CN1272785A - Micro-osmotic controlled drug delivery system - Google Patents

Micro-osmotic controlled drug delivery system Download PDF

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CN1272785A
CN1272785A CN99800925A CN99800925A CN1272785A CN 1272785 A CN1272785 A CN 1272785A CN 99800925 A CN99800925 A CN 99800925A CN 99800925 A CN99800925 A CN 99800925A CN 1272785 A CN1272785 A CN 1272785A
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pharmaceutical compositions
core
therapeutic agent
hpmc
pastille
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S·N·塔拉芙哈拉
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EMD Chemicals Inc
EM Ind Inc
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

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Abstract

Disclosed herein are compositions and methods related to pharmaceutical compositions that employ a micro-osmotic core for the controlled delivery of a therapeutic agent. The invention particularly relates to therapeutic agents which are present in some portion in a solid state solution in the composition.

Description

Micro-osmotic controlled drug delivery system
Background of invention
The present invention relates to be used for the treatment of the field of the permeability delivery system of agent controlled release.The permeability delivery system medicament is changed according to the osmotic pressure in the dosage form and from dosage form controlled release become easy.The permeability delivery system is all useful to discharging the big therapeutic agent of poorly soluble and dissolubility.
Brief summary of the invention
According to the present invention, developed a kind of micro-osmotic controlled drug delivery system.This little osmosis system comprises with the lower part: little infiltration core, ingredient optionally, also can comprise controlled release matrix and/or clothing layer.
Little infiltration core comprises at least a penetrating agent, optionally, also can comprise sweller and/or gellant.Penetrating agent makes the aqueous biological fluid enter little infiltration core easily.Penetrating agent for example comprises Sorbitol, mannitol, xylitol, sodium chloride or the good and pharmaceutically useful excipient of any other this class dissolubility.Preferable penetrating agent for example comprises spray-dired Sorbitol, Sorbitol Instant (the EMIndustries company product of New York Hawthorne) especially, and its surface area is～1m 2/ g; Spray-dired mannitol; Have polymorphic and form the mannitol of (drying regime), it contains and is no less than " δ " type mannitol of about 85%; The combination of Sorbitol-mannitol-xylitol, be preferably, described in German patent application DE 196 47 282 A1, P96 47282-DE and International Patent Application WO 44 39 858, PCT/EP95/04059, Sorbitol 〉=90%, mannitol 〉=4%, xylitol 〉=4%.
Optionally, little infiltration core also can contain sweller.Sweller can make volumetric expansion when contacting with the aqueous biological fluid, thereby changes the volume of little infiltration core.The manyfold of the volume when sweller preferably can make volumetric expansion to its drying regime.Preferable sweller for example comprises Explotab, cross-linking sodium carboxymethyl cellulose, cellulose and microcrystalline Cellulose.
Optionally, little infiltration core also can contain gellant.The effect of gellant is, keeps the integrity of sweller, keeps the integrity of little infiltration core thus.Gellant is water-soluble polymer preferably.Preferable gellant for example comprises hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and derivant thereof, Tragacanth, arabic gum, guar gum, carrageenin and other carbohydrate-derived natural gum, alginic acid and derivant thereof, and carbomer (carbomers).
Little infiltration core is that diameter is about the 2-3000 μ m small particle of (be about 200-3000 μ m preferably, better be about 200-1500 μ m).These microgranules can be micro tablets, for example can use soluble oil (as PEG8000) to form.Also little infiltration core can be extruded and round as a ball one-tenth bead and/or spraying condense into microgranule.Penetrating agent/sweller/gellant can 100/0/0 to 0.05/99.9/0.05 to 99.9/0.05/0.05 to 0.05/0.05/99.9 the weight ratio combination.1/8/1,2/7/1,3/6/1,4/5/1,6/2/2,7/1/2,8/1/1,9/0.5/0.5 and 5/4/1 ratio of preferable penetrating agent/sweller/gellant is:.
Be coated with little infiltration core of the present invention to obtain the fuse of pastille with ingredient." coating " speech is meant that at this any physics contacts between ingredient and the little infiltration core.For example, ingredient can be coated with wholly or in part little infiltration core, perhaps dipping.The diameter of the core of pastille is about 2-3000 μ m, is about 200-3000 μ m preferably, preferably is about 200-1500 μ m.Ingredient comprises at least a therapeutic agent.Therapeutic agent in the ingredient can be for example solid, solid solution, solid solution-dispersion, differential prose style free from parallelism system, solution-suspension (for example aqueous, alcohol or water-alcohol) or their any combination.Therapeutic agent can mix with selected excipient and/or binding agent.Optionally, the therapeutic agent of solution-suspension-type can also comprise hydrophilic agent outside water, alcohol or water-pure system, as HPMC, HPC, PVP, Sorbitol and/or natural gum (as arabic gum).
" solid solution " speech is meant the solution of solid-state therapeutic agent at this.The feature of the solid solution of therapeutic agent is, do not have the fusing point peak at the fusing point place of therapeutic agent, and showing does not have solid-state therapeutic agent." solid solution-dispersion " speech is meant such system at this: part therapeutic agent wherein is a solid solution, and the part therapeutic agent is abundant dispersed solids.Be preferably, the total therapeutic agent content more than 1% is present in the solution in the system, perhaps is present in solid phase, semi-solid phase or the liquid phase.The feature of this system is that also at least a therapeutic agent can be used as solid dispersion and exists.The therapeutic agent of any part that exists as solid dispersion preferably has such particle size distribution: the diameter of about 90% microgranule is less than about 10 μ m.
In solid solution-dispersion, the ratio of dissolved therapeutic agent/dispersed therapeutic agent is 1/99 to 100/0.Be preferably, about 30% to about 100% therapeutic agent exists in solution, and is more preferably, and about 60% to about 90% therapeutic agent exists in solution.The amount of the therapeutic agent that exists with the solid solution form can easily use thermoanalysis technology (as differential scanning calorimetry (DSC), thermogravimetry (TGA) and differential scanning microcalorimetric method) to be determined with the ratio of the amount that exists with the solid dispersion form.The crystallinity of therapeutic agent can easily be determined with X-ray diffraction method.
An example of (in particular for the therapeutic agent of poorly water-soluble) solid solution-dispersion system is saturated glyceride (saturated polyglycolyzed glycerides) (for example, the Gelucire that handles through Polyethylene Glycol described in U.S. Patent application No.09/050913 and the U.S. Provisional Patent Application No.60/080163,60/085417,60/085333 and 60/092767 for example , Gattefosse company product), polyoxypropylene-polyoxyethylene block copolymer (for example, Pluronic NF surfactant, BASF AG's product) and the mixture of therapeutic agent.The glyceride component through the Polyethylene Glycol processing of pharmaceutical carriers compositions can comprise the saturated and undersaturated glyceride through the Polyethylene Glycol processing of all grades, preferably includes the glyceride through the Polyethylene Glycol processing of hydrophile-lipophile balance (HLB)＞10.The preferable glyceride of handling through Polyethylene Glycol for example comprises Gelucire 44/13 and Gelucire 50/13.Mixture also can comprise the polyoxypropylene-polyoxyethylene block copolymer of all grades, preferably includes the polyoxypropylene-polyoxyethylene block copolymer of HLB＞10.Preferable polyoxypropylene-polyoxyethylene block copolymer for example comprises Pluronic L44, Pluronic F68, Pluronic F108 and Pluronic F127.Can the extremely weight ratio combination of about 99.0/0.10 of about 0.10/99.9 through glyceride/polyoxypropylene-polyoxyethylene block copolymer that Polyethylene Glycol is handled.Preferable ratio 1/9,2/8,3/7,4/6,6/4,7/3,8/2,9/1 and 5/5.The fusing point of the mixture of saturated glyceride/polyoxypropylene-polyoxyethylene block copolymer of handling through Polyethylene Glycol is good with about 30-70 ℃, better is about 50-70 ℃.During glyceride/polyoxypropylene that use is handled through Polyethylene Glycol-polyoxyethylene block copolymer mixture, the amount of mixture in the final composition of ingredient is about 0.10-99.9%, preferably is about 5-75%.The amount of the therapeutic agent in the final composition of ingredient is about 0.10-99.9%, preferably is about 5-75%.
The example of the therapeutic agent that can use in the present invention comprises: dihydropyridine compounds (for example comprising nifedipine, felodipine, nicardipine), cyclic peptide (for example comprising ciclosporin), omeprazole, spironolactone, furosemide, terbutaline, riboflavin, gemfibrozil, indomethacin, ibuprofen, phenytoin and glibenclamide.In addition, any intrinsic solubility is considered as a part of the present invention less than the therapeutic agent that about 10.0g/L and in following field any have therapeutic activity: in the activity of cardiovascular system; immunosuppressive activity; the cholesterol reducing activity; antihypertensive active; antiepileptic activity; hormonal activity; hypoglycemic activity; antiviral activity; anti-histamine activity; alleviate the activity of nasal congestion; antimicrobial acivity; antiarrhythmic activity; analgesic activities; the mycobacteria activity; active anticancer; diuretic activity; antifungal activity; the parasiticide activity; activity as central nervous system (CNS) stimulant; activity as the CNS inhibitor; activity as the 5-HT inhibitor; the schizophrenia activity; anti-degenerative brain disorder activity; the psoriasis activity; antiulcer activity; activity as proton pump inhibitor; the asthma activity; activity and thrombus dissolving activity as bronchodilator.Therapeutic agent can be for example protein, peptide, cyclic peptide, steroid quasi-molecule, vitamin, oligonucleotide, or any little or big molecule, or any combination of aforesaid compound.
Except that one or more therapeutic agents, optionally, ingredient can comprise excipient.Excipient is good with about 5-95 weight % of the final composition that accounts for ingredient, is more preferably and accounts for 10-70%.The example of suitable excipient includes but not limited to: ascorbic palmitate, tocopherol acetate, glycerol, glyceryl monooleate, glyceryl monostearate, Palmic acid tristerin (glyceryl palmitosterate), triglyceride, Diglyceride, monoglyceride, stearic acid, magnesium stearate, Pulvis Talci, the diester of Polyethylene Glycol (PEG), the monoesters of PEG, Polyethylene Glycol, polyoxyethylene fatty acid glyceride; Polyoxyethylene polyethylene glycol fatty acid glyceride and ether, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Myrj 45, polyvinyl alcohol, Explotab, sorbitan fatty acid esters, KIKKOL MYS-40, polyethylene glycol hydroxystearate, the polyoxyethylene alcohols, anion, cation, amphoteric compound, lecithin, phospholipid, carbohydrate (for example comprises lactose, maltodextrin, sucrose and starch), polyhydric alcohol (for example comprises Sorbitol, mannitol and xylitol), microcrystalline Cellulose, vitamin (for example comprising ascorbic acid and nicotiamide), bioflavonoids (for example comprises quercetin, different quercetin, naringin, rutin etc.), inorganic compound (for example comprises calcium carbonate, dicalcium phosphate) and any combination of above-mentioned substance.
Can wrap with suitable polymers clothing layer and/or with polymer-matrix plastidome with little infiltration core (core of pastille) of ingredient coating and to mix.Polymer coating or polymeric matrix can play the therapeutic agent release characteristics of the core of change pastille.Polymer clothing layer for example can comprise: hydrophilic polymer, for example HPMC, HPC, cellulose derivative, starch derivatives, PVP and PVP derivant, carbomers; Insoluble polymer, for example ethyl cellulose, cellulose acetate, polymethacrylate polymer (Eudragit for example Polymer) and the pseudo-gums of above-mentioned polymer breast dispersion; Enteric polymer, for example Lac, Cellacefate; Plasticizer, for example dibutyl sebacate, glyceryl triacetate, acetyl group tributyl phthalic acid ester; Pearly-lustre pigment, for example Candurin TMPigment series (the EMIndustries company product of New York Hawthorne).The known pharmaceutical technology in available this area is given (comprising technology such as Wurster coating method, rotation coating method and/or pan coating method) the core coating of pastille.
Polymeric matrix comprises at least a hydrophilic polymer, for example cellulose and derivant thereof (comprising for example HPMC, HEC, Carbomers (as Carbopol P934, Carbopol P974)) and alginic acid and derivant thereof.The molecular weight of the hydrophilic polymer of polymeric matrix preferably is about 100-4,000,000.Hydrophilic polymer also preferably is used in combination with at least a hydration reinforcing agent of the faster hydration of hydrophilic polymer that can make.The hydration reinforcing agent for example comprises Sorbitol, mannitol, xylitol and microcrystalline cellulose rope and their any combination.Preferable hydration reinforcing agent is special-purpose spraying condensation type Sorbitol (commercially available product has SorbitolInstant, the EM Industries company product of New York Hawthorne), and its surface area is 1m 2/ g.The hydrophilic polymer of different molecular weight and different chemical character can be made up to obtain required therapeutic agent release characteristics.
Can be with the core and the polymeric matrix dry blending of pastille, use suitable solvent (for example aqueous and/or organically) to granulate then and/or be processed into beadlet or spherolite, perhaps be pressed into tablet with examples of suitable lubricants.Be applicable to that the lubricant with the dry mixture tabletting of the core of pastille and polymeric matrix for example comprises sodium stearyl fumarate, magnesium stearate, PEG 8000.Also can use the part of flow improver additive (as colloidal silica) as the tabletting step.
Can (this product comprises the core of pastille with the product that obtained by above-mentioned steps; coating can be arranged; can there be coating yet; optionally; can mix with polymeric matrix; form dry mixture, and can optionally further be processed into granule, beadlet, spherolite or tablet) further be processed into following final dosage form.As an example, granule, spherolite, beadlet or dry mixture can be pressed into tablet, and can optionally give gained tablet bag, to change the release characteristics of therapeutic agent with polymer clothing layer.Polymer coating is coating as mentioned above basically.As another example, available aforesaid basically polymer clothing layer is given beadlet, spherolite or granule coating.Can will be pressed into tablet during beadlet, spherolite or the granule of coating incapsulate or with suitable pharmaceutical excipient then.
In the present invention, final dosage form can comprise the core of polytype pastille.For example, can same therapeutic agent will be contained but the core of the different pastille of release characteristics is incorporated in the final dosage form.The polymer coating that contains the core of inclusions that the different release characteristics of core of the pastille of same therapeutic agent for example can be by changing little infiltration core or pastille obtains.Perhaps, also the core with pastille of different therapeutic agents can be incorporated in the same final dosage form.
The invention still further relates to the manufacture method of pharmaceutical compositions.This method may further comprise the steps: form little infiltration core, be coated with the core that little infiltration core forms pastille with ingredient, optionally, the core of pastille is mixed with above-mentioned final dosage form.
The invention still further relates to the method that one or more therapeutic agents is released into the physiology target site.This method comprises the step that forms following compositions of the present invention and the pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.Pharmaceutical compositions is imported the physiology target site for example can be realized by topical, subcutaneous administration, muscle administration, intraperitoneal administration, nose administration, pulmonary administration, vagina administration, rectally, ear's administration, oral administration or dosing eyes.The contemplated preferred approach that at least a therapeutic agent is released into the physiology target site of the present invention is an oral administration.
The simple declaration of accompanying drawing
Fig. 1 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 17.
Fig. 2 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 18.
Fig. 3 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 19.
Fig. 4 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 20.
Fig. 5 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 21.
Fig. 6 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 22.
Fig. 7 is the extracorporeal releasing characteristic curve chart of the felodipine in the tablet of embodiment 23.
Need not to further describe, can believe, those skilled in the art can farthest utilize the present invention according to the description of front.Therefore, the following preferable specific embodiment should be thought and only illustrates, and should not think limitation of the invention.
Embodiment
In the following embodiments, all parts and percentage ratio all by weight, except as otherwise noted.
Among the embodiment 17-23 below, use following composition.
1.Pruv TMSodium stearyl fumarate, Mendell company product
2.Avicel TMPH200 ... microcrystalline Cellulose NF, FMC Corp.'s product
3.Sorbitol Instant P300 ... Sorbitol NF, Merck KGaA company product
4.Methocel TME4M Premium CR ... hydroxypropyl emthylcellulose NF, Dow Chemical company product
5.Methocel TMK100M ... hydroxypropyl emthylcellulose NF, Dow Chemical company product
6.Triacetin TMGlycerol triacetate, Spectrum Quality Products company product
7.Eudragit NE30D ... 30% aqueous dispersion of acrylate copolymer, Roehm company product
8.Eudragit L30D ... 30% aqueous dispersion of methacrylic acid/methacrylate copolymer, Roehm company product
9.PVP30 ... polyvinyl pyrrolidone (MW:44,000-54,000), trade name is Kollidon 30, BASF AG's product
10.Gelucire 50/13 ... (glyceride of the saturated hydrogenated vegetable oil of handling through Polyethylene Glycol comprises glyceride and PEG-ester), Gattefosse company product
11.Pluronic F68 ... polyoxypropylene-polyoxyethylene block copolymer, BASF AG's product embodiments 1: the preparation of little infiltration core
Available various material prepares little infiltration core by any technology known in the art.Be several in these technology and the material below:
(1) use crystal type or spraying condensation type Sorbitol as little infiltration core;
(2) Sorbitol, Explotab and HPMC are mixed, use PEG8000 to be pressed into micro tablet (for example, diameter＜1mm) as lubricant;
(3) Sorbitol powder and Explotab are mixed, and mixture is extruded and round as a ball formation spherolite;
(4) the Explotab spraying is condensed on the Sorbitol.
In the available said method any or with the known little infiltration core of other any technology (comprising granulation) preparation in this area.Embodiment 2: as the preparation of the therapeutic agent of solid solution-dispersion
The glyceride that to handle through Polyethylene Glycol and the mixture heated of polyoxypropylene/polyoxyethylene block copolymer are to the temperature (～50 ℃) higher 20 ℃ than fusing point.Therapeutic agent is joined in the fused mixture gradually.Preferably therapeutic agent is worn into microgranule, the diameter that makes at least 90% microgranule is less than about 75 microns.Mixture is remained in the high 20 ℃ temperature of fusing point than the mixture of glyceride of handling through Polyethylene Glycol and polyoxypropylene/polyoxyethylene block copolymer.Selection can be dissolved in the mixture therapeutic agent of (preferably 30-100%) more than 1% through the glyceride of Polyethylene Glycol processing and the ratio of polyoxypropylene/polyoxyethylene block copolymer.Embodiment 3: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 little infiltration core 2. nifedipines, American Pharmacopeia 90 active component 3.Gelucire 50,/13 90 excipient 4.Pluronic F68 90 excipient 5.HPMC E4M (CR level) 300 hydrophilic polymer thing 6.Sorbitol Instant P300 75 hydration reinforcing agents 7. microcrystalline celluloses 75 hydration reinforcing agents 8. dolomols 6.8 lubricants
With Sorbitol Instant P300 as the infiltration core.Gelucire 50/13, Pluronic F68 and nifedipine are processed together, obtain containing the ingredient of therapeutic agent nifedipine, nifedipine is solid solution-dispersion and exists.Then the ingredient spraying is condensed on the Sorbitol Instant.The core of the pastille that makes is above mixed with the polymeric matrix that contains Sorbitol Instant P300, HPMC E4M (CR level), microcrystalline Cellulose and magnesium stearate.With the core of pastille and the mixture tabletting of polymer formulators, obtain controlled release tablet then.Embodiment 4: the controlled release tablet that contains felodipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 swellers 3. felodipines, American Pharmacopeia 90 active component 4.Gelucire 50,/13 90 excipient 5.Pluronic F68 90 excipient 6.HPMC E4M (CR level) 300 hydrophilic polymer thing 7.Sorbitol Instant P300 75 hydration reinforcing agents 8. microcrystalline celluloses 75 hydration reinforcing agents 9. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are combined to form little infiltration core.Gelucire50/13, Pluronic F68 and felodipine are mixed, obtain containing the ingredient of the felodipine that is solid solution.Then the ingredient spraying is condensed on little infiltration core.The core of the pastille that makes is above mixed with SorbitolInstant P300, HPMC E4M (CR level), microcrystalline Cellulose and magnesium stearate.With the core of pastille and the mixture tabletting of polymer formulators, obtain controlled release tablet then.Embodiment 5: contain benzene appropriate because of controlled release tablet
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 sweller 3.HPMC E4M 10 gelling agents 4. 5,5-Diphenyl-2,4-imidazolidinediones, American Pharmacopeia 95 active component 5.Gelucire 50,/13 90 excipient 6.Pluronic F68,90 excipient 7.HPMC (K100 level) 300 hydrophilic polymer thing 8.Sorbitol Instant P300 150 hydration reinforcing agents 9. dolomols 6.8 lubricants
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.Gelucire 50/13, Pluronic F68 and benzene is appropriate in processing together, and it is appropriate in the solid solution in substrate to obtain benzene.This ingredient spraying is condensed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC E4M (CR level), microcrystalline Cellulose and magnesium stearate.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 6: the controlled release tablet that contains indomethacin
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 sweller 3.HPMC E4M 10 gelling agents 4. Indomethacins, American Pharmacopeia 100 active component 5.PVP 90 excipient, adhesive 6.HPMC (K100 level) 300 hydrophilic polymer thing 7.Sorbitol Instant P300 150 hydration reinforcing agents 8. dolomols 6.8 lubricants
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.PVP and indomethacin are processed together, obtain the suspension in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMCE4M (CR level), microcrystalline Cellulose and magnesium stearate.With above-mentioned preparation tabletting, obtain controlled release tablet.Embodiment 7: the controlled release tablet that contains chlorphenamine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 sweller 3.HPMC E4M 10 gelling agents 4. chlorpheniramines 10 active component 5.PVP 20 excipient, adhesive 6.HPMC (K100 level) 300 hydrophilic polymer thing 7.SorbitolInstant P300 150 hydration reinforcing agents 8. crystallite stearate 6.8 lubricants
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.PVP and chlorphenamine are processed together, obtain aqueous solution.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC E4M (CR level), microcrystalline Cellulose and magnesium stearate.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 8: the controlled release tablet of hydrochloric diltiazem
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 160 bleeding agents 2. Explotabs 40 sweller 3.HPMCE4M 20 gelling agents 4. diltiazem hydrochloride 300 active component 5.PVP 60 excipient, an amount of anticaking agent of an amount of plasticizer 8. talcum powder of an amount of hydrophilic polymer thing 7. dibutyl sebacates of adhesive 6. ethyl cellulose dispersions
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.PVP and diltiazem hydrochloride are processed together, obtain aqueous solution.This drug system is sprayed on little infiltration core.Will be with coating on the little infiltration core of the drug system that the plastifying ethylcellulose dispersion of dibutyl sebacate makes in the above.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 9: the capsule that contains the chlorphenamine controlled release micro pill
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 sweller 3.PVP 10 gelling agents 4. chlorpheniramines 10 active component 5.PVP 20 excipient, an amount of anticaking agent of an amount of plasticizer 8. talcum powder of an amount of hydrophobicity polymer 7. dibutyl sebacates of adhesive 6.Eudragit RS30D dispersion
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.PVP and chlorphenamine are processed together, obtain aqueous solution.This drug system is sprayed on little infiltration core.Coating on the little infiltration core of drug system that will make in the above with the plastifying Eudragit RS30D of dibutyl sebacate (polymethacrylate copolymer) dispersion.During controlled release micro pill incapsulated.Embodiment 10: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 sweller 3.HPMC E4M 10 gelling agents 4. nifedipines, American Pharmacopeia 90 active component 5.PVP 90 excipient, adhesive 6. locust bean gums 175 hydrophilic polymer things 7. xanthans 175 hydrophilic polymer thing 8.Sorbitol Instant P300 150 hydration reinforcing agents 9. calcium chloride 25 crosslinking agents 10. dolomols 6.8 lubricants
Sorbitol Instant P300, HPMC E4M and Explotab are processed into little infiltration core together.PVP and nifedipine are processed together, obtain the suspension solution in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, locust bean gum, xanthan gum, calcium chloride, mix with magnesium stearate at last.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 11: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 swellers 3. nifedipines, American Pharmacopeia 90 active component 4.PVP 90 excipient, adhesive 5.HPMC (K100 level) 300 hydrophilic polymer thing 6.Sorbitol Instant P300 150 hydration reinforcing agents 7. ethyl celluloses 100 hydrophilic polymer things 8. glycerol triacetates 25 plasticizer 9. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are processed into little infiltration core together.PVP and nifedipine are processed together, obtain the suspension in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC (K100 level), use the granulation of forming by ethyl cellulose and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate, mixes with magnesium stearate at last.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 12: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 swellers 3. nifedipines, American Pharmacopeia 90 active component 4.PVP 90 excipient, adhesive 5.HPMC (K100 level) 300 hydrophilic polymer thing 6.Sorbitol Instant P300 150 hydration reinforcing agents 7. ethyl celluloses 100 hydrophobicity polymer 8. glycerol triacetates 25 plasticizer 9.HPMC E4M 10 hydrophilic polymer things 10. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are processed into little infiltration core together.PVP and nifedipine are processed together, obtain the suspension solution in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC (K100 level), use the granulation of forming by ethyl cellulose, HPMC E4M and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate, mixes with magnesium stearate at last.With above-mentioned prescription tabletting, obtain controlled release tablet.Embodiment 13: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 swellers 3. nifedipines, American Pharmacopeia 90 active component 4.PVP 90 excipient, adhesive 5.HPMC (K100 level) 300 hydrophilic polymer thing 6.Sorbitol Instant P300 150 hydration reinforcing agents 7. ethyl celluloses 100 hydrophobicity polymer 8. glycerol triacetates 25 plasticizer 9.HPMC E4M 10 hydrophilic polymer things 10. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are processed into little infiltration core together.PVP and nifedipine are processed together, obtain the suspension in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC (K100 level), use the granulation of forming by ethyl cellulose and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate, mixes with magnesium stearate at last.With above-mentioned prescription tabletting, obtain controlled release tablet.Use the semipermeability polymer coating system of forming by ethyl cellulose, HPMC E4M and glycerol triacetate with these tablet coatings.Embodiment 14: the controlled release tablet that contains nifedipine
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 50 bleeding agents 2. Explotabs 20 swellers 3. nifedipines, American Pharmacopeia 90 active component 4.PVP 90 excipient, adhesive 5.HPMC (K100 level) 300 hydrophilic polymer thing 6.Sorbitol Instant P300 150 hydration reinforcing agent 7.Eudragit NE30D 100 hydrophobicity polymer 8. dibutyl sebacates 25 plasticizer 9.HPMC E4M 10 hydrophilic polymer things 10. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are processed into little infiltration core together.PVP and nifedipine are processed together, obtain the outstanding liquid that mixes in ethanol.This drug system is sprayed on little infiltration core.The little infiltration core of the drug system that makes is above mixed with Sorbitol Instant P300, HPMC (K100 level), use the granulation of forming by Eudragit NE30D (polymethacrylate copolymer dispersion) and glycerol triacetate to make granule with solvent, dry, agglomerate is pulverized, mixed with magnesium stearate at last.With above-mentioned prescription tabletting, obtain controlled release tablet.Use the semipermeability polymer coating system of forming by Eudragit NE30D (polymethacrylate copolymer dispersion), HPMC E4M and glycerol triacetate with these tablet coatings.EXAMPLE l 5: the controlled release tablet of hydrochloric verapamil
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 220 bleeding agents 2. Explotabs 40 swellers 3. verapamil hydrochlorides 240 active component 4.PVP 60 excipient, adhesive 5.HPMC (K100 level) 300 hydrophilic polymer 6.Sorbitol Instant P300 50 hydration reinforcing agent 7.Eudragit NE30D 150 hydrophobic polymer 8.Eudragit L30D 100 hydrophobic polymers 9. dibutyl sebacates 75 plasticizer 10.HPMC E4M 10 hydrophilic polymers 11. dolomols 6.8 lubricants
Sorbitol Instant P300 and Explotab are mixed, form little infiltration core.PVP and verapamil hydrochloride are processed together, obtain aqueous solution.This drug system is sprayed on little infiltration core.The little infiltration core of medicine is divided into two parts.Portion in the little infiltration core of the drug system that makes is above mixed with SorbitolInstant P300, HPMC (K100 level), use the granulation of forming by Eudragit NE30D (polymethacrylate copolymer dispersion) and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate.Another part in the little infiltration core of the drug system that makes above mixed with Sorbitol Instant P300, HPMC (K100 level), use the granulation of forming by Eudragit L30D (polymethacrylate copolymer dispersion) and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate.The material that will obtain in step c and d merges, and mixes with magnesium stearate.With above-mentioned prescription tabletting, obtain controlled release tablet.Use the semipermeability polymer coating system of forming by Eudragit NE30D (polymethacrylate copolymer dispersion), HPMC E4M and glycerol triacetate with these tablet coatings.Embodiment 16: the capsule of hydrochloric verapamil
Become component (mg/ sheet) effect 1.Sorbitol Instant P300 220 bleeding agents 2. Explotabs 40 swellers 3. verapamil hydrochlorides 240 active component 4.PVP 6 excipient, an amount of anticaking agent of adhesive 5.HPMC (K100 level) 300 hydrophilic polymer 6.Sorbitol Instant P300 50 hydration reinforcing agent 7.Eudragit NE30D, 100 hydrophobic polymer 8.Eudragit L30D 150 hydrophobic polymers, 9. dibutyl sebacate 75 plasticizer, 10. talcum powder
Sorbitol Instant P300 and Explotab are processed into little infiltration core together.PVP and verapamil hydrochloride are processed together, obtain aqueous solution.This drug system is sprayed on little infiltration core.The little infiltration core of medicine is divided into two parts.Portion in the little infiltration core of the drug system that makes is above mixed with SorbitolInstant P300, HPMC (K100 level), use the granulation of forming by Eudragit NE30D (polymethacrylate copolymer dispersion) and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate.Use then by the plastifying Eudragit L30D of dibutyl sebacate (polymethacrylate copolymer) system these granule coating.Another part in the little infiltration core of the drug system that makes above mixed with SorbitolInstant P300, HPMC (K100 level), form micropill, use the granulation of forming by Eudragit L30D (polymethacrylate copolymer dispersion) and glycerol triacetate to make granule with solvent, drying is pulverized agglomerate.The material that will obtain in step c and d merges, and mixes with Pulvis Talci, in incapsulating.
Among the embodiment 17-23 below, use following felodipine matrix components:
Felodipine, American Pharmacopeia 1.5g
Gelucire?50/13????????????????1.5g
Pluronic?F68??????????????????1.5g
Sorbitol?Instant?P300?????????4.0g
Gelucire and Pluronic are melted in together.Be dissolved in felodipine in the mixed liquor and solution joined among the Sorbitol Instant P300 and stir simultaneously.Mixture is fully mixed, allow it condense.Make agglomerative mixture by the #20 mesh sieve then.Embodiment 17: the extracorporeal releasing characteristic with felodipine tablet of little infiltration core
Excipient mg/ sheet supplier
HPMC E4M 112.5 Dow Chemical companies
Sorbitol P300 66 EMI companies
Avicel PH200 209.48 FMC Corp.
Felodipine substrate 60.98 EMI companies
Pruv 1 Mendell company
HPMC, Sorbitol Instant, Avicel and felodipine substrate are merged.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (450mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 1 of face as follows.
Time (hour) ????t 1/2 % discharges Standard deviation
?????0 ????0 ????0
?????2 ????1.41421356 ????20.43 ????3.07
?????4 ????2 ????38.56 ????3.24
?????6 ????2.44948974 ????55.3 ????3.03
?????8 ????2.82842712 ????70.51 ????4.22
?????10 ????3.16227766 ????86.79 ????6.54
?????12 ????3.46410162 ????95.24 ????1.4
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
Felodipine ????0.9739667 ????28.60726 ????-10.1986
Discharge according to zero level:
Tablet ????r Slope Intercept
Felodipine ????0.9952701 ????8.042679 ????4.148214
Embodiment 18: the extracorporeal releasing characteristic with felodipine tablet of little infiltration core
Excipient mg/ sheet supplier
HPMC E4M Premium CR 112.5 Dow Chemical companies
Sorbitol P300 67.5 EMI companies
Avicel PH200 212.3 FMC Corp.
Felodipine substrate 56.7 EMI companies
Pruv 1 Mendell company
Operate by the method identical with the foregoing description 17.Measurement result is harmony in the exterior Fig. 2 of face as follows.
Time (hour) ????t 1/2 7-8KP % discharges Standard deviation 6-7KP % discharges Standard deviation
????0 ????0 ????0 ????0 ????0 ???0
????2 ????1.41 ????66.59 ????13.5 ????59.88 ???5.33
????4 ????2 ????88.9 ????8.13 ????85.88 ???2.27
????6 ????2.45 ????95.87 ????2.88 ????99.47 ???2.57
????8 ????2.83 ????97.79 ????3.64 ????102.06 ???3.38
????10 ????3.16 ????97.46 ????3.08 ????101.72 ???3.42
????12 ????3.46
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
????7-8KP ????0.98997 ????40.6174942 ????3.335371
????6-7KP ????0.99881 ????41.2926417 ????0.81378
Discharge according to zero level:
Tablet ????r Slope Intercept
????7-8KP ????0.91526 ????15.496 ????16.352
????6-7KP ????0.95079 ????16.2205 ????12.646
Embodiment 19: the extracorporeal releasing characteristic of felodipine tablet
Excipient mg/ sheet supplier
E4M ﹠amp; The K100M prescription:
HPMC E4M 106.88 Dow Chemical companies
HPMC K100M 5.62 Dow Chemical companies
Sorbitol P300 73.39 EMI companies
Avicel PH200 227.76 FMC Corp.
Felodipine substrate 30.36 EMI companies
Pruv 0.99 Mendell company
The E4M prescription:
HPMC E4M 112.5 Dow Chemical companies
Sorbitol P300 73.39 EMI companies
Avicel PH200 227.76 FMC Corp.
Felodipine substrate 30.36 EMI companies
Pruv 0.99 Mendell company merges HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine composition.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (445mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 3 of face as follows.
Time (hour) ???t 1/2 ?95％E4M& ??K100M 100%E4M % discharges Standard deviation
% discharges Standard deviation
???0 ???0 ????0 ????0 ????0 ????0
???2 ???1.41 ????14.63 ????2.13 ????15.99 ????6.15
???4 ???2 ????41.5 ????3.86 ????42.53 ????7.24
???6 ???2.45 ????63.26 ????6.21 ????64.29 ????5.4
???8 ???2.83 ????75.85 ????6.79 ????78.23 ????5.23
???10 ???3.16 ????90.14 ????6.24 ????88.78 ????4.66
???12 ???3.46 ???96.6 ???6.56 ???95.92 ???3.06
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
??E4M?&?K100M ????0.95949 ????29.55133836 ????-10.80056
??E4M ????0.96362 ????29.5771156 ????-10.11314
Discharge according to zero level:
Tablet ????r Slope Intercept
??E4M?&?K100M ????0.99329 ????10.1065 ????-1.018
??E4M ????0.99509 ????10.238 ????-0.746
Embodiment 20: the extracorporeal releasing characteristic of felodipine tablet
Excipient mg/ sheet supplier
HPMC E4M 101.25 Dow Chemical companies
HPMC K100M 11.25 Dow Chemical companies
Sorbitol P300 73.39 EMI companies
Avicel PH200 227.76 FMC Corp.
Felodipine substrate 30.36 EMI companies
Pruv 0.99 Mendell company
HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine composition are merged.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (445mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 4 of face as follows.
Time (hour) ????t 1/2 HydroSolve% discharges Standard deviation
??????0 ????0 ??????0
??????2 ????1.41 ??????19.6 ????3.54
??????4 ????2 ??????36.96 ????2.46
???6 ????2.45 ????54.39 ????0
???8 ????2.83 ????68.86 ????0.62
???10 ????3.16 ????79.83 ????3.73
???12 ????3.46 ????89.04 ????10.54
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ??r Slope Intercept
Felodipine ??0.9779732566 ????26.8444051 ????-8.90112
Discharge according to zero level:
Tablet ??r Slope Intercept ??T 90
Felodipine ??0.9922566 ??7.49071429 ??4.8671429 ??11.3651187
Embodiment 21: the extracorporeal releasing characteristic of felodipine tablet
Excipient mg/ sheet supplier
The K100M prescription:
HPMC K100M 50.75 Dow Chemical companies
Sorbitol P300 33.2 EMI companies
AvicelPH200 103.3 FMC Corp.
Felodipine substrate 15.18 EMI companies
Pruv 0.45 Mendell company
E4M ﹠amp; The K100M prescription:
HPMC E4M 40.6 Dow Chemical companies
HPMC K100M 10.15 Dow Chemical companies
Sorbitol P300 33.2 EMI companies
Avicel PH200 103.3 FMC Corp.
Felodipine substrate 15.18 EMI companies
Pruv 0.45 Mendell company
HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine composition are merged.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (203mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 5 of face as follows.
Time (hour) ??t 1/2 ????K100M E4M ﹠ K100M % discharges Standard deviation
% discharges Standard deviation
????0 ??0 ???0 ????0 ????0 ????0
????2 ??1.41421 ???15.82 ????2.59 ????18.64 ????2.94
????4 ??2 ???34.46 ????2.59 ????46.89 ????7.64
????6 ??2.44949 ???57.63 ????10.31 ????71.75 ????5.45
????8 ??2.82843 ???72.32 ????9.79 ????86.44 ????7.38
????10 ??3.16228 ???79.82 ????10.66 ????89.83 ????11.11
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
??K100M ????0.9598 ????26.6965209 ????-9.402476
??E4M?&?K100M ????0.9655 ????31.1539762 ????-9.293658
Discharge according to zero level:
Tablet ????r Slope Intercept
??K100M ????0.9977 ????9.3225 ????-1.244
??E4M?&?K100M ????0.9953 ????11.2995 ????-0.454
Embodiment 22: the extracorporeal releasing characteristic prescription I (10% D-sorbite) of the tablet of being made by hydrosolve: the excipient mg/ sheet supplier HPMC E4M 50.75 Sorbitol P300 of the Dow Chemical company 33.2 Avicel PH200 of EMI company 103.3 FMC Corp.'s felodipine matrix 15.18 Pruv of EMI company 0.45 Mendell company
HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine composition are merged.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (203mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 6 of face as follows.
Time (hour) ????t 1/2 HydroSolve% discharges Standard deviation
?????0 ????0 ????0 ??????0
?????2 ????1.414213562 ????53.41 ??????3.89
?????4 ????2 ????85.31 ??????6.06
?????6 ????2.449489743 ????98.33 ??????1.76
?????8 ????2.828427125 ????101.75 ??????1.76
?????9 ????3 ????101.75 ??????1.76
?????10 ????3.15227766
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
Felodipine ????0.9907336 ????38.00593 ????1.6895071
Discharge according to zero level:
Tablet ????r Slope Intercept
Felodipine ????0.9261162 ????12.421 ????18.076
Embodiment 23: the extracorporeal releasing characteristic excipient mg/ sheet supplier HPMC E4M 62.19 Sorbitol P300 of the Dow Chemical company 30.45 Avicel PH200 of EMI company 94.73 FMC Corp.'s felodipine matrix 15.18 Pruv of EMI company 0.45 Mendell company of felodipine tablet
HPMC, Sorbitol Instant, Avicel and Hydrosolve-felodipine composition are merged.Pruv joined in the said mixture and with mixture fully mix.With 2 tons pressure the sample (203mg) of said mixture is pressed into tablet with the Carver tablet machine.Each sheet put into changes basket, stirs with 50rpm with oar, measures it and contains extracorporeal releasing characteristic in the deionized water solution of 1% sodium lauryl sulphate at 900mL.Take liquor sample at different time, measure its absorbance at 362nm.Measurement result is harmony in the exterior Fig. 7 of face as follows.
Time (hour) ????t 1/2 HydroSolve% discharges
?????0 ????0 ?????0
?????2 ????1.41421356 ?????20.27
?????4 ????2 ?????48.65
?????6 ????2.4494897 ?????67.12
According to Higuchi equation: %=Kt 1/2+ constant
Tablet ????r Slope Intercept
Felodipine ????0.9723567 ??31.17882739 ????-9.19942
According to the zero level method for releasing:
Tablet ????r Slope Intercept
Felodipine ????0.9897404 ????9.729285714 ????3.755238
Can repeat previous embodiment and obtain similar success by the respective reaction thing and/or the operating condition of replacing in the previous embodiment with reactant general description of the present invention or specifically described and/or operating condition.
Need not to further describe, can believe, those skilled in the art can farthest utilize the present invention according to the description of front.Therefore, the aforementioned preferable specific embodiment should be thought and only illustrates, and should not think any qualification of the present invention.
The full content of Yin Shu all patent applications, patent and publication is received at this and is reference herein.
According to the description of front, those skilled in the art can easily determine essential feature of the present invention and can make variations and modifications so that it is fit for various uses and condition to the present invention under the situation that does not depart from its essence and scope.

Claims (21)

1. pharmaceutical compositions, it comprises:
The core of pastille, the core of this pastille scribble little infiltration core of one deck ingredient above being,
Wherein, described little infiltration core comprises at least a little penetrating agent, and described ingredient comprises at least a therapeutic agent.
2. pharmaceutical compositions as claimed in claim 1, wherein, at least a little penetrating agent is Sorbitol, mannitol, xylitol or sodium chloride.
3. pharmaceutical compositions as claimed in claim 1, wherein, described little infiltration core also comprises at least a sweller or at least a gellant.
4. pharmaceutical compositions as claimed in claim 1, wherein, at least a portion of at least a Patent Office in the described ingredient is solid solution.
5. pharmaceutical compositions as claimed in claim 4, wherein, described ingredient comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer composition of handling through Polyethylene Glycol.
6. pharmaceutical compositions as claimed in claim 5 wherein, is solid solution at least a portion d mixture of at least a therapeutic agent, and this mixture comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer composition of handling through Polyethylene Glycol.
7. pharmaceutical compositions as claimed in claim 6, wherein, the described a part of therapeutic agent that is solid solution accounts for the 30-100% of the therapeutic agent in the ingredient.
8. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille is surrounded by the polymer coat.
9. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille mixes with polymeric matrix.
10. pharmaceutical compositions as claimed in claim 6, wherein, the core of described pastille is surrounded by the macromolecule coat and mixes with polymeric matrix.
11. pharmaceutical compositions as claimed in claim 1, wherein, the diameter of the core of described pastille is 2 μ m to 3mm.
12. pharmaceutical compositions as claimed in claim 6, wherein, described therapeutic agent is a dihydropyridine compounds.
13. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:
Provide claim 6 described pharmaceutical compositions;
The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.
14. method as claimed in claim 13, wherein, described physiology target site is an intestines and stomach.
15. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:
Provide claim 7 described pharmaceutical compositions;
The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.
16. method as claimed in claim 15, wherein, described physiology target site is an intestines and stomach.
17. at least a therapeutic agent is released into the method for physiology target site, and it may further comprise the steps:
Provide claim 1 described pharmaceutical compositions;
The pharmaceutical compositions of pharmacy effective dose is imported the physiology target site.
18. the method for preparation pharmaceutical compositions, it may further comprise the steps:
Prepare little infiltration core,
Painting medicine composition on this little infiltration core.
19. method as claimed in claim 18, wherein, described ingredient comprises glyceride composition and the polyoxypropylene-polyoxyethylene block copolymer mixture of ingredients of handling through Polyethylene Glycol.
20. method as claimed in claim 19, wherein, at least a portion of at least a therapeutic agent is solid solution in mixture.
21. method as claimed in claim 20, wherein, the part of described at least a therapeutic agent accounts for 30-100%.
CN99800925A 1998-06-11 1999-06-11 Micro-osmotic controlled drug delivery system Pending CN1272785A (en)

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