CN1189774A - Controlled release formulations for poorly soluble drugs - Google Patents
Controlled release formulations for poorly soluble drugs Download PDFInfo
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Abstract
A controlled release formulation for oral administration comprises a solid dispersion of a poorly soluble active ingredient in a hydrophilic poloxamer, the solid dispersion being a component of a core and the core as such or following coating of the core with a polymeric coating being effective to achieve therapeutic levels of the active ingredient over extended periods of time (24 hours or longer) following oral administration. The formulation can be in a multi-particulate form such as pellets or mini-tablets or in the form of tablets. Examples of active ingredients whose solubility and therapeutic effectiveness can be improved with the formulation are cisapride, cyclosporin, diclofenac, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, terfenadine and theophylline.
Description
Technical field
The present invention relates to the oral medication controlled release preparation of insoluble drug.
Background technology
The pharmaceutical preparation of various control absorption/releases is because of having special dispersing mode, and causes the control of active component to absorb, and therefore becomes more efficiently medicament.The application of various active substances in treatment becomes complicated because of its solubility.Adopted the whole bag of tricks promoting its dissolubility for insoluble drugs, as made its micronization, form noncrystalline coprecipitate, or prepared the doped and compounded thing with cyclodextrin.In various different dosage forms, also use various surfactants, to promote the dissolubility of various insoluble compounds.
Some medicines as nifedipine, are non-disassociation types, and in gastronintestinal system lower dissolubility are arranged.It is acid or alkaline that other drug is, and show the dissolubility that influenced by pH at the different parts of gastronintestinal system.One of them example is cisapride (cisapride), himself is alkalescence, and lower dissolubility is arranged under the acid condition of gastronintestinal system epimere, then shows more weak dissolubility when further moving down.
European patent EP 0232155B1 and EP0274176 disclose the application of adsorbate in drug delivery system.EP0232155B1 discloses a kind of adsorbate, and it is that mixture by a kind of active constituents of medicine and a kind of inert matter is adsorbed on the crosslinked polymer and makes its granulating and form.This adsorbate mixes with a kind of polymer or several mixture of polymers, forms a kind of drug delivery system of lasting release.EP 0274176 discloses the capsule and the Tabules of sustainable release, it is to be adsorbed on the crosslinked polyvinylpyrrolidone at the mixture of the polyvinylpyrrolidone more than 55000 (pvp) by active constituents of medicine dihydropyridine and a kind of mean molecule quantity to form, this adsorbate and at least a polymer mixed that can gelation in the presence of water are with the effect that obtains to continue to discharge.
The purpose of this invention is to provide a kind ofly, can increase and the bioavailability of the drug activity composition of the low biological utilisation of control effectively through improved drug delivery system.
Another object of the present invention provides a kind of sustained release dosage form of slightly solubility active component, so that this composition keeps the level of therapeutic dose in 24 hours of the half-life that depends on this composition or longer time.
Of the present invention open
The invention provides a kind of controlled release preparation of oral administration, it comprises the solid dispersed phase that the slightly solubility active component forms in hydrophilic poloxamer (poloxamer) polymer.Said solid dispersed phase is the component of sheet nuclear, and described nuclear or through the sheet nuclear coating of polymer coating can make above-mentioned active component can reach the therapeutic dose level in one period persistent period behind oral medication.
The present invention adds the dosage form that obtains in the solid dispersed phase by the slightly solubility active component, can increase the dissolubility or the wettability of medicine significantly, and make above-mentioned active component reach the therapeutic dose level in vivo in a persistent period.
More useful is that solid dispersed phase becomes sub-material to examine in flakes with one or more tablettings, examines or examine coating with the sheet of polymer coating for described to make above-mentioned active component reach treatment level in one period persistent period after oral.
The method of the dissolubility of adjusting different activities composition as mentioned above.Solid dispersed phase may need to comprise that one or more components are to promote the dissolubility or the wettability of active component.
Therefore, solid dispersed phase can comprise surface active agent composition.Surfactant can be anionic, cationic or nonionic.Surface active agent composition can further be preferably selected from sodium lauryl sulphate, carboxylic acid sodium, alkyl sodium sulfate ester, macrogol ester, polyvinylether, Isosorbide Dinitrate, ethyoxyl Isosorbide Dinitrate and halogenated alkyl trimethylammonium and their mixture.
Selectively, described solid dispersed phase can comprise acidic components.Preferred acidic components select oneself diacid, ascorbic acid, citric acid, fumaric acid (fumaroyl), malic acid (hydroxyl succinic acid), succinic acid (succinic acid) or tartaric acid (2,3 dihydroxybutanedioic acid).
In addition, selectively, solid dispersed phase can comprise basic component.Preferred basic component is selected from calcium carbonate, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate and sodium hydroxide.
The preferred weight ratio of surfactant, acidity or basic component and active component is 0.01: 1.0 to 5.0: 1.0.
Hereinafter surfactant, acidity or basic component are referred to as adjuvant.
In addition, the preferred weight ratio of active component and poloxamer is 0.1: 1.0 to 10.0: 1.0.
At this, poloxamer also refers to the combination of two or more poloxamers.
The poloxamer polyhydric alcohol is oxirane and the maximally related block copolymer of expoxy propane series.
Specifically, the poloxamer polyhydric alcohol is alpha-hydro-omega-hydroxypoly oxygen ethylene-polyoxypropylene-polyoxyethylated block copolymer, is commonly referred to as poly-second-polypropylene glycol copolymer, or polyoxyethylene-polyoxypropylene copolymer.
Preferred poloxamer refers to that the weight of those polyoxyethylene parts accounts for 60%-90%, especially at the polymer of 70%-80% scope.
The polyoxyethylene segment is a hydrophilic, and the polyoxypropylene segment then is a hydrophobicity.All poloxamer chemical compositions are similar, and the oxirane of adding when only being to prepare and the relative populations of expoxy propane do not exist together.Can account for 15%-90% in the hydrophilic segment poloxamer molecule on the berth.As mentioned above, the present invention recommends the kind used, and hydrophilic polyoxyethylene segment or sequence account for the 60%-90% of molecular wt, especially at 70%-80%.Such poloxamer polyhydric alcohol, poloxamer hereinafter referred to as is by titled with trade name Polyethylene Glycol (Lutrol), polypropylene glycol (Monolan) and pluronic (Pluronic).
Poloxamer also can define with numeral.The front two numeral multiply by 100, the mean molecule quantity of polyoxypropylene part (POP) in the corresponding molecule.The 3rd figure place multiply by 10, the percentage by weight of polyoxyethylene part (POE) in the corresponding molecule.When being claimed with its pluronic title, the front two numeral multiply by 1000, the expression total molecular weight, and the 3rd bit digital multiply by 10, represents about percentage composition of polyoxyethylene part in the molecule.The capitalization that links with numeral has indicated its physical state: L=liquid, the soft paste of P=, F=solid." European medicament technology " (the Pharmaceutical Technology Europe) that publishes from May, 1994 can obtain further information.
Poloxamer, especially F68, F108 and the F127 of the preferred F series of the present invention preferably use Polyethylene Glycol F68, (Lutrol F68), pluronic F108 (Pluronic F108) and the Polyethylene Glycol F127 (Lutrol F127) of BASF AG.
From the technical information table that BASF (Ireland) company limited provides, can obtain about the further information of these poloxamers.
With the poloxamer fusing, then medicine activity component and other medicinal adjuvants are scattered in wherein.
Poloxamer is suitable to be melted in rustless steel container.Active component and pharmaceutic adjuvant, and the inert filler that may use slowly add the fusion phase in the preparation process.In the cooling procedure of mixture, to stir, and it is ground to granular size, in 30～300 mu m ranges.
Perhaps, active constituents of medicine, medicinal adjuvant and poloxamer are dissolved in one or more organic solvents, and with solvent evaporation, fused poloxamer cools off, and it is milled to granular size in 30～300 mu m ranges.
Having found that various slightly solubility active component can be changed places is scattered in the molten state of the used poloxamer of the present invention.Work as active component, when medicinal adjuvant that may adopt and the cooling of the mixture of poloxamer, form a kind of drying and hard solid, it is more easily pulverized.Therefore the present invention selects the polymeric matrix of poloxamer as solid dispersed phase.
Solid dispersed phase of the present invention can comprise various excipient, as inert filler.It is water miscible that inert filler is suitably, and wherein an example is a lactose, especially lactose-hydrate.The adding of inert filler such as lactose can reduce the fusing point of poloxamer.
The adding inert filler is scattered in the dissolubility that obtains in the solid dispersed phase to the property composition does not have harmful effect.Yet it can significantly improve overall preparations shaping performance, and forms a kind of attritive powder shape thing that is suitable for preparing tablet.The suitable consumption of inert filler is 3%～35% of a gross weight.
Active component can be above-mentioned any slightly solubility material.For example: cisapride (cisapride), cyclosporin (cyclosporin), diclofenac (diclofenac), felodipine (felodipine), ibuprofen (ibuprofen), indomethacin (indomethacin), nicardipine (nicadipine), nifedipine (nifedipine), teldane (terfenadine) and theophylline (theophylline).
The objective of the invention is the slightly solubility active component.As cisapride, make its far-end more easily dissolve and absorb, thereby reach the lasting absorption of medicine in gastronintestinal system.The water solublity of cisapride self is low and depend on pH value significantly.When its NATURAL DISTRIBUTION during in the more far-end of gastronintestinal system, partial water content and pH are unfavorable for its dissolving, and water solublity is limited.Though the present invention is not limited to theoretical explanation, can expects to be suitable for the microenvironment that cisapride dissolves and absorbs, thereby increase the dissolubility of cisapride by using solid dispersion system mentioned above, causing.Further, add hydroxyl-containing acid in the solid dispersed phase, controlled release system synergism is therewith further promoted the solubility property that cisapride is revealed by the area table of release rate profile.
Other insoluble drug active component hereinafter described can obtain similar effects.
The solid oral dosage form of the present invention's preparation can be a capsule.
Therefore, can contain the described dosage form that exists with many particle shapes of invention according to capsule of the present invention, as ball granule and tablet.
The ball granule or the micro tablet that contain solid dispersed phase mentioned above that comprise some in the capsule aptly are to reach the instant-free of active component.
Can comprise various many particle shapes in the capsule, or a spot of discrete unit.
Can adopt soft or hard gelatine capsule.
Solid oral dosage form of the present invention also can be a tablet.
Tablet can be made up of the sheet nuclear that is scattered in the hydrogel matrix.This sheet nuclear is formed by a kind of solid dispersed phase as mentioned above.In the tablet of this form, solid dispersed phase is pressed into and contains the dosage form that one or more meet the polymer of water expandable gelization.The rate of release of active component from this dosage form is subjected to from the tablet agglomerate of water-swellable the control that diffusion and tablet surface corrode two aspect factors.The rate of release of active component is subjected to the influence of the consumption and the polymeric adhesive of polymer in the tablet.
Meet the water swellable polymer and be suitably the hydroxypropyl emthylcellulose (HPMC) that accounts for gross weight 5%～75%, it represents the combination of multiple hydroxypropyl emthylcellulose at this.
Hydroxypropyl emthylcellulose or other are met the expandable cellulosic polymer consumption of water and be should be 5%～75% of gross weight, and especially 10%～60%.
The preferred hydroxypropyl emthylcellulose of the present invention is that trade name is the kind of methylcellulose (Methocel).
HPMC or other consumption of meeting the expandable gel of water depend on their viscosity.Usually, the polymer of high viscosity uses and can obtain ideal release characteristics on a small quantity.
Suitable methylcellulose kind is methylcellulose K15M (MethocelK15M), and its solution of 2% can obtain the viscosity of 15,000 centipoises.Other available kind comprises Methocel K4M K100M K100LV or ranks such as E, F, J, depends on required release characteristics.
As mentioned above, the use of hydrogel matrix is expanded tablet, and discharges medicine by the tablet surface corrosion with from tablet agglomerate diffusion inside dual mode.The cellulosic polymer of selecting different inherent viscosity is with the control rate of dissolution.
Hydrophilic gel is can expansible linear polymeric in water or body fluid.Change the release that following parameter can change this system:
The kind of polymer and viscosity grade; And used concentration.
The kind of selective polymer of the present invention at first depends on the dissolution characteristics with downtrodden solid dispersed phase.Viscosity grade depends on the desired rate that active component discharges from the sheet base.
Tablet hardness is another parameter that hydrogel sheet need be considered.Suitable hardness should be in 60～260N scope.
For tabletting, use diluent usually or claim excipient, as microcrystalline Cellulose.Often select the microcrystalline Cellulose of commodity Avicel by name for use, as Avicel pH101.
Other excipient can also comprise lubricant such as magnesium stearate, and fluidizer such as silicon dioxide colloid, commodity are called silica gel (Aerosil).
Solid oral dosage form of the present invention also can be the tablet of another type, and the rate-controlling membrane that it contains a porosity and looseness wraps up the sheet nuclear that aforementioned solid dispersed phase forms.Solid dispersed phase is the sheet nuclear of instant-free, and its direct compression wraps then with rate-controlling membrane.The principal element that this kind dosage form will be considered is to select suitable tablet ingredients to produce ideal effect when the tabletting.For reaching immediate release film releasing nuclear, the consubstantiality decentralized photo will mix with the tablet excipient of standard, as sheet base, tabletting sucrose, solubilizing agent, the lubricant of standard.The release of the active component of this dosage form is subjected to the control of flooding mechanism.
The hardness of tablet and fragility are the key properties of film-coated tablet.Sheet nuclear must be enough solid to stand coating processing.
For obtaining being suitable for the ideal release profile of administration once a day, the medicinal film former of preparation rate-controlling membrane should comprise the non-soluble polymer of larger proportion and less water-soluble polymer.
As mentioned below, term water-soluble polymer used herein comprises can be by the polymer of water free permeation, and the term non-soluble polymer comprises the polymer that can only faintly be permeated by water.
Preferably, water-soluble polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, agar, carrageenin (carrageenan), xanthan gum (xanthan), Polyethylene Glycol, or their mixture.
In the coating polymer, add various hydrophilizing agents, can in above-mentioned coatings, form passage, can produce linear release rate usually.These hydrophilizing agents comprise fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, fumaric acid sodium, sodium carbonate, monosaccharide and disaccharidase.Glucose is a kind of suitable monosaccharide.
Water-soluble polymer in the rate-controlling membrane also can be replaced by the copolymer of acrylate and methacrylate, and it can freely be permeated by water and active component and pass through.
The polymer of commodity EUDRAGITRL by name is suitable for the free permeation of various insoluble active component and water.
Insoluble polymer in the rate-controlling membrane is preferable over following various: the hexyl cellulose, cellulose acetate, cellulose propionate is (low, in, high molecular), cellulose acetate-propionate, cellulose acetate-butyrate, acetic acid-phthalic acid ester cellulose, cellulosic triacetate, polyisobutylene acid methyl ester, the polyisobutylene acetoacetic ester, the polyisobutylene acid butyl ester, polyisobutylene acid isobutyl ester, the own ester of polyisobutylene acid, polyisobutylene acid isodecyl ester, polyisobutylene acid dodecane ester, the polyisobutylene acid phenenyl ester, polymethyl acrylate, the polyacrylic acid isopropyl ester, polyisobutyl acrylate, polyacrylic acid octadecane ester, polyethylene, low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene, poly(ethylene oxide), poly-terephthalic acids ethyl ester, polyvinyl isobutyl ether, polyvinyl acetate, polrvinyl chloride or polyurethane, or their mixture.
Insoluble polymer in the rate-controlling membrane also can contain natural polymer or resin.
Other preferred natural insoluble polymer is selected from Lac, takes off several butyl esters of acetyl, juniper gum, or their natural polymers such as mixture.
Water-insoluble in the film is polymeric also can be replaced by the copolymer of acrylate and methacrylate, and it can only be faintly by water and active component infiltration.
The polymer of commodity EUDRAGIT RS by name, or the permeance property commodity relevant with the pH condition polymer that is called EUDRAGITL, EUDRAGITS or EUDRAGITE is suitable for the faint infiltration of the active substance and the water of various low solubilities.Especially preferred EUDRAGITS series among this.
The polymer of EUDRAGIT series is the polymerization NC Nitroncellulose class material that is formed by acrylate and/or methacrylate.With the polymeric material that trade name EUDRAGIT RL and EUDRAGIT RS sell, be the acrylic resin that contains acrylate and methacrylate copolymer, it has the quaternary ammonium group of low content.In Messrs.RohmPharma GmbH (1984) " EUDRAGIT " handbook, described the physicochemical data of these products in detail.Ammonium group exists with the form of salt, can improve the permeability of glued membrane.EUDRAGITRL and RS represent free permeation (RL) and faint infiltration (RS) respectively, and its performance depends on pH separately.
EUDRAGIT S is by methacrylic acid and the synthetic resin anion (R.A.) of methyl methacrylate.It is insoluble in acid and pure water.But when it becomes solvable owing to forming salt with alkali in neutrality to weakly alkaline environment.The permeability of EUDRAGIT S is relevant with pH.PH is higher than 6.0, and the permeability of polymer increases.Describe the physicochemical data of EUDRAGIT S series of products in the handbook of Messrs.Rohm PharmaGmbH (1986) " EUDRAGIT S " in detail.
Before parcel polymer rate-controlling membrane, solid dispersed phase can conventional method be applied on the inert core.
Can make binding agent with polymeric material, be applied to as on the inert core such as sucrose or starch sheet base solid dispersed phase is sticking, sucrose or starch sheet base average diameter are 0.2～1.4mm, are preferably in 0.3-0.8mm.
The polymeric material that is used for the inert core coating is based on the water solublity pharmaceutically acceptable polymer.
Inert core is replaced the parcel that overlaps by multilamellar pulverulent solids decentralized photo and polymeric material.The consumption of polymer should guarantee that all solids decentralized photo is all sneaked into sheet and examined.
The polymeric material that is used to form sheet nuclear can be same with the polymer phase of above-mentioned preparation rate-controlling membrane.
During coating, the solution of composite and solid dispersed phase or suspension alternately are wrapping on the inert core at center, thereby form the multiple structure of nuclear in habitual coating pan.And in automatic coating system, the solution of polymeric material and solid dispersed phase or suspension normally wrap on the sheet nuclear simultaneously.
The solution of the polymeric material that coating is used or suspension are one or more polymer dissolution or be suspended in the mixed liquor of a kind of The suitable solvent or several solvents.The concentration of polymeric material wherein depends on the viscosity of the solution or the suspension of formation.Be more preferably, 5～50 parts of centre idler are corresponding to 1 part of solid dispersed phase.Add plasticizer in the prescription for the elasticity and the stability that increase polymeric film in polymer solution or suspension, the variation that prevents polymer penetration in the long-term storage process may be necessary.
These change can influence release rate of drugs.Suitable manufacturing methods comprises the acetylated monoglycerides of Polyethylene Glycol, propylene glycol, glycerol, glycerol triacetate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, CitroflexA-2, Oleum Ricini and percentage.
Another kind of mode is that solid dispersed phase and polymeric material are added on the center active nucleus.Solid dispersed phase and polymeric material mix and form the homogenizing powder, and a part is made centronucleus through shaping, with remaining mixture and polymer-bonded liquid alternately or be wrapped in simultaneously on the centronucleus, and from a kind of layer structure of heart nuclear formation hereinto.
Therefore, can prepare active nucleus by solid dispersed phase and polymeric material are mixed into the homogenizing powder.Part mixture is made centronucleus through shaping, and remaining mixture and polymer coating solution alternately are wrapping on the active nucleus continuously, forms a kind of multiple structure, and this process is carried out in habitual coating pan.Perhaps the coating system selects remaining mixture and polymer coating solution are wrapped on the active nucleus simultaneously automatically.Habitual automatic coating system comprises as CF facility for granulating or Glatt fluid bed.The seed activity distributed components that makes like this, adjuvant spreads all over each several part.
Give the active nucleus coating that contains solid dispersed phase with a kind of special permeable membrane, make the active component dissolving and from the microenvironment of active nucleus, diffuse out.Suitable coating materials is cellulose and polymethacrylates series polymer.Polymer coating suits to carry out in C.F.360 granulator.
Preferred solvent is acetone, isopropyl alcohol when polymer use and coating, industrial methylated spirit.
Those skilled in the art can obtain being used for encapsulated microplate and granule respectively by the above-mentioned method for preparing hydrogel matrix tablet and tool rate-controlling membrane tablet.
Based on above information, other combine to reach promotion dissolubility and wettability above-mentioned solid dispersion, and the method for control drug absorption and release is to it will be readily apparent to those skilled in the art that.
Brief Description Of Drawings
After Fig. 1 is the preparation of oral embodiment 1 and 2, in the blood plasma nifedipine concentration (mg/ml) to the time (hour) curve;
After Fig. 2 is the preparation of oral embodiment 3 and 4, in the blood plasma nifedipine concentration (ng/ml) to the time (hour) curve;
After Fig. 3 is the preparation and Related product of oral embodiment 5, in the blood plasma nifedipine concentration (ng/ml) to the time (hour) curve;
After Fig. 4 is the tablet of oral embodiment 6 and 7, in the blood plasma cisapride concentration (ng/ml) to the time (hour) curve, wherein:
Curve is a) corresponding with the film-making agent of embodiment 6;
Curve b) tablet with embodiment 7 is corresponding; And
After Fig. 5 is the preparation and Related product of oral embodiment 8～11, in the blood plasma cisapride concentration (ng/ml) to the time (hour) curve.
Embodiments of the present invention
The present invention will be further specified by following example.
The preparation of embodiment 1 (comparative example) tablet
The following tablet ingredients of mixed shown in pressing is to prepare tablet:
Composition weight %
Nifedipine 12.82
Methylcellulose K15M 64.10
Microcrystalline Cellulose pH101 22.22
Magnesium stearate 0.86
Mixture is pressed into the tablet that average hardness is 55N with Killian RTS tablet machine.With the dissolubility of USP ApparatusII (oar formula) type Instrument measuring tablet in glass drying oven.Condition determination is: rotating speed 100r.p.m., 1.25% sodium lauryl sulphate (SLS) aqueous solution, pH6.8, liquor capacity 900ml, 37 ℃ ± 0.5 ℃ of temperature.
Obtain following result:
Time (hour) release percentage rate (%)
1.0?????????????????2.5
2.0?????????????????8.7
4.0?????????????????21.7
6.0?????????????????30.3
8.0?????????????????43.3
10.0????????????????52.5
24.0????????????????101.0
The preparation of embodiment 2 solid dispersed phase
Polyethylene Glycol (Lutrol) F127 (500g) is heated to 80 ℃ of fusions.Slowly add nifedipine therein and make it to be uniformly dispersed.Continue to mix after 2 hours making the solid dispersed phase cool to room temperature, grind subsequently.The preparation of tablet
Mixed shown in solid dispersed phase and following tablet ingredients pressed makes tablet.
Composition weight %
Solid dispersed phase 23.43
Methylcellulose K15M 56.30
Microcrystalline Cellulose pH101 19.52
Magnesium stearate 0.75
Mixture is pressed into the sheet that average hardness is 52N with Killian RTS tablet machine.Under the regulations identical, measure its dissolubility in glass container with embodiment.Obtain following result:
Time (hour) release %
1.0????????????5.3
2.0????????????8.2
4.0????????????20.3
6.0????????????31.6
8.0????????????42.3
10.0???????????53.6
24.0???????????110.8
Embodiment 1 and 2 pharmacokinetic data available are relatively listed in table 1 and accompanying drawing 1.
Table 1
| Parameter | Example 1 | Example 2 |
| ??AUC *(0-24) | ??85.54±54.12 | ??153.10±75.85 |
| ????C max ** | ????8.58±4.32 | ????16.10±9.21 |
| ????T max *** | ????12.89±9.05 | ????12.78±9.25 |
*Plasma drug level is to the area under the time graph
*Maximum blood plasma Chinese medicine concentration
* *Maximum blood plasma Chinese medicine concentration time corresponding
Add the effect that solid dispersed phase (embodiment 2) increases bioavailability by relatively can clearly be seen that of embodiment 1 (only containing raw material) and embodiment 2.
The preparation of embodiment 3 solid dispersed phase
Polyethylene Glycol (Lutrol) F127 (1500g) is heated to 80 ℃ of fusions, adds nifedipine (500g) therein gradually and makes it to be uniformly dispersed.Lasting mixing with the solid dispersed phase cool to room temperature, was ground after 2 hours.The preparation of tablet
Mixed shown in solid dispersed phase and following component pressed, the preparation tablet.
Composition weight %
Solid dispersed phase 35.29
Methylcellulose K15M 30.00
Methylcellulose K100LV 0.1
Microcrystalline Cellulose pH101 33.35
Magnesium stearate 0.86
High dispersive silica gel 200 0.4
In Fette E1 tablet machine, mixture is pressed into the tablet that average hardness is 73N.Under the condition identical, measure the dissolubility of tablet in glass container with embodiment 1.Obtain following result:
Time (hour) release %
1.0???????????9.8
2.0???????????19.3
4.0???????????41.7
6.0???????????55.8
8.0???????????67.5
10.0??????????77.3
12.0??????????88.6
24.0??????????103.9
The preparation of embodiment 4 solid dispersed phase
Prepare solid dispersed phase by embodiment 3 methods.The preparation of tablet
With solid dispersed phase and following component by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 35.29
Methylcellulose K15M 0.10
Methylcellulose K100LV 40.00
Microcrystalline Cellulose pH101 23.35
Magnesium stearate 0.86
High dispersive silica gel 200 0.40
In Fette E1 tablet machine, mixture is pressed into the tablet that average hardness is 73N.Press the condition of embodiment 1 and measure the dissolubility of tablet in glass container, obtain following result:
Time discharges %
1.0????22.2
2.0????38.5
4.0????67.9
6.0????92.1
8.0????103.1
10.0???105.6
12.0???105.5
24.0???106.2
Table 2
| Parameter | Example 3 | Example 4 |
| ????AUC ss | ??305.22±132.25 | ??321.34±109.66 |
| ????C max | ????23.38±8.75 | ??43.04±15.40 |
| ????T max | ????3.70±2.63 | ????2.75±0.98 |
Embodiment 3 is owing to contain the high viscosity methylcellulose (comparing with embodiment 4) of higher proportion, show slower solubility curve, thereby plasma concentration curve is comparatively mild in the body, shows the variation that can produce the said medicine curve by the methylcellulose that is suitable for different size.
The preparation of embodiment 5 solid dispersed phase
Polyethylene Glycol (Lutrol) F127 (4500g) is heated to 80 ℃ of fusions, adds nifedipine (1500g) therein gradually and is uniformly dispersed, and continues to mix 2 hours, is cooled to room temperature, grinds.The preparation of tablet
Mixed shown in solid dispersed phase and following component pressed:
Composition weight %
Solid dispersed phase 35.29
Methylcellulose K15M 15.00
Methylcellulose K100LV 0.1
Microcrystalline Cellulose pH101 47.95
Magnesium stearate 0.86
High dispersive silica gel 200 0.8
Mixture is pressed into the tablet that average hardness is 90N with Fette E1 tablet machine.Press embodiment 1 condition and measure the dissolubility of tablet in glass container, obtain following result:
Time (hour) release %
1.0???????????15.7
2.0???????????40.0
4.0???????????63.9
6.0???????????81.7
8.0???????????103.8
10.0??????????109.9
The tablet of embodiment 5 preparation and take once nifedipine tablet (below be called reference substance) pharmacokinetic data available a kind of commercially available every day relatively see Table 3 and Fig. 3.
Table 3
| Parameter | Embodiment 5 | Contrast |
| AUC(0-36) | ??374.93±107.68 | ??376.24±135.45 |
| ????C max | ????39.25±13.54 | ????40.87±15.09 |
| ????T max | ????3.60±1.43 | ????3.45±1.17 |
| ??F％ **** | ????1.04±0.22 |
* * *The ratio of F%=embodiment sample and contrast
The preparation of embodiment 6 solid dispersed phase
The Polyethylene Glycol F127 (463g) of BASF (Ireland) company limited is heated to 80 ℃ of fusions.The lactose (150g) of the cisapride (237g) of Janssen Pharmaceutica N.V. company, the tartaric acid (150g) of R.B. chemical company, Forum chemical company slowly joins among the fused Polyethylene Glycol F127 and is uniformly dispersed, continue to mix 0.5 hour until adding lactose, the solid dispersed phase cool to room temperature of gained grinds.The preparation of tablet
With solid dispersed phase and following component by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 24.2
Methylcellulose K15M 20.0
Microcrystalline Cellulose pH101 55.3
Magnesium stearate 0.5
Tablet mixture is pressed into the tablet that average hardness is 129N with Killian RTS tablet machine.
U.S.P.Apparatus ∏ (oar formula) device with standard is measured the tablet dissolution in vitro degree that makes.Operating condition: rotating speed 50r.p.m., dissolve medium 0.01M HCl, volume 900ml, 37 ℃ ± 0.5 ℃ of temperature.The 6ml that at every turn from measure liquid, takes a sample, and be the filter filtration of 0.45 μ m with the aperture.With 0.01MHCl filtrate is diluted to 4/10 of original content, compares, measure trap at 270nm with 0.01MHCl.Obtain following result:
Time (hours) discharges %
0.5????????????13.8
1.0????????????16.7
2.0????????????22.2
4.0????????????33.0
6.0????????????41.5
8.0????????????49.9
10.0???????????57.0
12.0???????????61.3
16.0???????????67.3
24.0???????????81.2
Measured the plasma concentration after 10 healthy male volunteers are taken the cisapride tablet of this embodiment preparation, the results are shown in Fig. 4, wherein a) corresponding this embodiment of curve.
The preparation of embodiment 7 solid dispersed phase
Polyethylene Glycol F127 (463g) is heated to 80 ℃ of fusions.Cisapride (237g), tartaric acid (150g), lactose (150g) slowly join in the fused Polyethylene Glycol and are uniformly dispersed, and continue to mix 0.5 hour until adding remaining lactose, and the solid dispersed phase cool to room temperature of gained grinds.The preparation of tablet
With solid dispersed phase and following tablet ingredients by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 24.2
Methylcellulose K100LV 40.0
Microcrystalline Cellulose pH101 35.3
Magnesium stearate 0.5
Mixture is pressed into the tablet that average hardness is 139N with Killian RTS tablet machine.
Measure the tablet dissolution in vitro degree that makes by embodiment 6 conditions.Obtain following result:
Time (hours) discharges %
0.5?????????????8.4
1.0?????????????12.0
2.0?????????????21.3
4.0?????????????43.4
6.0?????????????54.1
8.0?????????????70.5
10.0????????????87.6
12.0????????????98.7
16.0????????????108.3
24.0????????????112.5
Ditto measured the plasma concentration behind the cisapride tablet that 10 healthy volunteers take this embodiment preparation, the results are shown in Fig. 4, wherein curve b) corresponding this embodiment.
******
Carried out research in the body of tablet of embodiment 6,7 preparations, every group of 10 volunteers, everyone every day each oral 40mg tablet.
Can clearly be seen that from Fig. 4 the tablet of embodiment 6,7 preparations has lasting absorption and blood plasma level curve.The absorption phase of every kind of preparation, pro-had initial absorption speed faster in 4 hours, and had slower absorption rate thereafter 12-16 hour.
The embodiment 6 and the main distinction of embodiment 7 goods on blood distiller line be, the latter has higher peak concentration (Cmax) and the former has absorption and the curve of blood plasma that continues.These two kinds of preparations have identical solid dispersed phase, have used other cellulose-based polymer of different viscosities level of control speed and have different release characteristics.
Pharmacokinetic parameters is summarized in table 4 in the body of embodiment 6,7.
Table 4
| Parameter | Embodiment 6 (40mg) | Embodiment 7 (40mg) |
| AUC (0-∞) ngxh/ml Cmax ng/ml Tmax hour Kel*****1/ hour T1/2****** hour | 1148.10±595.10 ????44.14±16.01 ????7.30±4.72 ????0.082±0.027 ????9.24±2.78 | ????1125.85±276.37 ????55.71±9.72 ????5.70±3.83 ????0.079±0.023 ????9.78±4.13 |
* * * * medicine rate of disappearance constant
The * * * * * half-life of medicine in blood plasma
The preparation of embodiment 8 solid dispersed phase
Polyethylene Glycol F68 (2087.4g) is heated to 80 ℃ of fusions.Cisapride (522.4g), tartaric acid (391.4g) slowly join in the fused Polyethylene Glycol and are uniformly dispersed, and continue to mix 1 hour, and the solid dispersed phase cool to room temperature of gained grinds.The preparation of tablet
With solid dispersed phase and following tablet ingredients by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 32.8
Methylcellulose K100LV 40.0
Methylcellulose K15M 0.1
Microcrystalline Cellulose pH101 26.1
High degree of dispersion silica gel 200 0.5
Magnesium stearate 0.5
Mixture is pressed into the tablet that average hardness is 125N with Killian RTS tablet machine.Measure the dissolubility of tablet in glass container that makes by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5???????????6.3
1.0???????????8.5
2.0???????????14.4
4.0???????????28.6
6.0???????????37.9
8.0???????????51.1
10.0??????????60.7
24.0??????????104.6
The preparation of embodiment 9 consubstantiality decentralized photos
Tartaric acid 156.4g is dissolved in the 833g ethanol, in another container cisapride 500g is dissolved in the 5000g acetone, adds 2001.7g Polyethylene Glycol F68 subsequently.Two solution heat up under vacuum condition and make solvent evaporation 50 ℃ of mixing.The fused solid dispersed phase of gained is cooled to room temperature, grinds.The preparation of tablet
With solid dispersed phase and following tablet ingredients by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 30.35
Methylcellulose K100LV 5.0
Methylcellulose K15M 10.0
Microcrystalline Cellulose pH101 53.65
High dispersive silica gel 200 0.5
Magnesium stearate 0.5
Mixture is pressed into the tablet that average hardness is 108N with Killian RTS tablet machine.Measure the tablet dissolution in vitro degree that makes by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5???????????6.6
1.0???????????10.2
2.0???????????16.7
4.0???????????26.1
6.0???????????32.8
8.0???????????40.0
10.0??????????44.3
24.0??????????84.1
The preparation of embodiment 10 solid dispersed phase
Prepare solid dispersed phase by embodiment 9 methods.The preparation of tablet
With solid dispersed phase and following tablet ingredients by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 30.35
Methylcellulose K100LV 40.0
Methylcellulose K15M 0.1
Microcrystalline Cellulose pH101 28.55
High dispersive silica gel 200 0.5
Magnesium stearate 0.5
Mixture is pressed into the tablet that average hardness is 115N with Killian RTS tablet machine.Measure the tablet make at external dissolubility by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5????????????5.0
1.0????????????9.5
2.0????????????16.0
4.0????????????28.4
6.0????????????40.1
8.0????????????49.5
10.0???????????65.7
24.0???????????103.9
The preparation of embodiment 11 solid dispersed phase
Prepare solid dispersed phase by embodiment 9 methods.The preparation of micro tablet
With solid dispersed phase and following tablet ingredients by shown in mixed prepare micro tablet:
Composition weight %
Solid dispersed phase 29.57
Microcrystalline Cellulose pH101 58.93
High dispersive silica gel 200 2.0
Magnesium stearate 0.5
Mixture is pressed into the tablet that average hardness is 75N with Killian RTS tablet machine.The coating of micro tablet
With the 500g micro tablet in Hi-Coater (trade mark) coating pan with following solution coating, 10.7%. will increase weight behind the coating
Composition weight %
Acrylic acid (Eudragit) L12.5 50.0
Diethyl phthalate 1.25
Talcum 1.50
Isopropyl alcohol 44.4
Pure water 2.85
The microplate 500g that obtains with following solution coating, will increase weight 8.6% behind the coating in Hi-Coater (trade mark) coating pan.
Composition weight %
Acrylic acid S12.5 50.0
Diethyl phthalate 1.25
Talcum 1.55
Isopropyl alcohol 44.35
Pure water 2.85 final dosage forms
Final dosage form is a capsule at two zero point, wherein contains 3 parts of not coating microplates, 3 parts of acrylic acid (Eudragit) L coating microplate, 3 parts of acrylic acid (Eudragit) S coating microplate.This dosage form has a kind of level and smooth plasma concentration curve in a lasting cycle as shown in Figure 5.
The not microplate of coating disintegrate (＜7 minutes) fast in acid in the capsule, 95% dissolving release in 0.01NHCl.The tablet of enteral coating is no quick disintegrate (can reach 60 minutes) in acid, and 100% dissolving discharges in the buffer of the pH6.8 that contains SLS (sodium lauryl sulphate).
The pharmacokinetic data available of the preparation of embodiment 8-11 preparation and commercially available Prepulsid product (hereinafter referred to as contrast) is summarized in Fig. 5 of table 5 and back.
Table 5
| | Embodiment | 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Contrast |
| ??AUC ??(0-∞) | ??2027.58 ??±554.90 | ??1747.99 ??±765.87 | ??1982.09 ??±860.97 | ??1820.12 ??±619.91 | ?2124.80 ±650.96 | |
| ??Cmax | 111.54 | ????92.36 | ????84.24 | ????85.81 | ??101.94 |
| ??±31.34 | ??±40.51 | ??±21.86 | ??±22.27 | ??±24.45 | |
| ??Tmax | ????4.30 ????±0.95 | ????4.20 ????±1.23 | ????7.40 ????±4.25 | ????3.90 ????±1.60 | ????13.55 ????43.7 |
| ????F％ | ????99.2 ????±27.3 | ????82.2 ??±?23.1 | ????94.7 ????±31.0 | ????88.6 ????±28.5 |
The preparation of embodiment 12 solid dispersed phase
With Polyethylene Glycol F127 (866g) heating and melting.Cisapride (300g) joins in the fused Polyethylene Glycol and is uniformly dispersed, and tartaric acid (60.7g) adds in the mixed liquor of Polyethylene Glycol and cisapride and is uniformly dispersed, and the gained solid dispersed phase is ground in cooling.The preparation of uncoated tablets
With the solid dispersed phase weight that as above makes 24% with following component by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 240
Microcrystalline Cellulose pH101 45.3
KCl?????????????10.0
Sorbitol 20.0
Magnesium stearate 0.5
High dispersive silica gel 200 0.2
Mixture is pressed into the tablet that average hardness is 110-150N with Killian RTS tablet machine.
Measure the external dissolubility of uncoated tablets that makes by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5???????????104.6
1.0 the preparation of 111.6 coated tablets
The tablet that as above makes is used the conventional method coating in C.F.130 coating equipment, coating solution is ethyl cellulose: polyvinylpyrrolidone (7: 3), weightening finish 2%.
Measure the external dissolubility of coated tablet that makes by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5????????????6.5
1.0????????????19.9
2.0????????????89.6
4.0????????????100.7
The preparation of embodiment 13 solid dispersed phase
With Polyethylene Glycol F127 (866g) heating and melting.Cisapride (300g) joins in the fused Polyethylene Glycol and is uniformly dispersed, and tartaric acid (60.7g) adds in the mixed liquor of Polyethylene Glycol and cisapride and is uniformly dispersed, and the gained solid dispersed phase is ground in cooling.The preparation of uncoated tablets
With the solid dispersed phase weight that as above makes 24% with following component by shown in mixed prepare tablet:
Composition weight %
Solid dispersed phase 240
Microcrystalline Cellulose pH101 45.3
KCl??????????????10.0
Sorbitol 20.0
Magnesium stearate 0.5
High dispersive silica gel 200 0.2
Mixture is pressed into the tablet that average hardness is 110-150N with Killian RTS tablet machine.
Measure the external dissolubility of uncoated tablets that makes by embodiment 6 conditions.Obtain following result:
Time (hour) release %
0.5???????????104.6
1.0 the preparation of 111.6 coated tablets
The tablet that as above makes is used the known method coating in C.F.130 coating equipment, coating solution is acrylic acid RS: acrylic acid RL (6: 4), weightening finish 2%.
Measure the external dissolubility of coated tablet that makes by embodiment 6 conditions.Obtain with lower curve:
Time (hour) release %
1.0???????????2.0
2.0???????????7.7
4.0???????????24.1
6.0???????????33.7
8.0???????????46.1
12.0??????????55.2
24.0??????????72.6
Claims (21)
1. oral controlled release preparation, comprise the solid dispersed phase that the slightly solubility active component forms in hydrophilic poloxamer polymer, this solid dispersed phase is the ingredient of sheet nuclear, examines or examine coating through the sheet of polymer coating for described to make described active component reach the therapeutic dose level in one period persistent period after oral.
2. the described a kind of preparation of claim 1, the mixed nuclear in blocks of wherein said solid dispersed phase and one or more tablet ingredients is examined or is examined coating through the sheet of polymer coating for described and can make described active component reach the therapeutic dose level in one period persistent period after oral.
3. claim 1 or 2 described preparations, wherein solid dispersed phase comprises surface active agent composition.
4. the described preparation of claim 3, surface active agent composition wherein is selected from sodium lauryl sulphate, carboxylic acid sodium, alkyl sodium sulfate ester, macrogol ester, polyvinylether, Isosorbide Dinitrate, ethyoxyl Isosorbide Dinitrate, halogenated alkyl trimethylammonium and their mixture.
5. according to aforementioned arbitrary claimed formulations, wherein solid dispersed phase comprises acidic components.
6. the described preparation of claim 5, acidic components select oneself diacid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid or tartaric acid.
7. the arbitrary claimed formulations of claim 1-4, wherein solid dispersed phase comprises basic component.
8. the preparation of claim 7, wherein basic component is selected from calcium carbonate, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate or sodium hydroxide.
9. according to the arbitrary claimed formulations of claim 3-8, wherein the weight ratio of surfactant, acidic components or basic component and active component is 0.01: 1.0 to 5.0: 1.0.
10. according to aforementioned arbitrary claimed formulations, wherein the weight ratio of active component and poloxamer is 0.1: 1.0 to 10.0: 1.0.
11. according to aforementioned arbitrary claimed formulations, wherein poloxamer comprises the polyoxyethylene of 60%-90% weight.
12., be a kind of many granules dosage form according to aforementioned arbitrary claimed formulations.
13., be a kind of microplate dosage form according to the preparation of claim 12.
14. according to the preparation of claim 12 or 13, comprising a certain amount of described solid dispersed phase to reach instant-free.
15., be Tabules according to the arbitrary claimed formulations of aforementioned claim 1-11.
16. according to aforementioned claim 2-11 and 15 arbitrary claimed formulations, sheet nuclear wherein is the described solid dispersed phase that is scattered in the hydrogel matrix.
17. according to the preparation of claim 16, hydrogel matrix wherein is by the water permeability polymer formation.
18. according to the preparation of claim 17, water permeability polymer wherein is a hydroxypropyl emthylcellulose, consumption accounts for 5%-75% weight.
19. according to the preparation of claim 15, sheet nuclear wherein is by porous rate-controlling membrane parcel.
20. according to aforementioned arbitrary claimed formulations, active component wherein is selected from cisapride, cyclosporin, diclofenac, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, teldane and theophylline.
21. an oral controlled release preparation, basically as previously mentioned and for example.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96195173A CN1189774A (en) | 1995-07-03 | 1996-07-01 | Controlled release formulations for poorly soluble drugs |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE950492 | 1995-07-03 | ||
| US60/000,897 | 1995-07-06 | ||
| CN96195173A CN1189774A (en) | 1995-07-03 | 1996-07-01 | Controlled release formulations for poorly soluble drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1189774A true CN1189774A (en) | 1998-08-05 |
Family
ID=5129032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195173A Pending CN1189774A (en) | 1995-07-03 | 1996-07-01 | Controlled release formulations for poorly soluble drugs |
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| CN (1) | CN1189774A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100413491C (en) * | 2004-06-14 | 2008-08-27 | 北京德众万全药物技术开发有限公司 | Sustained release preparation of solution resistant medicine |
| CN102028687A (en) * | 2010-12-10 | 2011-04-27 | 浙江昂利康制药有限公司 | Nifedipine composition and preparation method thereof |
| CN103038699A (en) * | 2010-07-30 | 2013-04-10 | 诺瓦提斯公司 | A silicone hydrogel lens with a crosslinked hydrophilic coating |
| CN107875132A (en) * | 2016-09-30 | 2018-04-06 | 常州市第四制药厂有限公司 | A kind of felodipine sustained-release preparation composition and preparation method thereof |
-
1996
- 1996-07-01 CN CN96195173A patent/CN1189774A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100413491C (en) * | 2004-06-14 | 2008-08-27 | 北京德众万全药物技术开发有限公司 | Sustained release preparation of solution resistant medicine |
| CN103038699A (en) * | 2010-07-30 | 2013-04-10 | 诺瓦提斯公司 | A silicone hydrogel lens with a crosslinked hydrophilic coating |
| CN103038699B (en) * | 2010-07-30 | 2015-03-18 | 诺华股份有限公司 | A silicone hydrogel lens with a crosslinked hydrophilic coating |
| CN102028687A (en) * | 2010-12-10 | 2011-04-27 | 浙江昂利康制药有限公司 | Nifedipine composition and preparation method thereof |
| CN107875132A (en) * | 2016-09-30 | 2018-04-06 | 常州市第四制药厂有限公司 | A kind of felodipine sustained-release preparation composition and preparation method thereof |
| CN107875132B (en) * | 2016-09-30 | 2020-10-20 | 常州市第四制药厂有限公司 | Felodipine sustained-release preparation composition and preparation method thereof |
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