JP2021169423A - Method for administering pharmaceutical preparation - Google Patents

Abstract

To effectively enhance immune functions.SOLUTION: A method for administering a pharmaceutical preparation comprises: orally administering "an active oxygen removing agent for oral administration" within a time zone in which sympathetic nerve is dominant (for example, from 5 a.m. to 5 p.m); orally administering "an antitumor agent causing parasympathetic nerve dominance and lymphocyte activation by upper gastrointestinal tract-mucosal absorption (antitumor agent)" within a time zone in which parasympathetic nerve is dominant (for example, from 5 p.m. to 5 a.m. next morning); and causing these agents to be absorbed at the organs having concentrated lymphatic vessels which have the immune response of detecting microorganisms and transmitting the detection of microorganisms to the brain.SELECTED DRAWING: None

Description

The present invention relates to a method for administering a preparation, and more particularly to a method for administering a preparation that effectively enhances immune function.

Today, most medical doctors and pharmaceutical companies in Japan and around the world say that the drug as an "antitumor agent" for cancer is "immune checkpoint inhibitor / molecular target drug that inhibits immune cell failure (runaway)". Development and sales competition continues at a huge cost.

On the other hand, the late Toru Anbo, an emeritus professor at Niigata University, wrote in the "Preface" of the "Original Proceedings" that "the failure (runaway) of immune cells was caused by the expression of the old immune system before the organism landed. It is a purposeful reaction to eliminate abnormal self caused by aging and intense stress. It is not caused by the failure (runaway) of the immune system. "

Therefore, the present inventor is supported by this theory that "it is not a failure (runaway) of immune cells", and a drug that can be expected to have a healing effect on the weaving of a huge number of immune cells in the living body is like a molecular target drug. Considering that it is impossible to prepare a "one specified substance represented by one chemical structural formula", the development was switched to a natural material preparation (see, for example, Patent Documents 1 and 2).

Japanese Unexamined Patent Publication No. 2017-079342 JP-A-2017-09516

In order to maximize the effect of such a natural material preparation, an administration method that effectively enhances a person's immune function is desired.

The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for administering a preparation that effectively enhances an immune function.

In order to achieve the above object, the preparation administration method according to the present invention uses an active oxygen scavenger during a time period in which the sympathetic nerve is dominant, and a lymphocyte activation antidrug during a time period in which the parasympathetic nerve is dominant. Each tumor agent is orally ingested, a microorganism is detected, and the tumor agent is absorbed by an organ in which lymphatic vessels in the oral cavity have an immune response that transmits the detection of the microorganism to the brain.

According to the present invention, it is possible to provide a method for administering a preparation that effectively enhances an immune function.

Hereinafter, the present invention will be described, but the present invention is not limited to the following specific forms, and can be arbitrarily modified within the scope of the technical idea.

In addition to the five established sensations of smell, touch, taste, sight, and hearing, the proprioceptive sensation that senses the position and movement of the body is known as the sixth sense. Furthermore, as a seventh sense, the present inventor detects microorganisms, and the immune response that transmits the information (detection of microorganisms) to the brain is an organ in which lymphatic vessels in the oral cavity are concentrated (the part of the ella in fish). I found that it was in. Therefore, in the preparation administration method according to the present invention, the "active oxygen remover for oral ingestion" is predominant in the time zone when the sympathetic nerve is predominant (for example, after 5 am to 5 pm), and the parasympathetic nerve is predominant. During the time period (for example, after 5 pm to 5 am the next day), "parasympathetic nerve-dominant lymphocyte-activated antitumor agent (antitumor agent)" is orally ingested to detect microorganisms, and detection of microorganisms is performed in the brain. It is characterized in that it is absorbed by an organ in which lymphatic vessels in the oral cavity have an immune response to transmit to. Here, the "active oxygen scavenger for oral ingestion" and the "antitumor agent" are orally ingested in very small amounts in order to obtain a homeopathic effect.

The first agent, "active oxygen scavenger for oral intake," is a special product in which vegetable oils such as ω3 fatty acids are added and mixed with more than a dozen kinds of natural plant fermenting materials containing antioxidases and antioxidative substances. It is obtained by applying various oils. Due to such special oiling, the active oxygen scavenger for oral intake receives the natural plant fermenting material by the receptor of the cell membrane which is a lipid and introduces it into the cell, so that normal cell division can be easily performed. Details of the active oxygen scavenger for oral ingestion are described in Japanese Patent No. 1768652, Japanese Patent No. 21258887, the specification of Japanese Patent Application No. 2019-153432 and Japanese Patent Application No. 2019-153433, claims, and drawings. ..

When a person is aged or under severe stress, the ancient old immune system before the landing of the organism is expressed and activated, and in an attempt to eliminate the abnormal self, the unilateral enhancement direction of macrophages and granulocytes becomes stronger, and the organism becomes a living body. It is filled with bad active oxygen, inhibits normal cell division, and forms the initial cancerous area. By suppressing the active oxygen released from the granules, the function of immune cells can be regulated, but in order to suppress the active oxygen and stabilize the living body from the active oxygen, "active oxygen remover for oral intake" Is extremely effective. By ingesting this, the increased active oxygen can be reduced, and macrophages, which are the control tower of the immune foetation, transmit signals to cytokines that the living body has become normal and regulate immune cells (for example, runaway). Suppress). Then, by ingesting the immunostimulatory agent after that, lymphocytes are properly produced and activation is achieved, and tumor cell reduction, disease recovery, and the like are realized.

An active oxygen scavenger for oral ingestion converts superoxide, which is first generated in intracellular mitochondria, into oxygen and hydrogen peroxide to make final water. In addition, hydrogen peroxide, singlet oxygen, and hydroxyl radicals that have come out of the cell are also inactivated by naturally occurring components (low molecular weight antioxidant compounds) contained in the active oxygen scavenger for oral intake of the present invention. Can be made to. Further, the "active oxygen scavenger for oral intake" is obtained by adding an oil such as ω3 fatty acid and mixing it so as to be easily accepted by the receptor of the cell membrane which is a lipid. By doing so, it is accepted by the receptor, enters the cell, and preferably exerts the effect of removing active oxygen.

An active oxygen remover for oral intake is a plant seed or its germ roasted under appropriate conditions, then fermented by adding microorganisms, and further added with vegetable oils such as ω3 fatty acids obtained from roasted plants. There is an embodiment in which vitamin C, a vitamin C derivative, or a plant containing these is added to any one or more of them.

In general, small molecule anti-active oxygen substances such as flavonoids, polyphenyls, tannins, tocopherols and vitamin B2 are present in plant seeds, especially in their germs, but these substances may be associated with each other or with other components. It chemically bonds, produces molecular compounds, and forms complex complexes and highly polymer compounds by adsorption and inclusion. As a result, even if it is ingested as it is, its anti-active oxygen effect is so small that it cannot be used for the treatment or prevention of diseases.

However, when these plant seeds and their germs are roasted under mild conditions, the anti-active oxygen substances contained in them are released from the complex to some of the original small molecule simple substances, or some of them are chemically changed. In response, an active functional group is generated and activated. As a result, the anti-active oxygen action is significantly enhanced as compared with that before roasting. Here, if the plant seeds and germs are burnt by intense high-temperature heating, the active oxygen-suppressing substances contained therein are inactivated and the activity is rather lowered. Therefore, the heating method, heating temperature, time, etc. Need attention.

The term "roasting" as used in the present invention refers to applying the heating required for activation under appropriate heating conditions such as not burning, but the heating conditions differ depending on the target seeds and the like, the heating time, and the like. Therefore, it cannot be unconditionally specified, but a heating temperature of 50 to 150 ° C., usually about 50 to 100 ° C. is appropriate. In order to carry out such roasting, it is necessary to have a method of uniformly heating while minimizing the temperature difference between the inner layer and the outer layer of particles such as plant seeds and their germs. Methods such as uniform heating in a constant temperature bath and heating in a fluidized bed can be adopted, but are not limited thereto.

Examples of the far-infrared heating method include a method using a far-infrared lamp, a method of indirect heating with a material that emits far-infrared rays such as stone, sand, brick, ceramics, earthenware, and ceramics, and the latter is particularly easy to carry out. It is considered to be advantageous.

Examples of plant seeds that can be used in the present invention include rice, wheat, barley, soybean, corn, hatomugi, adzuki beans, and pea, but any plant seed that has a strong anti-active oxygen effect may be used. Not limited. The germ may be any of the above plant seed germs, and bran, komugi germ and the like can be preferably used. The amount of germ used is preferably 5% by weight or more, particularly 10% by weight or more of the total amount of plant seeds and germs of the present composition.

After roasting, microorganisms are added to these plant seeds or their germs to ferment them.

The term "fermentation" as used herein refers to fermentation in a broad sense, and means that organic substances are decomposed by microorganisms, and does not mean only when metabolites become simple compounds. For example, it also includes mild decomposition by koji mold, yeast, etc., and is rather preferable. In this fermentation process, the action of an enzyme such as a protease contained in Jiuqu or the like causes the above-mentioned small molecule anti-active oxygen substance to be liberated in a larger amount, and its anti-active oxygen action is enhanced.

In the present invention, after the above roasting and fermentation steps, vegetable oil such as ω3 fatty acid obtained from the roasted plant is added thereto. By adding such vegetable oil, anti-active oxygen substances such as tocopherol are enhanced, and the active oxygen suppressing action is further enhanced. In some cases, it may be desirable to separate the soluble and insoluble portions of the vegetable oil and use them properly according to the target disease.

Examples of the raw material of such vegetable oil include, but are not limited to, sesame, soybean, cottonseed, corn, safflower, evening primrose, bran, rapeseed, olive and the like used for food or medicine. Of these, sesame seeds are preferred.

The present invention also provides a composition obtained by adding vitamin C, a vitamin C derivative, or a plant containing these to the composition obtained in the above step (roasting + fermentation + addition of roasted vegetable oil). Vitamin C or a derivative thereof is a strong reducing substance, which itself has an anti-active oxygen action, suppresses self-destructive action such as koji, stabilizes the composition, and liberates the tocopherols and polyphenols. , Flavonoids, tannins, vitamin B2 and other low molecular weight substances have further enhanced anti-active oxygen effects, and these synergistic effects further enhance the anti-active oxygen effects, which is preferable.

Examples of vitamin C derivatives include salts such as sodium vitamin C and esters such as vitamin C palmitate. As the plant body containing these vitamin Cs or derivatives thereof, various plants such as young leaves and roots of barley and radish, lemon and citron fruit, green tea, spinach and the like can be used, but of course, they are not limited thereto.

These plants may be crushed and added as they are, squeezed juice may be added, or dried ones may be added as long as vitamin C is contained. Moreover, the order of addition of each of these components is arbitrary.

The active oxygen scavenger for oral ingestion of the present invention includes, if necessary, supplementary pharmaceutical or health-effective ingredients such as vitamins, metals necessary for the human body, chemical components such as iodine, flavoring agents, and fragrances. , Colorants, surfactants, excipients, etc. are optional.

The active oxygen scavenger for oral ingestion of the present invention includes adult diseases such as arteriosclerosis, stroke, myocardial infarction, diabetes, rheumatoid arthritis, Beechet's disease, Clone's disease, ulcerative colitis, Reynaud's disease, and intractable diseases. It is effective as a healthy food for the treatment, prevention, prevention of carcinogenesis and maintenance of health of various pollution diseases, stains, freckles, burns, trauma, fatigue, intoxication, constipation and the like.

Orally ingestible active oxygen scavenger of the present invention, four kinds of active oxygen i.e. _O ² _-, because they act on all the H ₂ O _2, OH · and ¹ O _2, is more effective than SOD (Super Oxide disumutase) It has a great advantage.

In addition, the active oxygen scavenger for oral intake of the present invention is stable against gastric acid, and the molecular weight of the active oxygen scavenger is reduced by the gastric acid, and the antiactive oxygen effect is increased (Niwa et al .: Inflammation 10, No. 179 1986). It is possible to treat, prevent, and maintain health. In addition to oral administration, burns, general trauma wounds, and skin diseases can be treated by directly adhering to the affected area.

The next second tablet, "anti-tumor agent," contains an active ingredient containing choline or choline derivative, and sugar or sugar derivative, and is in the form of powder or granules. It is used for the purpose of predominantly parasympathetic nerves and activating lymphocytes by absorbing it from the mucous membrane of the upper gastrointestinal tract by keeping it in contact with saliva for 30 seconds or more. It is characterized by containing a winter worm summer grass extract derived from wild silkworm, a propolis extract, an agarix mushroom extract, and a saliva extract.

The antitumor agent of the present invention has a dosage form that can be taken orally, such as powder or granules, and is used for oral ingestion. Further, it is used for the purpose of keeping it in the oral cavity for 30 seconds or more and contacting it with saliva, and is used for the purpose of making the parasympathetic nerve superior to the sympathetic nerve by excitement / stimulation or the like.
Furthermore, the antitumor agent of the present invention is used for the purpose of activating lymphocytes. Since lymphocytes have acetylcholine receptors, when the antitumor agent of the present invention is administered and acetylcholine is secreted due to the predominance of parasympathetic nerves, the lymphocytes are activated and have an antitumor effect. Play.

After oral ingestion, the antitumor agent of the present invention is kept in the oral cavity for 30 seconds or longer, and is brought into contact with saliva to be absorbed through the mucous membrane of the upper gastrointestinal tract (particularly the oral mucosa). That is, the effect of predominantly parasympathetic nerves and activating lymphocytes can be obtained. In the antitumor agent of the present invention, it is preferable that the mucous membrane of the upper gastrointestinal tract is the oral mucosa. That is, the antitumor agent of the present invention can obtain the above effect by keeping it in the oral cavity for 30 seconds or more and allowing it to come into contact with saliva and absorb it through the oral mucosa.

Conversely, the antitumor agent of the present invention has the effect of predominantly parasympathetic nerves and activating lymphocytes by suppressing absorption from the lower gastrointestinal tract having Peyer's patches.
Traditionally, it has been generally believed that the (at least conventional) immune-enhancing active ingredient exerts its immune function by being absorbed from the Peyer's patch of the mesentery of the lower gastrointestinal tract.
The present invention provides for consciously keeping the active ingredient in the oral cavity for 30 seconds or longer, limiting the dosage form and excipient, preferably setting an upper limit on the single intake of the active ingredient. The effect was demonstrated by establishing a "regulation in the direction of suppressing absorption from Peyer's patches (suppression of intestinal immune function)" that "promotes absorption from the oral mucosa by contacting with saliva". ..

In addition, the antitumor agent of the present invention has a function as an immune response that detects microorganisms and transmits the detection of microorganisms to the brain by absorbing them from an organ in which lymphatic vessels in the oral cavity are concentrated.

In other words, the antitumor agent of the present invention is an "anticancer agent", and the tumor (cancer) also includes tumors of blood cells (leukemia and the like).

The antitumor agent of the present invention contains, as an active ingredient, a Cordyceps sinensis extract derived from wild silkworms, a propolis extract, an agaricus mushroom extract, and a Reishi extract.
In the present invention, the "extract" refers to a raw material from which the solvent has been removed after undergoing a "step including extraction using a solvent". The extraction may be performed once or a plurality of times, the extraction solvent may be changed each time, or the extraction may be performed with a supercritical fluid. However, the mass of the powder P obtained in the step (6) described later is used to specify the content (mass) of the extract.

Of these, the "wild silk moth" in the "caterpillar fungus extract derived from wild silk moth" refers to larvae or pupae of wild insects that produce silk threads, other than domesticated silk moths (household silk moths).
Cordyceps sinensis refers to mushrooms (fruiting bodies) when fungi such as ascomycetes parasitize underground insects or pupae and produce mushrooms (fruiting bodies) on the ground. , Originating from wild silkworm larvae or pupae.
Most of the conventional Cordyceps sinensis, which is said to be effective for antitumor, originate from ants (particularly, pseudo-black polyrhachis ant), but the Cordyceps sinensis in the antitumor agent of the present invention originates from wild silkworms. It produces a remarkable effect of the present invention. It has been confirmed that the extract from domesticated silk moth (Hoxal silk moth) does not sufficiently show the effect of the present invention.

Propolis is a mixture of resins and the like collected from plant sources by honeybees and the like.

Agaricus mushroom is a mushroom belonging to the genus Agaricus in the family Agaricaceae, and is also known as Mushroom Himematsutake Kawari Haratake and Himematsutake.

Reishi is a mushroom of the family Ganoderma lucidum, and is also called Ganoderma lucidum or Reishi grass.

The origins of Cordyceps sinensis, propolis, Agaricus mushrooms, and Reishi mushrooms derived from wild silkworms, and subspecies, which are subclasses, are not particularly limited. Further, as the raw material actually used for the antitumor agent of the present invention, it may be collected from the natural world or cultivated.

The antitumor agent of the present invention is used in the whole antitumor agent.
The content of the above Cordyceps extract is 0.5-10% by mass,
The content of the propolis extract is 0.1 to 10% by mass,
The content of the above agaricus mushroom extract is 0.1 to 8% by mass, and
The content of the above Reishi extract is 0.03 to 5% by mass,
Is preferable.

Also, more preferably, in the whole antitumor agent,
The content of the above Cordyceps extract is 0.7 to 7% by mass,
The content of the propolis extract is 0.5 to 7% by mass,
The content of the above agaricus mushroom extract is 0.2 to 5% by mass, and
The content of the Reishi extract is 0.05 to 3% by mass.

Furthermore, particularly preferably, in the whole antitumor agent,
The content of the above Cordyceps extract is 0.8-5% by mass,
The content of the propolis extract is 1 to 5% by mass,
The content of the above agaricus mushroom extract is 0.3 to 3% by mass, and
The content of the Reishi extract is 0.1 to 1% by mass.

All of the above-mentioned four kinds of extracts are "active ingredients" in the present invention, and all four kinds are based on the mass of powder P obtained by performing steps (1) to (6) which are preferable production methods described later. Is to be.
The extract in the present invention is not limited to the one obtained by performing all the steps (1) to (6) described later (thus, steps (1) to (8)), but in defining the "extract". , "Mass of extract" is defined as "mass of powder P obtained by performing steps (1) to (6)". That is, the above four kinds of extracts contain niacinamide but not "sugar or sugar derivative". Here, the "amount of niacinamide used" used in the definition of "mass of extract" is 1 part by mass with respect to 1 part by mass of the whole raw material used in the step (1).

The values of the contents of the above-mentioned four kinds of extracts can be exchanged (replaced) with each other between a preferable range, a more preferable range, and a particularly preferable range.
When the upper limit of the contents of Cordyceps sinensis extract, Propolis extract, Agaricus mushroom extract, and Reishi extract is not more than the above, the above-mentioned effect of the present invention is particularly exhibited.

As will be described later, the antitumor agent of the present invention is most preferably about 1 g per packet (piece), and about 1 packet (piece) to about 3 packets (pieces) are ingested at a time, and about 3 times a day. It is taken about 4 times, but if the upper limit of each content is less than the above, absorption into the body by one ingestion is mainly performed from the oral cavity or esophagus, and the mesentery of the jejunum or ileum. Since the amount of the active ingredient absorbed from the Peyer's patch present in the ileum is reduced, the effect lasts for a long period of time. If the content of each active ingredient is too high, a relatively large amount of the active ingredient is absorbed from the Peyer's patch, and the enhancement of immune function due to this is weakened in about one month. If a large amount of the drug is continuously ingested, the effect of the present invention may decrease.

When the upper limit of each content is not more than the above, absorption from the mucous membrane of the upper gastrointestinal tract (particularly, the mucous membrane in the oral cavity) is preferably performed, and the active ingredient is efficiently taken into the body. If the content of each active ingredient is too high, that is, if the single intake of the active ingredient is too high, absorption from the mucous membrane of the upper gastrointestinal tract (particularly, the oral mucosa) may be suppressed.

On the other hand, when the lower limit of each content is equal to or higher than the above, it is not said that the amount of each active ingredient, which is the four kinds of extracts, is too small to exert the effect, and the four kinds of extracts act synergistically. Then, the above-mentioned effect is exhibited.

In addition to the above active ingredient and the "sugar or sugar derivative" described later, the antitumor agent of the present invention may contain other ingredients. As the "other components", known substances such as inorganic fine particles, organic fine particles other than the "sugar or sugar derivative in the present invention", stabilizers, flavor modifiers and the like can be used. The "other components" are not particularly limited, but the content in the entire antitumor agent of the present invention is preferably 10% by mass or less, more preferably 3% by mass or less, and particularly preferably 1% by mass or less. Most preferably, it is not contained.

The antitumor agent of the present invention contains the above-mentioned "active ingredient" and the "sugar or sugar derivative" described later. The active ingredient has an insect flavor, a mushroom flavor, other miscellaneous flavors, and the like, and is extremely unpleasant by itself. By blending a "sugar or sugar derivative" (particularly preferably maltitol), the unpleasant taste of the active ingredient is reduced.
The antitumor agent of the present invention must be kept in the oral cavity for 30 seconds or longer, and it is effective to keep it in the oral cavity. A "sugar or sugar derivative" is extremely important in that it does not give a taste.

In the antitumor agent of the present invention, other than the above-mentioned "active ingredient" and "other ingredients", it is a "sugar or sugar derivative". Therefore, the content of the "sugar or sugar derivative" is preferably 70 to 99% by mass, more preferably 75 to 98.5% by mass, and particularly preferably 80 to 98% by mass with respect to the entire antitumor agent. ..

Examples of the sugar include monosaccharides, disaccharides, oligosaccharides, polysaccharides (including starch, cellulose, gum, etc.), and examples of the sugar derivative include sugar alcohols, esterified sugars, methoxylated sugars, and sugars. Examples thereof include hydroxypropylated products of the above, decomposition products of sugars, and the like. The "sugar or sugar derivative" is preferably solid at room temperature in order to form the dosage form of the antitumor agent into powder or granules. In addition, it is preferable that the calorie content is low and that there is no unpleasant taste. Further, it is preferable that the effect of the active ingredient is difficult to block.

For example, monosaccharides such as glucose (dextrose) and fructose (fructose); disaccharides such as sucrose (sucrose) and trehalose, and polysaccharides such as starch have unnecessary calories. Trehalose may also be too high in calories, and may remain sticky and unpleasant in the mouth (especially in the morning when taken at night).

More preferably, it is a sugar alcohol from the viewpoint of easy retention of the antitumor agent of the present invention in the oral cavity, easy production, etc., and particularly preferably, it is difficult to block the effect of the active ingredient, there is no unpleasant taste, and the like. It is maltitol from the point of view. Sugar alcohols are generally preferable because they have low calories, but xylitol and erythritol may have an unpleasant taste.
Since it is essential that the antitumor agent of the present invention is kept in the oral cavity for 30 seconds or more without being swallowed immediately, it is particularly important that there is no unpleasant taste and that a sticky feeling cannot occur. In addition to being painful to the cancer patient, the unpleasant taste may cause immediate exhalation or, conversely, immediate swallowing (before 30 seconds have passed).

The "sugar or sugar derivative" in the present invention is an excipient that suppresses unpleasant taste and stickiness, and in particular, in order to suppress the upper limit of the single intake of the antitumor agent of the present invention and obtain the above-mentioned effect. is important. That is, it is particularly important because the antitumor agent of the present invention is retained in the oral cavity and absorbed from the upper gastrointestinal tract (from the oral cavity to the duodenum), particularly from the oral cavity or esophagus, and not much to the mesentery. Is.
Increasing the dose of the "sugar or sugar derivative" may increase the single ingestion of the antitumor agent of the present invention sufficiently to promote saliva secretion, or increase the dose of the active ingredient in the antitumor agent once. It is important to keep the intake low. As mentioned above, if the single intake of the active ingredient is kept low, the absorption of the active ingredient from the mucous membrane in the oral cavity is promoted, or the absorption of the active ingredient from the Peyer's patch of the intestine is reduced, and the active ingredient is continuously ingested for a long period of time. The effect lasts.

When the antitumor agent of the present invention is ingested, it is absorbed by the mucous membrane in the oral cavity, and the effect of lymphocytes stimulated and activated by the mucous membrane in the oral cavity spreads throughout the body (mucosa or lymphocytes). Conceivable. The effect is greatly enhanced by keeping it in the oral cavity for 30 seconds or longer after ingestion and bringing it into contact with saliva. It is preferably kept in the oral cavity for 45 seconds or longer, and particularly preferably for 1 minute or longer. It is also preferable not to consciously swallow.
Therefore, the antitumor agent of the present invention is also a mucosal immunostimulatory agent, an upper gastrointestinal mucosal mucosal immunological activator, a craniofacial mucosal immunological activator, and particularly an oral mucosal mucosal immunological activator. be.

Although not limited, it is preferable to remove the "lipid bound to the active ingredient" by performing, for example, step (2) described later in the production of the antitumor agent of the present invention. Since the concentration of the active ingredient is substantially increased when the lipid is removed in this way, the present invention is compared with the conventional one in which excess lipid is bound to wastefully increase the mass (blending amount). The single intake of the antitumor agent is preferably kept even lower.

The antitumor agent of the present invention further exerts the above-mentioned effects when taken when the parasympathetic nerve is dominant. In particular, it is preferable to take the drug after 5 pm to 5 am the next day because the time zone is generally predominantly parasympathetic. Particularly preferably, it is taken after 7:00 pm by 5:00 am the next day. When it is taken a plurality of times a day, it is preferable to take it at least once in the above-mentioned time zone, but it is particularly preferable to take it all times in the above-mentioned time zone from the above-mentioned point.
Ingestion while granulocytes in the blood are activated may diminish the "antitumor effect of lymphocyte activation".

For 30 minutes or more (preferably 1 hour or more before and after) of oral intake, acidic foods and drinks such as fruits, juices, vinegars, and vitamin C; alcohol-containing foods and drinks such as alcohol; toothpastes such as toothpaste and toothpaste; Polyphenols (containing foods and drinks); tea, coffee, (kara) peppers (containing foods), stimulants such as cigarettes; chlorine-containing tap water; etc. can be absorbed through the mucous membrane of the upper digestive tract without eating or drinking. , It is preferable to efficiently exert the above effect. Furthermore, it is particularly preferable not to take the above-mentioned food and drink for 1 hour or more before oral ingestion. The above-mentioned foods and drinks may suppress the absorption of the antitumor agent of the present invention from the oral mucosa.

In addition, it is effective from the oral mucosa not to drink or eat tap water, physiological saline, water such as pure water; other foods; etc. for 1 hour or more (preferably 1.5 hours or more) after ingestion. Preferred for absorbing components. By doing so, the sensitivity of the mucous membrane of the upper gastrointestinal tract (oral cavity) can be increased.

Furthermore, the antitumor agent of the present invention is preferably absorbed through the mucosa of the upper gastrointestinal tract without using morphine and / or an anticancer agent. When the antitumor agent of the present invention is taken while using morphine and / or an anticancer agent, lymphocytes may not be activated, immune function may not be activated, etc., and as a result, the antitumor effect may be reduced. be.
In addition, since the number of lymphocytes is generally drastically reduced when an existing anticancer drug is administered, sufficient lymphocyte activation (increase in number) may not be achieved even if the antitumor drug of the present invention is taken.

The period during which morphine and / or an anticancer drug is not used (for example, 1 day or more before and after, 2 days or more before and after, 3 days before and after 60 days is further preferable, and 4 days before and after 30 days before and after is particularly preferable. ), It is desirable to take the antitumor agent of the present invention.
The antitumor agent of the present invention does not directly attack the tumor (cancer) unlike the conventional anticancer agent, but acts on the immune function to indirectly attack the tumor (cancer).

The antitumor agent of the present invention is taken orally and kept in the oral cavity for 30 seconds or more so as to be in contact with saliva, taken when the parasympathetic nerve is dominant, from 5 pm to 5 am the next day. It is particularly preferable to use it as an antitumor agent having a limited use, such as one to be taken.

The active ingredient of the antitumor agent of the present invention contains "choline or choline derivative". "Choline" is a quaternary ammonium cation represented by the following formula.
(CH3) 3N + (CH2) 2OH X-
Here, "X-" is a counter anion such as chloride ion, hydroxide ion, and tartrate ion.
The "choline derivative" refers to a derivative having the above-mentioned "choline" skeleton in its chemical structure and a chemical structure having a chemical structure converted to acetylcholine in the human body as its main chemical structure.
Examples of the "choline or choline derivative" include choline, acetylcholine, phosphocholine, glycerophosphocholine, phosphatidylcholine, and a part of sphingomyelin.

The antitumor agent of the present invention preferably contains "choline or choline derivative" in an amount of 0.01% by mass or more, preferably 0.03% by mass, based on the total amount of the active ingredient excluding "sugar or sugar derivative". The content is more preferably 0.1% by mass or more, and particularly preferably 0.1% by mass or more.

The antitumor agent of the present invention contains, as its active ingredient, a winter worm summer grass extract derived from wild silkworm, a propolis extract, an agaricus mushroom extract, and a Reishi extract, and the active ingredient is a measurement example of Examples. As described in the above, it was confirmed that it contained "choline or a choline derivative" called acetylcholine.
This supports that the antitumor agent of the present invention is effective in the application of parasympathetic nerve dominance. In addition, as described in Examples, ingestion of the antitumor agent of the present invention makes the patient sleepy, which confirms that the antitumor agent of the present invention is effective for the purpose of parasympathetic nerve dominance. The antitumor agent of the present invention is useful both as a parasympathetic nerve dominant agent and as a sleep-inducing agent because it promotes sleep.

The antitumor agent of the present invention is in the form of powder or granules. In addition to containing "sugar or sugar derivative", "powder or granules", when ingested orally, the upper gastrointestinal tract (range from the oral cavity, esophagus, stomach to the duodenum), especially the oral cavity or esophagus. It is easily absorbed into the body and exerts the above-mentioned effect of the present invention.
The antitumor agent of the present invention is a powder or granule, and one packet (1 unit) of the antitumor agent as a whole preferably contains 0.3 g or more and 3 g or less, and preferably 0.5 g or more and 2 g or less. It is more preferable, and it is particularly preferable to contain 0.7 g or more and 1.5 g or less.
When the antitumor agent per packet (1 unit) is in the above range, for example, when it is ingested in a particularly preferable range of "pack / dose", it becomes a suitable single intake amount.

Therefore, a suitable single intake of the antitumor agent of the present invention is in the range of a value obtained by multiplying the number of packets taken at one time by the amount of the antitumor agent contained in the above 1 packet (1 unit). .. That is, it is preferably 0.3 g or more and 5 g or less, more preferably 0.5 g or more and 4.5 g or less, and particularly preferably 0.7 g or more and 4 g or less.

When the amount of the antitumor agent per packet (1 unit) or the single intake of the antitumor agent is not more than the above upper limit, the above-mentioned "effect when the content of the active ingredient is not more than the above upper limit" is obtained. It becomes easier to exert. On the other hand, if it is equal to or more than the above lower limit, the intake amount is sufficient, and it cannot be said that the intake amount is too small to exert the effect of the present invention.

The above antitumor agent is preferably produced by a production method including the following steps (1) to (9). That is, the present invention is a method for producing a parasympathetic-dominant lymphocyte-activated antitumor agent by absorption of the upper gastrointestinal mucosa, which comprises the following steps (1) to (9). It is also a method for producing an activated antitumor agent.

(1) At least one raw material selected from the group consisting of Cordyceps sinensis derived from wild silkworm, Propolis, Agaricus mushroom, and Reishi is immersed in a mixed solvent X of alcohol and water, and then allowed to stand at room temperature. A step of filtering to obtain the filtrate A.
(2) A step of adding a lipolytic enzyme to the filtrate A obtained in step (1) to perform enzymatic treatment, and then filtering to obtain filtrate B.
(3) A step of distilling off the mixed solvent from the filtrate B obtained in step (2) to obtain a solid product F.
(4) A step of obtaining a solid G from the solid F obtained in the step (3) by using a supercritical extraction method.
(5) A step of dissolving the solid substance G obtained in step (4) in a mixed solvent Y of alcohol and water, and further dissolving niacinamide therein to obtain a solution J.
(6) A step of obtaining powder P from the solution J obtained in step (5) or the concentrated solution of the solution J by a spray-drying method.
(7) A step of dissolving the powder P obtained in step (6) and the above sugar or sugar derivative in a mixed solvent Z of alcohol and water to obtain a solution K.
(8) A step of obtaining powder Q from the solution K obtained in step (7) or the concentrated solution of the solution K by a spray-drying method.
(9) In step (1), if there is a raw material not selected from the group consisting of Cordyceps sinensis derived from wild silkworm, propolis, agaricus mushroom, and Reishi, the step of mixing the extract of the unselected raw material. ..

The above steps (1) to (9) are performed on at least one of wild silkworm-derived Cordyceps sinensis, Propolis, Agaricus mushroom, or Reishi, but at least wild silkworm-derived Cordyceps sinensis is preferably subjected to the above step. At least, it is more preferable to carry out the above-mentioned steps for Cordyceps sinensis and Propolis derived from wild silkworms, and it is particularly preferable to carry out the above-mentioned steps for all of Cordyceps sinensis, Propolis, Agaricus mushrooms and Reishi derived from wild silkworms.

From the group consisting of Cordyceps sinensis, propolis, agaricus mushroom, and Reishi derived from wild silkworms, first select one species, perform steps (1) to (8), and then perform steps (1) to (8) separately for the other three species (1). It is most preferable to carry out ~ (8) and finally mix them in step (9). In that case, the above steps are performed for all the above four types.

The raw materials that are preferably subjected to the above steps (1) to (9) are those for which static extraction in the step (1) is particularly effective, and the effect of enzymatically treating in the step (2) to mainly remove lipids. Those having a particularly high effect, those having a high effect of niacinamide added in the step (5), and the like.

In step (1), at least one raw material selected from the group consisting of wild silkworm-derived Cordyceps sinensis, propolis, agaricus mushroom, and Reishi is immersed in a mixed solvent X of alcohol and water and allowed to stand at room temperature. After that, filtration is performed to obtain filtrate A.

The raw material may be undried or dried. The ratio of the total mass (kg) of all the raw materials to the volume (L) of the mixed solvent X is not particularly limited and may follow a conventional method, but is preferably 1: [0.6 to 10], and 1: [1]. ~ 5] is more preferable, and 1: [2 to 3] is particularly preferable. Within this range, the solvent is not wasted, it does not take time and cost to distill off the solvent, and immersion and stirring are preferably performed to improve the extraction efficiency.

The alcohol is determined from the extraction efficiency, safety to a living body, boiling point, etc., and examples thereof include ethanol, propanol, butanol, propylene glycol, ethylene glycol, butylene glycol, and glycerin. Among them, ethanol is particularly preferable from the above points and the like.

The ratio of alcohol (preferably ethanol) and water in the mixed solvent X is preferably 45 to 98% by volume, preferably 60 to 98% by volume of alcohol (particularly preferably ethanol) with respect to the total mixing volume of both when preparing the mixed solvent X. 95% by volume is more preferable, 75 to 90% by volume is particularly preferable, and 80 to 85% by volume is most preferable.

Filtration is performed after allowing to stand at least at room temperature, but it is sufficient if there is a period of standing, and stirring or vibration may be applied in the middle. The total period of standing is preferably 1 day or more, more preferably 2 to 10 days, and particularly preferably 3 to 6 days. It suffices if there is at least a period of standing at room temperature, and there may be a period of heating (preferably 60 ° C. or less) in the middle. The above-mentioned "room temperature" means 5 ° C. to 40 ° C., preferably 10 ° C. to 35 ° C., and particularly preferably 15 ° C. to 30 ° C.

The above-mentioned filtration may follow a conventional method, and examples thereof include suction filtration, pressure filtration, and natural filtration. Filter media and the like are also appropriately selected. Decantation may be added before filtration or the like.

In the step (2), a lipolytic enzyme is added to the filtrate A obtained in the step (1) for enzymatic treatment, and then filtration is performed to obtain a filtrate B.
Examples of the lipolytic enzyme include lipase that decomposes an ester of glycerin to release a fatty acid, phospholipase that decomposes a phospholipid, and the like, and lipase is preferable.

The enzyme treatment is carried out, for example, at room temperature (the definition and the preferable range are the same as above), preferably 1 to 10 hours, more preferably 2 to 6 hours. It is preferable to add stirring as appropriate during the treatment.
The mass of the lipolytic enzyme added to the volume of the filtrate A is not particularly limited, but is preferably 3 g to 300 g, more preferably 10 g to 100 g, and 20 g to 60 g with respect to 1 L of the filtrate A. Especially preferable.

The filtration for obtaining the filtrate B by filtration may be performed according to a conventional method, and examples thereof include suction filtration, pressure filtration, and natural filtration. Filter media and the like are also appropriately selected. Decantation may be added before filtration or the like.

In the step (3), the mixed solvent is distilled off from the filtrate B obtained in the step (2) to obtain a solid F. The mixed solvent is mainly derived from the mixed solvent X added in the step (1). It is preferable to distill off the mixed solvent by heating and / or reducing the pressure.
The above-mentioned "solid substance F" includes an anti-solid substance, a substance in a Harz state, a substance containing a small amount of a mixed solvent, and the like.

In the step (4), a solid G is obtained from the solid F obtained in the step (3) by using a supercritical extraction method. The supercritical extraction method is performed according to a conventional method. Carbon dioxide is preferable as the extraction fluid used in the supercritical extraction method. That is, in step (4), it is preferable to use the supercritical carbon dioxide extraction method.

In the step (5), the solid substance G obtained in the step (4) is dissolved in a mixed solvent Y of alcohol and water, and niacinamide is further dissolved therein to obtain a solution J.
The actually used composition of the mixed solvent Y may be different from the actually used composition of the mixed solvent X, but the preferable composition range of the mixed solvent Y is the same as the above-mentioned preferable composition range of the mixed solvent X. It is the same.

Although niacinamide is dissolved, it is preferable that the niacinamide is once dissolved in a solvent and then the solution is dissolved in the mixed solvent Y of the solid G. The preferable range of the solvent is the same as the above-mentioned preferable composition range of the mixed solvent X.
By using niacinamide, the niacinamide (derived product) remains in the final antitumor agent, and parasympathetic dominance and / or lymphocyte activation of the antitumor agent is promoted.

The amount of niacinamide used is preferably 0.3 parts by mass or more and 3 parts by mass, and more preferably 0.5 parts by mass or more and 2 parts by mass with respect to 1 part by mass of the entire raw material used in the step (1). 0.7 parts by mass or more and 1.5 parts by mass are particularly preferable.

In step (6), powder P is obtained from the solution J obtained in step (5) or the concentrated solution of the solution J by a spray-drying method. The spray-drying method is carried out according to a conventional method.
As a method for obtaining the concentrated solution from the solution J, a method of distilling off the solvent is preferable, and distilling under reduced pressure is particularly preferable. Regarding the concentration rate, it is preferable to concentrate to a concentration, viscosity, etc. that can be preferably used by the spray-drying method.

In the step (7), the powder P obtained in the step (6) and the sugar or sugar derivative are dissolved in a mixed solvent Z of alcohol and water to obtain a solution K.
The preferred ones and ranges of the "sugar or sugar derivative" used here are as described above. As the "sugar or sugar derivative", maltitol is particularly preferable. Moreover, the preferable composition range of the mixed solvent Z is the same as the above-mentioned preferable composition range of the mixed solvent X.

The preferable amount of the "sugar or sugar derivative" (preferably maltitol) to be used is such that the ratio of the above-mentioned "active ingredient to the" sugar or sugar derivative "is the above-mentioned preferable ratio. That is, the "sugar or sugar derivative" is added so that the content of the active ingredient in the antitumor agent becomes the above-mentioned preferable content.

Although not limited, specifically, when the step is performed on all of Cordyceps sinensis, Propolis, Agaricus mushroom, and Reishi derived from wild silkworms, the four active ingredients are applied to the entire antitumor agent. On the other hand, for example, when all of them are set to 5% by mass, the four kinds of extracts, which are the active ingredients, are each about 20% by mass (5% by mass x 4 kinds) with respect to the total amount of the antitumor agent. A "sugar or sugar derivative" (preferably Martinol) is added so that the powder Q obtained in the step (8) is finally mixed in equal amounts.

The powder P obtained in the step (6) may be used as a solution, and the “sugar or sugar derivative” may also be used as a solution, and the two solutions may be mixed to obtain a solution K dissolved in the mixed solvent Z.

In step (8), powder Q is obtained from the solution K obtained in step (7) or the concentrated solution of the solution K by a spray-drying method. The spray-drying method is carried out according to a conventional method.
Regarding the concentration, it is preferable to concentrate to a concentration, viscosity, etc. that can be preferably used by the spray-drying method.

In step (9), if there is a raw material not selected from the group consisting of Cordyceps sinensis, propolis, agaricus mushroom, and Reishi from wild silkworm in step (1), an extract of the unselected raw material is used. Mix. The extraction method of the raw materials not selected is not particularly limited.
As described above, in step (1), one of four types is selected, steps (1) to (8) are performed, and then steps (1) to (8) are separately performed for the other three types. Finally, in step (9), it is most preferable to mix them, but in step (1), two or more kinds are selected, starting from the two or more kinds of mixed raw materials, and simultaneously in steps (1) to (8). May be done.

In the above step (1), it is preferable that at least one raw material selected from the group consisting of wild silkworm-derived Cordyceps sinensis, propolis, agaricus mushroom, and Reishi mushroom is wild silkworm-derived Cordyceps sinensis. In other words, at least "Caterpillar fungus derived from wild silkworm" is more preferably extracted through the above steps (1) to (8).
Further, it is particularly preferable to perform all of the above steps (1) to (9) to extract all of the caterpillar fungus, propolis, agaricus mushroom, and Reishi derived from wild silkworms.

It is such that it is manufactured by using the "manufacturing method including steps (1) to (9)" in the above-mentioned manufacturing method of "parasympathetic nerve-dominant lymphocyte activation antitumor agent by absorption of upper gastrointestinal mucosa". A certain antitumor agent exerts the above-mentioned effect of the present invention more.

Antineoplastic agents, such as those produced using the "manufacturing method including steps (1) to (9)", are considered to contain hundreds or more of the components, and the components should be identified. , It is impossible or almost impractical to identify a small number of effective substances that exert the effects of the present invention from those components (there are "impossible / impractical circumstances").
For objects containing multiple types of natural products, beyond the difficulty of identifying the structure of the contained components, there is no simple laboratory method for determining whether or not they are active ingredients, so directly in mammals. Ultimately, it must be done in humans, and even more so, it is impossible or almost impractical (there are "impossible / impractical circumstances").
Therefore, there is no method other than specifying the particularly preferable "antitumor agent of the present invention" by the production method.

The antitumor agent of the present invention can be administered to a patient with a malignant tumor, cancer, etc., but as an administration to a patient other than the patient, the antitumor agent for the purpose of preventing cancer, etc. It can also be used for deep sleep and sleep induction. The antitumor agent of the present invention is also useful as a cancer preventive agent, a parasympathetic nerve dominant agent, and a sleep-inducing agent.

In the method of ingesting the antitumor agent of the present invention, it is essential to keep it in the oral cavity for 30 seconds or more so that the active ingredient of the antitumor agent of the present invention is absorbed into the body in the upper gastrointestinal tract (particularly the oral cavity). Is. It is preferably allowed to stay for 45 seconds or longer, more preferably 1 minute or longer. In addition, it is preferable not to swallow it intentionally. It is also preferable to use water to prevent swallowing. A "sugar or sugar derivative" (particularly preferably maltitol) reduces the unpleasant taste of the active ingredient even if the active ingredient is retained in the oral cavity.
It has been actually confirmed in Examples that the antitumor agent of the present invention exerts its effect when ingested so as to remain in the oral cavity for 30 seconds or longer. When it reaches the lower gastrointestinal tract and is absorbed there, the effect of the antitumor agent of the present invention may be reduced as described above.

Since the effect of the antitumor agent of the present invention is enhanced by staying in the oral cavity, the antitumor agent of the present invention is absorbed by the mucous membrane in the oral cavity when ingested, and the effect of lymphocytes activated by the mucous membrane. Is thought to have spread to lymphocytes throughout the body.
Therefore, the antitumor agent of the present invention is also an immunostimulatory agent, a mucosal immunological activator, a craniofacial mucosal immunological activator, and particularly an oral mucosal mucosal immunological activator.

The antitumor agent of the present invention is preferably taken at least once a day, more preferably twice a day or more, and particularly preferably three times or more a day. The upper limit is not particularly limited, but it is preferable to take it 7 times or less a day, and it is particularly preferable to take it 5 times or less a day.

The antitumor agent of the present invention is preferably taken after 5 pm by 9 am the next day, and particularly preferably after 5 pm by 5 am the next day. The parasympathetic nerve can be further predominant during the time period when the parasympathetic nerve is already predominant. It is particularly preferable to take it after 7 pm and by 5 am the next day.
When ingested multiple times a day, it is preferable to take at least once in the above-mentioned time zone, and it is more preferable to take at least half of the ingestion times in the above-mentioned time zone. Is particularly preferable to be ingested during the above time period.
Patients with tumors (cancer patients) often wake up multiple times in the middle of the night, but by taking each time, it is possible to take multiple times (preferably almost all times) during the above time period. It becomes.

The antitumor agent of the present invention exerts its effect by being ingested into the human body by a specific method and absorbed through the mucous membrane of the upper gastrointestinal tract (particularly the oral mucosa).
As described above, the proof that the "antitumor agent limited to a specific method of administration" of the present invention is absorbed into the human body through the mucous membrane of the upper gastrointestinal tract (particularly the oral mucosa) is as described above (for example, [ [Effect of the invention], etc.), and further, the principle of action that absorption from the mucosa of the upper gastrointestinal tract (particularly the mucosa of the oral cavity) is effective for the manifestation of the antitumor effect is considered as follows. There is.

A mucosal immune system different from the systemic immune system is constructed in the mucosa, and some cells have been specifically identified as cells responsible for the mucosal immune system.
Furthermore, mucosal immune mechanisms present in the oral cavity including tonsils, sublingual, etc .; nasal cavity; eyes including conjunctiva, lacrimal sac, etc.; Is becoming clear.

If a living body is likened to a thick cylinder, one thick cylinder runs from the oral cavity to the anus. The outer surface of the cylinder is covered with skin, the inner surface of the cylinder is covered with mucous membranes, and various organs are arranged in a thick portion between them. The mucous membrane covering the inner surface of the cylinder, including the villous structure of the digestive tract and the alveolar structure of the lung, has an area of about 360 m2 in humans, which is about 200 times or more that of the skin which is the outer surface of the cylinder. It has an area and is in contact with the outside world (inside the digestive tract).
Therefore, 60% to 70% or more of lymphocytes in the living body are distributed in the mucous membrane, and necessary substances are absorbed and unnecessary substances are excluded from the outside world (inside the digestive tract). ..
And these lymphocytes not only form the mucosal immune system to protect the mucosal surface, but also affect the systemic immune system.

Thus, the upper gastrointestinal mucosal immunology, and the craniofacial mucosal immunology, especially the oral mucosal immunology, are extremely large (large) in terms of the area of the mucosa and the number of lymphocytes, and thus dominate the antitumor effect. It is considered that it has an influence on the target.
Since the antitumor agent of the present invention is made of a natural material, it is easily absorbed through the mucous membrane, and it is considered that the antitumor agent exerts an antitumor effect by effectively acting on the immune system originally possessed by humans.

In the method for administering the preparation according to the present invention, an active oxygen scavenger for oral ingestion is orally ingested during the time when the sympathetic nerve is dominant, and an antitumor agent is orally ingested during the time when the parasympathetic nerve is dominant. Microorganisms are detected and absorbed by the mucosa of the upper gastrointestinal tract, which has an immune response that transmits the detection of microorganisms to the brain. As a result, the immune function could be effectively enhanced.

These two drugs are the world's first, do not require anti-cancer drugs or radiation therapy, have no side effects, are much cheaper than molecular-targeted drugs, and can be used for most cancer patients other than "lymphatic leukemia". In particular, patients with "end-stage myeloid leukemia" who have to perform bone marrow fluid transplant surgery by forcibly reducing white blood cells to zero, which is extremely harsh to the living body, can eliminate the need for transplant surgery with the above two drugs and do their own work. Can be relieved.
In addition, the two agents are made with natural formulations. For this reason, the antitumor agent predominates in the parasympathetic nerve by its ingestion, so that it can also be a "sustainable telomere reinforcing agent" that allows sufficient sleep and further reduces stress. In addition, the active oxygen scavenger for oral ingestion also serves as a "protective agent for telomere and DNA damage".

Claims (1)

The active oxygen scavenger was orally ingested during the time when the sympathetic nerve was dominant, and the lymphocyte-activating antitumor agent was orally ingested during the time when the parasympathetic nerve was dominant.
Detecting microorganisms and absorbing them in areas of concentration of lymphatic vessels in the oral cavity that have an immune response that transmits the detection of the microorganisms to the brain.
A method for administering a pharmaceutical product.