CN111166725A - Metoprolol sustained-release tablet composition and preparation method thereof - Google Patents
Metoprolol sustained-release tablet composition and preparation method thereof Download PDFInfo
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- CN111166725A CN111166725A CN202010058938.4A CN202010058938A CN111166725A CN 111166725 A CN111166725 A CN 111166725A CN 202010058938 A CN202010058938 A CN 202010058938A CN 111166725 A CN111166725 A CN 111166725A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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Abstract
The invention relates to a metoprolol sustained-release tablet composition and a preparation method thereof, belonging to the field of pharmaceutical preparations. The composition comprises sustained-release pellets, a diluent and a lubricant, and optionally comprises a coating material; the sustained-release pellet comprises a drug-loading pellet and a sustained-release layer, wherein the drug-loading pellet comprises a blank pellet core and an active ingredient. The method adopts the mixed solution with high solid content to coat the blank pellet core to prepare the drug-loading pellet, adopts the hot-melt coating technology to prepare the slow-release pellet, has quick and smooth process and short relative time, reduces the production cost and ensures the product quality.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a metoprolol sustained-release tablet composition and a preparation method thereof.
Background
metoprolol is a selective β 1 receptor blocker, and is one of common medicines for treating hypertension, coronary heart disease, chronic heart failure and arrhythmia.A common metoprolol tablet has a clearing half-life of 3-4h and needs to be taken more than 2 times per day, and the selectivity of metoprolol has the characteristic of dose dependence.
In the prior art, a plurality of metoprolol sustained-release preparations exist, and in the preparations, a plurality of components are required to be used to obtain a preparation with a sustained-release effect through multiple processes, the prescription composition is complex, the preparation process is tedious, the production period is long, if bottom-spraying fluidized bed coating is adopted, the coating time is too long, the cost is too high, or organic reagent ethanol is adopted to carry out bottom-spraying sustained-release layer coating, and the dosage is large; the processes have more working procedures, long production period and high cost, and are not beneficial to obtaining the final preparation; therefore, there is still a need to develop a formulation and a preparation method of metoprolol sustained release preparation.
Disclosure of Invention
Definition of terms:
the terms "optional" or "optionally" or "optional" mean that the subsequently described event or circumstance may, but need not, occur. For example, "optionally other pharmaceutically acceptable excipients" means that other pharmaceutically acceptable excipients may or may not be present.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
"pharmaceutically acceptable" means herein: a substance or compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
"consisting of" means that the composition contains no other components except the components, water and inevitable impurities.
The solid content refers to the weight percentage of the nonvolatile substances in the solution or the mixed solution to the total weight of the solution or the mixed solution.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Detailed Description
According to an embodiment of the present invention, there is provided a metoprolol sustained release tablet composition. A metoprolol sustained release tablet composition comprising: sustained release pellets, a diluent and a lubricant, optionally containing a coating material; the sustained-release pellet comprises a drug-loading pellet and a sustained-release layer, wherein the drug-loading pellet comprises a blank pellet core and an active ingredient.
The blank pellet core can adopt medicinal pellet cores with the average particle size of 100-500 microns. The blank pellet core can be a microcrystalline cellulose pellet core, a sucrose pellet core and the like. In some embodiments, the blank pellet core can be a pharmaceutical pellet core with an average particle size of 150-250 microns.
The blank pill core can account for 5-10% of the total weight of the composition, which is beneficial to obtaining the sustained-release tablet.
The active ingredient may be metoprolol, metoprolol succinate, metoprolol tartrate, or a combination thereof. In some embodiments, the active ingredient is metoprolol succinate.
The active ingredient may be present in an amount of 8% to 42% by weight of the total composition. In some embodiments, the active ingredient is metoprolol succinate and the active ingredient can be 20% to 35% of the total weight of the composition.
The weight of the active ingredients is 2-6 times of the weight of the blank pill core, which is beneficial to obtaining the sustained-release tablet. In some embodiments, the total weight of the active ingredient and binder is 2-6 times the weight of the empty pellet core, which is advantageous for obtaining a sustained release tablet.
The drug-loading pellet optionally contains a binder. The binder may be polyvinylpyrrolidone (PVP), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), or a combination thereof. In some embodiments, the mass ratio of the binder to the active ingredient in the drug-loaded pellets is from 0:1 to 1: 3.
In some embodiments, the drug delivery pellet is a mixture of a blank pellet core, an active ingredient, and a binder.
In some embodiments, the drug delivery pellet is a mixture of empty pellet core, metoprolol succinate and at least one of binders polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, wherein the total weight of the metoprolol succinate and at least one of binders polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose is 2-6 times of the weight of the empty pellet core; is favorable for obtaining the sustained-release tablet.
In some embodiments, the active ingredient is mixed with water, optionally with a binder, and heated to provide a clear solution of the coated pellet; and coating the blank pellet core with the coating solution of the coated pellets by using hot-melt coating equipment to obtain the coated pellets.
The sustained-release pellet comprises a drug-loading pellet and a sustained-release layer. The sustained-release layer accounts for 10-50% of the weight of the pellet. In some embodiments, the sustained release layer is 25% to 50% of the weight of the pellet. In some embodiments, the sustained-release layer accounts for 25% -35% of the weight of the pellet, which is beneficial to obtaining a sustained-release tablet composition with better sustained-release effect. In some embodiments, the sustained-release layer is 30% of the weight of the pellet, which is beneficial to obtain a sustained-release tablet composition with better sustained-release effect.
The sustained release layer includes a controlled release material.
The controlled release material is at least one of octadecanol, hydrogenated castor oil, carnauba wax, white wax, long-chain fatty acid, long-chain fatty alcohol, stearate and fatty glyceride. In some embodiments, the controlled release material is stearyl alcohol and hydrogenated castor oil.
The slow release layer may or may not include a pore-forming agent. The porogen may be 0-30% (w/w) of the weight of the controlled release material. The pore-forming agent may be polyethylene glycol 6000, polyvinylpyrrolidone (PVP), Hydroxypropylmethylcellulose (HPMC), or Hydroxypropylcellulose (HPC), or a combination thereof.
In some embodiments, the sustained release layer is comprised of a controlled release material.
In some embodiments, a porogen is included in the sustained release layer. In some embodiments, the sustained release layer includes a controlled release material and a pore-forming agent therein. In some embodiments, the sustained release layer is comprised of a controlled release material and a pore-forming agent.
In some embodiments, the extended release layer comprises stearyl alcohol, hydrogenated castor oil, and polyethylene glycol 6000. In some embodiments, the sustained release layer is octadecanol, hydrogenated castor oil and polyethylene glycol 6000; is beneficial to obtain the sustained-release tablet composition and the preparation thereof.
In some embodiments, the weight ratio of octadecanol to hydrogenated castor oil in the sustained-release layer is 3: 1.
In some embodiments, the porogen is 15% of the total mass of the octadecanol and the hydrogenated castor oil.
In some embodiments, the sustained release layer is octadecanol, hydrogenated castor oil and polyethylene glycol 6000, wherein the mass ratio of octadecanol to hydrogenated castor oil is 3:1, and the polyethylene glycol 6000 is 15% of the total mass of octadecanol and hydrogenated castor oil; is beneficial to obtaining the sustained-release tablet and preparing the sustained-release tablet.
The sustained-release pellet can be prepared by coating a sustained-release layer material consisting of a sustained-release layer or a sustained-release layer material containing a sustained-release layer on the pellet.
In some embodiments, the drug-loaded pellets are coated by the material of the sustained release layer, and the weight of the coating of the sustained release layer is increased by 10 to 50 percent. In some embodiments, the coated pellets are coated by the material of the sustained release layer, and the weight of the coating of the sustained release layer is increased by 25 to 50 percent. In some embodiments, the coated pellets are coated with the sustained release layer material, and the weight of the sustained release layer coating is increased by 30%. The calculation method of the weight gain of the coating of the slow release layer comprises the following steps: the weight gain of the sustained-release coating is (weight of sustained-release pellets-weight of the drug-loading pellets)/weight of the drug-loading pellets.
In some embodiments, the metoprolol extended release tablet composition comprises a coating material.
In some embodiments, the metoprolol extended release tablet composition comprises: sustained release pellets, a diluent and a lubricant, optionally containing a coating material; wherein, the sustained-release pellet comprises a drug-loading pellet and a sustained-release layer, and the sustained-release layer accounts for 10 to 50 percent of the weight of the drug-loading pellet; the drug-loading pellet comprises a blank pellet core and an active ingredient, wherein the drug-loading pellet optionally contains a binder, and the total weight of the active ingredient and the binder is 2-6 times of the weight of the blank pellet core.
In some embodiments, the sustained release pellets are mixed with other desired excipients such as diluents and/or lubricants, compressed to obtain a plain tablet, which is optionally coated with a coating material to obtain a coated tablet.
The diluent is at least one selected from microcrystalline cellulose, lactose, mannitol, silicified microcrystalline cellulose, powdery microcrystalline cellulose, cellulose lactose complex and starch.
The weight ratio of the sustained-release pellets to the diluent can be 1:4-4: 1.
The lubricant is at least one selected from sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate and calcium stearate.
The coating material contains polyvinyl alcohol-polyethylene glycol copolymer (PVA-PEG). In some embodiments, the coating material is a premix containing polyvinyl alcohol-polyethylene glycol copolymer (PVA-PEG). By adopting the purified water, the coating material can be prepared into a premix with the coating material content or the solid content of 20-35% (mass ratio, w/w), the premix has good film performance and good adhesion, and has good moisture-proof and oxygen-isolating performance after being coated on plain tablets. In some embodiments, the coating material is Opadry QX321A620016, and has better moisture resistance and oxygen insulation performance after coating the plain tablet. In some embodiments, the opadry QX321a620016 is mixed with water to prepare a premix with solid content of 20-35% (mass ratio, w/w), which has good film properties, good adhesion, and good moisture and oxygen barrier properties after coating of the tablet.
In some embodiments, the metoprolol extended release tablet composition comprises: sustained-release pellets, a diluent, a lubricant and a coating material; wherein the sustained-release pellet comprises a drug-loading pellet and a sustained-release layer, and the drug-loading pellet comprises a blank pellet core and an active ingredient; the blank pill core has the average particle size of 150-250 microns, and accounts for 5-10% (w/w) of the total weight of the composition; the active ingredient is metoprolol succinate, and the active ingredient accounts for 20-35% (w/w) of the total weight of the composition; the drug-loading pellet optionally contains a binder, and the total weight of the active ingredient and the binder is 2-6 times (w/w) of the weight of the blank pellet core; the slow release layer is made of octadecanol, hydrogenated castor oil and polyethylene glycol 6000; the sustained-release layer is 25-50% (w/w) of the weight of the pellet or 25-50% (w/w) of the weight gain of the coating of the sustained-release layer; the coating material is a premix containing polyvinyl alcohol-polyethylene glycol copolymer.
The invention also provides a method for preparing the sustained-release tablet composition. The inventor finds in research that in the preparation process of the metoprolol sustained-release pellet, the coating liquid of the drug-loading pellet with high solid content is adopted to coat the blank pellet core to prepare the drug-loading pellet, so that the coating time can be shortened; the sustained-release pellets are prepared by adopting a hot-melt coating technology, so that organic solvents can be reduced or not used, and the coating time is shortened; the coating suspension with high solid content is adopted to coat the plain tablets, so that the coating time can be shortened, the adhesion is good, and the coated plain tablets have good moisture resistance and oxygen isolation performance; the whole process is rapid and smooth, has short relative time, reduces the production cost and ensures the product quality.
Accordingly, the present invention provides a method for preparing the aforementioned metoprolol extended release tablet composition, comprising the steps of:
(1) coating the empty pellet core with a coating liquid of the medicine-loading pellets containing active ingredients and optionally containing a binding agent to prepare the medicine-loading pellets, wherein the solid content of the coating liquid of the medicine-loading pellets is 30-100 percent;
(2) carrying out slow-release layer coating on the drug-loaded pellets by adopting a hot-melt coating method to obtain the slow-release pellets, wherein the weight of the slow-release layer coating is increased by 10-50%;
(3) mixing the sustained-release pellets, a diluent and a lubricant, and tabletting to obtain a plain tablet; optionally, optionally
(4) Adding the coating material into water to prepare coating suspension with the solid content of 20-35%, and performing pan coating to obtain the coated tablet.
In some embodiments, a method of making the aforementioned metoprolol extended release tablet composition comprises:
1a) mixing the active ingredients with water, optionally adding an adhesive, stirring, heating, and completely dissolving to obtain a mixed solution, wherein the mixed solution is prepared into a coating solution of the traditional Chinese medicine micro-pill with the solid content of 30-100%;
1b) taking a prescription amount of blank pellet cores, starting instrument equipment and setting experimental parameters, and carrying out liquid spraying and medicine feeding on the coating liquid of the medicine-feeding pellets obtained in the step 1a) when the temperature of the material reaches the set temperature, wherein the parameters are respectively as follows: air inlet temperature is 65-75 deg.C, material temperature is 45 + -3 deg.C, and atomization pressure is 1.5bar-2.0bar to obtain pellet;
2a) mixing, heating, stirring and melting the materials of the slow release layer according to the prescription amount, and continuously stirring the materials after melting to obtain the materials of the slow release layer for later use;
2b) placing the above-mentioned micropills in fluidized bed, using the slow-release layer material obtained in step 2a) to make slow-release layer coating, and making all the parameters respectively be as follows: the air inlet temperature is 50-60 ℃, the material temperature is 35 +/-3 ℃, and the atomization pressure is 1.5-2.0bar, so as to obtain the sustained-release pellets;
(3) uniformly mixing the sustained-release pellets, a diluent and a lubricant, and tabletting to obtain a plain tablet; and
(4) adding the coating material in the prescription amount into purified water to prepare coating suspension with the solid content of 20-35%, and performing pan coating to obtain the coated tablet.
The composition provided by the invention is relatively simple in components, easy to prepare and low in cost. The preparation method provided by the invention is simple and easy to implement, has less working procedures, short time and low cost, is suitable for industrial production, and can prepare sustained-release tablet compositions or sustained-release preparations meeting the quality requirements.
Drawings
FIG. 1: dissolution profile of the product prepared in example 1 versus the reference formulation;
FIG. 2: dissolution profile of the product prepared in example 2 versus the reference formulation;
FIG. 3: dissolution profile of the product prepared in example 3 versus the reference formulation;
FIG. 4: dissolution profiles of the product prepared in example 4 versus the reference formulation.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Remarking: rpm indicates revolutions per minute; PVP-K30 refers to polyvinylpyrrolidone K30; bar means bar; μ m means μm; mg means mg; h represents an hour.
Dissolution test method:
the pellets, capsules or tablets obtained in the examples were investigated with respect to their dissolution behavior with reference formulations: the method comprises the following steps: referring to the second part of the Chinese pharmacopoeia of 2015 edition, a second dissolution method (paddle method) is 50 rpm;
the instrument comprises the following steps: DISTEK dissolution apparatus;
dissolution medium: 500ml of phosphate buffer solution with the pH value of 6.8;
reference formulation: metoprolol succinate sustained release tablets 200mg or 50mg, trade name: TOPROL-XL, manufacturer: aralez Pharmaceuticals Inc.
Example 1:
the preparation method comprises the following steps:
(1) preparing a medicine-feeding pellet:
1a) dissolving polyvinylpyrrolidone K30 with the prescription amount in water, adding metoprolol succinate under stirring, heating to 80 ℃ after uniformly stirring, maintaining the obtained mixed solution at 80 ℃ after completely dissolving, and preparing the mixed solution with the solid content of 50%;
1b) weighing microcrystalline cellulose pill cores according to the prescription amount, starting instrument equipment, setting experiment parameters, and carrying out liquid spraying and medicine application on the mixed liquid in the step 1a) by using a Romaco Innojet air fluidized bed when the temperature of the material reaches the set temperature, wherein the parameters are as follows: the air inlet temperature is 65-75 deg.C, the material temperature is 45 + -3 deg.C, and the atomization pressure is 1.5-2.0bar to obtain medicinal micro-pill;
(2) preparing sustained-release pellets:
2a) mixing the formula amount of octadecanol, hydrogenated castor oil and polyethylene glycol 6000 uniformly, heating while stirring, heating to 90 ℃ until the mixture is completely melted, and continuously stirring to obtain a slow release layer material for later use;
2b) placing the drug-loaded pellets in a Romaco Innojet air fluidized bed, and coating the drug-loaded pellets with the sustained-release layer material obtained in the step 2a), wherein the parameters are respectively as follows: the air inlet temperature is 50-60 ℃, the material temperature is 35 +/-3 ℃, and the atomization pressure is 1.5-2.0 bar; obtaining the sustained-release pellets;
(3) tabletting: uniformly mixing the sustained-release pellets, microcrystalline cellulose 102 and sodium stearyl fumarate, and tabletting to obtain a tablet;
(4) coating: adding the Opadry QX321A620016 into purified water according to the prescription amount to prepare coating suspension with the solid content of 25%, and performing pan coating on plain tablets to obtain coated tablets.
And detecting the dissolution curve after obtaining the coated tablet.
As can be seen from fig. 1: the sustained-release pellet provided by the invention is close to the sustained-release tablet in dissolution, the pellet is broken less in the tabletting process, the sustained-release tablet provided by the invention is close to the reference preparation in dissolution, f2 is more than or equal to 50, and the prepared metoprolol succinate sustained-release tablet can achieve a dissolution curve similar to that of the reference preparation.
Example 2
The preparation method comprises the following steps:
(1) preparing a medicine-feeding pellet:
1a) heating metoprolol succinate in a prescription amount to 145 ℃, maintaining the metoprolol succinate at 145 ℃ after the metoprolol succinate is completely dissolved, and preparing a molten solution with the solid content of 100%;
1b) weighing microcrystalline cellulose pill cores according to the prescription amount, starting instrument equipment, setting experiment parameters, and carrying out liquid spraying and medicine feeding on the molten solution in the step 1a) by using a Romaco Innojet air fluidized bed when the temperature of the material reaches the set temperature, wherein the parameters are as follows: the air inlet temperature is 65-75 deg.C, the material temperature is 45 + -3 deg.C, and the atomization pressure is 2.0-2.5bar to obtain the pellet;
(2) preparing sustained-release pellets:
2a) evenly mixing the beeswax and polyvinylpyrrolidone K30 according to the prescription amount, heating and stirring the mixture, heating the mixture to 90 ℃ until the mixture is completely melted, and continuously stirring the mixture to obtain a slow release layer material for later use;
2b) placing the drug-loaded pellets in a Romaco Innojet air fluidized bed, and coating the sustained-release layer material obtained in the step 2a), wherein the parameters are respectively as follows: the air inlet temperature is 50-60 ℃, the material temperature is 32 +/-3 ℃, and the atomization pressure is 2.0-2.5 bar; obtaining the sustained-release pellets;
(3) tabletting: mixing the sustained-release pellets, lactose monohydrate FLOW 100 and glyceryl behenate uniformly, and tabletting to obtain a plain tablet;
(4) coating: adding the Opadry QX321A620016 into purified water according to the prescription amount to prepare coating suspension with the solid content of 35%, and performing pan coating on plain tablets to obtain coated tablets.
As can be seen from fig. 2: the sustained-release pellet provided by the invention is close to the sustained-release tablet in dissolution, the pellet is broken less in the tabletting process, the sustained-release tablet provided by the invention is close to the reference preparation in dissolution, f2 is more than or equal to 50, and the prepared metoprolol succinate sustained-release tablet can achieve a dissolution curve similar to that of the reference preparation.
Example 3
The preparation method comprises the following steps:
(1) preparing a medicine-feeding pellet:
1a) adding hydroxypropyl cellulose E3 of a prescription amount into water, heating the mixture to 70 ℃ after uniformly stirring, adding metoprolol succinate of the prescription amount into the water under stirring after completely dissolving, stirring, and maintaining the mixed solution at 70 ℃ after completely dissolving to prepare mixed solution with the solid content of 30%;
1b) weighing sucrose pill cores according to the prescription amount, placing the sucrose pill cores in a Romaco Innojet air fluidized bed, starting instrument equipment and setting experimental parameters, and carrying out liquid spraying and medicine feeding on the mixed liquid obtained in the step 1a) when the temperature of the material reaches the set temperature, wherein the parameters are as follows: the air inlet temperature is 70-80 deg.C, the material temperature is 48 + -3 deg.C, and the atomization pressure is 2.0-2.5bar to obtain medicinal micro-pill;
(2) preparing sustained-release pellets:
2a) heating and stirring the palmitic acid stearin according to the prescription amount, heating the palmitic acid stearin to 80 ℃ until the palmitic acid stearin is completely melted, and continuously stirring to obtain a slow release layer material for later use;
2b) placing the drug-loaded pellets in a Romaco Innojet air fluidized bed, and coating the drug-loaded pellets with the sustained-release layer material obtained in the step 2a), wherein the parameters are respectively as follows: the air inlet temperature is 40-50 deg.C, the material temperature is 30 + -3 deg.C, and the atomization pressure is 1.5-2.0bar to obtain sustained-release pellet;
(3) tabletting: mixing the sustained-release pellet, the cellulose lactose compound 80 and the stearic acid uniformly, and tabletting to obtain a plain tablet;
(4) coating: adding the Opadry QX321A620016 into purified water according to the prescription amount to prepare coating suspension with the solid content of 35%, and performing pan coating on plain tablets to obtain coated tablets.
As can be seen from fig. 3: the sustained-release pellet provided by the invention is close to the sustained-release tablet in dissolution, the pellet is broken less in the tabletting process, the sustained-release tablet provided by the invention is close to the reference preparation in dissolution, f2 is more than or equal to 50, and the prepared metoprolol succinate sustained-release tablet can achieve a dissolution curve similar to that of the reference preparation.
Example 4
The preparation method comprises the following steps:
(1) preparing a medicine-feeding pellet:
1a) adding hydroxypropyl methylcellulose E5 of a prescription amount into water, heating to 80 ℃ after uniformly stirring, adding metoprolol succinate of the prescription amount into the water under stirring after completely dissolving, stirring, and maintaining the temperature of the mixed solution at 80 ℃ after completely dissolving to prepare mixed solution with the solid content of 50%;
1b) weighing microcrystalline cellulose pill cores in a prescription amount, placing the pill cores in a Romaco Innojet air fluidized bed, starting instrument equipment and setting experimental parameters, and carrying out liquid spraying and medicine application on the mixed liquid obtained in the step 1a) when the temperature of the material reaches the set temperature, wherein the parameters are as follows: the air inlet temperature is 60-70 deg.C, the material temperature is 42 + -3 deg.C, and the atomization pressure is 1.5-2.0bar to obtain medicinal micro-pill;
(2) preparing sustained-release pellets:
2a) uniformly mixing stearic acid and glyceryl behenate in the formula amount, heating while stirring, heating to 85 ℃ until the mixture is completely melted, continuously stirring and maintaining at 85 ℃ to obtain a slow release layer material for later use;
2b) placing the drug-loaded pellets in a Romaco Innojet air fluidized bed, and coating the drug-loaded pellets with the sustained-release layer material obtained in the step 2a), wherein the parameters are respectively as follows: the air inlet temperature is 40-50 deg.C, the material temperature is 30 + -3 deg.C, and the atomization pressure is 1.5-2.0bar to obtain sustained-release pellet;
(3) tabletting: mixing the sustained-release pellet, silicified microcrystalline cellulose HD90, and stearic acid, and tabletting to obtain tablet;
(4) coating: adding the Opadry QX321A620016 into purified water according to the prescription amount to prepare coating suspension with the solid content of 35%, and performing pan coating on plain tablets to obtain coated tablets.
As can be seen from fig. 4: the sustained-release pellet provided by the invention is close to the sustained-release tablet in dissolution, the pellet is broken less in the tabletting process, the sustained-release tablet provided by the invention is close to the reference preparation in dissolution, f2 is more than or equal to 50, and the prepared metoprolol succinate sustained-release tablet can achieve a dissolution curve similar to that of the reference preparation.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (11)
1. A metoprolol extended release tablet composition comprising: sustained release pellets, a diluent and a lubricant, optionally containing a coating material; wherein, the sustained-release pellet comprises a drug-loading pellet and a sustained-release layer, and the sustained-release layer accounts for 10 to 50 percent of the weight of the drug-loading pellet; the drug-loading pellet comprises a blank pellet core and an active ingredient, and optionally contains a binder; the active ingredient is metoprolol, metoprolol succinate, metoprolol tartrate, or a combination thereof.
2. The composition of claim 1, wherein the mean particle size of the white pellet core is from 100 microns to 500 microns, the white pellet core comprising from 5% to 10% by weight of the total composition; or the active ingredient accounts for 8 to 42 percent of the total weight of the composition.
3. The composition of claim 1, wherein the total weight of the active ingredient and optional binder is 2-6 times the weight of the empty pellet core.
4. The composition of claim 1, wherein the binder is polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, or a combination thereof, and the mass ratio of the binder to the active ingredient is 0:1 to 1: 3.
5. The composition of claim 1, the sustained release layer comprising a controlled release material, optionally comprising a pore-forming agent; the controlled release material is at least one of octadecanol, hydrogenated castor oil, carnauba wax, white wax, long-chain fatty acid, long-chain fatty alcohol, stearate and fatty glyceride; the pore-forming agent is polyethylene glycol 6000, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose or a combination thereof, and the pore-forming agent accounts for 0-30% of the weight of the controlled release material.
6. The composition of claim 1, wherein the sustained release layer is comprised of a controlled release material or the sustained release layer is comprised of a controlled release material and a pore-forming agent.
7. The composition of claim 1, wherein the sustained release layer is octadecanol, hydrogenated castor oil and polyethylene glycol 6000; the mass ratio of the octadecanol to the hydrogenated castor oil is 3:1, and the mass of the polyethylene glycol 6000 is 15% of the total mass of the octadecanol and the hydrogenated castor oil.
8. The composition of claim 1, wherein the diluent is selected from at least one of microcrystalline cellulose, lactose, mannitol, silicified microcrystalline cellulose, powdered microcrystalline cellulose, cellulose lactose complex, starch; or the lubricant is selected from at least one of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate and calcium stearate; or the coating material contains polyvinyl alcohol-polyethylene glycol copolymer.
9. The composition of claim 1, wherein the weight ratio of the sustained release pellets to the diluent is 1:4 to 4: 1.
10. A process for preparing the composition of any one of claims 1 to 9, comprising the steps of:
(1) coating the empty pellet core with a coating liquid of the medicine-loading pellets containing active ingredients and optionally containing a binding agent to prepare the medicine-loading pellets, wherein the solid content of the coating liquid of the medicine-loading pellets is 30-100 percent;
(2) carrying out slow-release layer coating on the drug-loaded pellets by adopting a hot-melt coating method to obtain the slow-release pellets, wherein the weight of the slow-release layer coating is increased by 10-50%;
(3) mixing the sustained-release pellets, a diluent and a lubricant, and tabletting to obtain a plain tablet; optionally, optionally
(4) Adding the coating material into water to prepare coating suspension with the solid content of 20-35%, and performing pan coating to obtain the coated tablet.
11. The method of claim 10, comprising:
1a) mixing the active ingredients with water, optionally adding an adhesive, stirring, heating, and completely dissolving to obtain a mixed solution, wherein the mixed solution is prepared into a coating solution of the traditional Chinese medicine micro-pill with the solid content of 30-100%;
1b) taking a prescription amount of blank pellet cores, starting instrument equipment and setting experimental parameters, and carrying out liquid spraying and medicine feeding on the coating liquid of the medicine-feeding pellets obtained in the step 1a) when the temperature of the material reaches the set temperature, wherein the parameters are respectively as follows: the air inlet temperature is 65-75 ℃, the material temperature is 45 +/-3 ℃, and the atomization pressure is 1.5-2.0bar, so as to prepare the drug-loading micro-pill;
2a) mixing, heating, stirring and melting the materials of the slow release layer according to the prescription amount, and continuously stirring the materials after melting to obtain the materials of the slow release layer for later use;
2b) placing the above-mentioned micropills in fluidized bed, using the slow-release layer material obtained in step 2a) to make slow-release layer coating, and making all the parameters respectively be as follows: the air inlet temperature is 50-60 ℃, the material temperature is 35 +/-3 ℃, and the atomization pressure is 1.5-2.0bar, thus obtaining the sustained-release pellet.
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