WO2007000967A1 - Remedy for cerebral infarction - Google Patents

Abstract

A remedy for cerebral infarction which contains glycyrrhizin and/or a pharmaceutically acceptable salt thereof as the active ingredient. As the pharmaceutically acceptable salt, use may be appropriately made of glycyrrhizin ammonium salt, an alkali metal salt such as glycyrrhizin sodium salt or potassium salt, glycyrrhizin choline salt, etc. It is also possible to use calcium salt, magnesium salt, aluminum salt and so on.

Description

 Specification

 Cerebral infarction drug

 Technical field

 [oooi] The present invention relates to a therapeutic agent for cerebral infarction containing glycyrrhizin and Z or a pharmaceutically acceptable salt thereof as active ingredients.

 This application is published on June 28, 2005. This application is filed in Japanese Patent Application No. 2005—188876. This is a priority claim and the contents thereof are incorporated herein by reference.

 Background art

 [0002] Cerebral infarction is a highly prevalent disease that develops mainly due to damage to brain tissue as a result of embolization such as thrombus in cerebral blood vessels, resulting in a decrease in cerebral blood flow. If appropriate treatment is not performed at the time of onset, particularly in the acute phase, various dysfunctions remain as sequelae, resulting in a significant increase in medical and care costs thereafter.

 Therefore, the ability to reduce damage to brain tissue due to cerebral blood flow damage that occurs in the acute phase is an important point in treating cerebral infarction.

 [0003] Cerebral infarction is a disease that develops through a complex mechanism, and various therapeutic agents have been developed according to each stage.

 For example, the anticoagulant heparin, the antiplatelet drug ozadarel sodium, the antithrombotic drug argatroban, the brain protective drug edaravone, etc. can be mentioned as conventional cerebral infarction drugs.

 In the chronic phase, antiplatelet drugs such as aspirin may be administered orally.

[0004] However, the anticoagulant heparin, the antiplatelet drug ozadarel sodium, the antithrombotic drug argatroban, etc. may cause cerebral hemorrhage as a side effect. End up.

 In addition, edaravone, a neuroprotective drug, may cause renal dysfunction as a side effect, particularly in the elderly, and is particularly problematic for exacerbation when there is a decrease in renal function.

[0005] Therefore, there is a strong demand for the development of new therapeutic agents with few side effects that can replace these conventional therapeutic agents. For example, glycyrrhizin has been used as a therapeutic agent for liver disease or an antiallergic disease agent for many years (see Non-Patent Documents 1 to 4).

[0006] Further, glycyrrhizin has been confirmed to be a therapeutic drug with few side effects from its many years of use, and has an established reputation for its safety. One of the few side effects observed at the time of administration is hypokalemia. It is known that it is relatively easy to suppress by combination with the anti-aldosterone drug spironolatone.

Thus, it would be very useful if a highly safe drug that has been used in this way and has been confirmed to have few side effects can be used as a therapeutic agent for cerebral infarction. Non-patent document 1: Hiroshi Suzuki et al .: Therapeutic effect of strong neominophagen C on chronic hepatitis [Tetsu, Ayumi, No. 102, 562 (1977)

 Non-Patent Document 2: Yano et al .: Examination of therapeutic effect of double-blind treatment of Glicyrone Tablets No. 2 for chronic hepatitis, clinical trial and research, Vol. 66, 2629 (1989)

 Non-Patent Document 3: Strong Mino C Clinical Research Group: A clinical study of a powerful neominophagen for drug eruption 'addiction eruption and urticaria, West Japan Dermatology, Vol. 56, 603 (1994)

 Non-Patent Document 4: Kikuo Minami: Experience with Glycylon Tablets in the Dermatology Field, Research and Research, No. 78, 187 (2001)

 Disclosure of the invention

 Problems to be solved by the invention

[0007] However, glycyrrhizin has not been reported to date as a therapeutic agent for cerebral infarction and its clinical effect.

 Therefore, an object of the present invention is to provide a novel therapeutic agent for cerebral infarction using glycyrrhizin, which has a high therapeutic effect and few side effects, which is different from conventional therapeutic agents. Means for solving the problem

[0008] As a result of diligent research to solve the above problems, the present inventors have surprisingly found that glycyrrhizin, which is known to have low side effects and high safety, is cerebral infarction, particularly suddenly. The present invention has been completed by finding that it is effective for the treatment of sexual lacunar infarction.

That is, the first invention of the present invention is glycyrrhizin and Z or a pharmaceutically acceptable product thereof. It is a therapeutic agent for cerebral infarction containing a salt as an active ingredient.

 [0010] A second invention of the present invention is the therapeutic agent for cerebral infarction according to the first invention, wherein the pharmaceutically acceptable salt is a monoammodium salt.

 [0011] A third invention of the present invention is the therapeutic agent for cerebral infarction according to the first invention or the second invention, wherein the cerebral infarction is lacunar infarction.

 [0012] A fourth invention of the present invention is the therapeutic agent for cerebral infarction according to any one of the first to third inventions, which is for acute cerebral infarction.

 The invention's effect

 [0013] The therapeutic agent for cerebral infarction of the present invention exhibits an effective therapeutic effect with few side effects on cerebral infarction, particularly lacunar infarction in the acute phase.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0014] Hereinafter, the present invention will be described in detail.

 The therapeutic agent for cerebral infarction of the present invention contains glycyrrhizin and Z or a pharmaceutically acceptable salt thereof as active ingredients.

 Glycyrrhizin used in the present invention can be obtained, for example, by extracting licorice power, but commercially available ones can also be used.

 In addition, the pharmaceutically acceptable salt thereof is obtained by allowing glycyrrhizin and an inorganic or organic base to act at a certain molar ratio, and preferable examples include glycyrrhizin monoammodium salt and glycyrrhizin diammonium salt. Examples thereof include alkali salts such as um salt, glycyrrhizin monosodium salt, glycyrrhizin disodium salt, glycyrrhizin monopotassium salt and glycyrrhizin dikali salt, or glycyrrhizin choline salt. In addition to these, calcium salts, magnesium salts, aluminum salts, and the like can also be used. Among these, glycyrrhizin monoammonium salt is particularly preferable.

 These may be used alone or in combination of two or more.

[0015] The preparation form of the therapeutic agent for cerebral infarction of the present invention is not particularly limited, but in general, oral preparations such as tablets, powders, granules, capsules, fine granules, liquid medicines, inhalants, suppositories, or injections It can be a parenteral agent such as a drug.

These can be produced by a conventionally known method. [0016] As described above, oral preparations can be tablets, powders, granules, capsules, fine granules, liquids, and the like. These preparations are prepared according to conventional methods by incorporating excipients, lubricants, surfactants, binders, disintegrants, stabilizers, corrigents, buffering agents, etc. that are usually used in the manufacture of these preparations. can do. Examples of the excipient include lactose, potato starch, mannitol, ethinoresenorelose, sodium canoleoxy methinorescenellose, hydroxypropyl pill cellulose, calcium carbonate, and sodium alginate. Examples of the lubricant include magnesium stearate or calcium stearate. In addition, gelatin, gum arabic, cellulose ester, polybulurpyrrolidone and the like may be used as a binder.

 [0017] When used as a parenteral preparation such as an inhalant or injection, the solvent includes distilled water for injection, a sterile non-aqueous solvent, or a suspension. As the base of the non-aqueous solvent or suspending agent, it is preferable to use propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil, ethyl oleate or the like.

 In addition to these, a buffer, an antiseptic, an antioxidant, and the like can be appropriately added as necessary as optional pharmaceutically acceptable components within a range not impeding the effects of the present invention.

 [0018] The administration method can be selected from oral and parenteral.

 The dose varies depending on the age, symptoms, etc. of the patient, but in the case of oral administration, the amount of glycyrrhizin or a salt thereof is preferably 25 to 500 mg, more preferably 150 to 225 mg per adult day. A powerful range of glycyrrhizin can be administered once or multiple times daily.

 In addition, the parenteral dosage is preferably 40 to 400 mg as an amount of glycyrrhizin or a salt thereof per day for each adult. A powerful range of glycyrrhizin can be administered once or in multiple divided doses per day.

[0019] The therapeutic agent for cerebral infarction of the present invention exhibits an effective therapeutic effect on acute cerebral infarction patients and lacunar infarction patients, particularly on acute lacuna infarction patients.

 Example

Hereinafter, the present invention will be described in more detail with specific examples. (Formulation example 1)

 <Tablets>

 A mixture having the following composition was made into tablets by a conventional method.

 Daricinoreritin 25mg

 Potato starch 270mg

 Magnesium stearate 5mg

 300mg total

[0021] (Formulation example 2)

 <Sugar-coated tablets>

 A mixture of the following composition was made into sugar-coated tablets by a conventional method.

 Daricinoreritin 25mg

 Aminoacetic acid 25mg

 Methionine 25mg

 Precipitated calcium carbonate

 Lactose appropriate amount

 Carboxymethyl cellulose

 300mg total

[0022] (Formulation example 3)

 <Granule>

 A mixture having the following composition was made into granules by a conventional method.

 Glicinoreritin 25mg

 Lactose 210mg

 Starch 60mg

 Gelatin 5mg

 300mg total

[0023] (Formulation Example 4)

 Injection>

Dissolve 200 mg of glycyrrhizin in physiological saline to make 100 ml, and use an ordinary method for injection. It was.

 [0024] (Formulation Example 5)

 Injection>

 Guditinoresin 200 mg, aminosuccinic acid 2000 mg, and cysteine lOOmg were dissolved in physiological saline to make 100 ml, and an injection was prepared by a conventional method.

[Therapeutic effect of the therapeutic agent of the present invention]

 Hereinafter, the therapeutic effect of a therapeutic agent for cerebral infarction containing glycyrrhizin of the present invention and Z or a pharmaceutically acceptable salt thereof as an active ingredient will be described based on the results of clinical trials.

[0026] <Test subject>

 The subjects of the study were patients with mild cerebral infarction (ratana infarction), which is not suitable for rehabilitation in order to exclude the therapeutic effects of rehabilitation. The subjects were 42 patients diagnosed with acute cerebral infarction in the acute phase within 7 days of onset (24 males, 18 females; age 40-90 years; average age 70.5 years).

 The subjects were extracted based on their medical history, medical history, neurological examination by a neurologist certified by the Japanese Society of Neurology, head CT, and head MRI.

 Symptoms were mild neurological symptoms such as hemiplegia, wandering, dull sensation, and dysarthria.

[0027] <Use drug>

 As a therapeutic agent for cerebral infarction containing glycyrrhizin and Z or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention, a powerful neominophagency (registered trademark, manufactured by Minofagen Pharmaceutical Co., Ltd.), which is an intravenous injection, is used. It was. The ingredients in 1 ampoule (20 ml) of the powerful neominophagenshi are as shown below.

[0028] ◎ Strong Neo-Minophagen C

 Glycyrrhizin monoammonium salt 40mg (in terms of glycyrrhizin)

 A acetic acid 400mg

 L Cysteine hydrochloride 20mg

 Sodium sulfite 16mg

Amount of ammonia Sodium chloride appropriate amount

 [0029] <Test method>

 Randomized 42 patients with mild cerebral infarction, 7 patients with only blood dilution therapy (1 day maintenance infusion 1000ml x 7 days, hereinafter abbreviated as dilution therapy) Eleven patients who were treated with the antiplatelet drug ozadarel sodium (160mgZ day x 7 days) as a therapeutic agent for the above, and the brain protective drug edaravone (60mgZ 8 patients group who was added to the dilution therapy (day X 7 days), administration of the glycyrrhizin monoammodium salt of the present invention (40-80 mgZ day X 7 days) was added to the dilution therapy The patient groups were divided into 16 patients and their progress was observed.

 [0030] As the antiplatelet drug ozadarel sodium, xanthone injection (registered trademark) manufactured by Kitsei Pharmaceutical Co., Ltd. was used.

 [0031] As a cerebral protective drug edaravone, an injection Rajcut (registered trademark) manufactured by Mitsubishi Wellpharma Co., Ltd. was used. The active ingredients in 1 ampoule (20 ml) of Radicut are as follows.

 ◎ Radi cut

 Edaravone 30mg

 Sodium bisulfite 20mg

 L cysteine hydrochloride monohydrate lOmg

 Sodium chloride 135mg

 Sodium hydroxide appropriate amount

 Phosphoric acid

[0032] The evaluation for determining the effect was performed according to the number of days until the symptoms disappeared based on patient interviews, nursing records, and doctors' observations, and was divided into the above four groups for comparison.

 In addition, peripheral blood tests, liver function tests, kidney function tests, urinalysis, and other tests were also performed, and the course of side effects was also observed.

[0033] The results are shown in Tables 1 to 4. Table 1 shows the group of patients with hemodilution therapy only, Table 2 shows the group of patients who received ozadaler sodium in addition to the dilution therapy, and Table 3 shows the patients with edaravone in addition to the dilution therapy Table 4, Table 4 shows the injection of glycyrrhizin monoammonium salt. The results of the patient groups that were given in addition to the dilution therapy are shown respectively.

 [table 1]

 Dilution therapy only

 (): MRS before onset

[Table 2]

Dilution therapy + year-old Zadareruna

(): MRS 3 before onset]

Dilution therapy + edaravone

(): MR S 4 before onset]

Dilution therapy + glycyrrhizin

 (): M S before onset

[0038] In all patients, seizure symptoms almost disappeared within 80 days. Compared to the group with dilution therapy only, the remaining three groups with the addition of ozadarel sodium or edaravone or glycyrrhizin monoammodium salt to the dilution therapy all showed significant time to symptom resolution. Shortening was observed. In addition, among the three groups to which the administration of the three therapeutic agents was added, the period until the symptom disappeared was the shortest in the glycyrrhizin monoammodium salt addition group, and the tendency was seen.

[0039] On the other hand, regarding the side effects, in the glycyrrhizin monoammodium salt addition group, the peripheral No side effects were observed in various tests such as blood tests, liver function tests, kidney function tests, and urinalysis.

 [0040] From the above results, the therapeutic agent of the present invention has the effect of promoting the improvement of cerebral infarction symptoms, and has the same or better symptom-improving effect than the existing therapeutic agents ozadarel sodium or edaravone. It was confirmed to be seen.

 Also, unlike existing treatments, it was confirmed that it is superior to existing treatments in that it has few side effects.

 Therefore, the therapeutic agent for cerebral infarction of the present invention containing glycyrrhizin monoammonium salt as an active ingredient is particularly effective as a therapeutic agent for lacunar infarction in the acute phase because it has an effect of improving symptoms with almost no side effects.

 Industrial applicability

[0041] The therapeutic agent for cerebral infarction of the present invention has a therapeutic effect equivalent to or higher than that of existing therapeutic agents and has almost no side effects, and therefore, particularly, acute cerebral infarction patients, lacunar infarction patients, In particular, it can be widely provided to the medical industry as an effective treatment for patients with lacunar infarction in the acute phase.

Claims

The scope of the claims  [1] A therapeutic agent for cerebral infarction comprising glycyrrhizin and / or a pharmaceutically acceptable salt thereof as an active ingredient.  [2] The therapeutic agent for cerebral infarction according to claim 1, wherein the pharmaceutically acceptable salt is a monoammodium salt.  3. The therapeutic agent for cerebral infarction according to claim 1 or 2, wherein the cerebral infarction is lacunar infarction.  [4] The therapeutic agent for cerebral infarction according to any one of claims 1 to 3, which is used for acute cerebral infarction.