CN103040720A - Insoluble matrix controlled-release preparation - Google Patents
Insoluble matrix controlled-release preparation Download PDFInfo
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- CN103040720A CN103040720A CN 201110315119 CN201110315119A CN103040720A CN 103040720 A CN103040720 A CN 103040720A CN 201110315119 CN201110315119 CN 201110315119 CN 201110315119 A CN201110315119 A CN 201110315119A CN 103040720 A CN103040720 A CN 103040720A
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Abstract
The invention belongs to the technical field of medicines, discloses a design method of the formulation of an insoluble matrix controlled-release preparation by applying a pharmaceutical compound or the salt of the pharmaceutical compound, and provides a preparation way of the controlled-release product. The controlled-release preparation is especially suitable for medicine products with medium or high drug loading capacity. The invention provides a platform of preparation design, and is especially suitable for 1) the medicine products with medium to high dosage and 2) the design of medicine controlled-release formulation with the medium to high medicine solubility.
Description
Technical field
The invention belongs to medical technical field, related to a kind of controlled release preparation method for designing and preparation method that is applicable to oral administration.Be specifically related to a kind of be applied to medical compounds or its salt the pharmaceutical formulation method for designing of insoluble framework controlled release administration, and provide the preparation method of this controlled release product.The invention provides the platform of a kind of preparation design, be specially adapted to 1) in the drug products of high dose by the time; 2) drug solubility is therefrom waited until high medicine controlled releasing dosage form design.
Background technology
Most of oral drugs in the market belong to rapid release plain film dosage form, often need repeatedly take every day.For the rapid release plain film, product immediately disintegrate and stripping release in stomach were absorbed subsequently after clothes were lower.The typical pharmacokinetic curve of immediate release drug is blood drug level in just reaching the most substantially after taking medicine in the short period, and fast-descending arrives the lowest point level afterwards, and the situation of quick rising, fast-descending can appear in blood drug level again after the administration next time.In many cases, this causes the drug level in the patient body undesirable fluctuation to occur thereby can not reach best therapeutic effect.In addition, vivo medicine concentration is too high may cause various side effect.In many cases, low patient's compliance has all fallen in medication number of times and side effect, thereby affects drug effect.
Many medicines be well in the control volume blood drug level a more constant level to reach desirable therapeutic effect.Normally use controlled release form obtain 12 hours or the longer time in discharge gradually in vivo medicine.Compare with traditional quick releasing formulation, controlled release preparation provides a lot for the treatment of advantages, as patient's fitness improves greatly after the frequency reduction of taking medicine, and stable blood drug level has improved drug effect, lowered toxic and side effects, the dosage of slow release formulation is often low than the rapid release plain film, thereby safer.
Dissimilar medicines has different controlled release form methods for designing.The medicine that dissolubility is very low because its bioavailability is limited by dissolution, has the controlled release attribute in essence.For the medium medicine of dissolubility, its controlled release design can be used various models, such as DIFFUSION CONTROLLED MODEL, stripping model, osmotic pumps etc.The medicine high to dissolubility, the design of controlled release preparation become very challenging.In order to reach controlled-release effect, drug loading remains in the lower scope usually, because the stronger diffusion motive power that needs the adjuvant of the more control rate of release of use to bring to offset the drug solubility height.
The matrix type controlled release preparation is a kind of controlled release drug product design scheme commonly used: high polymer adjuvant forms skeleton, and medicine, release rate modifier and other adjuvants evenly distribute wherein.In the drug-eluting process, the solubility skeleton is released by slow corrosion medicine thereupon; And the interior medicine of insoluble skeleton progressively dissolves and is released to external diffusion by the passage between skeleton.In conventional formulation, the high drug load product, namely drug loading reaches more than 50%, is to be difficult to obtain the control releasing effect.Along with using of the new technology, such as the development of hot-melt extruded technology and the application of novel high polymer adjuvant, drug loading also has report up to 80% product.But the high-dissolvability of high drug load and drug molecule is each other restriction often, is difficult to realize in same product.
Controlled release preparation technology platform patent has various designs.A kind of medicine controlled releasing pump such as patent US5209746.Pharmaceutical pack is rolled in the macromolecule coating.A macromolecule area that can absorb water and an independent medicament region are arranged in the coating.A micropore is arranged as the drug release passage on the coating of medicament region.Including high polymer adjuvant imbibition promotion medicine discharges by micropore.This class design can keep the zero level of medicine to discharge, but drug loading is limited.It is the controlled release preparation of skeleton that patent US4657757 has designed a kind of hydroxyl second methylcellulose.This is a kind of common controlled release preparation method for designing.The medicine one side discharges along with the corrosion of skeleton to the external diffusion one side, is highly suitable for the common medicine of dissolubility.Patent US6058854 has designed a kind of lower controlled release preparation technology of dissolubility that is applicable to.Gelatin is used as skeleton and forms adjuvant.The medicine of indissoluble discharges by the corrosion of gelatin skeleton.
Summary of the invention
The present invention relates to the medicine preparation prescription, can be implemented in drug molecule or its salt of continuous release in external and the body.The purpose of this invention is to provide a kind of new pharmaceutical preparation prescription and preparation method thereof, can be used for 1) for medium or high a kind of slow release formulation prescription of drug provision and the preparation method of dissolubility, 2) index method of the form formula of the product of high drug load by the time in the preparation.
The present invention relates to the controlled release preparation prescription.In one embodiment, the prescription of the controlled release formulations for oral administration of medicine of the present invention or its salt comprises
A) medical compounds or its pharmaceutically acceptable salt of therapeutic activity are arranged,
B) can form the water-fast high polymer adjuvant of skeleton,
C) be used for slightly soluble or the insoluble adjuvant of adjustment release speed
D) lubricant and/or fluidizer.
In another embodiment, the prescription of the controlled release formulations for oral administration of medicine of the present invention or its salt comprises
A) medical compounds or its pharmaceutically acceptable salt of therapeutic activity are arranged,
B) can form the water-fast high polymer adjuvant of skeleton,
C) be used for the lower or insoluble adjuvant of solubility of adjustment release speed,
D) one or more bulking agents,
E) lubricant and/or fluidizer.
In yet another embodiment, the prescription of the controlled release formulations for oral administration of medicine of the present invention or its salt comprises
A) medical compounds or its pharmaceutically acceptable salt of therapeutic activity are arranged,
B) can form the water-fast high polymer adjuvant of skeleton,
C) be used for slightly soluble or the insoluble adjuvant of adjustment release speed
D) for the plasticizer that improves hot-melt extruded process effect,
E) lubricant and/or fluidizer.
Wherein, drug molecule or its salt have medium or high dissolubility.And product can have higher drug loading.
In other embodiment, the prescription of the controlled release formulations for oral administration of medicine of the present invention or its salt comprises
A) medical compounds or its pharmaceutically acceptable salt of therapeutic activity are arranged,
B) can form the water-fast high polymer adjuvant of skeleton,
C) be used for slightly soluble or the insoluble adjuvant of adjustment release speed
D) for the plasticizer that improves hot-melt extruded process high polymer adjuvant flowability,
E) one or more filleies,
F) lubricant and/or fluidizer.
Wherein, medical compounds or its salt have medium or high dissolubility, and the drug loading of product is between 30-85%.
As follows for the various term definitions of using among the application:
Dissolubility:
" dissolubility " word refers to the quality of the active component that can dissolve in one milliliter solvent in this application.If do not specify, water is the solvent of acquiescence.In addition, the medicine that dissolubility surpasses 10 mg/ml has been considered to high-dissolvability, and the medicine of dissolubility between the 0.5-10 mg/ml is considered to medium dissolubility.
Discharge:
" release " word refers to that a drug oral controlled release product constantly enters the solution of exterior circumferential at the process Chinese medicine molecule with extraneous fluid contact in this application.A given dosage form is namely called its in vivo release with certain speed stripping drug molecule in human body in the inherent regular hour.The release of dosage form may be different speed and/or different sustained release time, may be continuous, also may be pulsed.
Drug loading:
" drug loading " is the mass percent that the medicine of therapeutic activity is arranged in final drug products in this application.In addition, drug loading is equal to or higher than 50% and is considered to high drug loading.
The rapid release plain film:
" rapid release plain film " refers to discharge immediately the reagent combination of drug molecule in this application, and namely form formula of special design does not have the release of the drug molecule of therapeutic activity with control.
Controlled release:
" controlled release " refers to that drug products uses special pharmaceutical formulation design or/and manufacture method can be pacified according to required speed release, even also medicine discharges its active component in a long time active drug molecule or its salt within the required time in this application.Generally speaking, the controlled release that is used in the present patent application refers to that drug molecule surpasses 5 hours, preferably 12 hours or higher release time.This controlled release preparation has multiple design, the kernel that contains medicine such as the coating parcel by controlled pharmacy diffusion rate is controlled drug release rate, perhaps prepare the framework formula that homogeneous distributes, control drug release rate by the speed that erosion rate or the drug molecule of skeleton diffuses out insoluble skeleton.
Direct compression:
" direct compression " refers to direct compression after medicine or its salt and the even mixing of other adjuvants is made the process of finished product in this application.
Wet granulation
" wet granulation " refers to the process that a solid powder particle increases among the application, and namely medicine or its salt and other adjuvants mix limit spray water or aqueous or solvent borne binder solution, pressed powder formation bulky grain bonded to each other in shear action bottom usually.Subsequently, through wet screening, dried and screened, produce the granule with better processing performance, such as large, the few electric charge of particle diameter, moderate density and compressibility, and better flow etc.
Dry granulation
" dry granulation " refers to the process that a solid powder particle increases among the application, and namely medicine or its salt and other adjuvants are bonded to each other by the mode of compacting, forms bulk or band.Compacting material out subsequently by chopping, produce the granule with better processing performance, such as large, the few electric charge of particle diameter, moderate density and compressibility, and better flow etc.
Melt granulation
" melt granulation " refers to the process that a solid powder particle increases among the application, and namely medicine or its salt and other adjuvants are extruded after usually at high temperature fully mixing and formed band or larger fragment.Subsequently, through cooling, shred and sieve, produce the granule with better processing performance, such as large, the few electric charge of particle diameter, moderate density and compressibility, and better flow etc.Granule mixes necessary extra particulate adjuvant, and is lubricated, and compression in flakes.Further " hot-melt extruded " is a kind of melt granulation process, thereby its Chinese medicine and adjuvant partly or entirely melt under high temperature and high shear, mix showing and increase medicine and the interaction of adjuvant on molecular level, thereby make the maximizing efficiency of skeleton shape material.
Diffusion
Among the application " diffusion " refer to that drug molecule passes the process that medium molecule enters low concentration region from high concentration region under dissolved state.
Corrosion:
Among the application " corrosion " be used for describing the medicine finished product in dissolution medium or body without disintegrate, but gradually by liquid wearing and tearing, corrode this process of final complete obiteration.
The present invention relates to a kind of method for designing of oral controlled-release tablet form prescription of medicine.This controlled release tablet contains drug molecule or its salt, forms the insoluble high polymer adjuvant of skeleton, slightly soluble or the water-fast adjuvant of control rate of release, and required adjuvant such as filler, lubricant and/or the fluidizer etc. of other tablettings.The preferred dosage form component design contains drug molecule or its salt, form the insoluble high polymer adjuvant of skeleton, slightly soluble or the water-fast adjuvant of control rate of release, the adjuvant that the plasticizer of improvement hot melt effect and other preparation tablets are required such as filler, lubricant, fluidizer etc.
Controlled release tablet involved in the present invention can be used conventional preparation method manufacturing.Granulate such as direct compression process, wet granulation process, dry granulation method or hot melt.Direct compression process is simple, is applicable to the lower and medicine material physical property of drug loading and is suitable for the medicine of direct processing.Make the wet granulation of water or organic solvent, particularly organic or mixed solvent wet granulation has one's own knack in processing high solubility agents and high polymer adjuvant, and the example of wet granulation is as described below.Further example comprises dry granulation.This process as described below avoids using liquid and dry run, Simple energy-saving, and process is easy to regulate.The hot-melt extruded method of granulating is preferred, because this technique avoids using liquid and extra dry run on the one hand, mixing under high-temperature and the high shear force is showing the mixing efficiency that has improved medicine and skeleton formation adjuvant and adjusting sustained release rate adjuvant on the other hand, make the maximizing efficiency of controlled release adjuvant, thereby make the product of high drug load become possibility.
The adjuvant that controlled release tablet is used among the present invention includes but are not limited to, and diluent or filler, binding agent, flowable, skeleton form adjuvant, plasticizer, lubricant and the combination thereof of high polymer adjuvant, control rate of release.
Suitable filler includes but not limited to, derivant, calcium hydrogen phosphate, low-substituted hydroxypropyl cellulose (L-HPC), hydroxyethyl-cellulose, the hydroxypropyl emthylcellulose of microcrystalline Cellulose, mannitol, sucrose or other saccharides or sugar, and combination.Be preferably microcrystalline Cellulose.In the present invention the amount ranges of filler be account for sheet heavy 1% to 40%, preferable range be account for sheet heavy 5% to 30%.
The high polymer adjuvant of the suitable insoluble skeleton of formation is including, but not limited to ethyl cellulose, polyethylene, polypropylene, polrvinyl chloride, hydroxyethylmethyl-cellulose, polymethacrylates, ethene-vinyl acetate (EVA) copolymer, sodium carboxymethyl cellulose, cellulose acetate-phthalate, polyvinyl acetate phthalic acid, cellulose acetate, chitosan, hypromellose phthalate, hypromellose, hypromellose acetic acid succinic acid, polymethyl methacrylate, poly hydroxy ethyl acrylate and combination thereof.The amount ranges that forms in the present invention the high polymer adjuvant of insoluble skeleton be account for sheet heavy 1% to 40%, preferable range be account for sheet heavy 5% to 30%.
The slightly soluble or the insoluble regulator that are fit to the regulating medicine rate of release include but not limited to methylcellulose (low substituting), ethyl cellulose (substitution degree is less than 1.8), hydroxypropyl emthylcellulose (hypromellose), hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, Eudragit RS and combination thereof.The amount ranges that forms in the present invention the regulator of regulating medicine rate of release be account for sheet heavy 1% to 40%, preferable range be account for sheet heavy 5% to 30%.
Suitable plasticizer includes but not limited to polyethylene glycol (PEG) (such as PEG400), water, Sorbitol, maltose alcohol, xylitol, triacetyl glycerine, triethyl citrate, decanedioic acid and combination thereof.In the present invention the amount ranges of plasticizer be account for sheet heavy 1% to 20%, preferable range be account for sheet heavy 2% to 10%.
Suitable granulation liquid includes but not limited to water, ethanol, isopropyl alcohol and composition thereof.The mixture of water and ethanol preferably, preferred mixed proportion is from 50%/50% to 1%/99% (mass percent).
In first embodiment, the drug oral controlled release form of inventing is tablet form.Further embodiment of the present invention is the preparation process of controlled release tablet.For example, a tablet can be made via following direct compression technique: (1) fully mixes required medicine, form the adjuvant of insoluble skeleton, the slightly soluble of regulating medicine rate of release or insoluble regulator and other adjuvants such as filler, lubricant etc., 2) tabletting.Concrete adjuvant is selected above to list.
The preparation of controlled release tablet also can be via following wet granulation technology manufacturing: (1) fully is mixed with the required medicine of granule, form slightly soluble or insoluble regulator and other adjuvants such as the filler etc. of the adjuvant regulating medicine rate of release of insoluble skeleton, then add while stirring suitable granulation liquid, form the controlled release wet granular; (2) optional suitable drying means oven dry wet granular; (3) sieve; (4) optionally mix such as filler, fluidizer, lubricant etc. with outside adjuvant; (5) tabletting.The selection of concrete adjuvant and granulation liquid is above listed.
The selection process of controlled release tablet preparation is to use dry granulation: (1) fully is mixed with the required medicine of granule, forms preparation composite material (2) composite materials such as the slightly soluble of adjuvant regulating medicine rate of release of insoluble skeleton or insoluble regulator and other adjuvants such as filler, fluidizer, lubricant and sieves; (3) again mix the rear material that sieves, formed final compound; (4) composite material is pressed into silver or piece/large grain; (5) smash and sieve and obtain being suitable for the granule of tabletting; (6) mix with outside adjuvant, such as filler, fluidizer and lubricant etc.; (7) tabletting.Concrete adjuvant is selected above to list.
To use the hot-melt extruded granulation in another preferred controlled release tablet preparation technology.Hot-melt extruded is granulated and normally undertaken by making in the following method: (1) fully is mixed with the required medicine of granule, form the slightly soluble of adjuvant, regulating medicine rate of release of insoluble skeleton or insoluble regulator, plasticizer and other adjuvants such as filler, fluidizer, lubricant etc., form a kind of composite material; (2) melt extrude composite material; (3) extrudate cool to room temperature, (4) fall the extrudate of cooling and smash, are screened into granule; (5) mix with outer adjuvant, such as plasticizer and other adjuvants such as filler, fluidizer, lubricant; (6) tabletting.Concrete adjuvant is selected above to list.
In the insoluble framework controlled release piece preparation method that the present invention proposes, with the obvious advantage in subsequent technique is processed by the granule that the hot-melt extruded legal system is standby, and also the quality of the final products of making is also the most stable.In addition, the standby medicine of hot-melt extruded legal system can be realized than other three kinds of methods high drug loading all.Therefore, the extra advantage of hot-melt extruded method of granulating is the size that can be used for reducing tablet, thereby improves patient's compliance.
Beneficial effect of the present invention
The invention has the advantages that controlled release form design not only provides practicable recipe design scheme to the high drug load product, and covering scope is wide, namely from medium drug loading to high drug load very.Preparation technology is simple and clear simultaneously, is easy to amplify, and is suitable for commercial production.
The specific embodiment
In the specific embodiment below the present invention is further specified, but do not limit the present invention.
Embodiment one dry granulation prepares the salicylic acid controlled release tablet
| The milli g/piece | The % mass percent | |
| Salicylic acid | 240 | 40 |
| Hydroxypropyl methylcellulose K100M | 156 | 26 |
| Ethyl cellulose | 180 | 30 |
| Sodium carboxymethyl cellulose | 18 | 3 |
| Magnesium stearate | 6 | 1 |
| Amount to | 600 | 100 |
Salicylic acid controlled release tablet prescription sees the above table.Salicylic acid, hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose and part of stearic acid magnesium placed be mixed and made into compound in the blender.Compound is added the roll dry granulating machine roll slivering.The compacting bar is smashed the granulation that sieves.Granule and remaining lubricant placed in the blender be pressed into tablet with rotary tablet machine behind the mix homogeneously.
Embodiment two dry granulations prepare the salicylic acid controlled release tablet
| The milli g/piece | The % mass percent | |
| Salicylic acid | 240 | 40 |
| Ethyl cellulose | 180 | 30 |
| Hydroxypropyl methylcellulose K100M | 90 | 15 |
| Calcium hydrogen phosphate | 84 | 14 |
| Magnesium stearate | 6 | 1 |
| Amount to | 600 | 100 |
Salicylic acid controlled release tablet prescription sees the above table.Salicylic acid, hydroxypropyl methylcellulose and cellulose, calcium hydrogen phosphate and part of stearic acid magnesium placed be mixed and made into compound in the blender.Compound is added the roll dry granulating machine roll slivering.The compacting bar is smashed the granulation that sieves.Granule and remaining lubricant placed in the blender be pressed into tablet with rotary tablet machine behind the mix homogeneously.
The standby mycophenolic acid slow releasing tablet of embodiment three hot-melt extruded legal systems
Mycophenolic acid controlled release tablet prescription sees the above table.Mycophenolic acid, ethyl cellulose, Kollidon VA64, sorbitol and a minute magnesium stearate placed be mixed and made into compound in the blender.Compound is added hot-melt extruded granulator roll slivering.The compacting bar is smashed the granulation that sieves.Granule and remaining lubricant placed in the blender be pressed into tablet with rotary tablet machine behind the mix homogeneously.
The standby mycophenolic acid slow releasing tablet of embodiment four hot-melt extruded legal systems
| The milli g/piece | The % mass percent | |
| Mycophenolic acid | 480 | 80 |
| Ethyl cellulose | 28 | 13 |
| Eudragit E udragit RS PO | 24 | 4 |
| Maltose alcohol | 12 | 2 |
| Magnesium stearate | 6 | 1 |
| Amount to | 600 | 100 |
Mycophenolic acid controlled release tablet prescription sees the above table.Mycophenolic acid, ethyl cellulose, Eudragit RS, maltose alcohol and part of stearic acid magnesium placed be mixed and made into compound in the blender.Compound is added hot-melt extruded granulator roll slivering.The compacting bar is smashed the granulation that sieves.Granule and remaining lubricant placed in the blender be pressed into tablet with rotary tablet machine behind the mix homogeneously.
Claims (16)
- A kind of insoluble framework controlled release preparation1. oral insoluble framework controlled release pharmaceutical formulation, it is characterized in that containing following several main component: a) one or more have medicine or its salt of clinical therapeutic efficacy; B) can form the insoluble macromolecular material adjuvant of skeleton; C) one or more slightly solubles or insoluble adjuvant are as the regulator of regulating medicine rate of release; D) other adjuvants that need.
- 2. oral insoluble framework controlled release pharmaceutical formulation, it is characterized in that containing following several main component: a) one or more have medicine or its salt of clinical therapeutic efficacy; B) can form the insoluble macromolecular material adjuvant of skeleton; C) the lower or insoluble adjuvant of one or more water solublity is as the regulator of regulating drug rate of release; D) one or more are for increasing the plasticizer of macromolecular material flowability in the heat treatment process; E) other required adjuvants.
- 3. according to claim 1,2 described pharmaceutical formulations, it is characterized in that having the medicine of clinical therapeutic efficacy or its salt that medium above water solublity is arranged, namely in the water dissolubility more than or equal to 0.5 mg/ml.
- 4. according to claim 1,2 described pharmaceutical formulations, it is characterized in that having the medicine of clinical therapeutic efficacy or its salt that highly-water-soluble is arranged, namely in the water dissolubility more than or equal to 10 mg/ml.
- 5. according to claim 1,2 described pharmaceutical formulations, it is characterized in that having the medicine of clinical therapeutic efficacy or its salt is 30% to 85% in the mass percent that final preparation produces in the crystalline substance, preferred mass percentage ratio is 50% to 85%.
- 6. according to claim 1,2 described pharmaceutical formulations, the mass percent of insoluble macromolecular material adjuvant in final formulation products that it is characterized in that forming skeleton is 5% to 50%.
- 7. according to claim 1,2 described pharmaceutical formulations, it is characterized in that slightly soluble or the water-fast drug release rate regulator mass percent in final formulation products is 5% to 50%.
- 8. pharmaceutical formulation according to claim 2 is characterized in that the mass percent of plasticizer agent in final formulation products is 1% to 20%.
- 9. according to claim 1,2 described pharmaceutical formulations, it is characterized in that employed insoluble skeleton forms the macromolecular material adjuvant including, but not limited to ethyl cellulose, polyethylene, polypropylene, polrvinyl chloride, hydroxyethylmethyl-cellulose, polymethacrylates, ethene-vinyl acetate (EVA) copolymer, sodium carboxymethyl cellulose, cellulose acetate-phthalate, the polyvinyl acetate phthalic acid, cellulose acetate, chitosan, the hypromellose phthalate, hypromellose, hypromellose acetic acid succinic acid, polymethyl methacrylate, poly hydroxy ethyl acrylate and combination thereof.
- 10. according to claim 1,2 described pharmaceutical formulations, it is characterized in that employed drug release rate regulator includes but not limited to methylcellulose (low substitute), ethyl cellulose (substitution degree is less than 1.8), hydroxypropyl emthylcellulose (hypromellose), hydroxypropyl cellulose, carboxymethyl cellulose rope sodium, hydroxyethyl-cellulose, hydroxypropyl cellulose, Eudragit RS and combination thereof.
- 11. pharmaceutical formulation according to claim 2 is characterized in that employed plasticizer includes but not limited to polyethylene glycol (PEG) (such as PEG400), water, Sorbitol, maltose alcohol, xylitol, triacetyl glycerine, triethyl citrate, decanedioic acid and combination thereof.
- 12. according to claim 1,2 described pharmaceutical formulations, it is characterized in that employed granulation liquid includes but not limited to water, ethanol, isopropyl alcohol and composition thereof.
- 13. pharmaceutical formulation according to claim 1 is characterized in that the solid preparation with the preparation of direct compression technique.
- 14. pharmaceutical formulation according to claim 1 is characterized in that the solid preparation with the wet granulation technology preparation.
- 15. pharmaceutical formulation according to claim 1 is characterized in that the solid preparation with the preparation of dry granulation technique.
- 16. according to claim 1,2 described pharmaceutical formulations, it is characterized in that solid preparation with the hot-melt extrusion process preparation.
Priority Applications (1)
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|---|---|---|---|
| CN 201110315119 CN103040720A (en) | 2011-10-17 | 2011-10-17 | Insoluble matrix controlled-release preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110315119 CN103040720A (en) | 2011-10-17 | 2011-10-17 | Insoluble matrix controlled-release preparation |
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| CN103040720A true CN103040720A (en) | 2013-04-17 |
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| CN 201110315119 Pending CN103040720A (en) | 2011-10-17 | 2011-10-17 | Insoluble matrix controlled-release preparation |
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Application publication date: 20130417 |