CN1980636A - Compositions comprising drospirenone molecularly dispersed - Google Patents
Compositions comprising drospirenone molecularly dispersed Download PDFInfo
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- CN1980636A CN1980636A CNA2005800150652A CN200580015065A CN1980636A CN 1980636 A CN1980636 A CN 1980636A CN A2005800150652 A CNA2005800150652 A CN A2005800150652A CN 200580015065 A CN200580015065 A CN 200580015065A CN 1980636 A CN1980636 A CN 1980636A
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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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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- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
The present invention relates to pharmaceutical composition comprising steroidal drugs, such as drospirenone, in molecularly dispersed form. Preferably, the compositions are provided as solid, semi-solid or liquid forms, which in turn preferably are adapted for oral administration and preferably to be absorbed from the gastro-intestinal tract. Such compositions are found to have high bioavailability, good chemical stability, and fast in-vitro dissolution release and can be produced under conditions, which do not require costly equipment or safety guards.
Description
Technical field
The present invention relates to the pharmaceutical preparation scientific domain, particularly improve dissolubility and the method for bioavailability, the particularly drospirenone of lipophilic compound such as steroid molecule.The General Principle that provides with the dispersive drospirenone of molecular forms is provided concrete preparation technique of the present invention.
Background technology
The absorption of the drospirenone of un-formulated in gastrointestinal tract is bad, and part is because its poor solubility and dissolution rate in water in water is low.In addition, drospirenone comprises that at sour environment the chemical stability in the environment that is provided by gastric juice in the stomach is relatively poor.In fact, after drospirenone and pH were about 1 hydrochloric acid solution and contact, almost 50% drospirenone was degraded to the isomer of its no therapeutic activity in 30 minutes.Therefore can advise adopting enteric coating.Consider drospirenone in essence as the steroid molecule, should be on the top in gastrointestinal tract (GI road), as being absorbed at gastric mucosa and/or duodenal mucosa place, this just requires drospirenone just should dissolve fully in GI road starting point.
Found that when drospirenone provided with micronized form, its dissolution rate in vitro was higher.For example, during after dissolution test begins 30 minutes, at least 70% drospirenone stripping.Yet micronization technology requires that specific equipment is arranged, and these equipment are comparatively expensive and may be difficult to operation.
May need to comprise alternative (altemative) preparation of those forms of micronization form drospirenone.
Well-known different preparation technique can be used for preparing wherein active component and the mutually blended pharmaceutical composition of liquid, semisolid or solid excipient.Yet this technology only is intended to obtain described active substance and is dispersed in very fine granule in the carrier, and is not that described reactive compound is dispersed in the excipient with molecular level.In addition, this preparation technique is not pointed out and is prepared wherein reactive compound and be dissolved in the carrier in the beginning critical step, and this carrier constitutes final composition then or constitutes the method for compositions of the part of final composition at least.
WO 02 45693 has described the active substance dosage form that is applicable to the occasion that needs taste masking or the breakage of expectation coating.This dosage form contains disperses equably or is dissolved in reactive compound in the substrate that is selected from following group: paraffin, aliphatic alcohol, triglyceride and fatty ester.
US 5,789,442 relate to be used for parenteral route or intestinal canal administration, wherein reactive compound and conventional excipients such as the mutually blended preparation of liquid, semiliquid, SOLID ORGANIC or inorganic carrier.
US 5,569, and 652 relate to by reactive compound and carrier and diluent are together processed the active agent preparations that gets.
US 5,656, and 622 relate to the new derivative of estradiol, and the combination of it and drospirenone can be provided with the form of capsule or tablet.
EP 1 260 225 relates to and comprises estrogenic compositions.
WO 2004/041289 describes the drospirenone in the drug tablet formulation, and said preparation is by conventional fluidization preparation.
WO 2004/0222065 relates to the compositions of the progestogen (wherein mentioning drospirenone) that comprise testosterone derivative and choose wantonly, and wherein said medicine is present in aqueous or oil-based suspension.
The reactive compound of micronization form is adopted in the other technologies suggestion, to improve bioavailability by obtaining the quick stripping of reactive compound in water.
WO 01/52857 mentions the compositions that comprises drospirenone, and wherein drospirenone was dissolved in suitable solvent for example in methanol or the ethyl acetate (ethyl actetate) before being sprayed on the inert carrier.
Peroral administration bioavailability obtains certain improvement although previous effort has made drospirenone, and the initial stripping step of drospirenone in gastro-intestinal Fluid before described medicine can be absorbed do not removed in these effort.
Summary of the invention
A kind of pharmaceutical composition now is provided, and it comprises at least a steroid drug such as progestogen (for example drospirenone, progesterone, eplerenone, etonogestrel) and/or the estrogen (estradiol and ester thereof) that exists with the form of molecular dispersion.That is to say that described compositions comprises steroid drug, drospirenone preferably, it exists with non-particulate form in compositions.Exist with the form of molecular dispersion and to be meant that medicine is present in the excipient with dissolved state.Because with the stripping immediately when the dosage unit disintegrate of the dispersive medicine of molecular forms, so the release of medicine will be very fast.Medicine is with in the dispersive pharmaceutical composition of molecular forms therein, and in fact disintegration time is exactly the rate of drug release deciding step, this means that the present invention can improve bioavailability significantly.
Preferably, described compositions provides with solid, semisolid or with liquid form, and form of ownership all preferably is applicable to oral administration, and preferably will contact with gastric juice, is absorbed from gastrointestinal tract then.It is found that this compositions has high bioavailability, good chemical stability and external fast stripping, and can must not expensive device or the condition of safety devices under produce.
The present invention not only relates to pharmaceutical composition, also relates to the described method for compositions of preparation, and the application of described compositions.
Provide the method for the present composition may further comprise the steps:
A) provide drospirenone and one or more to plant carrier; And
B) drospirenone is dissolved in fully in described one or more kind carriers; And
C) randomly, with the mixture drying of step b) gained.
The specific embodiment
Found that the pharmaceutical composition that comprises the drospirenone that exists with the molecular dispersion form shows superior performance aspect the bioavailability in preparation method, physics or chemical stability, external stripping, people's colon cell body outer osmotic and body.
In first aspect, the invention provides and comprise the compositions that is dispersed in the drospirenone in the materia medica acceptable carrier with molecular forms.In other words, the compositions that comprises drospirenone is contained in the present invention, and wherein no matter described compositions is solid, semisolid or exists with the form of liquid that drospirenone all is present in the materia medica acceptable carrier with dissolved form.The common trait of all compositionss is: need not to adopt the form of conventional drospirenone solution, drospirenone promptly can be dissolved in the materia medica acceptable carrier by molecular level, and shows and the similar character of dissolved drospirenone.Typically, drospirenone can not be analyzed by X-ray diffraction or be detected by other method such as optical microscope, ultramicroscope or strippings that are fit to.Because described medicine exists with dissolved form, that is to say with molecular forms and disperse, therefore medicine stripping immediately when dosage unit generation disintegrate.Therefore, the common trait of dosage unit is: when the disintegration time of dosage form is compared with dissolution time, within the error relevant with analytical method, they will take place simultaneously.
In other words, the present invention is contained and no matter comprised described compositions to be solid, semisolid or to exist with liquid form, and drospirenone all is present in compositions in the materia medica acceptable carrier with dissolved form.The common trait of all compositionss is: need not to adopt the form of conventional drospirenone solution, drospirenone promptly can be dissolved in the materia medica acceptable carrier by molecular level, and shows and the similar character of dissolved drospirenone.
Advantageously, compositions table of the present invention reveals drospirenone in external quick stripping.Fast stripping is defined as: during after external dissolution test begins 30 minutes time point, the stripping in described compositions of at least 70% drospirenone, especially, when external dissolution test begins back 20 minutes time point, the drospirenone of stripping at least 80 weight %, even more preferably, when external dissolution test begins back 15 minutes time point, the drospirenone of stripping at least 85 weight %.Described test is following to be carried out: the 900ml water that adopts 37 ℃ is as dissolution medium, adopts USP XXVIII slurry subtraction unit 2 as the dissolution test device, 50～100rpm as 50 or 75rpm under operate.
As previously mentioned, can obtain high bioavailability by using micronized medicine.But this technology has some shortcomings, because micronized medicine is easy to flocculation in process of production, and its personnel that handle is exposed in its dust in operating process easily.These shortcomings can be avoided by production method of the present invention, and this method needs less step, can reduce the formation of dust in the production process, increase and hold (containment) level, improve environment and occupational safety, reduce production costs, improve mixing homogeneity and improve dose uniformity.
Preferably, compositions of the present invention is the form of solid, semisolid or liquid.
According to the present invention, solid composite can be known as solid solution (solid solution).
According to the present invention, semi-solid and fluid composition is used to define the solution of the drospirenone that contains dissolved form, and wherein said solvent has can determine whether described compositions is the viscosity and/or the fusing point of semisolid or fluid composition.
Term " with molecular forms disperse () " or " molecular dispersoid " be used to describe component A (as drospirenone) wherein and be dispersed in any solid, semisolid and liquid system among the another kind of B component (as solvent or polymer) with molecular level, therefore, should not detect the component A of crystal form by the X-ray diffraction analytic process, no matter be to exist, also should not detect the component A of particle form by microscope simultaneously with crystal form or amorphous form.Term " molecular dispersoid " should be understood to the character regardless of B, and drospirenone all is dissolved in the B component.That is to say that term " disperses with molecular forms " and can " dissolve " mutual alternative with molecular forms with term.
Term " solid dispersion " is meant that drospirenone wherein exists with non-particulate form basically and is scattered in situation in the polymeric matrix.This situation also can be called " solid solution ".Selectively, drospirenone exists with crystal form and is dispersed in the polymeric matrix, to such an extent as to described crystal so trickle they can not be gone out by the X-ray diffraction analyzing and testing.Be used for herein term " non-particulate basically " and mean that wherein the drospirenone greater than 90% is the situation of non-particulate form.
Selectively, can check not existing of particulate matter such as crystal and amorphous granular by microscope.Be used for herein term " non-particulate basically " and mean that wherein surpassing 90% drospirenone when adopting microscope to analyze is the situation of non-particulate form.
Term " solid solution " is used to describe wherein a kind of component and is dispersed in any solid system among the another kind of component with molecular level.
In special form, solid solution is characterised in that to contain with molecular forms and is dispersed in drospirenone (or another kind of active component) in the solvent that wherein said solvent absorbs when absorbing described solvent and still can remain on the solid carrier.That is to say that drospirenone is dissolved in the solvent that is present in carrier surface fully.The method that forms this solid solution is as follows: drospirenone is dissolved in the solvent fully, by the solid carrier that adds the energy lyosoption solvent is converted into solid then, and keeps the dissolved form of drospirenone simultaneously.Solid solution comprises with molecular forms and is dispersed in drospirenone in the compositions, more particularly, comprises the drospirenone that is dispersed in the solvent.
Term " solution " is used to describe wherein a kind of component and is dispersed in any semisolid and liquid system in the another kind of component with molecular level.
Therefore it should be understood that the present composition comprises the drospirenone of non-particulate form, for example, wherein drospirenone is not that form with micronized granule or nano-scale particle is present in the compositions.So; term " disperses " to have got rid of substantially wherein very trickle drospirenone granule such as micronized particle or nano-scale particle and acceptable composition of materia medica or the blended compositions of carrier drying with molecular forms, perhaps wherein final composition still comprises the compositions of the drospirenone of particle form.
The concentration that term " supersaturated solution " is used to describe contained drug is higher than the solution of its saturated concentration of at room temperature measuring.That is to say that although the content of drospirenone is higher, also not having crystalline pharmaceutical can be gone out by the powder x-ray diffraction analyzing and testing.Basically, supersaturated solution is considered to thermodynamic instability, will generate the medicine of saturated solution and recrystallization.
Term " stable supersaturated solution " is used to describe the supersaturated solution that does not wherein have the recrystallization medicine to be gone out by the X-ray diffraction analyzing and testing.For example, can implement stabilisation by adding the recrystallization inhibitor.
Term " microemulsion " is used to describe when its component contacts with aqueous medium can be spontaneous or spontaneously form basically, (non-opaque) or the opaque basically colloidal dispersion of opaque a little, milky, non-opacity.Microemulsion has thermodynamic stability, contains average diameter less than the droplet (droplet) of about 2 μ m or the granule of liquid " nanometer " size.Typically, the lipophilic drugs of incorporating in the microemulsion is present within described droplet or liquid state " nanometer " size particles with dissolved form.
Term " concentrate (micro-emulsion pre-concentrate) before the microemulsion " means at aqueous medium for example in water, it is 1: 1～1: 10 for example at dilution factor, as 1: 10 o'clock, perhaps in gastric juice, can spontaneously form the compositions of microemulsion in oral back.
In a specific embodiments of the present invention, described compositions is a liquid form.Therefore, described compositions comprises under the room temperature and is lower than 40 ℃ materia medica acceptable solvent for liquid or fusing point.This solvent can be selected from hereinafter listed h) to u).
In another embodiment, described materia medica acceptable solvent at room temperature is that semisolid and/or fusing point are lower than 40 ℃.This solvent can be selected from hereinafter listed h) to u).
Generally speaking, be used for liquid of the present invention or semi-solid combination and at room temperature include but not limited to: ethanol for liquid or semisolid solvent, isopropyl alcohol, glycerol, propylene glycol, transcutol (ethylene diethylene glycol monoethyl ether (ethylendiglycolmonoethylether)), polyhydric alcohol, citrate, monoglyceride, diglyceride, vegetable oil, vegetable oil esters, semi-synthetic (partial synthetic) triglyceride (for example medium chain triglyceride (MCT) is as miglyol ), synthetic glycerine three esters, glycerine fatty acid ester admixture such as Imwitor , aliphatic alcohol, fatty alcohol ether, fatty acid, fatty acid ester, wax, paraffin, purified water and their mixture.In addition, also can use surfactant and cosolvent.
Those skilled in the art will recognize that the fusing point of some kinds of above-mentioned solvents for example depends on the length of hydrocarbon chain and the degree of replacement.Therefore, those skilled in the art can easily select appropriate solvent, to produce liquid or semi-solid combination.
Preferably, described solvent is selected from following group: ethanol, propylene glycol, semi-synthetic triglyceride or vegetable oil.
Typically, examples of polyhydric alcohols is glycerol, propylene glycol, sorbitol, mannitol, inositol, tetramethylolmethane, maltose alcohol, lactose.
Typically, the example of citrate is tributyl citrate (tributylcitrat), triethyl citrate (triethylcitrat), citroflex A-4, glyceryl stearate citrate (glycerylstearate citrate).
Typically, the example of monoglyceride is glyceryl monostearate, glycerol monopalmitate, glycerin mono-fatty acid ester, glycerol list linoleate.
Typically, the example of diglyceride is glycerol two behenates, glycerol distearate.
Typically, the example of vegetable oil is olive oil, Oleum Arachidis hypogaeae semen, Oleum Ricini.
Typically, Zhi Fang example has Adeps Sus domestica.
Typically, example synthetic and semi-synthetic triglyceride is neutral oil, softisan , witepsol , suppocire .
Typically, the example of fatty acid glyceride is Monooctamoin, glycerol monolaurate, caprylic/capric (caprylaic/capric) glyceride, glyceryl stearate.
Typically, the example of aliphatic alcohol is capryl alcohol, decanol, lauryl alcohol, tetradecyl alchohol, spermol, octadecanol, oleyl alcohol, inferior oleyl alcohol (linolyl alcohol), Semen Ricini alcohol (ricinol).
Typically, the example of fatty alcohol ether is oleyl oleate (oleyloleate), cetyl cetylate, ethyl oleate.
Typically, the example of fatty acid is capric acid, sad, lauric acid, Palmic acid (palmitiylic acid), palmitic acid, stearic acid (stearylic acid), oleic acid, linoleic acid.
Typically, the example of fatty acid ester is lauric acid, sad, capric acid, stearic ester.
Typically, the example of wax is cera alba, Cera Flava.
Suitable surfactant comprises but is not limited to:
A) lecithin
B) block copolymer of oxirane and expoxy propane is as Pluronic and Poloxamer grade
C) glyceride, polyoxyethylene glyceride and their mixture are as Gelucire , Labrafil and Labrasol grade
D) propylene glycol ester is as Lauroglycol and Capryol grade
E) sucrose fatty acid ester is as Sucroesters
F) fatty acid esters of sorbitan, polyoxyethylene sorbitan fatty acid ester and their mixture are as Span and Tween grade
G) polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene glycerol list, two and three esters, and their mixture are as Cremophor grade.
In the interesting specific embodiments of the present invention, liquid of the present invention and semi-solid combination comprise following solvent:
H) medium chain triglyceride
I) Oleum Ricini
J) Imwitor 308 (Monooctamoin)
k)CremophorEL
L) Cremophor RH 40 (polyoxyethylene-40-glycerol-hydroxy stearic acid ester)
M) PEG400
N) transcutol P (ethylene diethylene glycol monoethyl ether)
O) triethyl citrate
P) mixture of 7 weight % glycerol and 93 weight % PEG400s
Q) mixture of 50 weight %Imwitor 308 and 50 weight % PEG400s
R) mixture of 50 weight % Oleum Ricini and 50 weight % tributyl citrate
S) mixture of 50 weight % Oleum Ricini and 50 weight % PEG400s
T) mixture of 75 weight %Imwitor 742 and 25 weight % PEG400s
U) 75 weight %Imwitor , 742,15 weight % PEG400s and the alcoholic acid mixture of 10 weight %, perhaps any solvent h) to u) mixture.
Therefore, in specific embodiments more of the present invention, described at least a materia medica acceptable carrier is selected from following group: medium chain triglyceride, Oleum Ricini, Monooctamoin (Imwitor 308), caprylic/capric glyceride (Imwitor 742 ), polyoxyethylene-35-glycerol-three ricinoleate ester (Cremophor EL ), polyoxyethylene groups-40-glycerol-hydroxy stearic acid ester (Cremophor RH 40), PEG400, ethylene diethylene glycol monoethyl ether (transcutol P), triethyl citrate and their mixture.The particularly mixture of the mixture of mixture, Oleum Ricini and the PEG400 of mixture, Oleum Ricini and the tributyl citrate of the mixture of glycerol and PEG400, Monooctamoin (Imwitor 308) and PEG400, caprylic/capric glyceride (Imwitor 742) and PEG400, caprylic/capric glyceride (Imwitor 742) and PEG400 and alcoholic acid mixture.
By and large, the amount of drospirenone is preferably 8mg in this liquid of 2g or the semi-solid combination in 1mg～30mg scope.
All these fluid compositions all can incapsulate, as in the Perle of packing into.
In the other specific embodiments of the present invention, described compositions is the form of concentrate before the microemulsion.By and large, this specific embodiments comprises above-mentioned liquid and semi-solid solvent, but also can further comprise at least a emulsifying agent.
Suitable emulsifying agent of the present invention relates to polyoxyethylene-35-ricinoleidin (Cremophor EL), polyoxyethylene-40-glycerol-hydroxy stearic acid ester (Cremophor RH40), the single ricinoleate ester of polyoxyethylene-400-, polyoxyethylene fatty acid glyceride (Gelucire , Labrafil , Labrasol ) etc.Described emulsifying agent and suitable co-emulsifier (co-emulgator) and/or cosolvent such as ethylene diethylene glycol monoethyl ether (Transcutol P), Monooctamoin (Imwitor 308) and propylene glycol ester (Lauroglycol , Capryol ) can be mixed mutually.
In other specific embodiments of the present invention, described compositions is a solid form.
In an one specific embodiments, it at room temperature is that solid and/or fusing point are higher than 40 ℃ as the materia medica acceptable carrier in 40～80 ℃ of scopes that described compositions comprises.Can mention the mixture such as the Imwitor of solid polyethylene glycol such as polyethylene glycol 6000, plant oil ﹠ fat, semi-synthetic triglyceride, synthetic glycerine three esters, fatty acid glyceride as suitable solid carrier, the mixture of monoglyceride, diester, three esters, polyoxyethylene fatty acid glyceride such as Gelucire , fatty acid, fatty acid ester, wax, paraffin or their mixture.
In its some specific embodiments, described molecular dispersoid comprises the drospirenone that is evenly dispersed in basically in the substrate, and described substrate is made of the mixture that comprises at least a aliphatic alcohol and at least a hard paraffin.In other specific embodiments, described substrate comprises at least a triglyceride and at least a hard paraffin, perhaps at least a semi-synthetic glyceride and at least a hard paraffin, perhaps at least a fatty acid ester and at least a hard paraffin.In this preparation, preparation preferably comprises microsphere.
In the solid composite of the another kind of form of the present invention, described materia medica acceptable carrier is a polymer.Described polymer is preferably the hydrophilic polymer that comprises free hydrophilic group, as containing functional group such as free hydrophilic functional group in the side chain, as the polymer of carboxyl, ester group, hydroxyl, amino, amide, halogen or sulfo group (sulfo-).
The representative instance of water miscible hydrophilic polymer includes but not limited to: polyvinylpyrrolidone (Povidone , Kollidon ); Polyvinyl acetate; Polyvinyl alcohol, polyvinyl alcohol phthalic acid ester; Polyethylene Glycol (PEG); Poly(ethylene oxide); Gelatin; Carbomer; Methacrylic acid copolymer; Amino (ammonio) methacrylate copolymer; Cellulose; Carboxymethyl cellulose; Methylcellulose; Hydroxyethyl-cellulose; Hydroxypropyl emthylcellulose (HPMC); Hydroxypropyl cellulose (HPC); Cellulose acetate phthalate; And Hydroxypropyl Methylcellulose Phathalate ester; Perhaps their copolymer or mixture.
Described hydrophilic polymer can be an insoluble polymer also, includes but not limited to: polyvinylpolypyrrolidone, sodium starch glycolate and croscarmellose.
Preferably, described polymer is selected from following group: polyvinylpyrrolidone (Povidone , Kollidon ) and Polyethylene Glycol (PEG), especially preferably polyethylene ketopyrrolidine.When using insoluble polymer, preferred polyvinylpolypyrrolidone.
All aforementioned polymer are well known in the art.
Polyvinylpyrrolidone means the polymer of l-vinyl-2-pyrrolidone.It is commercially available that it can be used as Povidione or the Kollidon of mean molecule quantity in about 2,000～about 1,500,000 scope.By and large, the mean molecule quantity of used polyvinylpyrrolidone is preferably about 28,000～about 54,000 in about scope of 7000～about 54,000.
Polyvinylpolypyrrolidone means the synthesizing cross-linked homopolymer of the water-insoluble of N-vinyl-2-Pyrrolidone.By and large, the particle diameter of polyvinylpolypyrrolidone is about 20 μ m～about 250 μ m, be preferably about 50 μ m～about 250 μ m (for example referring to Kollidon, the pharmaceuticals industry polyvinylpyrrolidone, BASF).
Preferably, the ratio of drospirenone and polymer is about 1: 1～about 1: 100, more preferably is about 1: 2～about 1: 20, is most preferably about 1: 5～about 1: 10.
When drospirenone and described polymer dissolution are prepared molecular dispersoid of the present invention in the mixture of organic solvent or organic solvent, suitable organic solvent includes but not limited to dichloromethane, methanol, ethanol, isopropyl alcohol, acetone, oxolane or their mixture.
Can remove by the means of routine and desolvate: for example, evaporate down except that desolvating at fume hood (hood); Adopt twin-roll drum drier or spray dryer or adopt supercritical fluid extraction.
Should understand, except drospirenone, the present composition can also be applied to the other drug molecule, and the combination of two or more types of drug molecules.Therefore, compositions of the present invention can comprise and anyly be lipotropy and the relatively poor chemical compound of water solublity in the time of 25 ℃.By and large, described chemical compound dissolubility in water in the time of 25 ℃ is lower than 1mg/ml, as is lower than 0.5,0.1,0.05 or 0.01mg/ml.Typically, described chemical compound is general (in general) steroid molecule and/or hormone/hormone antagonist.Other active pharmaceutical ingredients of vast scope can have benefited from prior art, as albendazole, aminogluthethimide, aminosallcylic acid (3-, 4-or 5-aminosalicylic acid) amiodarone, astemizole, azathioprine, beclamide, benorylate, benperidol, bezafibrate, biotin, bromocriptine, bromocriptine methanesulfonate, bumetanide, busulfan, cabergoline, carbamazepine, cefixime, chenodeoxycholic acid, chlorambucil, chloroquine, chlorpropamide, chlorprothixene, chlortalidone, cinnarizine, cinoxacin, clobazam, clofazimine, clofibrate, clonazepam, navidrex, cyclosporin A, dapsone, demeclocycline, diazoxide, diflunisal, digitophyllin, digoxin, disulfiram, domperidone, droperidol, enoxacin, Epothilones (epothilone), ethionamide, etretinate, felodipine, fenbufen, fexofenadine, flumazenil (flumazenil), folic acid, furosemide, glipizide, gliquidone, griseofulvin, haloperidol, hydrochlorothiazide, hydroflumethiazide, ibuprofen, iloprost, indomethacin, isocarboxazid, isosorbide dinitrate, isotretinoin, Isradipine, itraconazole, ketazolam, ketoconazole, ketoprofen, lansoprazole, Cyronine, lisuride, loperamide, loratadine, lorazepam, lovastatin, mebendazole, medazepam, mefenamic acid, menadione, mequitazine, methotrexate, misoprostol, morphine, niclosamide, nifedipine, nimodipine, nitrazepam, omeprazole, oxazepam, oxytetracycline, pantoprazole, perphenazine, Phenylbutazone, pimozide, pindolol, probenecid, probucol, Pyrantel Pamoate, pyrimethamine, vitamin A, riboflavin, simvastatin, diethylstilbestrol, sulindac, sulfadiazine, Sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, temazepam, thiabendazole, thioguanine, tocopherol, tolbutamide, tretinoin, triamterene, triazolam, trimethoprim and zopiclone.
As mentioned above, The compounds of this invention can be steroid molecule or hormone, and that wherein can mention has:
Androgen, as testosterone and ester (testosterone enanthatas, testosterone undecanoate, depo-testosterone, Testosterone Propionate) thereof.
Estrogen/estrogen antagonist, adjust (downregulators) down as estradiol and ester (estradiol valerate, estradiol enanthate, estradiol cypionate, estradiol undecylate) thereof, estriol, estrone, conjugated estrogen hormone, 1,3,5,7-estratetraen-3-ol-17-one, ethinylestradiol, fenestrel, mestranol, nilestriol (nylestriol), quinestrol, clomifene, estrogen receptor alfa agonists, estrogen receptor alpha-2 antagonists, estrogen receptor beta-agonists, estrogen receptor beta antagonists, estrogen receptor.
Corticosteroid hormone, as cortisone and glucocorticoid, for example beclomethasone dipropionate, betamethasone, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fludrocortisone acetate, prednisolone, prednisolone.
Progestogen/antiandrogen, as cyproterone, etonogestrel, desogestrel, gestodene, levonorgestrel, norethindrone (norethisterones), norgestimate, norethindrone (norethindrone), norethindrone acetate, norethynodrel, norgestimate, norgestrel, medrogestone, medroxyprogesterone acetate, progesterone, progesterone receptor A ligands specific, progesterone receptor B ligands specific, middle progesterone (mesoprogestins), progesterone antagonist, asoprisnil, asoprisnil ecamate.
Aldosterone antagonist is as spironolactone, eplerenone, canrenoate, canrenone, dicirenone, U.S. sharp hydrochlorate, the third sharp hydrochlorate, epostane, mespirenone, pregnant hydrochlorate difficult to understand, spirorenone, spiroxasone, prorenone.
The vitamin D hormone, as alfacalcidol, calcifediol, vitamin D2, calcitriol.
Should understand, the present composition can comprise and surpass a kind of active drug substance, for example, comprises the combination of two or more drug substances.For example, the present composition can comprise drospirenone for the treatment of effective dose and the estrogen for the treatment of effective dose.
The formation of pharmaceutical preparation
Randomly, the compositions that comprises molecular dispersoid may further include one or more and plants other active component and/or be selected from excipient in following group: disintegrating agent, lubricant, fluidizer, artificial sweetening agent, filler, coloring agent and one or more are planted flavouring agent.
The described compositions that comprises molecular dispersoid can be prepared into solid dosage forms.Solid dosage forms comprises tablet, thin membrane coated tablet, granule, pellet, pill, capsule and powder, comprise for example any modified releasing pattern of described dosage form, as have the dosage form of delayed release coating, sustained release coating, enteric coating, but quick releasing formulation, effervescent dosage form and chewable dosage forms.Capsule comprises for example Perle, hard gelatin capsule, hydroxypropyl emthylcellulose (HPMC) capsule and chondrus ocellatus Holmes (carrageenan) capsule.
In some specific embodiments, described compositions may be fit to preparation and be used for oral cavity or sublingual administration.For example, adopt lozenge (lozenge) form that comprises the molecular dispersoid of drospirenone in being added with (flavoured) substrate of flavouring agent; Perhaps drospirenone is present in pastille (pastille) form in inert base such as gelatin, glycerol, sucrose or the arabic gum.Equally, the drospirenone solid solution in the polymeric film does not need to further process, and just can directly be placed on the oral mucosa.Fluid composition goes for the oral cavity or sublingual spraying is used.
All dosage forms all can prepare by means commonly known in the art.
Typically, in about 1～about 50 weight % scopes, be preferably about 5～about 50 weight % with the amount of drospirenone in the dispersive compositions of molecular forms; It accounts for about 0.1～about 5.0 weight % of pharmaceutical dosage form such as tablet, granule, micro tablet or powder, is preferably about 1.0～about 5.0 weight %.That is to say, typically, account for about 5～100 weight % of described pharmaceutical dosage form, be preferably about 10%～about 50 weight % with the dispersive compositions of molecular forms.
Excipient
As mentioned above, except that required polymer, solvent, surfactant and crystallization inhibitor, the present composition also comprises many other excipient.
Suitable disintegrating agent is selected from following group: cross-linked carboxymethyl cellulose sodium (cross linked polymer of sodium carboxymethyl cellulose), polyvinylpolypyrrolidone, starch NF; Polacrilin (polacrilin) sodium or potassium and sodium starch glycolate.It will be appreciated by those skilled in the art that but compressed tablets disintegrate in 30 minutes is favourable, in 10 minutes disintegrate more favourable, disintegrate is the most favourable in 5 minutes; Therefore, used disintegrating agent preferably makes tablet in 30 minutes, more preferably in 10 minutes, and most preferably disintegrate in 5 minutes.
The lubricant that is fit to comprises: Pulvis Talci, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable wet goods.Preferably use magnesium stearate.
The fluidizer that is fit to comprises: pyrogenic silica (pyrogenic silica), Pulvis Talci etc.
The filler that is fit to comprises: xylitol, mannitol, compressible sugar (compressible sugar), lactose, calcium phosphate and microcrystalline Cellulose.
The artificial sweetening agent that is fit to comprises: glucide, cyclamate (cyclamate) and aspartame.
If desired, can be with known flavouring agent and known FD ﹠amp; The C coloring agent is added in the compositions.
The method of spiral shell molecular dispersoid is bent in preparation
1. can prepare the present composition by the method that comprises following steps:
A) provide drospirenone and one or more to plant carrier; And
B) drospirenone is dissolved in fully in described one or more kind carriers; And
C) randomly, with the mixture drying of gained in the step b).
In said method, preferably, implementation step b) being selected from heating, supersound process, acutely mixing, stirring and/or melt extruding the dissolved step of drospirenone in section.
The exsiccant method of gained mixture in the step b) is comprised spray drying or other methods known in the art.
Should understand, can use said medicine acceptable carrier and above-mentioned reactive compound to implement described method.
The method and composition of concentrate before the preparation microemulsion has been described among the embodiment 1 to 6.By and large,,, liquid or semi-solid solvent or their mixture are mixed mutually with drospirenone, with concentrate before the preparation microemulsion as under 50 ℃, utilizing ultrasonic water bath by under the condition that guarantees fully drospirenone to be dissolved in described liquid/semi-solid solvent.For example, the example of liquid or semi-solid solvent as mentioned above, h especially)～u) solvent listed of item.Concentrate can be that every 1500mg concentrate contains in the concentrate of 1mg drospirenone～every 100mg and contains the 1mg drospirenone before the gained, be preferably in the concentrate that every 1000mg contains 1mg drospirenone～every 150mg and contain the 1mg drospirenone, as containing the 1mg drospirenone in every 750mg concentrate or the every 250mg concentrate.
Randomly, also in liquid/semisolid, add at least a aforesaid emulsifying agent.
In the time of in water being added to preceding concentrate, spontaneously form the milky microemulsion that to take at once.Typically, the amount of the water that is added is every 1g concentrate 2ml～100ml, as every 1g concentrate 4ml～80ml, as every 1g concentrate 5ml～70ml.
The gained microemulsion was not seen any sedimentation or crystallization at least 3 days, and centrifugal (6000U, 10 minutes) can not cause any sedimentation or crystallization yet.
Described among the embodiment 7 and prepared method and the preferred compositions that contains with the fluid composition of the dispersive drospirenone of molecular forms.The fluid composition that contains with the dispersive drospirenone of molecular forms is prepared as follows: under 25～40 ℃ of stirrings, a certain amount of drospirenone is dissolved in as defined above at room temperature in the solvent of liquid.Typically, use with the amount of 1mg～30mg, preferred 8mg drospirenone in every 2g liquid.Typically, the example of appropriate solvent as mentioned above, h particularly)～u) in listed solvent.
Compositions according to embodiment 1～7 can incapsulate.Basically, preferably will be according to the compositions of embodiment 1～6 hard capsule of packing into, and after filling, capsule is sealed; The compositions of embodiment 7 is preferably packed in the soft capsule.
Embodiment 8 shows that the selection of solvent and surfactant does not change the dissolution rate and the permeability of drospirenone in liquid of the present invention and the semi-solid combination; In the preparation that all are studied, drospirenone is all absorbed rapidly.Yet unexpectedly finding provides the degraded of drospirenone than low degree according to the preparation of embodiment 2.
Embodiment 9～13 and 24 describes the method for preparing solid solution and preferred preparation:
Basically, two kinds of methods that prepare solid solution are arranged.In a specific embodiments (embodiment 12,13 and 24), reactive compound and dried powder polymer or mixture of polymers and optional additive such as surfactant such as sucroester are mixed mutually.This mixture is extruded under the rotating speed of 10～100rpm continuously by utilizing single screw extrusion machine (single screw extruder) or double screw extruder (twin screw extruder) or similar devices.Randomly, can be with the temperature of extruder respectively by heating and cooling control, so that processing temperature for example is controlled in 40～150 ℃ of scopes.In this course of processing, all mixture liquefies under final pressure and temperature, thereby reactive compound is dissolved in the polymer.Can or break into pieces the cutting of the weight of gained solidified (resolidified) extrudate, be used for further processing through grinding with after sieving.The external stripping data of gained can be referring to embodiment 25.
In other specific embodiments (embodiment 10 and 11), solid solution is prepared as follows: spray drying contains reactive compound, polymer and the optional additive such as the solution of surfactant of dissolved form.One skilled in the art will appreciate that and to regulate the spray drying condition according to employed equipment.Spray dried products is further dry in drying baker, perhaps spray dried products is stored in and uses desiccant as further dry in the exsiccator of five phosphorous oxide.
As previously mentioned, described polymer is preferably the hydrophilic polymer that comprises free hydrophilic radical, as containing functional group such as free hydrophilic functional group in the side chain, as the polymer of carboxyl, ester group, hydroxyl, amino, amide, halogen or sulfo group (sulfo-).The representative instance of water miscible hydrophilic polymer includes but not limited to: polyvinylpyrrolidone (Povidone , Kollidon ); Polyvinyl acetate; Polyvinyl alcohol; The polyvinyl alcohol phthalic acid ester; Polyethylene Glycol (PEG); Poly(ethylene oxide); Gelatin; Carbomer; Methacrylic acid copolymer; The amino methyl acrylate copolymer; Cellulose; Carboxymethyl cellulose; Methylcellulose; Hydroxyethyl-cellulose; Hydroxypropyl emthylcellulose (HPMC); Hydroxypropyl cellulose (HPC); Cellulose acetate phthalate; And Hydroxypropyl Methylcellulose Phathalate ester; Perhaps their copolymer or mixture.Described hydrophilic polymer can be an insoluble polymer also, includes but not limited to: polyvinylpolypyrrolidone, sodium starch glycolate and croscarmellose.Preferably, described polymer is selected from following group: polyvinylpyrrolidone (Povidone , Kollidon ) and Polyethylene Glycol (PEG), especially preferably polyethylene ketopyrrolidine.When using insoluble polymer, preferred polyvinylpolypyrrolidone.
Embodiment 14～17 has described the method for solid solution being incorporated into peroral dosage form such as tablet.The technical staff should imagine easily, and similar preparation also can be packed in the hard capsule.Preferred preparation consists essentially of aforesaid hydrophilic polymer, distributes in intestinal fluid to quicken medicine.
Be described in the method for preparing solid solution in the thin polymer film among the embodiment 18.Basically, in the film calender (film drawing machine) of the scraper (knife) in using 100～1000 mu m ranges, the solution or the suspension of reactive compound and above-mentioned polymer and optional additive rolled into thin film.Place drying baker dry the gained film, cut into set unit then.This compositions can oral administration (embodiment 20) and oral cavity and sublingual administration (embodiment 19).The latter has the advantage that can easily regulate dosage according to each patient's individual need.The external stripping data of gained can be referring to embodiment 26.
Embodiment 21～23 has described the another kind of method of oral cavity and sublingual administration, this method provide have be low to moderate moderately viscous, directly be sprayed to the solution of absorption site.
Embodiment
Embodiment 1
Concentrate is prepared as follows before the microemulsion: under 50 ℃, 18.9g Cremophor RH 40,2.1g Transcutol P and 9.0g medium chain triglyceride are mixed.Add the drospirenone of 40mg then and under 50 ℃, utilize ultrasonic water bath to mix 10 minutes.The drospirenone that contains 1mg before the 750mg gained microemulsion in the concentrate.
When adding the water of 100ml, spontaneously form milky microemulsion.The gained microemulsion did not demonstrate any sedimentation or crystallization at least 3 days.Centrifugal (6000 U, 10 minutes) do not cause any sedimentation or crystallization.
When adding the water of 2000ml, observed unanimity as a result.
Embodiment 2
According to embodiment 1, use the preparation of 120mg rather than 40mg drospirenone preparation to have identical characteristics, but contain the drospirenone of 1mg before the 250mg gained microemulsion in the concentrate.
Embodiment 3
Concentrate is prepared as follows before the microemulsion: under 50 ℃, 18.9g Cremophor EL, 2.1gTranscutol P and 9.0g medium chain triglyceride are mixed.Add the 40mg drospirenone then and under 50 ℃, utilize ultrasonic water bath to mix 15 minutes.The drospirenone that contains 1mg before the 750mg gained microemulsion in the concentrate.
When adding 100ml water, spontaneously form slight lighttight microemulsion.The gained microemulsion did not demonstrate any sedimentation or crystallization at least 3 days.Centrifugal (6000 U, 10 minutes) do not cause any sedimentation or crystallization.
When adding the water of 2000ml, observed unanimity as a result.
Embodiment 4
According to embodiment 3, use the preparation of 120mg rather than 40mg drospirenone preparation to have identical characteristics, but contain the drospirenone of 1mg before the 250mg gained microemulsion in the concentrate.
Embodiment 5
Concentrate is prepared as follows before the microemulsion: under 50 ℃, with the Oleum Ricini mixing of 18.9g Cremophor EL, 2.1gTranscutol P and 9.0g.Add the 40mg drospirenone then and under 50 ℃, utilize ultrasonic water bath to mix 5 minutes.The drospirenone that contains 1mg before the 750mg gained microemulsion in the concentrate.
When adding 100ml water, spontaneously form milky microemulsion.The gained microemulsion did not demonstrate any sedimentation or crystallization at least 3 days.Centrifugal (6000 U, 10 minutes) do not cause any sedimentation or crystallization.
When adding the water of 2000ml, observed unanimity as a result.
Embodiment 6
According to embodiment 15, use the preparation of 120mg rather than 40mg drospirenone preparation to have identical characteristics, but contain the drospirenone of 1mg before the 250mg gained microemulsion in the concentrate.
Embodiment 7
Under 25～40 ℃ of stirrings, will be in 1mg～30mg scope, the drospirenone of the amount of preferred 8mg is dissolved in 1, in one of following liquid of 992g, comprise fluid composition with the dispersive drospirenone of molecular forms with preparation:
H) medium chain triglyceride
I) Oleum Ricini
J) Monooctamoin (for example Imwitor 308)
K) polyoxyethylene-35-glycerol-three ricinoleate ester (for example Cremophor EL)
I) polyoxyethylene-40-glycerol-hydroxy stearic acid ester (Cremophor RH 40)
M) PEG400
n)transcutol?P
O) triethyl citrate
P) mixture of 7% glycerol and 93% PEG400
Q) mixture of 50% Monooctamoin (for example Imwitor 308) and 50% PEG400
R) mixture of 50% Oleum Ricini and 50% tributyl citrate
S) mixture of 50% Oleum Ricini and 50% PEG400
T) mixture of 75% caprylic/capric glyceride (for example Imwitor 742) and 25% PEG400
U) 75% caprylic/capric glyceride (for example Imwitor 742), 15% PEG400 and 10% alcoholic acid mixture
If use the 8mg drospirenone to be prepared, contain the drospirenone of 1mg so before the 250mg gained microemulsion in the concentrate.
All these compositionss and their mixture all can incapsulate, in the soft capsule of for example packing into.
Embodiment 8
Outer stripping of coalition and body outer osmotic test are to studying according to containing with the compositions of the dispersive drospirenone of molecular forms of embodiment 2,4,6 and 7.The various compositionss of 250mg are dispersed in the 250mL isotonic buffer saline solution.In the Caco-2 permeability test, measure 1mL gained liquid, continue 120 minutes.The principle write up of Caco-2 test is in document such as Haltner E, Schmitz S, Gindorf C.In vitro Permeabilit tsuntersuchungen als Ersatz f ü r Tier-undHumanstudien-welche Voraussetzungen m ü ssen erf ü llt sein? ALTEX18 (2001): 81-87 and Le Ferrec E, Chesne C, Artursson P, Brayden D, Fabre G, Gires P, Guillou F, Rousset M, Rubas W.In vitro models of the intestinalbarrier:The report and recommendations of ECVAM workshop 46.ATLAAlternatives to Laboratory Animals.29 (2001): among the 649-668.Mainly measured the infiltration that chemical compound passes the human colon cancer cell monolayer.In addition, also studied digestive tract metabolism and the chemical stability that drospirenone is converted into its nonactive isomer.External stripping is measured as follows: the 900mL water that uses 37 ℃ uses USP XXVIII slurry subtraction unit 2 as the stripping test set as dissolution medium, operates under 50rpm.
Tried in the compositions at all, drospirenone sees through the apparent permeability of people's colon cell between 200～350nm/s, shows that drospirenone has high permeability and there was no significant difference.Yet, aspect the degree of isomerization degraded, detect difference at drospirenone.In beginning (after preparing described compositions)---after stripping, beginning permeability test before---and in the end, the latter stage of permeability test, promptly contact 120 minutes with colon cell after, the degraded (promptly being converted into the isomer of non-activity) of mensuration drospirenone:
| Compositions | The percentage rate (%) of drospirenone degraded | ||
| Beginning | At last | Difference | |
| According to embodiment 2 (RH40, Transcutol , MCT) according to embodiment 4 (EL, Transcutol , MCT) according to embodiment 6 (EL, Transcutol , Semen Ricini) according to embodiment 7j (Imwitor 308) according to embodiment 7k (EL) according to embodiment 7l (RH40) according to embodiment 7m (PEG 400) according to embodiment 7n (Transcutol ) according to embodiment 7o (triethyl citrate) according to embodiment 7q (PEG 400, Imwitor 308) | 2.0 3.8 4.8 6.5 4.9 4.5 3.4 7.6 3.8 5.8 | 3.1 4.7 5.4 7.5 5.7 5.1 3.9 7.9 5.3 6.4 | +1.1 +0.9 +0.6 +1.0 +0.8 +0.6 +0.5 +0.3 +1.5 +0.6 |
Embodiment 9
The semi-solid combination that comprises with the dispersive drospirenone of molecular forms is prepared as follows: by about 100 ℃ and stir under with all the components fusion, the drospirenone of the amount of 1mg～30mg is dissolved in the mixture of 1.5g cera alba, 2g medium chain triglyceride and 0.07g lecithin.
Said composition can pack into Perle or hard gelatin capsule.
Embodiment 10
The solid solution for preparing drospirenone by spray drying: under stirring 1g drospirenone, 8gKollidon K30 and 1g sucroester WE15 are dispersed in the 300mL purified water.Dispersion is heated to 60 ℃ also to be continued to stir to dissolve until all the components.With gained solution Mini Spray DryerB ü chi 190 (120 ℃ of inlet temperatures, 80 ℃ of outlet temperatures, flow velocity 4g/min) spray drying.Adopting five phosphorous oxide to store at least 24 hours in as the exsiccator of desiccant spray dried products.
Embodiment 11
The solid solution for preparing drospirenone by spray drying: under stirring 1g drospirenone, 8g vinylpyrrolidone-vinylacetate-copolymer (Kollidon VA 64) and 1g Gelucire 44/14 are dispersed in the 300mL purified water.Dispersion is heated to 60 ℃ also to be continued to stir to dissolve until all the components.With gained solution Mini Spray Dryer B ü chi 190 (120 ℃ of inlet temperatures, 80 ℃ of outlet temperatures, flow velocity 4g/min) spray drying.Adopting five phosphorous oxide to store at least 24 hours in as the exsiccator of desiccant spray dried products.
Embodiment 12
By melt extruding the solid solution of preparation drospirenone: 10% drospirenone, 50% polyvinylpyrrolidone and 50% sucrose monooleate acid esters are mixed.Under 60 ℃ and 50rpm, continue to extrude described mixture by single screw extrusion machine.
Embodiment 13
By melt extruding the solid solution of preparation drospirenone: 30% drospirenone, 30% polyethylene glycol 6000 and 40% sucrose monooleate acid esters are mixed.Under 60 ℃ and 50rpm, continue to extrude described mixture by single screw extrusion machine.
Embodiment 14
Compositions according to embodiment 10～12 can be processed into tablet., various compositionss of 300g and 490g microcrystalline Cellulose are mixed for this reason, add the 10g magnesium stearate then, mixture was mixed 1 minute once more.The gained material directly is pressed into tablet, and obtaining sheet heavily is the tablet of 80mg.Every tablet of tablet comprises the drospirenone of 3mg.
Embodiment 15
Compositions according to embodiment 10～12 can be processed into tablet., various compositionss of 300g and 490g lactose are mixed for this reason, add the magnesium stearate of 10g then, mixture was mixed 1 minute once more.The gained material directly is pressed into tablet, and obtaining sheet heavily is the tablet of 80mg.Every tablet of tablet comprises the drospirenone of 3mg.
Embodiment 16
Compositions according to embodiment 10～12 can be processed into tablet., the various compositionss of 300g and the microcrystalline Cellulose of 490g are mixed for this reason, add the pyrogenic silica of 10g then, mixture was mixed 1 minute once more.The gained material directly is pressed into tablet, and obtaining sheet heavily is the tablet of 80mg.Every tablet of tablet comprises the drospirenone of 3mg.
Embodiment 17
100g is mixed according to compositions and the 395g microcrystalline Cellulose of embodiment 13, add the 5g magnesium stearate then, mixture was mixed 1 minute once more.The gained material directly is pressed into tablet, and obtaining sheet heavily is the tablet of 50mg.Every tablet of tablet comprises the drospirenone of 3mg.
Embodiment 18
By stirring 1g drospirenone and 1g polyoxyethylene-polyoxypropylene copolymer are dissolved in the ethanol of 94g.In gained solution, add 17g hydroxypropyl cellulose and the cellulosic mixture of powders of 17g equably.On the suitable film calender that uses 500 μ m scrapers, the gained suspension is rolled into thin film.Getting albescent slightly thickness after the drying is the paper shape film (paper-like film) of about 180 μ m.A unit of this film, promptly about 3cm
2A slice contain the drospirenone of 1mg.
Embodiment 19
Compositions according to embodiment 18 can be cut into about 1～about 15cm
2Directly to the sheet of mouth mucosa drug administration, it discharges 0.33～5mg drospirenone to oral mucosa.
Embodiment 20
Can be with compositions dicing according to embodiment 18, these sheets are packed into is used for oral administration behind the hard capsule.
Embodiment 21
By stirring 5g drospirenone, 1g tocopheryl acetate and 5 Oleum menthae are dissolved in ethanol and add ethanol to 1000mL.With pack into 10mL vial and cover pump spray-head (pump spraynozzle) of gained solution.Applied once discharges the 0.1mL solution that contains the 0.5mg drospirenone.
Embodiment 22
By stirring 5g drospirenone, 1g ascorbyl palmitate (ascorbyl palmitate), 50g medium chain triglyceride, 300g Cremophor EL and 20g monoglyceride are dissolved in ethanol and add ethanol to 1000mL.With pack into 10mL vial and cover pump spray-head of gained solution.The applied once ejection contains the 0.1mL solution of 0.5mg drospirenone.
Embodiment 23
Will be individually dosed as sublingual spraying according to the solution of embodiment 21 and 22, for example 6 * spraying discharges the 3mg drospirenone.The time of staying of the prolongation on oral mucosa is provided according to the preparation of embodiment 22.
Embodiment 24
By melt extruding the solid solution of preparation drospirenone:
10% drospirenone and 90% polyethylene glycol 6000 are mixed.Under 60 ℃ and 50rpm, continue to extrude described mixture by using single screw extrusion machine.
Embodiment 25
In following external dissolution test 30mg is studied according to the preparation of embodiment 24: the water that adopts 37 ℃ of 900mL adopts USP XXVIII slurry subtraction unit 2 as the dissolution test device as dissolution medium, operates under 50rpm.Contained drospirenone was dissolved in 10 minutes fully in the preparation.
Therefore should understand, this quick stripping has taken place in the dosage form disintegration time.Therefore, stripping step is not the rate-determing step that drospirenone discharges.Therefore should understand, the drospirenone in the present embodiment exists with " dissolved form ", as disperseing to exist with molecular forms, not so can not obtain stripping so fast.
Embodiment 26
To cut into 9cm according to the compositions of embodiment 18
2Sheet (containing the 3mg drospirenone), be used to carry out following external dissolution test: the water that adopts 37 ℃ of 900mL adopts USP XXVIII slurry subtraction unit 2 as the dissolution test device as dissolution medium, operates under 50rpm.Find following result: after 10 minutes, discharge 95.0% drospirenone, after 20 minutes, discharge 97.1% drospirenone, and the drospirenone that after 30 minutes, discharges 97.2%.
Claims (20)
1. compositions, it comprises with molecular forms and is dispersed in drospirenone at least a materia medica acceptable carrier.
2. compositions as claimed in claim 1, it is liquid or semi-solid form, and wherein at least a described materia medica acceptable carrier is selected from following group: mixture, aliphatic alcohol, fatty alcohol ether, fatty acid, fatty acid ester, wax, paraffin and their mixture of glycerol, propylene glycol, ethylene TC, polyhydric alcohol, citrate, monoglyceride, diglyceride, vegetable oil, Vegetable oil lipoprotein, semi-synthetic triglyceride, synthetic glycerine three esters, fatty acid glyceride.
3. compositions as claimed in claim 2, it further comprises at least a emulsifying agent.
4. each compositions in the claim as described above, wherein said at least a materia medica acceptable carrier is selected from following group: medium chain triglyceride, Oleum Ricini, Monooctamoin, caprylic/capric glyceride, polyoxyethylene-35-glycerol-three ricinoleate ester, polyoxyethylene-40-glycerol-hydroxy stearic acid ester, PEG400, diethylene glycol monoethyl ether, triethyl citrate and their mixture.
5. compositions as claimed in claim 4, wherein said at least a materia medica acceptable carrier is selected from following group: the mixture of the mixture of the mixture of the mixture of glycerol and PEG400, Monooctamoin and PEG400, Oleum Ricini and tributyl citrate, Oleum Ricini and PEG400, caprylic/capric glyceride and PEG400, caprylic/capric glyceride and PEG400 and alcoholic acid mixture.
6. each compositions in the claim as described above, it is the form of concentrate before the microemulsion.
7. compositions as claimed in claim 1, it is a solid form, wherein at least a described materia medica acceptable carrier is at room temperature for solid and/or have fusing point in 40～80 ℃ of scopes, and be selected from following group: the mixture of polyethylene glycol 6000, vegetable oil, Vegetable oil lipoprotein, semi-synthetic triglyceride, synthetic glycerine three esters, fatty acid glyceride, the mixture of monoglyceride, diester and three esters, polyoxyethylene fatty acid glyceride, fatty acid, fatty acid ester, wax, paraffin and their mixture.
8. compositions as claimed in claim 1, wherein said materia medica acceptable carrier is a polymer, preferably hydrophilic polymer.
9. compositions as claimed in claim 8, wherein said hydrophilic polymer are selected from following group: polyvinylpyrrolidone; Polyvinyl acetate; Polyvinyl alcohol; The polyvinyl alcohol phthalic acid ester; Polyethylene Glycol; Poly(ethylene oxide); Gelatin; Carbomer; Methacrylic acid copolymer; The amino methyl acrylic copolymer; Cellulose; Carboxymethyl cellulose; Methylcellulose; Hydroxyethyl-cellulose; Hydroxypropyl emthylcellulose; Hydroxypropyl cellulose; Cellulose acetate phthalate; And Hydroxypropyl Methylcellulose Phathalate; Polyvinylpolypyrrolidone; Sodium starch glycolate; Croscarmellose; And their copolymer, and their mixture.
10. as each compositions in the claim 1～9, wherein said compositions further comprises estrogen.
11. one kind provides the method that is dispersed in the drospirenone in the materia medica acceptable carrier with molecular forms, said method comprising the steps of:
A) provide drospirenone and one or more to plant carrier; And
B) drospirenone is dissolved in fully in described one or more kind carriers; And
C) randomly, the mixture of gained drying steps b).
12. as the method for claim 11, the step of wherein said dissolving drospirenone is undertaken by the means that are selected from following group: heating, supersound process, acutely mix, stir and melt extrude.
13. as each method in the claim 11 to 12, wherein said carrier is liquid or semi-solid form, and wherein at least a described materia medica acceptable carrier is selected from following group: mixture, aliphatic alcohol, fatty alcohol ether, fatty acid, fatty acid ester, wax, paraffin and their mixture of glycerol, propylene glycol, ethylene diethylene glycol monoethyl ether, polyhydric alcohol, citrate, monoglyceride, diglyceride, vegetable oil, vegetable oil esters, semi-synthetic triglyceride, synthetic glycerine three esters, fatty acid glyceride.
14. as each method in the claim 11 to 13, wherein said carrier further comprises at least a emulsifying agent.
15. as each method in the claim 11 to 14, wherein said at least a materia medica acceptable carrier is selected from following group: medium chain triglyceride, Oleum Ricini, Monooctamoin, caprylic/capric glyceride, polyoxyethylene-35-glycerol-three ricinoleate ester, polyoxyethylene-40-glycerol-hydroxy stearic acid ester, PEG400, diethylene glycol monoethyl ether, triethyl citrate and their mixture.
16. as each method in the claim 11 to 14, wherein said at least a materia medica acceptable carrier is selected from following group: the mixture of the mixture of the mixture of the mixture of glycerol and PEG400, Monooctamoin and PEG400, Oleum Ricini and tributyl citrate, Oleum Ricini and PEG400, caprylic/capric glyceride and PEG400, caprylic/capric glyceride and PEG400 and alcoholic acid mixture.
17. as each method in the claim 11 to 16, wherein said step b) or c) in the mixture of gained be the form of concentrate before the microemulsion.
18. as each method in claim 11 or 12, wherein at least a described materia medica acceptable carrier is at room temperature for solid and/or have fusing point in 40～80 ℃ of scopes, and be selected from following group: the mixture of polyethylene glycol 6000, vegetable oil, Vegetable oil lipoprotein, semi-synthetic triglyceride, synthetic glycerine three esters, fatty acid glyceride, the mixture of monoglyceride, diester and three esters, polyoxyethylene fatty acid glyceride, fatty acid, fatty acid ester, wax, paraffin and their mixture.
19. as each method in claim 11 or 12, wherein said materia medica acceptable carrier is a polymer, preferably hydrophilic polymer.
20. as the method for claim 19, wherein said hydrophilic polymer is selected from following group: polyvinylpyrrolidone; Polyvinyl acetate; Polyvinyl alcohol; The polyvinyl alcohol phthalic acid ester; Polyethylene Glycol; Poly(ethylene oxide); Gelatin, carbomer; Methacrylic acid copolymer; The amino methyl acrylate copolymer; Cellulose; Carboxymethyl cellulose; Methylcellulose; Hydroxyethyl-cellulose; Hydroxypropyl emthylcellulose; Hydroxypropyl cellulose; Cellulose acetate phthalate; And Hydroxypropyl Methylcellulose Phathalate; Polyvinylpolypyrrolidone; Sodium starch glycolate; Croscarmellose; And their copolymer, and their mixture.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04075713 | 2004-03-10 | ||
| US60/551,355 | 2004-03-10 | ||
| EP04075713.0 | 2004-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1980636A true CN1980636A (en) | 2007-06-13 |
Family
ID=34928104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800150652A Pending CN1980636A (en) | 2004-03-10 | 2005-03-10 | Compositions comprising drospirenone molecularly dispersed |
Country Status (12)
| Country | Link |
|---|---|
| CN (1) | CN1980636A (en) |
| AR (1) | AR048002A1 (en) |
| DE (1) | DE602005022952D1 (en) |
| GT (1) | GT200500044A (en) |
| MY (1) | MY143870A (en) |
| PA (1) | PA8625901A1 (en) |
| PE (1) | PE20060004A1 (en) |
| RS (1) | RS50975B (en) |
| SV (1) | SV2005002043A (en) |
| TW (2) | TW200840587A (en) |
| UA (1) | UA90263C2 (en) |
| UY (1) | UY28802A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106109420A (en) * | 2016-08-11 | 2016-11-16 | 吴启旸 | Eplerenone solid dispersion and preparation thereof |
-
2005
- 2005-03-09 MY MYPI20050960A patent/MY143870A/en unknown
- 2005-03-10 SV SV2005002043A patent/SV2005002043A/en not_active Application Discontinuation
- 2005-03-10 PE PE2005000278A patent/PE20060004A1/en not_active Application Discontinuation
- 2005-03-10 UY UY28802A patent/UY28802A1/en not_active Application Discontinuation
- 2005-03-10 GT GT200500044A patent/GT200500044A/en unknown
- 2005-03-10 RS RSP-2009/0307A patent/RS50975B/en unknown
- 2005-03-10 TW TW097123405A patent/TW200840587A/en unknown
- 2005-03-10 CN CNA2005800150652A patent/CN1980636A/en active Pending
- 2005-03-10 DE DE602005022952T patent/DE602005022952D1/en active Active
- 2005-03-10 AR ARP050100923A patent/AR048002A1/en unknown
- 2005-03-10 PA PA20058625901A patent/PA8625901A1/en unknown
- 2005-03-10 UA UAA200610358A patent/UA90263C2/en unknown
- 2005-03-10 TW TW094107361A patent/TW200609000A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106109420A (en) * | 2016-08-11 | 2016-11-16 | 吴启旸 | Eplerenone solid dispersion and preparation thereof |
| CN106109420B (en) * | 2016-08-11 | 2018-07-06 | 吴启旸 | Eplerenone solid dispersions and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| UY28802A1 (en) | 2005-10-31 |
| PE20060004A1 (en) | 2006-02-16 |
| TW200840587A (en) | 2008-10-16 |
| TW200609000A (en) | 2006-03-16 |
| RS50975B (en) | 2010-10-31 |
| DE602005022952D1 (en) | 2010-09-23 |
| GT200500044A (en) | 2005-10-31 |
| UA90263C2 (en) | 2010-04-26 |
| AR048002A1 (en) | 2006-03-15 |
| MY143870A (en) | 2011-07-15 |
| PA8625901A1 (en) | 2006-07-03 |
| SV2005002043A (en) | 2005-11-04 |
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