CN106729730B - slow-release medicine and preparation method thereof - Google Patents
slow-release medicine and preparation method thereof Download PDFInfo
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- CN106729730B CN106729730B CN201611204632.5A CN201611204632A CN106729730B CN 106729730 B CN106729730 B CN 106729730B CN 201611204632 A CN201611204632 A CN 201611204632A CN 106729730 B CN106729730 B CN 106729730B
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release medicament and a preparation method thereof, in particular to a metaxalone tablet and a zileuton sustained-release tablet prepared by using the method, wherein the sustained-release medicament comprises a water-insoluble material. Compared with the prior art, the method of the invention can reduce the usage amount of the auxiliary materials by at least 10-20% and even more than 50% on the premise of achieving the same effect of controlling the release of the drug, thereby obviously reducing the volume of the final preparation and being easier to swallow.
Description
Technical Field
The invention belongs to the field of medicinal preparations, particularly relates to a sustained-release medicament and a preparation method thereof, and particularly relates to a metaxalone tablet and a zileuton sustained-release tablet prepared by using the method.
background
With the development of pharmaceutical science and pharmaceutical preparation technology, people recognize that it is very important to control the release rate of oral solid preparations, and proper drug release rate can achieve ideal therapeutic effect and reduce the occurrence of side effects. In practical application, in order to achieve the purpose of controlling drug release, more excipients for controlling drug release are often needed, however, the use of a large amount of excipients inevitably results in a larger weight and volume of the final preparation, and for drugs with larger dosage (for example, drugs with active ingredient content of more than 500 mg/tablet), the volume of the final preparation is more difficult to swallow, which brings inconvenience to patients to take the drugs. According to FDA statistics in the united states, 1600 ten thousand people in the united states have difficulty swallowing, with 8% of them having experienced a situation where the formulation is too large to swallow without strict medication, and 4% of them having failed to use the formulation for treatment. Therefore, for the medicine with larger dosage, the problem of controlling the dosage of the auxiliary materials can not only achieve good effect of controlling release, but also have the smallest preparation volume, which is a very practical topic. One of the objectives of the present invention is to provide a method for controlling the release rate of an oral solid pharmaceutical preparation, which can achieve the desired controlled release effect with a small amount of excipients.
Metaxalone is a central muscle relaxant, can block the multi-synaptic pathway of the spinal cord, has a sedative effect, and also has the effects of resisting choline, relieving fever and easing pain. The traditional Chinese medicine composition is mainly used for assisting rest, physical therapy and relieving discomfort caused by acute skeletal muscle pain in clinic. The metaxalone formulations currently on the market are mainly 800mg size tablets, the original formulation manufactured by King pharmaceutical company, usa under the trade name
oral solid tablets are generally divided into ordinary preparations and sustained-release preparations in terms of the speed of drug release, the ordinary preparations are generally disintegrated and completely released within 45 minutes, and the sustained-release preparations are released for more than several hours. Although the metaxalone tablet is classified as a common preparation in the classification of medicines, the release behavior is more characterized by a sustained release preparation. For example, the united states pharmacopoeia specifies that the release standard of metaxalone tablets is such that the release amount is not less than 60% of the indicated amount in 60 minutes under the conditions of 100 rpm by paddle method, 900 ml of a solution containing 0.5% Sodium Lauryl Sulfate (SLS) as a dissolution medium, and 37 ℃. In the above release rate method, the conditions of 100 rotations of the paddle method are very drastic, and the release standard (60%) is also much lower than the usual 80% end-point release standard of the conventional formulation. If the speed of the paddle is reduced to 50 rpm which is commonly used in the above conditions and other conditions are not changed, more than 4 hours are needed for the metaxalone tablet to reach more than 80% release, so that the actual release behavior of the metaxalone tablet has obvious slow release characteristics.
Zileuton is a leukotriene inhibitor, and is used as a medicine for preventing and treating asthma. The slow-release formulation sold on the market is a tablet manufactured by CHIESI USA INC under the trade name Zyflo CR, which has a slow-release effect for 12 hours. The dose of zileuton is 600 mg/tablet, so that the slow-release tablet is large in size and difficult to swallow. It is therefore another object of the present invention to prepare a zileuton sustained release tablet which achieves the desired sustained release effect with only a small amount of excipients.
CN 104434844A discloses a felodipine metoprolol succinate sustained release tablet and a preparation method thereof, wherein felodipine sustained release particles are prepared by adopting a method of co-granulating a medicament and hydroxypropyl methylcellulose K100M. In the traditional wet granulation method, in order to achieve the effect of controlling the release rate of the drug, water-soluble high polymer materials with higher viscosity (such as hydroxypropyl methylcellulose, povidone, sodium alginate, polyoxyethylene and the like) are used together with the drug for granulation, and due to the existence of the water-soluble high polymer materials, the higher viscosity slows down the disintegration rate of the particles, so the effect of delaying the release of the drug can be achieved. However, the method has the limitation that the sustained-release effect of the prepared granules is limited, the granules gradually disintegrate along with the dissolution of the water-soluble high polymer material, and the drug is dissolved and released along with the dissolution of the water-soluble high polymer material, and if the good sustained-release effect is achieved, the dosage of the sustained-release high polymer material needs to be greatly increased, so that the volume of the preparation is increased.
Disclosure of Invention
the invention aims to provide a sustained-release medicament and a preparation method thereof, and the medicament can control the release time of the medicament, reduce the dosage of auxiliary materials, reduce the volume of the medicament and be easier to swallow.
In order to achieve the purpose, the invention adopts the following technical scheme:
In a first aspect, the present invention provides a sustained release medicament comprising a water insoluble material.
In the invention, the solution of the water-insoluble material is used as a binder to prepare the drug-containing sustained-release granules, and the granules can form a three-dimensional network structure formed by the water-insoluble material in the inner part after being dried, so that the granules are basically not disintegrated in the release process, and the drug release rate is controlled.
preferably, the sustained-release drug further comprises an organic solvent dissolving the water-insoluble material.
In the invention, the organic solvent is used for dissolving the material which is difficult to dissolve in water, so that the medicine and other auxiliary materials can be uniformly dispersed and bonded, and the effect of releasing the controlled release medicine is achieved.
Preferably, the water-insoluble material is any one of cellulose acetate, ethyl cellulose, acrylic resin or polyvinyl acetate or a combination of at least two of them.
Preferably, the organic solvent is any one of methanol, ethanol, isopropanol, propylene glycol, dichloromethane, acetone or chloroform, or a combination of at least two thereof.
In a second aspect, the present invention provides a method for preparing a sustained-release drug as described in the first aspect, comprising the steps of:
(1) Preparing a binder solution of a water-insoluble material;
(2) Granulating the active medicament with the therapeutic dose or the mixture of the active medicament and the auxiliary materials added internally with the adhesive solution prepared in the step (1), and then drying and granulating to obtain the medicament-containing granules.
the granulation method disclosed by the invention can be used for granulation by using a common wet granulation machine, and can also be used for granulation by adopting a fluidized bed.
Preferably, the method further comprises the step of mixing the prepared drug-containing granules with an additional auxiliary material and then compressing the mixture into tablets.
Preferably, the method further comprises the step of filling the prepared drug-containing granules and external auxiliary materials to prepare capsules.
preferably, the active drug is metaxalone and/or zileuton.
Preferably, the adjuvant is any one or a combination of at least two of excipient, diluent, carrier, flavoring agent, binder and filler.
in a third aspect, the present invention provides a pharmaceutical composition comprising a sustained release medicament as described in the first aspect.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention adopts the solution of the water-insoluble material to granulate the bulk drug and the added auxiliary materials, so that the water-insoluble material bonds the drug (or the mixture of the drug and the auxiliary materials) together in the granulation process, and forms a three-dimensional network structure formed by the insoluble material in the granules, and in the release process, the three-dimensional network structure can not be dissolved, thereby objectively limiting the disintegration of the granules and achieving good effect of controlling the release of the drug;
(2) Compared with the prior art, the method of the invention can reduce the usage amount of the auxiliary materials by at least 10-20% and even more than 50% on the premise of achieving the same effect of controlling the release of the drug, thereby obviously reducing the volume of the final preparation and being easier to swallow.
Drawings
Fig. 1 release profile of metaxalone tablets of the invention;
Figure 2 is a release profile of zileuton sustained release tablets of the present invention.
Detailed Description
the technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
the experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of metaxalone tablets
(1) According to the components and the dosage in the table 1, firstly, ethyl cellulose and 95% ethanol are prepared into a solution;
(2) Adding the metaxalone bulk drug and microcrystalline cellulose containing the drug granules into a wet granulator, and mixing for 3 minutes under the conditions of the rotating speed of a stirring paddle of 75 revolutions per minute and the rotating speed of a cutter of 500 revolutions per minute;
(3) Keeping the rotating speed of a stirring paddle of the wet granulator unchanged (still 75 revolutions per minute), increasing the rotating speed of a cutter to 1000 revolutions per minute, and slowly adding the ethyl cellulose solution into the wet granulator for about 2 minutes;
(4) Sieving the wet particles in the step (3) by a Quadro Comil for wet granulation, then drying by a fluidized bed, sampling every 5 minutes at the air inlet temperature of 45 ℃ and the fan frequency of 20 Hz, determining the drying weight loss, stopping drying until the drying weight loss value is less than 1%, then crushing by the Quadro Comil and sieving by a 20-mesh sieve;
(5) Mixing the obtained granule with additional adjuvants (microcrystalline cellulose, crospovidone and starch) at 25 r/min for 10 min, adding magnesium stearate, and mixing at 25 r/min for 1 min;
(6) and (3) pressing the granules obtained in the step (5) into tablets containing 800mg of metaxalone in a capsule shape of 19 x 7.9 mm.
TABLE 1
The release curve of the metaxalone tablet is shown in figure 1, and from figure 1, the metaxalone tablet can still slowly release the drug for 120 minutes under the violent condition of 100 revolutions per minute by a paddle method, and shows good slow release effect.
Experimental example 2 preparation of zileuton sustained-release tablet
(1) According to the components and the dosage in the table 2, firstly, preparing polyvinyl acetate and absolute ethyl alcohol into a solution, and then adding isopropanol into the solution to be uniformly mixed;
(2) adding zileuton raw material into a shearing granulator with the working volume of about 1 liter, opening a cutter, and slowly adding the adhesive solution prepared in the step (1) into a wet granulator, wherein the adding process lasts for about 1 minute;
(3) Sieving the wet particles in the step (2) by a Quadro Comil for wet granulation, then drying by a fluidized bed, sampling every 5 minutes at the air inlet temperature of 50 ℃ and the fan frequency of 10 Hz, determining the drying weight loss, stopping drying until the drying weight loss value is less than 1%, then crushing by the Quadro Comil and sieving by a 20-mesh sieve;
(4) mixing the obtained granule with additional adjuvants (hypromellose, microcrystalline cellulose and hydroxypropyl cellulose) at 25 r/min for 10 min, adding stearic acid at 25 r/min for 1 min, and punching into 600mg tablets with 17 × 8.5mm ellipse shape.
TABLE 2
The release curve of the zileuton sustained-release tablet is shown in figure 2, and as can be seen from figure 2, under the relatively violent condition of 75 revolutions by a paddle method, the prepared zileuton sustained-release tablet can slowly release the drug for 12 hours, and shows excellent sustained-release performance.
The applicant states that the present invention is illustrated by the above examples of the process of the present invention, but the present invention is not limited to the above process steps, i.e. it is not meant that the present invention must rely on the above process steps to be carried out. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Claims (6)
1. A sustained-release drug, characterized in that the sustained-release drug comprises a water-insoluble material and an organic solvent which dissolves the water-insoluble material;
The water-insoluble material is polyvinyl acetate;
the organic solvent is a combination of ethanol and isopropanol;
The sustained-release medicine is prepared by adopting the following preparation method, and the preparation method comprises the following steps:
(1) preparing a binder solution of a water-insoluble material;
(2) Granulating the mixture of zileuton with therapeutic dose and the internally added auxiliary materials and the adhesive solution prepared in the step (1), and then drying and granulating to obtain the drug-containing granules.
2. a process for the preparation of a sustained release medicament according to claim 1, comprising the steps of:
(1) Preparing a binder solution of a water-insoluble material;
(2) Granulating the mixture of zileuton with therapeutic dose and the internally added auxiliary materials and the adhesive solution prepared in the step (1), and then drying and granulating to obtain the drug-containing granules.
3. The preparation method according to claim 2, further comprising mixing the prepared drug-containing granules with an additional adjuvant and compressing into tablets.
4. the preparation method of claim 2, further comprising filling the prepared drug-containing granules with additional excipients to prepare capsules.
5. the method according to claim 2, wherein the excipient is any one or a combination of at least two of a diluent, a carrier, a flavoring agent, a binder and a filler.
6. A pharmaceutical composition comprising the sustained-release drug of claim 1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611204632.5A CN106729730B (en) | 2016-12-23 | 2016-12-23 | slow-release medicine and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611204632.5A CN106729730B (en) | 2016-12-23 | 2016-12-23 | slow-release medicine and preparation method thereof |
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| CN106729730A CN106729730A (en) | 2017-05-31 |
| CN106729730B true CN106729730B (en) | 2019-12-17 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102232938A (en) * | 2010-05-06 | 2011-11-09 | 杭州赛利药物研究所有限公司 | Metaxalone capsule and preparation method thereof |
| CN102379857A (en) * | 2011-05-30 | 2012-03-21 | 深圳信立泰药业股份有限公司 | Levetiracetam slow release medicinal composite and preparation method thereof |
| CN102429872A (en) * | 2011-11-25 | 2012-05-02 | 舒泰神（北京）生物制药股份有限公司 | Zileuton-containing membrane-controlled slow release pellets and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201118198D0 (en) * | 2011-10-21 | 2011-12-07 | Jagotec Ag | Improvements in or relating to organic compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102232938A (en) * | 2010-05-06 | 2011-11-09 | 杭州赛利药物研究所有限公司 | Metaxalone capsule and preparation method thereof |
| CN102379857A (en) * | 2011-05-30 | 2012-03-21 | 深圳信立泰药业股份有限公司 | Levetiracetam slow release medicinal composite and preparation method thereof |
| CN102429872A (en) * | 2011-11-25 | 2012-05-02 | 舒泰神（北京）生物制药股份有限公司 | Zileuton-containing membrane-controlled slow release pellets and preparation method thereof |
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Effective date of registration: 20230505 Address after: Room 203, Building 9, No. 337 Zhouzhu Road, Zhoupu Town, Pudong New Area, Shanghai, 201318 Patentee after: SALUS PHARMA TECHNOLOGY (SHANGHAI) Co.,Ltd. Address before: Room 707 and 809, No. 781 Cailun Road, Pudong New Area, Shanghai, March 2012 Patentee before: SHANGHAI XINXIN MEDICINE TECHNOLOGY CO.,LTD. |
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