CN110898037A - Frovatriptan succinate controlled-release capsule and preparation method thereof - Google Patents
Frovatriptan succinate controlled-release capsule and preparation method thereof Download PDFInfo
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- CN110898037A CN110898037A CN201911264743.9A CN201911264743A CN110898037A CN 110898037 A CN110898037 A CN 110898037A CN 201911264743 A CN201911264743 A CN 201911264743A CN 110898037 A CN110898037 A CN 110898037A
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- succinate
- furotriptan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
Abstract
The invention discloses a furotriptan succinate controlled-release capsule which is prepared by preparing an inner core of furotriptan succinate by an inclusion technology and then preparing a controlled-release coating. The invention also discloses a preparation method of the furotriptan succinate controlled-release capsule. Compared with the prior art, the controlled release capsule can slowly release the medicine in a specified release medium at a constant speed, effectively improves the release rate and the bioavailability of the furotriptan succinate, can quickly release the medicine effect in the initial period of taking, slowly release the medicine at the constant speed in the later period, maintain the normal blood concentration, maintain the medicine effect for a long time without generating toxic and side reactions, cause medicine accumulation poisoning, improve the curative effect, and is safe and quick. Meanwhile, the preparation method in the method is suitable for expanded production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a furotriptan succinate controlled-release capsule and a preparation method thereof.
Background
Migraine is the most common clinical primary headache type, and clinically, the headache is mainly manifested by paroxysmal moderate and severe and pulsatile headache, mostly is deviated, generally lasts for 4-72 hours, can be accompanied by nausea and vomiting, and can be aggravated by light and sound stimulation or daily activities, and the headache can be relieved by resting in a quiet environment. 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.
Disclosure of Invention
At present, furotriptan succinate is mainly available in the market of China as oral tablets, troches and injections, the oral tablets and troches are convenient to take but affected by factors such as disintegration, drug release and the like, the absorption effect is not ideal, the injections are quick in curative effect but inconvenient to carry and use, and the furotriptan succinate is unstable in aqueous solution.
In recent years, the research and development of controlled release capsules are gradually paid attention to, the controlled release capsules are released according to a zero-order rate rule, the drug release is not influenced by time and released at a constant speed, and 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 capsule can reduce the medicine taking times of a patient, the medicine taking frequency is reduced by half compared with that of a 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 furotriptan succinate controlled-release capsule through screening a large number of tests on auxiliary materials and optimizing the process, and the controlled-release capsule has stable quality, uniform drug release and simple preparation process.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention aims to solve the technical problem of providing a furotriptan succinate controlled-release capsule so as to solve the problem of poor clinical effect of the existing furotriptan succinate product.
The invention also aims to solve the technical problem of providing a preparation method of the furotriptan succinate controlled-release capsule.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a furotriptan succinate controlled release capsule comprises a furotriptan succinate inner core and a controlled release envelope from inside to outside;
wherein the mass ratio of the furotriptan succinate inner core to the controlled release coating is 6-15: 100 (solid content ratio);
(1) the controlled release coating comprises the following components in parts by weight:
coating liquid of Sulisi E-7-19040100 parts
Pore-foaming agent hypromellose E55-8 parts
(2) The furotriptan succinate inner core comprises the following components in parts by weight:
frovatriptan succinate 1 part
β -cyclodextrin 2-5 parts
0.2-1 part of ethyl cellulose
0.02-0.1 part of sodium carboxymethylcellulose
1-3 parts of water
The preparation method of the furotriptan succinate controlled release capsule comprises the following steps:
(1) mixing β -cyclodextrin with water, heating to 60-90 ℃, adding furotriptan succinate, and stirring for 30-60 min;
(2) carrying out spray drying on the mixed system obtained in the step (1) through a spray drying tower to obtain furotriptan succinate soluble powder;
(3) mixing the furotriptan succinate soluble powder obtained in the step (2), ethyl cellulose and sodium carboxymethyl cellulose, and centrifuging
Granulating by a fluidized granulation coating method, drying, and screening out particles with the particle size of 40-60 meshes to obtain a furotriptan succinate inner core;
(4) the coating liquid of the styril E-7-19040 is diluted by water and then is mixed with the pore-forming agent of hydroxypropyl methylcellulose E5 evenly and then is atomized in an atomizing chamber
Melting, and spraying the melted mixture on the surface of the furotriptan succinate inner core obtained in the step (3) to obtain furotriptan succinate controlled-release particles;
(5) filling the furotriptan succinate controlled-release particles prepared in the step (4) into a blank capsule to obtain a furotriptan succinate controlled-release capsule;
wherein in the step (1), the mass ratio of β -cyclodextrin to furotriptan succinate is 2-5: 1;
wherein in the step (2), the air inlet temperature is 160-200 ℃, the air inlet pressure is 0.3-0.4 Mpa, and the air outlet temperature is 75-95 ℃;
wherein in the step (3), the drying temperature is 40-80 ℃, and the drying time is 1-3 h;
in the step (4), the mass ratio of the coating liquid, namely the styril E-7-19040, to the dilution water is 2: 3.
compared with the prior art, the invention has the following advantages:
1. the invention firstly adopts cyclodextrin inclusion technology to effectively improve the solubility and bioavailability of furotriptan succinate, and solubility experiments show that the solubility of furotriptan succinate bulk drug is less than 300ppm at room temperature, and the solubility reaches 3000ppm after the inclusion compound is formed. The area under the curve is obviously increased when the furotriptan succinate is taken as a medicine, which shows that the bioavailability is improved;
2. the controlled release capsule prepared by the invention takes the furotriptan succinate clathrate compound as a capsule pill core, and takes the mixture of ethyl cellulose and hydroxypropyl methylcellulose as a film coating material. The ethyl cellulose has excellent slow release performance and can prevent the burst release of the medicine; a small amount of hypromellose forms hydrophilic channels in the coating film to help the drug to be released from the interior of the capsule in sufficient and lasting manner. The release characteristics of the drug are controlled by adjusting the ratio of the two coating materials;
3. the invention combines the cyclodextrin inclusion technology and the controlled release coating technology, the prepared furotriptan succinate controlled release capsule can be rapidly released at the initial stage of taking to generate drug effect, and slowly and stably released at the later stage, and the drug effect can be maintained for a long time without generating toxic and side reactions;
4. the material used by the invention has high safety and is easy to purchase. The adopted spray drying technology and the centrifugal-fluidization granulation coating technology are suitable for expanded production.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Example 1
Frovatriptan succinate 3.91g
β -Cyclodextrin 106g
Ethyl cellulose 6.62g
Sodium carboxymethylcellulose 0.66g
Stilsilk E-7-1904021.33 g
Hydroxypropyl methylcellulose E50.26g
And a proper amount of purified water.
The preparation method comprises the following steps:
(1) heating a proper amount of purified water to 80 ℃, adding β -cyclodextrin, stirring for dissolving, adding furatriptan succinate, and stirring for 30min to form a furatriptan succinate solution;
(2) adjusting the air inlet temperature of a spray dryer to 160 ℃, the air outlet temperature of 80 ℃ and the pressure of 0.3MPa, and carrying out spray drying on the furotriptan succinate solution to obtain furotriptan succinate soluble powder;
(3) 66.25g of the furotriptan succinate soluble powder, ethyl cellulose and sodium carboxymethyl cellulose are mixed, 26.47g of water is added, and soft materials are prepared by mixing;
(4) granulating by a centrifugal-fluidized granulation coating method, drying for 2 hours at 60 ℃, and screening particles of 40-60 meshes;
(5) diluting Stilsilk E-7-19040 with water, and mixing with hydroxypropyl cellulose E5 to obtain coating solution; placing 56g of the inner core prepared in the step (4) in a fluidized bed for fluidization, and spraying the atomized coating liquid on the surface of a pill core to obtain furotriptan succinate controlled-release particles;
(6) and (4) filling the furotriptan succinate controlled-release granules prepared in the step (5) into a blank capsule to obtain the furotriptan succinate controlled-release capsule.
Example 2
Frovatriptan succinate 3.91g
β -Cyclodextrin 106g
Ethyl cellulose 6.62g
Sodium carboxymethylcellulose 0.662g
Stilsilk E-7-1904017.07 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Example 3
Frovatriptan succinate 3.91g
β -Cyclodextrin 96g
Ethyl cellulose 8.31g
Sodium carboxymethylcellulose 0.332g
Stilsilk E-7-1904024.81 g
Hydroxypropyl methylcellulose E50.49g
Proper amount of purified water
The specific preparation method is as in example 1.
Example 4
Frovatriptan succinate 3.91g
β -Cyclodextrin 96g
Ethyl cellulose 6.62g
Sodium carboxymethylcellulose 0.662g
Stilsilk E-7-1904017.5 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Example 5
Frovatriptan succinate 3.91g
β -Cyclodextrin 96g
Ethyl cellulose 8.31g
Sodium carboxymethylcellulose 0.662g
Stilsilk E-7-1904021.33 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Comparative example 1
Frovatriptan succinate 3.91g
Ethyl cellulose 8.31g
Sodium carboxymethylcellulose 0.662g
Stilsilk E-7-1904021.33 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Comparative example 2
Frovatriptan succinate 3.91g
β -Cyclodextrin 96g
Sodium carboxymethylcellulose 0.662g
Stilsilk E-7-1904021.33 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Comparative example 3
Frovatriptan succinate 3.91g
β -Cyclodextrin 96g
Ethyl cellulose 8.31g
Stilsilk E-7-1904021.33 g
Hydroxypropyl methylcellulose E50.21g
Proper amount of purified water
The specific preparation method is as in example 1.
Test example 1 content measurement of Long-term stability test
The sample to be put on the market is placed at the temperature of 25 ℃ and the relative humidity of 60% for 36 months, and is sampled and measured by high performance liquid chromatography (0512 in the four ministry of the national pharmacopoeia 2015) at the time of 0, 3, 6, 12, 24 and 36 months respectively, and octadecylsilane chemically bonded silica is used as a filler; 0.1% phosphoric acid (triethylamine adjusted to pH 2.5) -methanol (81:19) was used as the mobile phase, and the detection wavelength was 245 nm. The separation degree of the furotriptan succinate peak and the adjacent impurity peak is not less than 1.5. The results are shown in table 1 and show that the stability of the active ingredient, furatriptan succinate, in the controlled release capsule of furatriptan succinate of the invention (example 5) is significantly better than that of the comparative examples.
It can be seen that the furotriptan succinate controlled-release capsule of example 5 has good stability, which is obviously superior to that of the comparative example. The controlled release capsule of furotriptan succinate has high bioavailability. Meanwhile, the preparation method in the method is suitable for expanded production.
Claims (6)
1. A furotriptan succinate controlled release capsule is characterized by comprising a furotriptan succinate inner core and a controlled release envelope from inside to outside; wherein the mass ratio of the furotriptan succinate inner core to the controlled release coating is 6-15: 100:
(1) the controlled release coating comprises the following components in parts by weight:
coating liquid of Sulisi E-7-19040100 parts
Pore-foaming agent hypromellose E55-8 parts
(2) The furotriptan succinate inner core comprises the following components in parts by weight:
frovatriptan succinate 1 part
β -cyclodextrin 2-5 parts
0.2-1 part of ethyl cellulose
0.02-0.1 part of sodium carboxymethylcellulose
1-3 parts of water.
2. A method of preparing a furotriptan succinate controlled release capsule according to claim 1, comprising the steps of:
(1) mixing β -cyclodextrin with water, heating to 60-90 ℃, adding furotriptan succinate, and stirring for 30-60 min;
(2) carrying out spray drying on the mixed system obtained in the step (1) through a spray drying tower to obtain furotriptan succinate soluble powder;
(3) mixing the furotriptan succinate soluble powder obtained in the step (2), ethyl cellulose and sodium carboxymethylcellulose, granulating by a centrifugal-fluidized granulation coating method, and drying to obtain a furotriptan succinate inner core;
(4) diluting the coating solution sulbactam E-7-19040 with water, uniformly mixing with a pore-forming agent hydroxypropyl methylcellulose E5, atomizing in an atomizing chamber, and spraying on the surface of the frovatriptan succinate inner core obtained in the step (3) to obtain frovatriptan succinate controlled-release particles;
(5) and (5) filling the furotriptan succinate controlled-release granules prepared in the step (4) into a blank capsule to obtain the furotriptan succinate controlled-release capsule.
3. The preparation method according to claim 2, wherein in the step (1), the mass ratio of β -cyclodextrin to furotriptan succinate is 2-5: 1.
4. The preparation method according to claim 2, wherein in the step (2), the inlet air temperature is 160-200 ℃, the inlet air pressure is 0.3-0.4 Mpa, and the outlet air temperature is 75-95 ℃.
5. The preparation method according to claim 2, wherein in the step (3), the drying temperature is 40 to 80 ℃ and the drying time is 1 to 3 hours.
6. The preparation method according to claim 2, wherein in the step (4), the mass ratio of the coating liquid, i.e., the styril E-7-19040, to the diluting water is 2: 3.
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| CN201911264743.9A CN110898037A (en) | 2019-12-11 | 2019-12-11 | Frovatriptan succinate controlled-release capsule and preparation method thereof |
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| CN201911264743.9A CN110898037A (en) | 2019-12-11 | 2019-12-11 | Frovatriptan succinate controlled-release capsule and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111544416A (en) * | 2020-04-29 | 2020-08-18 | 正大制药（青岛）有限公司 | Adelacitol controlled-release capsule and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412023A (en) * | 2015-12-07 | 2016-03-23 | 青岛正大海尔制药有限公司 | Frovatriptan succinate controlled-release granule and preparation method thereof |
| CN107115325A (en) * | 2017-05-18 | 2017-09-01 | 青岛正大海尔制药有限公司 | Smooth capsules of a kind of butanedioic acid furan Luo Qu and preparation method thereof |
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2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412023A (en) * | 2015-12-07 | 2016-03-23 | 青岛正大海尔制药有限公司 | Frovatriptan succinate controlled-release granule and preparation method thereof |
| CN107115325A (en) * | 2017-05-18 | 2017-09-01 | 青岛正大海尔制药有限公司 | Smooth capsules of a kind of butanedioic acid furan Luo Qu and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111544416A (en) * | 2020-04-29 | 2020-08-18 | 正大制药（青岛）有限公司 | Adelacitol controlled-release capsule and preparation method thereof |
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