CN101642443B - Isosorbide mononitrate osmotic pump type controlled-release preparation and preparation method thereof - Google Patents
Isosorbide mononitrate osmotic pump type controlled-release preparation and preparation method thereof Download PDFInfo
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- CN101642443B CN101642443B CN2008101461902A CN200810146190A CN101642443B CN 101642443 B CN101642443 B CN 101642443B CN 2008101461902 A CN2008101461902 A CN 2008101461902A CN 200810146190 A CN200810146190 A CN 200810146190A CN 101642443 B CN101642443 B CN 101642443B
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Abstract
The invention relates to an isosorbide mononitrate osmotic pump type controlled-release preparation and a preparation method thereof. The preparation can release the isosorbide mononitrate at a constant medicament release rate. The preparation mainly comprises a tablet core, a semipermeable coating film and medicament release pores, wherein the tablet core is prepared from the isosorbide mononitrate, a penetrating agent, a filling agent and other pharmaceutic adjuvants; and the semipermeable coating film is prepared from cellulose acetate or ethylcellulose, a plasticizer and a pore former. The osmotic pressure on the inner side and the outer side of a semipermeable film is taken as a driving force, and a medicament is released at a zero level release rate to maintain stable internal blood concentration. The preparation has the characteristics of moderate internal medicament action time, small side effect, and less drug resistance for repeated dose.
Description
Technical field:
The present invention relates to medical technical field, exactly it is a kind of long-term treatment that is used for coronary heart disease, prevention vasospasm type and mixed type angina pectoris, also be applicable to treatment after the myocardial infarction and chronic heart failure long-term treatment-isosorbide mononitrate single layer osmotic pump regulated-release preparations and preparation method thereof.
Background technology:
Isosorbide mononitrate, molecular formula: C
6H
9NO
6Molecular weight: 191.14
Molecular structural formula:
Isosorbide mononitrate can impel vascular smooth muscle relaxation and distend the blood vessels, and its topmost effect is that venectasia is refluxed to reduce intravenous blood, thereby reduces the loading of heart, and isosorbide mononitrate also makes systemic arterial and main coronary artery expansion.Therefore take the oxygen supply that the different Pyrusussuriensis of single nitric acid can reduce the cardiac load amount and promote oxygen supply or balance myocardial ischemia.Be mainly used in the long-term treatment of coronary heart disease clinically, prevention vasospasm type and mixed type angina pectoris also are applicable to the treatment after the myocardial infarction and the long-term treatment of chronic heart failure.
Commercially available preparation comprises conventional tablet and matrix sustained release tablet at present.Commercially available ordinary tablet needs every day takes medicine 2 times; Sustained-release matrix tablets is taken medicine 1 time every day.
Isosorbide mononitrate is the organic acid medicine, is easy to generate the multiple dose drug resistance in the process of medication, must increase dosage after promptly the patient repeatedly takes medicine and just can keep drug effect.Main cause is before being administered into administration in second day the previous day, and left drug can cause that the drug effect of rechallenge reduces, and causes must increasing the dose maintenance drug effect behind the multiple dosing.The elimination half-life is about 5 hours in the body of isosorbide mononitrate.Ordinary tablet is administered twice every day, adopts asymmetric administering mode, promptly carries out administration second time in 7 hours after the administration for the first time, and interval 17 hours between second day the administration first time.Matrix sustained release tablet is administration once a day, and slow-release time is about 20%＜1h＜40%, 45%＜4h＜75%, 8h＞80%.Matrix sustained release tablet is that typical Higuchi (false one-level) discharges, and its release characteristics are that early stage is very fast and the later stage is slower.Because its slow release mechanism is gel skeleton type slow releasing tablet, discharge medicine by corrosion and flooding mechanism, its rate of releasing drug is subjected to such environmental effects such as feed, gastrointestinal motility very big, cause drug release inside and outside dependency poor, individual variation was bigger after the patient took medicine, and was difficult to guarantee patient's drug safety.
Qian Yu (Chinese Pharmaceutical, 2007 the 16th the 5th phases of volume) its research situation of having reported to the isosorbide mononitrate osmotic pump controlled release tablet, dosage is 50mg, use cellulose acetate to be semipermeable membrane material, 2,4,6,8,10, the release in vitro degree measurement result of 12h is respectively 16.2%, 40.6%, 57.0%, 70.5%, 79.2%, 91.5%, but do not provide detailed prescription, can't learn the supplementary product kind and the consumption of its preparation compositions.The shortcoming of this design is that the bigger release of dosage is slower, increased the burden of organism metabolism, body residual fraction medicine still when causing rechallenge, be easy to produce drug resistance, and the maximum problem of isosorbide mononitrate application forces the patient to have to interrupt taking medicine with regard to being the drug resistance that drug residue causes, eliminate residual dose in the body, and interrupt the big increase of having a big risk of its morbidity of period in a medicine.
Summary of the invention:
The objective of the invention is for a kind of convenient drug administration, stable curative effect, isosorbide mononitrate osmotic pump controlled release preparation that toxic and side effects is little are provided.
The object of the present invention is achieved like this:
At first the invention provides a kind of osmotic pump preparation that contains isosorbide mononitrate, by medicine and osmo active substance, filler, lubricant, make label, and one deck contains the film coating of the semi-permeable character of macromolecular material, plasticizer and porogen, have small delivery aperture on this coating membrane, medicine discharges from aperture.Described label contains the component of following quality percentage composition:
Isosorbide mononitrate 1～20%
Play the adjuvant 30～90% of controlled release effect
Other adjuvant surpluses
The described adjuvant that plays the controlled release effect comprises osmo active substance, framework material and plays the membrane material of controlled release effect, and wherein, osmo active substance accounts for 20～70% of label quality, and framework material accounts for 5～20% of label quality; Other adjuvants comprise binding agent, wetting agent, filler, plasticizer, opacifier, porogen and lubricant.
Described osmo active substance is selected from one or more of sucrose, sorbitol, mannitol, glucose, lactose, fructose, sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium sulfate; Described framework material is selected from one or more in polyoxyethylene, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, the arabic gum; The membrane material that plays the controlled release effect is selected from one or more of cellulose acetate, ethyl cellulose, acrylic resin, hydroxypropyl emthylcellulose, polyethylene, polyethylene glycols, phthalate, citrate, Hair two diethyl phthalates, preferred, ethyl; Filler described in other adjuvants is selected from one or more in lactose, sucrose, starch, cellulose, the dextrin; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, starch, the paraffin; Described adhesive is selected from a kind of usefulness in polyvinylpyrrolidone, methylcellulose, the hydroxypropyl methylcellulose or several; Described wetting agent comprises the ethanol-water solution of water, dehydrated alcohol, various concentration; Porogen comprises sucrose, mannitol, Polyethylene Glycol (for example polyethylene glycol 1500, Macrogol 2000, Macrogol 4000, polyethylene glycol 6000 etc.) etc.; Plasticizer comprises Methyl Benzene-o-dicarboxylate and/or triethyl citrate, diethyl phthalate, Hair two diethyl phthalates, Polyethylene Glycol; Opacifier comprises titanium dioxide, Pulvis Talci, silicon dioxide.
The osmotic pump preparation of isosorbide mononitrate of the present invention, outside are surrounded by moistureproof isolation coat layer.
The osmotic pump preparation of above-mentioned isosorbide mononitrate can be made single chamber punching matrix, single chamber micropore matrix, double-deck punching matrix, sees accompanying drawing 1,2,3.
Isosorbide mononitrate osmotic pump controlled release tablet of the present invention, can produce according to the preparation method of the known general osmotic pump preparation of pharmaceuticals industry, drug release hole at the one or both sides of coated tablet is laser boring, mechanical punching or compacting hole packaging technique, and the aperture is 0.2～1.2 millimeter.
Advantage of the present invention is: compare with conventional tablet, that this preparation only needs be administered once, act in one day is lasting, stable curative effect, toxic and side effects are little; Compare with common slow releasing tablet, controlled release tablet can discharge by more effective controlled release drug, makes blood drug level keep relatively low level.Compare with the slow releasing tablet of one-level rate of release, because its rate of release is a zero level, reduced the waste on the drug dose that initial release causes more greatly, controlled release preparation can be kept effective blood drug level under the less situation of dosage, and the residual quantity of medicine when reducing the next day administration, effectively avoid and delay the chemical sproof generation of multiple dose, can effectively reduce the using dosage of medicine, and then alleviate the burden of organism metabolism medicine.
The problem that exists during according to the pharmacokinetic characteristics of isosorbide mononitrate and clinical application, we improve heavy dose of isosorbide mononitrate preparation.We discover, isosorbide mononitrate t
1/2About 5h, gastrointestinal absorption rapidly and fully, mainly with the original shape medicine through renal metabolism, the conventional tablet of using can't be realized the effective blood medicine of long term maintenance slow release, need be administered twice every day, though and common slow releasing preparation preparation has been realized administration once a day, but because in the onset rapidly of administration baseline medicine, may miss nearest drug treating time for patients with coronary heart disease, in addition because the residual quantity of the slow release of medicine medicine when having increased the next day administration, induce body to produce drug resistance easily, therefore ideal isosorbide mononitrate preparation should be: in the onset rapidly of administration initial stage, can keep effective blood drug concentration after reaching effective blood drug concentration, and remain on the residual quantity of relatively low level medicine when reducing the next day administration, effectively avoid chemical sproof generation.
The present invention plays the preferred domestic existing pharmaceutic adjuvant of the membrane material ethyl cellulose of controlled release effect, avoided using the cellulose acetate of import, reduce production cost, and helped the production domesticization of osmotic pump preparation, broken the situation of external drugmaker monopolization osmotic pump preparation.
Controlled release preparation of the present invention will be used for the long-term treatment of coronary heart disease clinically, and prevention vasospasm type and mixed type angina pectoris also are applicable to the treatment after the myocardial infarction and the long-term treatment of chronic heart failure.
Prescription is main to be formed:
Isosorbide mononitrate 10～60g
Osmo active substance 30～200g
Play the membrane material 5～30g of controlled release effect
Plasticizer 3～20g
Porogen 3～15g
Other adjuvant 1～10g
Make 1000
Description of drawings:
Fig. 1 elementary osmotic pump punching matrix sketch map
Fig. 2 elementary osmotic pump micropore matrix sketch map
Fig. 3 double-layer osmotic pump tablet sketch map
Fig. 4 is according to the releasing curve diagram of the isosorbide mononitrate monolayer controlled release tablet of embodiment 1 preparation
Fig. 5 is according to the releasing curve diagram of the isosorbide mononitrate monolayer controlled release tablet of embodiment 2 preparations
Fig. 6 is according to the releasing curve diagram of the isosorbide mononitrate monolayer controlled release tablet of embodiment 3 preparations
Fig. 7 is according to the releasing curve diagram of the isosorbide mononitrate monolayer controlled release tablet of embodiment 4 preparations
Fig. 8 is according to the releasing curve diagram of the isosorbide mononitrate monolayer controlled release tablet of embodiment 5 preparations
Fig. 9 list nitre controlled release tablet and slow releasing tablet begle dog blood drug level-time graph (embodiment 2)
Figure 10 list nitre controlled release tablet and slow releasing tablet begle dog blood drug level-time graph (embodiment 1)
The specific embodiment:
Embodiment 1: the present embodiment that adopts the known method of pharmaceuticals industry to make.
Tablet contains following composition by weight percentage:
Label is formed:
Isosorbide mononitrate 40g
Hydroxypropyl methylcellulose 60g
Lactose 160g
8% polyvinylpyrrolidone K30 alcoholic solution is an amount of
Magnesium stearate 3g
Be prepared into 1000
The semipermeable membrane coating solution is formed:
Cellulose acetate 8g
Macrogol 4000 4g
Diethyl phthalate 2g
Acetone/water (14/5/1) 200ml
Coating weightening finish 6%
Moistureproof coating liquid is formed:
Hydroxypropyl methylcellulose 6cp 4g
PEG-400 1g
Pulvis Talci 1.5g
Titanium dioxide 1.5g
Ethanol/water (60/40) 100ml
Coating weightening finish 3%
Adopt film-coated technique, isosorbide mononitrate is made mono-layer osmotic pump controlled release tablets, its single face is carried out laser or mechanical punching, aperture 0.5mm is to reach the purpose of controlled release.
Embodiment 2: the present embodiment that adopts the known method of pharmaceuticals industry to make.
Tablet contains following composition by weight percentage:
Label is formed:
Isosorbide mononitrate 20g
Fructose 50g
Lactose 50g
Magnesium stearate 2g
3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Be prepared into 1000
The semipermeable membrane coating solution is formed:
Ethyl cellulose 12g
Macrogol 4000 1.5g
Hydroxypropyl methylcellulose 2.5g
Ethanol/water (80/20) 400ml
Moistureproof coating liquid is formed:
Hydroxypropyl methylcellulose 5g
Polyethylene Glycol 1g
Pulvis Talci 1g
Titanium dioxide 1g
Ethanol/water (60/40) 100ml
Adopt film-coated technique, isosorbide mononitrate is made mono-layer osmotic pump controlled release tablets, its one or both sides are carried out laser or mechanical punching, aperture 0.5mm is to reach the purpose of controlled release.
Embodiment 3: the present embodiment that adopts the known method of pharmaceuticals industry to make.
Tablet contains following composition by weight percentage:
Label is formed:
Isosorbide mononitrate 40g
Mannitol 160g
Sodium alginate 50g
Sodium stearyl fumarate 2g
3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Be prepared into 1000
The semipermeable membrane coating solution is formed:
Cellulose acetate 10g
Macrogol 4000 4g
Diethyl phthalate 3ml
Acetone/water (14/5/1) 250ml
Coating weightening finish 7%
Moistureproof coating liquid is formed:
Hydroxypropyl methylcellulose 6cp 4g
Polyethylene glycol 1500 1g
Pulvis Talci 1.5g
Titanium dioxide 1.5g
Ethanol/water (60/40) 100ml
Adopt film-coated technique, isosorbide mononitrate is made mono-layer osmotic pump controlled release tablets, its one or both sides are carried out laser or mechanical punching, aperture 0.8mm is to reach the purpose of controlled release.
Embodiment 4: the present embodiment that adopts the known method of pharmaceuticals industry to make.
Tablet contains following composition by weight percentage:
Label is formed:
Isosorbide mononitrate 40g
Lactose 150g
Polyoxyethylene (molecular weight 300,000) 30g
Magnesium stearate 2g
3% methylcellulose, 80% alcoholic solution is an amount of
Be prepared into 1000
The semipermeable membrane coating solution is formed:
Ethyl cellulose 12g
Macrogol 4000 2g
Hydroxypropyl methylcellulose 2.5g
Ethanol/water (80/20) 400ml
Moistureproof coating liquid is formed:
Hydroxypropyl methylcellulose 6cp 5g
Polyethylene Glycol 1g
Pulvis Talci 1g
Titanium dioxide 1g
Ethanol/water (60/40) 100ml
Adopt film-coated technique, will make the isosorbide mononitrate mono-layer osmotic pump controlled release tablets, its one or both sides are carried out laser or mechanical punching, aperture 0.8mm is to reach the purpose of controlled release.
The present embodiment that embodiment 5 adopts the known method of pharmaceuticals industry to make.
Tablet contains following composition by weight percentage:
Label is formed:
Medicated layer:
Isosorbide mononitrate 40g
Mannitol 100g
Magnesium stearate 2g
3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
The boosting layer:
Polyoxyethylene (molecular weight 5,000,000) 40
90% ethanol water is an amount of
Be prepared into 1000
The semipermeable membrane coating solution is formed:
Ethyl cellulose 12g
Macrogol 4000 2.5g
HPMC 2.5g
Diethyl phthalate 1.5ml
Ethanol/water (80/20) 400ml
Coating weightening finish 5.5%
Moistureproof coating liquid is formed:
Hydroxypropyl methylcellulose 6cp 4g
Polyethylene glycol 1500 1g
Pulvis Talci 1.5g
Titanium dioxide 1.5g
Ethanol/water (60/40) 100ml
Adopt film-coated technique, isosorbide mononitrate is made mono-layer osmotic pump controlled release tablets, its one or both sides are carried out laser or mechanical punching, aperture 0.8mm is to reach the purpose of controlled release.
Claims (6)
1. an osmotic pump preparation that contains isosorbide mononitrate comprises label, and the film coating of the semi-permeable character of one deck, have small delivery aperture on this coating membrane, medicine discharges from aperture, it is characterized in that: the described osmotic pump preparation that contains isosorbide mononitrate has following prescription and forms:
Described osmo active substance is selected from one or more in sucrose, sorbitol, mannitol, glucose, lactose, fructose, sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, the sodium sulfate;
Described framework material is selected from one or more in polyoxyethylene, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone, the arabic gum;
The described membrane material that plays the controlled release effect is selected from one or more in cellulose acetate, ethyl cellulose, acrylic resin, hydroxypropyl emthylcellulose, the polyethylene;
Described plasticizer is selected from Methyl Benzene-o-dicarboxylate and/or triethyl citrate, diethyl phthalate, ethyl sebacate, Polyethylene Glycol;
Described porogen is selected from one or more in sucrose, mannitol, the Polyethylene Glycol, and described Polyethylene Glycol is polyethylene glycol 1500, Macrogol 2000, Macrogol 4000 or polyethylene glycol 6000;
Described other adjuvants comprise binding agent, wetting agent, filler, opacifier and lubricant, and wherein, described binding agent is selected from one or more in polyvinylpyrrolidone, methylcellulose, the hydroxypropyl methylcellulose; Described wetting agent is selected from one or more in the ethanol-water solution of water, dehydrated alcohol, various concentration; Described filler is selected from one or more in lactose, sucrose, starch, cellulose, the dextrin, and opacifier comprises one or more in titanium dioxide, Pulvis Talci, the silicon dioxide; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, starch, the paraffin.
2. isosorbide mononitrate controlled release tablet according to claim 1 is characterized in that, the outside is surrounded by moistureproof isolation coat layer.
3. isosorbide mononitrate controlled release tablet according to claim 2 is characterized in that having following prescription and forms:
Label is formed:
The semipermeable membrane coating solution is formed:
Moistureproof coating liquid is formed:
4. isosorbide mononitrate controlled release tablet according to claim 2 is characterized in that having following prescription and forms:
The semipermeable membrane coating solution is formed:
Moistureproof coating liquid is formed:
5. isosorbide mononitrate controlled release tablet according to claim 2 is characterized in that having following prescription and forms:
Label is formed:
The semipermeable membrane coating solution is formed:
Moistureproof coating liquid is formed:
6. isosorbide mononitrate controlled release tablet according to claim 2 is characterized in that having following prescription and forms:
Label is formed:
The semipermeable membrane coating solution is formed:
Moistureproof coating liquid is formed:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101461902A CN101642443B (en) | 2008-08-08 | 2008-08-08 | Isosorbide mononitrate osmotic pump type controlled-release preparation and preparation method thereof |
| HK10107655.9A HK1141226A1 (en) | 2008-08-08 | 2010-08-10 | Isosorbide mononitrate osmotic pump type controlled-release formulation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101461902A CN101642443B (en) | 2008-08-08 | 2008-08-08 | Isosorbide mononitrate osmotic pump type controlled-release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101642443A CN101642443A (en) | 2010-02-10 |
| CN101642443B true CN101642443B (en) | 2011-09-21 |
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| CN2008101461902A Active CN101642443B (en) | 2008-08-08 | 2008-08-08 | Isosorbide mononitrate osmotic pump type controlled-release preparation and preparation method thereof |
Country Status (2)
| Country | Link |
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| CN (1) | CN101642443B (en) |
| HK (1) | HK1141226A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101744783B (en) * | 2008-12-18 | 2012-04-18 | 北京华素制药股份有限公司 | Isosorbide mononitrate controlled release tablet and preparation method thereof |
| CN102423305A (en) * | 2011-12-23 | 2012-04-25 | 中国药科大学 | Isosorbide mononitrate micro-porous osmotic pump tablet and preparation method thereof |
| CN107802610B (en) * | 2017-11-22 | 2020-10-20 | 乐普药业股份有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| CN107929253A (en) * | 2017-12-26 | 2018-04-20 | 合肥立方制药股份有限公司 | A kind of isosorbide mononitrate osmotic pump controlled release tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1846693A (en) * | 2005-04-12 | 2006-10-18 | 潘卫三 | Control released permeation bump tablet of venlafaxine hydrochloride and its prepn process |
| CN1923184A (en) * | 2006-10-16 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Multiple apertures releasing osmosis pump and preparation process thereof |
-
2008
- 2008-08-08 CN CN2008101461902A patent/CN101642443B/en active Active
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2010
- 2010-08-10 HK HK10107655.9A patent/HK1141226A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1846693A (en) * | 2005-04-12 | 2006-10-18 | 潘卫三 | Control released permeation bump tablet of venlafaxine hydrochloride and its prepn process |
| CN1923184A (en) * | 2006-10-16 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Multiple apertures releasing osmosis pump and preparation process thereof |
Non-Patent Citations (3)
| Title |
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| 张宇等.《单硝酸异山梨醋渗透泵型控释片的制备及体外释药机制考察》.《中国新药杂志》.2007,第16卷(第21期),第1784-1785页. * |
| 杨泗兴等.《星点设计2效应面法优化单硝酸异山梨酯微孔渗透泵片处方》.《药学与临床研究》.2008,第16卷(第3期),第175-178页. * |
| 钱渝.《单硝酸异山梨酯渗透泵控释片的研制》.《中国药业》.2007,第16卷(第5期),第32-33页. * |
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| CN101642443A (en) | 2010-02-10 |
| HK1141226A1 (en) | 2010-11-05 |
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