CN113274365B - Ramelteon quick-release slow-release double-release preparation and preparation method thereof - Google Patents
Ramelteon quick-release slow-release double-release preparation and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- 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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A61P25/20—Hypnotics; Sedatives
Abstract
The invention provides a ramelteon quick-release and slow-release double-release preparation, which comprises a quick-release part and a slow-release part; the preparation form of the ramelteon quick-release and slow-release double-release preparation is a double-layer tablet, a granule or a capsule; wherein, the quick-release part comprises the following raw materials in parts by weight: 1-30 parts of ramelteon, 20-160 parts of a first filler, 0.5-10 parts of a disintegrant and 0.1-5 parts of a first lubricant; the sustained-release part comprises the following raw materials in parts by weight: 1-30 parts of ramelteon, 20-160 parts of a second filler, 5-30 parts of a slow release material and 0.2-10 parts of a second lubricant; the slow release material is selected from at least one of hypromellose, polyvinylpyrrolidone, hyprolose, sodium alginate, calcium alginate, guar gum and xanthan gum. The preparation has high initial stage release rate, and prolonged action time.
Description
Technical Field
The invention relates to the field of medicines, in particular to a ramelteon quick-release and slow-release double-release preparation and a preparation method thereof.
Background
Ramelteon, chemical name (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno- [5,4-b]Furan-8-yl) ethyl]Propionamide, named Ramelteon in English, has a molecular formula of C16H21NO2Molecular weight of 259.34, and chemical structural formula as follows:
ramelteon is a medicament for treating insomnia developed by Wutian pharmaceutical company in Japan, is the first melatonin receptor agonist applied to clinically treating insomnia, can selectively activate melatonin type 1 receptors and melatonin type 2 receptors, does not act on melatonin type 3 receptors, and has the characteristics of strong effect and high selectivity. In addition, ramelteon does not bind to neurotransmitter receptors such as GABA receptors, and does not interfere with the activity of most enzymes within a certain range. The ramelteon can increase the chronic wave sleep and the quick eye movement sleep without reducing the quick eye movement sleep of a human body, can be used for treating insomnia which is difficult to fall asleep, has exact curative effect on chronic insomnia and short-term insomnia, is safe to use, wide in treatment window and less in adverse reaction, and does not generate dependence after long-term administration.
The traditional ramelteon medicinal preparation is quick in drug release, can enable a patient to enter a sleep state in a short time, but is short in drug effect maintaining time, so that the patient is easy to wake up early and cannot fall asleep again after waking up, the sleep quality is reduced, and the mental state of the patient is seriously affected.
The conventional sustained-release preparation can continuously release the drug over a long period of time to maintain the drug effect, but the sustained-release preparation has a low rate at the initial stage of release, meaning that the therapeutic effect cannot be rapidly exerted, which is disadvantageous for the drug for treating insomnia.
Disclosure of Invention
Based on the above, the invention provides a ramelteon quick-release slow-release dual-release preparation which has a higher initial-stage release speed, can quickly exert the drug effect, and can maintain sufficient drug concentration for a longer time and prolong the drug action time.
The invention is realized by the following technical scheme.
A ramelteon quick-release and slow-release double-release preparation comprises a quick-release part and a slow-release part; the ramelteon quick-release and slow-release double-release preparation is in a dosage form of a double-layer tablet, a granule or a capsule;
wherein, the quick-release part comprises the following raw materials in parts by weight:
1 to 30 parts of ramelteon,
20 to 160 parts of a first filler,
0.5 to 10 parts of disintegrating agent,
0.1-5 parts of a first lubricant;
the sustained-release part comprises the following raw materials in parts by weight:
1 to 30 parts of ramelteon,
20 to 160 parts of a second filler,
5-30 parts of slow-release material,
0.2-10 parts of a second lubricant;
the slow release material is selected from at least one of hypromellose, polyvinylpyrrolidone, hyprolose, sodium alginate, calcium alginate, guar gum and xanthan gum.
In one embodiment, the quick-release part comprises the following raw materials in parts by weight:
4-6 parts of ramelteon,
80 to 140 parts of a first filler,
3-6 parts of a disintegrating agent,
1-1.5 parts of a first lubricant;
the sustained-release part comprises the following raw materials in parts by weight:
4-6 parts of ramelteon,
80 to 130 parts of a second filler,
10-15 parts of slow-release material,
and 1.5-2.5 parts of a second lubricant.
In one embodiment, the weight ratio of the quick release part to the sustained release part is 1 (0.11-9).
In one embodiment, the weight ratio of the quick release part to the sustained release part is 1 (0.66-1.5).
In one embodiment, the first filler and the second filler are each independently selected from at least one of lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, and dibasic calcium phosphate.
In one embodiment, the disintegrant is selected from at least one of croscarmellose sodium, sodium carboxymethylcellulose, crospovidone, sodium starch glycolate, low substituted hydroxypropylcellulose and corn starch.
In one embodiment, the first lubricant and the second lubricant are each independently selected from at least one of silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, and polyethylene glycol.
In one embodiment, the dose of the ramelteon in the ramelteon quick-release and slow-release double-release preparation is 8-16 mg.
The invention also provides a preparation method of the ramelteon quick-release and slow-release double-release preparation, which comprises the following steps:
mixing the ramelteon, the first filler and the disintegrant for the first time, then adding the first lubricant, and mixing to prepare the quick-release part;
and mixing the ramelteon, the second filler and the slow-release material for the second time, then adding the second lubricant, and mixing to prepare the slow-release part.
In one embodiment, the first mixing further comprises the following steps: wet granulating with ethanol or water; and/or
The method also comprises the following steps after the second mixing: wet granulating with ethanol or water.
Compared with the prior art, the rapid-release slow-release double-release preparation of ramelteon has the following beneficial effects:
the inventor selects at least one of hypromellose, polyvinylpyrrolidone, hyprolose, sodium alginate, calcium alginate, guar gum and xanthan gum as a slow release material, compounds the slow release material with ramelteon, a second filler, a slow release material and a second lubricant according to a certain proportion to prepare a slow release part, compounds the ramelteon, the first filler, a disintegrating agent and the first lubricant to form a quick release part, compounds the quick release part and the slow release part to form the ramelteon quick release and slow release double release preparation which has a higher release speed in the initial stage, can quickly exert curative effect and enable a patient to enter a sleep state as soon as possible, and simultaneously can ensure that the preparation can continuously release medicines in a longer time, maintain enough medicine concentration and enable the patient to have sufficient sleep time and avoid premature awakening.
Furthermore, the ramelteon quick-release and slow-release double-release preparation has simple process, can realize the enlarged industrial production and has wide application prospect.
Drawings
Fig. 1 is a drug release curve of a ramelteon quick-release slow-release dual-release preparation provided by embodiments 1-8 of the invention;
fig. 2 is a drug release curve of the ramelteon preparation provided by comparative examples 1-3 of the present invention.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the accompanying examples. The examples set forth preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The words "preferably," "more preferably," in the present disclosure refer to embodiments of the disclosure that may, in some instances, provide certain benefits. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
The invention provides a ramelteon quick-release and slow-release double-release preparation, which comprises a quick-release part and a slow-release part;
wherein, the quick-release part comprises the following raw materials in parts by weight:
1 to 30 parts of ramelteon,
20 to 160 parts of a first filler,
0.5 to 10 parts of disintegrating agent,
0.1-5 parts of a first lubricant;
the sustained-release part comprises the following raw materials in parts by weight:
1 to 30 parts of ramelteon,
20 to 160 parts of a second filler,
5-30 parts of slow-release material,
0.2-10 parts of a second lubricant;
the slow release material is at least one of hypromellose, polyvinylpyrrolidone, hyprolose, sodium alginate, calcium alginate, guar gum and xanthan gum.
Preferably, the slow release material is selected from hypromellose.
In a specific example, the quick-release part comprises the following raw materials in parts by weight:
3 to 6 parts of ramelteon,
80 to 140 parts of a first filler,
3-6 parts of a disintegrating agent,
0.5-1.5 parts of a first lubricant;
the sustained-release part comprises the following raw materials in parts by weight:
3 to 6 parts of ramelteon,
80 to 130 parts of a second filler,
7-15 parts of slow-release material,
0.5-2.5 parts of a second lubricant.
In a specific example, the weight ratio of the quick-release part to the sustained-release part is 1 (0.11-9). It is understood that, in the present invention, the weight ratio of the immediate release part to the sustained release part includes, but is not limited to, 1:0.11, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1: 9.
Preferably, the weight ratio of the quick-release part to the sustained-release part is 1 (0.66-1.5).
In a specific example, the first filler and the second filler are each independently selected from at least one of lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, and dibasic calcium phosphate.
Preferably, the first filler and the second filler are each independently selected from at least one of lactose and microcrystalline cellulose. More preferably, the first and second fillers are a mixture of lactose and microcrystalline cellulose.
In a specific example, the disintegrant is selected from at least one of croscarmellose sodium, sodium carboxymethylcellulose, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropylcellulose, and corn starch.
Preferably, the disintegrant is selected from croscarmellose sodium.
In a specific example, the first lubricant and the second lubricant are each independently selected from at least one of silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, and polyethylene glycol.
Preferably, the first lubricant and the second lubricant are each independently selected from at least one of magnesium stearate and silicon dioxide.
More preferably, the first lubricant is magnesium stearate; the second lubricant is a mixture of magnesium stearate and silicon dioxide.
In a specific example, the ramelteon quick-release and slow-release double-release preparation is in the form of a double-layer tablet, a granule or a capsule.
In a specific example, the dose of the ramelteon in the ramelteon quick-release and slow-release double-release preparation is 8-16 mg. It is understood that in the present invention, the dosage of ramelteon in the immediate release/sustained release double release formulation of ramelteon includes, but is not limited to, 8mg, 9mg, 10mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg and 16 mg. Preferably, the dose of ramelteon in the ramelteon immediate release/sustained release dual release formulation is 10 mg.
The invention also provides a preparation method of the ramelteon quick-release slow-release double-release preparation, which comprises the following steps:
mixing ramelteon, a first filler and a disintegrating agent for the first time, then adding a first lubricant, and mixing to prepare a quick-release part;
and mixing ramelteon, a second filler and the slow-release material for the second time, then adding a second lubricant, and mixing to prepare a slow-release part.
In one particular example, a double tablet compression is performed with an immediate release portion and a sustained release portion.
In a specific example, the first mixing further comprises the following steps: wet granulating with ethanol or water.
In a specific example, the second mixing further comprises the following steps: wet granulating with ethanol or water.
The immediate release and sustained release double-release preparation of ramelteon and the preparation method thereof are further described in detail with reference to the specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a ramelteon quick-release slow-release double-release preparation, and the specific formula is as follows
The preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
The ramelteon, the lactose, the microcrystalline cellulose PH102 and the croscarmellose sodium are mixed uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
Tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of granules of the two parts, wherein the sustained-release part is 100mg, and the quick-release part is 150mg, and pressing the double-layer tablets.
Example 2
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
The ramelteon, the lactose, the microcrystalline cellulose PH102 and the croscarmellose sodium are mixed uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 125mg, and the quick-release part is 125mg, and pressing the double-layer tablets.
Example 3
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
The ramelteon, the lactose, the microcrystalline cellulose PH102 and the croscarmellose sodium are mixed uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
Tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of granules of the two parts, wherein the sustained-release part is 150mg, and the quick-release part is 100mg, and pressing the double-layer tablets.
Example 4
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
The ramelteon, the lactose, the microcrystalline cellulose PH102 and the croscarmellose sodium are mixed uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 25mg, and the quick-release part is 225mg, and pressing the double-layer tablets.
Example 5
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
The ramelteon, the lactose, the microcrystalline cellulose PH102 and the croscarmellose sodium are mixed uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 225mg, and the quick-release part is 25mg, and pressing the double-layer tablets.
Example 6
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
Mixing ramelteon, lactose, microcrystalline cellulose and sodium carboxymethyl starch uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 125mg, and the quick-release part is 125mg, and pressing the double-layer tablets.
Example 7
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
Mixing ramelteon, lactose, microcrystalline cellulose and crospovidone uniformly. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 125mg, and the quick-release part is 125mg, and pressing the double-layer tablets.
Example 8
The embodiment provides a ramelteon quick-release slow-release double-release preparation, which has the following specific formula:
the preparation method comprises the following steps:
ramelteon, mannitol, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing to obtain delayed release part.
Uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102 and sodium carboxymethyl starch. Adding magnesium stearate, and mixing to obtain quick-release part.
And tabletting the sustained-release part and the quick-release part of the ramelteon by using a double-layer tablet press, adjusting the filling amount of the granules of the two parts, wherein the sustained-release part is 125mg, and the quick-release part is 125mg, and pressing the double-layer tablets.
Comparative example 1
The comparative example provides a ramelteon preparation, the specific prescription is as follows:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose SuperTab 11SD, microcrystalline cellulose PH102 and sodium carboxymethylcellulose. Adding magnesium stearate, and mixing. Tabletting, wherein the weight of the tablet is 250mg, and the hardness is 3-10 kg.
Comparative example 2
The comparative example provides a ramelteon preparation, the specific prescription is as follows:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH101, hydroxypropyl cellulose Klucel EXF PHARM and silicon dioxide. Slowly adding 95% ethanol solution into the above mixture, and stirring while adding. The soft material is suitable for hardness, and can be held into a ball and then dispersed by touching. The soft mass was granulated through a 10 mesh screen and the resulting granules were dried in an oven at 60 ℃. After drying for 1 hour, the drying weight loss of the granules was measured until the drying weight loss was < 3%, and drying was stopped. Adding magnesium stearate into the dried granules, and uniformly mixing. Tabletting, wherein the weight of the tablet is 250mg, and the hardness is 3-10 kg.
Comparative example 3
The comparative example provides a ramelteon preparation, the specific prescription is as follows:
the preparation method comprises the following steps:
uniformly mixing ramelteon, lactose, microcrystalline cellulose PH102, hydroxypropyl methyl cellulose K4M and silicon dioxide. Adding magnesium stearate, and mixing. Tabletting, wherein the weight of the tablet is 250mg, and the hardness is 3-10 kg.
Effect test
The effect tests of the above examples 1 to 8 and comparative examples 1 to 3 include the test of the dissolution curve of the sample, and the specific test method is as follows:
dissolution conditions an apparatus according to the second method was used, rotating at 50rpm, at 37 ℃, with a release medium of 900mL, purified water, detection method UV, detection wavelength 287 nm.
The release curves of examples 1 to 8 are shown in fig. 1, and it can be seen that the release rate of ramelteon at the initial stage is significantly increased, and as the proportion of the quick-release components is increased, the dissolution rates at 0.25 hour and 0.5 hour are significantly increased, and the curative effect can be rapidly exerted. Can be completely released within 3-4 hours, maintains enough drug release time, and ensures that a patient cannot be awakened in advance after sleeping.
The drug release curves of the comparative examples 1-3 are shown in fig. 2, when the components are released at a medium speed in the prescription, the dissolution rate of the ramelteon drug is extremely high, and the ramelteon drug can be completely released within 30 minutes. When only slow-release components are contained in the prescription, the dissolution rate of the ramelteon medicine is slow, the dissolution rate is low within 30 minutes, and the ramelteon medicine can be completely released within 3-6 hours.
The results of the specific data of the dissolution curves of the drug samples of examples 1 to 8 and comparative examples 1 to 3 are shown in table 1.
TABLE 1 dissolution Curve results
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.
Claims (6)
1. The rapid-release and slow-release double-release preparation of the ramelteon is characterized by comprising a rapid-release part and a slow-release part; the ramelteon quick-release and slow-release double-release preparation is in a dosage form of a double-layer tablet, a granule or a capsule;
wherein, the quick-release part comprises the following raw materials in parts by weight:
4-6 parts of ramelteon,
91.2 to 136.8 parts of a first filler,
3.8 to 5.7 parts of disintegrating agent,
1-1.5 parts of a first lubricant;
the sustained-release part comprises the following raw materials in parts by weight:
4-6 parts of ramelteon,
84.5 to 126.75 parts of a second filler,
10-15 parts of slow-release material,
1.5-2.25 parts of a second lubricant;
the slow release material is selected from hydroxypropyl methylcellulose;
the first filler and the second filler are: a mixture of lactose and microcrystalline cellulose;
the disintegrant is selected from croscarmellose sodium or sodium carboxymethyl starch;
the weight ratio of the quick release part to the slow release part is 1 (0.66-1.5).
2. The immediate release and sustained release ramelteon dual-release formulation according to claim 1, wherein the disintegrant is selected from the group consisting of croscarmellose sodium.
3. The ramelteon quick-release and slow-release dual-release preparation according to any one of claims 1-2, wherein the first lubricant and the second lubricant are respectively and independently selected from at least one of silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate and polyethylene glycol.
4. The rapid-release slow-release dual-release ramelteon preparation according to any one of claims 1-2, wherein the dosage of ramelteon in the rapid-release slow-release dual-release ramelteon preparation is 8-16 mg.
5. A method for preparing ramelteon quick-release slow-release double-release preparation according to any one of claims 1 to 4, which comprises the following steps:
mixing the ramelteon, the first filler and the disintegrant for the first time, then adding the first lubricant, and mixing to prepare the quick-release part;
and mixing the ramelteon, the second filler and the slow-release material for the second time, then adding the second lubricant, and mixing to prepare the slow-release part.
6. The method for preparing ramelteon quick-release slow-release dual-release preparation according to claim 5, wherein the first mixing step further comprises the following steps: wet granulating with ethanol or water; and/or
The method also comprises the following steps after the second mixing: wet granulating with ethanol or water.
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| WO2009149920A1 (en) * | 2008-06-12 | 2009-12-17 | Merz Pharma Gmbh & Co. Kgaa | 1-amino-alkylcyclohexane derivatives for the treatment of sleep disorders |
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| CN103394087A (en) * | 2004-10-28 | 2013-11-20 | 雅戈泰克股份公司 | Dosage form time-lagged of drugs for therapy of insomnia |
| WO2009149920A1 (en) * | 2008-06-12 | 2009-12-17 | Merz Pharma Gmbh & Co. Kgaa | 1-amino-alkylcyclohexane derivatives for the treatment of sleep disorders |
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