CN103169679A - Calcium dobesilate medical composition with high drug loading capacity - Google Patents
Calcium dobesilate medical composition with high drug loading capacity Download PDFInfo
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- CN103169679A CN103169679A CN2011104421769A CN201110442176A CN103169679A CN 103169679 A CN103169679 A CN 103169679A CN 2011104421769 A CN2011104421769 A CN 2011104421769A CN 201110442176 A CN201110442176 A CN 201110442176A CN 103169679 A CN103169679 A CN 103169679A
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Abstract
The invention provides a calcium dobesilate medical composition with high drug loading capacity. The composition comprises a quick release part and a slow release part and is combined by the two parts in a single unit or multiple units. The calcium dobesilate in the quick release part accounts for 10-40% of total weight of calcium dobesilate, while the calcium dobesilate in the slow release part accounts for 60-90% of total weight of calcium dobesilate. The single dose of the composition comprises 500-100mg of calcium dobesilate. According to Chinese pharmacopoeia, in pH6.8 buffer liquid, the quick release part of the calcium dobesilate medical composition is quickly released within 30 minutes by a dissolution rate detection slurry method, and the total release amount of calcium dobesilate reaches over 80% of the total weight in 12-16 hours. According to the invention, not only is medicine in initial period relatively more released to solve the problem of over-slow effect of the medicine, but also good slow release effect can be obtained just by relatively less amount of slow release auxiliary materials because calcium dobesilate in the slow release part is reduced, thereby avoiding the problem that the preparation in unit dosage is overlarge and hard to swallow. The composition has greater clinical application value. The composition provided by the invention is simple and accessible and is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to the phenolsulfonic acid calcium medicine compound of high drug load.
Background technology
" diabetes " are the diseases of the easy overheap of glucose in a kind of blood.Its another name is " reticent killer " (Silent Killer), particularly " adult diabetes mellitus ", and it is high especially that the middle age more than 40 years old is caught rate.In case suffer from " diabetes ", will reduce 10 years more than life-span, and contingent complication spread all over whole body.In these complication, what occurrence rate was the highest is retinopathy, nephropathy and neurological disorder, is called as " the three large complication " of " diabetes ".When controlling the treatment diabetes, must treat for these complication.Calcium dobesilate has its unique curative effect on the treatment retinopathy, the high penetration effect that calcium dobesilate causes by suppressing vaso-active substance (histamine, 5-hydroxy tryptamine, Kallidin I, hyaluronidase, prostaglandin), thus the biosynthesis of basement membrane collagen improved.It can reduce the blood capillary high-permeability, reduces blood-high-viscosity, reduces the platelet high activity, thus alleviate retina ooze out, hemorrhage, reduce microangioma etc.Calcium dobesilate by reducing permeability, stabilised blood one retinal barrier of blood capillary, can reduce retina blood and exosmose simultaneously, keeps the normal dilution factor of blood.By reducing the macromole plasma protein and reducing Rigidity of red cells and coherency, can improve blood circulation, by reducing hematoblastic high coherency, can prevent that ischemia from occuring.
Calcium dobesilate by Austrian Yi Biwei large pharmaceutical factory in 2000 first at Discussion on Chinese Listed.Because the plasma half-life of calcium dobesilate is about 5 hours, so require to take in one day the level that 2-3 medicine kept blood drug level.But inferior taking medicine, obviously can reduce patient's compliance more than a day, affects the treatment of the state of an illness.Simultaneously, because ordinary preparation initial release dose comparison is large, rate of release is than very fast, and the rising of blood drug level level is very fast, easily causes untoward reaction.Therefore, for compliance, safety and the effectiveness that improves clinical application, design a kind of special slow releasing preparation, just seem very necessary.Chinese patent CN1939291A discloses slow, the controlled release preparation of calcium dobesilate, comprises that sustained-release matrix is controlled release and the coating membrane controlled release is put.Chinese patent CN100512802C provides slow releasing tablet of calcium dobesilate and preparation method thereof, makes matrix tablet by the sustained-release matrix material and controls release.In the slow release method of field of pharmaceutical preparations comparative maturity, generally comprise framework material slow release method and film-controlled slow-release technology at present.The framework material slow release method is with tabletting after medicine and some macromolecular material mix homogeneously, be dispersed in sheet after medicine and framework material mix homogeneously, in the process of drug release, framework material is formed with the skeleton of some strength, the permeable pressure head that forms after slow corrosion, dissolving or medicine dissolution by framework material reaches the purpose of slow release medicine, so framework material must reach a certain amount of good slow release effect that just has.Because the dose comparison of calcium dobesilate itself is large, add and must use a certain amount of framework material, just might cause the tablet of unit dose excessive, the compliance that patient takes medicine reduces.Also there is same problem in the film-controlled slow-release technology, need to wrap relatively a large amount of release membranes for the good calcium dobesilate of water solublity and just can reach desirable slow release effect, also exists the volumes of formulation of unit dose excessive, the problem that the compliance of taking medicine reduces.Simultaneously, calcium dobesilate fast-release tablet 6 hours blood drug level after administration just can reach maximum, onset is slower, and film-controlled slow-release preparation does not often discharge medicine substantially in discharging in earlier stage 1-2 hour, and slower release can't meet clinical needs relatively.Therefore, need to seek better pharmaceutical dosage form.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and the research design calcium dobesilate comprises the novel form of rapid release and slow release demand.
The invention provides a kind of phenolsulfonic acid calcium medicine compound of high drug load, described compositions comprises a kind of immediate release section and a kind of slow-released part, forms with both single unit or complex unit combination in any.Wherein immediate release section calcium dobesilate amount accounts for the 10%-40% of calcium dobesilate total amount, preferred 20%-30%; Slow-released part calcium dobesilate amount accounts for the 60%-90% of calcium dobesilate total amount, preferred 70%-80%.
Described immediate release section is grouped into by the one-tenth of following weight percent proportioning:
| Composition | The weight percent proportioning |
| Calcium dobesilate | 60％-99％ |
| Diluent | 0％-20％ |
| Disintegrating agent | 0％-10％ |
| Binding agent | 0％-30％ |
| Fluidizer | 0％-2％ |
| Lubricant | 0％-1％ |
| The rapid release coating material | 0％-30％ |
；
Described slow-released part is grouped into by the one-tenth of following weight percent proportioning:
| Composition | The weight percent proportioning |
| Calcium dobesilate | 70％-95％ |
| Diluent | 0％-15％ |
| Binding agent | 0％-10％ |
| Fluidizer | 0％-2％ |
| Lubricant | 0％-1％ |
| Antiplastering aid | 0％-25％ |
| The slow release macromolecular material | 5％-29％ |
。
In calcium dobesilate Pharmaceutical composition of the present invention, single dose of drug contains calcium dobesilate 500-1000mg, preferred 500mg, 750mg or 1000mg.
The rapid release unit of immediate release section of the present invention comprises:
1. fast-release tablet or release pills.
2. rapid release substrate: formed by powder, granule etc.
3. rapid release coatings: for containing the quick release coating of medicine.
The slow release unit of slow-released part of the present invention comprises:
1. sustained-release matrix tablets.
2. sustained release coating: the film-controlled slow-release coating that does not contain medicine.
Pharmaceutical composition of the present invention is above-mentioned any rapid release unit and any slow release unit, combines with single unit or complex unit.Simultaneously, the preparation of above-mentioned rapid release unit and slow release unit separately being taken is also included within scope of the present invention.
Pharmaceutical composition of the present invention can be selected but be not limited to following dosage form: single-layer sheet, multilayer tablet, multiple coatings sheet and capsule.In pharmaceutical composition of the present invention, adjuvant is selected as described belowly, but is not limited only to these adjuvants.Diluent is selected from as microcrystalline Cellulose, mannitol, sorbitol or lactose etc.Disintegrating agent is selected from as polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium etc.Binding agent is selected from polyvidone, hypromellose, hyprolose etc.The slow release macromolecular material is selected from ethyl cellulose, polyacrylic resin, cellulose acetate, hypromellose, hyprolose, polyoxyethylene etc.The rapid release coating material is selected from hydroxypropyl emthylcellulose, polyacrylic resin, polyvidone, hyprolose, sodium carboxymethyl cellulose or polyvinyl alcohol etc.Fluidizer is colloidal silica.Lubricant is selected from magnesium stearate, stearic acid, polyethylene glycol 6000 or sodium stearyl fumarate etc.Antiplastering aid is selected from Pulvis Talci or glyceryl monostearate etc.
The multiple dosage form of description is to explanation of the present invention, and scope of the present invention is not limited to these dosage forms.
Another object of the present invention has been to provide the preparation method of the phenolsulfonic acid calcium medicine compound of described high drug load.It is one of following that the method comprises:
(1) multiunit pastille slow-release coated pellets and the mixing of pastille rapid release substrate are pressed into single-layer sheet
Formula:
After calcium dobesilate (1), diluent, disintegrating agent are mixed, use the binding agent wet granulation, 40 to 60 ℃ of dryings make the pastille immediate-release granules.After calcium dobesilate (2), mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille piller, after 40 to 60 ℃ of dryings, coordinate the slow release macromolecular material to carry out coating to the pastille piller with antiplastering aid, make the pastille slow-release micropill.To be pressed into single-layer sheet after the pastille immediate-release granules that make, pastille slow-release micropill, diluent, binding agent, disintegrating agent, fluidizer, mix lubricant.
(2) one deck immediate release drug layer and one deck slow releasing pharmaceutical are laminated into double-layer tablet
Formula:
。
After calcium dobesilate (1), diluent, disintegrating agent are mixed, add mix lubricant to make the release layer final mixture.After calcium dobesilate (2), mixing diluents, use the binding agent wet granulation, 40 to 60 ℃ of dryings add slow release macromolecular material, lubricant, are mixed and made into the slow release layer final mixture.Use the double-layer tablet tablet machine that two parts final mixture is pressed into double-layer tablet.
(3) the multiple coatings sheet of one deck pastille rapid release coatings and one deck sustained release coating layer is arranged
Formula:
。
After calcium dobesilate (1), mixing diluents, use the binding agent wet granulation, drying makes immediate-release granules, is pressed into label after adding fluidizer, mix lubricant; Coordinate the slow release macromolecular material to carry out coating to containing tablet with antiplastering aid, make the sustained release coating sheet; Calcium dobesilate (2), rapid release coating material are dissolved in water, this solution bag to the sustained release coating sheet, is formed pastille rapid release coatings; Wrap one deck rapid release coatings as protective layer with the rapid release coating material outside pastille rapid release coatings, make the multiple coatings sheet.
(4) multiunit sustained release coating piller is filled with into capsule with the multiple-unit release pills.
Formula:
。
After calcium dobesilate (1), mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille release pills, after 40 to 60 degree dryings, makes the pastille release pills; After calcium dobesilate (2), mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille release pills, after 40 to 60 degree dryings, coordinate the slow release macromolecular material to carry out coating to the pastille release pills with antiplastering aid, make slow-release micro-pill.With the release pills that makes with fill with into capsule after slow-release micro-pill mixes.
(5) one or more fast-release tablets are filled with into capsule with one or more sustained-release matrix tablets.
Formula:
。
After calcium dobesilate (1), mixing diluents, use the binding agent wet granulation, drying makes immediate-release granules, is pressed into fast-release tablet after adding fluidizer, mix lubricant; After calcium dobesilate (2), mixing diluents, use the binding agent wet granulation, drying is made slow releasing tablet after adding slow release macromolecular material, mix lubricant; According to dosage need, one or more fast-release tablets are filled with into capsule with one or more sustained-release matrix tablets.
The described preparation method that contains drug particles of the inventive method comprises wet granulation process and dry granulation method, but is not limited to this two kinds of methods.
Wet granulation method:
(1) with after calcium dobesilate, mixing diluents, use binding agent, use the High Speed Stirring Machine wet granulation; Or
(2) diluent is loaded in fluid bed, calcium dobesilate and binding agent are dissolved in solution, be sprayed onto on diluent and granulate.
Dry granulation method:
(1) with after calcium dobesilate, binding agent and mixing diluents, granulate with dry granulating machine; Or
(2) will be pressed into sheet after calcium dobesilate, binding agent, diluent, fluidizer and mix lubricant, then use the granulator granulation.
The preparation method of the described pastille micropill of the inventive method comprises and extrudes spheronization, solution medicine-feeding method and powder medicine-feeding method, but is not limited to this three kinds of methods.
The described spheronization of extruding is with after calcium dobesilate, mixing diluents, makes wet stock with the binding agent wet method, uses extruder that wet stock is extruded into strip, and Aspect Ratio is 4: 1-20: 1, then throw the disconnected round as a ball pastille piller made from spheronizator.
Described solution medicine-feeding method is that celphere is put into the fluid bed preheating, and the solution that contains calcium dobesilate and binding agent that then will prepare is sprayed onto on preheated celphere, and drying is made the pastille piller.
Described powder medicine-feeding method is that celphere is put into the fluid bed preheating, then respectively the solution of phenolsulfonic acid calcium powder and binding agent is sprayed onto on preheated celphere, and drying is made the pastille piller.
After product of the present invention is taken, discharge rapidly in the early stage the medicine of certain predose, onset rapidly.Then continue in vivo slowly to discharge remaining medicine, keep effective blood drug level of long period.Owing to having adopted slow controlled-release technology, improve the bioavailability of medicine, reduce poison and pay effect.
According to Chinese Pharmacopoeia dissolution detection method, use the oar method, in pH6.8 buffer solution, immediate release section discharged rapidly in 30 minutes, and the time remaining that slow-released part slowly discharges was by 12-20 hour.It is as follows that comprehensive two parts discharge result:
Burst size 15% to 50% in 30 minutes
Burst size 20% to 60% in 1 hour
Burst size 50% to 90% in 8 hours
Burst size was more than 80% in 16 hours.
Because the unit dose of phenolsulfonic acid calcium preparation is larger, the present invention is divided into immediate release section and slow-released part with the calcium dobesilate Pharmaceutical composition, medicine is had relatively more in the early stage to be discharged, solved the excessively slow problem of drug effect, simultaneously, due to the minimizing of slow-released part calcium dobesilate amount, make as long as slow-release auxiliary material relatively still less just can reach good slow release effect, avoided the weight of formulation of unit dose too large, the problem of dysphagia.Larger clinical value is arranged.The inventive method is simple, is suitable for suitability for industrialized production.
The specific embodiment
Raw materials used commercially available the obtaining of following examples.
Embodiment 1
Formula:
Preparation: press the slow-released part prescription, 25 gram hypromelloses are made into 10% aqueous solution, with 450 gram calcium dobesilates, 25 gram microcrystalline Cellulose mix homogeneously, aqueous solution with hypromellose E3 makes wet stock in High Speed Stirring Machine, use is extruded spheronizator wet stock is extruded the round as a ball pastille micropill (extrusion screen cloth 1.0mm) that makes, with pastille micropill under 50 ℃ dry 2-4 hour, the micropill of collecting between 0.4mm-1.4mm after dry was fast release micropill; The another coating aqueous dispersion that polyacrylic resin NE30D (30% solid content) and the 50 gram Pulvis Talci of 167 grams are made into 20% solid content carries out coating to the pastille micropill of collecting, and makes the sustained release coating micropill.
By the immediate release section prescription; with 85 gram hypromellose E3,15 gram polyvinylpolypyrrolidone and 500 gram calcium dobesilate mix homogeneously, add 120 gram purified water wet granulation in High Speed Stirring Machine, under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry, make immediate-release granules.
Get granule 48 grams after the immediate release section drying, slow-released part coated micropill 480 grams, 4 gram silicon dioxide and 2 gram magnesium stearate mix after tabletting.
Embodiment 2:
Formula:
Preparation: 15 gram hypromellose E6 of slow-released part are made into 10% aqueous solution; aqueous solution with hypromellose E6 is granulated 300 gram calcium dobesilates in High Speed Stirring Machine; under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry; after dried particles after sieving, 100 gram hypromellose K15M, 4 gram silicon dioxide and 1 gram magnesium stearate are mixed, standby.
10 gram hypromellose E6 and 200 gram calcium dobesilate mix homogeneously with immediate release section; add 80 gram purified water wet granulation in High Speed Stirring Machine; under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry; after dried particles after sieving, 2 gram silicon dioxide and 0.5 gram magnesium stearate are mixed, standby.
Use the double-layer tablet tablet machine with two parts granule in slow-released part account for 60%, immediate release section accounts for 40% ratio and is pressed into double-layer tablet.
Embodiment 3:
Formula:
Preparation: 25 gram hypromellose E3 of slow-released part are made into 10% aqueous solution; with 450 gram calcium dobesilates, 45 gram microcrystalline Cellulose mix homogeneously; aqueous solution with hypromellose E3 makes wet stock in High Speed Stirring Machine; under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry; after rear granule, 4 gram silicon dioxide and the 1 gram magnesium stearate of sieving mixed, tabletting.With the polyacrylic resin NE30D (30% solid content) of 167 grams of slow-released part and the coating aqueous dispersion that 50 gram Pulvis Talci are made into 20% solid content, above-mentioned label is carried out coating, make the sustained release coating sheet.
15 gram polyacrylic resin E100 of immediate release section and 50 gram calcium dobesilate dispersing and dissolvings in 800 gram isopropyl alcohols, are carried out coating to above-mentioned sustained release coating sheet, make the multiple coatings sheet.
15 gram Opadry 85G are made into 20% aqueous dispersion, above-mentioned multiple coatings sheet is carried out the protective coating.
Embodiment 4:
According to the Chinese Pharmacopoeia dissolution detection method, use the oar method, under 50 rev/mins, at 900ml, in 37 degree pH6.8 buffer solution, the bilayer tablet of producing by embodiment 2 is carried out dissolution detect, discharge as follows at each setting-up time point: discharged 46% in 30 minutes, discharged 51% in 1 hour, discharge 65%, 8 hour in 4 hours and discharge release 87% in 77%, 12 hour, discharge 95%, 20 hour in 16 hours and discharge 98%.
Embodiment 5:
Formula:
Preparation: immediate release section 20 gram hypromellose E3 are made into 10% aqueous solution, with 320 gram calcium dobesilates, 60 gram microcrystalline Cellulose mix homogeneously, aqueous solution with hypromellose E3 makes wet stock in High Speed Stirring Machine, use is extruded spheronizator wet stock is extruded the round as a ball pastille micropill (extrusion screen cloth 1.0mm) that makes, with pastille micropill under 50 ℃ dry 2-4 hour, the micropill of collecting between 0.4mm-1.4mm after dry was fast release micropill;
slow-released part 10 gram hypromellose E3 are made into 10% aqueous solution, with 320 gram calcium dobesilates, 60 gram microcrystalline Cellulose mix homogeneously, aqueous solution with hypromellose E3 makes wet stock in High Speed Stirring Machine, use is extruded spheronizator wet stock is extruded the round as a ball pastille micropill (extrusion screen cloth 1.0mm) that makes, with pastille micropill under 50 ℃ dry 2-4 hour, collect the micropill between 0.4mm-1.4mm after dry, 200 gram Aquacoats (30% solid content) are made into the coating aqueous dispersion of 20% solid content, the pastille micropill of collecting is carried out coating, make the sustained release coating micropill.
After the slow-release micro-pill of the fast release micropill of weight ratio 18% and 82% is mixed, fill with into capsule.
Embodiment 6:
Formula:
Preparation: 350 gram calcium dobesilates, 100 gram hypromellose K100M and the 4 gram silicon dioxide of slow-released part were mixed 15 minutes, add 1 gram magnesium stearate to mix 3 minutes, with the stamping of 7mm, make slow releasing tablet.
300 gram calcium dobesilates, 90 gram PVP K30s and the 4 gram silicon dioxide of immediate release section were mixed 15 minutes, add 1 gram magnesium stearate to mix 3 minutes, with the stamping of 3mm, make fast-release tablet.
Weight ratio being accounted for 30% fast-release tablet and weight ratio accounts for 70% slow releasing tablet and fills with into capsule.
Embodiment 7:
Formula:
Preparation: 25 gram hypromellose E3 of slow-released part are made into 10% aqueous solution; aqueous solution with hypromellose E3 is granulated 400 gram calcium dobesilates in High Speed Stirring Machine; under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry; after dried particles after sieving, 80 gram hypromellose K15M, 5 gram silicon dioxide and 1 gram magnesium stearate are mixed, standby.
13 gram hypromellose E3 and 200 gram calcium dobesilate mix homogeneously with immediate release section; add 80 gram purified water wet granulation in High Speed Stirring Machine; under 50 ℃ dry 2-4 hour; cross the 1.4mm screen cloth after dry; after dried particles after sieving, 4 gram silicon dioxide and 1 gram magnesium stearate are mixed, standby.
Use double-layer tablet tablet machine (as Fette 102i) that 1022 milligrams of slow-released part granules and 218 milligrams of immediate release section granules are pressed into double-layer tablet, wherein slow-released part and immediate release section contain respectively calcium dobesilate 800mg and 200mg.
Embodiment 8:
According to the dissolution detection method of Chinese Pharmacopoeia, the double-layer tablet that embodiment 7 is pressed into is detected.
Use the oar method, under 50 rev/mins, in the hydrochloric acid solution of 37 ℃ of 900ml 0.1mol/L, the bilayer tablet of producing by embodiment 7 is carried out dissolution detect, discharge as follows at each setting-up time point: discharged 26%, 1 hour and discharge 35% in 30 minutes, discharged 59% in 4 hours, discharge 77%, 12 hour in 8 hours and discharge release 98% in 89%, 16 hour.
Claims (10)
1. the phenolsulfonic acid calcium medicine compound of a high drug load, is characterized in that, described compositions comprises a kind of immediate release section and a kind of slow-released part, forms with both single unit or complex unit combination in any; Described immediate release section calcium dobesilate amount accounts for the 10%-40% of calcium dobesilate total amount, preferred 20%-30%; Slow-released part calcium dobesilate amount accounts for the 60%-90% of calcium dobesilate total amount, preferred 70%-80%; Contain calcium dobesilate 500-1000mg in the single dose of described compositions, preferred 500mg, 750mg or 1000mg.
2. a kind of phenolsulfonic acid calcium medicine compound of high drug load according to claim 1, is characterized in that, described immediate release section is grouped into by the one-tenth of following weight percent proportioning:
Described slow-released part is grouped into by the one-tenth of following weight percent proportioning:
。
3. phenolsulfonic acid calcium medicine compound according to claim 1, is characterized in that, the rapid release unit of described immediate release section is selected from fast-release tablet or release pills; By the rapid release substrate of powder, granulometric composition or contain single unit or complex unit in the rapid release coatings of quick release coating of medicine; The slow release unit of described slow-released part is selected from sustained-release matrix tablets or does not contain single unit or complex unit in the film-controlled slow-release coatings of medicine; Described pharmaceutical composition is single-layer sheet, multilayer tablet, multiple coatings sheet or capsule.
4. phenolsulfonic acid calcium medicine compound according to claim 2, is characterized in that, described diluent is selected from microcrystalline Cellulose, mannitol, sorbitol or lactose; Disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium; Binding agent is selected from polyvidone, hypromellose or hyprolose; The slow release macromolecular material is selected from ethyl cellulose, polyacrylic resin, cellulose acetate, hypromellose, hyprolose or polyoxyethylene; The rapid release coating material is selected from hydroxypropyl emthylcellulose, polyacrylic resin, polyvidone, hyprolose, sodium carboxymethyl cellulose or polyvinyl alcohol; Fluidizer is colloidal silica; Lubricant is selected from magnesium stearate, stearic acid, polyethylene glycol 6000 or sodium stearyl fumarate; Antiplastering aid is selected from Pulvis Talci or glyceryl monostearate.
5. the preparation method of the phenolsulfonic acid calcium medicine compound of high drug load as claimed in claim 1, is characterized in that, the method is pressed into single-layer sheet for multiunit pastille slow-release coated pellets and pastille rapid release substrate are mixed:
Formula:
Preparation method:
After calcium dobesilate 1, diluent, disintegrating agent are mixed, use the binding agent wet granulation, 40 to 60 ℃ of dryings make the pastille immediate-release granules; After calcium dobesilate 2, mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille piller, after 40 to 60 ℃ of dryings, coordinates the slow release macromolecular material to carry out coating to the pastille piller with antiplastering aid, makes the pastille slow-release micropill; To be pressed into single-layer sheet after the immediate-release granules that make, pastille slow-release micropill, diluent, binding agent, disintegrating agent, fluidizer, mix lubricant.
6. the preparation method of the phenolsulfonic acid calcium medicine compound of high drug load as claimed in claim 1, is characterized in that, the method is for to be laminated into double-layer tablet with one deck immediate release drug layer and one deck slow releasing pharmaceutical:
Formula:
After calcium dobesilate 1, diluent, disintegrating agent are mixed, add mix lubricant to make pastille release layer final mixture; After calcium dobesilate 2, mixing diluents, use the binding agent wet granulation, 40 to 60 ℃ of dryings add slow release macromolecular material, lubricant, are mixed and made into pastille slow-release layer final mixture; Use the double-layer tablet tablet machine that pastille release layer and pastille slow-release layer two parts final mixture are pressed into double-layer tablet.
7. the preparation method of the phenolsulfonic acid calcium medicine compound of high drug load as claimed in claim 1, is characterized in that, the method will be for there being the multiple coatings sheet of one deck pastille rapid release coatings and one deck sustained release coating layer:
Formula:
；
Preparation method:
After calcium dobesilate 1, mixing diluents, use the binding agent wet granulation, drying makes the pastille immediate-release granules, is pressed into sheet after adding fluidizer, mix lubricant; Coordinate slow release macromolecule coating material to carry out coating to containing tablet with antiplastering aid, make the pastille slow-release coated tablet; Calcium dobesilate 2, rapid release coating material are dissolved in water, this solution bag to the sustained release coating sheet, is formed pastille rapid release coatings; Wrap one deck rapid release coatings as protective layer with the rapid release coating material outside pastille rapid release coatings, make the multiple coatings sheet.
8. the preparation method of the phenolsulfonic acid calcium medicine compound of high drug load as claimed in claim 1, is characterized in that, the method is for to fill with into capsule with multiunit pastille slow-release coated pellets with multiple-unit pastille release pills:
Formula:
；
Preparation method:
After calcium dobesilate 1, mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille release pills, after 40 to 60 degree dryings, makes the pastille release pills; After calcium dobesilate 2, mixing diluents, make wet stock with the binding agent wet method, use is extruded spheronizator and is made the pastille release pills, after 40 to 60 degree dryings, coordinate the slow release macromolecular material to carry out coating to the pastille release pills with antiplastering aid, make the pastille slow-release micropill; With the pastille release pills that makes with fill with into capsule after the pastille slow-release micropill mixes.
9. the preparation method of the phenolsulfonic acid calcium medicine compound of the described high drug load of claim 1, is characterized in that, the method is for to fill with into capsule with one or more pastille fast-release tablets with one or more pastille slow-release matrix tablets:
Formula:
Preparation method:
After calcium dobesilate 1, mixing diluents, use the binding agent wet granulation, drying makes the pastille immediate-release granules, is pressed into the pastille fast-release tablet after adding fluidizer, mix lubricant; After calcium dobesilate 2, mixing diluents, use the binding agent wet granulation, drying is made the pastille slow-release sheet after adding slow release macromolecular material, mix lubricant; One or more fast-release tablets are filled with into capsule with one or more sustained-release matrix tablets.
10. the preparation method of the phenolsulfonic acid calcium medicine compound of the described high drug load of any one according to claim 5-9, is characterized in that, the described preparation that contains drug particles comprises wet granulation process or dry granulation method; Described wet granulation method is:
(1) with after calcium dobesilate, mixing diluents, use binding agent, use the High Speed Stirring Machine wet granulation; Or
(2) diluent is loaded in fluid bed, calcium dobesilate and binding agent are dissolved in solution, be sprayed onto on diluent and granulate;
Described dry granulation method is:
(1) with after calcium dobesilate, binding agent and mixing diluents, granulate with dry granulating machine; Or
(2) will be pressed into sheet after calcium dobesilate, binding agent, diluent, fluidizer and mix lubricant, then use the granulator granulation;
The preparation method of described pastille micropill is selected from spheronization, solution medicine-feeding method or the powder medicine-feeding method extruded; The described spheronization of extruding makes wet stock for after calcium dobesilate, mixing diluents with the binding agent wet method, uses extruder that wet stock is extruded into strip, and Aspect Ratio is 4: 1-20: 1, then throw the disconnected round as a ball pastille piller made from spheronizator; Described solution medicine-feeding method is for to put into the fluid bed preheating with celphere, and the solution that contains calcium dobesilate and binding agent that then will prepare is sprayed onto on preheated celphere, and drying is made the pastille piller; Described powder medicine-feeding method is for to put into the fluid bed preheating with celphere, then respectively the solution of phenolsulfonic acid calcium powder and binding agent is sprayed onto on preheated celphere, and drying is made the pastille piller.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104421769A CN103169679A (en) | 2011-12-26 | 2011-12-26 | Calcium dobesilate medical composition with high drug loading capacity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104421769A CN103169679A (en) | 2011-12-26 | 2011-12-26 | Calcium dobesilate medical composition with high drug loading capacity |
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| CN103169679A true CN103169679A (en) | 2013-06-26 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018154161A1 (en) * | 2017-02-22 | 2018-08-30 | Belac Invest, S.L. | Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of personalised supply units and the corresponding manufacturing method |
| CN117257747A (en) * | 2023-11-21 | 2023-12-22 | 泊诺(天津)创新医药研究有限公司 | Bupropion hydrochloride tablet and preparation method thereof |
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| US20070010581A1 (en) * | 2002-11-29 | 2007-01-11 | Jose Esteve-Soler | Use of 2,5-dihydroxybenzenesulfonic compounds for the treatment of disorders based on an impairment of no production and/or of regulation of edhf function |
| CN101953833A (en) * | 2009-07-13 | 2011-01-26 | 天津药物研究院 | Slowly-controlled release formulation containing rizatriptan benzoate, preparation method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070010581A1 (en) * | 2002-11-29 | 2007-01-11 | Jose Esteve-Soler | Use of 2,5-dihydroxybenzenesulfonic compounds for the treatment of disorders based on an impairment of no production and/or of regulation of edhf function |
| CN101953833A (en) * | 2009-07-13 | 2011-01-26 | 天津药物研究院 | Slowly-controlled release formulation containing rizatriptan benzoate, preparation method and application thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018154161A1 (en) * | 2017-02-22 | 2018-08-30 | Belac Invest, S.L. | Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of personalised supply units and the corresponding manufacturing method |
| ES2680293A1 (en) * | 2017-02-22 | 2018-09-05 | Belac Invest, S.L. | Pharmaceutical composition comprising 2,5-dihydroxybenzenesulfonic acid or a pharmaceutically acceptable salt thereof in the form of individualized delivery units and corresponding manufacturing process (Machine-translation by Google Translate, not legally binding) |
| CN110290784A (en) * | 2017-02-22 | 2019-09-27 | 博拉克投资有限公司 | In the pharmaceutical composition and corresponding manufacturing method comprising 2,5- dihydroxy benzenes sulfonic acid or its pharmaceutically acceptable salt of personalized supply unit form |
| CN117257747A (en) * | 2023-11-21 | 2023-12-22 | 泊诺(天津)创新医药研究有限公司 | Bupropion hydrochloride tablet and preparation method thereof |
| CN117257747B (en) * | 2023-11-21 | 2024-01-30 | 泊诺(天津)创新医药研究有限公司 | Bupropion hydrochloride tablet and preparation method thereof |
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Application publication date: 20130626 |