CN1319004A - New pharmaceutical formulation - Google Patents

New pharmaceutical formulation

Info

Publication number
CN1319004A
CN1319004A CN99811100A CN99811100A CN1319004A CN 1319004 A CN1319004 A CN 1319004A CN 99811100 A CN99811100 A CN 99811100A CN 99811100 A CN99811100 A CN 99811100A CN 1319004 A CN1319004 A CN 1319004A
Authority
CN
China
Prior art keywords
preparation
solubilizing agent
felodipine
hydrophilic gel
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN99811100A
Other languages
Chinese (zh)
Inventor
M·埃克伦德
J·E·勒弗罗斯
M·松德格伦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of CN1319004A publication Critical patent/CN1319004A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/143—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 inorganic compounds
    • 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
    • A61K9/14—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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An extended relase preparation of felodipine containing the active compound dissolved or dispersed in a solubilizer as well as a process for the preparation thereof.

Description

New pharmaceutical formulation
Invention field
The present invention relates to the medicinal method that delays delivery formulations and the such preparation of preparation of felodipine.
The objective of the invention is to obtain to have the solid preparation that good biological availability and active component delay to discharge.
Background of invention
Because their dissolution rate slowly has very poor water miscible medicine and has formulation problems.Their effect is severely limited and big interindividual variation can take place.Felodipine is the medicine with low-down dissolubility.Felodipine generally classifies as calcium antagonist, and it is widely used in treatment cardiovascular disease for example ischemic heart disease and Arterial Hypertention.Under 25 ℃, felodipine only has the dissolubility of 0.5mg/l in water.
The method of several increase drug absorption has formerly been described in the document.A kind of method is described in DE-A-3024858, wherein is the absorption that obtains the increase of reactive compound from intestinal, and sl. sol. substituted-dihydro pyridine nicardipine uses with its amorphism.Another kind method is described in EP-A-47899, wherein for increasing bioavailability, has used the very little crystallization of extremely undissolved dihydropyridine nifedipine.In " medicament solubilization technology ", S.H.Yalkowsky edits, and Drugs and the pharmaceutical sciences has also described these methods and other method in the 12nd volume.Special relevant with the present invention is to use the surface active agent solubilization agent to have the bioavailability of medicament of low-down dissolubility with increase.Its improvement that proposes absorbent properties can be owing to three kinds of methods: (1) increases moistening, and (2) increase permeability of the membrane and (3) solubilising.The publication of being quoted has described several embodiment and to relating to medicament solubilization, this area present situation that has the bioavailability of medicament of low-down dissolubility in particular for increase is made good summary.
Known sustained release preparation from DE-A-3400106 comprises one or more natural, partial synthesis or synthetic polymer, one or more lipotropys and/or hydrophilic solvent or the thickening agents with one or more medicinal activity compounds.In an embodiment, it is described with a certain amount of (weight) (for reactive compound amount much less than 1: 1) and uses solubilizing agent.
For example in the therapeutic treatment in cardiovascular, gastrointestinal tract and chemotherapy field, it is favourable giving medicine with constant density in blood in multiple disease.Therefore, require from pharmaceutical formulation, to delay to discharge medicine.
In whole therapeutic dose interim, delaying the delivery formulations transmission, need to be used for keeping enough medicines with amount stepless action be important.This generally means medicine should give uniform concentration with constant speed in blood medicine.This is that to have only the medicine of little difference between valid density and the toxic concentration be particular importance for having little therapeutic index.When be current with big local concentration, delay with constant release medicine also be important to local excitation medicine or to medicine with short elimination half-life with the potential risk that causes gastrointestinal disturbance.In the later case, use the preparation that delays to discharge of comparing with regular dosage form can obtain more low-frequency administration and can obtain so better patient's compliance (referring to .Clin.Pharm.Ther. (1977) such as Hayes R.B., 22, the 125-130 pages or leaves).
Generally delay the medicine of releasing pattern by oral route.But preparation should preferably delay with the medicine that can repeat to discharge and help multiple absorption, and does not have toxicity or stimulation component and also be suitable for high dose medicament.Conventional reaching from the stripping of the medicine in the dosage form and/or diffusion by control delays to discharge.Different materials is used for this purpose, for example wax, fatty material, polymer, natural, synthetic and semisynthetic natural gum.In these natural gum and since its do not rely on pH character with and semi-synthetic source, HYDROXY PROPYL METHYLCELLULOSE (HPMC) constitutes an important class.By Alderman D.A.Int.J.Pharm.Tech.﹠amp; Prod.Mfr (1984), 5 (3) 1-9 provide the summary of the cellulose ethers in the hydrophilic matrix of oral sustained release dosage form.Open chemical treatment HPMC is with the structure of generation requirement and the purposes of these quality in US3087790, US4226849, US4357469 and US4369172.SE-A-8008646-5 describes combining of HPMC and hydroxy propyl cellulose, is used to control the rate of release of medicinal activity compound.
When using hydrophilic matrix, after tablet was exposed to gastrointestinal fluid or saliva, soluble polymer formed layer as a form of gel around tablet.Drug release is subjected to water and infiltrates through and the restriction (Bamba etc., Int.J.Pharm. (1979), 2,307) of drug diffusion by the speed of the gel of formation.The erosion of gel structure also is the important mechanisms that medicine discharges from system.Employed polymer hydration rapidly avoids quick stripping (Alderman 1984) with the protection tablet.
Medicine with low-down dissolubility is closely related from absorption rate and dissolution rate that intestinal enters the circulation.Because low dissolution rate causes low bioavailability usually, it is difficult therefore reducing absorption rate, promptly increases the persistent period and does not reduce bioavailability simultaneously.
US4803081 openly have low-down dissolubility reactive compound delay delivery formulations, said preparation contain dissolving or be dispersed in semisolid or the liquid nonionic solubilizing agent reactive compound and thus the amount of described solubilizing agent (weight) equal the amount (weight) of reactive compound at least.
The present invention describes
Purpose of the present invention provides the preparation of felodipine, it shows prolongation during at least 24 hours and constant drug absorption speed and keep high bioavailability simultaneously almost.Another purpose provides the preparation that is easy to prepare.Another object of the present invention provides the preparation that contains the solubilizing agent of low amount.The solubilizing agent that the present invention suits is as giving a definition.Reactive compound preferably is dissolved in or is scattered in this solubilizing agent.In described solution, pharmaceutical pack is contained in the micellar structure that is formed by solubilizing agent.The mixture of medicine and solubilizing agent is admixed in the pharmaceutical formulation that provides prolongation release.
In first embodiment, what the present invention relates to felodipine delays to discharge solid preparation, it comprises and is dissolved in or is scattered in the felodipine that is selected from the following solubilizing agent, comprising: Spheron MD 30/70, polyoxy ethylization ethylene glycol one ether, polyoxyethylated alkylphenol, poloxamer, castor oil derivatives, Myrj 45 or with another kind of fatty acid ester, glyceride, Isosorbide Dinitrate and the sucroglyceride of PEG.
In another embodiment, the present invention relates to prepare the method that delays to discharge solid preparation of felodipine, thereby reactive compound is dissolved in or is scattered in be selected from felodipine delay to discharge in the solubilizing agent of solid preparation, it is characterized in that it comprises is dissolved in or is scattered in the felodipine that is selected from the following solubilizing agent, comprise: Spheron MD 30/70, polyoxy ethylization ethylene glycol one ether, polyoxyethylated alkylphenol, poloxamer, castor oil derivatives, Myrj 45 or with the another kind of fatty acid ester of PEG, glyceride, Isosorbide Dinitrate and sucroglyceride are incorporated into this mixture in the suitable Controlled Release System with known method afterwards and form pharmaceutical dosage unit.
The solubilizing agent that is suitable for preparation of the present invention is semisolid or the liquid nonionic surfactants under the ambient temperature, for example the nonionic ester and/or the ether of Polyethylene Glycol:
A) list of Spheron MD 30/70-sorbitol and it-and part ester of two-acid anhydride and the about compound mixture of the ethylene oxide condensation of molal quantity.Example-tween, Crillets, Capmul derivant, Liposorbs etc.(document with the back is the pharmaceutical excipient handbook herein, the 2nd edition referring to the 375th page; Editor: A Wade and PJ Woller, Pharmaceutical Press 1994).
B) polyoxy ethylization ethylene glycol one ether (polyoxyethylene alkyl ether) promptly contains the alkyl chain of ethylene oxide chain.Example is C16E7 (seven oxygen ethylene glycol list cetyl ethers), Cetomacrogol 1000 BPC, Brij or Atlas series.Referring to the 367+556 page or leaf.
C) polyoxyethylated alkylphenol is as Tritons.
D) poloxamer, i.e. the block copolymer of PEO-PPO-PEO type, PEO=poly(ethylene oxide) and PPO=contain the poly(propylene oxide) (also being referred to as Pluronics) of different chain length degree here.Referring to the 352nd page.
E) castor oil derivatives-with the oxirane of (hydrogenant) Oleum Ricini ((hydrogenant) stearic triglyceride) reaction.Example has Chremophors.Referring to the 371st page.
F) Myrj 45 and with other the fatty acid ester of PEG.Example is Solutol and Labrasol.Referring to the 379th page.
G) particular matter, for example TPGS (fertility phenolic group polyethanediol succinate); Glycofurol (referring to the 213rd page).
Be suitable for preparation of the present invention, other the solubilizing agent that does not belong to nonionic ester and/or Polyethylene Glycol ethers is:
H) glyceride (monoglyceride), for example Monoolein (glyceryl monooleate), Caopmul, Captex, Imwitor, Gelucire, Myverol etc.Referring to the 207th page.
I) list of Isosorbide Dinitrate-sorbitol and it-and two-acid anhydride and oleic part ester, for example span etc.Referring to the 473rd page.
J) sucrose ester of sucroglyceride-fatty acid.
K) particular matter-cyclodextrin solid; Referring to the 147th page.
Particularly preferred solubilizing agent in catalogue a)-g) in:
-dissimilar Chremophor:Cllremophor EL, RH40, RH60
-Pluronics F127 or F68 (poloxamer 407 and 188)
-Solutol?HS?15
-Labrasol
-Cetomacrogol 1000 or Brij97
And in catalogue h)-k) in:
-Gelucire 44/14 or Gelucire 50/13
-Imwitor?742
-with the bonded Monoolein of medium chain monoglyceride (glyceryl monooleate), i.e. Myverol18-99+Capmul
-span 20 or sorbester p17.
Will with the blended reactive compound of solubilizing agent be incorporated into different types of known control delivery system for example the hydrophilic gel system, with control rate film coated granules (this film can be to postpone diffusion coating or disintegrate coating) or contain in the tablet of inertia porous matrix.According to the present invention, can by the medicine of solubilising preferably with the hydrophilic gel system be hydrophilic swollen matrix for example HPMC mix.The sustained release mechanism of this form is the approach that suits to the micellar release of control medicine and solubilizing agent.Technological property is good and the interior performance of body also is good.In the different water wetted material that is tried, HPMC is that HYDROXY PROPYL METHYLCELLULOSE is best gellant.Other example that influences the suitable chemical compound that reactive compound discharges from the hydrophilic gel system is guar gum, xanthan gum, carboxyl polymethylene, different cellulosic material such as hydroxy ethyl cellulose, sodium carboxy methyl cellulose and hydroxy propyl cellulose, lactose, aluminium silicate and poly(ethylene oxide).
Preparation of the present invention comprises 20-80% (weight), the hydrophilic gel system of preferred 30-50% (weight).
Use has 4-12% (weight), the hydroxypropyl content of particularly about 8.5% (weight) and be lower than 100cps, for example 6.15 and/or the HPMC of 50cps viscosity be particularly preferred.In American Pharmacopeia X XI version, viscosity is measured in the standard method of describing in 1985, the 672 pages by for example.
Last preparation is the form of example gel tablet.Through careful filler and binding agent and the gellant selected, described formulation preparation can be become acceptable form on the market, for example comprise particulate tablet of gelling or hard-gelatin capsules, it demonstrates the action time of beyond thought good absorption of reactive compound and prolongation.In preparation of the present invention, the ratio between reactive compound and the solubilizing agent changed in the scope at 1: 0.01 to 1: 10, preferably changed in the scope at 1: 0.1 to 1: 8, and most preferably changed in the scope at 1: 0.5 to 1: 6.When selecting any solubilizing agent a)-g), ratio is preferably in 1: 0.01 to 1: 1 scope.
Also can use the sustained release preparation of other type according to the present invention, for example contain the inertia porous matrix tablet, comprise and have the capsule that postpones diffusion coating or disintegrate coated granule.
By making medicine and solubilizing agent and water-soluble polymer or wax and being mixed together, obtain containing the tablet of inertia porous matrix with filler and binding agent.Polyvinylacetate, polrvinyl chloride, ethyl cellulose, paraffin and cellulosic phthalic acetate can be as suitable delay propagate polymerization things.Filler and binding agent are solid, powdery carrier for example lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivative, gelatin or other suitable carrier.With solvent for example water or ethanol or the solution-wet mixture formed by for example water and polymer such as polyvinylpyrrolidone.Also can add lubricant for example magnesium stearate, calcium stearate, stearyl fumarate and polyethylene glycol wax.Then mixture is formed tablet.
Contain the core material of medicine and solubilizing agent and filler by preparation, can obtain comprising and have the particulate capsule that postpones releasing properties.Then with the surface that postpones diffusion insoluble polymer or wax Dragees.Then with particles filled in hard gelatin capsule.For example, by with medicine and solubilizing agent and the careful filler of selecting for example lactose, sorbitol, starch, cellulose derivative or other suitable filler be mixed together, can prepare core material.With solvent mixture as described in water or ethanol or the solution-wet formed as polyvinylpyrrolidone by for example water and polymer for example.For example, described material is formed granule by extruding and spheronizing.With solvent dichloromethane and/or isopropyl alcohol and the insoluble polymer surface of the solution core that coating forms formed of ethyl cellulose for example for example.With particles filled in hard gelatin capsule.
Operation embodiment
Following examples are illustrated the present invention.In all experiments, prepare described preparation with dissimilar polymer and solubilizing agent.The polymer that uses is: having molecular weight is 4,000,000g/mol (PEO 4 '), 2,000,000g/mol (PEO 2 ') and 900, the PEO (poly(ethylene oxide)) of 000g/mol (PEO 0.9 '), have the HPMC (HYDROXY PROPYL METHYLCELLULOSE) of two kinds of different viscosities (60SH50 and 10,000) and have height (HEC HHX), in the HEC (hydroxy ethyl cellulose) of (HEC HX) and low (HECM) molecular weight.Employed surfactant is: SDS (sodium lauryl sulphate), CTAB (cetyl trimethyl ammonium bromide), Gelucire And sulfobetaine.Filler and lubricant are AMS (aluminium-magnesium silicate) and SSF (stearyl fumarate).Generally, felodipine prepares tablet in the ethanol by being dissolved in.Then AMS and surfactant mixtures are granulated with felodipine solution.Under 50 ℃,, and mix with polymer and SSF then about 16 hours of particle drying.Prepare tablet (diameter=9mm) with the Kilian hydraulic press of being furnished with round punch then.
External stripping (drug release)
Use USP digestion instrument II, contain test tablets among the phosphate buffer pH6.5 of 0.4% cetyl trimethyl ammonium bromide (CTAB) at 500ml.For keeping tablet in the locating hole in the stripping container, use the square steel wire basket of special preparation.Stir speed (S.S.) is that 100rpm and temperature are 37 ℃.Surfactant CTAB is joined in the dissolution medium to obtain setting condition.With sample extraction analysis (in the 1cm pond under 362nm the trap of felodipine).From the calibration curve that the measured value based on the trap of the standard felodipine solution of the same media of using obtains, measure the burst size of felodipine release experiment.Felodipine preparation among the PEO 4 ' of embodiment 1. felodipines/surfactant=1/1 (w/w)
Felodipine ????5 ????5 ????5 ????5 ?mg
?EtOH99.9 ????30 ????30 ????30 ????30 ?mg
?PEO4’ ????160 ????160 ????160 ????160 ?mg
?AMS ????30 ????30 ????30 ????30 ?mg
?SDS ????5 ?mg
?CTAB ????5 ?mg
?Gelucire ????5 ?mg
Sulfobetaine ????5 ?mg
?SSF ????2 ????2 ????2 ????2 ?mg
Result: the release % of felodipine from the different preparations of embodiment 1
Time/hour ????SDS ????CTAB ????Gelucire Sulfobetaine
????1 ????4 ????4 ????4 ????5
????2 ????13 ????13 ????12 ????11
????4 ????29 ????28 ????28 ????27
????6 ????48 ????45 ????45 ????42
????8 ????66 ????62 ????64 ????61
????10.3 ????84 ????79 ????82 ????77
Felodipine preparation among the PEO4 ' of embodiment 2. felodipines/surfactant=1/0.1 (w/w)
Felodipine ????5 ????5 ????5 ????5 ????mg
?EtOH99.9 ????30 ????30 ????30 ????30 ????mg
?PEO4’ ????160 ????160 ????160 ????160 ????mg
?AMS ????30 ????30 ????30 ????30 ????mg
?SDS ????0.5 ????mg
?CTAB ????0.5 ????mg
?Gelucire ????0.5 ????mg
Sulfobetaine ????0.5 ????mg
?SSF ????2 ????2 ????2 ????2 ????mg
Result: the release % of felodipine from the different preparations of embodiment 2
Time/hour ????SDS ?CTAB ?Gelucire Sulfobetaine
????1 ????4 ????4 ????5 ????6
????2 ????8 ????9 ????9 ????11
????4 ????23 ????21 ????24 ????26
????6 ????40 ????40 ????42 ????44
????8 ????57 ????55 ????56 ????62
????11 ????80 ????78 ????79 ????86
Felodipine preparation among the PEO2 ' of embodiment 3. felodipines/surfactant=1/1 (w/w)
Felodipine ????5 ????mg
EtOH99.9 ????30 ????mg
PEO?2’ ????160 ????mg
AMS ????30 ????mg
SDS ????5 ????mg
SSF ????2 ????mg
Result: the release % of felodipine from the preparation of embodiment 3.The result is from the repeated experiments of report
Time/hour ????SDS ????SDS
????1 ????9 ????9
????2 ????20 ????24
????4 ????34 ????36
????6 ????58 ????61
????8 ????77 ????79
Felodipine preparation among the PEO0.9 ' of embodiment 4. felodipines/surfactant=1/1 (w/w)
Felodipine ????5 ????mg
?EtOH?99.9 ????30 ????mg
?PEO?0.9’ ????160 ????mg
?AMS ????30 ????mg
?SDS ????5 ????mg
?SSF ????2 ????mg
Result: the release % of felodipine from the preparation of embodiment 4.The result is from the repeated experiments of report.Tablet dissolves fully before 6 hours.
Time/hour ????SDS ????SDS
????1 ????15 ????15
????2 ????38 ????35
????4 ????85 ????87
Felodipine preparation among the PEO4 ' of embodiment 5. felodipines/surfactant=1/7 (w/w)
Felodipine ????5 ????mg
?EtOH99.9 ????30 ????mg
?PEO?4’ ????160 ????mg
?AMS ????15 ????mg
?SDS ????35 ????mg
?SSF ????2 ????mg
Result: the release % of felodipine from the preparation of embodiment 5.
Time/hour ????SDS
????1 ????8
????2 ????16
????4 ????31
????6 ????53
????8 ????63
Felodipine preparation among the HPMC 60SH50/10000 of embodiment 6. felodipines/surfactant=1/1 (w/w).
Felodipine ????5 ????5 ????5 ????5 ?mg
?EtOH?99.9 ????30 ????30 ????30 ????30 ?mg
?HPMC?60SH50 ????56 ????56 ????56 ????56 ?mg
?HPMC?10?000 ????104 ????104 ????104 ????104 ?mg
?AMS ????30 ????30 ????30 ????30 ?mg
?SDS ????5 ?mg
?CTAB ????5 ?mg
?Gelucire ????5 ?mg
Sulfobetaine ????5 ?mg
?SSF ????2 ????2 ????2 ????2 ?mg
Result: the release % of felodipine from the different preparations of embodiment 6.
Time/hour ????SDS ????CTAB ?Gelucire Sulfobetaine
????1 ????5 ????5 ????4 ????5
????2 ????11 ????10 ????11 ????10
????4 ????25 ????21 ????24 ????24
????6 ????41 ????36 ????39 ????39
????7.5 ????53 ????46 ????51 ????51
????10.5 ????77 ????68 ????73 ????77
Felodipine preparation among the HPMC 60SH50/10000 of embodiment 7. felodipines/surfactant=1/0.1 (w/w).
Felodipine ????5 ????5 ????5 ????5 ????mg
?EtOH?99.9 ????30 ????30 ????30 ????30 ????mg
?HPMC?60SH50 ????56 ????56 ????56 ????56 ????mg
?HPMC?10000 ????104 ????104 ????104 ????104 ????mg
?AMS ????30 ????30 ????30 ????30 ????mg
?SDS ????0.5 ????mg
?CTAB ????0.5 ????mg
?Gelucire ????0.5 ????mg
Sulfobetaine ????0.5 ????mg
?SSF ????2 ????2 ????2 ????2 ????mg
Result: the release % of felodipine from the different preparations of embodiment 7.
Time/hour ???SDS ?CTAB ?Gelucire Sulfobetaine
????1 ????5 ????5 ????4 ????5
????2 ????12 ????14 ????12 ????14
????4 ????25 ????28 ????23 ????25
????6 ????39 ????45 ????38 ????42
????8 ????55 ????60 ????53 ????56
Felodipine preparation among the HEC HHX of embodiment 8. felodipines/surfactant=1/1 (w/w).
Felodipine ????5 ????5 ????5 ????5 ????mg
?EtOH?99.9 ????30 ????30 ????30 ????30 ????mg
?HEC?HHX ????160 ????160 ????160 ????160 ????mg
?AMS ????30 ????30 ????30 ????30 ????mg
?SDS ????5 ????mg
?CTAB ????5 ????mg
?Gelucire ????5 ????mg
Sulfobetaine ????5 ????mg
?SSF ????2 ????2 ????2 ????2 ????mg
Result: the release % of felodipine from the different preparations of embodiment 8.
Time/hour ????SDS ?CTAB ?Gelucire Sulfobetaine
????1 ????3 ????4 ????4 ????4
????2 ????6 ????7 ????6 ????7
????4 ????9 ????10 ????9 ????9
????10 ????27 ????30 ????27 ????26
????16.3 ????46 ????54 ????57 ????56
????18 ????51 ????61 ????62 ????61
????20 ????58 ????69 ????68 ????67
????22 ????67 ????75 ????72 ????74
????24.5 ????76 ????82 ????78 ????79
Felodipine preparation among the HEC HHX of embodiment 9. felodipines/surfactant=1/0.1 (w/w).
Felodipine ????5 ????5 ????5 ????5 ?mg
?EtOH?99.9 ????30 ????30 ????30 ????30 ?mg
?HEC?HHX ????160 ????160 ????160 ????160 ?mg
?AMS ????30 ????30 ????30 ????30 ?mg
?SDS ????0.5 ?mg
?CTAB ????0.5 ?mg
?Gelucire ????0.5 ?mg
Sulfobetaine ????0.5 ?mg
?SSF ????2 ????2 ????2 ????2 ?mg
Result: the release % of felodipine from the different preparations of embodiment 9.
Time/hour ????SDS ?CTAB ?Gelucire Sulfobetaine
????1 ????5 ????6 ????5 ????6
????4.6 ????12 ????10 ????9 ????10
????6 ????14 ????14 ????14 ????15
????8 ????21 ????20 ????20 ????22
????16 ????42 ????43 ????43 ????45
????18 ????47 ????49 ????49 ????60
????22 ????61 ????56 ????56 ????65
????24 ????67 ????62 ????62 ????72
Felodipine preparation among the HEC M of embodiment 10. felodipines/surfactant=1/1 (w/w)
Felodipine ????5 ????mg
?EtOH?99.9 ????30 ????mg
?HEC?M ????160 ????mg
?AMS ????30 ????mg
?SDS ????5 ????mg
?SSF ????2 ????mg
Result: the release % of felodipine from the preparation of embodiment 10.Report is from the result of repeated experiments
Time/hour ????SDS ????SDS
????1 ????9 ????9
????2 ????18 ????21
????4 ????28 ????30
????6 ????46 ????49
????8 ????67 ????65
Ground, non-Lip river preparation among the HEC HX of embodiment 11. felodipines/surfactant=1/1 (w/w)
Felodipine ????5 ????mg
?EtOH?99.9 ????30 ????mg
?HEC?HX ????160 ????mg
?AMS ????30 ????mg
?SDS ????5 ????mg
?SSF ????2 ????mg
Result: the release % of felodipine from the preparation of embodiment 11.Report is from the result of repeated experiments
Time/hour ????SDS ????SDS
????1 ????3 ????3
????2 ????8 ????10
????4 ????24 ????25
????10 ????66 ????76

Claims (24)

1. the felodipine solid preparation that delays to discharge, it comprise be dissolved in or be scattered in be selected from Spheron MD 30/70, polyoxy ethylization ethylene glycol one ether, polyoxyethylated alkylphenol, poloxamer, castor oil derivatives, Myrj 45 or with the solubilizing agent of another kind of fatty acid ester, glyceride, Isosorbide Dinitrate and the sucroglyceride of PEG in felodipine.
2. the preparation of claim 1, wherein said solubilizing agent is polyoxy ethylization ethylene glycol one ether.
3. the preparation of claim 2, wherein said solubilizing agent is Cetomacrogol 1000 or Brij97.
4. the preparation of claim 1, wherein said solubilizing agent is a poloxamer.
5. the preparation of claim 4, wherein said solubilizing agent is Pluronics F127 or F68.
6. the preparation of claim 1, wherein said solubilizing agent is the weight of castor oil derivatives and felodipine: the ratio of the weight of described solubilizing agent is in 1: 0.01 to 1: 1 scope.
7. the preparation of claim 6, wherein said solubilizing agent is Chremophor.
8. the preparation of claim 1, wherein said solubilizing agent be Myrj 45 or with the another kind of fatty acid ester of PEG.
9. the preparation of claim 8, wherein said solubilizing agent is Solutol HS 15 or Labrasol.
10. the preparation of claim 1, wherein said solubilizing agent is a glyceride.
11. the preparation of claim 10, wherein said solubilizing agent be Gelucire 44/14, Gelucire50/13, Imwitor742, with the bonded monoolein of medium chain monoglyceride.
12. the preparation of claim 1, wherein said solubilizing agent are Isosorbide Dinitrate.
13. the preparation of claim 12, wherein said solubilizing agent are span 20 or sorbester p17.
14. the preparation of any one, the wherein weight of felodipine in the previous claim: the ratio of the weight of described solubilizing agent is in 1: 0.01 to 1: 10 scope, preferably in 1: 0.1 to 1: 8 scope, and most preferably in 1: 0.5 to 1: 6 scope.
15. the preparation of any one in the previous claim is wherein by inertia porous matrix, delay diffusion coating or disintegrate coating sustained release.
16. the preparation of any one in the previous claim is wherein by hydrophilic gel system sustained release.
Branch constitutes the 20-80% (weight) of preparation 17. the preparation of claim 16, wherein said hydrophilic gel congeal into.
18. the preparation of claim 16 and 17, wherein said hydrophilic gel system comprises HYDROXY PROPYL METHYLCELLULOSE.
19. the preparation of claim 18, wherein said HYDROXY PROPYL METHYLCELLULOSE have the hydroxypropyl content of 4-12% (weight).
20. one or multinomial preparation among the claim 16-19, wherein said hydrophilic gel system contains the carboxyl polymethylene.
21. one or multinomial preparation among the claim 16-19, wherein said hydrophilic gel system contains guar gum or xanthan gum.
22. one or multinomial preparation among the claim 16-19, wherein said hydrophilic gel system contains cellulosic material such as hydroxy ethyl cellulose, sodium carboxy methyl cellulose or hydroxy propyl cellulose.
23. one or multinomial preparation among the claim 16-19, wherein said hydrophilic gel system contains lactose, aluminium silicate or poly(ethylene oxide).
24. preparation contains the method for the solid preparation that felodipine delays to discharge, it is characterized in that reactive compound is dissolved in or is scattered in the solubilizing agent that is selected from the solid preparation that felodipine delays to discharge, it is characterized in that this method comprises felodipine is dissolved in or is scattered in is selected from the following solubilizing agent, comprise: Spheron MD 30/70, polyoxy ethylization ethylene glycol one ether, polyoxyethylated alkylphenol, poloxamer, castor oil derivatives, Myrj 45 or with the another kind of fatty acid ester of PEG, glyceride, Isosorbide Dinitrate and sucroglyceride are incorporated into this mixture in the suitable Controlled Release System with known method afterwards and form pharmaceutical dosage unit.
CN99811100A 1999-07-20 1999-12-22 New pharmaceutical formulation Pending CN1319004A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE99027427 1999-07-20
SE9902742A SE9902742D0 (en) 1999-07-20 1999-07-20 New pharmaceutical formultion

Publications (1)

Publication Number Publication Date
CN1319004A true CN1319004A (en) 2001-10-24

Family

ID=20416534

Family Applications (1)

Application Number Title Priority Date Filing Date
CN99811100A Pending CN1319004A (en) 1999-07-20 1999-12-22 New pharmaceutical formulation

Country Status (9)

Country Link
EP (1) EP1113786A1 (en)
JP (1) JP2003504392A (en)
KR (1) KR20010078703A (en)
CN (1) CN1319004A (en)
AU (1) AU3095600A (en)
CA (1) CA2328102A1 (en)
NO (1) NO20004816L (en)
SE (1) SE9902742D0 (en)
WO (1) WO2001005376A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101103964B (en) * 2006-07-14 2010-09-29 海南盛科生命科学研究院 Sustained-release preparation containing felodipine and preparation method thereof
CN102784128A (en) * 2012-07-31 2012-11-21 北京协和药厂 Felodipine sustained release preparation and preparation method of felodipine sustained release preparation

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030211149A1 (en) * 2002-05-07 2003-11-13 Sherman Bernard Charles Extended release tablets comprising felodipine
GB0222612D0 (en) * 2002-09-30 2002-11-06 Univ Gent Controlled delivery system for bioactive substances
EP1812072B1 (en) * 2004-11-17 2008-10-22 Ares Trading S.A. Benzothiazole formulations and use thereof
KR100841877B1 (en) * 2006-08-31 2008-06-27 조선대학교산학협력단 Locally solubilized controlled release matrix tablet of poorly soluble drugs

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8601624D0 (en) * 1986-04-11 1986-04-11 Haessle Ab NEW PHARMACEUTICAL PREPARATIONS
DE3738236A1 (en) * 1987-11-11 1989-05-24 Euro Celtique Sa BIT CAPSULE
US5773025A (en) * 1993-09-09 1998-06-30 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems--amorphous drugs
IE80467B1 (en) * 1995-07-03 1998-07-29 Elan Corp Plc Controlled release formulations for poorly soluble drugs
JP2001520984A (en) * 1997-10-27 2001-11-06 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Solid-state solvents and solid dispersions of poorly water-soluble drugs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101103964B (en) * 2006-07-14 2010-09-29 海南盛科生命科学研究院 Sustained-release preparation containing felodipine and preparation method thereof
CN102784128A (en) * 2012-07-31 2012-11-21 北京协和药厂 Felodipine sustained release preparation and preparation method of felodipine sustained release preparation

Also Published As

Publication number Publication date
WO2001005376A1 (en) 2001-01-25
KR20010078703A (en) 2001-08-21
AU3095600A (en) 2001-02-05
JP2003504392A (en) 2003-02-04
SE9902742D0 (en) 1999-07-20
EP1113786A1 (en) 2001-07-11
NO20004816L (en) 2000-11-02
NO20004816D0 (en) 2000-09-26
CA2328102A1 (en) 2001-01-20

Similar Documents

Publication Publication Date Title
KR950002147B1 (en) Pharmaceutical preparations with extended release
ES2360102T3 (en) SYSTEM FOR CONTROLLED RELEASE OF MORPHINE.
JP5406530B2 (en) Dual controlled release matrix system based on hydrophilic vehicle
JP5934312B2 (en) Drug delivery composition
JP5406529B2 (en) Dual controlled release matrix system based on lipophilic vehicle as capsule filler
JP5563731B2 (en) Controlled release formulation of opioid and non-opioid analgesics
KR101434334B1 (en) Micellar nanoparticles of chemical substances
KR20070043894A (en) Controlled release nanoparticle active agent formulation dosage forms and methods
CN101652141A (en) The adjustment release dosage form of tacrolimus
ZA200603304B (en) OROS push-stick for controlled delivery of active agents
WO2009066146A2 (en) Stable solutions of sparingly soluble actives
AU2003208713B2 (en) Oral solid solution formulation of a poorly water-soluble active substance
KR102490397B1 (en) Solid formulation containing dutasteride and method for preparing the same
Zahirul Khan Recent trends and progress in sustained or controlled oral delivery of some water soluble drugs: morphine salts, diltiazem and captopril
JP6666352B2 (en) Dutasteride-containing solid dispersion and composition containing the same
WO2003013481A1 (en) The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients
Pi et al. Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability
CN1791390A (en) Oral sustained release pharmaceutical composition
CN1319004A (en) New pharmaceutical formulation
AP1192A (en) Solubilized sertraline compositions.
CN104188926A (en) Micellar nanoparticles of chemical substances
CN1261792A (en) Gelatine encapsulated solution dosage forms of sertraline
CN101351202A (en) Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms
CN1043957C (en) Novel dosage form
JPWO2016117642A1 (en) Film formulation

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication