JPH075484B2 - Blood-brain barrier crossing pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a blood-brain barrier crossing pharmaceutical composition using higher unsaturated fatty acids.

More specifically, the present invention is a composition composed of a higher unsaturated fatty acid derived from a mixed-race animal brain and a drug, which increases the distribution of a drug that is difficult to distribute in the brain due to the blood-brain barrier to the brain. Permeable pharmaceutical composition.

<Prior Art> Blood vessels in the brain of warm-blooded animals have a special structure and prevent disordered distribution of components in blood or drugs absorbed in blood into brain tissue. Therefore, this special structure, namely the blood brain barrier, plays a role in maintaining normal brain function.

However, when there is a disease in the brain and it is not necessary to deliver the drug to the affected area, this blood-brain barrier becomes a large barrier. Even if a drug administered by a method such as oral administration, intravenous injection, or intramuscular injection is taken into the circulating blood, it is not transferred into the brain tissue and most of the administered drugs are wasted.

<Problems to be Solved by the Invention> Therefore, many methods for efficiently transferring a drug into the brain through the blood-brain barrier have been attempted.

For example, SIRapoport et al. Tried to administer a hypertonic solution such as mannitol at the same time as a drug to change the osmotic pressure to open the blood-brain barrier and promote the uptake of coexisting drugs into the brain (Federation Proceedings Vol.43. No.2
P214 to P219 (1984)). However, according to this method, there is a risk that the blood-brain barrier cells will be altered due to changes in osmotic pressure and sequelae will develop.

Japanese Unexamined Patent Publication (Kokai) No. 57-146710 discloses a method for promoting uptake of a drug into the brain by means of blood-brain barrier permeable liposome microcapsules. However, this method has a drawback that the preparation method is complicated and reproducibility is not sufficient.

Generally, the blood and brain barrier permeability of a drug is correlated with the lipophilicity of the drug, and the higher the lipophilicity, the higher the permeability. Therefore, many methods of converting a drug into a derivative having improved lipophilicity have been studied. However, derivatives with improved lipophilicity do not selectively promote uptake into the target organ of the brain, but are distributed widely to organs such as the liver and spleen, and thus to derivatives other than the target organ. It does not help reduce side effects due to the distribution of.

Therefore, it has been desired to develop a blood-brain barrier crossing pharmaceutical composition which is easy to prepare, has a selective distribution of the drug in the brain, and has no side effects such as sequelae.

<Means for Solving Problems> As a result of earnest studies of various lipids as drug carriers, the present inventor has found that certain higher unsaturated fatty acids, more specifically, higher unsaturated fatty acids derived from warm-blooded animal brains. It was found that when a pharmaceutical composition comprising a drug and a drug is administered to a mixed-blooded animal, delivery of the drug to the brain is promoted, the blood-brain barrier function after administration is unchanged, and the preparation method is easy.

There are many lipids such as phospholipids and glycolipids in the brain of warm-blooded animals, but the fatty acid composition of them is becoming more and more clear at present. That is, since the lipids are present in a very small amount and are unstable, it is necessary to develop a high-level analytical method for structural determination. To date, docosapentaenoic acid, docosahexaenoic acid, etc. are known. However, the physiological actions of these higher unsaturated fatty acids are almost unknown, and, so to speak, attempts to utilize these higher unsaturated fatty acids as carriers for drugs have been unknown techniques that have never been known.

The present inventors have found that administration of a composition of these higher unsaturated fatty acids and a drug to a mixed race animal promotes the distribution of the drug to the brain as compared with the conventional method.

Accordingly, the inventors have found that a pharmaceutical composition comprising a higher unsaturated fatty acid and a drug can be formulated to obtain a drug product with an increased distribution of the drug in the brain, and the present invention has been completed.

That is, the present invention is a blood-brain barrier crossing pharmaceutical composition comprising higher unsaturated fatty acids and a drug.

Preferred higher unsaturated fatty acids used in the present invention is the same as higher unsaturated fatty acids and higher unsaturated fatty acids constituting the lipid within a warm-blooded animal brain, higher unsaturated fatty acids C ₁₈ -C ₂₆ Specifically, specifically, 4,7,10,13,16-docosapentaenoic acid (C ₂₂ H ₃₄ O ₂ ), 4,7,1
0,13,16,19- docosahexaenoic acid _{(C 22 H 32 O 2)} , 4,7,10,
13-docosatetraenoic acid _{(C 22 H 36 O 2)} , 7,10,13,16- docosatetraenoic acid _{(C 22 H 36 O 2)} , 4,8,12,16- Ikosatetoraen acid (C ₂₀ H ₃₂ O ₂ ), 5,8,11,14-icosatetraenoic acid (C ₂₀ H ₃₂ O ₂ ), 5,8,11-icosatrienoic acid (C ₂₀ H ₃₄ O ₂ ),
11,14 Ikosajien acid _{(C 20 H 36 O 2)} , 15- tetracosenoic acid _{(C 24 H 46 O 2)} , 2- hydroxy-15-tetracosenoic acid _{(C 24 H 46 O 3)} , ( hydroxy nervonic acid) Etc.

Among these, 4,7,10,13,16-docosapentaenoic acid, 4,7,10,13,16,19-docosahexaenoic acid, 4,7,10,13-docosatetraenoic acid, 7,10, 13,16-docosatetraenoic acid is particularly preferred.

The drug used in the present invention may be any drug as long as it is advantageous to supply a large amount to the brain of a mixed-race animal. Examples of such drugs include drugs having an action point of the drug in the brain and effective drugs for diseased parts in the brain. More specifically, the following drugs may be mentioned.

Hypnotic sedatives include promvalerylurea, metacaron, glutethimide, chloral hydrate, estazolam, flurazepam, triazolam, nitrazepam, nimetazepam, haloxazolam, flunitrazepam, amobarbitan, barbital, phenobarbital, phenobarbital, propariroro, propariroro. Examples include xobarbital, pentobarbital, etinamate, butoctamide semisuccinate, patsiflora extract, perlapin, and secobarbital.

Antiepileptic agents include acetylphenetride, ethylphenacemide, ethtoin, phenytoin, trinetadione, netalbital, nefobarbital, pricidone, sultiam, ethosuximide, carbapazepine, clonazepam, valproic acid and the like.

Antipyretic and analgesic anti-inflammatory agents include acetaminophen, phenacetin, flufenamic acid, mefenamic acid, benzydamine, aspirin, etenzamid, sazapyrine, salicylamide, salicylate choline, antipyrine, isopyropyrantipyrine, oxyphenbutazone, clofuezone, ketophenylbuta. Zon, sulpirine, niphenazone, phenylbutazone, miglenin, alclofenac, ibuprofen, emorfazone, tiaramid, tinolidine, lefetamine, perisoxal, graphenin, kridanak, chlorobutanol, ketoprofen,
Diclofenac, diflunisal, sulindag, sodium trimethine, naproxen, piroxicam, phenylacetylglycine dimethylamide, phenoprofen,
Examples include fuentiazac, fuenbufuen, pucolome, planoprofen, flurbiprofen, flurbiprofen, protidic acid, dimethotheazine methylate, methiazinic acid, mepyrizole, and thiaprofuefic acid.

Excitatory stimulants include methane ethane, strychnine, bemeglide and the like.

Examples of the antispasmodic agents include dimenhydrinate, meclizine, diphenidol, isoprenaline, promethazine, thiethylperazine, betahistine and the like.

Psychiatry and nerve agents include meprobamate, chlorpromazine, spicromazine, thioridazine, triflupromazine, fluphenazine, thioproperazine, perazine,
Perphenazine, propericiadine, perphenazine,
Trifluoperazine, prochlorperazine, levomepromazine, alprazolam, chlordiazepoxide, oxazepam, cloxazolam, chlordiazepoxide, diazepam, fludiazepam, promazepam, mexozolamine, pramipramipramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine, pramipramine.
Carpipramine, trimipramine, amoxapine, etizolam, amitriptyline, chlorprothixene, dibenzepine, nortriptyline, hydroxyzine, pipanperone, piperadol, flupentixol, maprotiline, mianserin, methylphenidate, melitracene, moperone, oxypentyl, clothiazepam , Chlorprothixene, spiperone, sulpiride, thiothixene, timiperone, haloperidol, pimozide, phenylisohydantoinzotepine and the like.

Examples of the drug for central nervous system include γ-amino-β-hydroxybutyric acid, fopanthenic acid, calcium fopantenate and the like.

Examples of the antispasmodic agent include pipetanate, ethyl pipetanate bromide, methylbenactidium bromide, scopolamine, butylscopolamine bromide, butropium bromide, methylatropine bromide, methylanisotropic, bromide, N-methylscopolamine, and iodine. Thimonium chloride, atropine, papaverine, amantadine, trihexyphenidyl, biperidene, pyroheptin, prophenamine, mazathicol, benztropine, levodova, afloqualone, etomidrine, eperisone, diphenylenylhydroxypropionate hydrochloride diaminoethylethyl, diphenenylpiperidinobutinol , Triperizone, methixene, timepidium bromide,
Examples include baclofuen, furopropion, funnel extract, magnesol, piperidene, levodopa, timepidium bromide, and acamilofenin.

Examples of the antihypertensive agent include dihydroergotoxin, clonidine, methyldopa, mebutamate and the like.

Examples of the vasoconstrictor include ergotamine, dihydroergotamine, phenylephrine, methoxacin and the like.

Examples of vasodilators include efloxaate, etafenone,
Oxyphedrine, carbomecron, dilazep, diltiazem, trimetazidine, verapamil, dipyridamole, isosorbide nitrate, trapidil, nicorandil, nitroglycerin, niphedipine, prenylamine, molsidomine, inositol hexanicotinate, isoxpurine, niridrin, citric acid nitricinate, nacranderine , Nicotinic alcohol, hepronicart, etc.

Examples of agents for circulatory organs include nicardipine, pyrithioxine, meclofenoxate, gamma-aminobutyric acid, infuenprodil, cytochrome C, tocopherol nicotinate, pyridinol carbamate, pyrithioxine, vinpocetine, pentoxyfilin, cinepazide maleate, etc. To be

Hormonal agents include human growth hormone, oxytocin, vasopressin, insulin, neurophysin,
Examples include glucagon, motilin, gastrin, cerulein, cholecystokinin, substance P, neurotensin, and calcitonin.

Antitumor agents include thiotepa, mercaptopurine,
Examples include methotrexate, asegraton, procarbazine, carbocon, carmofur, tamoxifen citrate, krestin, cyclophosphamide thioinosine, degafur, improsulfan tosylate, pipobroman, busulfan-5-fluorouracil, mitobronitol, melphalan, and estramustine phosphate. To be

Prostaglandins include prostaglandins
D _2, prostaglandin D ₂ methyl ester, 7-thiaprostaglandin E ₁ include, thia prostaglandin E ₁ compound, 5
-Thiaprostaglandin E ₁ , 4-thiaprostaglandin E ₁ , 7-fluoroprostaglandin I ₂ , isocarbacycline (9 (0 ⁾ -methano-Δ6 ^(9α) -PG
I ₁₎ include, 7-oxo-prostaglandin E ₁ compound, carbacyclin (9 (0) - methano -PGI ₁₎ class, 6 (9.alpha) - Lee plasminogen prostaglandin I _1, and the like can be mentioned.

The composition of the present invention is obtained by mixing such a drug with the higher unsaturated fatty acid, but the drug is dissolved or dispersed in the higher unsaturated fatty acid, or the drug is dissolved in the higher unsaturated fatty acid. Alternatively, it can be obtained by uniformly dispersing the higher unsaturated fatty acids in water. Above all, it is more preferable that the thin product is dissolved or dispersed in higher unsaturated fatty acids and the higher unsaturated fatty acids are uniformly dispersed in fine particles in water.

When a drug is dissolved or dispersed in higher unsaturated fatty acids, the content of the drug varies depending on the drug, but generally 100 m
The range is g to 0.1 ng / ml.

The drug is dissolved or dispersed in higher unsaturated fatty acids, and when the higher unsaturated fatty acids are uniformly dispersed in water, the drug dissolved or dispersed in higher unsaturated fatty acids is added to water. It is carried out by making an oil-in-water type dispersion with a suitable homogenizer. In the process of producing the composition of the present invention as described above, a dispersion aid, a stabilizer, an antiseptic, an isotonicity agent, an antioxidant and the like can be added if necessary.

Examples of the dispersion aid include phospholipids such as phosphatidycholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and sphingomyelin; cholic acid, deoxycholic acid, lithocholic acid,
Bile acids such as chenodeoxycholic acid and salts thereof; non-ionic surfactants such as polyalkylene glycol, polyoxyalkylene copolymer, hydrogenated castor oil polyoxyalkylene derivative, castor oil polyoxyalkylene derivative; albumin, polyvinylpyrrolidone Kind and the like.

Examples of stabilizers include cholesterol, sitosterol, fucosterol, phosphatidic acid and the like.

Preservatives include parabens and sorbic acids.

Examples of the tonicity agent include glycerin and glucose.

Examples of antioxidants include ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, and propyl gallate. When the drug is dissolved or dispersed in higher unsaturated fatty acids and the higher unsaturated fatty acids are finely dispersed in water, the ratio of higher unsaturated fatty acids to water is 95: 5 to 5:95. (Weight ratio), and more preferably
It is 80:20 to 20:80 (weight ratio). The drug content varies depending on the drug but is usually in the range of 100 mg to 0.1 ng / ml.

When the drug is dissolved or dispersed in higher unsaturated fatty acids and the higher unsaturated fatty acids are finely dispersed in water together with other components such as a dispersion aid, 5 to 80 parts of higher unsaturated fatty acids are used. , 0.25 to 30 parts of dispersion aid, proper amount of water and 1 part or less of stabilizer, 1 part or less of preservative, 1 part or less of tonicity agent, 1 part or less together with antioxidant of 100 parts in total And eggplant The drug content varies depending on the drug, but is usually 100 mg.
The range is ~ 0.1 ng / ml.

The composition of the present invention is administered in the form of a solution or dispersion, and in the case of a dispersion obtained by dissolving or dispersing a drug in higher unsaturated fatty acids and dispersing the higher unsaturated fatty acids in water, It is preferably oil-in-water type and has a smaller oil droplet particle size. Usually several 10μ to 0.001μ and several μ to 0.0
About 1 μm is more preferable. The dispersion having these average particle diameters is produced by homogenizing with a pressure jet homogenizer, an ultrasonic homogenizer, or the like.

The composition of the present invention is preferably parenterally administered as an injection as it is, and more preferably intravenous administration.

<Effect of the Invention> According to the pharmaceutical composition of the present invention, it becomes possible to effectively deliver a drug that does not easily pass through the blood-brain barrier into the brain,
To provide a novel pharmaceutical composition for treating brain diseases, which is effective not only for treating brain tumors but also for enhancing efficacy of neuropsychiatric agents, cerebral blood flow improving agents, cerebral metabolism activating agents, etc. and reducing side effects As a matter of fact, the significance of the present invention is great.

<Example> Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 4,7,10,13,16- docosapentaenoic 60 parts penta-enoic acid, 2 parts of phosphorene full Aci choline, 38 parts of water and [N- methyl - ³ H] - take diazepam, homogenizer (Polytron PT75TODS
Ultrasonic homogenizer (SMURT NR-2)
(Type 0) to obtain a homogeneous dispersion. [N-methyl-
^{The 3} H] -diazepam concentration was 20 μCi / ml.

0.5 ml of the above dispersion was injected into the tail vein of SD rat (male, body weight: about 160 g), and 5 minutes after the injection, the blood was killed by bleeding, and the cranium of the skull was taken out and homogenized as usual in brain tissue. Was measured. At the same time, the radioactivity was similarly measured for the liver.

At the same time, oleic acid was used instead of 4,7,10,13,16-docosapentaenoic acid, and otherwise 0.2% arabic gum suspension of control example 1 and diazepam prepared in exactly the same manner as in example 1 ([ N- methyl - ³ H] - diazepam concentration = 20μCi / ml)
The same test was performed for Control Example 2 which is

Table 1 shows the results of calculating the amount of radioactivity per gram of brain and gram of liver and comparing the three cases of Example 1 and Controls 1 and 2.

Compared with Control Examples 1 and 2, the brain concentration of diazepam in Example 1 using 4,7,10,13,16-docosapentaenoic acid was remarkably increased, and the concentration in the liver was not increased as much as the brain. Recognize.

Example 2 4,7,10,13,16-docosahexaenoic acid was used in place of 4,7,10,13,16-docosapentaenoic acid of Example 1, and homogeneous dispersion was carried out as in Example 1. A liquid was prepared.

In Control Example 3, oleic acid was used instead of 4,7,10,13,16,19-docosahexaenoic acid, and in Control Example 4, a suspension of diazepam in gum arabic was used. Both are [N-methyl-
^{The 3} H] -diazepam concentration was adjusted to 20 μCi / ml.

In the same manner as in Example 1, SD rats were intravenously injected, and after 5 minutes, the amounts of radioactivity in the brain and liver were measured and compared.

It can be seen that the brain concentration of diazepam of Example 2 using 4,7,10,13,16,19-docosahexaenoic acid is higher than that of Control Examples 3 and 4, and that the concentration in the liver is not as high as in the brain. .

Example 3 4,7,10,13,16- docosapentaenoic 60 parts penta-enoic acid, 2 parts of phosphorene full Aci choline, 38 parts of water and 5-fluoro [6- ¹⁴ C]
Take uracil and homogenize (Polytron PT75TODS
Ultrasonic homogenizer (SMURT NR-2)
(Type 0) to obtain a homogeneous dispersion. 5-fluoro [6
- ¹⁴ C] uracil concentration was found to be 20μCi / ml.

0.5 ml of the above dispersion was injected into the tail vein of an SD rat (male, body weight: about 160 g), and 5 minutes after the injection, the blood was killed by bleeding. The skull was split and the brain was taken out and homogenized in the usual manner. The amount of radioactivity was measured. At the same time, the radioactivity was similarly measured for the liver.

At the same time, oleic acid was used in place of 4,7,10,13,16-docosapentaenoic acid, and otherwise 0.2% arabic gum suspension of Control 5 and 5-fluorouracil prepared exactly as in Example 3. (5- Furuorofu [6- ¹⁴ C] uracil concentration = 20μCi / ml) were similarly tested control example 6 is.

Table 3 shows the results of calculating the amount of radioactivity per gram of brain and gram of liver and comparing the results for Example 3, Controls 5 and 6.

5-Fluorouracil in Example 3 using 4,7,10,13,16-docosapentaenoic acid showed a marked increase in the brain concentration and that in the liver was not so elevated as compared with Control Examples 5 and 6. I understand.

Example 4 In the same manner as in Example 3, except that 4,7,10,13,16-docosapentaenoic acid in Example 3 was replaced with 4,7,10,13,16,19-docosahexaenoic acid, a homogeneous dispersion was obtained. A liquid was prepared.

In Comparative Example 7, oleic acid was used instead of 4,7,10,13,16,19-docosahexaenoic acid, and in Comparative Example 8, a suspension of 5-fluorouracil in gum arabic was used. Both 5-fluoro [6- ¹⁴ C] uracil concentration was adjusted to be 20μCi / ml.

SD rats were intravenously injected in the same manner as in Example 3, and 5 minutes later, the amounts of radioactivity in the brain and liver were measured and compared. The results are shown in Table 4.

5-Fluorouracil of Example 4 using 4,7,10,13,16,19-docosahexaenoic acid had a higher intracerebral concentration than that of Control Examples 7 and 8, and the concentration in the liver was not as high as in the brain. I understand.

EXAMPLE 5 60 parts of 4,7,10,13,16-docosapentaenoic acid, 2 parts of phosphatidycholine, 38 parts of water and [ ³ H] -prostaglandin D ₂ methyl ester were taken and homogenized (polytron).
After stirring with PT75TODS type, ultrasonic homogenizer (SMUR
T NR-20 type) to obtain a homogeneous dispersion. [ ³ H]-
Prostaglandin D ₂ methyl ester concentration is 20 μCi / ml
It was.

0.5 ml of the above dispersion was injected into the tail vein of an SD rat (male, body weight: about 160 g), and 5 minutes after the injection, the blood was killed by bleeding. The skull was split and the brain was taken out and homogenized in the usual manner. The amount of radioactivity was measured. At the same time, the radioactivity was similarly measured for the liver.

At the same time, oleic acid was used in place of 4,7,10,13,16-docosapentaenoic acid, and other conditions were the same as in Example 1 except that Control Example 9 and prostaglandin D ₂ methyl ester 0.
2% gum arabic suspension ^([3 H] - prostaglandin D
_{The same} test was performed for Control Example 10 in which the concentration of ₂ methyl ester = 20 μCi / ml).

Table 5 shows the results of calculating the amount of radioactivity per gram of brain and gram of liver and comparing the results for Example 5, Control Examples 9 and 10.

Compared with Control Examples 9 and 10, prostaglandin D ₂ methyl ester of Example 5 using 4,7,10,13,16-docosapentaenoic acid showed a marked increase in brain concentration and liver concentration. You can see that it does not rise as much as the brain.

Example 6 In the same manner as in Example 5, except that 4,7,10,13,16-docosapentaenoic acid of Example 5 was replaced with 4,7,10,13,16,19-docosahexaenoic acid, a homogeneous dispersion was obtained. A liquid was prepared.

In Control Example 11, oleic acid was used instead of 4,7,10,13,16,19-docosahexaenoic acid, and in Control Example 12, a gum arabic suspension of prostaglandin D ₂ methyl ester was used. In each case, the concentration of [ ³ H] -prostaglandin D ₂ methyl ester was adjusted to 20 μCi / ml.

In the same manner as in Example 5, SD rats were intravenously injected, and after 5 minutes, the amounts of radioactivity in the brain and liver were measured and compared. The results are shown in Table 6.

The prostaglandin D ₂ methyl ester of Example 6 using 4,7,10,13,16,19-docosahexaenoic acid had a higher intracerebral concentration and an intracerebral concentration higher than those of Controls 11 and 12. You know that you haven't.

Example 7 Nicardipine was dissolved in 4,7,10,13,16-docosapentaenoic acid to a concentration of 100 μg / ml to obtain a composition of the present invention. This product is used as it is in an intact form.

Claims (8)

[Claims] 1. A blood-brain barrier crossing pharmaceutical composition comprising a higher unsaturated fatty acid and a drug. 2. The blood-brain barrier crossing pharmaceutical composition according to claim 1, wherein the higher unsaturated fatty acids are the same higher unsaturated fatty acids as the constituents of the brain lipids of warm-blooded animals. 3. The blood-brain barrier crossing pharmaceutical composition according to claim 1 or 2, wherein the higher unsaturated fatty acid is a C _{18 to} C ₂₆ higher unsaturated fatty acid. 4. The higher unsaturated fatty acid is 4,7,10,13,16-docosapentaenoic acid (C ₂₂ H ₃₄ O ₂ ), 4,7,10,13,16,19-docosahexaenoic acid ( _{C 22 H 32 O 2),} 4,7,10,13- docosatetraenoic acid _{(C 22 H 36 O 2)} , 7,10,13,16- docosatetraenoic acid _{(C 22 H 36 O 2)} , 4,8,12,16-Icosatetraenoic acid (C ₂₀ H ₃₂
O ₂ ), 5,8,11,14-icosatetraenoic acid (C ₂₀ H ₃₂ O ₂ ), 5,
8,11 Ikosatorien acid _{(C 20 H 34 O 2)} , 11,14- Ikosajien acid _{(C 20 H 36 O 2)} , 15- tetracosenoic acid (C ₂₄ H ₄₆ O ₂₎
And 2-hydroxy-15-tetracosenoic acid (C ₂₄ H ₄₆ O ₃ ).
The blood-brain barrier crossing pharmaceutical composition according to any one of claims 1 to 3, which is one or more selected from the group consisting of: 5. The drug is a hypnotic sedative, antiepileptic agent, antipyretic analgesic / antiinflammatory agent, excitatory stimulant, analgesic agent, neuropsychiatric agent, central nervous system agent, antispasmodic agent, antihypertensive agent, vasoconstrictor, vasodilator. The blood-brain barrier crossing pharmaceutical composition according to any one of claims 1 to 4, which is a cardiovascular agent, hormones, antineoplastic agent, or prostaglandins. 6. The drug according to any one of claims 1 to 4, wherein the drug is an antiepileptic agent, a neuropsychiatric agent, a cardiovascular agent, an antineoplastic agent, hormones or prostaglandins. The blood-brain barrier crossing pharmaceutical composition described. 7. The blood-brain barrier crossing pharmaceutical composition according to any one of claims 1 to 6, wherein the drug is dissolved or dispersed in a higher unsaturated fatty acid. 8. The drug according to any one of claims 1 to 6, wherein the drug is dissolved or dispersed in higher unsaturated fatty acids and the higher unsaturated fatty acids are uniformly dispersed in water.
A blood-brain barrier crossing pharmaceutical composition according to the above item.