JP6945874B2 - Pharmaceutical composition for oral administration - Google Patents

Description

The present invention relates to a pharmaceutical composition for oral administration, and more particularly to a pharmaceutical composition for oral administration containing testosterone.

In humans, it is known that hormones that bring about the endogenous bliss (Euphorigenic hormone) synthesized in the human body are produced by exercise, light, or skinship between mother and child. As such hormones, for example, endorphin, enkephalin, oxytocin, serotonin and the like are known (Non-Patent Documents 1 to 4). In addition to these, it has been clarified that testosterone and melatonin, which are one of the classic steroid hormones well known as the virilization function in the original development and differentiation, also have such an action ( Non-patent documents 4, 5).

Testosterone is known as a key substance for virilization in the development and differentiation of living organisms, but since it is also a precursor of the female hormone estradiol, its deficiency and decrease are substances that also affect women. ..

Testosterone has recently been found to be involved in clinical patient medical conditions and complaints in the psychiatric field. That is, testosterone has been identified as a substance associated with many cardiac kinetics, and its decrease is due to various human morale, curiosity, ED (Erectile dysfunction), decreased sperm count, and pups in mice. Decreased numbers, sleep disorders, 8050 problems (a situation where parents in their 80s are feeding a withdrawal child in their 50s), and 7040 problems (also a withdrawal child in their 40s is a parent in their 70s) (Non-Patent Document 2), which is deeply involved in human emotions, such as withdrawal, depression (including some bipolar disorders), and other mental illnesses. ~ 4).

In addition to these, it is thought that Alzheimer's disease (AL) and dementia are also caused by chronic microcirculatory insufficiency (blood flow insufficiency) in the brain, but this may be due to multiple causes including serotonin. However, among them, blood flow in the brain is considered to be one of the causes of arteriosclerosis and stenosis of blood vessels. Dementia, Alzheimer's disease, or ED, which are psychiatric disorders that are extensions of this, are also considered to have something in common.

In this regard, a peripheral blood flow improving effect based on a vasodilatory effect of nitric oxide (NO) is known. NO is indispensable for the opening of blood flow by this vasodilation, and there is a nitro agent as a therapeutic agent for angina pectoris, but L-arginine, which is a normal food-derived amino acid, is a raw material in the living body.
In addition, citrulline is important because it is associated with arginine and is involved in arginine production. In addition, ornithine is a precursor of citrulline synthesis (the so-called urea cycle) and is equally important. Further, the depolarization factors in the expansion of the thinnest capillary cell level (Depolarization factor) is involved are also known, which is active oxygen O ₂ ^· produced in vivo ^- will by SOD (superoxide dismutase) _{, It has been proved that H 2} O ₂ produced by being reduced (inactivated) is the true cause of the causative factor. That is, the antioxidant enzyme SOD and other antioxidants suppress the oxidative disappearance of NO, thus prolonging the in vivo life of NO, and the antioxidants indirectly dilate (vascular relaxation) in the same manner as NO. Action → antihypertensive / blood pressure lowering action). That is, it is shown that SOD as an antioxidant component improves peripheral blood flow as well as NO.

In general, adult females have an inherent estrogen-dependent physiology (menstruation) that undergoes menopause with diminished ovarian function. The chief complaint at that time presents with the so-called menopausal symptoms. For the disorder, hormone replacement therapy by supplementation of the so-called female hormone estrogen is known in women. On the other hand, even in men, various disorders due to the depletion of androgens are said (Non-Patent Documents 2 to 5), but their spread is extremely small compared to hormone replacement therapy in women.

The reason is that testosterone is regarded as dangerous in Japan and its administration is a painful injection target. Testosterone, which is soluble only in oil, may have hepatotoxic side effects when administered as it is, and no suitable oral administration agent or efficient application agent (transdermal absorption agent) has been developed so far.

In the United States, there is an Ointment or liposome product called Androgel, which is highly reliable due to the patient's usage (massage and frequency), constitution and low transdermal absorption efficiency of the drug. However, it is not generalized. Furthermore, these are not multi-component compositions, but are composed of one drug component and an absorption aid.

It can be said that the safety of testosterone replacement therapy has been established for the time being. The target males aged 65 and over were effective for morale, antidepressant action, and sexual function, but were most worried about the heart, disorders for cardiovascular disease, and the increase and promotion of prostate cancer. It has been reported that there was no problem (Non-Patent Document 6).

In addition, until now, mainly artificially synthesized foreign chemical substances have been developed as drugs in the psychiatric field, and are generally used in the categories of antidepressants, sedatives, antidepressants, sedatives, anesthetics, etc. There is. Its action was centered on inhibition of neurotransmitters and their receptors and activation of their release. However, few antipsychotics are fully satisfactory, and even sleeping pills are less than ideal.

W.F. Ganong, Review of Medical Physiology, pp. 1-774, Lange Medical Books., Network, CT, USA, especially Chapter 23, PP. 375-413. W. Regelson & C. Colman, The Super-hormone promise-Nature ’s Antidote to Aging, pp.11-346, Simon & Schuster, N.Y, 1996 J.J. Wurtman & S. Suffes, The Serotonin solution, Fawcett Columbine / New York, pp. 1-287, 1996 W. Pierpaoli, W. Regelson, C. Colman, The Melatonin Miracle: Nature's Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone. Simon & Schuster, N.Y. London Shigeo Horie, I feel like I'm crazy! The Strongest Men's Medical Care, Bungei Shinsho, pp. 1-207 (2013) Snyder P.J. et al, New England J. Med. 374 (7), 611-624, 2016

The subject of the present invention is to release the suppression of mental and behavior such as withdrawal, depression, refusal to attend school, suicide and the state of mind of human beings by inducing motivation of human beings, and to make such people into the world as working people. It is to provide a pharmaceutical composition for allowing participation, particularly a pharmaceutical composition that can be orally administered.

As a result of diligent studies to solve the above problems, the present inventors have included testosterone, which is one of the steroid hormones of an endogenous substance synthesized in the human body, which has been known for a long time, as an active ingredient, and further. We have found that the above problems can be solved by preparing a pharmaceutical composition for oral administration containing a substance capable of improving or promoting the absorption of the active ingredient from the intestinal mucosa, and have completed the present invention.
That is, the present invention includes the following aspects.
[1] A pharmaceutical composition for oral administration, which comprises testosterone or a derivative thereof, an absorption enhancer, and a pharmaceutically acceptable carrier.
[2] The pharmaceutical composition according to [1], wherein the absorption enhancer is at least one selected from the group consisting of phospholipids, surfactants, and bile acids and pharmaceutically acceptable salts thereof.
[3] The absorption enhancer is at least one selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylserine, polyoxyethylene sorbitan fatty acid ester, and deoxycholic acid and pharmaceutically acceptable salts thereof, [2]. The pharmaceutical composition according to.
[4] The pharmaceutical composition according to any one of [1] to [3], wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of lipids and water.
[5] The pharmaceutical composition according to [4], wherein the lipid is at least one selected from the group consisting of cooking oil and medium-chain fatty acid triglyceride.
[6] The pharmaceutical composition according to any one of [1] to [4], further comprising another active ingredient.
[7] Other active ingredients are testosterone precursors, cofactors of reactive oxygen scavenging enzyme SOD (superoxide dismutase), antioxidants, endogenous hormones, and vascular endothelial cell-dependent nitric oxide (NO) synthase (NO). The pharmaceutical composition according to [6], which is at least one selected from the group consisting of a substrate of eNOS) and a choline ester.
[8] The pharmaceutical composition according to [7], wherein the other active ingredient is at least one selected from the group consisting of the following active ingredients.
DHEA (dehydroepiandrosterone) or its derivative Zinc compound tocopherol or its derivative Melatonin or its derivative Arginine or its derivative Ornithine or its derivative Citrulline or its derivative Ascorbic acid or its derivative [9] Emulsion, [1] to [8] ] The pharmaceutical composition according to any one of.
[10] The pharmaceutical composition according to [8] or [9], which comprises the combination of the following formulations (A) and (B).
(A) Preparation containing the following ingredients Testosterone or its derivative DHEA (dehydroepiandrosterone) or its derivative Tocopherol or its derivative Melatonin or its derivative Lecithin Edible oil Medium chain fatty acid triglyceride

(B) Preparation containing the following components Zinc compound Arginine or a derivative thereof Citrulline or a derivative thereof Ascorbic acid or a derivative thereof Ornithine or a derivative thereof [11] The pharmaceutical product according to [10], wherein the preparation (A) is a softgel capsule. Composition.
[12] The pharmaceutical composition according to [10] or [11], wherein the preparation (B) is at least one selected from the group consisting of an aqueous preparation, a capsule, and a tablet.
[13] The pharmaceutical composition according to any one of [1] to [12] for inducing motivation.

The pharmaceutical compositions of the present invention can motivate, motivate, and motivate humans, thus resulting in mental and behavioral conditions such as withdrawal, depression, refusal to attend school, suicide, and the state of the human mind. It is possible to release the restraint of such people and allow such people to participate in the world as members of society. Furthermore, according to the present invention, it is possible to activate human emotions and solve the problem of declining birthrate.
In addition, testosterone used in the present invention is safe because it does not have a protein synthesis enhancing effect unlike anabolic hormones.
Furthermore, when the pharmaceutical composition of the present invention is orally administered, it is further mixed with bile acids and the like in the intestinal tract to become chylomicrons (ultrafine particles) in the intestinal tract, which are mainly collected by the lymphatic system and sequentially reach the blood. Can be done. That is, since the pharmaceutical composition of the present invention does not have a direct influx from the intestinal tract → portal vein blood flow → liver, it is possible to avoid liver damage that may occur when testosterone is directly administered. In addition, the pharmaceutical composition of the present invention has an advantage that it remains in the body for a long time and has a long action time because it moves slowly in the lymphatic system.

FIG. 1 shows the time course of the blood testosterone concentration when the pharmaceutical product A described in Test Example 1 was orally administered to mice. FIG. 2 shows the time course of the blood testosterone concentration when the pharmaceutical product B described in Test Example 1 was orally administered to mice.

The pharmaceutical composition of the present invention comprises testosterone or a derivative thereof.
"Testosterone" in the present invention (formula _C 19 _H 28 _{O 2,} the chemical name 17β- hydroxy-4-androstene-3-one) is a steroid hormone that belongs to androgen, which is one of male hormones.
In addition, the "testosterone derivative" in the present invention includes testosterone, an ester of testosterone, an alkylated testosterone, and other derivatives, such as methyltestosterone, testosterone cypionate, and testosterone enanthate. (testosterone enanthate), testosterone propionate, testosterone ketolaurate, testosterone phenylacetate, testosterone undecanoate, testosterone decanoate, testosterone decanoate (Testosterone phenylpropionate) etc. are included.
The testosterone and its derivatives can be produced by a known method, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. In addition, one of these testosterone and its derivatives can be used alone or in combination of two or more.
When the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of testosterone or a derivative thereof is not particularly limited, but is, for example, 0.1% by mass or more, 1% by mass or more, 5% by mass or more, and 10% by mass. % Or more and 40% by mass or more, for example, 90% by mass or less and 60% by mass or less.

The pharmaceutical composition of the present invention contains an absorption enhancer (also referred to as a gastrointestinal absorption enhancer or an intestinal absorption enhancer) in addition to the testosterone or a derivative thereof.
The "absorption-promoting agent" in the present invention is not particularly limited as long as it can improve or promote the intestinal mucosal absorption of the testosterone and its derivatives, but for example, phospholipids (resitin, phosphatidylcholine, phosphatidylserine, etc.), surfactants, etc. (Nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester), bile acids (cholic acid, deoxycholic acid, ursodeoxycholic acid, glycocholic acid, taurocholic acid, etc.) and pharmaceutically acceptable salts thereof, Examples thereof include chelating agents (salicylic acid, EDTA, etc.), fatty acids (capric acid, lauric acid, oleic acid, etc.) and pharmaceutically acceptable salts thereof. Preferred include phospholipids, surfactants, bile acids and pharmaceutically acceptable salts thereof, and more preferably lecithin, phosphatidylcholine, phosphatidylserine, polyoxyethylene sorbitan fatty acid ester, deoxycholic acid and pharmaceutically acceptable salts thereof. Allowable salts and the like can be mentioned. These absorption enhancers can be produced by known methods, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. In addition, one of these absorption promoters can be used alone or in combination of two or more.
In addition, when a phospholipid such as lecithin or a nonionic surfactant such as polyoxyethylene sorbitan fatty acid ester is used as an absorption enhancer, chylomicrons (ultrafine particles) occur in the intestinal tract. The promotion of absorption of the derivative is further enhanced, and the uptake into the lymphatic system is promoted rather than that of the portal system.
In the composition of the present invention, the absorption enhancer is, for example, 0.0001 parts by mass or more, 0.001 parts by mass or more, 0.01 parts by mass or more, and 0.1 parts by mass with respect to 1 part by mass of testosterone and its derivative. Parts or more, 1 part by mass or more, 5 parts by mass or more, for example, 100 parts by mass or less, 50 parts by mass or less, 10 parts by mass or less, 1 part by mass or less, 0.1 parts by mass or less.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the absorption promoter is not particularly limited, but for example, 0.001% by mass or more, 0.01% by mass or more, 0.1% by mass or more. 1, 1% by mass or more, 5% by mass or more, for example, 30% by mass or less, 10% by mass or less, 5% by mass or less, and 1% by mass or less.

Examples of the above-mentioned "lecithin" include soy lecithin, enzymatically decomposed soy lecithin, hydrogenated soy lecithin, egg yolk lecithin, hydrogenated phospholipid, milk-derived phospholipid, lysolecithin, phosphatidylcholine, phosphatidylserine and the like. Preferred examples include soybean lecithin and egg yolk lecithin. These lecithins can be produced by a known method such as using a homogenizer, or commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. In addition, one of these lecithins can be used alone or in combination of two or more.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of lecithin is not particularly limited, but is, for example, 0.01% by mass or more, 0.1% by mass or more, and 1% by mass or more, for example. It is 30% by mass or less, 10% by mass or less, 5% by mass or less, and 1% by mass or less.

The above-mentioned "polyoxyethylene sorbitan fatty acid ester" is a fatty acid ester polyoxyethylene ether in which a part of the hydroxyl group of anhydrous sorbitol is esterified with a fatty acid. For example, polyoxyethylene monolaurate (20) sorbitan (NIKKOL TL-10, polysorbate 20, Tween 20), polyoxyethylene monopalmitate (20) sorbitan (NIKKOL TP-10V, polysorbate 40, Tween 40), polyoxy monostearate. Ethylene (20) sorbitan (NIKKOL TS-10MV, polysorbate 60, Tween60), polyoxyethylene trioxyethylene (20) sorbitan (NIKKOL TS-30V, polysorbate 65), polyoxyethylene monoisostearate (20) sorbitan (NIKKOL TI) -10V), polyoxyethylene monooleate (20) sorbitan (NIKKOL TO-10MV, polysorbate 80, Tween80), polyoxyethylene trioleate (20) sorbitan (NIKKOL TO-30V, polysorbate 85) and the like. Preferably, polyoxyethylene (20) sorbitan monooleate (NIKKOL TO-10MV, polysorbate 80, Tween 80) and the like can be mentioned.
These polyoxyethylene sorbitan fatty acid esters can be produced by known methods, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. Further, one of these polyoxyethylene sorbitan fatty acid esters can be used alone or in combination of two or more.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the polyoxyethylene sorbitan fatty acid ester is not particularly limited, but is, for example, 0.01% by mass or more, 0.1% by mass or more, and 1% by mass. The above is, for example, 30% by mass or less, 10% by mass or less, 5% by mass or less, and 1% by mass or less.

The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier.
The "pharmaceutically acceptable carrier" in the present invention is not particularly limited as long as it is a pharmaceutically acceptable liquid carrier, but for example, lipids, water, various organic solvents, for example, alcohols (ethanol, glycerin, propanol, etc.), etc. Examples thereof include esters (ethyl acetate and the like), ethers (tetrahydrofuran (THF), diethyl ether and the like), aprotonic polar solvents (dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like) and the like. One of these pharmaceutically acceptable carriers may be used alone or in combination of two or more.
The pharmaceutically acceptable carrier in the composition of the present invention is, for example, 0.1 part by mass or more, 1 part by mass or more, 10 parts by mass or more, 50 parts by mass or more, based on 1 part by mass of testosterone and its derivative. It is 100 parts by mass or more, for example, 1000 parts by mass or less, 500 parts by mass or less, 100 parts by mass or less, and 50 parts by mass or less.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the pharmaceutically acceptable carrier is not particularly limited, but for example, 10% by mass or more, 30% by mass or more, 50% by mass or more, 80% by mass. % Or more, for example, 90% by mass or less, 60% by mass or less.

The above-mentioned "lipid" means a compound that is insoluble in water and soluble in an organic solvent, and is not particularly limited. For example, fats and oils such as cooking oil, fatty acid triglycerides that can be extracted from fats and oils, and these are separated and hydrogenated. , Oils and fats processed by ester exchange and the like (for example, hydrogenated oils), their partial glycerides, fatty acids, phospholipids, glycolipids, sterols and the like, and edible oils, fatty acid triglycerides and the like are preferable. These lipids can be produced by known methods, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. In addition, one of these lipids can be used alone or in combination of two or more.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the lipid is not particularly limited, but for example, 5% by mass or more, 10% by mass or more, 30% by mass or more, 50% by mass or more, 80% by mass. % Or more, for example, 90% by mass or less, 60% by mass or less, 50% by mass or less, 20% by mass or less.

The above-mentioned "edible oil" is not particularly limited, but for example, sesame oil, rapeseed oil, soybean oil, palm oil, palm oil, palm kernel oil, flaxseed oil, camellia oil, brown rice germ oil, rice oil, peanut oil, corn oil. , Wheat germ oil, egoma oil, cotton seed oil, sunflower seed oil, capoc oil, evening primrose oil, shea butter, monkey fat, cacao butter, saflower oil, olive oil, pomegranate oil, niggauri oil and other vegetable fats and oils; pork fat, milk fat, Examples thereof include animal oils and fats such as fish oil and beef oil. Preferred are vegetable oils and fats such as sesame oil, rapeseed oil, soybean oil, and corn oil. These cooking oils can be produced by known methods, and commercially available ones can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia or the Japanese Agricultural Standard (JAS) can be used. In addition, one of these cooking oils can be used alone or in combination of two or more.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the edible oil is not particularly limited, but for example, 0.5% by mass or more, 1% by mass or more, 5% by mass or more, and 10% by mass or more. , 30% by mass or more, 50% by mass or more, for example, 90% by mass or less, 60% by mass or less, 50% by mass or less, 20% by mass or less.

Examples of the fatty acid triglyceride that can be extracted from the above-mentioned fats and oils include triglycerides of medium-chain fatty acids having 6 to 12 carbon atoms, preferably 8 to 12 carbon atoms (MCT (Medium Chain Triglcerides), also referred to as medium-chain fatty acid fats and oils). Be done. Specific examples of the medium-chain fatty acid triglyceride include triglycerides such as n-hexanoic acid (caproic acid), n-octanoic acid (caprylic acid), n-decanoic acid (caprylic acid), and n-dodecanoic acid (lauric acid). Be done. These medium-chain fatty acid triglycerides can be produced by known methods, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia or the Japanese Agricultural Standard (JAS) can be used. In addition, one of these medium-chain fatty acid triglycerides can be used alone or in combination of two or more. In particular, the medium-chain fatty acid triglyceride is preferably used in combination with vegetable oils such as sesame oil, rapeseed oil, soybean oil, and corn oil.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the medium chain fatty acid triglyceride is not particularly limited, but for example, 0.5% by mass or more, 1% by mass or more, 5% by mass or more, 15% by mass. % Or more, for example, 50% by mass or less and 20% by mass or less.

The above-mentioned "water" is not particularly limited as long as it is suitable for pharmaceuticals, and examples thereof include purified water, distilled water, pure water, ion-exchanged water, ultra-pure water, RO water and the like.
When the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of water is not particularly limited. For example, when the pharmaceutical composition of the present invention is an oil droplet (O / W type) emulsion in water, for example, 30% by mass. % Or more, 50% by mass or more, 80% by mass or more, 90% by mass or more, for example, 98% by mass or less, 96% by mass or less, 90% by mass or less.
When the pharmaceutical composition of the present invention is a water droplet (W / O type) emulsion in oil, it is, for example, 0.1% by mass or more and 3% by mass or more, for example, 10% by mass or less and 5% by mass or less. ..

The pharmaceutical composition of the present invention may further contain other active ingredients.
The "other active ingredients" in the present invention include those that can contribute to solving the above-mentioned problems of the present invention, and those that can contribute to the stability of the pharmaceutical composition of the present invention and the above-mentioned ingredients. Although not particularly limited, for example, a precursor of testosterone, a cofactor of active oxygen scavenging enzyme SOD (superoxide dismutase), an antioxidant, an endogenous hormone (sleep hormone, anti-aging hormone, etc.) that decreases with age, vascular endothelial cells, etc. Examples thereof include substrates for dependent nitric oxide (NO) synthase (eNOS), choline esters, and the like.

The above-mentioned other active ingredients can be produced by a known method, and commercially available products can be obtained and used. For example, those conforming to the Japanese Pharmacopoeia can be used. In addition, one of these other active ingredients may be used alone or in combination of two or more. In addition, the content of other active ingredients in the pharmaceutical composition of the present invention can be appropriately set based on the common general technical knowledge in the field of pharmaceuticals.

Examples of the above-mentioned "precursor of testosterone" include DHEA (dehydroepiandrosterone) or a derivative thereof.
Examples of the above-mentioned "DHEA (dehydroepiandrosterone) or a derivative thereof" include DHEA, a pharmaceutically acceptable ester thereof, other known derivatives and the like, and specifically, DHEA and dehydroepiandrosterone sulfate. (DHEA-S) and the like. DHEA is a precursor of testosterone and is known to decrease with age.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of DHEA or a derivative thereof is not particularly limited, but is, for example, 1% by mass or more and 10% by mass or more, for example, 10% by mass or less, 5 It is less than mass%.

Examples of the above-mentioned "cofactor of active oxygen scavenging enzyme SOD (superoxide dismutase)" include zinc compounds and the like.
Examples of the above-mentioned "zinc compound" include zinc and pharmaceutically acceptable salts of zinc, and specific examples thereof include zinc acetate and zinc chloride. Zinc is significantly reduced in patients with withdrawal and ED.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of the zinc compound is not particularly limited, but for example, 0.001% by mass or more, 0.01% by mass or more, 0.1% by mass or more. It is 1% by mass or more, for example, 10% by mass or less, 5% by mass or less, and 1% by mass or less.

Examples of the above-mentioned "antioxidant" include tocopherol or a derivative thereof, ascorbic acid or a derivative thereof, and the like.
Examples of the above-mentioned "tocopherol or a derivative thereof" include tocopherol, a pharmaceutically acceptable ester thereof, and other known derivatives, and specific examples thereof include α-tocopherol, β-tocopherol, γ-tocopherol, and δ. -Tocopherol, tocopherol nicotinic acid ester and the like can be mentioned. Tocopherol is known as Vitamin E and is used as an oil-soluble antioxidant.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of tocopherol or a derivative thereof is not particularly limited, but for example, 1% by mass or more, 5% by mass or more, 10% by mass or more, 20% by mass or more. For example, 40% by mass or less and 20% by mass or less.

Examples of the above-mentioned "ascorbic acid or a derivative thereof" include ascorbic acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and other known derivatives, and specifically, L-ascorbic acid. Examples thereof include acids, sodium L-ascorbic acid, calcium L-ascorbic acid, and fatty acid esters of ascorbic acid. Ascorbic acid is known as Vitamin C and is used as an antioxidant.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of ascorbic acid or a derivative thereof is not particularly limited, but is, for example, 0.1% by mass or more, 1% by mass or more, and 10% by mass or more. For example, 20% by mass or less, 10% by mass or less, and 5% by mass or less.

Examples of the above-mentioned "endogenous hormone" include melatonin or a derivative thereof. Melatonin is an endogenous hormone that decreases with age, and examples of the above-mentioned "melatonin or its derivatives", which are said to be sleep hormones and anti-aging hormones, include melatonin, melatonin esters, and other known derivatives. ..
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of melatonin or a derivative thereof is not particularly limited, but for example, 0.05% by mass or more, 0.1% by mass or more, 1% by mass or more, It is 5% by mass or more and 10% by mass or more, for example, 60% by mass or less and 40% by mass or less.

Examples of the above-mentioned "substrate for vascular endothelial cell-dependent nitric oxide (NO) synthase (eNOS)" include arginine or a derivative thereof, citrulline or a derivative thereof, ornithine or a derivative thereof, and the like.
Examples of the above-mentioned "arginine or a derivative thereof" include arginine, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and other known derivatives, and specifically, L-arginine and L. -Arginine hydrochloride, L-arginine ester and the like can be mentioned. Arginine is known as a substrate for eNOS.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of arginine or a derivative thereof is not particularly limited, but for example, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, It is 10% by mass or more, for example, 60% by mass or less, 50% by mass or less, 10% by mass or less, 1% by mass or less, 0.5% by mass or less.

Examples of the above-mentioned "citrulline or its derivative" include citrulline, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and other known derivatives, and specifically, L-citrulline and citrulline. -Examples include malate and the like. L-citrulline is converted in the body to L-arginine, a direct substrate for eNOS.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of citrulline or a derivative thereof is not particularly limited, but for example, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, It is 10% by mass or more, for example, 60% by mass or less, 50% by mass or less, and 10% by mass or less.

Examples of the above-mentioned "ornithine or a derivative thereof" include ornithine, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, other known derivatives and the like, and specifically, L-ornithine, L. -Ornithine hydrochloride and the like can be mentioned. Ornithine is a precursor of citrulline synthesis and is converted in the body via L-citrulline to L-arginine, a direct substrate for eNOS.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of ornithine or a derivative thereof is not particularly limited, but for example, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, It is 10% by mass or more, for example, 60% by mass or less, 50% by mass or less, and 10% by mass or less.

Examples of the above-mentioned "choline ester" include acetylcholine, butyrylcholine, propionylcholine, lactoylcholine and the like, and one of these may be used alone or in combination of two or more.
Further, when the total amount of the pharmaceutical composition of the present invention is 100% by mass, the content of choline ester is not particularly limited, but for example, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, and 10% by mass. % Or more, for example, 60% by mass or less, 50% by mass or less, and 10% by mass or less.

The following active ingredients are preferably mentioned as the above-mentioned other active ingredients.
DHEA (dehydroepiandrosterone) or its derivatives Zinc compound tocopherol or its derivatives Melatonin or its derivatives Arginine or its derivatives Citrulline or its derivatives Ornithine or its derivatives Ascorbic acid or its derivatives

As used herein, the term "pharmaceutically acceptable salt" refers to commonly used non-toxic salts such as alkali metal salts (eg sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg calcium salts, magnesium). Salts with inorganic bases such as (salts, etc.), ammonium salts; for example, amine salts (eg, methylamine salts, dimethylamine salts, cyclohexylamine salts, benzylamine salts, piperidine salts, ethylenediamine salts, ethanolamine salts, diethanolamine salts, triethanol). Organic bases such as amine salts, tris (hydroxymethylamino) ethane salts, monomethyl-monoethanolamine salts, procaine salts, caffeine salts, etc.), basic amino acid salts (eg, arginine salts, lysine salts, etc.), tetraalkylammonium salts, etc. And salt can be mentioned. These salts can be prepared, for example, from the corresponding acids and bases by conventional reactions or by salt exchange.

As used herein, the "pharmaceutically acceptable ester" refers to an aliphatic ester such as a methyl ester, an ethyl ester, a propyl ester, an isopropyl ester, a butyl ester, an isobutyl ester, a t-butyl ester, a pentyl ester, 1-. Lower alkyl esters such as cyclopropyl ethyl esters; lower alkenyl esters such as vinyl esters and allyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters; hydroxy (lower) alkyl esters such as hydroxyethyl esters; methoxymethyl esters, 1- Lower alkoxy (lower) alkyl esters such as methoxyethyl esters; and optionally substituted aryls such as, for example, phenyl esters, trill esters, t-butylphenyl esters, salicyl esters, 3,4-dimethoxyphenyl esters, benzamide phenyl esters and the like. Esters; examples include aryl (lower) alkyl esters such as benzyl esters, trityl esters and benzhydryl esters.

In addition to the above components, the pharmaceutical composition of the present invention may contain additives known in the field of oral administration. Examples of such additives include stabilizers, preservatives, buffers, flavoring agents, suspending agents, emulsifiers, flavoring agents, solubilizing agents, colorants, thickeners and the like. These additives are used in conventional amounts in the field of pharmaceutical technology. In addition, one of these additives may be used alone or in combination of two or more.

The pharmaceutical composition of the present invention may be in the form of an oil-based solution, various emulsions (oil droplet (O / W type) emulsion in water, water droplet (W / O type) emulsion in oil, etc.) and the like. These can be produced by conventionally known methods.

The oily solution contains, for example, lipids (eg, edible oils and medium-chain fatty acids), testosterone or derivatives thereof, and absorption enhancers (lecithin, etc.) that dissolve in the lipids, and other active ingredients and additives as necessary. It can be produced by adding, mixing, stirring and dissolving.

The emulsion can be produced by emulsifying (1) an oil phase containing a fat-soluble component, (2) an aqueous phase containing a water-soluble component, and (3) an emulsifier such as a surfactant. can. The emulsifier can be included in the aqueous phase and / or the oil phase in advance, or can be added when the aqueous phase and the oil phase are mixed.
The oil phase may be either the fat-soluble component itself or a fat-soluble component dissolved in a lipid. Further, the aqueous phase may be either the water-soluble component itself or a water-soluble component dissolved in water.
The fat-soluble component may include, if necessary, a fat-soluble absorption promoter, other active ingredients and additives in addition to testosterone or a derivative thereof, and the water-soluble component may contain a water-soluble absorption promoter, other effective ingredients. May include ingredients and additives.

As the emulsifier, an absorption enhancer may be used, or another emulsifier may be used, but it is preferable to use an absorption enhancer. If another emulsifier is used, the absorption enhancer may be pre-included in the aqueous and / or oil phase.
When an absorption enhancer (lecithin, polyoxyethylene sorbitan fatty acid ester, bile acid, etc.) is also used as an emulsifier, the amount used is 1 to 20% by mass, preferably 2 to 3% with respect to lipid and water. It is mass%.

Specifically, testosterone or a derivative thereof, and if necessary, other fat-soluble active ingredients and additives are added to the aqueous phase containing an absorption enhancer (lecithin, polyoxyethylene sorbitan fatty acid ester, bile acid, etc.). An emulsion can be produced by mixing, stirring and emulsifying.

The temperature of each phase and the temperature at the time of mixing may be appropriately set according to the thermal stability, viscosity, solubility, miscibility, etc. of the components, and can be, for example, in any range from room temperature to 80 ° C. As the device used for mixing, stirring, and emulsification, a device conventionally known in the pharmaceutical field can be used, and examples thereof include a normal stirrer, a homomixer, a continuous flow shearing device, a high-pressure homogenizer, and an ultrasonic disperser.

As the emulsion, an oil droplet (O / W type) emulsion in water is preferable, and the emulsion diameter of the fat-soluble component at that time is preferably smaller from the viewpoint of transparency, gastrointestinal absorbability, etc., for example, 500 nm or less, 150 nm or less, It is preferably 100 nm or less and 50 nm or less. An emulsion having such a small emulsion diameter can be produced by using a strong stirrer such as a high-pressure homogenizer.

The pharmaceutical composition of the present invention can be formulated into various dosage forms (for example, liquids, emulsions, emulsions, capsules, softgel capsules, etc.) by conventionally known methods. When the pharmaceutical composition of the present invention is an oily solution or an emulsion, it is preferably a capsule, and particularly preferably a soft gel capsule (particularly, a soft gelatin capsule composed of gelatin gel). In this case, the encapsulation amount of the pharmaceutical composition of the present invention per capsule is preferably about 100 mg. The capsules used for capsules and softgel capsules are not particularly limited, and capsules known in the pharmaceutical field can be used.

Further, in the pharmaceutical composition of the present invention, an oily solution or emulsion containing testosterone or a derivative thereof and a fat-soluble ingredient may be separately formulated as an aqueous preparation containing a water-soluble active ingredient, or a powder capsule or tablet. .. For example, it may be a pharmaceutical composition containing a combination of two or more kinds of preparations as described below.
(A) Preparation containing the following components (oil-based solution or emulsion)
Testosterone or its derivatives DHEA (dehydroepiandrosterone) or its derivatives Tocopherol or its derivatives Melatonin or its derivatives Lecithin Cooking oil Medium chain triglyceride

(B) Preparation containing the following ingredients (aqueous preparation, powder capsule or tablet)
Zinc compound Arginine or its derivative Citrulline or its derivative Ornithine or its derivative Ascorbic acid or its derivative

The above-mentioned preparation (B) may contain water as a carrier.
In such a case, two or more kinds of preparations can be administered simultaneously, continuously or intermittently separately.

The pharmaceutical composition of the present invention is for oral administration for humans, and can be orally administered to human subjects in various dosage forms (for example, liquid preparations, emulsions, emulsions, capsules, etc.).

The dose of the pharmaceutical composition of the present invention may be appropriately selected according to the age, sex, degree of disease, and other conditions of the subject, and usually, testosterone or a derivative is used per 1 kg of body weight per day in terms of testosterone. It can be administered in 1 to several divided doses so as to be 0.01 to 1000 mg, preferably 0.1 to 500 mg. Since this dose varies under various conditions, a dose smaller than the above range may be sufficient, or a dose exceeding the above range may be required.

The pharmaceutical compositions of the present invention can be used to motivate.
"Inducing motivation" in the present invention includes motivation and motivation, which in turn includes mental and behavioral conditions such as withdrawal, depression, refusal to attend school, suicide, and the state of the human mind. It also includes releasing restraints and allowing such people to participate in the world as members of society.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

[Example 1] Preparation of the oil-based preparation A The oil-based preparation A was prepared by the ratio of the following formulation.
[Prescription of formulation A]
Testosterone Propionate (Wako Pure Chemical Industries, Ltd.) 5 mg
Sesame oil (commercially available) 200 mg
Medium-chain fatty acid fats and oils (Nisshin MCT Oil HS, manufactured by Nisshin Oillio Group Co., Ltd.) 20 mg
Soy lecithin (Wako Pure Chemical Industries) 50 mg

Specifically, each of the above components was well stirred with a homogenizer as shown to obtain a homogeneous oil-based preparation A.
In the above formulation, the amount of testosterone may be 1 to 50 mg.

[Example 2] Preparation of emulsion preparation B Emulsion preparation B was prepared by the ratio of the following formulation.
[Prescription of formulation B]
Testosterone Propionate (Wako Pure Chemical Industries, Ltd.) 5 mg
Tween 80 2% aqueous solution 250 μL

Specifically, testosterone propionate was added to a Tween 80 2% aqueous solution and sonicated for 1 to 2 minutes to obtain a stable oil / water emulsion (emulsion preparation B).

[Test Example 1] Measurement of Blood Testosterone Concentration The preparations A or B according to Examples 1 and 2 were applied to 40 to 50 g of male ddY mice aged about 20 to 25 weeks using a sonde. o. A single dose (testosterone equivalent 100 mg / kg; oil-based preparation: 270 μL / kg for 50 g mice, emulsion preparation: 250 μL for 50 g mice).
Plasma was collected from the non-administered group and heparin blood collected 1, 3, 6, 18, 36, and 54 hours after administration (n = 3 in each group). The non-administered group was regarded as a normal value. After collection, it was stored at -80 ° C.
Then, the plasma testosterone concentration was measured by the CLIA method for plasma (n = 2 in each group) 3, 6, 18, 36, 54 hours after administration without administration. The measurement was performed using a testosterone assay kit (Japan Aging Control Laboratory (Fukuroi City, Shizuoka Prefecture)) according to the instruction method attached to the kit. The results are shown in Tables 1 and 2, FIGS. 1 and 2.

The blood concentration of testosterone was the highest 3 hours after administration of all the preparations. In addition, no significant difference was observed between the oil-based preparation A and the emulsion preparation B.

[Test Example 2] Measurement of blood testosterone concentration and blood alkaline phosphatase (ALP) concentration The oil-based preparation A according to Example 1 was orally administered to rats at 3, 10, 30 mg / kg as a testosterone equivalent in a sonde. .. Plasma testosterone concentration was measured by the CLIA method in the same manner as in Test Example 1 after no administration and 3, 6, 20, 48, 72 hours after administration. At the same time, the blood alkaline phosphatase (ALP) concentration (IU / L) was measured. ALP is measured by the alkaline phosphatase assay kit of Funakoshi Co., Ltd. (Tokyo). This was a reaction in which P-nitrophenyl phosphate was used as a substrate and converted to P-nitrophenol (λmax 405 nm) + phosphoric acid by ALP, and the intensity of the dye at 405 nm was measured and quantified. The results are shown in Tables 3 and 4.

The dose to the rat is 0.48, 1.6, 4.8 mg / kg in terms of human equivalent dose (HED), and 24, 90, 240 mg / 50 kg, assuming that the human body weight is 50 kg. It becomes. This is about the same as the dose of commercially available testosterone intramuscular injection. That is, the dose of a commercially available testosterone preparation: testosterone depot (testosterone enanthate) (Mochida Pharmaceutical Co., Ltd., Tokyo) is 100 to 250 mg / human, and it is used by intramuscular injection every 1 to 4 weeks (Reference: Interview form of the company). Specified). At the time of intramuscular injection in humans, the blood concentration peaked 1 week after administration and could not be detected 21 days later.

On the other hand, when the rat oral administration (sonde) was performed with the oily preparation A: 10, 30 mg / kg, the blood concentration peaked (305.8 ng / dl) after 3 to 4 hours (humans 3 to 4 hours after the rat). Even after 72 hours (corresponding to about 30 days in humans), the value was 1.2 to 1.7 times the normal value (corresponding to the time on the 1st and 2nd days).
In addition, in the oily preparation A, if 100% is absorbed by oral administration of 30 mg / kg and transferred to the blood, the blood concentration will be 1300 μg / ml (assuming that the blood volume of the rat is 64 ml / kg), and administration 3 After hours, the measured blood concentration of this test was 305.8 ng / dl (6 times the normal value of 48.8 ng / dl), and sufficient transfer to blood was observed. At that time, it was used as a liver function marker in rats. There was no significant increase in ALP (alkaline phosphatase), and it can be said that the safety of this drug was confirmed.
The human testosterone reference value (male) is 131-871 ng / dl (from Falco Biosystems). The reference value of ALP in human blood is 110 to 354 (U / L) (from Falco Biosystems).

As far as the concentrations of hepatic functional enzymes (alkaline phosphatase, lactate dehydrogenase (LDH), etc.) in the serum shown in Table 4, hepatic function and renal dysfunction were not observed by oral administration of this oil-modified testosterone preparation.

下記処方の水性製剤を水を使用して調製し、１００ｍｇ全成分／１カプセル程度の割合でカプセルに封入してカプセル剤を得る。また、下記処方を、既知の方法により粉末カプセル剤または錠剤としてもよい。

上記油性製剤ソフトゲルカプセル剤および水性製剤カプセル剤（あるいは粉末カプセル剤または錠剤）を、同時に、または連続的または間欠的に別々に投与する。 [Pharmaceutical example 1]
An oil-based preparation having the following formulation is prepared and encapsulated in a softgel capsule at a ratio of about 100 mg of all ingredients / capsule to obtain a softgel capsule.

An aqueous preparation having the following formulation is prepared using water and encapsulated at a ratio of about 100 mg of all ingredients / capsule to obtain a capsule. In addition, the following formulation may be made into powder capsules or tablets by a known method.

The above-mentioned oil-based soft gel capsules and aqueous-prepared capsules (or powdered capsules or tablets) are administered simultaneously, continuously or intermittently separately.

Since the pharmaceutical composition of the present invention can motivate, motivate, and improve human motivation, mental and behavioral conditions such as withdrawal, depression, school refusal, and suicide, and the state of the human mind. Unsuppress and
It is useful as a pharmaceutical composition that can enable such people to participate in the world as members of society.

Claims (13)

(1) Selected from the group consisting of testosterone, methyltestosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, testosterone ketraurat, testosterone phenylacetate, testosterone undecanoate, testosterone decanoate, and testosterone phenylpropionate. At least one testosterone
(2) At least one selected from the group consisting of DHEA (dehydroepiandrosterone) and dehydroepiandrosterone sulfate (DHEA-S), and
(3) Substrate of vascular endothelial cell-dependent nitric oxide (NO) synthase (eNOS),
(4) Absorption promoter and
(5) A pharmaceutical composition for oral administration, which comprises a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 1, wherein the absorption enhancer is at least one selected from the group consisting of phospholipids, surfactants, and bile acids and pharmaceutically acceptable salts thereof. The second aspect of claim 2, wherein the absorption enhancer is at least one selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylserine, polyoxyethylene sorbitan fatty acid ester, and deoxycholic acid and pharmaceutically acceptable salts thereof. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of lipids and water. The pharmaceutical composition according to claim 4, wherein the lipid is at least one selected from the group consisting of edible oils and medium-chain fatty acid triglycerides. Substrate vascular endothelial cell-dependent nitric oxide (NO) synthase (eNOS) is at least one selected arginine, citrulline, ornithine, and the acceptable salts or Ranaru group their pharmaceutically, wherein Item 8. The pharmaceutical composition according to any one of Items 1 to 5. Further, according to any one of claims 1 to 6, further comprising at least one selected from the group consisting of cofactors of active oxygen scavenging enzyme SOD (superoxide dismutase), antioxidants, endogenous hormones, and choline esters. Pharmaceutical composition. The cofactor of the active oxygen scavenging enzyme SOD (superoxide dismutase) is a zinc compound,
Antioxidants are selected from the group consisting of tocopherols, α-tocopherols, β-tocopherols, γ-tocopherols, δ-tocopherols, tocopherol nicotinic acid esters , ascorbic acid, pharmaceutically acceptable salts thereof, and fatty acid esters thereof. At least one
Endogenous hormones, a melatonin, pharmaceutical composition according to claim 7. The pharmaceutical composition according to any one of claims 1 to 8, which is an emulsion. A combination agent for oral administration, which comprises the combination of the following formulations (A) and (B).
(A) Formulations containing the following ingredients (a1) Testosterone, methyltestosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, testosterone ketraurate, testosterone phenylacetate, testosterone undecanoate, testosterone decanoate, and testosterone phenylpropi At least one selected from the group consisting of onerts,
(A2) At least one selected from the group consisting of DHEA (dehydroepiandrosterone) and dehydroepiandrosterone sulfate (DHEA-S),
(A3) At least one selected from the group consisting of tocopherol, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and tocopherol nicotinic acid ester,
(A4) melatonin,
(A5) Lecithin,
(A6) Cooking oil,
And (a7) Medium Chain Triglyceride

(B) Preparation containing the following ingredients (b1) Zinc compound,
(B2) arginine, and at least one selected from a pharmaceutically acceptable salt or Ranaru group,
(B3) citrulline, and at least one selected from a pharmaceutically acceptable salt or Ranaru group,
(B4) At least one selected from the group consisting of ascorbic acid, a pharmaceutically acceptable salt thereof, and a fatty acid ester thereof.
And (b5) ornithine, and at least one selected from a pharmaceutically acceptable salt or Ranaru group The combination agent according to claim 10, wherein the preparation (A) is a softgel capsule. The combination agent according to claim 10 or 11, wherein the preparation (B) is at least one selected from the group consisting of an aqueous preparation, a capsule, and a tablet. The pharmaceutical composition according to any one of claims 1 to 9 or the combination agent according to any one of claims 10 to 12 for motivating.

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