CN103169705A - Compound orally disintegrating tablet containing chlorpheniramine and dextromethorphan - Google Patents
Compound orally disintegrating tablet containing chlorpheniramine and dextromethorphan Download PDFInfo
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- CN103169705A CN103169705A CN2011104374109A CN201110437410A CN103169705A CN 103169705 A CN103169705 A CN 103169705A CN 2011104374109 A CN2011104374109 A CN 2011104374109A CN 201110437410 A CN201110437410 A CN 201110437410A CN 103169705 A CN103169705 A CN 103169705A
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Abstract
The invention relates to a compound orally disintegrating tablet containing chlorpheniramine maleate and dextromethorphan hydrobromide and a preparation method thereof. The compound orally disintegrating table comprises covered granules containing chlorpheniramine maleate, dextromethorphan hydrobromide and at least one stabilizer, a filling agent, a disintegrating agent and a lubricating agent. The compound orally disintegrating tablet provided by the invention is good in stability, high in dissolution rate, simple in preparation technology and environmentally friendly.
Description
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Technical field:
The present invention is field of pharmaceutical preparations, is specifically related to a kind of compound oral disintegrating tablet and preparation method that contains chlorphenamine maleate and dextromethorphan hydrobromide.
Technical background:
Common cold is also referred to as the acute viral nasopharyngitis, be a kind of gentleness, the self limiting infectious disease, can cause by more than 100 kinds of different virus.Wherein, approximately the flu of 50-70% is caused by rhinovirus and coronavirus.The self limiting normally because catch a cold, therefore treatment mainly concentrates on relief of symptoms persistent period and intensity, and reduce the risk of complication.Cold symptoms is varied, mainly comprises fever, rhinorrhea, cough, nasal obstruction etc., and these symptoms are not often all to occur simultaneously, and the coldrex of " Almightiness type " often contains a or two kind of composition for symptom not occurring.The treatment financial burden that this has additionally increased the patient undoubtedly more seriously may cause unnecessary side effect.The particular formulations treatment of alleviating the cold symptoms of making us uncomfortable most with specific aim is wiser.
Chlorphenamine maleate and dextromethorphan hydrobromide determined curative effect, the clinical application experience reaches decades, and is safe and effective, and chlorphenamine maleate can effectively suppress sneeze, nose or throat pruritus, rhinorrhea, is shed tears at the eye pruritus that causes because of pollinosis; Dextromethorphan hydrobromide is antitussive effectively, and Papillary can effectively suppress the common cold symptom, comprises the upper airway symptoms such as cough, watery nasal discharge, sneeze, nasal obstruction.
This dosage form of oral cavity disintegration tablet is namely in order to satisfy the Compliance problem of special population at the beginning of establishment, can be in the situation that need not to drink water, and (in 60 seconds) disintegrate rapidly is convenient to the patient and is swallowed.
Triaminic Softchews Cough ﹠amp, Runny Nose(active component: chlorphenamine maleate 1mg, dextromethorphan hydrobromide 5 mg) be that Novartis Co.,Ltd uses the OTC (over-the-counter) coldrex in the child in the America ﹠ Canada listing in 2002, to be Novartis Co.,Ltd cooperate with laboratory company Triaminic Softchews series oral cavity disintegration tablet, adopt the product of Cima taste masking Orally disintegrating chip technology (OraSolv) exploitation, it adopts the phase coacervation to prepare respectively chlorphenamine maleate and dextromethorphan hydrobromide microcapsule, then with filler, binding agent, disintegrating agent, lubricant, fluidizer, the tabletting such as effervescent and sweeting agent or essence pharmacy adjuvant mix homogeneously, tabletting, the preparation oral cavity disintegration tablet.But there is the problem of following several respects in this technology: 1. need with an organic solvent thiacyclohexane as the solvent of coating material and principal agent, increase environmental pollution and to the risk of producers' physical impairment; 2. may exist two kinds of microcapsules to mix inhomogeneous risk; 3. need special preparation process equipment.
The present invention pulverizes chlorphenamine maleate and dextromethorphan hydrobromide, sieve, add the filler mix homogeneously, add binding agent to adopt the mode of centrifugal granulating to prepare granule, then adopt at the bottom of fluid bed the spray art for coating to carry out the taste masking coating and prepare coated granule, with respect to the OraSolv technology, advantage with following several respects: 1. the coated granule particle diameter of preparation is 60～100 orders, is prepared into oral cavity disintegration tablet and obviously reduces grittiness; 2. eliminate two kinds of coated granules and mix inhomogeneous risk; 3. preparation technology simplifies, and is easy to quality control and suitability for industrialized production; 4. adopt the production equipment of common oral solid formulation, have stronger production adaptability; 5. avoid using cyclohexane extraction, the risk of elimination environmental pollution reaches the physical impairment to producers.
Therefore, the invention provides a kind of oral cavity disintegration tablet and preparation method that contains chlorphenamine maleate and dextromethorphan hydrobromide composition.
Summary of the invention:
Purpose of the present invention provides a kind of chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet of containing, and this comprises this oral cavity disintegration tablet:
A chlorphenamine maleate and dextromethorphan hydrobromide coated granule, wherein, its grain diameter of described coated granule is 60～100 orders, described coated granule comprises the granule that contains chlorphenamine maleate, dextromethorphan hydrobromide and at least a stabilizing agent and the coating material that is applied to described particle surface, and described coating material comprises ethyl cellulose or methacrylic acid aminoalkyl ester copolymer;
The pharmaceutic adjuvant that b is suitable.
Preferably, the compound oral disintegrating tablet of the invention described above comprises:
A chlorphenamine maleate and dextromethorphan hydrobromide coated granule, wherein, its grain diameter of described coated granule is 60～100 orders, described coated granule comprises the granule that contains chlorphenamine maleate, dextromethorphan hydrobromide and at least a stabilizing agent and the coating material that is applied to described particle surface, and described coating material comprises ethyl cellulose or methacrylic acid aminoalkyl ester copolymer;
The b filler is selected from Pearlitol 200 SD(vertical compression mannitol), in mannitol, Microcrystalline cellulose a kind of, two kinds or multiple;
The c disintegrating agent is selected from crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium;
The d lubricant is Pulvis Talci or magnesium stearate.
the invention described above contain chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet, preferably, the content of described dextromethorphan hydrobromide is 5mg, the content of described chlorphenamine maleate is 1mg, described filler is Parteck deltaM (Pearlitol 200 SD), mannitol, Microcrystalline cellulose or their mixture, described disintegrating agent is crospolyvinylpyrrolidone, described lubricant is magnesium stearate, wherein the consumption of disintegrating agent be sheet heavy 3～10%, the consumption of filler Pearlitol 200 SD be sheet heavy 0～75%, the consumption of filler mannitol be sheet heavy 0～75%, the Microcrystalline cellulose consumption be sheet heavy 1～10%, preferably, the consumption of filler Pearlitol 200 SD is that sheet weighs 25～75%, the consumption of filler mannitol is that sheet weighs 25～75%, the Microcrystalline cellulose consumption is that sheet weighs 1～10%.This oral cavity disintegration tablet also further comprises binding agent, fluidizer, effervescent, sweeting agent or essence, described binding agent, fluidizer, effervescent, sweeting agent or essence are the conventional pharmaceutic adjuvant in this area, its consumption is conventional amount used, preferably, described binding agent is microcrystalline Cellulose (not only plays the filler effect but also can play the binding agent effect in oral cavity disintegration tablet of the present invention), described fluidizer is at least a of silicon dioxide, sodium stearyl fumarate, preferred silicon dioxide; Described effervescent is at least a in citric acid, tartaric acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or their any mixture, optimization citric acid and sodium bicarbonate composition, and wherein citric acid accounts for the heavy 0.38-2.3% of sheet; Sodium bicarbonate accounts for the heavy 0.5-3% of sheet; Described sweeting agent is at least a in aspartame, sucralose, sucrose or their any mixture, preferred sucralose; Described essence is at least a in orange essence, glucose essence, cherry essence or their any mixture, preferred orange essence.
The invention described above contain chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet, wherein, described stabilizing agent is selected from citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine, be preferably citric acid, tartaric acid, malic acid, its consumption is 10～1000% of chlorphenamine maleate weight.
the invention described above contain chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet, wherein, the described granule that contains chlorphenamine maleate and dextromethorphan hydrobromide also contains filler and binding agent, described stabilizing agent is selected from citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine, be preferably citric acid, tartaric acid, malic acid, its consumption is 10～1000% of chlorphenamine maleate weight, described filler is sucrose or microcrystalline Cellulose, its consumption be sheet heavy 5～10%, or described binding agent is sucrose solution or 5% polyvinylpyrrolidone aqueous solution, and described coating material also comprises antiplastering aid magnesium stearate and solvent dehydrated alcohol, the consumption of described coating material is for making medicine-containing particle (or claiming granule) weightening finish 20～50%(in methacrylic acid aminoalkyl ester copolymer E type or ethyl cellulose), described methacrylic acid aminoalkyl ester copolymer is preferably methacrylic acid aminoalkyl ester copolymer E type.
In a preferred embodiment, chlorphenamine maleate and the dextromethorphan hydrobromide compound oral disintegrating tablet of containing of the present invention, this comprises this oral cavity disintegration tablet:
A chlorphenamine maleate and dextromethorphan hydrobromide coated granule, wherein, its grain diameter of described coated granule is 60～100 orders, described coated granule comprises the granule that contains chlorphenamine maleate and dextromethorphan hydrobromide and the coating material that is applied to described particle surface, and described coating material is methacrylic acid aminoalkyl ester copolymer E type;
The b filler is vertical compression mannitol (Pearlitol 200 SD), mannitol, Microcrystalline cellulose or their mixture;
The c disintegrating agent is crospolyvinylpyrrolidone;
The d lubricant is Pulvis Talci or magnesium stearate.
in above-mentioned preferred embodiment, chlorphenamine maleate and the dextromethorphan hydrobromide compound oral disintegrating tablet of containing of the present invention, preferably, the content of described dextromethorphan hydrobromide is 5mg, the content of described chlorphenamine maleate is 1mg, described filler is mannitol, Microcrystalline cellulose or their mixture, described disintegrating agent is crospolyvinylpyrrolidone, described lubricant is magnesium stearate, wherein, the consumption of disintegrating agent crospolyvinylpyrrolidone be sheet heavy 3～10%, the consumption of filler Pearlitol 200 SD be sheet heavy 0～75%, the consumption of filler mannitol be sheet heavy 0～75%, the consumption of filler Microcrystalline cellulose be sheet heavy 1～10%, preferably, the consumption of filler Pearlitol 200 SD be sheet heavy 25～75%, the consumption of filler mannitol be sheet heavy 25～75%, the Microcrystalline cellulose consumption is that sheet weighs 1～10%, the consumption of described lubricant is conventional amount used.This oral cavity disintegration tablet also further comprises binding agent, fluidizer, effervescent, sweeting agent or essence, described binding agent, fluidizer, effervescent, sweeting agent or essence are the conventional pharmaceutic adjuvant in this area, its consumption is conventional amount used, preferably, described binding agent is microcrystalline Cellulose (not only plays the filler effect but also can play the binding agent effect in oral cavity disintegration tablet of the present invention), described fluidizer is at least a of silicon dioxide, sodium stearyl fumarate, preferred silicon dioxide; Described effervescent is at least a in citric acid, tartaric acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or their any mixture, optimization citric acid and sodium bicarbonate composition, wherein, citric acid accounts for the heavy 0.38-2.3% of sheet; Sodium bicarbonate accounts for the heavy 0.5-3% of sheet; Described sweeting agent is at least a in aspartame, sucralose, sucrose or their any mixture, preferred sucralose; Described essence is at least a in orange essence, glucose essence, cherry essence or their any mixture, preferred orange essence.
In above-mentioned preferred embodiment, the compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide of the present invention, wherein, described stabilizing agent is selected from citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine, be preferably citric acid, tartaric acid, malic acid, its consumption is 10～1000% of chlorphenamine maleate weight.
In above-mentioned preferred embodiment, chlorphenamine maleate and the dextromethorphan hydrobromide compound oral disintegrating tablet of containing of the present invention, wherein, the described granule that contains chlorphenamine maleate and dextromethorphan hydrobromide also contains filler and binding agent, described filler is sucrose, and its consumption is the heavy 5-10% of sheet; Or described binding agent is sucrose solution or 5% polyvinylpyrrolidone aqueous solution, and described coating material also comprises antiplastering aid magnesium stearate and solvent dehydrated alcohol; Described methacrylic acid aminoalkyl ester copolymer is preferably methacrylic acid aminoalkyl ester copolymer E type, for making medicine-containing particle (or claiming granule) weightening finish 20～50%(in methacrylic acid aminoalkyl ester copolymer E type).
Another object of the present invention provides a kind of method that contains chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet for preparing, and the method comprises following process:
1) pulverize respectively sucrose or microcrystalline Cellulose, stabilizing agent, chlorphenamine maleate and dextromethorphan hydrobromide, cross 80 mesh sieves, mix, form uniform powder;
2) preparation sucrose solution or 5% polyvinylpyrrolidone aqueous solution are as binding agent;
3) with appropriate step 2) binding agent add in the powder of step 1) gained, adopt the pelletize of centrifugal granulating technology, drying is crossed and is used 60 mesh sieves, obtains medicine-containing particle;
4) preparation of coating solution: ethyl cellulose or methacrylic acid aminoalkyl ester copolymer E type are dissolved fully with dehydrated alcohol, add magnesium stearate, dispersed with stirring is crossed 60 mesh sieves, makes coating solution;
5) adopt spray packaging technique at the bottom of fluid bed to carry out coating to the medicine-containing particle of step 3) with the coating solution of step 4), get coated granule;
6) with the coated granule of step 5) and filler, disintegrating agent, lubricant pharmaceutic adjuvant mix homogeneously, direct compression makes the compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide.
the method of the invention described above, the content of described maleic acid dextromethorphan are 5mg, and the content of described dextromethorphan hydrobromide is 1mg, described filler is mannitol, Microcrystalline cellulose, sucrose or their mixture, described disintegrating agent is crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium, preferred crospolyvinylpyrrolidone, wherein, the consumption of disintegrating agent crospolyvinylpyrrolidone be sheet heavy 3～10%, the consumption of filler Pearlitol 200 SD be sheet heavy 0～75%, the consumption of filler mannitol be sheet heavy 0～75%, the consumption of filler Microcrystalline cellulose be sheet heavy 1～10%, preferably, the consumption of filler Pearlitol 200 SD be sheet heavy 25～75%, the consumption of filler mannitol be sheet heavy 25～75%, the Microcrystalline cellulose consumption is that sheet weighs 1～10%, described lubricant is Pulvis Talci or magnesium stearate, preferred magnesium stearate, consumption is conventional amount used, also comprise effervescent, binding agent, fluidizer, sweeting agent or essence in step 3).This oral cavity disintegration tablet also further comprises binding agent, fluidizer, effervescent, sweeting agent or essence, described binding agent, fluidizer, effervescent, sweeting agent or essence are the conventional pharmaceutic adjuvant in this area, its consumption is conventional amount used, preferably, described binding agent is microcrystalline Cellulose (not only plays the filler effect but also can play the binding agent effect in oral cavity disintegration tablet of the present invention), described fluidizer is at least a of silicon dioxide, sodium stearyl fumarate, preferred silicon dioxide; Described effervescent is at least a in citric acid, tartaric acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or their any mixture, optimization citric acid and sodium bicarbonate composition, wherein, citric acid accounts for the heavy 0.38-2.3% of sheet; Sodium bicarbonate accounts for the heavy 0.5-3% of sheet; Described sweeting agent is at least a in aspartame, sucralose, sucrose or their any mixture, preferred sucralose; Described essence is at least a in orange essence, glucose essence, cherry essence or their any mixture, preferred orange essence.
The invention described above method, described stabilizing agent is selected from citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine, be preferably citric acid, tartaric acid, malic acid, its consumption is 10～1000% of chlorphenamine maleate weight.
The invention described above method wherein, also contains filler and binding agent in step 1), described filler is sucrose, and its consumption is the heavy 5-10% of sheet; Or described binding agent is sucrose solution or 5% polyvinylpyrrolidone aqueous solution, and coating material described in step 4) also comprises antiplastering aid magnesium stearate and solvent dehydrated alcohol; The consumption of described coating material is for making medicine-containing particle (or claiming granule) weightening finish 20～50%(in methacrylic acid aminoalkyl ester copolymer E type or ethyl cellulose), described methacrylic acid aminoalkyl ester copolymer is preferably methacrylic acid aminoalkyl ester copolymer E type.
The present invention is with reference to the disintegration time mensuration method of describing in Chinese patent CN101756918 A, carry out the mensuration of disintegration, method is: the both ends open glass-tube that to get 6 diameters be 1.5cm, bottom cover 25 order stainless steel meshs (sieve diameter is about 710 μ m), the transparent pipe box of overcoat, device is placed in water bath with thermostatic control, bath temperature is 37 ± 1 ℃, add 12mL water (every pipe＜2mL), constant temperature, inspection method: get 6 of this product, add respectively in each glass-tube, the disintegrate situation is observed in timing, all should disintegrate in 1min, and without the block of assembling.
According to " Chinese pharmacopoeia 2010 version appendix X C dissolution method the second method (oar method) is carried out oral cavity disintegration tablet of the present invention and Triaminic Softchews Cough ﹠amp; Runny Nose(buys from market) at the dissolution of different medium, different time points, and draw stripping curve according to result, and estimate the stripping behavior of oral cavity disintegration tablet of the present invention in different medium, leaching condition is seen embodiment.
The maximal dose of chlorphenamine maleate is that 4mg, dissolubility are 160mg/ml, ClogP3.15, LogP3.62, pKa9.2, and according to LogP and ClogP value, chlorphenamine maleate is the medicine that belongs to the biopharmaceutics first kind (BCS I).Leslie Z. doctor Benet of University of California biopharmaceutics system thinks that dextromethorphan hydrobromide belongs to the medicine of the biopharmaceutics classification first kind (BCS I), be that chlorphenamine maleate and dextromethorphan hydrobromide all belong to high osmosis, high solvent medicine, can be rapidly absorbed in vivo.
According to " oral solid formulation Dissolution Rate Testing technological guidance principle ", for high-dissolvability, high-permeability (biopharmaceutics classification 1 class) medicine, its dissolution is 85% can guarantee that the bioavailability of medicine is not limited by stripping during 15min in 0.1N hydrochloric acid, in this case, the rate-limiting step of drug absorption is the gastric emptying time.Under fasting state, T50% Entogastric lingering (emptying) time average is 15～20min, therefore, that can guard thinks, if a kind of medicine is under the Dissolution Rate Testing condition of gentleness, be 85% at the 15min dissolution in 0.1N hydrochloric acid, namely the behavior of preparation and solution phase seemingly, think that generally should there be the problem of bioavailability in this medicine.
Oral cavity disintegration tablet of the present invention all is not less than 85% in different medium at the dissolution of 15min, meets the characteristics of oral cavity disintegration tablet rapid delivery of pharmaceuticals.
The compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide of the present invention has been avoided prior art (listing product Triaminic Softchews Cough ﹠amp; Runny Nose) adopt the phase coacervation to prepare respectively the complex operations of chlorphenamine maleate and dextromethorphan hydrobromide microcapsule and the two kind solvent thiacyclohexanes that employing is unfavorable for environmental protection thereof, therefore, compared with prior art (product Triaminic Softchews Cough ﹠amp goes on the market; Runny Nose), compound oral disintegrating tablet preparation technology of the present invention is simple, environmental protection, improving aspect taste, grittiness and disintegration and dissolution quite with the listing product at least, be better than especially listing product Triaminic Softchews Cough ﹠amp aspect dissolution; Runny Nose.The particularly important is, the inventor also finds not add under the condition of stabilizing agent at chlorphenamine maleate and dextromethorphan hydrobromide compound oral disintegrating tablet, chlorphenamine maleate is very unstable in its preparation process, but after adding stabilizing agent, especially after organic acid such as citric acid, tartaric acid, malic acid, chlorphenamine maleate keeps stable in the preparation process of oral cavity disintegration tablet of the present invention.
Figure of description:
Fig. 1 embodiment 3 and Triaminic Softchews Cough ﹠amp; The dissolution correlation curve of Runny Nose in water
Fig. 2 embodiment 3 and Triaminic Softchews Cough ﹠amp; The dissolution correlation curve of Runny Nose in pH1.2 chlorination of hydrochloric acid sodium solution
Fig. 3 embodiment 3 and Triaminic Softchews Cough ﹠amp; The dissolution contrast of Runny Nose in the pH4.5 acetate buffer
Fig. 4 embodiment 3 and Triaminic Softchews Cough ﹠amp; Runny Nose is at the dissolution correlation curve of pH6.8 phosphate buffer
Specific embodiment:
Following embodiment is used for further explaining the present invention, is not represent that the present invention only limits to following examples.
Embodiment 1:
Prescription:
Preparation technology:
1. the preparation of binding agent: take appropriate polyvinylpyrrolidone and be added in purified water, stirring and dissolving is mixed with 5%(w/v) the polyvinylpyrrolidone aqueous solution;
2. pulverize respectively chlorphenamine maleate, dextromethorphan hydrobromide and citric acid, cross 80 mesh sieves, get powder standby;
3. take respectively chlorphenamine maleate, dextromethorphan hydrobromide powder, microcrystalline Cellulose and the citric acid of recipe quantity, the mix homogeneously resulting mixture, standby.
4. granulate: the mixture of step 3 gained is added in centrifugal pellet processing machine granulates, the following device parameter that arranges: air feed unit frequency 10Hz, rotary speed 250rpm, hydrojet rotating speed 30rpm, spray gun pressure 0.02MPa, do wet degree according to material in pelletization and adjust parameter in good time, when granularity reaches approximately 60 order, stop hydrojet (polyvinylpyrrolidone aqueous solution), discharging;
5. dry: as the material tiling to be launched, be placed in 50 ℃ of baking ovens, forced air drying;
6. granulate: to dried medicine-containing particle granulate, make medicine-containing particle with 60 mesh sieves.
The coated granule preparation:
1, the preparation of coating solution: take the recipe quantity ethyl cellulose, be added in the recipe quantity dehydrated alcohol, after being stirred to dissolving fully, add the recipe quantity magnesium stearate, then dispersed with stirring sieves with 60 mesh sieves, and the filtering solid particle is made the taste masking coating solution.
2, fluidized bed coating: medicine-containing particle is added in fluidising chamber the following fluid bed parameter that arranges: blower fan frequency 25Hz, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, peristaltic pump rotating speed 12rpm.Carry out fluidized bed coating, after treating that coating is completed, keep temperature of charge, fluidized drying 10min, coated granule is made in discharging.
3, detect semi-finished product content.
Tabletting:
1, the pulverizing of adjuvant: pulverize citric acid, cross 100 mesh sieves, standby.
2, mix: take taste masking coated granule, vertical compression type mannitol, mannitol, microcrystalline Cellulose, polyvinylpolypyrrolidone, sucralose, essence, citric acid, sodium bicarbonate, the silicon dioxide of recipe quantity, mix homogeneously.
3, mix with magnesium stearate: the mixed material of step 2 preparation is mixed 2min with the magnesium stearate of recipe quantity, detect semi-finished product content, standby.
4, tabletting: control below the relative air humidity to 40% of tabletting chamber, assay result according to step 3, the heavy span of control of tab, to suppress in flakes with the plane punch die of Φ 13mm, tablet hardness is controlled at 3～4kg, namely gets the compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide composition.
5, prepared oral cavity disintegration tablet hardness, disintegration, outward appearance detect.
The average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 2: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Preparation technology:
The medicine-containing particle preparation:
1. the preparation of binding agent: take appropriate sucrose and be added in purified water, stirring and dissolving is mixed with 50%(w/v) the syrup binding agent.
2. pulverize respectively chlorphenamine maleate, dextromethorphan hydrobromide, sucrose and citric acid, cross 80 mesh sieves, standby.
3. take respectively chlorphenamine maleate, dextromethorphan hydrobromide fine powder, sucrose and the citric acid of recipe quantity, mix homogeneously, standby.
4. granulate: the mixture of 3 lower supplementary materials is added in centrifugal pellet processing machine, the following device parameter that arranges: air feed unit frequency 10Hz, rotary speed 250rpm, hydrojet rotating speed 30rpm, spray gun pressure 0.05MPa, do wet degree according to material in pelletization and adjust parameter in good time, when granularity reaches approximately 60 order, stop hydrojet (50% syrup), discharging.
5. dry: as the material tiling to be launched, be placed in 50 ℃ of baking ovens, forced air drying.
6. granulate: to dried medicine-containing particle granulate, make medicine-containing particle with 60 mesh sieves.
The coated granule preparation:
1, the preparation of coating solution: take recipe quantity methacrylic acid aminoalkyl ester copolymer E type, be added in the recipe quantity dehydrated alcohol, after being stirred to dissolving fully, add the recipe quantity magnesium stearate, then dispersed with stirring sieves with 60 mesh sieves, the filtering solid particle is made the taste masking coating solution.
2, fluidized bed coating: medicine-containing particle is added in fluidising chamber the following fluid bed parameter that arranges: blower fan frequency 25Hz, 50 ℃ of inlet temperature, 30 ℃ of temperature of charge, peristaltic pump rotating speed 12rpm.Carry out fluidized bed coating, after treating that coating is completed, keep temperature of charge, fluidized drying 10min, coated granule is made in discharging.
3, detect semi-finished product content.
Tabletting:
1, the pulverizing of adjuvant: pulverize citric acid, cross 100 mesh sieves, standby.
2, mix: take taste masking coated granule, vertical compression type mannitol, mannitol, microcrystalline Cellulose, polyvinylpolypyrrolidone, sucralose, essence, citric acid, sodium bicarbonate, the silicon dioxide of recipe quantity, mix homogeneously.
3, mix with magnesium stearate: the mixed material of step 2 preparation is mixed 2min with the magnesium stearate of recipe quantity, detect semi-finished product content, standby.
4, tabletting: control below the relative air humidity to 40% of tabletting chamber, assay result according to step 3, the heavy span of control of tab, to suppress in flakes with the plane punch die of Φ 13mm, tablet hardness is controlled at 3～4kg, namely gets the compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide composition.
5, prepared oral cavity disintegration tablet hardness, disintegration, outward appearance detect.
The average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 3: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 4: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 5: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 6: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 7: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 8: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Except pH adjusting agent is changed to malic acid by citric acid, medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 9: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Except pH adjusting agent is changed to tartaric acid by citric acid, medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Embodiment 10: prepare coated granule and tabletting take methacrylic acid aminoalkyl ester copolymer E type as coating material
Prescription:
Except not adding pH adjusting agent, medicine-containing particle, coated granule and tabletting preparation technology are with embodiment 2, and the average sheet of prepared oral cavity disintegration tablet is heavily 625mg, and hardness is 3～4kg, and disintegration is all less than 60s.
Dissolution determination
" method of Chinese pharmacopoeia version in 2010 is measured the oral cavity disintegration tablet and listing oral cavity disintegration tablet Triaminic Softchews Cough ﹠amp of embodiment 3 and embodiment 8 gained by reference; The dissolution of Runny Nose in different medium.
Oral cavity disintegration tablet and Triaminic Softchews Cough ﹠amp with embodiment 3 and embodiment 8 gained; The dissolution of Runny Nose oral cavity disintegration tablet in different medium compares, to estimate the quick drug release feature of oral cavity disintegration tablet of the present invention.With reference to " Chinese pharmacopoeia version appendix X C dissolution method the second method (oar method) in 2010, dissolution parameters is as follows:
| Project | Parameter |
| Medium | Be respectively water, pH1.2 chlorination of hydrochloric acid sodium solution, pH4.5 acetate buffer and pH6.8 phosphate buffer |
| The medium volume | 500mL |
| Rotating speed | 50rpm |
| Sampling time point | 5、10、15、30、45min |
The dissolution fluid that takes out with 0.45 μ m filtering with microporous membrane after, the employing high effective liquid chromatography for measuring is the content of chlorphenamine maleate and dextromethorphan hydrobromide wherein, and calculate the dissolution of each time point chlorphenamine maleate and dextromethorphan hydrobromide.
The oral cavity disintegration tablet of embodiment 3, embodiment 8 and Triaminic Softchews Cough ﹠amp; Runny Nose oral cavity disintegration tablet the results are shown in following table at each medium dissolution:
Table: dissolution contrast
By the result of upper table as can be known, the oral cavity disintegration tablet of the present invention's preparation is in 500mL water, pH1.2 chlorination of hydrochloric acid sodium solution, pH4.5 acetate buffer and pH6.8 phosphate buffer, adopting slurry method, rotating speed is to begin all to be not less than 85% to the 15min dissolution from stripping under the 50rpm condition, and its dissolution rate is than Triaminic Softchews Cough ﹠amp; Runny Nose is fast, and therefore, the middle dissolution of oral cavity disintegration tablet of the present invention is better than the product that goes on the market.
The oral cavity disintegration tablet of embodiment 1-10 is through the volunteer sensory test, and all without grittiness and abnormal flavour, mouthfeel is good.Therefore, compound oral disintegrating tablet preparation technology of the present invention is simple, environmental protection, improve aspect taste, grittiness and disintegration suitable with the listing product at least.
Determination of related substances
With reference to " Chinese pharmacopoeia version chlorphenamine maleate determination of related substances method in 2010 adopts high performance liquid chromatography to use the related substance of each important stage of oral cavity disintegration tablet of high-concentration and low-concentration blank determination embodiment 3, embodiment 8, embodiment 9 and embodiment 10 such as granulation, coating, granule, coated granule and oral cavity disintegration tablet that tabletting is corresponding.
Oral cavity disintegration tablet with embodiment 3, embodiment 8, embodiment 9 and embodiment 10 gained, granule to it in preparation process, coated granule and oral cavity disintegration tablet carry out related substance comparative study, to estimate the Stabilization to chlorphenamine maleate in preparation process of stabilizing agent in oral cavity disintegration tablet of the present invention.
Result of the test sees the following form:
Table: chlorphenamine maleate related substance (single maximum contaminant) contrast
By the result of upper table as can be known, the embodiment of the present invention 3, embodiment 8, embodiment 9 add after stabilizing agent in whole preparation process its single maximum contaminant to compare with raw material, almost unchanged, but embodiment 10 does not add stabilizing agent, after granule preparation, taste masking coating and tablet forming technique process, its single maximum contaminant significantly increases.Therefore, the present invention adds stabilizing agent in the granule prescription after, the stability that the maintenance of chlorphenamine maleate in preparation process is good.
Generally speaking, oral cavity disintegration tablet of the present invention is good stability not only, and dissolution is higher than the listing product, and preparation technology is simple, environmental protection, and improve aspect taste, grittiness and disintegration suitable with the listing product at least.
Claims (14)
1. one kind contains the compound oral disintegrating tablet that chlorphenamine and dextromethorphan form, and comprising:
A chlorphenamine maleate and dextromethorphan hydrobromide coated granule, wherein, its grain diameter of described coated granule is 60～100 orders, described coated granule comprises the granule that contains chlorphenamine maleate, dextromethorphan hydrobromide and at least a stabilizing agent and the coating material that is applied to described particle surface, and described coating material comprises ethyl cellulose or methacrylic acid aminoalkyl ester copolymer;
The pharmaceutic adjuvant that b is suitable.
2. oral cavity disintegration tablet according to claim 1, wherein, the content of described dextromethorphan hydrobromide is 5mg, the content of described chlorphenamine maleate is 1mg
Oral cavity disintegration tablet according to claim 1, described suitable pharmaceutic adjuvant comprises filler, disintegrating agent, lubricant, effervescent, fluidizer, sweeting agent, essence or their any mixture.
3. according to oral cavity disintegration tablet claimed in claim 3, described filler is vertical compression mannitol, mannitol, Microcrystalline cellulose or their mixture; Described disintegrating agent is selected from crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium; Described lubricant is Pulvis Talci or magnesium stearate, and described effervescent is citric acid and sodium bicarbonate.
4. oral cavity disintegration tablet according to claim 4, wherein, the consumption of described disintegrating agent crospolyvinylpyrrolidone be sheet heavy 3～10%; Or the consumption of described vertical compression mannitol be sheet heavy 0～75%, the consumption of described mannitol be sheet heavy 0～75%, the consumption of described Microcrystalline cellulose be sheet heavy 1～10%; Or described citric acid is the heavy 0.38-2.3% of sheet, and sodium bicarbonate is the heavy 0.5-3% of sheet.
5. oral cavity disintegration tablet according to claim 5, the consumption of described vertical compression mannitol be sheet heavy 25～75%, the consumption of described mannitol is that sheet weighs 25～75%.
6. oral cavity disintegration tablet according to claim 1, described stabilizing agent is citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine, be preferably citric acid, tartaric acid, malic acid, the consumption of described stabilizing agent is 10～1000% of chlorphenamine maleate weight.
7. oral cavity disintegration tablet according to claim 1, described granule also comprises filler and binding agent.
8. oral cavity disintegration tablet according to claim 8, described filler is sucrose or microcrystalline Cellulose, accounts for the heavy 5-10% of sheet; Or described binding agent is sucrose solution or polyvinylpyrrolidone aqueous solution.
9. oral cavity disintegration tablet according to claim 1, described methacrylic acid aminoalkyl ester copolymer is methacrylic acid aminoalkyl ester copolymer E type.
10. oral cavity disintegration tablet according to claim 10, the consumption of described methacrylic acid aminoalkyl ester copolymer E type is 20～50% of particle weight.
11. oral cavity disintegration tablet according to claim 1, described coating material also comprise antiplastering aid magnesium stearate and solvent dehydrated alcohol.
12. a method for preparing the arbitrary described compound oral disintegrating tablet of claim 1 to 12, the method comprises following process:
Pulverize respectively sucrose or microcrystalline Cellulose, chlorphenamine maleate, dextromethorphan hydrobromide and stabilizing agent, cross 80 mesh sieves, mix, form uniform powder;
Preparation sucrose solution or polyvinylpyrrolidone aqueous solution are as binding agent;
With appropriate step 2) binding agent add in the powder of step 1) gained, adopt the pelletize of centrifugal granulating technology, drying is crossed and is used 60 mesh sieves, obtains granule;
The preparation of coating solution: ethyl cellulose or methacrylic acid aminoalkyl ester copolymer E type are dissolved fully with dehydrated alcohol, add magnesium stearate, dispersed with stirring is crossed 60 mesh sieves, makes coating solution;
Adopt spray packaging technique at the bottom of fluid bed to carry out coating to the medicine-containing particle of step 3) with the coating solution of step 4), get coated granule;
With the coated granule of step 5) and filler, disintegrating agent, lubricant pharmaceutic adjuvant mix homogeneously, direct compression makes the compound oral disintegrating tablet that contains chlorphenamine maleate and dextromethorphan hydrobromide.
13. method according to claim 13, be citric acid, tartaric acid, malic acid, sodium sulfite, sodium pyrosulfite, disodiumedetate, calcio-disodium edetate, vitamin C, cysteine at the described stabilizing agent of step 3), be preferably citric acid, tartaric acid, malic acid, the consumption of described stabilizing agent is 10～1000% of chlorphenamine maleate weight.
14. method according to claim 13 also comprises effervescent, fluidizer, sweeting agent, essence or their any thing in step 3).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113164436A (en) * | 2018-11-27 | 2021-07-23 | 协和麒麟株式会社 | Pharmaceutical composition |
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| CN101756918A (en) * | 2008-12-12 | 2010-06-30 | 重庆医药工业研究院有限责任公司 | Orally disintegrating tablet containing paracetamol, pseudoephedrine hydrochloride and dextromethorphan hydrobromide and preparation method thereof |
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| CN1679525A (en) * | 2005-01-12 | 2005-10-12 | 复旦大学 | Oral disintegrant of compound paracetamol |
| CN1732938A (en) * | 2005-08-31 | 2006-02-15 | 上海医药(集团)有限公司 | Orally integrating tablet of compound paracetamol |
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| CN101756918A (en) * | 2008-12-12 | 2010-06-30 | 重庆医药工业研究院有限责任公司 | Orally disintegrating tablet containing paracetamol, pseudoephedrine hydrochloride and dextromethorphan hydrobromide and preparation method thereof |
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