JPH11189544A - Digestive enzyme-containing medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine useful as a therapeutic agent for gastric ulcer, duodenal ulcer, etc. SOLUTION: This medicine is obtained by combining a histamine H2 receptor antagonist such as cimetidine, ranitidine, famotidine or the like with a proton pump inhibitor such as omeprazole, lansoprazole, rabeprazole or the like and a digestive enzyme.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical containing a digestive enzyme. More specifically, at least histamine H
₂ receptor antagonists (hereinafter, H ₂ blockers hereinafter) and / or proton pump inhibitors (hereinafter referred to as PPI) it relates to a pharmaceutical comprising Kumiawashi digestive enzymes and. The medicament of the present invention is effectively used as a remedy for gastric ulcer, duodenal ulcer and the like.

[0002]

2. Description of the Related Art Gastric and duodenal ulcers cause mental stress,
It is a gastrointestinal disorder caused by various causes such as eating habits, intake of irritating beverages and foods. These are caused by autolysis of the mucous membrane by gastric juice and are collectively referred to as peptic ulcers. The mechanism of peptic ulcer development is classified into two types: a case where the aggressive factors such as stomach acid and pepsin are strengthened, and a case where the corresponding protective factors are weakened and cannot prevent the aggressive factors.

[0003] Pharmaceutical preparations used for the treatment of gastric and duodenal ulcers for suppressing the aggressive factors include antacids for neutralizing gastric acid, anti-pepsin agents, gastric mucosal protective agents, and anti-gastric acid secretion for suppressing gastric acid secretion. anticholinergic, parasympathetic blockers, H ₂ blockers and PPI, and the like.

Recently, the above-described H ₂ blocker is frequently used as antiulcer agents inhibit hydrochloric acid secretion pepsin from gastric juice secreting cells. Therefore, self-digestion in the stomach is suppressed,
The therapeutic effect of ulcers has been demonstrated. In addition, PPI inhibits the proton pump [(H ⁺ + K ⁺ ) -ATPase],
It exhibits a broader acid secretion inhibitory effect on various acid secretion stimuli than H ₂ blockers.

[0005] Conventionally to exhibit more the ulcer therapeutic effect, magnesium oxide with H ₂ blocker or PPI, aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, antacids such as magnesium carbonate or sodium citrate At the same time, they have been formulated and prescribed.

[0006]

Normally, digestion of food taken through the mouth is digested through a complicated process. Usually, first, it is decomposed by α-amylase secreted from salivary glands, decomposed by pepsin in the stomach under hydrochloric acid, and further decomposed by various enzymes secreted from the pancreas in the intestine, as nutrients from the intestinal wall. Absorbed.

[0007] For the purpose of ulcer treatment H ₂ blocker or PPI
As a matter of course, the secretion of hydrochloric acid and pepsin is suppressed by using, so that the digestive function of food normally performed in the stomach is significantly inhibited. That is, from that ulcer as described above is mainly due to autolysis of the stomach wall by gastric juice, most lines in the digestion of food in the stomach in ulcer treatment with such H ₂ blocker or PPI It has not been done.

However, it is necessary to maintain a good nutritional state in order to recover a disease state caused by various causes such as mental stress, and treatment is performed while maintaining the original digestive mechanism in the living body as much as possible. Is important.

[0009] According to the study of the present inventors, it has been found that digestion of food by gastric juice in vivo has an effect of promoting digestion by pancreatic juice and promoting nutrient absorption into the intestinal tract. Digestion was confirmed to be a very important factor in the whole living body digestion system. Thus, the gastric digestion of the presser is food with H ₂ blocker or PPI, a method of recovering without compromising the therapeutic effect of the ulcer by H ₂ blocker or PPI has been desired.

[0010]

Means for Solving the Problems The present inventors have intensively studied to solve the above problems and completed the present invention. That is, the present invention is the combined use of digestive enzymes that act in the stomach and H ₂ blockers and / or PPI, provides a pharmaceutical which can restore the digestion in the stomach, which was suppressed with H ₂ blockers and PPI . In the stomach is a situation where pH with H ₂ blocker or PPI is rising, it is possible to effect the pH of normal stomach also exhibit insufficient various digestive enzyme activities.

[0011] Since peptic ulcer is caused by auto-digestion by gastric juice, it is thought that the action of digestive enzymes, especially proteolytic enzymes, in the stomach may cause exacerbation of ulcer. However, according to the study of the present inventors, surprisingly, it is possible to digest food in the stomach without causing exacerbation of ulcers by using the digestive enzymes applied to the present invention. It was clarified that nutrient absorption in the intestinal tract could be promoted.

The present invention provides at least a H ₂ blocker and / or
Or a pharmaceutical product obtained by combining PPI and a digestive enzyme as active ingredients, and the pharmaceutical product of the present invention can exert an ulcer treatment effect and can restore the suppressed digestive function of food in the stomach. .

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The H ₂ blocker used in the present invention includes, for example, cimetidine, ranitidine, famotidine and the like. These can be used alone or in combination of two or more. The compounding amount of the H ₂ blocker in the present invention may be any amount as long as its therapeutic effect is generally expected, and is not particularly limited. Usually, 40 mg to 800 mg / day is used.

The PPI used in the present invention includes omeprazole, lansoprazole, rabeprazole and the like. These can be used alone or in combination of two or more. The compounding amount of the PPI in the present invention may be any amount as long as its therapeutic effect is generally expected, and is not particularly limited. Usually, 20 mg to 60 mg / day is used.

Further, the digestive enzyme used in combination with the above-mentioned H ₂ blocker or PPI can act at the pH in the stomach under the condition that the H ₂ blocker or PPI is administered and exacerbate the ulcer site. Any digestive enzyme capable of digesting food without any restriction can be used.

When H ₂ blocker or PPI is used,
The pH in the stomach rises and is usually 4-6. Furthermore, when an antacid is used in combination, the pH rises further and the pH increases.
Six or more states are observed for a short time. Thus, the enzymes that can be used vary depending on the pH of the stomach when the preparation is applied, but various commercially available digestive enzymes can be used.

[0017] Commercially available medical digestive enzymes include:
Various enzymes derived from animals, plants and microorganisms can be mentioned. In the present invention, enzymes derived from microorganisms are more preferably used. Examples of the types of enzymes include amylolytic enzymes, proteolytic enzymes, lipolytic enzymes, fibrinolytic enzymes, and the like, and complex digestive enzymes obtained by combining these.

In the present invention, H ₂ blocker or PP
In terms of supplementing the digestive function inhibited by I, proteases are more usefully utilized, but are not limited thereto. Any enzyme preparation containing protease activity is usefully utilized. .

More specifically, biodiastases, biodiastases 500, biodiastases 700, biodiastases 1000, biodiastases 2000, neurases, prozymes, prozymes 6, lipase AP4, lipase AP6,
Lipase AP12, Lipase M-AP5, Lipase M-AP10, Lipase M-AP20, Cellulase AP, Cellulase AP3, Cellulase T-AP2, Cellulase T-AP4, Cellulase T-AP6, Pancreatic digestive enzyme TA, Pancreatic digestive enzyme 8AP (Manufactured by Amano Pharmaceutical), biotamylase, biotamiolase S, biotalase A-1000, biotalase P-1000, denapsin 10 (manufactured by Nagase Seikagaku Corporation), cellulosin AP, prolysin (manufactured by Ueda Chemical), lipase seiken (Manufactured by Osaka Bacteria Research Institute), Takadiasutase (manufactured by Sankyo), Sumiteam (manufactured by Shin Nippon Chemical Co., Ltd.)
Lipase MY (Meito Sangyo) and the like. More preferably, Prozyme 6 as a proteolytic enzyme and Biodiastase 2000 as a complex digestive enzyme can be used.

The amount of digestive enzymes used is not particularly limited as long as the digestive enzymes can be sufficiently incorporated in the stomach when these enzymes are blended. The standard of compounding (medical use) is shown.

According to the digestion test method specified in the general test method of the 13th revision of the Japanese Pharmacopoeia, the activity label is 197 units or more for starch digestion and 15,000 units for protein digestion per dose. As described above, fat digestion is 300 units or more. These activities have the following activity values when measured according to the USP method or the FIP method.

Starch digestion Approximately 2,200 units or more (USP
Method), about 556 units or more (FIP method) Protein digestion power About 12,500 units or more (USP method), about 200 units or more (FIP method) Fat digestion power About 1,600 units or more (USP method), about 2,100 units or more (FIP method) )

In the present invention, the H ₂ blocker and / or PPI and the digestive enzyme may be used in combination and administered to a living body. These pharmaceuticals may be separately formulated and used in combination. is good, also H ₂ blockers and / or PPI and digestive enzyme may be simultaneously formulated in one formulation. In these formulations, other active ingredients can be formulated as necessary while taking into consideration the problem of contraindications. Of course, various auxiliaries can also be blended for formulation. For example, it can be used as a pharmaceutical product in which an antacid is combined with a digestive enzyme, an H ₂ blocker or PPI.

These pharmaceutical compositions can be provided in various pharmaceutical forms. Formulated with H ₂ blocker or PPI as described above, apart from the digestive enzyme formulated by combining these may be the preparation of a medicament in such forms are taken simultaneously. In addition, these active ingredients can be simultaneously formulated to prepare a pharmaceutical preparation. These pharmaceuticals are, for example, liquids, capsules, granules, pills, suspensions / emulsions, powders, tablets, syrups, limonades, etc., as long as they are in a dosage form in which the effect of the incorporated active ingredient is exhibited. It can take any form.

Hereinafter, the present invention will be described in detail with reference to Test Examples and Examples, but the present invention is not construed as being limited thereto, and is extended to a range that can be easily made by those skilled in the art. .

Test Example 1 For a digestive tract model using a mixed substrate
Method for confirming the importance of gastric digestion using a substrate solution consisting of 1.8% bovine serum albumin, 6.7% starch digest (PINE-DEX # 100, manufactured by Matsutani Chemical), 2.7% olive oil,
After adding 0.1% gastric mucosal mucin, 150 mM NaCl, 1 mM CaCl ₂ and acetate buffer, the pH was adjusted to 4.0 with hydrochloric acid.

The substrate solution (140 ml) was kept at 37 ° C., and 10 ml of 0.2% pepsin solution or 10 ml of water was added under gentle stirring to carry out the reaction. Five minutes after the start of the reaction, 4 ml of 0.2N hydrochloric acid was added. 0.2N every 15 minutes until after
4 ml of hydrochloric acid were added. Up to 120 minutes after the reaction, the environment in the stomach was set, and thereafter, 3.0 g of sodium bicarbonate, 0.31 g of sodium taurodeoxycholate, and 8AP of pancreatic digestive enzyme
150 mg (high titer pancreatin: Amano Pharmaceutical) was added to create an intestinal environment. The activity was determined by sampling during the reaction, stopping the reaction by adding trichloroacetic acid, and measuring the amount of free tyrosine in the supernatant by the Folin method. The results of the reaction time and the amount of tyrosine in the gastric environment are shown in FIG.

Results In FIG. 1,-○-indicates the result obtained by subtracting the tyrosine release amount when only pepsin was used from the tyrosine release amount when pepsin and pancreatin were used, and-●-indicates that only pancreatin was used. It shows the amount of released tyrosine when used. Therefore, as is apparent, when pancreatin was allowed to act after adding pepsin, the protein digestion by pancreatin was remarkably promoted as compared with the case where only pancreatin was allowed to act without adding pepsin. I have.

[0029]

[Table 1]

From these results, it is clear that digestion of ingested food by pepsin having digestive action in the stomach significantly promotes digestion by pancreatin contained in pancreatic juice, and the effect of pancreatic function is improved. It has been found that digestion of food in the stomach is important for performance.

Test Example 2 Effect of digestive enzymes on gastric ulcer
Examination Method of Digestive Enzymes [Biodiastase 2000 (amylase) and Prozyme 6 (protease): both manufactured by Amano Pharmaceutical Co., Ltd.] dissolved in water in a kissing gastric ulcer (rat chronic gastric ulcer model) prepared using acetic acid three times a day Oral administration was continued for 2 weeks, and the effect on the gastric ulcer site was compared with the control group.

The dosage of each digestive enzyme was set as follows. Biodustase 2000: 5mg / kg, 50mg / kg and 500mg / kg
kg (single dose) Prozyme 6: 5 mg / kg, 50 mg / kg and 500 mg /
kg (single dose)

FIG. 2 shows the above results. Also, 0.5% CMC
Of H ₂ blockers (ranitidine) 60 mg / kg is gastric ulcer therapeutic agents suspended in twice daily orally administered was examined combined action of the digestive enzymes. The dosage of each digestive enzyme was set as follows. Bioperastase 2000: 50 mg / kg and 500 mg / kg (single dose) Prozyme 6: 50 mg / kg and 500 mg / kg (single dose) The above results are shown in FIG.

The rats were fasted for 18 hours after the oral administration of the drug for two consecutive weeks. Thereafter, the stomach contents were collected by pylorus ligation, and the stomach was incised along the greater curvature, and the ulcer area (mm ² ) occurring on the anterior and posterior walls was measured under a microscope.

Results As is evident from FIG. 2, as a result of continuous administration of digestive enzymes (amylase agent and protease agent) for two weeks, there was no significant difference compared to the control group of acetic acid stomach ulcers, indicating that ulcers did not worsen. It became clear.

Further, as is apparent from FIG. 3, the healing effect of acetic acid ulcer was significantly observed in the case of using H ₂ blocker alone or in combination with digestive enzymes. From these results, it became clear that digestive enzymes did not become ulcer exacerbating factors.

Test Example 3 Proteolysis on amino acid absorption
Influence of Enzyme Under pentobarbital anesthesia, cannulation was performed on the portal vein and superior vena cava of 7-week-old Wister / ST male rats (Japan SLC 208.7-243.2 g). The cannulated rats were fasted individually for 24 hours until the next day. Rats were then given purified water or famotidine (0.3
3 mg / 5 ml / kg), and 30 minutes later, BSA was used as a substrate.
1.3 g / 10 ml / kg orally, and Prozyme 6 at 60 mg / 5 m
l / oral administration. The group to which famotidine was administered was administered an enzyme solution containing magnesium oxide. BSA administration5,
0.2m from portal vein and superior vena cava after 15,30,24 and 60 minutes
l Blood was collected. The blood was centrifuged at 3000 rpm for 15 minutes to obtain plasma.

An internal standard solution was added to 50 μl of plasma to make 20 ml. Amino acid analysis (NBD-F: precolumn method) was performed using a part of the sample. Each amino acid concentration was determined by subtracting each amino acid concentration of the superior vena cava from each amino acid concentration of portal vein blood. Administration group 1: Purified water + heat-inactivated prozyme 6 Administration group 2: Purified water + prozyme 6 Administration group 3: Famotidine + MgO + Heat-inactivated prozyme 6 Administration group 4: Famotidine + MgO + Prozyme 6 The results are shown in FIGS. Shown in

Results As is evident from the figure, the use of proteolytic enzymes caused the blood concentrations of various amino acids to rise with time without any effect even when the H ₂ blocker was administered. You can see that.

[0040]

EXAMPLE 1 H ₂ blocker and proteolytic enzyme
Combination (1) Method Male 7-week-old Wistar / ST rats (186.0
~ 208.5g) in purified water or cimetidine (5mg / 5ml / k
g) was administered, and 30 minutes later, 1.3 g / 10 ml / kg of bovine serum albumin (BSA) was orally administered as a substrate, and further, prozyme 6 was orally administered at 60 mg / 5 ml / kg. The group to which cimetidine was administered was administered an enzyme solution containing magnesium oxide. As a control, heat-inactivated Prozyme 6 (heated in boiling water for 20 minutes) was used. Fifteen minutes and thirty minutes after BSA administration, each was dissected under ether anesthesia, and the stomach was removed.

The stomach was incised, the contents were poured into a centrifuge tube using purified water, and 5 ml of 20% trichloroacetic acid (TCA) was added to the centrifuge tube containing the contents. 20
Centrifuge for minutes. The protein content of the TCA soluble fraction as the centrifugal supernatant was measured by the Folin method. Table 2 summarizes the results after 15 minutes and Table 3 summarizes the results after 30 minutes. The gastric digestibility was determined by the following equation. (Amount of gastric residual digest / BSA dose) x 100

[0042]

[Table 2]

[0043]

[Table 3]

In Tables 1 and 2, each administration group is as shown below. Administration group 1: purified water + heat-inactivated prozyme 6 Administration group 2: purified water + prozyme 6 Administration group 3: cimetidine + magnesium oxide + heat-inactivated prozyme 6 Administration group 4: cimetidine + magnesium oxide + prozyme 6 ** Indicates significant at 1% risk, and * indicates significant at 5% risk. The result after 15 minutes is shown in FIG. 10, and the result after 30 minutes is shown in FIG.
Shown in

Results As is evident from the figure, the administration of prozyme 6 alone significantly promoted gastric digestion at 15 minutes and 30 minutes after BSA administration as compared to the control group. When cimetidine alone was administered, gastric digestion tended to decrease or significantly decreased compared to the control group. It is considered that administration of cimetidine suppressed pepsin digestion in the stomach. On the other hand, when cimetidine and prozyme 6 were used in combination, significant promotion of gastric digestion was observed as compared with the cimetidine alone administration group, and the digestion suppressed by cimetidine was restored.

Example 2 H ₂ blocker and protease
(2) In the same manner as in Example 1, the measurement was carried out using ranitidine instead of cimetidine. Methods Male 7-week-old Wistar / ST rats (190.5 fasted for 24 hours)
Purified water or ranitidine (2.5mg / 5ml / k)
g) was administered, and 30 minutes later, 1.3 g / 10 ml / kg of bovine serum albumin (BSA) was orally administered as a substrate, and further, prozyme 6 was orally administered at 60 mg / 5 ml / kg. The group to which ranitidine was administered was administered an enzyme solution containing magnesium oxide. Fifteen minutes and thirty minutes after BSA administration, each was dissected under ether anesthesia, and the stomach was removed. The stomach is incised, the contents are poured into a centrifuge tube using purified water, and 5 ml of 20% trichloroacetic acid (TCA) is added to the centrifuge tube containing the contents, left on ice for 30 minutes, and then centrifuged at 3000 rpm for 20 minutes. did. The protein content of the TCA soluble fraction as the centrifugal supernatant was measured by the Folin method. Table 3 summarizes the results after 15 minutes and Table 5 summarizes the results after 30 minutes.

Example 3 H ₂ blocker and protease
(3) In the same manner as in Example 1, measurement was performed using famotidine instead of cimetidine. Methods Male 7-week-old Wistar / ST rats fasted for 24 hours (200.0 weeks)
Purified water or famotidine (0.33mg / 5ml)
30 minutes later, 1.3 g / 10 ml / kg of bovine serum albumin (BSA) was orally administered as a substrate, and further, prozyme 6 was orally administered at 60 mg / 5 ml / kg. The group to which famotidine was administered was administered an enzyme solution containing magnesium oxide. 15 minutes and 30 minutes after BSA administration, respectively,
The stomach was removed after dissection under Tel anesthesia. The stomach is incised, the contents are poured into a centrifuge tube using purified water, and 5 ml of 20% trichloroacetic acid (TCA) is added to the centrifuge tube containing the contents, and the mixture is placed on ice.
After standing for minutes, the mixture was centrifuged at 3000 rpm for 20 minutes. The protein content of the TCA soluble fraction as the centrifugal supernatant was measured by the Folin method. Table 4 summarizes the results after 15 minutes and Table 6 summarizes the results after 30 minutes.

[0048]

[Table 4]

[0049]

[Table 5]

[0050]

[Table 6]

[0051]

[Table 7]

In Tables 4 to 7, each administration group is as shown below. Administration group 1: Purified water + heat-inactivated prozyme 6 Administration group 2: Purified water + prozyme 6 (values of Example 1 are described) Administration group 3: Ranitidine + magnesium oxide + heat-inactivated prozyme 6 Administration group 4: Ranitidine + magnesium oxide + prozyme 6 administration group 5: famotidine + magnesium oxide + heat-inactivated prozyme 6 administration group 6: famotidine + magnesium oxide + prozyme 6 *** indicates a significance level of 0.1%, and ** indicates dangerous A rate of 1% indicates significant, and * indicates a significance of 0.1%. 15 of Example 2
The result after 30 minutes is shown in FIG. 12, and the result after 30 minutes is shown in FIG.
The result of Example 3 after 15 minutes is shown in FIG. 14, and the result after 30 minutes is shown in FIG.

Results When Ranitidine or Famotidine was used in combination with Prozyme 6, it was found that the gastric digestion suppressed by Ranitidine or Famotidine was restored by the combined use of Prozyme 6 as in Example 1.

Example 4 H ₂ blocker and complex digestive enzyme
(1) In Example 1, biodiastase 2000 was orally administered at 15 mg / 5 ml / kg instead of prozyme 6, and the TCA soluble fraction in the stomach was confirmed by the Folin method in the same manner as in Example 1 below. As a result, it was confirmed that the digestion in the stomach, which was clearly suppressed by the H ₂ blocker, was restored by the combined use of the digestive enzyme preparation.

Example 5 H ₂ blocker and complex digestive enzyme
In combination (2) Example 4, except using ranitidine as H ₂ blockers using the same method, was confirmed by Folin method for TCA soluble fraction in the stomach. As a result, it was confirmed that the digestion in the stomach, which was clearly suppressed by the H ₂ blocker, was restored by the combined use of the digestive enzyme preparation.

Example 6 H ₂ Blocker and Complex Digestive Enzyme
(3) In the same manner as in Example 4, except that famotidine was used as the H ₂ blocker, the TCA-soluble fraction in the stomach was confirmed by the Folin method. As a result, it was confirmed that the digestion in the stomach, which was clearly suppressed by the H ₂ blocker, was restored by the combined use of the digestive enzyme preparation.

Example 7 Method of Combining Use of PPI and Proteolytic Enzyme Seven-week-old male Wistar / ST rats (196.2) fasted for 24 hours
Purified water or various PPIs (omeprazole 30 mg / kg, lansoprazole 30 mg / kg, rabeprazole)
After 20 minutes, 1.3 g / 10 ml / kg of bovine serum albumin (BSA) was orally administered as a substrate, and further, prozyme 6 was orally administered at 60 mg / 5 ml / kg. As a control, heat-inactivated Prozyme 6 (heated in boiling water for 20 minutes) was used. Thirty minutes after administration of BSA, each was dissected under ether anesthesia, and the stomach was removed.

The stomach was incised, the contents were poured into a centrifuge tube using purified water, and 5 ml of 20% trichloroacetic acid (TCA) was added to the centrifuge tube containing the contents. 20
Centrifuge for minutes. The protein content of the TCA soluble fraction as the centrifugal supernatant was measured by the Folin method. The results are summarized in Tables 8 and 9. The gastric digestibility was determined by the following equation. (Amount of gastric residual digest / BSA dose) x 100

Administration group 1: purified water + heat-inactivated prozyme
6 administration group 2: purified water + prozyme 6 administration group 3: omeprazole + heat-inactivated prozyme 6 administration group 4: omeprazole + prozyme 6 administration group 5: lansoprazole + heat-inactivated prozyme 6 administration group 6: Lansoprazole + prozyme 6 administration group 7: rabeprazole + heat-inactivated prozyme 6 administration group 8: rabeprazole + prozyme 6

[0060]

[Table 8]

[0061]

[Table 9]

FIG. 16 shows the above results.

Results As is evident from the figure, administration of PPI such as omeprazole alone reduced gastric digestion as compared with the control group. It is considered that the administration of omeprazole or the like suppressed the digestion by pepsin in the stomach. On the other hand, when PPI such as omeprazole and prozyme 6 were used in combination, significant promotion of gastric digestion was observed as compared with the PPI alone administration group, and the digestion suppressed by PPI was restored.

[0064]

Effect of the Invention] According to the present invention, H ₂ blocker or PPI
It is possible to restore the suppressed digestion of food in the stomach without inhibiting the therapeutic effect of ulcer.

[Brief description of the drawings]

FIG. 1 is a diagram showing the results of Test Example 1.

[Explanation of symbols]

In the figure,-○-shows the value obtained by subtracting the amount of free tyrosine when only pepsin was used from the amount of free tyrosine when pepsin and pancreatin were used in combination.

FIG. 2 is a view showing the results of Test Example 2, and shows the results of using various digestive enzymes without affecting the ulcer site.

[Figure 3] is a graph showing the results of Test Example 2 show the results which do not affect the ulcer healing effect when used in combination with H ₂ blockers and enzyme agent.

[Explanation of symbols]

FIG. 4 is a view showing a measurement result of alanine in Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 5 is a view showing a measurement result of threonine in Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 6 is a graph showing the results of measurement of lysine in Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 7 is a view showing a valine measurement result of Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 8 is a view showing the measurement results of isoleucine in Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 9 is a view showing the measurement results of leucine in Test Example 3.

[Explanation of symbols]

In the figure, open circles indicate the results of administration group 1, black circles indicate the results of administration group 2,
The open squares indicate the results of the administration group 3, and the closed squares indicate the results of the administration group 4.

FIG. 10 is a view showing a result of Example 1 after 15 minutes.

FIG. 11 is a view showing a result after 30 minutes of Example 1.

FIG. 12 is a view showing a result of Example 2 after 15 minutes.

FIG. 13 is a view showing a result after 30 minutes of Example 2.

FIG. 14 is a view showing a result of Example 3 after 15 minutes.

FIG. 15 is a view showing a result of Example 3 after 30 minutes.

FIG. 16 is a diagram showing the results of Example 7.

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[Procedure amendment]

[Submission date] October 13, 1998

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0037

[Correction method] Change

[Correction contents]

Test Example 3 Proteolysis on amino acid absorption
Influence method of enzyme 7 weeks old Wister / ST under pentobarbital anesthesia
Male rats (Japan SLC 208.7-24
3.2 g) of the portal vein and superior vena cava were cannulated. The cannulated rats were fasted individually for 24 hours until the next day. Thereafter, rats were administered purified water or famotidine (0.33 mg / 5 ml / kg), and 30 minutes later, 1.3 g / BSA was used as a substrate.
Oral administration of 10 ml / kg and prozyme 6 for 60 m
g / 5 ml / oral administration. The group to which famotidine was administered was administered an enzyme solution containing magnesium oxide. B
At 5, 15, 30, 45 and 60 minutes after SA administration, 0.2 ml of blood was collected from the portal vein and superior vena cava, respectively. The blood was centrifuged at 3000 rpm for 15 minutes to obtain plasma.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0044

[Correction method] Change

[Correction contents]

In Tables 2 and 3, each administration group is as shown below. Administration group 1: purified water + heat-inactivated prozyme 6 Administration group 2: purified water + prozyme 6 Administration group 3: cimetidine + magnesium oxide + heat-inactivated prozyme 6 Administration group 4: cimetidine + magnesium oxide + prozyme 6 ** Indicates significant at 1% risk, and * indicates significant at 5% risk. The result after 15 minutes is shown in FIG. 10, and the result after 30 minutes is shown in FIG.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0046

[Correction method] Change

[Correction contents]

[0046] Example 2 _{H 2} blocker and proteolytic enzyme
(2) In the same manner as in Example 1, the measurement was carried out using ranitidine instead of cimetidine. Method: A 7-week-old Wistar / ST male rat (190.5-207.5 g) fasted for 24 hours was administered purified water or ranitidine (2.5 mg / 5 ml / kg).
After 0 minutes, bovine serum albumin (BSA) was used as a substrate.
3 g / 10 ml / kg was orally administered, and further, prozyme 6 was orally administered at 60 mg / 5 ml / kg. The group to which ranitidine was administered was administered an enzyme solution containing magnesium oxide. Fifteen and thirty minutes after BSA administration, each was dissected under ether anesthesia, and the stomach was removed. The stomach is incised, the contents are poured into a centrifuge tube using purified water, and 5 ml of 20% trichloroacetic acid (TCA) is poured into the centrifuge tube containing the contents.
And leave it on ice for 30 minutes, 3000 rpm, 20
Centrifuge for minutes. The protein content of the TCA soluble fraction as the centrifugal supernatant was measured by the Folin method. Tables 4 and 5 show the results after 15 minutes, and Tables 6 and 7 show the results after 30 minutes.
Summarized in

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0052

[Correction method] Change

[Correction contents]

In Tables 4 to 7, each administration group is as shown below. Administration group 1: Purified water + heat-inactivated prozyme 6 Administration group 2: Purified water + prozyme 6 (values of Example 1 are described) Administration group 3: Ranitidine + magnesium oxide + heat-inactivated prozyme 6 Administration group 4: Ranitidine + magnesium oxide + prozyme 6 administration group 5: famotidine + magnesium oxide + heat-inactivated prosime 6 administration group 6: famotidine + magnesium oxide + prozyme 6 *** indicates a significance level of 0.1%, ** Is the risk factor 1
% Indicates significance, and * indicates significance at a risk rate of 5%. FIG. 12 shows the results after 15 minutes of Example 2, and FIG. 1 shows the results after 30 minutes.
3 and the results after 15 minutes of Example 3 are shown in FIG.
The results after minutes are shown in FIG.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/415 606 A61K 31/415 606 31/425 601 31/425 601 31/44 613 31/44 613 38/43 45/06 38/46 37/48 45/06 37/54

Claims (6)

[Claims] 1. A pharmaceutical product comprising a combination of at least a histamine H ₂ receptor antagonist and / or a proton pump inhibitor and a digestive enzyme. 2. A medicament comprising a combination of at least a histamine H ₂ receptor antagonist and / or a proton pump inhibitor and a digestive enzyme. 3. The pharmaceutical product according to claim 1, wherein the digestive enzyme is an enzyme that acts at the pH of the stomach. 4. The pharmaceutical according to claim 1, wherein the histamine H ₂ receptor antagonist is at least one selected from cimetidine, ranitidine and famotidine. 5. The method according to claim 5, wherein the proton pump inhibitor is omeprazole,
4. The pharmaceutical product according to claim 1, which is at least one selected from lansoprazole and rabeprazole. 6. The pharmaceutical according to claim 1, wherein the digestive enzyme is a complex digestive enzyme or a proteolytic enzyme.