JP2005239737A - Method for producing new pharmaceutical composition for ameliorating quality of life and use of the composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a medicinal composition passing through, without being decomposed, the stomach causing decomposition therein and first dissolved in the duodenum when orally administering a bioactive protein as an active ingredient to improve clinical conditions and to promote health. <P>SOLUTION: The method for producing an enteric coated preparation comprises covering the surface layer of powder, granule or tablet containing, as an active ingredient, one or more selected from bioactive proteins such as enzyme, lactoferrin, immunoglobulin, lysozyme, amylase inhibitor of protein, protease inhibitor of protein, and the like, with an enteric coating film using a material selected, as a raw material of the covering coating film, from zein, shellac, hydroxymethylcellulose-phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylate copolymer, water-insoluble ethyl cellulose, and aminoalkylmethacrylate copolymer. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for effectively exerting physiological activity when a protein exhibiting physiological activity is orally administered. That is, the present invention has an enteric property in which an orally administered protein exhibiting physiological activity passes through the stomach without being inactivated, and reaches the lower gastrointestinal tract from the duodenum, which is the site of action, without losing the physiological activity. It relates to a pharmaceutical composition. Furthermore, the present invention relates to a disease that such a medicine can newly be treated / prevented. The method of the present invention is very effective for exerting the action because the bioactive protein reaches the action site without being decomposed.

  The small intestinal mucosa that controls the digestion and absorption of food is a structure in which the wall surface is filled with fine protrusions, and each protrusion is covered with the finer protrusions, thereby significantly increasing the surface area. According to one theory, the surface area of the human gastrointestinal tract is said to be one and a half of a tennis court, and the majority of the area is occupied by the small intestine. The lumen of the intestinal tract is the outside world for living organisms, and intestinal bacteria said to be inhabited by 150 trillion. It is in contact with the outside world in such a large area, but it is only a very thin mucosal layer that partitions the outside world. This thin mucosal layer is thought to respond to various stimuli applied from the outside, but what kind of stimulant reacts with the mucosa and how it reacts, the site on the mucous membrane that receives the stimulus is I don't know the specific details such as where it is, and the mysteries are exhausted. In any case, it is certain that the gastrointestinal mucosa plays an extremely important function for the living body.

  A good example of how the intestinal mucosa is responsive to stimulation is as a mucosal barrier that protects against the invasion of enteric bacteria. In other words, as long as the animal is healthy, intestinal bacteria rarely invade across the barrier, but when stressed during surgery, trauma, burns, or death, the intestinal bacteria immediately cross the mucosal layer and enter the body. Begin to invade into. That is, in a healthy state, some defense device that prevents intestinal bacteria that constantly invades should be operating. In addition to intestinal bacteria, viruses, food poisons, and the like may stimulate the intestinal mucosa. A large area of the intestinal mucosa should have a sensor that receives the stimulus and a reactor that reacts based on the sensor's information, but little is known about what sensor is working. For example, lactoferrin is known to have a receptor in the intestinal mucosa, but it is not known at all what kind of reaction occurs when bound to the receptor.

  The stomach secretes hydrochloric acid, and the inside is kept highly acidic with a pH of 1.0 to 3.0. The fact that the stomach is maintained in a strong acidity is very effective for sterilizing contaminated pathogens when ingesting food or drinking water contaminated with pathogenic bacteria. Furthermore, gastric juice contains an acidic protease, pepsin, which has an optimum pH for acidity, and hydrolyzes proteins into peptides. Most pathogens that contaminate food may be thought to die by exposure to pepsin action under strongly acidic conditions. In other words, the stomach is the first barrier to fight off the invasion of pathogenic bacteria. Unfortunately, digestion in the stomach is the biggest barrier when a protein that exhibits physiological activity is taken orally and the effect is expected. This is because the bioactive protein that has flowed into the stomach loses its folded three-dimensional structure under strongly acidic conditions and is hydrolyzed into peptides by pepsin. In such a state, it may be considered that the physiological activity of the protein is completely lost.

  Hydrolytic enzymes such as lactose degrading enzyme, amylase, protease or lipase are orally administered to assist in digestion and absorption of food. However, it is doubtful whether these hydrolases really hydrolyze food in the human body and help digestion and absorption. This is because when these digestive enzymes are dissolved in artificial gastric fluid having a pH of 1.2 containing 50 μg / ml of pepsin at a concentration of 1% and incubated at 37 ° C. for 1.5 hours, the enzyme activity is completely lost. Since the time during which food stays in the stomach can be estimated to be approximately 1.5 to 2.0 hours, it is clear that the effect of improving the pathological condition cannot be expected even by taking hydrolase.

  In addition, physiologically active proteins such as cerathiopeptidase exhibiting anti-inflammatory action and elastase said to lower serum cholesterol are also orally administered to patients as drugs. It is clear that when these bioactive proteins are dissolved in the stomach, they are degraded and deactivated in the same manner as the hydrolase.

  Egg white lysozyme is a popular ingredient that is added as one of the active ingredients in most common cold medicines and is also a classic cold medicine. Lysozyme is considered to be a bactericidal enzyme because it is contained in secretions that coat mucous membranes such as tears, saliva, and digestive juice, and has an enzymatic activity to hydrolyze muramyl peptides that constitute the cell walls of bacteria. However, strangely, it is said that when administered orally to a cold patient, it exerts an analgesic / anti-inflammatory action against acute inflammation such as sore throat. Naturally, a receptor that binds to lysozyme is present on the mucosal surface, and when lysozyme binds, a mechanism of releasing an opioid that is an in vivo narcotic is estimated, but this has not been experimentally proven. In addition to its analgesic and anti-inflammatory action, it does not show any toxicity to mammals, so that it can be added with peace of mind as a common cause of the active ingredient of cold medicine. The place where lysozyme exerts an analgesic / anti-inflammatory effect is considered to be the small intestine, which occupies most of the mucosal area. Again, if the cold medicine tablet disintegrates in the stomach, lysozyme cannot escape the hydrolytic action of pepsin. It is estimated that very little lysozyme escapes hydrolysis by pepsin and flows into the small intestine.

  In addition, relatively large proteins such as immunoglobulins and lactoferrin are also actively consumed as foods to promote health. The former is commended as having dairy cows immunized with a plurality of bacterial antigens, lactating antibodies (IgG1) against bacterial antigens into milk, and defatted defatted immune milk powder being useful for health promotion. However, immunoglobulin IgG1 in milk is sensitive to pepsin and is largely degraded when it passes through the stomach, so it is questionable whether a health promoting effect can be expected.

  Milk produced by dairy cows within one week of delivery is prohibited from milking as colostrum. Colostrum is qualitatively different from regular milk produced by dairy cows after one week of delivery, and contains a large amount of immunoglobulin IgG1, so that it is solidified in a tofu-like form when pasteurized or instantly sterilized at high temperatures, and cannot be sterilized. Degreased colostrum powder, which has been degreased and spray dried at low temperatures to avoid immunoglobulin deactivation, is also beginning to gain popularity in some countries as a health promotion ingredient. For example, in the United States, defatted colostrum powder is sold as a health food that complains about the effect of improving arthritis and hypertension. Again, as with immunized milk, most immunoglobulins are broken down in the stomach.

  In recent years, milk-derived lactoferrin has also been reported as a cancer prevention effect for colorectal cancer, and is attracting attention as a material for preventing carcinogenesis. Furthermore, research results have reported that when hepatitis C patients are orally administered large amounts of lactoferrin in milk, the condition is improved in mild patients with low viral virus titers. Eighty percent of patients with hepatitis C will die from liver cirrhosis and liver cancer, and if this research is confirmed in other medical facilities, it will be a great gospel for the patients. On the other hand, a high dose of 3.6 g per day is an obstacle to the practical use. When the dose is reduced and 1.8 g per day, no significant improvement in the pathological condition has been observed. Even in this case, it is certain that most of the orally administered lactoferrin is hydrolyzed in the stomach. A clinical trial was conducted with a formulation that released lactoferrin only after flowing into the duodenum without being hydrolyzed in the stomach, and at the same time, the dosage was reduced, and at the same time, the formulation was improved so that it could be improved in patients with severe hepatitis C Should be planned.

The total surface area of the gastrointestinal tract is 1.5 worth of tennis courts, but the surface area of the stomach is only slightly 900cm ^2. Moreover, no absorption of nutrients and drugs occurs in the stomach, and it has not been reported that physiologically active proteins such as lysozyme, immunoglobulin or lactoferrin improve the pathological condition by binding to the stomach wall. Furthermore, since the stomach wall is covered with a thick mucus layer, it is hopeless that these bioactive proteins pass through the mucus layer and bind to the mucosa before being hydrolyzed by pepsin. When ingesting a protein with physiological activity orally and exerting its medicinal effects, the biggest obstacle is degradation and inactivation in the stomach, and without solving it, the practical use of the physiologically active protein as a drug or food for the purpose of promoting health There is no possibility.

  For many years, the present inventors have conducted research on oral administration of enzymes, protein enzyme inhibitors and bioactive proteins for the improvement of pathological conditions and health promotion. Although there are exceptions such as lysine, protein is generally safe and can be an ideal therapeutic drug if it is effective by oral administration. The subject of study is mainly lactoferrin and immunoglobulin. Lactoferrin is a polymer with a molecular weight of about 80,000, but when it comes into contact with the mucous membrane, it seems to cause changes in the body. One is to increase the ability to defend against infection with pathogenic bacteria, and the other is analgesic action like opioids. In view of these effects, it seems that there is a structure on the mucosa that should be named the lactoferrin sensor, but little is known about its details.

  However, when these proteins are orally administered to experimental animals to observe the expression of physiological activity, the effects may or may not appear even if the same amount is administered to animals under the same conditions, and reproducibility is extremely poor. For example, in an experimental system in which 5-fluorouracil (5-FU) is orally administered to BALB / c mice at 50 mg / kg, bacteremia is induced from bacterial translocation (BT), and mice die due to multiple organ failure. Oral administration of lactoferrin derived from milk one day before and at the same time as FU administration can block BT in some cases and allow mice to survive. In addition, this BT inhibitory action was expressed with a statistically highly significant difference only by administering lactoferrin at a small dose of 2 mg / kg once. If BT caused by administration of anticancer drugs in mice can be suppressed by oral administration of 2 mg / kg, human BT caused by surgery, cancer, stress, etc. can be suppressed, and multiple organs caused by systemic inflammatory response syndrome from infection It can prevent failure and have a great impact on medical care.

  On the other hand, even if 100 mg / kg is orally administered under exactly the same conditions, it may not be expressed. This expression is true with a note. The reason for this is that the present inventors simply thought that the conditions were exactly the same, and because the conditions were actually different, the same phenomenon did not appear. When we investigated the cause of the poor reproducibility of the BT inhibitory effect of lactoferrin, we came to the degradation of lactoferrin in the digestive tract. In other words, the conclusion is that a bioactive protein exerts its physiological action only when its structure is completely retained and reaches the site of action, and it cannot be broken down before reaching the site of action. I was able to.

  That is, when a physiologically active protein such as lactoferrin is orally administered, most of it is partially degraded and loses its action when passing through the stomach. If these physiologically active proteins are administered orally by chance, they may act by chance, and only a small amount escapes degradation when passing through the stomach and flows into the duodenum. Therefore, the present inventors have sought a method for dissolving a physiologically active protein only when it is orally administered for improving a disease state and promoting health, passing through the stomach that causes degradation without breaking down, and flowing into the duodenum. Study was carried out.

  In conventional preparations, orally administered lactoferrin is only temporarily brought into contact with the mucous membrane of the oral cavity and esophagus, and when it flows into the stomach, it is considered to be decomposed into a polypeptide by pepsin and lose its efficacy. This high sensitivity to acidic proteases has prevented widespread application of lactoferrin. Lactoferrin is a minor component in milk and is relatively expensive. The greatest weakness was that it was sensitive to acidic proteases such as pepsin and papain and was easily hydrolyzed. However, it was found to be extremely resistant to other proteases and hardly decompose when left in the stool for 1 week (see Example 4 herein). Therefore, if it can pass through the stomach without being decomposed and flow into the duodenum, it is presumed that a small amount of oral administration can improve the pathological condition and promote health, and the present invention has been completed.

  That is, the present invention provides a release control means for containing one or more proteins having physiological activity as an active ingredient, and releasing a certain amount or more of the active ingredient into the lower gastrointestinal tract while maintaining the activity with almost no degradation. An oral formulation is provided.

  In the present specification, the term “oral preparation” may be any form of pharmaceuticals and pharmaceutical preparations to be taken orally. In addition, the composition of the present invention may be in the form of food and / or include food. The preparation of the present invention can be variously formed into tablets, capsules, pills, granules, and powders. Food includes functional foods, health foods and dietary supplements.

  The formulation of the present invention needs to have a controlled release means. The controlled release means herein means that at least 10% or more, preferably 20% or more, more preferably 50% or more, and further preferably 80% or more of the active ingredients in the preparation are irreversibly deactivated in the gastrointestinal tract. In order to reach the lower gastrointestinal tract (duodenum, small intestine) while maintaining activity (eg, the active ingredient is not released or dissolved in the gastrointestinal tract and is therefore not denatured and / or degraded) Means.

  As the release control means for the preparation of the present invention, various conventional techniques for drug release control can be applied. In such a method, for example, the mother nucleus containing the active ingredient is coated with an enteric coating or a coating made of a hydrophobic substance having an appropriate thickness, and the active ingredient is supported on a matrix under a predetermined environment. Allowing the active ingredient to be released.

  The present invention can be applied to any proteinaceous active ingredient that can be denatured and / or degraded in the gastrointestinal tract and deactivated. Such active ingredients include acidic proteases, ie proteins with physiological activity that are inactivated by pepsin and papain. More specifically, basic proteins such as lactoferrin and lysozyme that exhibit immunostimulatory and analgesic anti-inflammatory effects, immunoglobulins that inhibit the growth of pathogens, hydrolases to help digest and absorb food in the small intestine, and their hydrolysis Proteinaceous or peptidic inhibitors that inhibit the activity of the enzyme are included. Examples of hydrolases that help digest and absorb food include various proteases, amylases, and lipases. A particularly preferred active ingredient is lactoferrin. Lactoferrin can provide an immediate therapeutic effect for various diseases that have been difficult to treat (see the therapeutic effect section in the Examples herein).

  The present invention also relates to systemic inflammatory response syndrome; inflammatory bowel disease; lifestyle diseases including obesity, diabetes or hypertension; malignant tumors: pathogenic viruses including hepatitis C virus, rotavirus, herpes virus or cytomegalovirus For the treatment of autoimmune diseases and / or for the treatment or amelioration of various symptoms associated with these diseases or conditions that reduce the quality of life of the patient Can be applied.

  Systemic inflammatory response syndrome is a widespread inflammation in patients with a wide variety of diseases, including infection, pancreatitis, ischemia, multiple trauma, hemorrhagic shock, immune-mediated organ damage, and sepsis, and systemic inflammatory response Includes complications that often occur in the syndrome (acute lung injury; shock; renal failure; and multiple organ failure syndrome and the occurrence of organ system dysfunction). Inflammatory bowel disease includes Crohn's disease and ulcerative colitis.

  One embodiment of the present invention is a preparation in which the surface of a lactoferrin granule or tablet is coated with an enteric film that does not dissolve in the stomach but dissolves in the intestine. More specifically, it is as follows.

  Milk-derived lactoferrin lyophilized powder has a very low bulk specific gravity and is difficult to be directly compressed into tablets. Moreover, since it is unstable at moisture and high temperature, it is desirable to formulate it in a dry state. Therefore, lactoferrin is mixed with excipients, binders, and disintegrants, and the mixture is pressure-molded with a slag machine to form a thin large flat disk, which is crushed and sieved to prepare granules of a certain size. The granules can be covered with an enteric coating, and a certain amount can be filled into hard capsules to produce a product. In the case of commercialization as a tablet, a lubricant can be added to the granule for tableting, and the tablet can be covered with an enteric coating to produce a product.

  The lactoferrin enteric tablets and enteric granules thus prepared were dissolved in 2.0 g of sodium chloride by adding 24 ml of dilute hydrochloric acid and water to make 1000 ml of the first solution (pH 1.2), and 0.2 M phosphoric acid. Disintegration property was tested using 250 ml of potassium dihydrogen reagent solution (118 ml) and 0.2 ml of sodium hydroxide solution (water) (pH 6.8) to make 1000 ml (Japan Pharmacopoeia (9th revision), General Test Method) 41; or Japanese Pharmacopoeia (13 revisions) General Test Method 47, Disintegration Test Method, (6) Enteric preparations). The tablet or granule produced by the method of the present invention does not disintegrate when immersed in the first liquid for 120 minutes, and disintegrates when immersed in the second liquid for 60 minutes. That is, it is possible to complete a preparation in which lactoferrin is eluted by disintegration only after flowing into the duodenum without disintegrating and dissolving in the stomach.

  Excipients used in producing the enteric preparation of the present invention include monosaccharides or disaccharides such as lactose, sucrose and glucose, starches such as corn starch and potato starch, crystalline cellulose, light silica gel as inorganic substances, There are synthetic aluminum silicate, magnesium metasilicate aluminate, calcium hydrogenphosphate, and the like. Examples of the binder include starches, carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose-sodium salt, and polyvinylpyrrolidone. Examples of disintegrants used for the purpose of disintegrating them into primary particles in the lower gastrointestinal tract include starch, carboxymethylcellulose-sodium salt, carboxymethylcellulose-calcium salt, croscarmellose sodium, and carboxymethyl starch sodium. . As a coating agent for enteric coating of tablets and granules, it dissolves in hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer, zein, and alkaline regions that dissolve at pH 5-6. There is shellac.

  The preparation of the present invention generally contains about 0.1 mg to about 100,000 mg, preferably about 1 mg to about 50,000 mg, more preferably about 10 mg to about 10,000 mg once a day as an active ingredient. Or in divided portions can be administered to patients in need of treatment or improvement of condition with the formulations of the invention. The dosage can be individually determined according to the age, weight and purpose of administration of the patient to be administered.

<Example 1 (Experiment using pyloric ligation rat; Part 1)>
Six male Wistar rats, fasted overnight, weighed approximately 300 grams under ether anesthesia, a small incision was made in the abdomen at the top of the pylorus, and the joint between the pylorus and duodenum was lightly ligated with a surgical thread to prevent the stomach contents from flowing into the duodenum. Then the incision was sutured quickly. One hour after the rat awakened from anesthesia, lactoferrin extracted from milk and immunoglobulin (manufactured by Tatsua Milk Biologics Co., Ltd., about 90% and 75% respectively) were dissolved in 5 ml of distilled water and orally administered. did. Rats were sacrificed two by 15 minutes, 30 minutes and 1 hour after lactoferrin administration, and the stomach contents were washed into a 300 ml beaker, and the stomach wall was thoroughly washed with physiological saline. The stomach contents and the washing solution were combined, and the amount of the solution was accurately 200 ml to prepare a test solution. Lactoferrin and immunoglobulin IgG1 dissolved in the test solution were quantified by high performance liquid chromatography.

  As a result, as shown in the table, the remaining lactoferrin was 4.6% at 15 minutes after administration, no trace at 30 minutes, and 0 at 60 minutes.

<Example 2 (Experiment using pyloric ligation rat; Part 2)>
A small portion of the abdomen corresponding to the upper part of the pylorus was incised under ether anesthesia in 6 Wistar male rats weighing about 250 grams fasted overnight. The joint of the pylorus and duodenum was lightly ligated with a surgical thread, and the incision was quickly sutured. Rats awakened from anesthesia and lactoferrin extracted from milk 1 hour later and immunoglobulin IgG1 (manufactured by Tatsua Milk Biologics) 100 mg and 5 mg of pepstatin (pepsin inhibitor) dissolved in 5 ml of physiological saline were orally administered. did. Rats were sacrificed two by 15 minutes, 30 minutes, and 1 hour after lactoferrin administration, and the stomach contents were washed out as described in Example 1 to make the volume exactly 200 ml. Quantified by atography.

  As shown in the table, the remaining lactoferrin was 53% at 15 minutes after administration, 23% at 30 minutes, and 10% at 60 minutes. Compared with Example 1, the residual amount of lactoferrin is clearly large, and it is clear that pepsin is involved in its degradation in the stomach.

<Example 3>
A small incision was made in the abdomen of 6 Wistar male rats weighing approximately 300 grams, which received food and water ad libitum, under ether anesthesia, and the ileum was ligated between the pylorus and the upper cecum to create a small intestine loop. Next, 100 mg each of milk lactoferrin and immunoglobulin IgG1 (manufactured by Tatsua Milk Biologics, purity of about 90%) was dissolved in 5 ml of physiological saline and injected into the small intestine loop using a syringe. The abdominal incision is quickly sutured, and then the rat is returned to the cage. After 30, 60 and 120 minutes, the loop is removed, the contents are transferred to a beaker, the intestinal wall is washed with physiological saline, and the contents are combined. This was used as a test solution. The lactoferrin contained in the test solution was quantified by high performance liquid chromatography, and the values shown in the table were obtained.

  As can be seen from Table 3, lactoferrin is not degraded at all in the small intestine. However, immunoglobulin IgG1 is gradually degraded with a half-life of about 30 minutes.

<Example 4>
10 g of fresh stool from male Wistar rats was added to 50 ml of distilled water and homogenized using a Polytron homogenizer. 100 mg of milk-derived lactoferrin and immunoglobulin IgG1 were added to 10 ml of homogenate, dissolved, incubated in a nitrogen-substituted anaerobic jar at 37 ° C. for 24, 72 and 168 hours, and then dissolved lactoferrin and immunoglobulin were analyzed by high performance liquid chromatography. It was measured.

  As shown in Table 4, lactoferrin was hardly degraded even after 1 week of incubation with stool, but immunoglobulin disappeared completely after 72 hours of incubation. Thus, it can be seen that immunoglobulin IgG1 is hydrolyzed by enterobacteria, whereas lactoferrin is extremely resistant to proteases produced by enterobacteria.

<Example 5>
Enteric hard capsule of Japanese Pharmacopoeia No. 1 produced by molding and processing hydroxyalkyl cellulose (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) that does not dissolve at acidity of pH 3.0 or less but dissolves at neutral to weak alkalinity. 150 mg of a mixed powder of 10 parts of lactoferrin and 5 parts of carboxymethylcellulose calcium was filled, and the fitting part was sealed with an enteric base material to produce an enteric lactoferrin-hard capsule preparation.

<Example 6>
10 parts of bovine defatted colostrum containing 8% of immunoglobulin is mixed with 10 parts of microcrystalline cellulose, 150 mg is filled into the hard capsule of Example 5, the fitting part is sealed with an enteric base material, and enteric defatted initially A milk formulation was produced.

<Example 7>
After forming a jacket by a flat plate method using a 0.7 mm thick membrane prepared by adding water to 10 parts of gelatin and 20 parts of ribonucleic acid and heating and dissolving 10 mg of a tablet containing 50 mg of lactoferrin And dried to produce an enteric preparation.

<Example 8>
A tablet with a diameter of 8 mm and a weight of 180 mg containing 50 mg of lactoferrin is placed in a coating machine (Freund Sangyo Co., Ltd., High Coater HCT-48N), 9% carboxymethyl ethyl cellulose, 1% glycerin fatty acid ester, 45% ethanol, chloride An enteric coating solution consisting of 45% methylene was sprayed, and an enteric coating was applied at a weight ratio of 12% to the tablet to give a product.

<Example 9>
One tablet containing 50 mg lactoferrin in a diameter of 8 mm and a weight of 180 mg is placed in a coating machine (HC-MINI, manufactured by Freund Sangyo Co., Ltd.), and protein obtained from corn kernels, 8 parts of zein and 2 parts of glycerin are 70 parts. A solution dissolved in 150 parts of% ethanol was sprayed in a calculated amount to obtain a tablet coated with 10% by weight of the tablet.

<Example 10>
A tablet containing 50 mg lactoferrin in a tablet and having a diameter of 8 mm and a weight of 180 mg is put into a coating machine (Freund Sangyo Co., Ltd., NHC-60N), and 30 parts of shellac and 7 parts of castor oil are dissolved in 63 parts of isopropanol. A calculated amount was sprayed to produce a tablet with 10% coating on the tablet weight ratio.

<Therapeutic effect>
The effect of the enteric preparation produced in this way is surprising. For example, lactoferrin enteric preparations have shown immediate therapeutic effects on various diseases that have been difficult to treat.

  (1) When hepatitis C is infected through blood transfusion, acute hepatitis develops, then chronic hepatitis shifts to cirrhosis, and eventually liver cancer develops and the patient dies. It is said that the rate of hepatitis C patients developing liver cancer is high, reaching about 80%. It is believed that the effect of treating and treating intestinal solvent of lactoferrin (produced in Example 8 or 9 above) in hospitalized patients with advanced hepatitis C, developing liver cancer and collecting ascites It was so dramatic. That is, just taking 0.9 g of lactoferrin per day, ascites was absorbed and disappeared after 3 days, and jaundice was improved and blood markers of hepatitis C virus were greatly reduced. The patient, who was sentenced to life expectancy by the attending physician, was able to leave the hospital on foot one week after starting internal use.

  (2) In addition, a doctor who developed malignant lymphoma had suppressed cancer by chemotherapy, but suffered from frequent side effects, resulting in sleep and waking up. In order to get out of this state, various drugs were tried, but they were not effective, and they reached out to some folk remedies, but there was no improvement in symptoms. However, appetite began to appear 2 days after taking the lactoferrin enteric-coated tablets (0.45 g per day as lactoferrin) produced in Example 8 or 9 above, and after 3 days the clinical laboratory test values were Was surprisingly improved. The patient was suffering from dullness, vomiting, frequent infections, decreased appetite, and a very poor quality of life. Therefore, it was clear that the quality of life was improved by taking lactoferrin enteric-coated tablets.

  (3) After surgery for gastric cancer, lactoferrin enteric-coated tablets were taken in patients who had recurrent cancerous ascites. In this case, ascites was removed several times to reduce pain. However, ascites completely absorbed and disappeared one week after starting to take the lactoferrin enteric tablet produced in Example 8 or 9 (0.45 g per day as lactoferrin). This patient had a slight fever and had a typical systemic inflammatory response syndrome (SIRS), with 95 pulses per minute and 23 breaths per minute. One week after the start of taking tablets, these symptoms disappeared and appetite recovered.

  (4) Enteric lactoferrin tablets (as lactoferrin produced in Example 8 or 9 above) were given to female patients who had been suffering from atopic dermatitis for 13 years and had difficulty sleeping at night due to generalized pruritus. 0.45 g per day) was administered. The skin rash due to atopic dermatitis began to be relieved 2 days after the oral administration, and at the same time, it was released from pruritus and became able to sleep well. In other words, lactoferrin has an effect of releasing patients from stress caused by autoimmune diseases. In addition, when lactoferrin enteric-coated tablets were orally administered to patients whose saliva secretion decreased due to Sjogren's syndrome, the saliva pH increased and the secretion amount increased simultaneously, and the dryness of the oral cavity was greatly improved. Therefore, lactoferrin has the effect of clearly improving the quality of life associated with autoimmune diseases.

  (5) As described above, certain proteins exhibiting physiological activity often have a place where the action is exerted in the digestive tract below the duodenum. In this specification, lactoferrin has been mainly explained, but if it passes through the stomach without change and dissolves only after flowing into the small intestine, it may exert an unknown action or significantly reduce the dose. Lactoferrin is not the only bioactive protein that can be produced. Immunoglobulins and lysozyme are proteins that exhibit an effect similar to lactoferrin when formulated into enteric preparations. In addition, amylase, protease, and lipase that are orally administered to assist in digestion and absorption of food need to be made into an enteric preparation because the place where the action is exerted is the small intestine. Furthermore, it should be noted that obesity, which is common in modern humans, can be prevented by administering a digestive enzyme inhibitor secreted from the living body after meals, since the absorption of nutrients is reduced. It is known that certain proteins derived from plants inhibit digestive enzymes secreted by living organisms, and when amylase, lipase, protease inhibitors are entericized and administered orally after meals, obesity is prevented, type II Clearly improve lifestyle-related diseases such as diabetes, hypertension and arteriosclerosis. Therefore, the present invention is not limited to lactoferrin and can be applied to proteins exhibiting a wide range of physiological activities.

Claims (18)

  Proteins exhibiting physiological activity, such as enzymes, lactoferrin, immunoglobulins, lysozyme, protein amylase inhibitors, protein lipase inhibitors, protein protease inhibitors, etc., or one or more active ingredients As a raw material for coating the surface layer of powder, granules or tablets contained as zein, shellac, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, ethylcellulose insoluble in water A method for producing an enteric preparation, comprising coating with an enteric film using a raw material selected from aminoalkyl methacrylate copolymers.   Proteins exhibiting physiological activity, such as enzymes, lactoferrin, immunoglobulins, lysozyme, protein amylase inhibitors, protein lipase inhibitors, protein protease inhibitors, etc., or one or more active ingredients As a raw material selected from zein, shellac, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, phthalate acetate cellulose, methacrylic acid copolymer, water-insoluble ethylcellulose, aminoalkyl methacrylate copolymer A method for producing an enteric preparation, which comprises filling an enteric capsule.   3. The systemic inflammatory response syndrome according to claim 1, wherein the disease capable of improving the quality of life by reaching the lower digestive tract without inactivating the bioactive protein in the stomach is a systemic inflammatory response syndrome Manufacturing method of enteric preparation.   The intestine according to claim 1 or 2, wherein the disease capable of improving the quality of life by reaching the lower gastrointestinal tract without inactivating the bioactive protein in the stomach is an inflammatory bowel disease. A method for producing soluble preparations.   The disease capable of improving the quality of life by reaching the lower gastrointestinal tract without inactivating the bioactive protein in the stomach is a lifestyle-related disease such as obesity, diabetes, hypertension and the like. Or a method for producing an enteric preparation described in 2.   The enteric preparation according to claim 1 or 2, wherein the disease capable of improving the quality of life by reaching the lower gastrointestinal tract without inactivating the bioactive protein in the stomach is a malignant tumor. Manufacturing method.   The disease that can improve the quality of life by reaching the lower digestive tract without inactivating the bioactive protein in the stomach is a pathogenic virus infection such as rotavirus, herpes, cytomegalo, etc. Item 3. A method for producing an enteric preparation according to Item 1 or 2.   3. The disease according to claim 1 or 2, wherein the disease capable of improving the quality of life by reaching the lower gastrointestinal tract without inactivating the bioactive protein in the stomach is an infection caused by a pathogenic microorganism. Manufacturing method of enteric preparation.   The intestine according to claim 1 or 2, wherein the disease capable of improving the quality of life by reaching the lower gastrointestinal tract without inactivating the bioactive protein in the stomach is an autoimmune disease. A method for producing soluble preparations.   An enteric preparation obtained by the production method according to claim 1 or 2.   The enteric preparation according to claim 10, wherein the active ingredient is lactoferrin.   An oral preparation comprising, as an active ingredient, one or more proteins having a physiological activity selected from the group consisting of an enzyme, lactoferrin, immunoglobulin, lysozyme, amylase inhibitor, lipase inhibitor, and protease inhibitor, and a controlled release means And at least 10% or more of the active ingredient is released into the lower gastrointestinal tract while maintaining the activity.   The oral formulation according to claim 12, wherein the active ingredient is lactoferrin.   Systemic inflammatory response syndrome; inflammatory bowel disease; lifestyle-related diseases including obesity, diabetes or hypertension; malignant tumors; infections caused by pathogenic viruses including hepatitis C virus, rotavirus, herpesvirus or cytomegalovirus; pathogenicity 14. An oral formulation according to claim 12 or 13 for the treatment or amelioration of microbial infections; and autoimmune diseases; and / or symptoms associated with these diseases or conditions.   An oral preparation comprising, as an active ingredient, one or more proteins having a physiological activity selected from the group consisting of an enzyme, lactoferrin, immunoglobulin, lysozyme, amylase inhibitor, lipase inhibitor, and protease inhibitor, and a controlled release means And the release control means comprises an enteric coating.   The oral preparation according to claim 15, wherein the active ingredient is lactoferrin.   Systemic inflammatory response syndrome; inflammatory bowel disease; lifestyle-related diseases including obesity, diabetes or hypertension; malignant tumors; infections caused by pathogenic viruses including hepatitis C virus, rotavirus, herpesvirus or cytomegalovirus; pathogenicity 17. An oral formulation according to claim 15 or 16 for the treatment or amelioration of microbial infections; and autoimmune diseases; and / or symptoms associated with these diseases or conditions.   An enteric coating comprises a base selected from the group consisting of shellac, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, water-insoluble ethylcellulose and aminoalkyl methacrylate copolymer. The oral formulation of any one of Claims 15-17 containing.