CN102512398A - 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 controlling blood content of cholesterol and angiocardiopathy preventing.Clinically be used to treat hypercholesterolemia, coronary heart disease.
Simvastatin is global situation of selling well pravastatin, with the generic drug of independent composition and commodity famous medicine Zocor (Mo Shadong Merck) sells, also have with according to 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 (Scandinavia Simvastatin Survival Study to the multi-center randomized double of 4444 routine patients with coronary heart disease; 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 that simvastatin can make the TC level reduce by 25%, and LDL reduces 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%.Proved that first reinforcement blood fat reducing treatment except that 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.
2004, HPS (Cardioprotective research) observed the influence of simvastatin 40mgd-1 to prognosis to the high-risk patient that 20536 examples suffered from coronary heart disease and other atheromatosiss or diabetes in 40 ~ 80 years old.The result shows that 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 his ratio of spit of fland medicine 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 the risk that LDL-C (27%) and poor risk crowd suffer from 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 cardiovascular event in 10 years, occurs 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) pharmacokinetics result, 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 that every day, a slice simvastatin conventional tablet was taken in (24 hours), in the most of the time, is lower than treatment concentration.Simultaneously, conventional tablet has tangible blood drug level peak C max, the size of this value and myopathy risk positive correlation, and more greatly then the myopathy risk is big more for this value.
At present the formulation art technical staff attempts through using the control release technic of preparation the steady release of medicine to be provided, and avoids too high peak concentration value and reduces the myopathy risk, and it is interval and improve curative effect to prolong effectively treatment concentration simultaneously.
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 made up of lactose, fructose, 30 POVIDONE K 30 BP/USP 30.US5882682A also discloses the simvastatin osmotic pump tablet, and wherein label is made up 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 ideal 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 of desirable zero-order release, high, better stability of preparation of bioavailability of reaching, and release is complete, technology 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 administration once a day 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 the 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 for use adjuvant as filler with thickening power; 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; Release regulator can rapid expansible adjuvant 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; For example 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 possibly be a kind of material or multiple mixture, like 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; On its release-controlled film, preferably have one or two drug release hole, 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, and the release characteristics of medicine is not had influence.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 strange E100 of Eudragit You Te of Degussa-Rohm company); Other water-soluble polymers are selected from polyvidone (preferred 30 POVIDONE K 30 BP/USP 30) and copolymerization polyvidone or mainly contain polyvidone and the coating pre-mixing agent of copolymerization polyvidone, polyvinyl alcohol/polyethyleneglycol-graft copolymer or mainly contain the 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 be meant commercially available that prepared, convenient that use, mainly contain the coating intermixture that has mixed in advance of above-mentioned film material (also possibly contain 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 being suppressed should satisfy officinal requirement, 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 influence the osmotic pump tablet release characteristics at a distance from protection osmotic pump tablet such as wet protection against the tide, its film material can adopt the conventional thin film coating material in this area, and coating gain in weight definite also is that those skilled in the art pass through simple experiment and just can obtain; 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.Inventor of the present invention 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 disintegrating agent, antioxidant, correctives, aromatic, coloring agent, opacifier of medicament known etc.; For example; Disintegrating agent can be a 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, for example carmine, sunset yellow, indigo, viride nitens, red ferric oxide, yellow ferric oxide, Black Rouge etc.; Opacifier possibly be a kind of material or multiple mixture, like titanium dioxide, Pulvis Talci, micropowder silica gel.These optional ingredients 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 accomplish.
In special embodiment of the present invention, also preferably used polyoxyethylene as Osmolyte regulator.The polyoxyethylated molecular weight of selecting for use can be 100,000～1,000 ten thousand, and is preferred 10～8,000,000, most preferably 10～5,000,000, preferred especially 200～5,000,000.
Another object of the present invention also provides the method for preparing of above-mentioned simvastatin osmotic pump tablet, may further comprise the steps:
1) except that 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, method for preparing of the present invention also is included in the step of the outer protective film clothing of punched sheet bag.
Preferably, the method for preparing of simvastatin osmotic pump tablet of the present invention may further comprise the steps:
1) except that lubricant, other label constituent is mixed, add ethanol system soft material, 30 orders～40 mesh sieves are granulated, and drying adds lubricant, mixing;
2) will process granule and use 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, method for preparing 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 said ethanol.
Wherein, Said 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; Release regulator can rapid expansible adjuvant 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; For example 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 possibly be a kind of material or multiple mixture, like 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 said 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 disclosed technology in the prior art.For example, tabletting can adopt equipment such as single punch tablet machine, rotary tablet machine; Coating can adopt but be not limited to 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 in the certain hour scope, to discharge medicine with constant rate of releasing drug; And do not receive the influence of factors such as media environment pH value, gastrointestinal peristalsis and food; Has inside and outside dependency preferably; The phenomenon that the blood concentration fluctuation that can avoid common oral preparation to cause is bigger improves bioavailability, greatly improves 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 a 30 POVIDONE K 30 BP/USP 30.Yet following examples only are used to explain the present invention, are not to be used to limit 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 the present invention's protection.
Embodiment 1
?
| The release-controlled film clothing is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 7.2 | 90 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| Polyethylene Glycol-1500 | 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, subsequent use; Tween-80 added add above dry powder system soft material behind the dissolve with ethanol; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 6.4 | 80 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 is formed | Every consumption (mg) | Ratio (%) |
| Cellulose acetate | 7.2 | 90 |
| Polyethylene Glycol-1500 | 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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 system soft material; Soft material is granulated with 30 mesh sieves; Dry back 20 mesh sieve granulate add magnesium stearate, mixing then; To make granule and use the 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, investigation release wire implementations at 4-16 hour release profiles; And embodiment and comparative example investigated at 20 hours cumulative release degree.
The assay method of drug release rate is following:
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method); 0.01mol/L phosphate sodium dihydrogen buffer solution (regulating pH value to 7.0 with 50% sodium hydroxide solution) 900ml to contain 0.5% sodium lauryl sulphate is a release medium, and rotating speed is that per minute 50 changes, operation in accordance with the law; Got solution 5 ml respectively at 4 hours, 8 hours, 12 hours, 16 hours, 20 hours; Filter with 0.45 μ m filter membrane, and in process container, replenish medium 5ml immediately, get subsequent filtrate as need testing solution.It is an amount of that other gets the simvastatin reference substance, accurate claim fixed, add the stripping medium dissolves and quantitatively dilution process contain 24 μ g among every 1ml solution as reference substance solution.Detect according to following chromatographic condition: use octadecylsilane chemically bonded silica to be filler: be mobile phase with 0.025mlo/L sodium dihydrogen phosphate (regulating pH value to 4.5)-acetonitrile (35:65) with phosphoric acid or sodium hydroxide; The detection wavelength is 238nm; Each is an amount of to get simvastatin reference substance and lovastatin reference substance; Add discriminating (2) mixed solution dissolving and diluting down and process that each contains the solution of 20 μ g approximately among every 1ml; Get 20 μ g and inject chromatograph of liquid, calculate every burst size respectively, discharge and write music line chart referring to accompanying drawing 1-8 in different time points.
20 hours cumulative release degree results of prescription embodiment are following among the present invention, 0-16 hour release profiles linear fit R
2The result is (wherein, R as follows
2Near 1, prove that it has the zero-order release characteristic more more).
The cumulative release degree was 94.5% in embodiment 1:20 hour, R
2Be 0.9983
The cumulative release degree was 90.7% in embodiment 2:20 hour, R
2Be 0.9969
The cumulative release degree was 91.1% in embodiment 3:20 hour, R
2Be 0.9784
The cumulative release degree was 90.9% in embodiment 4:20 hour, R
2Be 0.9969
The cumulative release degree was 90.3% in embodiment 5:20 hour, R
2Be 0.9986
The cumulative release degree was 95.3% in embodiment 6:20 hour, R
2Be 0.9995
The cumulative release degree was 83.0% in comparative example 1:20 hour, R
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 to the influence of vitro drug release
(1) release degree research in the different pH value media
Drug release determination method in the reference implementation example 1 is selected different pH value media, to the release degree 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 pH=4.5 acetate buffer and the research of pH=6.8 phosphate buffer degree of release; 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 result sees the following form.
Preparation release degree result of the present invention under the different pH of table 1
The result shows that the medicine sustained release of preparation of the present invention changes not quite under different pH condition.
(2) different rotating speeds is studied the release degree
For investigating the influence of external force to drug release; The embodiment of the invention 6 is discharged similarity evaluation; 0.01mol/L phosphate sodium dihydrogen buffer solution (regulating pH value to 7.0 with 50% sodium hydroxide solution) 900ml to contain 0.5% sodium lauryl sulphate is a release medium; Under 50rpm, 75 rpm and 100rpm, carry out comparative Study on Release respectively, the result sees the following form.
Preparation drug release determination result of the present invention under table 2 different rotating speeds
50rpm is standard release conditions release degree result.Preparation of the present invention drug release determination result under 75rpm and 100rpm and under the standard conditions (50rpm) carries out the f2 similar factors relatively; It all is 90 that the f2 similar factors of self-control sample is respectively; It is thus clear that rotating speed does not exert an influence to the release degree of preparation of the present invention, embodied the medicine sustained release characteristic not affected by environment of osmotic pump preparation.
Experimental example 3 outer film coat are to the influence of tablet release degree 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 EATs, 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 following aeration-dryings 2 hours.Outer film coat liquid is write out a prescription 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 after the outer film coat 6 is carried out drug release determination with the tablet that does not carry out the embodiment 6 of outer film coat, and assay method is referring to experimental example 1, and the result sees the following form:
Table 4 outer film coat is to the research of release degree influence
Result of study shows that the outsourcing film-coat does not have influence to the release of preparation of the present invention.
Experimental example 4 release characteristics concordance researchs
Get 8 of the simvastatin osmotic pump tablets of embodiment 6 preparation,, carry out drug release determination with reference to drug release determination method in the experimental example 1.Concrete data see the following form:
Table 5 preparation release of the present invention degree concordance result
Discharge the homogeneity result of study and show that this sample is better at each sample point release consistency.
The test of experimental example 5 interior medicine dynamics
Adopt binary cycle trial design at random,, be divided into 2 groups at random, be A group and B group 8 Beagle dogs; 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.
Test dog overnight fasting before 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, obey with the filling of 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 got blood 3ml from trying dog hind leg vein, 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 ℃ are 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 following: 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 is seen 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; Inlet 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 inlet 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.The online switching of mass spectrum: 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 is seen 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 (10)
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 simvastatin, filler, penetrating agent, binding agent, release regulator and lubricant, and release-controlled film clothing layer comprises release-controlled film filmogen, plasticizer and/or porogen.
2. according to the tablet of claim 1, wherein contain in the label to account for the label total weight percent: 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%.
3. according to the tablet of claim 2, filler wherein contains microcrystalline Cellulose and dextrin; Penetrating agent contains sucrose and lactose.
4. according to the tablet of above each claim, wherein further contain surfactant in the label, wherein surfactant is a sodium lauryl sulphate.
5. according to the tablet of claim 4, surfactant wherein is a sodium lauryl sulphate.
6. according to the tablet of above each claim, wherein release regulator is selected from polyoxyethylene.
7. according to the tablet of above each claim, on release-controlled film, include drug release hole.
8. according to the tablet of above each claim, the outer surface of tablet further comprises the outer film coat layer.
9. according to the tablet of claim 1, form by following component in percentage by weight:
Label composition %
Simvastatin 8.0
PEO 2.0
Sucrose 32.0
Lactose 32.0
Dextrin 10.8
Microcrystalline Cellulose 6.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 90
Polyethylene Glycol-1,500 5
Triethyl citrate 5
Perhaps:
Label composition %
Simvastatin 8.0
PEO 2.0
Sucrose 16.0
Lactose 48.0
Dextrin 10.8
Microcrystalline Cellulose 6.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 80
Polyethylene Glycol-1,500 20
Perhaps:
Label composition %
Simvastatin 8.0
PEO 2.0
Sucrose 48.0
Lactose 16.0
Dextrin 10.8
Microcrystalline Cellulose 6.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 80
Polyethylene Glycol-1,500 20
Perhaps:
Label composition %
Simvastatin 8.0
PEO 0.8
Sucrose 34.0
Lactose 32.0
Microcrystalline Cellulose 4.0
Dextrin 12.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 80
Polyethylene Glycol-1,500 20
Perhaps:
Label composition %
Simvastatin 8.0
PEO 0.8
Sucrose 34.0
Lactose 32.0
Microcrystalline Cellulose 12.0
Dextrin 4.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 80
Polyethylene Glycol-1,500 20
Perhaps:
Label composition %
Simvastatin 8.0
PEO 0.8
Sucrose 34.0
Lactose 32.0
Microcrystalline Cellulose 8.0
Dextrin 8.0
Sodium lauryl sulphate 4.0
Polyvidone 4.0
Vitamin C 0.2
Magnesium stearate 1.0
The release-controlled film clothing is formed %
Cellulose acetate 80
Polyethylene Glycol-1,500 20.
10. the method for preparing of the tablet of above each claim may further comprise the steps:
1) except that 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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| CN112336697A (en) * | 2020-10-27 | 2021-02-09 | 广州新济药业科技有限公司 | Simvastatin pulse release tablet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006054307A2 (en) * | 2004-11-22 | 2006-05-26 | Dexcel Pharma Technologies Ltd. | Controlled absorption of statins in the intestine |
| 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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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006054307A2 (en) * | 2004-11-22 | 2006-05-26 | Dexcel Pharma Technologies Ltd. | Controlled absorption of statins in the intestine |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336697A (en) * | 2020-10-27 | 2021-02-09 | 广州新济药业科技有限公司 | Simvastatin pulse release tablet and preparation method thereof |
| CN112336697B (en) * | 2020-10-27 | 2022-12-13 | 广州新济药业科技有限公司 | Simvastatin pulse release tablet and preparation method thereof |
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