CN102512398B - Simvastatin osmotic pump preparation and preparation method thereof - Google Patents
Simvastatin osmotic pump preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses simvastatin monolayer osmotic pump sustained release tablets. Each simvastatin monolayer osmotic pump sustained release tablet comprises a tablet core and a controlled-release film coated layer, wherein the tablet core contains the following components in percentage by weight: 1 to 20 percent of simvastatin serving as a main medicine, 1 to 25 percent of filling agent, 50 to 90 percent of penetrating agent, 1 to 15 percent of adhesive, 0.5 to 5 percent of release conditioning agent and 0.5 to 3 percent of lubricating agent; the controlled-release film coated layer comprises a controlled-release film-forming material, a plasticizer and/or a pore-forming agent; the filling agent comprises microcrystalline cellulose and dextrin; and the penetrating agent contains cane sugar and lactose.
Description
Technical field
The present invention relates to the simvastatin sustained-release preparation, particularly a kind of simvastatin Oros preparation.
Background technology
Simvastatin (simvastatin) is Statins (statin) blood lipid-lowering medicine, be methyl hydroxyl glutaryl coenzyme A (HMG-COA) reductase inhibitor, suppress the synthetic of endogenous cholesterol, be used for content and the angiocardiopathy preventing of control Blood Cholesterol.The clinical hypercholesterolemia that is used for the treatment of, coronary heart disease.
Simvastatin is global situation of selling well pravastatin, with generic drug and commodity famous medicine Zocor(Mo Shadong, the Merck of independent composition) sell, also have with the compound preparation Torin of Ezetimibe and with the compound preparation Simcor of nicotinic acid.2004, the 10mg simvastatin can be purchased in pharmacy as the OTC medicine in Britain, and at present, simvastatin is the widest statins antilipemic drugs of domestic and international application.
Denmark, Finland, Iceland, Norway, Sweden five states united in 1987 and have initiated a perspective study for the multi-center randomized double of 4444 routine patients with coronary heart disease (Scandinavia Simvastatin Survival Study, be called for short 4S research), be intended to verify that can simvastatin improve the survival rate of patients with coronary heart disease when reducing TC.The result shows, simvastatin can make the TC level reduce by 25%, LDL to reduce by 35%, TG reduces by 10%, and makes HDL raise 8%, and mortality rate reduces by 42%, the sickness rate of coronary heart disease acute events reduces by 34%, and the general mortality rate that a variety of causes causes (containing cerebrovascular) reduces by 30%.Prove first the reinforcement lipid-lowering therapy except reducing the coronary events, also can reduce the mortality rate of coronary heart disease and non-cardiovascular disease, improved the survival rate of patients with coronary heart disease, prolonged patient's life.
, HPS(Cardioprotective research in 2004) high-risk patient of 20536 examples being suffered from coronary heart disease and other atheromatosiss or diabetes in 40 ~ 80 years old has been observed the impact of simvastatin 40mgd-1 on prognosis.The result shows, simvastatin can significantly reduce the mortality rate 13% of all reasons, and coronary heart disease death and non-lethality myocardial infarction reduce 25% simultaneously.It should be noted that this research finds that in the process of following up a case by regular visits to the treatment of having accepted statins up to 17% patient is arranged in placebo group.Obviously, if placebo group uses the ratio of statins lower, the clinical protection effect of simvastatin will be more remarkable.
The data show of a system review in 2003, the 10mg simvastatin can reduce LDL-C(27%) and the poor risk crowd suffer from the risk of coronary heart disease, but pravastatin 40mg, atorvastatin 10mg, lovastatin 20～40mg does not demonstrate the advantage of improving overall mortality rate in primary prevention research.Based on above data, on May 12nd, 2004, BMH approval simvastatin 10mg tablet (simvastatin) is nonprescription drugs (OTC), is used for the patient of coronary heart disease poor risk (danger that occurred cardiovascular event in 10 years is 10%-20%).Simvastatin becomes a unique Statins fat regulation medicine that is approved for nonprescription drugs.
According to Merck ﹠ Co., Inc.'s simvastatin (simvastatin sheet) pharmacokinetic results, take the simvastatin sheet after 4 hours blood drug level reach peak value, descend very soon afterwards, only eliminate surplus 10% after 12 hours.This just means, every day, (24 hours) took a slice simvastatin conventional tablet, is lower than treatment concentration within the most of the time.Simultaneously, conventional tablet has obvious blood drug level peak value Cmax, the size of this value and myopathy risk positive correlation, and the larger then myopathy risk of this value is larger.
At present the formulation art technical staff attempts to provide the steady release of medicine by using the control release technic of preparation, avoids too high peak concentration value and reduces the myopathy risk, prolongs simultaneously effectively treatment concentration interval and improve curative effect.
Chinese patent CN1951385A discloses a kind of simvastatin slow-release micropill, but its slow release effect awaits further improvement.CN101352425B discloses the compound osmotic pump preparation of acipimox and simvastatin, and label is double-layer tablet cored structure or single-layer sheet cored structure, and wherein the label of single-layer sheet core osmotic pump tablet mainly is comprised of lactose, fructose, PVP K30.US5882682A also discloses the simvastatin osmotic pump tablet, and wherein label is comprised of microcrystalline Cellulose, sodium polyacrylate, polyvidone or card pool nurse, sodium citrate, lactose, polyvidone.CN102028668A discloses a kind of osmotic pump tablet of asymmetric type, and it adopts ethyl cellulose and polyvidone as the semipermeable membrane filmogen, can overcome catabiosis.Yet above preparation still exists release not reach desirable zero-order release state, and bioavailability does not reach good state yet, and preparation cost is also corresponding higher.Therefore, prior art still needs a kind ofly to reach that desirable zero-order release, bioavailability are high, better stability of preparation, and release is complete, technique is simple, the simvastatin sustained-release preparation that cost is low.
Summary of the invention
The object of the present invention is to provide a kind of oral simvastatin sustained-release preparation, it is a kind of osmotic tablet, comprises label and release-controlled film clothing layer, and wherein label contains simvastatin, filler, penetrating agent, binding agent, release regulator and lubricant.Osmotic tablet of the present invention is a kind of single-layer sheet core osmotic pump tablet, and once a day administration can reach therapeutic effect.Osmotic tablet of the present invention slowly, stably discharges active medicine in vivo, and release is complete, and curative effect is sustainable more than 24 hours, compare with the simvastatin ordinary tablet, and long half time, peak concentration is low, and bioavailability is high, and medicine stability is also strengthened greatly.
Compositions of the present invention has good slow release effect, external burst size 4 hours, 8 hours, 12 hours and 16 hours is respectively below 30% of labelled amount, 30%～65%, more than 50%～85% and 75%, preferably, burst size 4 hours, 8 hours, 12 hours and 20 hours is respectively more than 5%～30%, 35%～65%, 50%～80% and 80%, the burst size of most preferably, 4 hours, 8 hours, 12 hours and 20 hours is respectively more than 10%～30%, 40%～60%, 55%～80% and 80%.Compositions of the present invention 20 hours cumulative release greater than 90%.
In the compositions of the present invention, usually select the adjuvant with thickening power as filler, these filleies comprise sodium alginate, microcrystalline Cellulose, agar powder, arabic gum, guar gum, propylene glycol alginate, sodium polyacrylate (100,000-200,000), carboxymethyl cellulose, beta-schardinger dextrin-, dextrin, starch etc. or their mixture, wherein preferred sodium alginate, carboxymethyl cellulose, microcrystalline Cellulose, starch, the most preferably mixture of microcrystalline Cellulose and dextrin; Penetrating agent comprises saccharide and/or salt, saccharide comprises mannitol, sorbitol, xylitol, glucose, lactose, fructose, sucrose etc. or their mixture, salt comprises sodium chloride, potassium chloride, calcium chloride, sulfate, phosphate etc. or their mixture, most preferably saccharide, the more preferably mixture of sucrose and lactose; Binding agent comprises starch, polyvinylpyrrolidone (polyvidone), hydroxypropyl methylcellulose, sodium carboxymethyl cellulose etc. or their mixture, preferably polyethylene ketopyrrolidine, hydroxypropyl methylcellulose or their mixture; Lubricant comprises magnesium stearate, stearic acid, calcium stearate, zinc stearate, Polyethylene Glycol, Pulvis Talci, micropowder silica gel, sodium benzoate, sulphuric acid sodium laurate, sulphuric acid Magnesium dilaurate, sodium acetate, enuatrol, boric acid, paraffin etc. or their mixture, preferred magnesium stearate, Pulvis Talci, stearic acid; The adjuvant that release regulator can expand rapidly for meeting water, in order to increase the release power of medicine, it comprises non-ionic polyalcohol and Ionomer, include but not limited to polyoxyethylene (polyethylene oxide, PEO), other hypromellose of high viscosity grade, carbomer, carmethose, the carbomer of preferred molecular weight 100,000～1,000 ten thousand polyoxyethylene, molecular weight 1,000,000～4,000,000, the hypromellose of molecular weight 10,000～100,000, the sodium carboxymethyl cellulose of molecular weight 100,000～700,000.
Release-controlled film clothing layer described in the compositions of the present invention comprises release-controlled film filmogen, plasticizer and/or porogen.The release-controlled film filmogen comprises cellulosic polymer, for example, can be cellulose acetate, ethyl cellulose, cellulose diacetate, cellulose triacetate etc. or its mixture, preferred cellulose acetate, ethyl cellulose; Plasticizer can be one or more the mixture in the known plasticizer, such as diethyl phthalate, ethyl phthalate, Polyethylene Glycol, glycerol, triethyl citrate, triglyceride etc. or their mixture, preferred diethyl phthalate, triethyl citrate, Polyethylene Glycol or their mixture; Porogen may be a kind of material or multiple mixture, such as glycerol, propylene glycol, polyvinyl alcohol, water-soluble inorganic salt, Polyethylene Glycol etc. or their mixture, preferably glycerine, Polyethylene Glycol or their mixture.
In this osmotic pump preparation, preferably have one or two drug release hole at its release-controlled film, medicine can discharge from this hole, most preferably in the coated tablet both sides one drug release hole is arranged respectively, this hole adopts laser to get through medicated layer from the outside usually, the diameter in hole is generally 0.2～1.2mm, preferred 0.3～1.0mm, more preferably 0.4～0.8mm.
Randomly, osmotic tablet of the present invention can also comprise the outer film coat layer further on the surface of controlled release coat layer.This film coating layer only plays a protective role, on the release characteristics of medicine without impact.Wherein, the filmogen of this film coating layer is selected from water miscible polymer with certain viscosity, is selected from cellulose ethers, acrylate copolymer and other water-soluble polymers.Cellulose ethers is selected from hydroxypropyl emthylcellulose (HPMC, for example the Methocel of Dow company is suitable for viscosity 5～50cps), hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxyethyl-cellulose (HEC) or mainly contains above cellulosic coating pre-mixing agent; Acrylate copolymer is selected from methacrylic acid amido ester copolymer (for example the acrylic resin IV of domestic production or mainly contain the pre-mixing agent of acrylic resin, the Eudragit of Degussa-Rohm company is strange E100 especially); Other water-soluble polymers are selected from polyvidone (preferred PVP K30) and copolymerization polyvidone or mainly contain polyvidone and the coating pre-mixing agent of copolymerization polyvidone, polyvinyl alcohol/polyethyleneglycol-graft copolymer or mainly contain coating pre-mixing agent (for example the Kollicoat IR of BASF BASF AG, Kollicoat IR white, Kollicoat IR protect) and the Polyethylene Glycol (PEG) of polyvinyl alcohol/polyethyleneglycol-graft copolymer.Wherein said coating pre-mixing agent refer to commercially available that prepared, convenient that use, mainly contain the coating intermixture that has mixed in advance of above-mentioned film material (also may contain a small amount of plasticizer, antiplastering aid, coloring agent and brightener in addition), the various stomach dissolution type coating pre-mixing agents produced of the Kollicoat IR of the stomach dissolution type Opadry of Colocorn company, above-mentioned BASF AG, Kollicoat IR white and Kollicoat IR protect, domestic corporation for example.
In yet another embodiment of the present invention, contain (by weight percentage) in the label: principal agent 1%-20%, filler 1-25%, penetrating agent 50-90%, binding agent 1-15%, release regulator 0.5-5% and lubricant 0.5-3%; More preferably, label contains principal agent 5%-10%, filler 5-20%, penetrating agent 60-80%, binding agent 1-5%, release regulator 0.5-2% and lubricant 0.5-2%.The tablet hardness of suppressing should satisfy the requirement of pharmacopeia, preferred 50-90N.Wherein, filler is the mixture of microcrystalline Cellulose and dextrin; Penetrating agent is the mixture of sucrose and lactose.The ratio of microcrystalline Cellulose and dextrin can be 1:100-100:1, preferred 1:10-10:1, more preferably 1:3-3:1; The ratio of sucrose and lactose can be 1:100-100:1, preferred 1:10-10:1, more preferably 1:3-3:1.Adopt above filler and penetrating agent, can make and improve its external zero-order release effect, improve the release concordance.
Simvastatin osmotic tablet controlled release coat film of the present invention contains (by weight percentage): release-controlled film filmogen 65-95%, plasticizer and/or porogen 5-35%; More preferably, contain release-controlled film filmogen 75-90%, plasticizer and/or porogen 10-25%.The weight of controlled release coat film accounts for 3%～15% of label weight, and is preferred 4%～12%, and more preferably 5%～10%.The diameter of laser hole is generally 0.2～1.2mm on the release-controlled film clothing, preferred 0.3～1.0mm, more preferably 0.4～0.8mm.Simvastatin osmotic pump tablet of the present invention randomly has one deck outer film coat layer at the outer surface of controlled release coat film; can play effect attractive in appearance, do not affect the osmotic pump tablet release characteristics every the protection osmotic pump tablet such as wet moistureproof; its film material can adopt the thin film coating material of this area routine; determining of coating gain in weight also is that those skilled in the art just can obtain by simple experiment; for example; can increase weight 0.5%～6%, preferably 1%～5%, more preferably 2%～4%.
In an embodiment of the invention, further contain surfactant in the label of compositions of the present invention.The present inventor finds to adopt sodium lauryl sulphate as surfactant through a large amount of experimentatioies and creative work, and with respect to the surfactant of other kinds, prepared osmotic pump preparation discharges more complete.The content of surfactant accounts for 1%～10% of label weight, and more preferably 4%～8%.Preferably, its 20 hours cumulative release greater than 90%.
The present composition can also randomly further comprise antioxidant, disintegrating agent, correctives, aromatic, coloring agent, opacifier etc., these all can be the known disintegrating agent in medicament field, antioxidant, correctives, aromatic, coloring agent, opacifier etc., for example, disintegrating agent can be low-substituted hydroxypropyl cellulose sodium, crospolyvinylpyrrolidone, carboxymethyl starch sodium, pregelatinized Starch, alginic acid, gas-producing disintegrant etc. or their mixture; Aromatic includes but not limited to menthol, eudesmol, syringyl alcohol etc.; Correctives comprises that A Siba is sweet, vanillin, artificial essence etc.; Antioxidant comprises vitamin C, Butylated hydroxyanisole (BHA), tertiarybutylhydroquinone (THBQ) etc.; Coloring agent can be one or more in the known coloring agent, such as carmine, sunset yellow, indigo, viride nitens, red ferric oxide, yellow ferric oxide, Black Rouge etc.; Opacifier may be a kind of material or multiple mixture, such as titanium dioxide, Pulvis Talci, micropowder silica gel.These optional compositions can join in label, controlled release coat layer and/or the outer film coat layer according to actual needs, this be those skilled in the art according to known technology not needs pay creative work and just can finish.
In special embodiment of the present invention, also preferably used polyoxyethylene as Osmolyte regulator.The polyoxyethylated molecular weight of selecting can be 100,000～1,000 ten thousand, and is preferred 10～8,000,000, most preferably 10～5,000,000, particularly preferably 200～5,000,000.
Another object of the present invention also provides the preparation method of above-mentioned simvastatin osmotic pump tablet, may further comprise the steps:
1) except lubricant, other label composition is mixed, to granulate, drying adds lubricant, mixing;
2) tablet machine tabletting;
3) label is carried out the release-controlled film coating;
4) at coated tablet two side perforatings.
Randomly, preparation method of the present invention also is included in the step of the outer protective film clothing of punched sheet bag.
Preferably, the preparation method of simvastatin osmotic pump tablet of the present invention may further comprise the steps:
1) except lubricant, other label constituent is mixed, add ethanol soft material processed, 30 orders～40 mesh sieves are granulated, and drying adds lubricant, mixing;
2) granulation is used the tablet machine tabletting;
3) release-controlled film filmogen, plasticity and/or porogen are dissolved in the solvent, label is carried out the release-controlled film coating;
4) each plays a drug release hole in the coated tablet both sides;
Randomly, preparation method of the present invention also is included in the step of the outer protective film clothing of punched sheet bag.
Wherein, the preferred dehydrated alcohol of described ethanol.
Wherein, described filler comprises sodium alginate, microcrystalline Cellulose, agar powder, arabic gum, guar gum, propylene glycol alginate, sodium polyacrylate (100,000-200,000), carboxymethyl cellulose, beta-schardinger dextrin-, dextrin, starch etc. or their mixture, wherein preferred sodium alginate, carboxymethyl cellulose, microcrystalline Cellulose, starch, the most preferably mixture of microcrystalline Cellulose and dextrin; Penetrating agent comprises saccharide and/or salt, saccharide comprises mannitol, sorbitol, xylitol, glucose, lactose, fructose, sucrose etc. or their mixture, salt comprises sodium chloride, potassium chloride, calcium chloride, sulfate, phosphate etc. or their mixture, most preferably saccharide, the more preferably mixture of sucrose and lactose; Binding agent comprises starch, polyvinylpyrrolidone (polyvidone), hydroxypropyl methylcellulose, sodium carboxymethyl cellulose etc. or their mixture, preferably polyethylene ketopyrrolidine, hydroxypropyl methylcellulose or their mixture; Lubricant comprises magnesium stearate, stearic acid, calcium stearate, zinc stearate, Polyethylene Glycol, Pulvis Talci, micropowder silica gel, sodium benzoate, sulphuric acid sodium laurate, sulphuric acid Magnesium dilaurate, sodium acetate, enuatrol, boric acid, paraffin etc. or their mixture, preferred magnesium stearate, Pulvis Talci, stearic acid; The adjuvant that release regulator can expand rapidly for meeting water, in order to increase the release power of medicine, it comprises non-ionic polyalcohol and Ionomer, include but not limited to polyoxyethylene (polyethylene oxide, PEO), other hypromellose of high viscosity grade, carbomer, carmethose, the carbomer of preferred molecular weight 100,000～1,000 ten thousand polyoxyethylene, molecular weight 1,000,000～4,000,000, the hypromellose of molecular weight 10,000～100,000, the sodium carboxymethyl cellulose of molecular weight 100,000～700,000.
Described release-controlled film clothing layer comprises release-controlled film filmogen, plasticizer and/or porogen.The release-controlled film filmogen comprises cellulosic polymer, for example, can be cellulose acetate, ethyl cellulose, cellulose diacetate, cellulose triacetate etc. or its mixture, preferred cellulose acetate, ethyl cellulose; Plasticizer can be one or more the mixture in the known plasticizer, such as diethyl phthalate, ethyl phthalate, Polyethylene Glycol, glycerol, triethyl citrate, triglyceride etc. or their mixture, preferred diethyl phthalate, triethyl citrate, Polyethylene Glycol or their mixture; Porogen may be a kind of material or multiple mixture, such as glycerol, propylene glycol, polyvinyl alcohol, water-soluble inorganic salt, Polyethylene Glycol etc. or their mixture, preferably glycerine, Polyethylene Glycol or their mixture.
Described solvent is selected from acetone, ethanol, isopropyl alcohol, dichloromethane, and their compositions; Preferred acetone, isopropyl alcohol.
The diameter in described hole is 0.2～1.2mm, preferred 0.3～1.0mm, more preferably 0.4～0.8mm.
Granulation, tabletting, punching and art for coating all can adopt published technology in the prior art.For example, tabletting can adopt the equipment such as single punch tablet machine, rotary tablet machine; Coating can adopt but be not limited to the equipment such as coating pan, high-efficiency coating pot, pipe laying coating pan, fluid bed, suspension coating machine; Punching can be adopted laser-beam drilling machine, calcination, physical method punching etc.
The advantage of the above-mentioned osmotic pump preparation that makes is to discharge medicine with constant rate of releasing drug in the certain hour scope, and be not subjected to the impact of the factors such as media environment pH value, gastrointestinal peristalsis and food, has preferably inside and outside dependency, the phenomenon that the blood concentration fluctuation that can avoid common oral preparation to cause is larger, improve bioavailability, greatly improve safety, effectiveness and the compliance of medicine.
Description of drawings
The tablet vitro drug release of the accompanying drawing 1 embodiment 1 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 2 embodiment 2 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 3 embodiment 3 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 4 embodiment 4 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 5 embodiment 5 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 6 embodiment 6 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 7 comparative examples 1 preparation line of writing music
The tablet vitro drug release of the accompanying drawing 8 comparative examples 2 preparation line of writing music
Blood drug level-time graph behind the accompanying drawing 9 beasle dog single-doses.
The specific embodiment
Unless stated otherwise, the premix thin film coating material that adopts in following examples is the stomach dissolution type Opadry II type (commercially available) of Colocorn company, and film coating adopts dissolve with ethanol, and polyvidone is PVP K30.Yet following examples only are used for explanation the present invention, are not be used to limiting practical range of the present invention.Those skilled in the art can carry out corresponding conversion to adjuvant and consumption thereof, preparation method according to ordinary skill knowledge fully after understanding technology contents of the present invention, these all should be within the scope of protection of the invention.
Embodiment 1
?
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 7.2 | 90 |
| PEG-4000 | 0.4 | 5 |
| Triethyl citrate | 0.4 | 5 |
Preparation technology:
Simvastatin, polyoxyethylene (2,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
Embodiment 2
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| PEG-4000 | 1.6 | 20 |
Preparation technology:
Simvastatin, polyoxyethylene (2,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, for subsequent use; Tween-80 added add above dry powder soft material processed behind the dissolve with ethanol; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
Embodiment 3
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| PEG-4000 | 1.6 | 20 |
Preparation technology:
Simvastatin, polyoxyethylene (2,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
Embodiment 4
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| PEG-4000 | 1.6 | 20 |
Preparation technology:
Simvastatin, polyoxyethylene (5,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| PEG-4000 | 1.6 | 20 |
Preparation technology:
Simvastatin, polyoxyethylene (5,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
Embodiment 6
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| PEG-4000 | 1.6 | 20 |
Preparation technology:
Simvastatin, polyoxyethylene (5,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
The comparative example 1
| The release-controlled film clothing forms | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 7.2 | 90 |
| PEG-4000 | 0.4 | 5 |
| Triethyl citrate | 0.4 | 5 |
Preparation technology:
Simvastatin, polyoxyethylene (2,000,000), sucrose, lactose, dextrin, microcrystalline Cellulose, polyvidone, sodium lauryl sulphate, the vitamin C of amount to be prepared are crossed 80 mesh sieves and fully mixing, add ethanol soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting; Release-controlled film clothing constitutive material is dissolved in the acetone, label is carried out the release-controlled film coating, coating weightening finish 6%～8%; Each makes a call to the aperture of a 0.4～0.8mm in release-controlled film coated tablet both sides with laser-beam drilling machine.
The comparative example 2
Preparation technology: simvastatin, microcrystalline Cellulose, lactose, starch, carboxymethyl starch sodium, the polyvidone of amount to be prepared are crossed 80 mesh sieves and fully mixing, add purified water soft material processed; Soft material is granulated with 30 mesh sieves; Then 20 mesh sieve granulate after dry add magnesium stearate, mixing; To make granule tablet machine tabletting.
The mensuration of experimental example 1 drug release rate
The preparation of embodiment 1-6 and comparative example 1-2 preparation is carried out drug release determination, embodiment and comparative example are carried out linear fit at 4-16 hour release profiles, investigate the release wire implementations; And embodiment and comparative example investigated at 20 hours cumulative release degree.
The assay method of drug release rate is as follows:
Get this product, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 C the second method), take the 0.01mol/L phosphate sodium dihydrogen buffer solution that contains 0.5% sodium lauryl sulphate (regulating pH value to 7.0 with 50% sodium hydroxide solution) 900ml as release medium, rotating speed is that per minute 50 turns, in accordance with the law operation, got respectively solution 5 ml at 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, filter with 0.45 μ m filter membrane, and immediately in process container, replenish medium 5ml, get subsequent filtrate as need testing solution.It is an amount of that other gets the simvastatin reference substance, accurately weighed, add the stripping medium dissolves and quantitatively dilution make the solution product solution in contrast that contains 24 μ g among every 1ml.Detect according to following chromatographic condition: be filler with octadecylsilane chemically bonded silica: take 0.025mlo/L sodium dihydrogen phosphate (regulating pH value to 4.5 with phosphoric acid or sodium hydroxide)-acetonitrile (35:65) as mobile phase; The detection wavelength is 238nm, each is an amount of to get simvastatin reference substance and lovastatin reference substance, add the lower mixed solution dissolving of discriminating (2) and dilute and make that each approximately contains the solution of 20 μ g among every 1ml, get 20 μ g injection liquid chromatographies, calculate respectively every in the burst size of different time points, the release curve chart is referring to accompanying drawing 1-8.
20 hours cumulative release degree results of prescription embodiment are as follows among the present invention, 0-16 hour release profiles linear fit R
2Following (wherein, the R of result
2More near 1, prove that it more has the zero-order release characteristic).
The cumulative release degree was 94.5%, R in embodiment 1:20 hour
2Be 0.9983
The cumulative release degree was 90.7%, R in embodiment 2:20 hour
2Be 0.9969
The cumulative release degree was 91.1%, R in embodiment 3:20 hour
2Be 0.9784
The cumulative release degree was 90.9%, R in embodiment 4:20 hour
2Be 0.9969
The cumulative release degree was 90.3%, R in embodiment 5:20 hour
2Be 0.9986
The cumulative release degree was 95.3%, R in embodiment 6:20 hour
2Be 0.9995
The cumulative release degree was 83.0%, R in comparative example 1:20 hour
2Be 0.9937
The cumulative release degree was 97.8% in comparative example 2:45 minute.
Experimental example 2 different pH value and different rotating speeds are on the impact of vitro drug release
(1) release research in the different pH value media
Drug release determination method in the reference example 1 is selected different pH value media, to the release research of the simvastatin osmotic pump tablet of the embodiment of the invention 6.Because simvastatin can comparatively fast be degraded in the pH=1.2 hydrochloric acid solution, the inventor is chosen in the pH=4.5 acetate buffer and the pH=6.8 phosphate buffer carries out release research, in addition, in order to guarantee the sink conditions of release medium, the inventor adds 0.5% sodium lauryl sulphate and increases the dissolubility of medicine in release medium in above-mentioned medium.The results are shown in following table.
Preparation release result of the present invention under the different pH of table 1
The result shows, the medicine control of preparation of the present invention be released in change under the different pH condition little.
(2) different rotating speeds is studied release
For investigating external force to the impact of drug release, the embodiment of the invention 6 is discharged similarity evaluation, take the 0.01mol/L phosphate sodium dihydrogen buffer solution that contains 0.5% sodium lauryl sulphate (regulating pH value to 7.0 with 50% sodium hydroxide solution) 900ml as release medium, under 50rpm, 75 rpm and 100rpm, carry out respectively comparative Study on Release, the results are shown in following table.
Preparation drug release determination result of the present invention under table 2 different rotating speeds
50rpm is standard release conditions release result.Preparation of the present invention carries out the f2 similar factors relatively with the lower drug release determination result of standard conditions (50rpm) under 75rpm and 100rpm, it all is 90 that the f2 similar factors of self-control sample is respectively, as seen rotating speed does not exert an influence to the release of preparation of the present invention, and the medicine control that has embodied osmotic pump preparation discharges feature not affected by environment.
Experimental example 3 outer film coat are on the impact of tablet release of the present invention
The simvastatin osmotic pump tablet of above embodiment preparation is carried out outer film coat with the high-efficiency coating pot, coating conditions is: 55～65 ℃ of inlet temperature, 40～55 ℃ of sheet bed tempertaures, atomizing pressure 0.3～0.4bar, coating pan rotating speed 3～5rpm, charging flow velocity 40～50g/min, coating weightening finish 6% was 40 ℃ of lower aeration-dryings 2 hours.Outer film coat liquid prescription is as follows:
Table 3 outer film coat prescription
| Form | Consumption (g) |
| Stomach dissolution type |
100 |
| 80% ethanol * | 1000 |
*Ethanol is removed between coating process and dry period
In the stomach dissolution type Opadry II type coating material stripping alcoholic solution, the osmotic pump tablet for preparing among the embodiment is carried out outer film coat.
The tablet of embodiment 6 after the outer film coat is carried out drug release determination with the tablet that does not carry out the embodiment 6 of outer film coat, and assay method the results are shown in following table referring to experimental example 1:
Table 4 outer film coat is on the research of release impact
Result of study shows, outer film coating on the release of preparation of the present invention without impact.
Experimental example 4 release characteristics agreements
Get 8 of the simvastatin osmotic pump tablets of embodiment 6 preparation, with reference to drug release determination method in the experimental example 1, carry out drug release determination.Concrete data see the following form:
Table 5 preparation release of the present invention concordance result
Discharge the homogeneity result of study and show, this sample is better at each sample point release consistency.
The test of experimental example 5 interior medicine dynamics
Adopt the random trial design of binary cycle, with 8 Beagle dogs, be divided at random 2 groups, be A group and B group; Difference oral test preparation (osmotic tablets of the embodiment of the invention 6 preparations) and reference preparation (comparative example's 2 preparations), the eluting phase was 2 weeks.
The front test dog overnight fasting of taking medicine, in morning next day the 7:00 (medicine) being taken before meal with 1 of 1 of test preparation simvastatin slow-release tablet or reference preparation simvastatin sheet, gavage with 60ml warm water, respectively at after (0h) and the administration before the administration 0.25,0.5,1.0,1.5,2.0,2.5,3.0,4.0,6.0,8.0,10,12,18,24 h are from tested dog hind leg venous blood sampling 3ml, put into heparin sodium anticoagulant test tube, the about 30s of jolting gently, under the 3000rpm condition centrifugal 15 minutes immediately, get supernatant and put into the EP pipe ,-20 ℃ freezing to be measured.Intersect after 2 weeks and take medicine;
Adopt the LC-MS/MS method to measure blood drug level, chromatographic condition is as follows: chromatographic column: Agilent zorbax extended C18(100mm * 2.1mm, 3.5 μ m); Mobile phase: A phase: acetonitrile (0.2% formic acid), B phase: 0.2% aqueous formic acid, flow velocity 0. 5ml/min; Carry out gradient elution, the gradient program sees Table 6, column temperature: 35 ℃; Injector temperature: 10 ℃; Sample size: 10 μ l.
Table 6 gradient program
| Time (minute) | |
| 0 | 95 |
| 2 | 95 |
| 4 | 20 |
| 7.5 | 0 |
| 7.6 | 95 |
| 10 | 95 |
Mass spectrum condition: ESI ion source; Spray voltage (IS): 5500V; Atomization air pressure Gas1 (GS1): 50psig; Assist gas pressure Gas2 (GS2): 40 psig; Ion source temperature (TEM): 500 ℃; Collision atmospheric pressure (CAD): 5 psig; Gas curtain atmospheric pressure (CUR): 10 psig; Interface heater (Ihe): ON; Entrance voltage (EP): simvastatin, lovastatin are respectively 10V, 11V; Remove a bunch voltage (DP): 40V; Collision energy (CE): simvastatin, lovastatin are respectively 25V, 20V; Collision cell entrance voltage (CEP): simvastatin, lovastatin are respectively 20V, 30V; Collision cell outlet voltage (CXP): 5V; The cation mode detects, and scan mode is multiple-reaction monitoring (MRM), is used for quantitative ion and is respectively simvastatin m/z: parent ion 419.3, daughter ion 199.3; Interior mark lovastatin m/z: parent ion 405.3, daughter ion 199.2; Be 0.2s sweep time.Mass spectrum switches online: sample incision mass spectral analysis in 5.5 ~ 7.5 minutes, all the other cut waste liquid.
Curve chart is seen accompanying drawing 9 during the medicine of single dose administration, and main pharmacokinetic parameter sees Table 7.
The main pharmacokinetic parameters of table 7 single-dose
| Parameter | Preparation of the present invention | The commercial preparation |
| C max(ng/ml) | 33.88±10.97 | 46.03±19.69 |
| T max(h) | 12.0±4.0 | 6.8±5.2 |
| AUC 0-48 (ng·h/ml) | 677.80±329.29 | 665.32±289.95 |
| T 1/2(h) | 10.30±3.76 | 8.84±1.54 |
| F(%) | 114.25±65.8 | ? |
Claims (6)
1. simvastatin osmotic pump tablet, it is a kind of mono-layer osmotic pump sheet, comprise label and release-controlled film clothing layer, wherein label contains 1-20% simvastatin, 1-25% filler, 50-90% penetrating agent, 1-15% binding agent, 0.5-5% release regulator and 0.5-3% lubricant, release-controlled film clothing layer comprises release-controlled film filmogen and porogen, wherein, filler is selected from the mixture of microcrystalline Cellulose and dextrin, penetrating agent is selected from the mixture of sucrose and lactose, release regulator is selected from polyoxyethylene, the release-controlled film filmogen is cellulose acetate, and porogen is selected from Polyethylene Glycol.
2. simvastatin osmotic pump tablet according to claim 1 wherein further contains surfactant in the label, and described surfactant is sodium lauryl sulphate.
3. simvastatin osmotic pump tablet according to claim 1, lubricant wherein is selected from magnesium stearate, and binding agent is selected from polyvidone.
4. each described simvastatin osmotic pump tablet according to claim 1-3, the outer surface of tablet further comprises the outer film coat layer.
5. simvastatin osmotic pump tablet according to claim 1 is grouped into by the one-tenth of following percentage by weight:
Perhaps:
The release-controlled film clothing forms %
Cellulose acetate 80
PEG-4000 20
Perhaps:
The release-controlled film clothing forms %
Cellulose acetate 80
PEG-4000 20
Perhaps:
The release-controlled film clothing forms %
Cellulose acetate 80
PEG-4000 20
Perhaps:
The release-controlled film clothing forms %
Cellulose acetate 80
PEG-4000 20
Perhaps:
The release-controlled film clothing forms %
Cellulose acetate 80
PEG-4000 20.
6. the preparation method of each described simvastatin osmotic pump tablet among the claim 1-5 may further comprise the steps:
1) except lubricant, principal agent and other label compositions are mixed, to granulate, drying adds lubricant, mixing;
2) tablet machine tabletting;
3) label is carried out the release-controlled film coating;
4) at coated tablet two side perforatings.
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| CN1903194A (en) * | 2005-07-26 | 2007-01-31 | 安徽省现代中药研究中心 | Slow-release, controlled-release prepn. of simvastatin, and method for preparing same |
| CN101352425A (en) * | 2007-07-27 | 2009-01-28 | 鲁南制药集团股份有限公司 | Compound osmotic pump controlled release preparation and preparation method thereof |
| CN102028668A (en) * | 2009-09-29 | 2011-04-27 | 鲁南制药集团股份有限公司 | Simvastatin osmotic pump controlled-release tablet |
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| CN1903194A (en) * | 2005-07-26 | 2007-01-31 | 安徽省现代中药研究中心 | Slow-release, controlled-release prepn. of simvastatin, and method for preparing same |
| CN101352425A (en) * | 2007-07-27 | 2009-01-28 | 鲁南制药集团股份有限公司 | Compound osmotic pump controlled release preparation and preparation method thereof |
| CN102028668A (en) * | 2009-09-29 | 2011-04-27 | 鲁南制药集团股份有限公司 | Simvastatin osmotic pump controlled-release tablet |
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