CN101269059B - Isosorbide dinitrate oral administration impulse pellet preparations - Google Patents
Isosorbide dinitrate oral administration impulse pellet preparations Download PDFInfo
- Publication number
- CN101269059B CN101269059B CN2007100569474A CN200710056947A CN101269059B CN 101269059 B CN101269059 B CN 101269059B CN 2007100569474 A CN2007100569474 A CN 2007100569474A CN 200710056947 A CN200710056947 A CN 200710056947A CN 101269059 B CN101269059 B CN 101269059B
- Authority
- CN
- China
- Prior art keywords
- layer
- ball core
- rapid release
- preparation
- release ball
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The invention discloses an oral pulse pellet pharmaceutical preparation of isosorbide esters, which consists of an immediate-release pellet core, an alkaline layer and a retardation layer containing isosorbide esters of 10 to 50 mg, wherein, the retardation layer contains polyacrylic resin 3, the weight increment of which is 80 to 200 percent of the immediate-release pellet core; the alkaline layer is a medicinal water-soluble alkaline adjuvant, the weight of which is 10 to 30 percent of the immediate-release pellet core. The pharmaceutical preparation has the characteristics that the drug does not release immediately after being taken orally, releases immediately from the pellet after 3 to 4 hours time lagging and the plasma concentration presents a pulse peak value. The pharmaceutical preparation can achieve the goal of preventing angina pectoris and other diseases from being triggered due to the rise of blood pressure and heart rate within a few hours after a patient awakens and wakes up in the early morning.
Description
Technical field
The present invention relates to the isosorbide dinitrate oral administration preparation, specifically the preparation method of the dosage form of isosorbide dinitrate oral administration impulse pellet preparations composition and said preparation.
Background technology
Along with the research and development of chronopharmacology, the outbreak that it is found that numerous disease all presents tangible circadian rhythm and changes, and especially, cardiovascular disease such as angina pectoris, myocardial infarction, the M ﹠ M of these diseases is the highest in morning.If according to the biorhythm of these seizures of disease, select best administration time, can make medicine when needing most, the maximum therapeutic effect of therapeutic dose performance with minimum farthest reduces toxic and side effects simultaneously.Open-loop system claims intelligent drug delivery system again, is according to chronopharmacology and division of day and night pharmacokinetics principle, regularly discharges the novel form of effective dose medicine.The pulse preparation has ordinary preparation or the incomparable advantage of slow releasing preparation, it can be taken medicine in advance according to the rhythmicity of patient's morbidity, make medicine time and drug release time that a time difference that is complementary with physiological period be arranged, thereby prevention morbidity, reduce the untoward reaction of medicine, and being difficult for producing toleration, improving the compliance of patient, is the new model of modern medicinal agents research.
Angina pectoris is the common sympton of ischemic cardiomyopathy, causes local cardiac blood supply deficiency by coronary atherosclerosis or spasm, the of short duration rapid ischemia of cardiac muscle, the caused clinical syndrome of anoxia.Early morning, intravital catecholamine levels, adrenergic release were increased, thereby systolic pressure, diastolic pressure and heart rate increase when awakening, so normal person's blood pressure is tangible daily rhythmicity, be bimodal-paddy type, promptly night, blood pressure was minimum, getting up early morning, the back is rapid rises, and is the time that oxygen consumption increases.On the basis of coronary artery pathological changes, it is to cause anginal main cause that cardiac muscle needs the increase of blood volume.According to statistics, early morning 6～10 are anginal peak periods, and are identical with the rule round the clock of sudden cardiac death.
If in the angina pectoris attacks peak period (being early morning 6～10 points) 1～2 hour before, medicine can reach effective blood drug level, just can prevent and reduce the generation probability of sudden cardiac death, that is to say and will be in morning 4～5 make drug level reach peak value, owing to can't take medicine in the sleep, this just requires drug-delivery preparation or is slow release, administration before the prerequisite of sleeping; Being exactly to prepare the pulsed administration, also is the preceding administration of prerequisite of sleeping, and can both reach medicine maximum effect concentration before awakening.If adopt the medicament slow release technology: need keep drug level for a long time, take before sleeping and to achieve the above object, but shortcoming is still to keep certain blood drug level in the disease low stage of attack in when sleep, be easy to generate toleration, and blood pressure is lower in the sleep, medication may cause blood pressure further to reduce, and increases hypotensive danger.So ideal mode of administration is the pulsed administration: take medicine before promptly sleeping, a period of time does not discharge medicine, at angina pectoris attacks peak period a large amount of medicines that discharge in early stage, reaches the purpose of prevention and treatment simultaneously, simultaneously can not administration when human body does not need medicine, reduce the toleration of human body to medicine.
Isosorbide dinitrate is a nitrate esters medicine, clinically is used for the treatment of the prevention angina pectoris.Commercially available common, slow release formulation that isosorbide dinitrate is arranged do not seen the pulsed dosage forms that the isosorbide dinitrate medicine is arranged at present.200410030824.X disclose isosorbide dinitrate slow releasing tablet and preparation method thereof; 200510013648.3 disclose isosorbide dinitrate drop pill and preparation method thereof; These patents all do not relate to the medicine-feeding technology that release combines with the division of day and night rule of angina pectoris, outbreak.
CN99814002.3 relates to a kind of many particle release compositions that discharges with pulse or bimodal mode, and the excipient and the composition that contain by the change coatings come sustained release, but preparation technology is complicated; CN02133886.8 discloses a kind of based on the pulsation-releasing preparation of expansion technique in osmotic pump principle, mainly containing core, swelling clothing layer and clothing film three parts forms, penetrate outer water-insoluble clothing film by water, swell layer swelling and make the clothing film release medicine that breaks.CN01804761.0 discloses the particulate timed pulsatile drug delivery systems of being made by one or more beadlet of multiple multiple coatings, except the beadlet of rapid release, each beadlet contains wherein a kind of envelope barrier of two-layered coating envelope barrier at least to be made up of enteric polymer.The composition of polymeric film barrier and thickness have determined the interval that sluggish period and medicine discharge from each beadlet.Use contains the organic acid intermediate coat with sluggish period of further adjusting and/or pharmaceutical release time interval.But the life-time service organic acid has stimulation to gastrointestinal tract.CN200410016125.X discloses a kind of albuterol time control pulse sustained-release oral preparation, and its segment pulse adopts water-soluble or/and enteric material is made block layer, the outer enteric film coat that coats.Though above-mentioned pulse formulation system or the pulse piller technology of preparing of relating to is all inequality with mentality of designing and composition therefor that the present invention adopts, and supplementary material is easy to get, and production technology is simple.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of oral pulsed release system for the treatment of anginal medicine isosorbide dinitrate, the oral back of said preparation medicine does not discharge immediately, but the hysteresis medicine discharges from micropill rapidly when certain, and blood drug level presents the pulsed peak value.Patient is as long as taking a medicine at bedtime, through a period of time (people is in physiological level and hangs down period) not release, 6～10 preceding releases fast of angina pectoris onset peak period in the morning, blood drug level arrives the treatment value rapidly, reach the purpose of prevention and treatment, solved take medicine at the night problem of difficulty of patient simultaneously.
Concrete technical scheme of the present invention is as follows:
A kind of isosorbide dinitrate oral administration impulse pellet preparations is characterized in that said preparation is the multiple coatings preparation, and basic structure is respectively pastille rapid release ball core, alkaline layer and sluggish layer from inside to outside.
The medicine that reaches of the present invention is an isosorbide dinitrate, comprising sorbide nitrate, also comprise its metabolite isosorbide mononitrate, and isosorbide mononitrate effect in the angina pectoris treatment of diseases is more outstanding.The therapeutic dose that sets is generally 10～50mg.The pastille rapid release ball core of being addressed is to be surrounded by the pill core that contains that the celphere of medicine layer or medicine and pharmaceutic adjuvant be mixed with, and the rapid release ball core of being addressed discharges at 1 hour giving drugs into nose and reaches more than 90%.
Above-mentioned isosorbide dinitrate oral administration impulse pellet preparations neutral and alkali layer is necessary, and alkaline layer is a medicinal soluble organic or inorganic basic auxiliary, and weight is 10～30% of pastille rapid release ball core weight.More excellent coating weightening finish alkaline layer is 15～20%.And after basic auxiliary is dissolved, the local pH value that forms should be greater than 7, and available basic auxiliary comprises one or more mixture of sodium carbonate, potassium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium acetate, potassium acetate, ammonium acetate, magnesium acetate, cellulose acetate hydrogen sodium, cellulose acetate hydrogen potassium, cellulose acetate hydrogen ammonium, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium phosphate etc.
Sluggish layer is necessary in the above-mentioned impulse pellet preparation.Mainly contain polyacrylic resin III, sluggish layer is 80～200% with respect to the coating weightening finish of pastille rapid release ball core; Preferred its weightening finish is 100～150%.Sluggish as required layer also contains plasticizer or antiplastering aid: its plasticizer comprises triethyl citrate, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, Oleum Ricini, glycerol, one or more mixture of propylene glycol; Antiplastering aid comprises Pulvis Talci, magnesium stearate, micropowder silica gel, one or more mixture of glyceryl monostearate.Contain weight in the preferred sluggish clothing layer of the present invention and be 60～80 parts polyacrylic resin III, can also contain weight and be antiplastering aid and 0～10 part of plasticizer of 1～10 part.Relevant auxiliary materials of the present invention refers to isosorbide dinitrate and is mixed and made into the rapid release ball core that contains principal agent, for example mixture of one or more of low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sucrose, starch etc.
Sluggish layer and alkaline layer constitute pulse clothing layer jointly in the pulse preparation of the present invention, and wherein sluggish layer and alkaline layer are isolating on physical arrangement, and the position of sluggish layer is at the alkaline layer skin.Control the time of the outside moisture infiltration of thickness (being the weightening finish of coating) may command of sluggish tunic, play a delay effect of 3～4 hours, guarantee that active substance seldom discharges in the given time or seepage (cumulative release is less than 10% of setting dosage); Alkaline layer plays the effect that causes inner active substance pulse release, by the polyacrylic resin III in the dissolving time lag clothing layer, destroy the structure of sluggish tunic, outside moisture can be infiltrated rapidly, the very fast dissolved and diffusion release of active substance, release complete substantially (cumulative release is greater than 90% of setting dosage) rapidly in 3 hours.Experimental result shows: the piller of preparation discharges indifference in water, in simulated gastric fluid (pH=1.0) and the simulated intestinal fluid (pH=6.8), promptly Zhi Bei pulse piller is not subjected to the influence of human gastrointestinal tract pH environment.
The preparation method of isosorbide dinitrate oral administration impulse pellet preparations of the present invention comprises the steps:
(1) preparation pastille rapid release ball core: method one: get some celphere and place in fluid bed or the coating pan, be sprayed on the celphere, promptly with the coating solution that contains isosorbide dinitrate; Method two: according to the method for the common ball core of preparation, isosorbide dinitrate is mixed with relevant auxiliary materials, the employing routine is extruded method such as round as a ball and can be made; Resulting pastille rapid release ball core is measured (900ml water is dissolution medium, basket method, 75 rev/mins) under the conventional capsule leaching condition of pharmacopeia regulation: cumulative leaching rate is greater than 90% in 1 hour;
(2) alkaline layer coating: in the water-soluble solution of basic auxiliary, adopt fluid bed or coating pan, pastille rapid release ball core is carried out coating;
(3) sluggish layer coating: adopt the organic solution or the aqueous dispersion of sluggish layer coating material, adopt fluid bed or coating pan that the pastille fast release micropill core that is surrounded by alkaline layer is carried out coating promptly.
Mentality of designing of the present invention: adopt suitable macromolecule coating material, the infiltration of moisture is only depended in the influence that requires the dissolving of this material not changed by the gastrointestinal tract pH value; Simultaneously on the basis of control moisture penetration time (lag time), with outer macromolecular material generation physical-chemical reaction generation film character sudden change, or form duct or path etc. behind the moisture that penetrates into by inner adjuvant contact, cause the release of preparation of Chinese medicine.Enforcement to scheme is included in the satisfactory medical substance of screening in numerous macromolecular materials, and the adjuvant that impels film to undergo mutation, and the two physical-chemical reaction can take place to destroy the constraint of clothing layer to medicine.By a large amount of tests, we find that alkaline not too strong water-soluble inorganic alkali and the combination of polyacrylic resin III can extraordinaryly reach above designing requirement, and strong basicity then can influence the stability of most drug usually, should not adopt; The polyacrylic resin III that contains in the time lag layer among the present invention, its chemical composition is: methacrylic acid and methyl methacrylate (1:2) copolymer, because of polyacrylic resin III does not dissolve in less than 7 environment at pH value, and the little intestinal segment of human body alimentary canal from stomach to colon top, the pH value of Digestive system is all less than 7, beginning pH value from colon just begins greater than 7, usually gastric content arrives colon and needs 6～8 hours, and the time lag design time of pulse preparation is 3～5 hours, preparation is no show colon place still, the pulse release process is finished substantially, and arrives colon pH〉7 environment can the sluggish layer of acceleration pulse micropill dissolving, make drug release more complete.Though thereby polyacrylic resin III is pH dependency material, pulse process is not influenced by the Digestive system pH value, can reach ideal release effect in human body.
The release mechanism of isosorbide dinitrate oral administration impulse pellet preparations of the present invention is: water sees through sluggish tunic slowly to the preparation internal penetration, can control the time of time lag by the thickness of controlling sluggish tunic, when alkaline layer is arrived in moisture penetration, the dissolving basic auxiliary, formed a pH value greater than 7 inside microenvironment, make the polyacrylic resin III in the time lag layer dissolve, sluggish tunic is destructurized, outside moisture infiltrates rapidly, the very fast dissolved and release of active substance reaches the pulse release effect of drugs.For the ease of the preparation of coatings, can add antiplastering aid such as Pulvis Talci etc. as required, the experimental result screening shows: the part by weight of polyacrylic resin III and antiplastering aid is 10 parts～90 parts polyacrylic resin III and 1 part～10 parts antiplastering aid.But antiplastering aid is sluggish and almost not effect of pulse release effect for the medicine of pastille core.
The present invention is the pulse preparation that designs according to the division of day and night rule that angina pectoris takes place.Its advantage is: (1) is on dosage form design, the prepared isosorbide dinitrate oral administration impulse pellet preparations of the present invention is according to the chronopharmacology characteristic Design of the division of day and night rhythmicity of angina pectoris morbidity and medicine, and not influenced by the pH value of intestines and stomach, sustained release time comparatively accurately, for angina pectoris and patient's treatment, improve the compliance of taking medicine and have great importance.(2) on formulation characteristic, the prepared isosorbide dinitrate oral administration impulse pellet preparations of the present invention belongs to the multiple-unit dosage form, form by many pillers, these pillers, just as one by one little diffusion cell release, error or the defective of indivedual pillers in preparation is unlikely to drug release behavior to whole preparation and produces and have a strong impact on, and the change of digestive tract microenvironment can be cancelled out each other generally, so the repeatability of its release rule, concordance aspect are better than ordinary preparation.(3) the present invention adopts the technology of innovation to prepare pulse isosorbide dinitrate impulse pellet according to anginal division of day and night pathology, taking the back lag time 3～5 hours, medicine does not discharge (cumulative release is less than 10% of setting dosage) substantially, rapid release reaches the effect of treatment to complete (cumulative release is greater than 90% of setting dosage) in ensuing 3 hours.Adopt fluid bed or coating pan coating simultaneously, preparation technology is simple and easy to realize suitability for industrialized production.
In order to verify release in vitro repeatability in vivo, we investigate this pulse capsule characteristics of pharmacokinetics and relative bioavailability in the beasle dog body: adopt method of randomization that 6 of beasle dogs are divided into two groups, with commercially available isosorbide dinitrate sheet is control formulation, intersect and gavage self-control this pulse capsule (embodiment 4) and commercially available isosorbide dinitrate sheet (20mg/ grain), adopt gas chromatogram electron capture method to measure blood drug level, the result: commercially available of isosorbide dinitrate is 0.25h in the intravital time lag of domesticated dog, the capsular time lag of pulse is 3.7h, and Cmax, (commercially available: Cmax:331 ± 47ng/ml of both no significant difference such as AUC, AUC:1926 ± ngh/ml, pulse capsule: Cmax:309 ± 53ng/ml, AUC:1832 ± ngh/ml), show that the pulse preparation that the present invention prepares has reached designing requirement, have the feature of sluggish and pulse release after the obvious administration, provide a good dosage form selection for preventing and treating cardiovascular disease outbreak in morning.
Description of drawings
Fig. 1 is embodiment 1 a gained pulse piller release profiles.
Fig. 2 is embodiment 2 gained pulse piller release profiles.
Fig. 3 is embodiment 3 gained pulse piller release profiles.
Fig. 4 is embodiment 4 gained pulse piller release profiles.
The specific embodiment
The used supplementary material of the present invention is the commercially available prod.The stripping of working sample photograph among the embodiment " Chinese pharmacopoeia version appendix in 2005 relevant regulations:
Pastille rapid release ball core stripping condition determination: basket method, 75 rev/mins, 37 ± 0.5 ℃; 900ml water is dissolution medium.Final pulse piller stripping condition determination: basket method, 75 rev/mins, 37 ± 0.5 ℃, 900ml release medium: in the hydrochloric acid solution of 0.1mol/L, put in the phosphate buffer of pH6.8 (release environment analogue body in) high effective liquid chromatography for measuring after 2 hours again.
Pastille rapid release ball core prescription:
Starch sucrose celphere 400g
Sorbide nitrate 100g
95% ethanol 1kg
Preparation technology: isosorbide dinitrate is dissolved in 95% ethanol, adopts fluidized bed coating, 32 ± 1 ℃ of temperature, flow velocity 8mL/min is wrapped in isosorbide dinitrate on the celphere, makes pastille rapid release ball core.45 minutes average accumulated dissolution rates 90%.
The alkaline layer prescription: sodium bicarbonate 10% (w/v) adds water to 100%
Preparation technology: sodium bicarbonate is water-soluble, adopt fluidized bed coating, 50 ± 1 ℃ of temperature, flow velocity 3mL/min is wrapped in sodium bicarbonate on the pastille rapid release ball core, and coating increases weight 20%, makes to contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 6.5
Magnesium stearate 1.2
Add 95% ethanol to 100%.
Preparation technology: adopt fluidized bed coating, 35 ± 1 ℃ of temperature, flow velocity 10mL/min is wrapped in above-mentioned coating solution and contains on the alkaline layered pills core, coating weightening finish 90%.Embodiment 1 gained pulse piller release profiles is seen appendix Fig. 1: sluggish about 3 hours, discharged fully in 2 hours then.
Pastille rapid release ball core prescription:
Starch sucrose celphere 600g
Isosorbide mononitrate 100g
95% ethanol 1kg
Art for coating is with embodiment 1.Get pastille rapid release ball core.45 minutes average accumulated dissolution rates 90%.
Alkaline layer: potassium dihydrogen phosphate 10% (w/v), add water to 100%, art for coating is with embodiment 1.Coating weightening finish 12% must contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 6
Micropowder silica gel 1.4
Add 95% ethanol to 100%,
Art for coating is with embodiment 1.Coating weightening finish 120%.Gained pulse piller release profiles is seen appendix Fig. 2: sluggish about 3.5 hours, discharged fully in 2 hours then.
Whole pastille rapid release ball core prescription w/w (%)
Sorbide nitrate 30
Low-substituted hydroxypropyl cellulose 40
Microcrystalline Cellulose 30
Preparation technology: 70% alcoholic solution of the HPMC of adding 5% is made soft material, and soft material is extruded through extruder sieve plate (aperture 0.8mm), and strip particle is put in the spheronizator round as a ball, and the ball core is in 50 ℃ of dry 5h, and screening 18～24 order medicated core make pastille rapid release ball core.45 minutes average accumulated dissolution rates 5%.
Alkaline layer: sodium carbonate 10% (w/v), add water to 100%, art for coating is with embodiment 1.Coating weightening finish 25%;
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 8
Glycerol 0.2
Pulvis Talci 1.5
Add 95% ethanol to 100%, art for coating is with embodiment 1, and coating increases weight 160%.
Gained pulse piller release profiles is seen appendix Fig. 3: sluggish about 3.5 hours, discharged fully in 2 hours then.
Pastille rapid release ball core prescription:
Starch sucrose celphere 500g
Isosorbide mononitrate 100g
95% ethanol 1kg
Art for coating is with embodiment 1.Get pastille rapid release ball core.45 minutes average accumulated dissolution rates 91%.
Alkaline layer: sodium acetate 10% (w/v), add water to 100%, art for coating is with embodiment 1.Coating weightening finish 28% must contain alkaline layered pills core.
Sluggish layer prescription w/v (%)
Polyacrylic resin III (Eudragit S100) 7
Triethyl citrate 1.8
Magnesium stearate 0.5
Add 95% ethanol to 100%, art for coating is with embodiment 1, and coating increases weight 200%.
Gained pulse piller release profiles is seen appendix Fig. 3: sluggish about 4 hours, discharged fully in 2.5 hours then.
Claims (7)
1. an isosorbide dinitrate oral administration impulse pellet preparations is characterized in that said preparation is the multiple coatings preparation, and basic structure is respectively pastille rapid release ball core, alkaline layer and sluggish layer from inside to outside; Pastille rapid release ball core wherein is to be surrounded by the ball core that the celphere of medicine layer or medicine and pharmaceutic adjuvant are mixed with; 1 hour giving drugs into nose of described pastille rapid release ball core discharges and reaches more than 90%; Described alkaline layer is a medicinal soluble organic or inorganic basic auxiliary, and weight is 10～30% of pastille rapid release ball core weight; Described sluggish layer contains polyacrylic resin III, and its weightening finish is 80～200% of pastille rapid release ball core.
2. the described impulse pellet preparation of claim 1, wherein pastille rapid release ball core contains 10～50mg isosorbide dinitrate.
3. the described impulse pellet preparation of claim 1, wherein sluggish layer weightening finish is 100～150% of pastille rapid release ball core.
4. the described impulse pellet preparation of claim 1, wherein sluggish layer also contains antiplastering aid and plasticizer: its plasticizer comprises triethyl citrate, dibutyl sebacate, dibutyl phthalate, glycerol triacetate, Oleum Ricini, glycerol, one or more mixture of propylene glycol; Antiplastering aid comprises Pulvis Talci, magnesium stearate, micropowder silica gel, one or more mixture of glyceryl monostearate.
5. the described impulse pellet preparation of claim 1, wherein consisting of of sluggish layer: 60～80 parts of polyacrylic resin III, 1～10 part of antiplastering aid and 0～10 part of plasticizer.
6. the application of the described isosorbide dinitrate oral administration impulse pellet preparations of claim 1 in preparation treatment angina pectoris in early morning, hypertensive episode peak period medicine, wherein said impulse pellet is made up of the rapid release ball core that contains 10～50mg isosorbide dinitrate, alkaline layer and sluggish layer.
7. the described application of claim 6, wherein said sluggish layer contains polyacrylic resin III, and its weightening finish is 80～200% of rapid release ball core; The alkaline layer weightening finish is 10～30% of rapid release ball core weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100569474A CN101269059B (en) | 2007-03-19 | 2007-03-19 | Isosorbide dinitrate oral administration impulse pellet preparations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100569474A CN101269059B (en) | 2007-03-19 | 2007-03-19 | Isosorbide dinitrate oral administration impulse pellet preparations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101269059A CN101269059A (en) | 2008-09-24 |
| CN101269059B true CN101269059B (en) | 2011-04-27 |
Family
ID=40003451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100569474A Active CN101269059B (en) | 2007-03-19 | 2007-03-19 | Isosorbide dinitrate oral administration impulse pellet preparations |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101269059B (en) |
-
2007
- 2007-03-19 CN CN2007100569474A patent/CN101269059B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101269059A (en) | 2008-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2548748C2 (en) | Compositions containing weakly basic drug substances, and controlled-release dosage forms | |
| AU2002330211B2 (en) | Timed, sustained release multi-particulate dosage forms of propranolol | |
| CN100579525C (en) | Sustained release preparation of licardipine hydrochloride and its preparing process | |
| US20040052844A1 (en) | Time-controlled, sustained release, pharmaceutical composition containing water-soluble resins | |
| AU2002330211A1 (en) | Timed, sustained release multi-particulate dosage forms of propranolol | |
| IL113516A (en) | Controlled-release dosage forms of azithromycin and process for their preparation | |
| KR20090065524A (en) | Programmable buoyant delivery technology | |
| CN103417505A (en) | Huperzine A controlled release preparation having biphasic release behavior, and preparation method thereof | |
| WO1998027967A1 (en) | Release-controlled coated tablets | |
| AU657573B2 (en) | Oral preparation for release in lower digestive tracts | |
| CN1682719B (en) | Enteric soluble coating slow releasing tablet containing huperzine A and preparing method | |
| US20060188563A1 (en) | Medicinal oral preparations for colon delivery, medicinal oral preparations for treating colon cancer and medicinal oral preparations for treating colitis | |
| CN101095681B (en) | Alfuzosin Hydrochloride permeating pump type controlled-release preparation and method for preparing the same | |
| CN100376230C (en) | Timing slow-releasing micrpill and its preparation | |
| CN103550183A (en) | Trimetazidine hydrochloride osmotic pump controlled-release tablet and preparation method thereof | |
| CN102247326B (en) | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts | |
| CN101269056B (en) | Metoprolol salt oral administration impulse pellet preparation | |
| CN102764243B (en) | Aspirin pulsed release pellets, its preparation and preparation method thereof | |
| CN101773482B (en) | Three-stage pulsed release controlled release tablet and preparation method thereof | |
| CN101636153A (en) | Time-specific delayed/pulsatile release dosage forms | |
| Jaiswal et al. | pulsatile drug delivery system: An Overview with special Emphasis on Losartan and Captopril | |
| CN101269059B (en) | Isosorbide dinitrate oral administration impulse pellet preparations | |
| KR100762846B1 (en) | Sustained-release formulations | |
| US20100080846A1 (en) | Dipyridamole and acetylsalicylic acid formulations and process for preparing same | |
| WO2015196956A1 (en) | Metoprolol sustained-release composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |