JP2003137809A - Protein composition used for oral hygienic application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for treating and/or preventing diseases of oral cavity, upper respiratory tract and esophagus which have had no suitable medicinal drugs or processed foods for treating and/or preventing the diseases and diseases or bad odors caused by abnormal growth of oral microorganisms. SOLUTION: This protein composition is a powdered medicine, contains one of more species selected from lactoferrin, lacto peroxidase, conalbumin and lysozyme as an active agent and is added with an immunoglobulin concentrate included in foremilk. The composition expresses various effects such as enhancement of saliva production, analgesic and antiphlogistic effect, immunological enhancement, healing of wounds, sterilization of oral organisms and the like by dissolving the composition in water in use and gargle and rinse the inside of the oral cavity.

Description

Description: TECHNICAL FIELD [0001] The present invention relates to a novel powder composition of a bioactive protein for oral hygiene use. More specifically, a powder composition containing one or more selected from lactoferrin, lactoperoxidase, conalbumin, and lysozyme, and a pharmaceutical composition that can be rinsed in water, gargled in the mouth, and washed when used. Related to goods or processed foods. Although the active ingredients lactoferrin, lactoperoxidase, conalbumin and lysozyme have bactericidal and antibacterial properties, bactericidal and antibacterial activities can be further enhanced by adding colostrum components containing various immunoglobulins. [0002] The present invention relates to diseases of the oral cavity, upper respiratory tract and esophagus caused by various causes, namely xerostomia, caries, periodontal disease, gingivitis, halitosis, stomatitis, upper respiratory inflammation. It is intended for treatment / prevention of reflux esophagitis and the like, and for suppressing abnormal growth of oral microorganisms. Salivary dysbiosis and anosiosis leading to xerostomia are a general term for conditions in which salivary secretion is reduced or depleted, resulting in dry mouth. It is a disease that cannot be overlooked and will have serious consequences if a large number of patients are left alone. Patients with dry mouth not only cause bad breath because saliva cannot be washed out of the oral cavity, but also make it difficult to chew and swallow food, and as it progresses, it becomes difficult to talk. Also,
It is also closely related to the dental area because of the rapid caries development. Disorders that lead to fluid loss (diabetes, diabetes insipidus, severe vocal stenosis with vomiting, severe diarrhea, atrophic kidney), severe systemic infection, ileus, acute peritonitis, stomatitis, gastric deficiency, especially cancer When a large amount of atropine, morphine, or arsenic is administered, dry mouth occurs due to blockage of salivary glands and mental shock. In Sjogren's syndrome, in which tears occur and dry eye occurs, concomitant dry mouth is an important criterion for diagnosis. The fact that the mouth becomes empty when nervous is due to a decrease in salivary secretion due to stress. Stomatitis is inflammation in the mouth, tongue, and gums of patients with severe illness, malnutrition, and acute infection. It occurs frequently in childhood, as seen in measles, but many heal naturally on standing. However, stomatitis associated with malignant tumors and AIDS patients is extremely refractory. In addition, most anticancer drugs have side effects that frequently cause intractable stomatitis,
It is said that over 90% of patients who have received anticancer treatment suffer from stomatitis. Treatment with anticancer drugs is based on the premise that the patient is receiving sufficient nutrition. However, refractory stomatitis is severely painful when eating meals, and greatly reduces the patient's appetite. Stomatitis, which prevents a patient from receiving sufficient nutrition, is one of the factors that hinders the improvement of treatment results. Intractable stomatitis also frequently occurs in AIDS, which is an obstacle to chemotherapy. Intractable stomatitis, which frequently occurs in these severe diseases, is not only a therapeutic disorder, but also significantly lowers the quality of life (QOL) of patients. Treatment of stomatitis is also urgently needed to improve QOL. Appetite is one of the basic needs of a patient, and fulfillment affects QOL. [0003] It has been estimated that at least 1 gram of microorganisms grows daily in the oral cavity of adults, but little is known about their physiological role. The majority of oral micro-organisms are occupied by obligate anaerobic microorganisms with little or no pathogenicity. However, it is certainly a health problem because it contains pathogens that cause dental caries and periodontal disease.
Oral microorganisms that grow at bedtime are said to grow in the bronchi and cause upper respiratory inflammation when swallowed. Pneumonia, which is a major cause of death of bedridden elderly people from late autumn to winter, has been attributed to oral microbial intake and drinking at bedtime. Bad breath is also considered to be due in part to the overgrowth of oral microorganisms, so keeping the mouth clean at all times is very important for health and hygiene, and gargles to maintain the oral cavity in a normal state are important. On the market. [0004] Techniques developed mainly for the action of drugs in the oral cavity include chewable preparations, oral patch preparations, and gargles. Chewable preparations are a form of preparations in which the active ingredient is dissolved in saliva by chewing or licking and gradually released into the oral cavity. In addition, the oral patch preparation is a preparation to which an adhesive substance is added, and is attached to the oral mucosa,
It is designed so that the active ingredient slowly dissolves in saliva and is released into the oral cavity. A gargle is one of the preparations in which the active ingredient is dissolved in the gargle water and the drug acts by gargle, and is used for oral disinfection. Currently, chewable tablets containing antimicrobial agents are commercially available for the purpose of relieving sore throat and treating / preventing pathogenic bacterial infections. However, these antibacterial agents can hardly inhibit the growth of oral microorganisms, which are dominated by obligate anaerobic bacteria. In addition, microbes that are sensitive to the antimicrobial agent used decrease in number, causing a bacterial replacement phenomenon in which insensitive microorganisms proliferate, and the antimicrobial agent is not safe enough for daily use. It is not suitable for applications that sterilize the inside and keep it clean. [0005] On the other hand, there is no chewable preparation on the market capable of promoting the production and secretion of saliva and treating dry mouth.
Chewing gum stimulates salivary secretion in healthy individuals, but is not applicable to xerostomia patients.
On the other hand, as oral remedies for intractable stomatitis with chronic exfoliative gingivitis, virane or ulcer, glossitis, and aphthous stomatitis, some oral patches containing the glucocorticoid triamcinolone acetonide as an active ingredient are on the market.
These are preparations expected for the anti-inflammatory action of glucocorticoids, and occasionally severe side effects may appear in induced infections, secondary adrenocortical dysfunction, peptic ulcer, diabetes, psychiatric disorders and the like. Glucocorticoids are in principle not applicable to cases with oral infections, but if unavoidable use is necessary, treatment with appropriate antibacterial and antifungal agents must be considered in advance. Furthermore, triamcinolone acetonide has no effect on stomatitis induced by malignant tumors, AIDS, anticancer drugs and the like. Although allobrinol gargle has been used in trials for the treatment of severe stomatitis by administration of an anticancer drug, the improvement effect is small, and it cannot be said that QOL of patients is improved. [0006] The problem to be solved by the present invention is to provide a suitable therapeutic / prophylactic agent or therapeutic / prophylactic agent.
The aim is to find a means of treating / preventing oral and esophageal diseases for which no processed food for prevention was present, or diseases caused by the growth of oral microorganisms. In particular,
By dissolving the powder composition containing the active ingredient in water, gargling the mouth, and washing, the active ingredient shows effects such as increased salivary secretion via the oral mucosa, analgesic anti-inflammatory, immunostimulation, wound healing, etc. It must also have a bactericidal action against microorganisms. In other words, the active ingredient is stable for a long time,
In addition to exhibiting the above pharmacological effects when the mouth is gargled and washed, oral microorganisms must be sterilized. Diseases to be treated / prevented by the pharmaceutical composition or processed food according to the present invention include a wide variety of diseases such as xerostomia, upper respiratory inflammation, periodontal disease, stomatitis, and caries. Also, although not ill, bad breath is also an object of improvement according to the present invention. Since oral hygiene powders having such an effect may be used for a long period of time, the active ingredient must not exhibit any systemic toxicity, and furthermore, dermal toxicity, mucosal toxicity, drug dependence, Teratogenicity,
There should be no specific toxicity such as mutagenicity. SUMMARY OF THE INVENTION The present inventors have prepared a powder composition containing one or more selected from lactoferrin, conalbumin which is an egg white lactoferrin, lactoperoxidase and lysozyme as an active ingredient. The substance is stable for a long period of time when it is not dissolved in water.If necessary, it is dissolved in water, gargles the mouth, and is washed to satisfy the above conditions, and to concentrate the polymer component contained in the colostrum. It has been found that the effect of improving the oral hygiene is greatly enhanced by adding the immunoglobulin concentrate thus obtained, and the present invention has been completed. These proteins are components of foods that humans have ingested for at least thousands of years as milk components of mammals or egg white components of birds, and are extremely safe despite having clear functionality. Lactoferrin, one of the active ingredients, is a polymer having a molecular weight of about 80,000 and has a property of forming a chelate with two ferric ions. It is thought that a receptor that specifically binds to lactoferrin is present on the mucous membrane, and when bound, causes a change in the living body. The changes are immunostimulatory, analgesic and anti-inflammatory, epithelial cell growth promoting, and antibacterial against certain pathogens, but little is known about the detailed mechanism. In addition, lactoferrin has a bactericidal effect and has a property of specifically binding to lipopolysaccharide of Gram-negative bacteria and detoxifying it. Lactoperoxidase is a protein with a molecular weight of about 80,000 daltons that chelates ferrous ions. In the presence of hydrogen peroxide, it oxidizes thiocyanate and halogen ions to peroxides that exert a strong bactericidal action. . Saliva contains 5 to 15 ppm thiocyanate ions, and oral microorganisms are mostly obligately anaerobic and do not have catalase to degrade hydrogen peroxide. That is,
Lactoperoxidase has ideal properties as an oral bactericide because of the presence of hydrogen peroxide and thiocyanate ions in the lesions where oral microorganisms grow. Lysozyme is an enzyme protein contained in secretions such as tears and egg white, and has an action of lysing the cell wall of Gram-positive bacteria. On the other hand, although the mechanism of action is not clear, it has an analgesic and anti-inflammatory effect and is added as an anti-inflammatory agent to a general cold remedy for pharmacies. Conalbumin is avian lactoferrin,
It is an inexpensive multifunctional protein contained in large amounts in egg white. In order to enhance the bactericidal activity of the active ingredient, the addition of an immunoglobulin concentrate containing a polymer component obtained by ultrafiltration of colostrum has a synergistic bactericidal effect, and
It has an immunostimulatory effect and is very effective. [0008] The pharmaceutical composition or processed food of the present invention is used for treatment /
There are numerous preventable oral-to-esophageal mucosal and upper respiratory illnesses. One is stomatitis. Although stomatitis is not a serious, life-threatening illness, it is very troublesome for treating severe debilitating diseases such as cancer, AIDS, and dentistry. In the dental field, if a patient has active stomatitis, dental treatment cannot be performed until the inflammation subsides. Moreover, to date, there is no drug that can cure stomatitis quickly. Even more serious is the case of cancer chemotherapy. 5-Fluorouracil, adriamycin, cisplatin, and the like, which are used as anticancer drugs, cause stomatitis in more than 90% of patients when administered over a long period of time. In addition, even if an anticancer drug is not administered, cancer patients often have severe stomatitis. When the stomatitis becomes severe and an oral ulcer is caused, severe pain occurs during food intake, so that food intake is significantly reduced. Because there is no immediate cure for stomatitis, it is difficult to continue drug treatment. Due to restricted nutrition, a vicious circle is reached in which the therapeutic effect of anticancer drugs is not improved. There is an urgent need to develop methods for treating / preventing stomatitis in order to improve the therapeutic effects of cancer chemotherapeutic agents. Both diseases cause financial losses,
In particular, periodontal disease is a disease that causes large losses so that the amount of damage is ranked second. Instead, attention to periodontal disease cannot be said to be high. Periodontal disease is an infectious disease caused by obligate anaerobic opportunistic pathogenic bacteria in the oral cavity growing in the gap between the teeth and the gingiva (pocket). Can be improved. However, the cause of periodontal disease is an opportunistic pathogen susceptible to special antibacterial agents such as tetracycline, chlorhexidine, and metronidazole, and it is extremely difficult to safely remove bacteria because it inhabits periodontal pockets. The powder composition or processed food for gargle of the present invention has a strong bactericidal action against oral microorganisms, and further has a local analgesic and anti-inflammatory effect and an immunostimulatory effect, so that periodontal disease can be effectively prevented. Can be treated / prevented. Although the oral odor is not a disease, it is a serious obstacle to social life, and its elimination is indispensable for a smooth interpersonal relationship. There are several causes of oral malodor, but malodor after drinking is outside the scope of the present invention. In most cases, the cause of oral malodors other than alcohol drinking is that the oral cavity cannot be washed out due to the decrease or depletion of saliva, and oral microorganisms have grown abnormally. The gargle powder composition or processed food of the present invention has an action of increasing salivary secretion and washing the oral cavity and a bactericidal action against oral microorganisms, so that the cause of the malodor can be effectively removed. Salivary hypotension and anosiosis are conditions in which salivary secretion is reduced or depleted, resulting in dry mouth. Diseases that decrease body fluids (diabetes, diabetes insipidus, atrophic kidney, age-related dehydration, Sjogren's syndrome, stress, severe vomiting pyloric stenosis, severe diarrhea, atrophic kidney), severe systemic infection, ileus, Acute salivitis, stomatitis, gastric acid deficiency, salivary or hyposalivation develops, for example, when a large amount of cancerous pollutants, atropine, morphine, or arsenic is administered, the salivary glands are blocked, or mental shock occurs. Glycerin is applied to the oral cavity, gargle with camphor is used, and symptomatic treatments such as pilocarpine are available.
It is not effective and lacks treatment. When the mouth of a patient suffering from salivary or hyposaliva is gargled and washed with a solution of the powder composition of the present invention, the pH of saliva increases and secretion increases, and these diseases can be treated. Previous studies have shown that an increase in salivary pH means an increase in saliva production. Upper respiratory tract inflammation caused by dropping into the nasal cavity of Klebsiella pneumoniae is a lethal infectious disease model. This pathological model is very similar to senile pneumonia, which occurs frequently from late autumn to winter and kills lives. Because salivary secretion decreases with aging, the elderly cannot wash away with saliva opportunistic pathogens that grow in the oral cavity at bedtime. Accidental ingestion of the grown pathogen into the bronchi is the cause of the development of senile pneumonia. Oral administration of an active ingredient such as lactoferrin has a clear life-saving effect on this disease state model, and a similar effect can be expected for gargle and washing in the oral cavity with a solution of the powder composition of the present invention.
That is, it is because gargle with a dissolving solution containing a bactericidal active ingredient, washing can suppress abnormal growth of oral microorganisms, and immunity is activated by immunity enhancing effects of lactoferrin, lysozyme, colostrum components, and the like. The novel pharmaceutical composition and the novel processed food according to the present invention have features unprecedented in various points in the past. First, the active ingredients are extremely safe. They are components of foods that humans have been ingesting, and do not exhibit any systemic toxicity when used in large excess for long periods of time, and furthermore, are not dermal, mucosal, drug dependent, teratogenic No special toxicity such as mutagenicity, carcinogenicity. Secondly, the selected active substance has a saliva production enhancing action,
It has desirable physiological activities such as an analgesic and anti-inflammatory effect, an immunopotentiating effect, a wound healing effect, and a bactericidal effect against oral microorganisms. Third, the active ingredient is unstable in an aqueous solution, but it can be stored stably for a long period of time by dissolving it in water when used as a powdery powder. It can be dissolved in water to exert its effect in the oral cavity. The content of the active ingredient used in the novel pharmaceutical composition or the novel processed food of the present invention is not particularly limited, but may be 5 or less as lactoferrin or conalbumin.
The amount is preferably 0 to 5000 mg, and the amount of colostrum-derived immunoglobulin to be added can be appropriately added to 50 to 5000 mg. As a general additive, in addition to skim milk, starch, dextran, carboxymethyl cellulose, hydroxypropyl cellulose and the like as a bulking agent, silica gel as a lubricant, sodium polyphosphate,
Sugars as flavoring agents, vitamins and amino acids as physiologically active substances, menthol as flavoring agents, and the like can be added, such as magnesium stearate and calcium stearate. EXAMPLES Example 1 A skim milk portion is obtained from fresh bovine colostrum by centrifugation. The skim milk is subjected to ultrafiltration having a molecular weight cutoff of 2,000 to remove low molecular substances such as lactose, minerals and nucleic acids. Then, it is spray-dried to obtain an immunoglobulin concentrate containing various colostrum proteins. To 4.0 kg of the colostrum-derived powder, 0.7 kg of lactoferrin and 0.3 kg of lactoperoxidase extracted from cow's milk were added, mixed with 10 kg of skim milk and 150 g of silica gel, and divided into 3 g per packet. Example 2 4 kg of colostrum-derived powder and 6 kg of skim milk were mixed with 5 kg of conalbumin extracted from egg white and 0.1 kg of lysozyme to give a package of 5 g per package. Example 3 1 kg of lactoferrin extracted from milk, 0.4 kg of lactoperoxidase, 0.5 kg of lysozyme chloride, 3 kg of colostrum-derived powder, and 20 g of magnesium stearate were mixed to give 3 g per packet. . Example 4 5-Fluorofuracil was administered for 6 weeks,
Example 1 An ulcer in a patient who had oral ulcers in the upper gingiva and two places in the lower gingiva and had difficulty in eating food.
Treated with powder. The powder was dissolved in water, gargled in the oral cavity and washed three times a day. The ulcer began to heal on day 5, 1
He was almost completely healed after 0 days. EXAMPLE 5 The powder of Example 2 was dissolved in water and gargled in the oral cavity before going to bed, washed, and put to bed in seven healthy adult males. It was continued for 7 days, saliva was collected before application and after rising on the 8th day, and the pH was measured. As is clear from the table, Example 2
The average pH of saliva was 7.
It increased from 05 ± 0.05 to 7.35 ± 0.05. Since it has been proved that an increase in salivary pH has a direct correlation with an increase in secretion amount, it can be seen that gargling by the powder of Example 2 clearly increases salivary secretion. Example 6 Four adult men and women (male 2) suffering from bad breath
, Two women) conducted the test. For 7 days, the powder of Example 3 was dissolved in water and the mouth was gargled and washed before going to bed. On day 8, the breath was collected in a polyethylene bag, and the breath before the test and the amount of the malodorous substance were compared. In each case, methyl mercaptan, a malodorous substance in breath, was significantly reduced. Example 7 Two women (51 years and 47 years old) with Sjogren's syndrome suffering from xerostomia were dissolved in the water of the powder of Example 2 in water three times a day after eating three times a day. Was. Just before the test and the day after the test is finished
Saliva secreted for a minute was collected and weighed. As a result, salivation increased by an average of 33%. Example 8 Two female volunteers dissolve the powder of Example 1 in water four times a day for four consecutive days, gargle the mouth, wash, and examine the effect on the number of oral microorganisms in saliva. did. As a result, it was found that the number of microorganisms in saliva decreased sharply compared to before the test.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61K 47/26 A61P 1/04 47/36 11/00 A61P 1/02 29/00 1/04 31/04 11/00 A61K 37/02 29/00 37/48 31/04 37/54 F term (reference) 4B018 MD20 MD71 ME09 MF01 4C076 AA12 AA29 BB03 BB22 BB23 CC01 CC16 CC31 CC40 DD29 DD51 DD67 EE38 FF07 FF16 FF68 GG47 4C084 AA02 DA41 DA44 DC01 DC02 DC22 MA02 MA05 MA17 MA43 NA14 ZA661 ZA671 ZB012 ZB351 ZC521

Claims (1)

Claims: 1. A powder composition containing, as an active ingredient, one or more selected from physiologically active proteins, lactoferrin, lactoperoxidase, conalbumin and lysozyme, Pharmaceutical composition effective for prevention and treatment of diseases caused by oral pathogens, which is characterized by washing in the mouth and washing in the mouth, and a process for producing processed foods. 2. A method for producing lactoferrin, lactoperoxidase, conalbumin And adding a concentrate of immunoglobulin contained in colostrum to the pharmaceutical composition or processed food of claim 1 which is a powder containing one or more selected from lysozyme as an active ingredient. A method for producing a pharmaceutical composition and a processed food, characterized by the fact that lactoferrin, lactoperoxidase, and conalbumi are used. And one or more selected from lysozyme and lysozyme [Claim 1] and [Claim 2]
A pharmaceutical composition and a method for producing a processed food, characterized in that the powder composition contains sugars such as sucrose, lactose, glucose, dextrin, starch, lactulose, lactitol and sorbitol. And one or more selected from conalbumin and lysozyme [Claim 1] and [Claim 2]
A method for producing a pharmaceutical composition and a processed food, characterized in that the powder composition contains low molecular weight physiologically active substances such as vitamins and various amino acids. 5. A method for producing lactoferrin, lactoperoxidase, conalbumin and lysozyme. Contains one or more selected ones [Claim 1] and [Claim 2]
A pharmaceutical composition comprising menthol and a method for producing a processed food, wherein the composition comprises one or more selected from lactoferrin, lactoperoxidase, conalbumin and lysozyme. [Claim 1] and [Claim 2]
A method for producing a pharmaceutical composition and a processed food, characterized in that the powder composition of (1) contains one or more substances corresponding to [Claim 3] to [Claim 5]. And a method for producing a processed food according to claim 1 to claim 6. A pharmaceutical composition according to claim 1 to claim 6 for sterilizing the oral cavity. 9. A method for producing processed foods and processed foods. 9. The method for producing processed foods according to claim 1 to claim 6, which prevents malodor in the oral cavity. 10. An increase in saliva production. ]
And a method for producing a pharmaceutical composition and processed food according to claim 6. 11. A pharmaceutical composition and processed food according to claim 1 for treating / preventing upper respiratory tract inflammation of a bedridden elderly person. [Claim 12] A method for producing or treating pharmaceutical compositions and processed foods for treating / preventing reflux esophagitis [Claim 1] to [Claim 6] [Claim 13] A pharmaceutical composition according to any one of claims 1 to 6 and a method for producing a processed food. 14. A pharmaceutical composition according to any one of claims 1 to 6, which relieves pain caused by stomatitis and promotes healing. And a method for producing a processed food. 15. A pharmaceutical composition for treating / preventing dental diseases such as dental caries, periodontal disease, and gingivitis, and a method for producing a processed food. 16. Relieving pain caused by inflammation of the upper respiratory tract [Claim 1] Luo pharmaceutical composition of [claim 6], as well as processed food preparation