JP2017137306A - Pharmaceutical composition comprising triptan and ascorbic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation with an improved analgesic action of triptan.SOLUTION: The present invention provides a triptan-containing pharmaceutical composition, in which ascorbic acid is contained in triptan to improve the pharmacological action of triptan.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition comprising a triptan selected from sumatriptan, rizatriptan, zolmitriptan, eletriptan and naratriptan or a pharmaceutically acceptable salt thereof and ascorbic acid.

  The pathology of migraine includes a vascular theory based on abnormal dilation of intracranial blood vessels, a neural theory based on excessive excitation of cerebral cortical neurons, a trigeminal vascular theory based on trigeminal nerves and surrounding neurogenic inflammation. The details of migraine are still unknown, but the trigeminal neurovascular theory is the most powerful.

  When the large blood vessel in the skull expands for some reason and compresses the trigeminal nerve, pain synchronized with the pulsation occurs in the unilateral head, which is called migraine. The trigeminal nerve that receives this pressure stimulus releases neuropeptides (pain-causing substances) and develops vasculitis. When this happens, the blood vessels swell more and create a vicious circle that further compresses the trigeminal nerve. When these stimuli are transmitted to the cerebrum, you will feel pain (headache).

  The trigeminal nerve is a mixed nerve that is divided into three parts, the optic nerve, the maxillary nerve, and the mandibular nerve, from the trigeminal ganglion deep in the temple position, and is the largest nerve in the cranial nerve. For this reason, in migraine where the trigeminal nerve is stimulated, a jagged light can be seen as a symptomatic symptom, or a part of the visual field can be difficult to see.

  Serotonin (hereinafter sometimes referred to as 5-HT or 5-hydroxytryptane) is a neurotransmitter involved in cerebral vasoconstriction discovered as a substance that regulates vascular tone and acts on serotonin receptors. The dilated cerebral blood vessels are then contracted back to their original condition to treat migraine. There are many types of serotonin (5-HT) receptors. Among them, serotonin 1B receptor (5-HT / 1B receptor, vasoconstrictive action) and serotonin 1D are widely distributed in the cerebral blood vessels. There is a receptor (5-HT / 1D receptor, vasodilator release inhibitory effect), and both can treat migraine.

  On the other hand, triptan, a migraine treatment, is similar in chemical structure to serotonin and acts as an agonist on both serotonin 1B and serotonin 1D receptors to constrict dilated blood vessels and vasodilatory neuropeptides. It is said that the trigeminal nerve activity is also sedated and normalized.

  Triptan preparations that can be used in Japan are five preparations of sumatriptan, zolmitriptan, eletriptan, rizatriptan and naratriptan. Both of them act selectively on 5-HT / 1B receptors present in cranial vascular smooth muscle and 5-HT / 1D receptors present on trigeminal nerve endings around cranial blood vessels, resulting in migraine Migraine is improved by selectively constricting the blood vessels inside and outside the skull. Further, it acts on the trigeminal nerve to suppress the release of inflammatory neuropeptides (Substance P, CGRP, etc.) and contributes to mitigation of migraine (for example, see Non-Patent Documents 1 to 5).

  As a prior art, it has been disclosed so far that the addition of ascorbic acid to a liquid preparation containing sumatriptan succinate increases the storage stability of sumatriptan succinate and suppresses the increase of related substances. (Patent Document 1).

  In addition, in a solution containing zolmitriptan, the stability of zolmitriptan decreases (decreases in content) when citric acid as a sour agent is added, but when an antioxidant (such as ascorbic acid) is added, the residual zolmitriptan remains It is disclosed that the rate is improved (Patent Document 2).

  Furthermore, it has been disclosed that when a liquid preparation containing eletriptan hemisulphate contains citric acid or ethanol, the content of eletriptan decreases, but when caffeine is added, the residual ratio of eletriptan improves. Further, it is described that the addition of an antioxidant (such as ascorbic acid) further increases the stability, but no data is disclosed (Patent Document 3).

  In addition, there is no known solid oral preparation containing triptan and ascorbic acid.

  On the other hand, when combined with vitamin B1 (benfotiamine) or vitamin C (ascorbic acid) in combination with ibuprofen, a nonsteroidal antipyretic analgesic / anti-inflammatory agent, the edema-inhibiting action (anti-inflammatory action) is reduced, and either loxoprofen has vitamin B1 or It has been reported that when vitamin C is used in combination, both are enhanced (Patent Document 4). Therefore, in general, the effect of using thiamine or ascorbic acid in combination with analgesics is not universal and seems to vary depending on the type of drug.

JP 2012-025676 A JP 2012-036166 A Special Table 2000-516262 JP 2011-168580 A

Immigrant Tablets 50 (sumatriptan succinate) package insert Package insert of maxalt tablet 10mg (Rizatriptan benzoate) Zomig tablet 2.5mg (Zolmitriptan) package insert Lerpac Tablets 20 (Eletriptan Hydrobromide) package insert Amerix Tablets 2.5mg (Naratriptan Hydrochloride) package insert

  An object of the present invention is to provide a preparation having a more excellent analgesic action of triptan, and thus to provide a triptan-containing pharmaceutical composition capable of reducing the side effects by reducing the dose of triptan. It is.

  In order to solve this problem, as a result of many years of research, it was found that adding a specific vitamin to triptan increases the pharmacological action of triptan, and the present invention has been completed.

That is, the present invention
(1) As an active ingredient, triptan selected from sumatriptan, rizatriptan, zolmitriptan, eletriptan and naratriptan, or a pharmacologically acceptable salt thereof, and ascorbic acid or a pharmacologically acceptable salt thereof. It is a pharmaceutical composition comprising, preferably
(2) The pharmaceutical composition according to (1) above, wherein the ascorbic acid or a pharmacologically acceptable salt thereof is calcium ascorbate,
(3) The above (1) or (2), wherein the triptan selected from sumatriptan, rizatriptan, zolmitriptan, eletriptan and naratriptan or a pharmacologically acceptable salt thereof is sumatriptan succinate A pharmaceutical composition according to
(4) The pharmaceutical composition according to any one of (1) to (3) above, which is for analgesia.
(5) The pharmaceutical composition according to any one of (1) to (3) above, which is for headaches,
(6) The pharmaceutical composition according to any one of (1) to (3), which is for migraine, or
(7) The pharmaceutical composition according to any one of (1) to (6), which is a solid preparation for internal use.

  The composition containing triptan and ascorbic acid according to the present invention expresses an excellent analgesic action, and as a result, since the dose of triptan can be reduced, side effects can also be reduced, so that it is extremely useful clinically.

  The triptan in the present invention refers to sumatriptan, zolmitriptan, eletriptan, rizatriptan and naratriptan or pharmacologically acceptable salts thereof. Preferred are sumatriptan succinate, zolmitriptan, eletriptan hydrobromide, rizatriptan benzoate and naratriptan hydrochloride, and more preferred is sumatriptan succinate.

  The triptan of the present invention can be synthesized by a known method, and sumatriptan succinate, zolmitriptan, eletriptan hydrobromide, rizatriptan benzoate and naratriptan hydrochloride can be synthesized in Japan. As it is sold as, it is easily available.

  The ascorbic acid of the present invention is not particularly limited, but is ascorbic acid or a salt thereof, and preferably ascorbic acid, calcium ascorbate, and sodium ascorbate.

  The ascorbic acid of the present invention is listed in the 16th revised Japanese Pharmacopoeia, and other ascorbic acids are also commercially available and can be easily obtained.

  The content of each triptan contained in the internal solid preparation of the present invention is 10 to 100 mg, preferably 25 to 75 mg in sumatriptan. This is administered as needed, but can be re-administered 2 hours later if necessary.

  In the case of eletriptan and rizatriptan, it is 2 to 70 mg, preferably 5 to 40 mg. This is administered as needed, but can be re-administered 2 hours later if necessary.

  In zolmitriptan, it is 0.5 to 10 mg, preferably 1 to 10 mg. This is administered as needed, but can be re-administered 2 hours later if necessary.

  In the case of naratriptan, it is 0.5 to 10 mg, preferably 1 to 10 mg. This is administered as needed, but can be re-administered 4 hours later if necessary.

  The solid preparation for internal use of the present invention can be produced as a tablet or granule according to the usual method described in the Japanese Pharmacopoeia. A sweetener, a coating agent, etc. can be added as needed.

  Hereinafter, the present invention will be described more specifically with reference to test examples and formulation examples.

(Formulation Example 1) Tablet (Table 1)
In 1 tablet (mg) a b c de
――――――――――――――――――――――――――――――――――――
Sumatriptan succinate 70----
Eletriptan hydrobromide-30---
Rizatriptan benzoate--15--
Zolmitriptan − − − 2.5 −
Naratriptan hydrochloride----2.8
Calcium ascorbate 250 250 250 250 250
Lactose 50 50 70 90 90
Crystalline cellulose 10 10 10 10 10
Hypromellose 20 15 10 10 10
Croscarmellose sodium Appropriate amount Appropriate amount Appropriate amount Appropriate amount Magnesium stearate Appropriate amount Appropriate amount Appropriate amount Appropriate amount ――――――――――――――――――――――――――――――――― ―――
Taking the above ingredients and amounts, tablets are produced according to the section “General Tablet Preparation Guidelines”.

(Formulation example 2) Granules (Table 2)
In 1 package (mg) a b c de
――――――――――――――――――――――――――――――――――――
Sumatriptan succinate 70----
Eletriptan hydrobromide-30---
Rizatriptan benzoate--15--
Zolmitriptan − − − 2.5 −
Naratriptan hydrochloride----2.8
Calcium ascorbate 250 250 250 250 250
Lactose 50 50 50 50 50
Crystalline cellulose 10 10 10 10 10
Hypromellose 10 10 10 10 10
Croscarmellose sodium Appropriate amount Appropriate amount Appropriate amount Appropriate amount Magnesium stearate Appropriate amount Appropriate amount Appropriate amount Appropriate amount ――――――――――――――――――――――――――――――――― ―――
Taking the above ingredients and amounts, granules are produced according to the section “Granule” of the General Rules for Preparations.

(Test example) Pain response latency test (1) Test substance Sumatriptan succinate is from SMS PHARMACEUTICALS, Benfotiamine is from Daiichi Sankyo Chemical Pharma, and calcium ascorbate is Eisai Food Chemical The one made by Alps Chemicals was used. As a medium, sodium carboxymethylcellulose (hereinafter sometimes referred to as CMC) manufactured by Kanto Chemical Co. was diluted with JP injection water manufactured by Otsuka Pharmaceutical Factory, and a 0.5% CMC aqueous solution was used. The test drug is as shown in Table 3, and the administration volume was the same 10 ml / Kg in all groups.

(Table 3)
Administration group Drug combination (mg / kg)
――――――――――――――――――――――――――――――――――――
Study drug 1 Control (CMC 0.5% aqueous solution)
Study drug 2 Sumatriptan succinate (0.01)
Study drug 3 sumatriptan succinate (0.01) + benfotiamine (25)
Study drug 4 Sumatriptan salt (0.01) + calcium ascorbate (500)
Study drug 5 sumatriptan succinate (0.01) + hesperidin (90)
――――――――――――――――――――――――――――――――――――

(2) Test animals and grouping ICR male mice (Crl: CD1) 3 weeks old were purchased from Japan Charles River and used. The animals were acclimated in an environment of 22 ± 3 ° C., humidity 50 ± 20%, and lighting time 8: 00-20: 00. From the day after arrival of the animals, an aqueous solution containing morphine hydrochloride (manufactured by Daiichi Sankyo Propharma) was given as drinking water. The concentration of morphine hydrochloride given was 0.1 mg / mL on the 0th to 1st days, 0.2 mg / mL on the 2nd to 3rd days, 0.3 mg / mL on the 4th to 5th days, with the next day of arrival of the animals as 0 days. From the sixth day onward, the concentration was 0.4 mg / mL.
On the 14th to 15th day (final day) of morphine treatment, acclimatization to a hot plate type analgesic effect measuring device (Muromachi Kikai) was performed. That is, the mouse was placed on a hot plate set at 35 ° C. to acclimate to the apparatus. After the acclimatization on the 14th day, the latency measurement was started at the same time when the mouse was individually placed on a hot plate set at 52 ° C. The time at which the pain reaction (foot licking, escape behavior) was shown was defined as the latency. Measure the latency of 2 times per animal, select the animals whose measurement value is in the range of 10-20 seconds and the difference is within 3 seconds, and perform grouping by stratified continuous randomization method It was.

(3) Drinking water was replaced with tap water (morphine removal) after the acclimatization on the next day (15th day) after grouping of test methods. We used a test method that caused migraine-like hypersensitivity by withdrawal after continuous use of morphine. 5 hours and 30 minutes after the removal of morphine, the 52 ° C. hot plate latency immediately before administration of the test drug was measured, and then the test drug was administered by oral sonde. The hot plate latency at 52 ° C. was measured again 60 minutes after administration of the test drug.

(4) Test result of pain response latency Table 4 shows the test result in each test drug group (n = 12).

(Table 4)
Group Latency before administration (seconds) Latency after administration (seconds)
―――――――――――――――――――――――――――――――
Study drug 1 10.2 ± 0.2 9.8 ± 0.5
Study drug 2 9.7 ± 0.2 11.8 ± 0.4 *
Study drug 3 10.3 ± 0.3 12.4 ± 0.6 **
Study drug 4 10.1 ± 0.2 13.1 ± 0.4 ** #
Study drug 5 10.3 ± 0.4 12.3 ± 0.5 **
―――――――――――――――――――――――――――――――
*: Significant difference from test drug 1 (control: CMC solution) Dunnett's method p <0.05
**: Significant difference from test drug 1 (control: CMC solution) Dunnett's method p <0.01
#: Significant difference from test drug 2 (triptan single agent) t-test p <0.05

  From the results shown in Table 4, the sumatriptan succinate single agent (test drug 2) significantly increased the latency compared to the control (CMC solvent only), confirming the effectiveness of this test system (p <0. 05). Sumatriptan succinate has no effect of prolonging latency when administered alone. When combined with benfotiamine, calcium ascorbate or hesperidin, any combination group significantly prolongs latency compared to controls. (P <0.01).

  However, when the sumatriptan succinate single agent (test drug 2) is compared with the combination group (test drugs 3-5), only the sumatriptan succinate and calcium ascorbate combination (test drug 4) is significantly latent. It was observed that the time was extended (p <0.05). Therefore, it was revealed that the combined use of calcium ascorbate with sumatriptan succinate significantly enhanced the analgesic action of sumatriptan succinate.

  The composition for treating migraine containing triptan and ascorbic acid according to the present invention is useful because it achieves a remarkable analgesic action. As a result, the amount of triptan can be reduced, so that the side effects of triptan can be reduced.

Claims (7)

  As an active ingredient, a triptan selected from sumatriptan, rizatriptan, zolmitriptan, eletriptan and naratriptan or a pharmacologically acceptable salt thereof and ascorbic acid or a pharmacologically acceptable salt thereof are blended. A pharmaceutical composition.   The pharmaceutical composition according to claim 1, wherein the ascorbic acid or a pharmacologically acceptable salt thereof is calcium ascorbate.   The pharmaceutical according to claim 1 or 2, wherein the triptan selected from sumatriptan, rizatriptan, zolmitriptan, eletriptan and naratriptan or a pharmacologically acceptable salt thereof is sumatriptan succinate. Composition.   The pharmaceutical composition according to any one of claims 1 to 3, which is used for analgesia.   The pharmaceutical composition according to any one of claims 1 to 3, which is used for headache.   The pharmaceutical composition according to any one of claims 1 to 3, which is for migraine.   The pharmaceutical composition according to any one of claims 1 to 6, which is a solid preparation for internal use.