CN101879146A - Controlled release preparation and preparation method thereof - Google Patents
Controlled release preparation and preparation method thereof Download PDFInfo
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- CN101879146A CN101879146A CN200910039283XA CN200910039283A CN101879146A CN 101879146 A CN101879146 A CN 101879146A CN 200910039283X A CN200910039283X A CN 200910039283XA CN 200910039283 A CN200910039283 A CN 200910039283A CN 101879146 A CN101879146 A CN 101879146A
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Abstract
The invention provides a controlled release preparation and a preparation method thereof. The controller release preparation is characterized in that dual-layer osmotic pump tablet semi-permeable membrane is covered by a drug-containing coating layer which can rapidly release partial drug active constituent of marked dosage; and a dual-layer osmotic pump tablet core is formed by two layers, one layer contains most drug active constituent of the marked dosage and permeation enhancing substances, the other layer contains permeable substances, the tablet core is covered by the semi-permeable membrane containing polymers, and a small hole is arranged on the semi-permeable membrane on the side of a drug-containing active constituent layer. The controlled release preparation solves the problem that the release of the dual-layer osmotic pump tablet in vitro and in vivo is lagged behind for 1-3 hour, and can reduce the incomplete release of the active constituent. The preparation method of the controlled release preparation comprises the following steps that the drug active constituent accounting for large part of the marked content is prepared in the dual-layer tablet and then the rest drug active constituent is covered in the coating layer of the dual-layer tablet. Preferably, felodipine is selected as the drug active constituent.
Description
Technical field
The invention belongs to pharmaceutical field, the preparation method of a kind of controlled release preparation and said preparation is provided.
Background technology
US4765989 discloses the patent of a kind of push-pull type (push-pull) osmotic pumps double-layer tablet principle, is applicable to poorly water-soluble or water-fast active constituents of medicine nifedipine, doxazosin and prazosin.The release of this osmotic pump tablet is subjected to the influence of release medium hardly.The double-layer tablet that its structure is wrapped up by semipermeable membrane, wherein one deck contains active constituents of medicine and polymer, and another layer contains the polymer that can produce hyperosmosis and swelliong power is arranged, and has an aperture to be used to discharge active constituents of medicine on the film of medicated layer side.Semipermeable membrane can only see through moisture, can not see through medicine etc.After meeting water, moisture slowly enters and contains medicine active component layer and osmotic swelling layer, and containing medicine active component layer, to be liquefied as suspendible gradually aqueous, and the osmotic swelling layer expands gradually the suspension that contains the medicine active component is discharged from aperture gradually.Because need time enough moisture just can enter in the sheet, making medicine layer absorb moisture begins liquefaction and makes the osmotic swelling layer absorb moisture to begin to expand, therefore such tablet all shows as 1～3 hour sluggishness with intravital release outside human body, be that active constituents of medicine does not during this period of time almost have release or burst size seldom (Toal CB.Formulation dependent pharmacokinetics--does the dosage form matter for nifedipine.J Cardiovasc Pharmacol, 2004; 44 (1): 82-6).The another one problem of this type of sheet is that active constituents of medicine discharges not exclusively, have 10% can not discharge approximately, therefore need to increase the dosage of the medicine in the medicine layer, be medicine layer contain than indicate content Duo 10% active constituents of medicine could with slow releasing tablet bioequivalence [document (1) the Swanson DR of ordinary tablet or other release mechanisms, Barclay BL, Wong PSL, Theeuwes F.Nifedipine gastrointestinal therapeutic system.Am J Med, 1987,83 (suppl 6B): 3-10.Document (2) Gan Yong etc. the preparation of glipizide double-layer osmotic pump controlled-release tablet and release in vitro degree are investigated Shenyang Pharmaceutical University's journal 2002,19 (3): 157-160].The defective that the active component that solution osmotic pumps double-layer tablet exists can not discharge fully, adopt at present than labelled amount and Duo the method for 10% actual content, for example the actual content of the osmotic pumps Nifedipine controlled-release tablet Adalat LA 20 (20mg/ sheet) of Bayer company, Adalat LA 30 (30mg/ sheet) and Adalat LA 60 (60mg/ sheet) is all Duoed 10% nifedipine than labelled amount, being every, to indicate content be the Nifedipine controlled-release tablet of 20mg/ sheet, 30mg/ sheet and 60mg/ sheet, the actual amount that contains nifedipine be respectively 22mg, 33mg and 66mg (
Http:// emc.medicines.org.uk/medicine/20531/SPC/Adalat+LA+20/ #COMPOSITION)But, can not solve this type tablet and outside human body, all show as 1～3 hour sluggish problem with intravital release.
Patent application CN1931167A discloses a kind of double layer osmotic pump controlled release felodipine medicine composition patent, and its active constituents of medicine also is all in double-layer tablet.
Summary of the invention
The invention provides a kind of a kind of new controlled release preparation that overcomes the above-mentioned defective of osmotic pumps double-layer tablet, it not only can solve the osmotic pumps double-layer tablet and all show as 1～3 hour sluggish problem with intravital release outside human body, and can reduce the incomplete release of active component.
The present invention also provides the preparation method of this novel controlled release preparation.
Novel controlled release preparation of the present invention is two parts that the active component that will indicate content places preparation unit respectively, wherein double-layer osmotic pump tablet contains the most of active constituents of medicine that indicates in the content, also is enclosed with one deck and contains the pastille coatings that indicates remainder active constituents of medicine in the content outside the semipermeable membrane of double-layer tablet.The release characteristic of this controlled release preparation shows as that the contained drug active component can discharge rapidly in the pastille coatings that is wrapped in semipermeable membrane, discharges sluggish; Reduced the incomplete release of double-layer osmotic pump tablet Chinese medicine active component simultaneously.
Especially when active component was felodipine, the actual content of felodipine equaled to indicate content in this controlled release preparation, do not need extra increase the active component of Duoing than sign content promptly can with other preparation bioequivalences of the identical active component of identical sign content.
A preparation unit of the present invention comprises with the lower part: label, wrap up this label semipermeable membrane (hereinafter referred to as semipermeable membrane), be wrapped in the coatings that contains the active constituents of medicine felodipine (hereinafter referred to as the pastille coatings) of the aperture that communicates with medicine layer in the semipermeable membrane central authorities of containing the medicine layer side and parcel semipermeable membrane.Above-mentioned label is a double-layer tablet, and wherein one deck is for containing medicine active component layer (hereinafter referred to as medicine layer), and another layer is osmotic swelling layer (hereinafter referred to as a promoting layer).
The active constituents of medicine that contains in the medicine layer of the present invention can account for and indicate 40%～99% of content.Sign content among the present invention is meant the total amount of the actual active constituents of medicine that contains in the unit preparation (a slice), the total amount of the felodipine that unit in the commercially available felodipine preparation of other that are equally applicable to mention among the present invention (a slice or) contains.
Medicine layer of the present invention also contains permeate substance and/or osmopolymer (infiltration promote material) except that active constituents of medicine, its effect is to absorb moisture and generation/keep osmotic pressure.Permeate substance among the present invention is meant the material that can be dissolved in water and produce osmotic pressure, comprises acceptable lactose, fructose, glucose, sucrose, mannitol and inorganic salt on the medicament.Inorganic salt comprises sodium chloride, potassium chloride, potassium sulfate, sodium dihydrogen phosphate etc. and their mixture.
Osmopolymer among the present invention is meant to have hydrophilic, water absorbing capacity and can remain on the high molecular polymer that promotes infiltration in the structure of polymer to moisture.Osmopolymer in the medicine layer of the present invention be selected from polyoxyethylene (Polyox of for example commercially available Dow company, molecular weight 100,000～1,000,000), low viscous hypromellose (viscosity 2cps～100cps), hyprolose, low viscous sodium carboxymethyl cellulose (10～100mPa.s), cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone (polyvidone), crospolyvinylpyrrolidone, carbopol etc. and their mixture.
Medicine layer of the present invention contains above-mentioned at least a permeate substance and at least a osmopolymer.
Also can contain the excipient that is convenient to produce preparation in the medicine layer simultaneously, for example lubricant is selected from pharmaceutically acceptable stearic acid, magnesium stearate etc.; For example anti-adhesive is selected from pharmaceutically acceptable Pulvis Talci, silicon dioxide and colloidal silica etc.The consumption of these excipient is 0.1%～5% of a medicine layer weight.Normally before tabletting, join in the granule that contains medicine mix homogeneously.
For tabletting, there are two kinds of methods to prepare medicine layer granule (Parikh DM.Handbook of Pharmaceutical Granulation Technology.Marcel Dekker Inc., New York.1997).A kind of is wet granulation process, with accounting for felodipine, penetrating agent and/or the osmopolymer mix homogeneously that indicates content 40%～99%, adds an amount of solvent that contains binding agent then and makes granule.Usually use and be dissolved with an amount of low viscous hypromellose (5～50cps) or dehydrated alcohol, ethanol or the ethanol water of polyvinylpyrrolidone (molecular weight 2500～3000000, molecular weight commonly used are 50000 be 30 POVIDONE K 30 BP/USP 30).Method with routine is granulated.Granule is being dried below 50 ℃, then granulate.Another method is a dry granulation, with active constituents of medicine, penetrating agent and/or osmopolymer mix homogeneously, places the dry granulation machine, adopts the screen cloth of suitable particle diameter to make granule.Add proper amount of lubricating agent and/or anti-adhesive in the granule that above-mentioned two kinds of methods are made, place the mixer mix homogeneously.
Contain permeate substance and osmopolymer (infiltration promotes material) in another layer (hereinafter referred to as promoting layer) of double-deck label among the present invention.The permeate substance that is fit in the promoting layer of the present invention is same as above.Osmopolymer in the controlled release preparation promoting layer of the present invention is selected from polyoxyethylene (polyethyle oxide, PEO, the Polyox of for example commercially available Dow company, molecular weight 100,000～1,000 ten thousand, preferred molecular weight is 3,000,000～7,000,000 polyoxyethylene), hypromellose (viscosity 5cps～12000cps, 1cps=mPa.s), high-viscosity sodium carboxymethyl cellulose (1500～12000mPa.s), carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone (polyvidone), crospolyvinylpyrrolidone, carbopol etc.
Promoting layer of the present invention contains above-mentioned at least a permeate substance and a kind of osmopolymer.
Also can contain the pharmaceutically acceptable excipient that is convenient to produce preparation in the promoting layer simultaneously, for example lubricant is selected from pharmaceutically acceptable stearic acid, magnesium stearate etc.; For example anti-adhesive is selected from pharmaceutically acceptable Pulvis Talci, silicon dioxide and colloidal silica etc.Consumption is 0.1%～5% of a promoting layer weight.Normally before tabletting, join in the granule that contains medicine mix homogeneously.
Promoting layer can also add coloring agent so that distinguish medicine layer and promoting layer simultaneously, coloring agent is selected from acceptable coloring agent on red ferric oxide, yellow ferric oxide, Brown Ferric Oxide, Black Rouge, purple ferrum oxide or other medicaments, common addition be promoting layer heavy 0.1%～4%.
Medicine layer granule of more than making and promoting layer granule place the hopper of bi-layer tablet press respectively, determine the weight of medicine layer and the weight of promoting layer, are pressed into the double-layer tablet of regulation hardness, become the label (to call label in the following text) of double-layer tablet of the present invention.The label of the double-layer tablet among the present invention contains the felodipine that accounts for 40%～99% sign content, preferably contains the felodipine that accounts for 60%～99% sign content.
Label is by one deck semipermeable membrane parcel (hereinafter referred to as semi-transparent rete).The characteristic of this semi-transparent rete be in aqueous solution or in human body, only allow moisture by and do not allow other compositions to comprise that active constituents of medicine passes through.This semipermeable membrane mainly contains cellulose acetate, also contains porogen and plasticizer.Acetate fiber have different substitution values, and its aqueous solution has different viscosity, the cellulose acetate that preferred substitution value is 2.4, viscosity is about 38cp, the CA-398-10NF of for example commercially available Eastman Yi Shi Man.The solvent of dissolving cellulose acetate is selected from dichloromethane, dichloromethane/isopropyl alcohol mixed solvent (90: 10), methyl acetate, acetone, acetone mixed solvent (90: 10) among the present invention.Porogen and plasticizer are selected from hypromellose (HPMC, preferred viscosities 5～75cps), Polyethylene Glycol (PEG, molecular weight 200～20000, preferred molecular weight 400～4000), hyprolose (HPC, molecular weight 80000～1150000), in the polyvidone one or both, also can select for use other that chemical compound of pore and plasticising function is arranged.Porogen is regulated the penetrating rate of semi-transparent film to water, and porogen is many, and the permeability of semipermeable membrane is big, and drug release is fast.Plasticizer can strengthen film strength.Above-mentioned HPMC, PEG and HPC can have the effect of pore and plasticizer simultaneously.Cellulose acetate and porogen be dissolved in make coating solution in the solvent, label is placed the coating machine, method is routinely carried out coating, forms skim parcel label, becomes double-layer tablet (to call double-layer tablet in the following text).
The medicine layer side semipermeable membrane central authorities of double-layer tablet have an aperture to be used for the release of medicine.Usually use laser-beam drilling machine to punch, certainly, also can punch with other method.The aperture is at 0.2～1mm.
Next contain the coatings (hereinafter referred to as the pastille coatings) that indicates the active constituents of medicine of remainder in the content at double-layer tablet outer wrapping one deck.For the active constituents of medicine with this part is wrapped on the double-layer tablet, need to select suitable coating materials.Coating materials of the present invention 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; The acrylate copolymer that uses among the present invention 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.The coating pre-mixing agent be meant commercially available that prepared, convenient that use, mainly contain the above-mentioned coating materials coating intermixture that has mixed in advance of (also containing small amount of plasticizer, anti-adhesive, 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.Also can directly adopt above-mentioned coating materials to add an amount of antitackiness agent (and coloring agent) (adding plasticizer in case of necessity) preparation coating solution.
The different solvent that can select for use according to different coating materials, for example water, alcoholic solution, isopropyl alcohol, acetone, dichloromethane, preferred water or alcoholic solution.Coating materials joined in the proper amount of solvent to stir make coating materials fully dissolve the back to add felodipine and stir, perhaps coating materials and felodipine are joined to stir in the proper amount of solvent together coating materials is fully dissolved, be prepared into coating solution, keep stirring; Double-layer tablet is placed the coating machine, adopt conventional method to carry out coating, the amount of felodipine reaches regulation content (the felodipine amount of this part equals to indicate content and deducts the felodipine amount that contains in the double-layer tablet) in coatings.The coating machine can adopt porose or atresia coating machine.Coatings of the present invention contains the felodipine that accounts for 1%～60% sign content, preferably contains the felodipine that accounts for 1%～40% sign content.
At last, can also play the effect of protection pastille coatings in the common coatings (hereinafter referred to as coatings) of pastille coatings outer wrapping.Material and the coating method selected for use in the same pastille coatings of the material of coating and method.The weight of coatings be generally sheet before the coating heavy 2%～10%.
Though unexpected find its felodipine actual content of felodipine controlled release formulation of the present invention and to indicate content consistent, do not need the extra common slow releasing preparation bioequivalence of felodipine that increases the felodipine of Duoing promptly can identical sign content with other than sign content.
Below provide some embodiment to set forth the present invention and preparation method thereof.It is apparent that in the scope of the invention other changes the pharmaceutical field technical staff, and its preparation is also known by this field personnel.These change not as the qualification to theme of the present invention.
Description of drawings:
Be subjected to blood drug level-time graph of reagent B and reference medicine R among Fig. 1---embodiment 1;
Be subjected to blood drug level-time graph of reagent C and reference medicine R among Fig. 2---embodiment 2;
The release in vitro degree of sheet C and reference medicine R is relatively among sheet B, the embodiment 2 among Fig. 3---embodiment 1.
Among the following embodiment, the release of felodipine is measured by following method:
The lucifuge operation.Get this product, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt the device of dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, first method), phosphate buffer (pH6.5) 500ml with 0.4% cetyl trimethyl ammonium bromide is a release medium, rotating speed is that per minute 150 changes, operation in accordance with the law.Get solution 5ml respectively at different time, filter, get subsequent filtrate, measure with high performance liquid chromatograph as need testing solution.Calculate every burst size by external standard method respectively with peak area at different time.Release is all calculated with the sign content of felodipine in a slice.
Embodiment 1
Prepare label by following prescription
(1), after under the exsiccant environment felodipine being crossed 100 mesh sieves,, adopt 20 eye mesh screens to make granule with the dry granulation machine with lactose, sodium chloride, the abundant mix homogeneously of polyoxyethylene by said medicine layer prescription.Add the magnesium stearate mix homogeneously, become the medicine layer granule.
(2) by above-mentioned promoting layer prescription (except magnesium stearate), after adopting conventional method mix homogeneously under the exsiccant environment, adopt 18 eye mesh screens to make granule with the dry granulation machine.Add the magnesium stearate mix homogeneously, become the promoting layer granule.
(3) medicine layer granule and promoting layer granule are placed the bi-layer tablet press hopper respectively, adopt the circular shallow arc punch die of diameter 8mm, the weight of regulating medicine layer and promoting layer is respectively the weight of approaching above-mentioned every medicine layer and promoting layer, carries out tabletting, obtain label, weight is about 275mg.
(4) (PEG 1450 with cellulose acetate (CA-398-10NF) and Polyethylene Glycol 1450, consumption=24% cellulose acetate weight) is dissolved in acetone, make solids content in the acetone (cellulose acetate+PEG 1450) be about 4.4%, stirring makes it to dissolve fully, becomes semipermeable membrane solution.Label is placed the coating machine, regulate 35～45 ℃ of inlet temperature, after the label preheating, semipermeable membrane solution is sprayed on the label until the weightening finish of label about 12.5%, make double-layer tablet.In 40～50 ℃ dry environment, placed about 24 hours.
(5) make a call to the aperture of the about 0.4～0.7mm of a diameter with laser-beam drilling machine in the film central authorities that contain felodipine layer side of double-layer tablet.Receive sheet be called sheet A.Release sees Table 1.
(6) with Opadry (Opadry, stomach dissolution type, what Colorcon company produced can promptly join the i.e. coating pre-mixing agent of usefulness, mainly contain low viscous HPMC, also contain Pulvis Talci, stearic acid etc., also can contain pigment and brightener as required) place 50% alcoholic solution, make that the content of Opadry is about 8% in the solution, fully stir with agitator and make the HPMC dissolving and keep stirring.Double-layer tablet is placed the coating machine, regulate about 45 ℃ of inlet temperature, coating solution is sprayed on the double-layer tablet until the weightening finish of sheet about 6%.The sheet that makes is called sheet B, and release sees Table 1 and Fig. 3.
Plendil: the felodipine sustained-release tablets that Sweden's AstraZeneca (Astra-Zeneca) pharmaceutical Co. Ltd produces, the 5mg/ sheet, release sees Table 1 and Fig. 3.
Compare sheet A and sheet B as seen, both do not have significant difference at release.Both all have the hangover more than 1 hour.
The release of table 1 A, sheet B and Plendil (average, %, n=6) and similar factors (f
2)
| Time (hour) | ??1 | ??2 | ??4 | ??6 | ??8 | ??10 | ??f 2 |
| Sheet A | ??5.5 | ??19.6 | ??47.2 | ??73.8 | ??77.0 | ??88.0 | ??93.7 |
| Sheet B | ??4.1 | ??20.3 | ??46.5 | ??74.5 | ??83.0 | ??88.5 | ??65.3 |
| Plendil | ??9.9 | ??21.5 | ??45.6 | ??65.6 | ??81.3 | ??95.7 | ??- |
f
2: similar factors, f2=50log{[1+ (1/n) ∑
T=ln(R
t-T
t)
2]
-0.5100} is the parameter that the release in vitro degree compares that is used for of U.S. FDA recommendation.Work as f
2At 50～100 o'clock, show that both release in vitro degree are similar.The f of sheet A in the table 1
2Be and sheet B result relatively to illustrate that parcel outer coatings layer does not influence release; The f of sheet B in the table 1
2Be and Plendil result relatively, illustrate that both release in vitro degree are similar.
(7) bioavailability study
Get sheet B as being subjected to test preparation (T), its actual content is the 5mg/ sheet with sign content; Plendil (felodipine sustained-release tablets), Sweden AstraZeneca pharmaceutical Co. Ltd produces, and the 5mg/ sheet as reference preparation (R), carries out the bioequivalence test.The unexpected discovery has a long way to go though sheet B external similar to reference preparation release, discharges in vivo, is subjected to not bioequivalence of test preparation and reference preparation.
Bioequivalence evaluation criterion: Pharmacopoeia of the People's Republic of China version in 2005 two appendix XIXB pharmaceutical preparation human bioavailability and bioequivalence test direction principle.
Adopt single-dose binary cycle trial design.6 dogs are divided into two groups at random, 3 every group, under the empty stomach state, gavage respectively in I, II stage and to be subjected to 2 of 2 of test preparations or reference preparations, 7 days cleaning phases.Before administration with administration after the identical time point stipulated extract limbs venous blood, adopt liquid chromatograph-mass spectrometer to measure felodipine blood drug level (ng/ml).Take blood drug level-time graph of T or R and see Fig. 1, (AUC ng/ml*h) sees Table 2 to lower area of blood concentration-time curve.
Table 2 be subjected to the AUC measured value of test preparation and reference preparation and be subjected to the relative bioavailability of test preparation (F, %)
The T medicine is for the AUC of R medicine
0～36And AUC
0～∞Through its corresponding 90% fiducial limit is checked and calculated to the laggard capable ANOVA check of number conversion, two one-side t.The result shows that the point estimate of the relative bioavailability of T medicine (0～36 hour) only is 58.8%; The AUC of T medicine
0～36And AUC
0～∞[1-2 α] confidence interval with respect to the bioavailability of R medicine is respectively 30.5%～113.6% and 30.6%～117.7% (α=0.05), and the bioavailability that shows the T medicine does not meet should be at 80%～125% criterion of acceptability; Two one side test also shows the AUC of T medicine
0～36And AUC
0～∞Low limit value with respect to the bioavailability of R medicine is all defective.The bioavailability that shows the T medicine is lower than the R medicine, both biological inequivalences.
Prepare label by following prescription
(1) with the preparation of (1)～(5) of embodiment 1, difference is that the amount that this double-deck label Chinese medicine layer that makes contains felodipine is about 4mg.
(2) Opadry is placed 70% alcoholic solution, make that the content of Opadry is about 8% in the solution, fully stir the hypromellose dissolving that makes wherein with agitator, add felodipine then and make that the content of felodipine is about 0.3% in the coating solution, fully stir with agitator or emulsification pretreatment device and make felodipine dissolving or abundant suspendible and keep stirring.The above-mentioned double-layer tablet that makes is placed the coating machine, regulate about 45 ℃ of inlet temperature, coating solution is sprayed on the felodipine that in coatings, contains the 1mg that has an appointment on the double-layer tablet.The medicine layer of this product double-layer tablet of making like this contains felodipine 4mg, and the pastille coatings contains felodipine 1mg, promptly contains felodipine in the pastille coatings and accounts for 20% of sign content.
(3) with embodiment 1 (6), in pastille coatings outer wrapping coatings.The sheet that makes is called sheet C, and release sees Table 3 and Fig. 3.The release of sheet C is obviously fast and release ratio is more complete than sheet B.The release of sheet C and Plendil release similar factors f relatively
2Value is 37.9, shows that both are in external release dissmilarity.
Table 3 a C release (average, %, n=6)
| Time (hour) | ??1 | ??2 | ??4 | ??6 | ??8 |
| Sheet C | ??24.3 | ??39.5 | ??68.0 | ??90.6 | ??94.0 |
(4) bioavailability relatively
Get sheet C as being subjected to test preparation (T), actual content is the 5mg/ sheet with sign content; Plendil (felodipine sustained-release tablets), Sweden AstraZeneca pharmaceutical Co. Ltd produces, and the 5mg/ sheet as reference preparation (R), carries out the bioequivalence test.The unexpected discovery, though sheet C in external and release dissmilarity reference preparation, bioequivalence then in vivo.
Bioequivalence evaluation criterion: Pharmacopoeia of the People's Republic of China version in 2005 two appendix XIXB pharmaceutical preparation human bioavailability and bioequivalence test direction principle.
6 dogs are divided into two groups at random, 3 every group, under the empty stomach state, gavage respectively and be subjected to 2 of 2 of test preparations or reference preparations; Clean the after date intersection in 7 days and gavage R or T.Before administration with administration after the identical time point stipulated extract limbs venous blood, adopt liquid chromatograph-mass spectrometer to measure felodipine blood drug level (ng/ml).Take blood drug level-time graph of T or R and see Fig. 2, (AUC ng/ml*h) sees Table 4 to lower area of blood concentration-time curve.
Table 4 is subjected to the AUC of test preparation and reference preparation
0-36Measured value and be subjected to test preparation relative bioavailability (F, %)
The T medicine is for the AUC of R medicine
0～36Through 90% fiducial limit is checked and calculated to the laggard capable ANOVA check of number conversion, two one-side t.ANOVA assay P=0.804 shows that the AUC difference of two kinds of medicines does not have significance, both equivalences; The AUC of T medicine
0～36Point estimate with respect to the bioavailability F of R medicine is 97.9%, and its [1-2 α] confidence interval is respectively 82.8%～115.9% (α=0.05), and meeting bioavailability should be at 80%～125% criterion of acceptability; Two one side test also shows the AUC of T medicine
0～36And AUC
0～∞With respect to the low limit value of the bioavailability of the R medicine lattice that are combined.The sheet C and the reference preparation bioequivalence that show present embodiment.
Embodiment 3
Prepare label by following prescription
(1) with step (1)～(3) of embodiment 1, makes the label that diameter is 9mm.
(2) cellulose acetate and PEG400 (consumption=18% cellulose acetate weight) are dissolved in dichloromethane, make the total solid content that contains cellulose acetate and PEG 400 in the dichloromethane be about 5%, stirring makes it to dissolve fully, becomes semipermeable membrane solution.Label is placed the coating machine, regulate 35～45 ℃ of inlet temperature, semipermeable membrane solution is sprayed on the label until the weightening finish of label about 14%, make double-layer tablet.
(3) make a call to the hole of the about 0.4～0.7mm of a diameter with laser boring in every medicine layer side form central authorities.Receive sheet be called sheet D.
(4) with stomach dissolved film coating pre-mix dose (Tianjin Ai Leyi medical material Science and Technology Ltd. produce can promptly join the i.e. coating pre-mixing agent of usefulness, mainly contain low viscous hypromellose, also contain and help Pulvis Talci that carries out art for coating etc., also can contain pigment and brightener as required) place 50% alcoholic solution, make the content of coating pre-mixing agent in the solution be about 6%, stirring is dissolved hypromellose fully.Add an amount of felodipine then, fully stir with agitator or emulsification pretreatment device and make felodipine dissolving or become suspension and keep stirring.The above-mentioned double-layer tablet that makes is placed the coating machine, regulate 40～45 ℃ of inlet temperature, the atomizing pressure of coating spray gun is at 0.1～0.4MPa, regulate between spray gun and sheet suitable distance is arranged, the rotating speed of regulating the coating machine makes the sheet wherein can be fully mobile, and coating solution is sprayed on the double-layer tablet every felodipine that contains the 0.5mg that has an appointment in coatings.Contain the 9.5mg felodipine of having an appointment in this product double-layer tablet medicine layer of making like this, the pastille coatings contains the felodipine of the 0.5mg that has an appointment, and promptly the felodipine that contains of pastille coatings accounts for and indicates 5% of content.Then,, wrap one deck protection coatings again, increase weight about 5% with (6) of embodiment 1.Release sees Table 5.As seen the release that discharged in 1 hour near 10%, 12 hour surpasses 95.6%.
Table 5 release (average, %, n=6)
| Time (hour) | ??1 | ??2 | ??4 | ??6 | ??8 | ??10 | ??12 |
| Release | ??9.6 | ??18.6 | ??41.6 | ??66.5 | ??86.7 | ??94.3 | ??95.6 |
Prepare label by following prescription
(1) with step (1)～(3) of embodiment 1, makes the label that diameter is 9mm.
(2) cellulose acetate and Polyethylene Glycol 3350 (=14% cellulose acetate weight) are dissolved in dichloromethane, make the total solid content that contains cellulose acetate and Polyethylene Glycol 3350 in the dichloromethane be about 4.4%, stirring makes it to dissolve fully, becomes semipermeable membrane solution.Label is placed the coating machine, regulate 35～45 ℃ of inlet temperature, semipermeable membrane solution is sprayed on the label until the weightening finish of label about 12%, make double-layer tablet.
(3) make a call to the about 0.4～1mm of diameter hole in every medicine layer side form central authorities with laser boring.
(4) hypromellose (meeting Chinese Pharmacopoeia version two ministerial standards in 2005) is placed 85% alcoholic solution, make to contain 5% the hypromellose of having an appointment in the solution, fully stir and make it dissolving; Add Pulvis Talci and make that talcous content is about 0.1% in the solution, fully mixing; Add an amount of felodipine then, fully stir with agitator and make felodipine dissolving or become suspension and keep stirring.The above-mentioned double-layer tablet that makes is placed the coating machine, regulate about 40～45 ℃ of inlet temperature, coating solution is sprayed on the felodipine that contains the 4mg that has an appointment on the double-layer tablet in every coating tablets layer, promptly get sheet E.Release sees Table 6.This product double-layer tablet medicine layer of making like this contains the 6mg felodipine of having an appointment, and the pastille coatings contains the felodipine of the 4mg that has an appointment, and promptly the felodipine that contains in the pastille coatings accounts for and indicates about 40% of content.
The release of table 6 E (average, %, n=6)
| Time (hour) | ??1 | ??2 | ??4 | ??6 | ??8 | ??10 | ??12 | ??14 |
| Release | ??38.1 | ??45.6 | ??56.2 | ??65.9 | ??75.2 | ??84.3 | ??89.8 | ??93.8 |
Embodiment 5
Prepare label by following prescription
(1) takes by weighing felodipine by prescription and cross behind 80 mesh sieves and mannitol, polyoxyethylene, hypromellose 5cps mix homogeneously, with the ethanol solution wet granulation that contains 2% 30 POVIDONE K 30 BP/USP 30.Granule after dry 48～72 hours, is crossed 20 mesh sieve granulate in 40 ℃ of baking ovens, add magnesium stearate and silicon dioxide mix homogeneously, becomes the medicine layer granule.
(2) take by weighing cross-linking sodium carboxymethyl cellulose, polyoxyethylene, sodium chloride and iron oxide red mix homogeneously by prescription after, with containing the ethanol solution wet granulation of 2% 30 POVIDONE K 30 BP/USP 30.Granule after dry about 48 hours, is crossed 20 mesh sieve granulate in 40 ℃ of baking ovens, add magnesium stearate and silicon dioxide mix homogeneously, becomes the promoting layer granule.
(3) medicine layer granule and promoting layer granule are placed the bi-layer tablet press tabletting respectively, make the label of diameter 9mm.
(4) cellulose acetate, Macrogol 2000 and hypromellose 5cps (amount of Polyethylene Glycol and hypromellose be respectively cellulose acetate weight 12% and 10%) are dissolved in dichloromethane, make the amount that contains cellulose acetate and Polyethylene Glycol in the dichloromethane be about 4.4%, stirring makes it to dissolve fully, becomes semipermeable membrane solution.Label is placed the coating machine, regulate 35～45 ℃ of inlet temperature, semipermeable membrane solution is sprayed on the label until the weightening finish of label about 16%, make double-layer tablet.
(5) make a call to the about 0.5～1mm of diameter hole in every medicine layer side form central authorities with laser boring.
(6) Opadry is placed 20% alcoholic solution, make that the content of Opadry is about 4% in the solution, stirring makes it fully, and the dissolving back adds an amount of felodipine, stirring is dissolved or abundant suspendible felodipine fully, and the same embodiment method is carried out coating to double-layer tablet and contain the about 1mg of felodipine in the pastille coatings.This product double-layer tablet medicine layer of making like this contains the 9mg felodipine of having an appointment, and the pastille coatings contains the felodipine of the 1mg that has an appointment, and promptly the felodipine that contains in the pastille coatings accounts for and indicates about 10% of content.
Get polyvinyl alcohol/polyethyleneglycol-graft copolymer (Kollicoat IR) and be dissolved in water, the concentration that makes copolymer in the water is 5%～12%, stirs to make dissolving fully; Add an amount of felodipine, stir and make felodipine dissolving or abundant suspendible.Sheet D among the embodiment 3 is placed the coating machine, be preheated to 40 ℃, regulate the suitable rotating speed of coating machine, regulate the about 25cm of distance between spray gun and slice, thin piece, the about 0.14Mpa of compressed air pressure carries out coating, contains the felodipine of the 0.5mg that has an appointment in the pastille coatings.
Embodiment 7
Getting 30 POVIDONE K 30 BP/USP 30 and Macrogol 4000 (latter amount be about the former 20%) is dissolved in 50% the ethanol, make the solids content in the solution be about 2%～6%, add an amount of felodipine, stir and make felodipine dissolving or abundant suspendible, add an amount of Pulvis Talci, keep stirring.Sheet D among the embodiment 3 is placed the coating machine, carry out coating, in the pastille coatings, contain the felodipine of the 0.5mg that has an appointment.
Get acrylic resin IV and be dissolved in the ethanol, make the solids content in the solution be about 4%～8%, add an amount of felodipine, stir and make felodipine dissolving or abundant suspendible, add an amount of Pulvis Talci, keep stirring.Sheet D among the embodiment 3 is carried out coating, in the pastille coatings, contain the felodipine of the 0.5mg that has an appointment.
Claims (10)
1. controlled release preparation, said preparation is characterised in that pastille coatings and/or coatings outside double-layer tablet, contain to account in double-layer tablet to indicate the most active constituents of medicine of content, and the pastille coatings contains and accounts for the active constituents of medicine that indicates remainder in the content.
2. according to the preparation of claim 1, it is characterized in that double-layer tablet is made up of the semi-transparent rete and the label of parcel label, there is an aperture in the semipermeable membrane central authorities of packaging medicine side.
3. according to the preparation of claim 2, wherein label contains medicine layer and promoting layer; Contain medicine layer and contain active component, permeate substance and infiltration promotion material; Promoting layer contains permeate substance and infiltration promotes material.
4. according to claim 2 preparation, wherein semi-transparent rete contains cellulose acetate, porogen and plasticizer; Porogen and plasticizer are selected from Polyethylene Glycol, hypromellose, hyprolose or their mixture.
5. according to the preparation of claim 3, wherein permeate substance is selected from fructose, glucose, sucrose, lactose, mannitol, inorganic salt and comprises sodium chloride, potassium chloride, potassium sulfate, sodium dihydrogen phosphate or their mixture; Infiltration promotes that material is selected from polyoxyethylene, hypromellose, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, crospolyvinylpyrrolidone or their mixture.
6. according to the preparation of claim 1, active constituents of medicine wherein is a felodipine.
7. according to the preparation of claim 6, the felodipine that double-layer tablet contains accounts for and indicates 60%～99% of content, and the felodipine that contains in the pastille coatings accounts for and indicates 1%～40% of content.
8. the controlled release preparation preparation method of claim 1, contain and have the following steps: will account for most of active constituents of medicine that indicates content and prepare in the medicine layer of double-layer tablet, to indicate the surplus active constituents of medicine dissolving in the content then or be suspended in the solvent that contains binding agent and double-layer tablet be carried out coating, reach the content that sign content deducts double-layer tablet Chinese medicine active component up to the content of pastille coatings Chinese medicine active component with the coating machine.
9. controlled release preparation preparation method according to Claim 8, coating binding agent wherein is selected from cellulose ethers, acrylate copolymer, polyvidone and copolymerization polyvidone, polyvinyl alcohol/polyethyleneglycol-graft copolymer or contains the coating pre-mixing agent of above polymer.
10. according to Claim 8 or the controlled release preparation preparation method in 9, active constituents of medicine wherein is a felodipine.
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| CN102302469A (en) * | 2011-07-13 | 2012-01-04 | 合肥华方医药科技有限公司 | Preparation method of felodipine two-layer osmotic pump controlled release tablet |
| CN102670551A (en) * | 2011-03-14 | 2012-09-19 | 北京天衡药物研究院南阳天衡制药厂 | Felodipine osmotic pump controlled release tablet |
| CN104784140A (en) * | 2015-04-30 | 2015-07-22 | 南通市康桥油脂有限公司 | Mizolastine sustained release preparation and preparation method thereof |
| CN104825415A (en) * | 2015-04-30 | 2015-08-12 | 南通市康桥油脂有限公司 | Cefaclor sustained release preparation and preparation method thereof |
| CN104840445A (en) * | 2015-04-30 | 2015-08-19 | 南通市康桥油脂有限公司 | Paroxetine sustained release preparation and preparation method thereof |
| CN109939077A (en) * | 2017-12-04 | 2019-06-28 | 深圳奥萨制药有限公司 | A kind of controlled release preparation containing 5-methyltetrahydrofolate |
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| CN104784140A (en) * | 2015-04-30 | 2015-07-22 | 南通市康桥油脂有限公司 | Mizolastine sustained release preparation and preparation method thereof |
| CN104825415A (en) * | 2015-04-30 | 2015-08-12 | 南通市康桥油脂有限公司 | Cefaclor sustained release preparation and preparation method thereof |
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| CN104840445B (en) * | 2015-04-30 | 2017-11-21 | 南通市康桥油脂有限公司 | A kind of paroxetine slow release preparation and preparation method thereof |
| CN109939077A (en) * | 2017-12-04 | 2019-06-28 | 深圳奥萨制药有限公司 | A kind of controlled release preparation containing 5-methyltetrahydrofolate |
| CN109939077B (en) * | 2017-12-04 | 2022-07-22 | 深圳奥萨制药有限公司 | Controlled release preparation containing 5-methyltetrahydrofolic acid |
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Application publication date: 20101110 |