tablet contains methacrylic acid copolymer 300
A solution in which 15 g of titanium oxide, 30 g of talc, and 30 g of triethyl citrate were dissolved and suspended in ethanol was coated using a fluidized bed apparatus to obtain enteric-coated tablets.

Example 6 Composition of core part> (1) Porcine insulin 275■ (2
) Tartaric acid 275■ (3) Mannitol 990■ (4) Crystalline cellulose
550■ (5) Cornstarch
330■(6) Polyvinylpyrrolidone
44 ■ (7) Magnesium stearate 11 ■ (
1) to (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate it. This granulated material is heated to about 40°C.
After drying and sieving through a 32-mesh sieve, (7) was mixed and tableted to obtain 10 tablets each weighing 225 square meters. To this tablet, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, followed by 300 g of hydroxypropyl methylcellulose phthalate and 15 g of titanium oxide.

A solution prepared by dissolving and suspending 30 g of talc and 30 g of Myvaset in a mixed solvent of 80% ethanol and water was sprayed using a fluidized bed apparatus to obtain enteric-coated tablets.

Example 7 Composition of nucleus part> (1) Salmon calcitonin 11■ (2)
Succinic acid 550■ (3) Mannitol 946■ (4) Crystalline cellulose
440■(5) Cornstarch
220■ (6) Polyvinylpyrrolidone 2
2■(7) Magnesium stearate 11■(1)
- (5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate it. The granulated product was dried at about 40°C, passed through a 32-mesh sieve, mixed with (7), and compressed to obtain 10 tablets each weighing 200 square meters. To this tablet, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, an intermediate coating was applied using a fluidized bed apparatus, and 300 g of hydroxypropyl methylcellulose phthalate and 15 g of titanium oxide were added to the tablet.
A solution prepared by dissolving and suspending 30 g of talc, 30 g of talc, and 30 g of myvaset in a mixed solvent of 80% ethanol and water was sprayed using a fluidized bed apparatus to obtain enteric-coated tablets.

Example 8 <Composition of core portion> (1) Elastase 275■ (2) Tartaric acid 330■ (3) Mannitol 990■ (4) Crystalline cellulose
550■ (5) Cornstarch
330■(6) Polyvinylpyrrolidone 4
4■(7) Magnesium stearate 11■(1)
-(5) are mixed in a mortar, and (6) is dissolved in ethanol and gradually added to granulate it. The granules were dried at about 40°C, passed through a 32-mesh sieve, and mixed with (7).
The mixture was compressed to obtain 10 tablets each weighing 230 square meters. To these tablets, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, followed by 300 g of hydroxypropyl methylcellulose phthalate and 15 g of titanium oxide.
.

A solution prepared by dissolving and suspending 30 g of talc and 30 g of Mybase in a mixed solvent of 80% ethanol and water was sprayed using a fluidized bed apparatus to obtain enteric-coated tablets.

Example 9 Composition of nucleus part> (1) Secretin 55■ (2)
Malic acid 220■ (3) Mannitol 1210■ (4) Crystalline cellulose
550■ (5) Cornstarch
330■(6) Polyvinylpyrrolidone
44■(7) Magnesium stearate 1
1) Mix (1) to (5) in a mortar, dissolve (6) in ethanol, and gradually add it to granulate. Approximately 4
After drying at 0°C and sieving through a 32-mesh sieve,
) were mixed and tableted to obtain 10 tablets each weighing 220 square meters. To these tablets, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus. Furthermore, 300 g of hydroxypropyl methyl cellulose phthalate, 15 g of titanium oxide, 30 g of talc, and 30 g of mybaset were dissolved in 80% ethanol. - Enteric-coated tablets were obtained by spraying a solution dissolved and suspended in a water mixed solvent using a fluidized bed device.

Example 10 Composition of nucleus portion> (1) Modified tissue plasminogen activator 275■ (2) Sodium dihydrogen phosphate 330■ (3)
Mannitol 990■ (4) Crystalline cellulose 550■ (5) Cornstarch 330■ (6) Polyvinylpyrrolidone 44■ (7) Magnesium stearate
11) Mix (1) to (5) in a mortar, dissolve (6) in ethanol, and gradually add it to granulate. The granules were dried at about 40°C, passed through a 32-mesh sieve, and then
) were mixed and compressed to obtain 10 tablets each weighing 230 square meters. To these tablets, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, and then 300 g of hydroxypropyl methylcellulose phthalate, 15 g of titanium oxide, 30 g of talc, and 30 g of mybaset were added to the tablets.
A solution suspended in a 0% ethanol/water mixed solvent was sprayed using a fluidized bed apparatus to obtain enteric coated tablets.

Example 11 Composition of core part> (1) Peptide 4 1250■ (
2) Citric acid 5000■ (3)
Mannitol 5750■ (4) Crystalline cellulose 3750■ (5) Cornstarch 1500■ (6) Polyvinylpyrrolidone 200■ (7) Magnesium stearate 50mg (1) to (5) are mixed in a mortar, (6)
is dissolved in ethanol and gradually added to granulate it. The granules were dried at about 40"C, passed through a 32-mesh sieve, mixed with (7), and compressed to obtain 48 tablets each weighing 350". A solution of 50 g of methyl cellulose dissolved in water was subjected to an intermediate coating using a fluidized bed apparatus, and a solution of 300 g of hydroxypropyl methylcellulose phthalate and rllll guchi 5 fu 15 dissolved and suspended in an 80% ethanol/water mixed solvent was coated using a fluidized bed apparatus. Enteric-coated tablets were obtained by spraying.

Reference Example 1 25 μg of Peptide 1 was dissolved in 5 ml of physiological saline Q and filled into capsules to obtain capsules.

Reference example 2 <Composition of core portion> (1) Peptide 1275 (2) Mannitol 1650 (3) Crystalline cellulose 990 (4) Cornstarch 330 (5) Polyvinylpyrrolidone 44 (6) Magnesium stearate 1 mg (1 ) to (4) are mixed in a mortar,
(5) is dissolved in ethanol and gradually added to granulate it.

The granulated product was dried at about 40°C, passed through a 32-mesh sieve, mixed with (6), and compressed to obtain 10 tablets each weighing 300 square meters. To these tablets, 50 g of hydroxypropyl cellulose and 10 g of magnesium stearate were dissolved and suspended in ethanol, and an intermediate coating was applied using a fluidized bed apparatus, followed by 300 g of hydroxypropyl methylcellulose and 15 g of titanium oxide.

A solution prepared by dissolving and suspending 30 g of talc and 30 g of myvaset in a mixed solvent of 80% ethanol and water was sprayed using a fluidized bed apparatus to obtain enteric-coated tablets.

Reference example 3 <Composition of core part> (1) Peptide 1275■ (2) Citric acid 275■ (3
) Mannitol 1375■ (4) Crystalline cellulose 990■ (5) Cornstarch 330■ (6) Polyvinylpyrrolidone 44■ (7) Magnesium stearate 11■ Mix (1) to (5) in a mortar, (6)
is dissolved in ethanol and gradually added to granulate it. The granulated product was dried at about 40°C, passed through a 32-mesh sieve, mixed with (7), and compressed to obtain 10 tablets each weighing 300 square meters.

Reference example 4 <Composition of core part> (1) Peptide 4 1250m
g(2) Mannitol 2500■(3)
Crystalline cellulose 1750■ (4) Corn starch 500■ (5) Polyvinylpyrrolidone 200■ (6) Magnesium stearate 50■ Mix (1) to (4) in a mortar, dissolve (5) in ethanol and gradually add. granulate,
The granules were dried at about 40°C, passed through a 32-mesh sieve, mixed with (6), and compressed to obtain 125 square tablets.

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

[Effects of the Invention] In order to confirm the effects of the peptide or protein preparation for internal use of the present invention, the following animal experiment was conducted.

Experimental Example 1 <Sample> The tablets prepared in Examples 1 to 3 were used as test samples. For comparison, the capsules of Reference Example 1 and Example 1 were prepared by directly dissolving the peptide or protein in physiological saline and filling the capsules.
In Example 1, the tablet of Reference Example 2, which had a composition containing no acid in the core portion, and the tablet of Reference Example 3, which did not have an intermediate coating or enteric coating, were used in Example 1.

Method: Beagles were used as the animal species. Since beagles often have low intragastric acidity, the intragastric acidity was adjusted using the method of China et al. (Japan Pharmaceutical Society 2nd Annual Meeting, Abstracts, p. 65).

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

Blood was collected 20 minutes, 40 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours after sample administration, and about 1 m7 of plasma was separated.

<Results> FIG. 1 shows the time course of plasma drug concentrations in Example 1 and Reference Examples 1 to 3. Example 1 compared to Reference Examples 1 to 3
showed high plasma drug concentrations.

Table 1 shows the area under the plasma drug concentration-time curve for Examples 1 to 3 and Reference Examples 1 to 3.

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

table Absorption comparison of various samples Experimental example 2 test Fee〉 Example 11 and Reference Example 4゜ Use the tablets obtained in step 5. there was.

How to go Law〉 Using 4 tablets of sample per peagle, experiment It was carried out in the same manner as in Example 1.

Results> Figure 2 shows the time course of the drug concentration in the blood of Example 11 and Reference Example 4.5. Example 11 showed a higher plasma drug concentration than Reference Example 4.5.

Table 2 shows the area under the plasma drug concentration-time curve for Example 11 and Reference Examples 4 and 5. The area under the plasma drug concentration-time curve of Example 11 was significantly higher than that of Reference Example 4.5.

Table 2

[Brief explanation of drawings]

Figure 1 is a graph showing the time course of plasma drug concentration in Example 1 and Reference Examples 1 to 3, and Figure 2 is a graph showing the time course of plasma drug concentration in Example 11 and Reference Examples 4.5. be. Figure time (time)

Claims (1)

[Scope of Claims] 1. An internal preparation containing a peptide or protein-containing core, characterized in that the core contains an acid and the core is coated with an enteric coating. New formulation. 2. The acid is citric acid, tartaric acid, fumaric acid, maleic acid,
The preparation according to claim 1, which is one or more acids selected from succinic acid, malic acid, malonic acid, sorbic acid, ascorbic acid, gluconic acid, and sodium dihydrogen phosphate. 3. Formulation 4 according to claim 1 or 2, wherein the amount of acid blended is 5% by weight or more based on the peptide or protein.
The formulation according to any one of claims 1 to 3, which is one or a combination of one or more arbitrarily selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymer.