CN102813633A - Method for preparing pharmaceutical composition containing macrolides antibiotics by using wet granulation - Google Patents
Method for preparing pharmaceutical composition containing macrolides antibiotics by using wet granulation Download PDFInfo
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- CN102813633A CN102813633A CN2011101647481A CN201110164748A CN102813633A CN 102813633 A CN102813633 A CN 102813633A CN 2011101647481 A CN2011101647481 A CN 2011101647481A CN 201110164748 A CN201110164748 A CN 201110164748A CN 102813633 A CN102813633 A CN 102813633A
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Abstract
The invention relates to a method for preparing a pharmaceutical composition containing macrolides antibiotics by using wet granulation. By the aid of the method, the durability of the macrolides antibiotics in an acid medium is guaranteed. The invention also discloses a method for preparing tablets and coated tablets of the composition.
Description
Invention field
The present invention relates to a kind ofly comprise the method for the pharmaceutical composition of macrolide antibiotics with wet granulation, said method guarantees the durability of macrolide antibiotics in acid medium; And the method for preparing of producing the tablet and the coated tablet of these compositionss.
Background technology
According to document, erythromycin and cyclic ester erythromycin (erythromycin cyclocarbonate) and in the acid of about 1.2 hydrochloric acid solution, be unsettled such as pH such as other macrolide antibiotics such as clarithromycin, azithromycin, Roxithromycins.It is suitable with people's gastric environment that these media are regarded as, thereby these medicines have similar reaction in gastric acid.Under the influence of acid medium, antibacterial properties is owing to the chemical change that takes place in the macrolide antibiotics granule is lost.Therefore, the macrolide antibiotics preparation that the expectation exploitation is such, said this drug substance of preparation protection avoids in acid medium, degrading.Make protection that material avoids in acid medium, degrading usually through with label being higher than soluble stomach juice-resistant polymer coating in 5.5 the medium at pH and realizing (coating quality be coated tablet quality about 10%), said polymer to this type of with capacity.In addition, the water solublity of macrolide antibiotics is bad, therefore need under physiological condition, for this tablet optimum dissolution conditions and optimum macrolide antibiotics release conditions be provided.
Summary of the invention
Surprisingly, above-mentioned purpose comprises the tablet of macrolide antibiotics method for compositions and these compositionss or the method for preparing of coated tablet realizes through providing with wet granulation.
Therefore, one aspect of the present invention relates to and a kind ofly comprises the method for the pharmaceutical composition of macrolide antibiotics through wet granulation production, and said method comprises:
(a) macrolide antibiotics and the optional pharmaceutically acceptable carrier that exists and the mixture of excipient are provided to binder solution; So that said macrolide antibiotics is suspended in the said binder solution, said binder solution comprises at least a binding agent, at least a diluent and water;
The mixture that (b) will derive from step (b) mixes, until obtaining expansible wet granular;
(c) said wet granular is dry under 70 ℃ or lower temperature, until obtaining dried granules; And
(d) said dried granules is ground, until the dried particles that obtains to grind.
On the other hand, the present invention relates to a kind of method of claim 1, said method comprises:
Prepare the solution of said binding agent in water;
Said macrolide antibiotics is suspended in the said binder solution;
Thus obtained mixture is mixed until obtaining expansible wet granular;
Said wet granular is homogenized until the wet granular that obtains homogenizing;
Be not higher than 6.5% dried granules until obtaining water content with the wet granular of said homogenizing is dry under 60 ℃ or lower temperature;
Said dried granules is homogenized until the dried particles that obtains homogenizing;
The dried particles of said homogenizing is mixed with carboxymethyl starch sodium, Talcum and magnesium stearate until obtaining second mixture;
Said second mixture is pressed into tablet; And
With coating mixture coating, said coating mixture comprises cellulose acetate phthalate, polyethylene glycol 6000, Talcum and titanium dioxide with said tablet.
The present invention includes the macrolide antibiotics wet granulation method and produce the method for tablet through using wet granulation method.This wet granulation method prevents that macrolide antibiotics from discharging and degraded subsequently in acid medium.And opposite with conventional method of granulating, wet granulation according to the present invention is suspended in macrolide antibiotics in the binder aqueous solution before pelletization.
According to some embodiments; The present invention includes the method for producing tablet through wet granulation; Said method comprises provides macrolide antibiotics, at least a diluent, at least a binding agent of tabletting, at least a disintegrating agent and the water of being used for, and wherein said disintegrating agent can be the identical material of binding agent that is used for tabletting; Said mixture is mixed until obtaining wet granular; Said wet granular is homogenized; Said wet granular is dry under 70 ℃ or lower temperature; And said dried granules homogenized.And said method can comprise adds at least a disintegrate material and at least a lubricant that is used for tabletting in fractionated dried particles.Tablet with this prescription production comes coating through following material is provided: the material of the polymeric film of the acid medium of at least a formation tolerance pH＜5.5; At least a film that makes has more elastic plasticizer; And at least a coating filler.
The tablet that obtains according to the present invention has following characteristic: their not disintegrates in the acid medium of pH=1.2.According to embodiments more of the present invention, even acid proof tablet coating decomposes in acid medium, but the not disintegrate under the environment of pH=1.2 of this tablet.According to embodiments more of the present invention, even the coating of the acid medium of pH=1.2 opposing is dissolved in acid medium, but this not disintegrate of tablet but form gel.According to embodiments more of the present invention, even the coating of the acid medium of pH=1.2 opposing is dissolved in acid medium, but this not disintegrate of tablet but form gel, and the amount of the macrolide antibiotics that discharges under these conditions is lower than 10%.
Tablet through wet granulation formulation of the present invention has such stripping curve: in the phosphate buffer of pH6.8, after 60 minutes, surpass 70% macrolide antibiotics dissolving.According to embodiments more of the present invention, the tablet through wet granulation formulation of the present invention has such stripping curve: in the hydrochloric acid solution of pH=1.2, after 60 minutes, be not higher than 10% macrolide antibiotics dissolving.
Have following characteristic through the wet granulation formulation and with the tablet of the present invention of the polymeric film coating of anti-pH＜5.5 acid mediums: the bitterness of macrolide antibiotics is swallowed and is covered in above-mentioned coating promotion.
According to embodiments more of the present invention, said macrolide antibiotics is selected from erythromycin, cyclic ester erythromycin, clarithromycin, azithromycin and Roxithromycin, is preferably selected from erythromycin and cyclic ester erythromycin.More preferably, said macrolide antibiotics is a cyclic ester erythromycin.
According to embodiments more of the present invention; Diluent is selected from calcium carbonate, calcium phosphate (two alkali or three alkali), one or more in calcium sulfate, cellulose powder, glucosan, dextrin, fructose, kaolin, lactose, Lactis Anhydrous, lactose monohydrate, maltose, mannitol, microcrystalline Cellulose, sorbitol, sucrose and the starch.According to embodiments more of the present invention, microcrystalline Cellulose is used as diluent.According to embodiments more of the present invention, the amount of diluent be tablet 10% to 80%w/w.
According to embodiments more of the present invention, binding agent is selected from one or more in arabic gum, alginic acid, carbomer, sodium carboxymethyl cellulose, carboxymethyl starch sodium, dextrin, ethyl cellulose, gelatin, hydroxypropyl cellulose, guar gum, hydroxypropyl emthylcellulose, maltose, methylcellulose, polyoxyethylene, polyvidone and the crospovidone.According to embodiments more of the present invention, carboxymethyl starch sodium or polyvidone are binding agent.According to embodiments more of the present invention, the amount of binding agent be tablet 5% to 20%w/w.
According to embodiments more of the present invention, disintegrating agent is carboxymethyl starch sodium or crospovidone.According to embodiments more of the present invention, the amount of disintegrating agent be tablet 5% to 20%w/w.
According to embodiments more of the present invention, lubricant is selected from one or more in calcium stearate, Compritol 888 ATO, magnesium stearate, mineral oil, Polyethylene Glycol, sodium stearyl fumarate, stearic acid, Talcum and the zinc stearate.According to embodiments more of the present invention, lubricant is Talcum and magnesium stearate.According to embodiments more of the present invention, the amount of lubricant be tablet 0.5% to 5%w/w.
According to embodiments more of the present invention, it is macromolecule polyalcohol that coating forms agent, and it is stomach juice-resistant and solvable under the condition of about pH 5.For example, coating formation agent is selected from one or more of EUDRAGIT S100 (like Eudragit), cellulose derivative (like cellulose acetate phthalate, hydroxypropyl emthylcellulose-acetyl group succinate, hydroxypropyl emthylcellulose phthalic acid acetas) and polyvinyl alcohol derivative (like polyvinyl acetate phthalate).According to embodiments more of the present invention, it is cellulose acetate phthalate or EUDRAGIT S100 (Eudragit) that coating forms agent.According to embodiments more of the present invention, the amount that coating forms agent be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the coating plasticizer is selected from polyethylene glycol 6000, propylene glycol, glycerol and glyceryl triacetate.According to embodiments more of the present invention, the coating plasticizer is a polyethylene glycol 6000.According to embodiments more of the present invention, the amount of plasticizer be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the coating filler is selected from one or more in Talcum and the titanium dioxide.According to embodiments more of the present invention, the coating filler is Talcum and titanium dioxide.According to embodiments more of the present invention, the amount of every kind of coating filler be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the amount of tablet coating be tablet 0.5% to 5%w/w.
According to embodiments more of the present invention, tablet is grouped into by following one-tenth: macrolide antibiotics, carboxymethyl starch sodium, polyvidone, crospovidone, microcrystalline Cellulose, Talcum, magnesium stearate, cellulose acetate phthalate, polyethylene glycol 6000 and titanium dioxide.
Be not any theory, think that the object of the invention passes through the special characteristic realization of label, this label obtains from the granule through wet granulation method preparation of the present invention.Opposite with conventional method of granulating; Wet granulation of the present invention may further comprise the steps: macrolide antibiotics and the optional pharmaceutically acceptable carrier that exists are provided to binder solution; Make said macrolide antibiotics before pelletization, be suspended in the said binder solution, said binder solution comprises at least a binding agent, at least a diluent and water.With the not disintegrate but form gel after being exposed to the acid medium of pH=1.2 of the label of said preparation of granules from wet granulation method of the present invention; But in the quick disintegrate down of the neutral environment (physiological condition of small intestinal) of for example pH=6.8, this allows the good dissolving of macrolide antibiotics and from the absorption of digestive system.Opposite with prior art, the coating that above-mentioned polymer is processed does not provide the protection to the acid medium of pH=1.2, and it only provides covering the macrolide antibiotics bitterness when swallow tablet.
Detailed Description Of The Invention
The problem relevant with the durability of macrolide antibiotics in acid medium requires exploitation can guarantee the tablet of active substance stability.Usually, this is through obtaining tablet coating with suitable acid resistance coating, but its restriction and delay macrolide antibiotics and discharge from tablet.Yet coating of the present invention only provides the assisting effect to the bitterness of covering macrolide antibiotics.The invention provides the alternative solution of the sour stabilizing pharmaceutical composition of exploitation macrolide antibiotics.
Particularly, the invention provides and a kind ofly comprise the method for the pharmaceutical composition of macrolide antibiotics through wet granulation, said method comprises:
(a) with macrolide antibiotics and the optional pharmaceutically acceptable carrier that exists and the mixture of excipient binder solution is provided; So that said macrolide antibiotics is suspended in the said binder solution, said binder solution comprises at least a binding agent, at least a diluent and water;
The mixture that (b) will derive from step (a) mixes, until obtaining expansible wet granular;
(c) said wet granular is dry under 70 ℃ or lower temperature, until obtaining dried granules; And
(d) said dried granules is ground, until the dried particles that obtains to grind.
According to embodiments more of the present invention, method of the present invention is further comprising the steps of:
(e) in the dried particles of said grinding, add at least a disintegrating agent and at least a lubricant; And
(f) dried particles with said grinding is pressed into tablet.
According to embodiments more of the present invention, method of the present invention is further comprising the steps of:
(g) with the coating mixture with said tablet coating, that said coating mixture comprises at least a stomach juice-resistant and be higher than polymer soluble under the condition of about pH5, at least a coating plasticizer and at least a coating filler.
Some embodiments according to the method for the invention, wet granular is dry under 60 ℃ or lower temperature.
Some embodiments according to the method for the invention, wherein the particle size distribution of macrolide antibiotics (d0.9) equals 500 μ m or littler.
According to embodiments more of the present invention, said macrolide antibiotics is selected from erythromycin, cyclic ester erythromycin, clarithromycin, azithromycin and Roxithromycin, is preferably selected from erythromycin and cyclic ester erythromycin.More preferably, said macrolide antibiotics is a cyclic ester erythromycin.
Some embodiments according to the method for the invention, cyclic ester erythromycin are crystal or amorphous form.
Some embodiments according to the method for the invention, diluent are selected from calcium carbonate, calcium phosphate (two alkali or three alkali), calcium sulfate, cellulose powder, glucosan, dextrin, fructose, kaolin, lactose, Lactis Anhydrous, lactose monohydrate, maltose, mannitol, microcrystalline Cellulose, sorbitol, sucrose, starch and their any combination.
Some embodiments according to the method for the invention, diluent are microcrystalline Cellulose.
Some embodiments according to the method for the invention, the amount of diluent be tablet 10% to 80%w/w.
Some embodiments according to the method for the invention, binding agent are selected from arabic gum, alginic acid, carbomer, sodium carboxymethyl cellulose, carboxymethyl starch sodium, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyoxyethylene, polyvidone and their any combination.
Some embodiments according to the method for the invention, binding agent are carboxymethyl starch sodium or polyvidone.
Some embodiments according to the method for the invention, the amount of binding agent be tablet 5% to 20%w/w.
Some embodiments according to the method for the invention, disintegrating agent are carboxymethyl starch sodium or crospovidone.
Some embodiments according to the method for the invention, the amount of disintegrating agent are 5% to 20%w/w.
Some embodiments according to the method for the invention, lubricant are selected from calcium stearate, Compritol 888 ATO, magnesium stearate, mineral oil, Polyethylene Glycol, sodium stearyl fumarate, stearic acid, Talcum, zinc stearate and their any combination.
Some embodiments according to the method for the invention, lubricant are magnesium stearate and steatitic combination.
Some embodiments according to the method for the invention, the amount of lubricant be tablet 0.5% to 10%w/w.
Some embodiments according to the method for the invention, the polymer in the coating mixture is selected from EUDRAGIT S100, cellulose derivative and polyvinyl alcohol derivative.
Some embodiments according to the method for the invention, polymer are cellulose acetate phthalate.
Some embodiments according to the method for the invention, coating plasticizer are selected from polyethylene glycol 6000, propylene glycol, glycerol (glycerine), glyceryl triacetate and their any combination.
Some embodiments according to the method for the invention, coating plasticizer are polyethylene glycol 6000.
Some embodiments according to the method for the invention, the amount of plasticizer be tablet 0.1% to 5%w/w.
Some embodiments according to the method for the invention, coating filler are selected from Talcum, titanium dioxide, reach their any combination.
Some embodiments according to the method for the invention, coating filler are the combination of Talcum and titanium dioxide.
Some embodiments according to the method for the invention, the amount of every kind of coating filler be tablet 0.1% to 5%w/w.
Some embodiments according to the method for the invention, the amount of tablet coating be coating 0.5% to 5%w/w.
Some embodiments according to the method for the invention, tablet stripping curve are after under the environment of pH=6.8 60 minutes, are not less than the macrolide antibiotics dissolving of the primary quantity of 70%w/w.
Some embodiments according to the method for the invention, tablet stripping curve are after under the environment of pH=1.2 60 minutes, are not higher than the macrolide antibiotics dissolving of the primary quantity of 10%w/w.
According to embodiments more of the present invention, said method comprises:
Prepare the solution of said binding agent in water;
Said macrolide antibiotics is suspended in the said binder solution;
Thus obtained mixture is mixed until obtaining expansible wet granular;
Said wet granular is homogenized until the wet granular that obtains homogenizing;
Be not higher than 6.5% dried granules until obtaining water content with the wet granular of said homogenizing is dry under 60 ℃ or lower temperature;
Said dried granules is homogenized until the dried particles that obtains homogenizing;
The dried particles of said homogenizing is mixed with carboxymethyl starch sodium, Talcum and magnesium stearate until obtaining second mixture;
Said second mixture is pressed into tablet; And
With coating mixture coating, said coating mixture comprises cellulose acetate phthalate, polyethylene glycol 6000, Talcum and titanium dioxide with said tablet.
The present invention includes through using the method that wet granulation obtains the macrolide antibiotics tablet.Usually, be difficult to suppress and composition that sponginess is not good through using wet granulation, can preparing.Granulating increases bulk density, thereby makes it possible to more preferably fill the punch die of tablet machine, and the tablet that compacting obtains has suitable parameters.Usually, wet granulation carries out through interpolation binder aqueous solution or water in powder.Wet granulation method of the present invention is granulated composition then and is carried out through the mixture from the powder for preparing in the granulator to binder solution, the suspension that are provided at.
The tablet manufacturing method of using wet granulation of the present invention may further comprise the steps: macrolide antibiotics, at least a diluent, at least a binding agent of tabletting, at least a disintegrating agent and the water of being used for are provided, and wherein said disintegrating agent can be the identical material of binding agent that is used for tabletting; Said mixture is mixed until obtaining wet granular; Said wet granular is homogenized; Said wet granular is dry under 70 ℃ or lower temperature; And said dried granules homogenized.And said method can comprise adds at least a disintegrating agent and at least a lubricant that is used for tabletting in the dried particles that grinds.Randomly, tablet comes coating through following material is provided: the material of the polymeric film of the acid medium of at least a formation tolerance pH＜5.5; At least a film that makes has more elastic plasticizer; And at least a coating filler.
The tablet that obtains according to the present invention has following characteristic: their not disintegrates in the acid medium of pH=1.2.According to embodiments more of the present invention, even acid proof tablet coating dissolves in acid medium, but the not disintegrate under the environment of pH=1.2 of this tablet.According to embodiments more of the present invention, even the coating of the acid medium of anti-pH=1.2 dissolves in acid medium, but this not disintegrate of tablet but form gel.According to embodiments more of the present invention,, form gel but this tablet does not dissolve, and the amount of the macrolide antibiotics that discharges under these conditions is lower than 10% in acid medium even the coating of the acid medium of anti-pH=1.2 dissolves.
Tablet through wet granulation formulation of the present invention has such stripping curve: in the phosphate buffer of pH6.8, after 60 minutes, surpass 70% macrolide antibiotics dissolving.According to embodiments more of the present invention, if having such stripping curve: in the hydrochloric acid solution of pH=1.2, after 60 minutes, be not higher than 10% macrolide antibiotics dissolving through the tablet of the present invention's preparation.
Through the wet granulation formulation and use the tablet of the present invention to the polymeric film coating of the acid medium of pH＜5.5 tolerance to have following characteristic: above-mentioned coating promotes to swallow and cover the bitterness of macrolide antibiotics.
Blend or blending constituent can be carried out through using method known to those skilled in the art in wet granulation.Those skilled in the art can define the acquisition required condition of wet granular and need not to carry out any experiment or over-drastic experiment.The amount and the time of the water that those skilled in the art can select to be used to granulate, thus the granule that grinds can have suitable parameters.
Drying stage carries out under 70 ℃ or lower temperature.According to embodiments more of the present invention, drying stage carries out under 60 ℃ or lower temperature.
Pressing stage can utilize tabletting tablet machine commonly used to carry out.For example can use tablet machine Kilian, Fette, Korsh to produce tablet.
According to embodiments more of the present invention, diluent is selected from one or more in calcium carbonate, calcium phosphate (two alkali or three alkali), calcium sulfate, cellulose powder, glucosan, dextrin, fructose, kaolin, lactose, Lactis Anhydrous, lactose monohydrate, maltose, mannitol, microcrystalline Cellulose, sorbitol, sucrose and the starch.According to embodiments more of the present invention, microcrystalline Cellulose is as diluent.According to embodiments more of the present invention, the amount of diluent be tablet 10% to 80%w/w.
According to embodiments more of the present invention, binding agent is selected from one or more in arabic gum, alginic acid, carbomer, sodium carboxymethyl cellulose, carboxymethyl starch sodium, dextrin, ethyl cellulose, gelatin, hydroxypropyl cellulose, guar gum, hydroxypropyl emthylcellulose, maltose, methylcellulose, polyoxyethylene, polyvidone and the crospovidone.According to embodiments more of the present invention, carboxymethyl starch sodium or polyvidone are binding agent.According to embodiments more of the present invention, the amount of binding agent be tablet 5% to 20%w/w.
According to embodiments more of the present invention, disintegrating agent is carboxymethyl starch sodium or crospovidone.According to embodiments more of the present invention, the amount of disintegrating agent be tablet 5% to 20%w/w.
According to embodiments more of the present invention, lubricant is selected from calcium stearate, Compritol 888 ATO, magnesium stearate, mineral oil, Polyethylene Glycol, sodium stearyl fumarate, stearic acid, Talcum and zinc stearate.According to embodiments more of the present invention, lubricant is Talcum and magnesium stearate.According to embodiments more of the present invention, the amount of lubricant be tablet 0.5% to 5%w/w.
According to embodiments more of the present invention, it is macromolecule polyalcohol that coating forms agent, and it is stomach juice-resistant and solvable under the condition of about pH 5.For example, coating formation agent is selected from one or more in EUDRAGIT S100 (like Eudragit), cellulose derivative (like cellulose acetate phthalate, hydroxypropyl emthylcellulose-acetyl group succinate, hydroxypropyl emthylcellulose phthalic acid acetas) and the polyvinyl alcohol derivative (like polyvinyl acetate phthalate).According to embodiments more of the present invention, it is cellulose acetate phthalate or EUDRAGIT S100 (Eudragit) that coating forms agent.According to embodiments more of the present invention, the amount that coating forms agent be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the coating plasticizer is selected from one or more in polyethylene glycol 6000, propylene glycol, glycerol and the glyceryl triacetate.According to embodiments more of the present invention, the coating plasticizer is a polyethylene glycol 6000.According to embodiments more of the present invention, the amount of plasticizer be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the coating filler is selected from one or more in Talcum and the titanium dioxide.According to embodiments more of the present invention, the coating filler is Talcum and titanium dioxide.According to embodiments more of the present invention, the amount of every kind of coating filler be tablet 0.1% to 5%w/w.
According to embodiments more of the present invention, the amount of tablet coating be tablet 0.5% to 5%w/w.
According to some embodiments, reach such stripping curve: after under the environment of pH=6.8 60 minutes, be not less than the initial macrolide antibiotics dissolving of 70%w/w through the tablet of using wet granulation production of the present invention.According to embodiments more of the present invention, reach such stripping curve: after under the environment of pH=1.2 60 minutes, be not higher than the initial macrolide antibiotics dissolving of 10%w/w through the tablet of using wet granulation production of the present invention.
Tablet can be produced through using said method.According to some embodiments, tablet is grouped into by following one-tenth: macrolide antibiotics such as cyclic ester erythromycin, microcrystalline Cellulose, carboxymethyl starch sodium, polyvidone, crospovidone, Talcum, magnesium stearate, EUDRAGIT S100, glyceryl triacetate, titanium dioxide.Randomly, tablet can also contain coloring agent.According to embodiments more of the present invention, tablet contains cyclic ester erythromycin, microcrystalline Cellulose, carboxymethyl starch sodium, polyvidone, crospovidone, Talcum, magnesium stearate, cellulose acetate phthalate, polyethylene glycol 6000 and titanium dioxide.
According to embodiments more of the present invention, tablet is grouped into by following one-tenth: cyclic ester erythromycin (250mg/ sheet), microcrystalline Cellulose (60mg/ sheet), carboxymethyl starch sodium (40mg/ sheet), polyvidone (10mg/ sheet), crospovidone (10mg/ sheet), Talcum (15mg/ sheet), magnesium stearate (7mg/ sheet), cellulose acetate phthalate (2mg/ sheet), polyethylene glycol 6000 (1mg/ sheet) and titanium dioxide (2mg/ sheet).
According to embodiments more of the present invention, tablet is grouped into by following one-tenth: cyclic ester erythromycin (250mg/ sheet), microcrystalline Cellulose (70mg/ sheet), carboxymethyl starch sodium (40mg/ sheet), Talcum (15mg/ sheet), magnesium stearate (7mg/ sheet), EUDRAGIT S100 (2mg/ sheet), glyceryl triacetate (1mg/ sheet) and titanium dioxide (2mg/ sheet).
With reference to the further example the present invention of embodiment.
Embodiment
Embodiment 1: through using the tablet that wet granulation comprises 250mg cyclic ester erythromycin
In granulator, obtain the binder solution that is grouped into by following one-tenth: pure water (4000g), carboxymethyl starch sodium (400g), polyvidone (100g).Cyclic ester erythromycin (2500g) and microcrystalline Cellulose (600g) are added in the binder solution of acquisition.With the mixture wet granulation.With homogenizing in the wet granular earthquake granulator, and dry in fluidized bed dryer, and inlet temperature is 55 ℃.Then, with homogenizing in the dried granules earthquake granulator, and mixed 3 minutes with crospovidone (100g) and Talcum (150g).Magnesium stearate (70g) is sieved and added in the mixture, mixed 1 minute.Then, utilize Kilian, Fette or Korsch tablet machine to be pressed into tablet in mixture.Obtain the coating solution of suspensoid form, it is grouped into by following one-tenth: acetone (1000g), isopropyl alcohol (1000g), cellulose acetate phthalate (60g), polyethylene glycol 6000 (30g) and titanium dioxide (60g).With tablet coating, thereby tablet quality increases by 2%.
Embodiment 2: through using the tablet that wet granulation comprises 250mg cyclic ester erythromycin
In granulator, obtain the binder solution that is grouped into by following one-tenth: pure water (4000g), carboxymethyl starch sodium (350g).Cyclic ester erythromycin (2500g) and microcrystalline Cellulose (700g) are added in the binding agent of acquisition.With the mixture wet granulation.With homogenizing in the wet granular earthquake granulator, and dry in fluidized bed dryer, and inlet temperature is 55 ℃.Then, with homogenizing in the dried granules earthquake granulator, and mixed 3 minutes with Talcum (150g) and carboxymethyl starch sodium (50g).Magnesium stearate (70g) is sieved and added in the mixture, mixed 1 minute.Then, utilize Kilian, Fette or Korsch tablet machine to be pressed into tablet in mixture.The coating solution that preparation is grouped into by following one-tenth: water (2000g), EUDRAGIT S100 (60g), glyceryl triacetate (30g) and titanium dioxide (60g).With tablet coating, thereby tablet quality increases by 2%.
Comparative example 1: with conventional wet granulation tablet
The binder solution that acquisition is grouped into by following one-tenth: pure water (8000g), carboxymethyl starch sodium (400g), polyvidone (100g).Add in the granulator cyclic ester erythromycin (2500g) and microcrystalline Cellulose (600g) and mixing.Mixture is used the binder solution wet granulation of preparation before.With homogenizing in the wet granular earthquake granulator, and dry in fluidized bed dryer, and inlet temperature is 55 ℃.Then, with homogenizing in the dried granules earthquake granulator, and mixed 3 minutes with crospovidone (100g) and Talcum (150g).Magnesium stearate (70g) is sieved and added in the mixture, mixed 1 minute.Then, utilize Kilian, Fette or Korsch tablet machine to be pressed into tablet in mixture.Obtain the coating solution of suspensoid form, it is grouped into by following one-tenth: acetone (1000g), isopropyl alcohol (1000g), cellulose acetate phthalate (60g), polyethylene glycol 6000 (30g) and titanium dioxide (60g).With tablet coating, thereby tablet quality increases by 2%.
The stripping test
Carry out the stripping test to compare the stripping curve of the tablet of preparation in embodiment 1 and comparative example 1.
The stripping test condition:
EP device 2 (slurry)
Rotating speed: 100rpm
Temperature: 37 ℃ ± 0.5 ℃
Dissolution medium prepares according to EP
Visible from last table, the coating cyclic ester erythromycin tablet through conventional wet granulation method preparation causes lower level stripping in the phosphate buffer of pH 6.8 in the decomposition that acid phase shows active substance.The stripping degree (*) of acid phase is expressed as the catabolite sum of cyclic ester erythromycin, and cyclic ester erythromycin decomposes under the condition of pH 1.2 fast.
Embodiment 3: through using the tablet that wet granulation comprises 250mg cyclic ester erythromycin
In granulator, obtain the binder solution that is grouped into by following one-tenth: pure water (4000g) and polyoxyethylene (500g).Cyclic ester erythromycin (2500g), lactose monohydrate (450g) and microcrystalline Cellulose (250g) are added in the binding agent of acquisition.With the mixture wet granulation.With homogenizing in the wet granular earthquake granulator, and dry in fluidized bed dryer, and inlet temperature is 55 ℃.Then, with homogenizing in the dried granules earthquake granulator, and mixed 3 minutes with Talcum (155g) and carboxymethyl starch sodium (50g).Magnesium stearate (75g) is sieved and added in the mixture, mixed 1 minute.Then, utilize Kilian, Fette or Korsch tablet machine to be pressed into tablet in mixture.Obtain the coating solution of suspensoid form, it is grouped into by following one-tenth: acetone (1000g), isopropyl alcohol (1000g), cellulose acetate phthalate (60g), polyethylene glycol 6000 (30g) and titanium dioxide (60g).With tablet coating, thereby tablet quality increases by 2%.
Comparative example 3: with conventional wet granulation tablet
The binder solution that acquisition is grouped into by following one-tenth: pure water (8000g) and polyoxyethylene (500g).Add in the granulator cyclic ester erythromycin (2500g), lactose monohydrate (450g) and microcrystalline Cellulose (250g) and mixing.Mixture is used the binder solution wet granulation of preparation before.With homogenizing in the wet granular earthquake granulator, and dry in fluidized bed dryer, and inlet temperature is 55 ℃.Then, with homogenizing in the dried granules earthquake granulator, and mixed 3 minutes with Talcum (155g) and carboxymethyl starch sodium (50g).Magnesium stearate (70g) is sieved and added in the mixture, mixed 1 minute.Then, utilize Kilian, Fette or Korsch tablet machine to be pressed into tablet in mixture.Obtain the coating solution of suspensoid form, it is grouped into by following one-tenth: acetone (1000g), isopropyl alcohol (1000g), cellulose acetate phthalate (60g), polyethylene glycol 6000 (30g) and titanium dioxide (60g).With tablet coating, thereby tablet quality increases by 2%.
The stripping test
Carry out the stripping test to compare the stripping curve of the tablet of preparation in embodiment 3 and comparative example 3.
The stripping test condition:
EP device 2 (slurry)
Rotating speed: 100rpm
Temperature: 37 ℃ ± 0.5 ℃
Dissolution medium prepares according to EP
Visible from last table, the coating cyclic ester erythromycin tablet through conventional wet granulation method preparation is in the decomposition that acid phase shows active substance, causes lower level stripping in the phosphate buffer of pH 6.8.The dissolution degree of acid phase (*) is expressed as the catabolite sum of cyclic ester erythromycin, and cyclic ester erythromycin decomposes under the condition of pH 1.2 fast.
Although describe the present invention in detail, require the present invention of protection should not be understood that to only limit to said specific embodiments with reference to specific embodiments.It will be appreciated by those skilled in the art that and to carry out various modifications and change and without departing from the spirit and scope of the present invention, therefore said modification and changing in the scope of the present invention that requires to protect.
Claims (31)
1. one kind comprises the method for the pharmaceutical composition of macrolide antibiotics through wet granulation, and said method comprises:
(a) macrolide antibiotics and the optional pharmaceutically acceptable carrier that exists and the mixture of excipient are provided to binder solution; So that said macrolide antibiotics is suspended in the said binder solution, said binder solution comprises at least a binding agent, at least a diluent and water;
The mixture that (b) will derive from step (a) mixes, until obtaining expansible wet granular;
(c) said wet granular is dry under 70 ℃ or lower temperature, until obtaining dried granules; And
(d) said dried granules is ground, until the dried particles that obtains to grind.
2. the method for claim 1, wherein that said wet granular is dry under 60 ℃ or lower temperature.
3. according to claim 1 or claim 2 method, wherein said method is further comprising the steps of:
(e) in the dried particles of said grinding, add at least a disintegrating agent and at least a lubricant; And
(f) dried particles with said grinding is pressed into tablet.
4. like claim 1,2 or 3 described methods, wherein said method is further comprising the steps of:
(g) with the coating mixture with said tablet coating, said coating mixture comprise at least a stomach juice-resistant and under the condition that is higher than about pH 5 polymer soluble, at least a coating plasticizer and at least a coating filler.
5. like each described method in the aforementioned claim, the particle size distribution of wherein said macrolide antibiotics (d0.9) equals 500 μ m or littler.
6. like each described method in the aforementioned claim, wherein said diluent is selected from calcium carbonate, calcium phosphate (two alkali or three alkali), calcium sulfate, cellulose powder, glucosan, dextrin, fructose, kaolin, lactose, Lactis Anhydrous, lactose monohydrate, maltose, mannitol, microcrystalline Cellulose, sorbitol, sucrose, starch and their any combination.
7. method as claimed in claim 6, wherein said diluent are microcrystalline Cellulose.
8. each described method as in the aforementioned claim, the amount of wherein said diluent be said tablet 10% to 80%w/w.
9. like each described method in the aforementioned claim, wherein said binding agent is selected from arabic gum, alginic acid, carbomer, sodium carboxymethyl cellulose, carboxymethyl starch sodium, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyoxyethylene, polyvidone and their any combination.
10. method as claimed in claim 9, wherein said binding agent are carboxymethyl starch sodium or polyvidone.
11. as each described method in the aforementioned claim, the amount of wherein said binding agent be said tablet 5% to 20%w/w.
12. like each described method in the aforementioned claim, wherein said disintegrating agent is carboxymethyl starch sodium or crospovidone.
13. as each described method in the aforementioned claim, the amount of wherein said disintegrating agent be said tablet 5% to 20%w/w.
14. like each described method among the claim 3-13, wherein said lubricant is selected from calcium stearate, Compritol 888 ATO, magnesium stearate, mineral oil, Polyethylene Glycol, sodium stearyl fumarate, stearic acid, Talcum, zinc stearate and their any combination.
15. method as claimed in claim 12, wherein said lubricant are magnesium stearate and steatitic combination.
16. like each described method among the claim 3-15, the amount of wherein said lubricant be said tablet 0.5% to 10%w/w.
17. like each described method among the claim 3-16, the polymer in the wherein said coating mixture is selected from EUDRAGIT S100, cellulose derivative and polyvinyl alcohol derivative.
18. method as claimed in claim 15, wherein said polymer are cellulose acetate phthalate.
19. like each described method among the claim 3-18, wherein said coating plasticizer is selected from polyethylene glycol 6000, propylene glycol, glycerol, glyceryl triacetate and their any combination.
20. method as claimed in claim 19, wherein said coating plasticizer is a polyethylene glycol 6000.
21. like each described method among the claim 3-20, the amount of wherein said plasticizer be said tablet 0.1% to 5%w/w.
22. like each described method among the claim 3-21, wherein said coating filler is selected from Talcum, titanium dioxide and their any combination.
23. method as claimed in claim 22, wherein said coating filler be the combination of Talcum and titanium dioxide.
24. like each described method among the claim 3-23, wherein the amount of every kind of said coating filler be said tablet 0.1% to 5%w/w.
25. like each described method among the claim 3-24, the amount of wherein said tablet coating be said tablet 0.5% to 5%w/w.
26. like each described method among the claim 3-25, wherein said tablet stripping curve is after under the environment of pH=6.8 60 minutes, is not less than the cyclic ester erythromycin dissolving of the primary quantity of 70%w/w.
27. like each described method among the claim 3-26, wherein said tablet stripping curve is after under the environment of pH=1.2 60 minutes, is not higher than the cyclic ester erythromycin dissolving of the primary quantity of 10%w/w.
28. the method for claim 1, said method comprises:
Prepare the solution of said binding agent in water;
Said macrolide antibiotics is suspended in the said binder solution;
Thus obtained mixture is mixed until obtaining expansible wet granular;
Said wet granular is homogenized until the wet granular that obtains homogenizing;
Be not higher than 6.5% dried granules until obtaining water content with the wet granular of said homogenizing is dry under 60 ℃ or lower temperature;
Said dried granules is homogenized until the dried particles that obtains homogenizing;
The dried particles of said homogenizing is mixed with carboxymethyl starch sodium, Talcum and magnesium stearate until obtaining second mixture;
Said second mixture is pressed into tablet; And
With coating mixture coating, said coating mixture comprises cellulose acetate phthalate, polyethylene glycol 6000, Talcum and titanium dioxide with said tablet.
29. like each described method in the aforementioned claim, wherein said macrolide antibiotics is a cyclic ester erythromycin.
30. like 29 described methods in the claim, wherein said cyclic ester erythromycin is crystal or amorphous form.
31. through compositions like the described method preparation of aforementioned each claim.
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| CN104688757A (en) * | 2013-12-09 | 2015-06-10 | 海南澳美华制药有限公司 | Dissolution rate increased erythromycin cydocarbonate oral composition |
| CN107998106A (en) * | 2017-12-25 | 2018-05-08 | 安徽永生堂药业有限责任公司 | A kind of macrolide antibiotics sustained-release micro-pill capsules |
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