阅读说明：本技术 一种含有琥珀酸呋罗曲坦的复方控释制剂 (Compound controlled release preparation containing furotriptan succinate ) 是由 陈阳生 王明刚 刘晓霞 孙桂玉 李秀秀 刘昭嵘 王婷婷 汪泓 于 2019-12-11 设计创作，主要内容包括：本发明公开了一种含琥珀酸呋罗曲坦和阿司匹林的复方药物的控释制剂,本发明还公开了含琥珀酸呋罗曲坦和阿司匹林的复方药物的控释制剂的制备方法。与现有技术相比,本发明的复方药物的控释制剂能够在规定的释放介质中缓慢地恒速释放药物,有效提高了复方药物的控释制剂的释放度及生物利用度,能在服用初期迅速释放产生药效,后期缓慢地恒速释放,维持正常的血药浓度,长时间维持药效而不产生毒副反应、不引起药物积累中毒,提高疗效、安全迅速。同时,本发明方法中的制备方法适合于扩大化生产。(The invention discloses a controlled release preparation of a compound medicine containing furotriptan succinate and aspirin, and also discloses a preparation method of the controlled release preparation of the compound medicine containing furotriptan succinate and aspirin. Compared with the prior art, the controlled release preparation of the compound medicine can slowly release the medicine at a constant speed in a specified release medium, effectively improves the release degree and the bioavailability of the controlled release preparation of the compound medicine, can quickly release and generate the medicine effect at the initial stage of taking, slowly releases at a constant speed at the later stage, maintains the normal blood concentration, maintains the medicine effect for a long time without generating toxic and side effects, does not cause medicine accumulation poisoning, improves the curative effect, and is safe and quick. Meanwhile, the preparation method in the method is suitable for expanded production.)

1. A compound controlled release preparation containing furotriptan succinate is characterized in that a controlled release part consists of a quick release part and a controlled release part, wherein the quick release part contains 0.5-2mg of furotriptan succinate, and the controlled release part contains 1.5-5mg of furotriptan succinate and 50-150mg of aspirin.

2. The controlled-release preparation according to claim 1, characterized in that the controlled-release part is prepared by mixing furotriptan succinate and aspirin which are prepared into controlled-release granules, controlled-release pellets or controlled-release tablets, respectively.

3. The controlled release formulation of claim 2, wherein the controlled release furotriptan succinate comprises 40-60% furotriptan succinate, 10-35% controlled release material and the balance other pharmaceutical excipients.

4. The controlled release formulation of claim 2, wherein the controlled release aspirin comprises 0.1-0.3% aspirin, 50-95% controlled release material, and the balance other pharmaceutical excipients.

5. The controlled release formulation of claim 3 or 4, wherein the controlled release material is selected from one or more of carbomer, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, stearic acid, glyceryl monostearate, stearyl alcohol, polyethylene, polypropylene, and acrylic resin.

6. The controlled release formulation of claim 1, wherein the immediate release furotriptan succinate comprises furotriptan succinate and other pharmaceutical excipients.

7. The controlled release formulation of claim 6, wherein the immediate release material is selected from one or more of lactose, sucrose, starch, pregelatinized starch, cellulose, powdered sugar, dextrin, glucose, calcium bicarbonate; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium; the adhesive is selected from one or more of water, alcohol, polyvinylpyrrolidone and starch slurry; the lubricant is selected from one or more of magnesium stearate, pulvis Talci, silica gel micropowder, sodium laurylsulfate or magnesium.

8. The controlled release formulation of claim 3 or 4 or 6, wherein the other pharmaceutical excipients are selected from one or more of fillers, disintegrants, binders, lubricants.

9. The controlled release formulation of claim 8, wherein the other pharmaceutical excipients are microcrystalline cellulose, crospovidone, hydroxypropyl methylcellulose, carbomer, ethylcellulose, lactose, magnesium stearate.

10. The controlled release formulation of claim 1, wherein the immediate release portion contains 1.0mg of furotriptan succinate and the controlled release portion contains 2.91mg of furotriptan succinate and 100mg of aspirin.

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a compound controlled release preparation containing furotriptan succinate, belonging to the technical field of medicines.

Background

Migraine is the most common clinical primary headache type, and is clinically mainly manifested by paroxysmal moderate and severe and pulsatile headache, the headache is mostly deviated and generally lasts for 4-72 hours, nausea and vomiting can be accompanied, the headache can be aggravated by light and sound stimulation or daily activities, and the headache can be relieved under quiet environment and rest controllably. Migraine is a common chronic neurovascular disease, mostly occurs in children and adolescence, reaches the peak of morbidity in middle and young age, is common in women, has the prevalence rate of 5-10 percent in people and has genetic background.

Migraine is primarily caused by dysfunction of the central nervous system, while vascular changes are secondary, with migraine attacks accompanied by numerous neuromediator disturbances in the blood and cerebrospinal fluid. It has also been proposed that neurogenic inflammation causes migraine, and it is believed that vasoactive peptides can be released by stimulating the peripheral vascular fibers of the trigeminal nerve, causing neurogenic inflammation of the dura mater and the tissues it supplies, which is primarily manifested as plasma protein extravasation and vasodilation. Recent studies have found that NO present in the central nervous system plays an important role in the central transmission of pain stimuli. However, in recent years, the theory of trigeminal neurovascular reflex has attracted much attention, which combines the three of nerves, blood vessels, and nerve mediators and unifies them in the trigeminal neurovascular system. This hypothesis suggests that by stimulating certain specific areas in the brain, a series of reactions cause cranial vasodilation and carotid vasodilation, resulting in headache. In this process, 5-HT released by platelets enhances the sensitivity of vascular receptors and plays an important role in pain production. This hypothesis better explains some of the clinical manifestations of migraine, providing a reasonable explanation for the use of drugs acting on both the central and peripheral nervous systems for the treatment of migraine.

Furotriptan succinate is an ex vivo cerebral vasoconstrictor in various species, including humans. The activity of furotriptan succinate as a vasoconstrictor was observed on isolated arterial vessels and compared to sumatriptan. In the middle cerebral artery of the human brain, furotriptan succinate is a partial agonist (relative to 5-HT) and has at least a 5-fold effect as compared to sumatriptan. Furotriptan succinate is a full agonist for the human basal artery, with about 8.3 times the effect of sumatriptan. Furotriptan succinate had 23 and 3 times greater effect on rabbit basal arteries and cat middle cerebral arteries than sumatriptan, respectively. In rabbits, furotriptan succinate is a partial agonist, whereas sumatriptan succinate is a full agonist, compared to 5-HT. In cats, both furotriptan succinate and sumatriptan succinate are partial agonists relative to 5-HT.

Aspirin is an ancient analgesic and antipyretic drug, and it can not only treat acute migraine attacks, but also prevent migraine recurrence. The mechanism of aspirin for preventing and treating migraine is as follows: (l) Controlling and stimulating the skin against pathogenic substances in the blood vessel wall. (2) Blocking or filling the painful nerve endings such that the painful stimuli do not reach the nerve endings. (3) Controlling inflammatory reaction. (4) Sedative effect and muscle relaxant effect. (5) Inhibiting cyclooxygenase, preventing synthesis of prostaglandin and thromboxane A2, and inhibiting platelet aggregation and platelet factor release. (6) Plays a role in the metabolic process of 5-hydroxytryptamine, and leads tryptophan to be released from the binding site of serum albumin, thereby improving the concentration of free amino acid required by the synthesis of 5-hydroxytryptamine and improving the function of a 5-hydroxytryptamine system.

Disclosure of Invention

The invention discloses a compound controlled release preparation containing furotriptan succinate, which can achieve the effects of drug controlled release, stable blood concentration, administration frequency reduction, small toxic and side effects and improvement of patient compliance. The invention has the advantages of rapid dissolution, rapid absorption, high bioavailability, good stability, convenient administration, etc.

By adopting a common pharmaceutical technology, furotriptan succinate and aspirin are crushed and sieved, controlled-release materials are uniformly mixed, crushed and sieved, then furotriptan succinate and the controlled-release materials are mixed to prepare quick-release granules, furotriptan succinate and aspirin are mixed with the controlled-release materials to prepare controlled-release granules, and finally the quick-release granules and the controlled-release granules are uniformly mixed and encapsulated to obtain the furotriptan and aspirin sustained-release capsules.

The preferable controlled release furotriptan succinate part of the invention contains 40 to 60 percent of furotriptan succinate, 10 to 35 percent of controlled release material and the balance of other pharmaceutic adjuvant; the preferred controlled-release aspirin part contains 0.1-0.3% of aspirin, 50-95% of controlled-release material and the balance of other pharmaceutic adjuvants.

The controlled release preparation changes the original single release form, organically combines the quick release with the controlled release, quickly generates the treatment effect within a certain time and maintains the treatment effect for a longer time. 15-30% is released within 1 hour, the therapeutic effect is immediately produced, and the rest is released within 2-24 hours later, thereby producing a sustained therapeutic effect.

In recent years, the research and development of controlled release preparations are gradually paid attention, the controlled release preparations are released according to a zero-order rate rule, the drug release is not influenced by time and released at a constant speed, more stable blood concentration can be obtained, and the fluctuation of the peak valley is smaller until the basic absorption is complete. The controlled release preparation can reduce the administration frequency of a patient, the administration frequency is reduced by half compared with the common preparation, the patient can conveniently take the medicine for a long time, the medicine taking compliance of the patient is obviously improved, the medicine is slowly absorbed at a proper speed through the control of the medicine release speed, the blood concentration is stable, the peak valley phenomenon is avoided or reduced, the toxic and side effect of the medicine is reduced, the curative effect is improved, the local concentration of the medicine in the gastrointestinal tract is reduced, and the irritation is reduced.

In order to overcome the defects of the prior art, the invention provides the compound controlled release preparation containing the furotriptan succinate through screening a large number of tests on auxiliary materials and optimizing the process, and the controlled release preparation has stable quality, uniform drug release and simple preparation process.

Detailed Description