CN101879140A - The nanoparticle and the sustained release compositions that comprise aryl-heterocyclic compounds - Google Patents

The nanoparticle and the sustained release compositions that comprise aryl-heterocyclic compounds Download PDF

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Publication number
CN101879140A
CN101879140A CN2010102092071A CN201010209207A CN101879140A CN 101879140 A CN101879140 A CN 101879140A CN 2010102092071 A CN2010102092071 A CN 2010102092071A CN 201010209207 A CN201010209207 A CN 201010209207A CN 101879140 A CN101879140 A CN 101879140A
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compositions
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ziprasidone
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granule
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Inventor
J·德韦恩
P·斯达克
N·范宁
G·瑞凯
S·简金斯
G·里弗斯德格
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Elan Pharma International Ltd
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Elan Pharma International Ltd
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Priority claimed from US11/372,857 external-priority patent/US20060240105A1/en
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    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • 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
    • A61K9/14—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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

The invention provides a kind of compositions that comprises Ziprasidone, be used for the treatment of and prevent schizophrenia and similar psychiatric disturbance.In one embodiment, said composition comprises the nanoparticle granule that contains Ziprasidone and at least a surface stabilizer.Effective mean diameter of this nanoparticle is less than about 2000nm.In another embodiment, said composition comprises the change release composition, and after being applied to the patient, it sends Ziprasidone with bimodal, multimodal or continuation mode.The present invention also provides the dosage form that comprises said composition, and is used for the treatment of and prevents the method for schizophrenia and similar psychiatric disturbance.

Description

The nanoparticle and the sustained release compositions that comprise aryl-heterocyclic compounds
The application is dividing an application of 2006800302325 patent application for application number.
Invention field
The present invention relates to be used to prevent and treat the compositions of schizophrenia and similar psychiatric disturbance.Especially, the present invention relates to comprise aryl-heterocyclic drug chemical compound, for example the compositions of Ziprasidone.In one aspect of the invention, said composition is the form of nanoparticle, and also comprises at least a surface stabilizer.In yet another aspect, the present invention also relates to control and send aryl-heterocyclic drug chemical compound, for example novel form of Ziprasidone and prevention and treatment schizophrenia and the similarly method of psychiatric disturbance.
Background of invention
Ziprasidone, chemistry 5-[2-[4-(1 by name, 2-benzisothiazole-3-yl)-and the 1-piperazinyl] ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, it is a kind of benzothiazole based piperazine derivative, be used for the treatment of psychiatric disorders for example schizophrenia, hallucination, vain hope, hostility and other bipolar disorders as major tranquilizer, and can not improve lipid and other blood fat.The empirical formula of Ziprasidone is C 21H 21ClN 4OS, molecular weight are 412.94 (free alkalis).
The chemical constitution of Ziprasidone is as follows:
Figure BSA00000156166500011
Ziprasidone can be used as the registrar name of an article of Pfizer Inc. in the U.S.
Figure BSA00000156166500012
The part of the dosage form that provides is used.With
Figure BSA00000156166500013
The Ziprasidone that capsule exists is the hydrochloride form of Ziprasidone, i.e. 5-(2-(4-(1,2-benzisothiazole-3-yl) piperazinyl) ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one list hydrochloric acid monohydrate.This salt is that white arrives the baby pink powder, and fusing point is 300 ℃, and empirical formula is C 21H 21ClN 4OS-HCl-H 2O, molecular weight are 467.42.
Figure BSA00000156166500021
Capsule is the capsule oral that is used for 20mg, 40mg, 60mg and 80mg.
Figure BSA00000156166500022
Non-active ingredient in the capsule comprises lactose, pregelatinized starch and magnesium stearate.Patient's common dose comprises that adult's dosage for the treatment of schizoid peroral dosage form (capsule) is 20 milligrams (mg), every day twice, uses with food.Higher dosage comprises the dosage of 80mg, twice of every day.
Ziprasidone can be used for intramuscular injection, and with the form of ziprasidone mesylate, commodity are called injection Injection
Figure BSA00000156166500024
The ziprasidone mesylate trihydrate that comprises lyophilized form, 5-(2-(4-(1,2-benzisothiazole-3-yl) piperazinyl) ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one, mesylate, trihydrate (empirical formula: C 21H 21ClN 4OS-CH 3SO 3H-3H 2O; Molecular weight: 563.09).Injection Can in single dose vial, be the ziprasidone mesylate that comprises 20mg Ziprasidone/mL.U.S. food and Drug Administration (FDA) have ratified Ziprasidone can treat schizophrenia, and the Ziprasidone of having ratified the intramuscular injection form can be used for schizophrenic's acute psychokinesia.
The elimination half-life of Ziprasidone is about 7 hours.In 1 to 3 day, reach Cpss.The bioavailability of Ziprasidone is about 60% when taking with food.Reported, increased to gradually
Figure BSA00000156166500026
The about twentieth patient of high dose (360mg every day) has shown cognitive remarkable improvement.
The Ziprasidone chemical compound has been described: U.S. patent 4,831,031 in following document; 6,110,918; 6,245,765; 6,150,366; 6,232,304; 6,399,777; With 6,245,766.U.S. Patent Publication 2004/0138237 and 2004/0146562 discloses the Injectable depot formulations of Ziprasidone, wherein uses the active Ziprasidone chemical compound of cyclodextrin solubilising to form suspending agent.
The patient that Ziprasidone is suffered from schizophrenia and similar mental disorder for therapeutic treatment has higher effect.But if satisfy the needs of taking 2 Ziprasidones every day and the further needs of one after each meal Ziprasidone, strict patient's compliance is a key factor of Ziprasidone treatment schizophrenia and similar mental disorder.In addition, so frequent use the concern that needs the hygiene care personnel usually, and therefore caused the cost relevant very high with the Ziprasidone treatment.Therefore, this area needs new Ziprasidone compositions, and it has overcome these problem and other problems relevant with its use when treating schizophrenia with similar psychosis.
In addition, Ziprasidone is water-soluble hardly.This relatively poor water solublity has caused relatively poor bioavailability.
The invention summary
One embodiment of the invention comprise a kind of nanoparticle compositions, comprise: (A) Ziprasidone; (B) at least a surface stabilizer.This surface stabilizer can adsorb or be attached on the particulate surface of nanoparticle.The particulate effective mean diameter of this nanoparticle is less than about 2,000nm.This nanoparticle compositions can be chosen wantonly and comprise additional activity composition and/or the acceptable excipient of one or more pharmacy that one or more are used to prevent and treat schizophrenia and similar psychiatric disturbance.In these embodiments, the patient that this nanoparticle compositions is applied under feed or the fasting state will be bioequivalent, can show similar pharmacokinetics.
The present invention also relates to change release composition, wherein first component of said composition comprises the granule that comprises active component and at least a particulate second component that comprises active component that comprises second portion of first, wherein every kind of component has different rates of release and/or persistent period and wherein at least a described component and comprises Ziprasidone.The granule of described second component at least is change to discharge (MR) form, and for example, bag is changed and discharges coating or comprise or mixed change release matrix material.After the patient was oral, said composition discharged one or more active component with bimodal or multimodal mode.This change release composition can comprise the Ziprasidone and at least a surface stabilizer of nanoparticle form, can choose wantonly to comprise additional activity composition and/or the acceptable excipient of one or more pharmacy that one or more are used to prevent and treat schizophrenia and similar psychiatric disturbance.
First component of this change release composition can show different release profiles, comprise that the nearly all active component that wherein comprises in first component discharges immediately behind form of administration, after postponing a period of time, discharge (postponing to discharge) immediately, or the curve that slowly discharges in a period of time.In one embodiment, the active component that comprises in this dosage form first component after being applied to the patient discharges rapidly.The release profiles that " discharging rapidly " used herein comprises, wherein the active component at least about 80% of the component of this dosage form is being used back release in about 1 hour, term " postpones to discharge " release profiles that comprises, wherein the active component of the component of this dosage form discharges (quick or slow) after postponing a period of time, the release profiles that term " sustained release " and " prolong discharge " comprise slowly discharges comprising the active component at least about 80% in the component of this dosage form.
Second component of this change release composition also shows a lot of release profiles, comprises release profiles immediately, postpones release profiles or sustained release curve.In one embodiment, this second component display delay release profiles, wherein the active component of this component discharges after postponing a period of time.In another embodiment, this second component shows sustained release curve, and wherein the active component of this component discharges in about 24 hours time using back about 12.
Component shows that the release profiles of this active component from said composition is bimodal in the bi-component embodiment of different release profiles therein.First component shows release profiles immediately therein, and in the embodiment of the second component display delay release profiles, being discharged into active component at active component from first component has a time delay between discharging from second component.Amount by change discharging coating and/or composition or by changing the release matrix amount of substance and/or forming in order to reach the persistence length that required release profiles changes time delay.Therefore, the persistence length of time delay can be designed for the required curve of blood plasma of simulation.
First component shows release profiles immediately therein, and second component shows that the active component in first and second components discharges in the embodiment of sustained release curve in the different time.In such embodiments, immediate-release component is used for by making from being administered to the treatment time minimum of effective plasma concentration level facilitation, and one or more subsequent component are used to make the variation of plasma concentration level minimum and/or keep the effective plasma concentration of treatment during dosing interval.In such embodiment, the active component rapid release in first component, the active component in second component discharge using in about 12 hours time of back.In another such embodiment, the active component rapid release in first component, the active component in second component discharge using in about 24 hours time of back.In another such embodiment, the active component rapid release in first component, the active component in second component are gone through about 12 hours time release after using.In another such embodiment, the active component rapid release in first component, the active component in second component are gone through about 24 hours time release after using.In another such embodiment, the time that the active component rapid release in first component, the active component in second component were gone through after using at least about 12 hours discharges.In another such embodiment, the time that the active component rapid release in first component, the active component in second component were gone through after using at least about 24 hours discharges.
Dosage form of the present invention comprises immediate-release component and at least a change discharges component, the curve of blood plasma of using this dosage form and producing is substantially similar to twice of continuous administration or the curve of blood plasma that produces of I R dosage form repeatedly, or uses the curve of blood plasma that IR and MR dosage form produce respectively.Change release composition of the present invention is useful especially for using the Ziprasidone of using 2 common every day.In one embodiment of the invention, said composition is sent Ziprasidone in bimodal mode.After using, said composition has produced a kind of curve of blood plasma, and its IR dosage of simulating basically according to typical twice Ziprasidone of therapeutic scheme continuous administration acquires curve of blood plasma.
According to another aspect of the present invention, said composition can be designed for the generation curve of blood plasma, and it makes and twice of continuous administration or the repeatedly relevant relevant minimum or disappearance of change of plasma concentration level of IR dosage form.In these embodiments, said composition can provide immediate-release component with by making from being administered to the time of treatment between the effective plasma concentration level the shortest and facilitation, and provides at least a change to discharge component to keep the effective plasma concentration level of treatment in whole dosing interval.Ziprasidone can be included in the nanoparticle granule that also comprises at least a surface stabilizer.
At people's such as Devane United States Patent (USP) 6,228,398 and 6,730, open and claimedly similarly change release composition in 325 with this paper.
The present invention also relates to dosage form by preparation of compositions of the present invention.In one embodiment, this dosage form is the solid oral dosage form that comprises change release composition of the present invention.This peroral dosage form can utilize, for example erodable preparation, DIFFUSION CONTROLLED preparation and infiltration control preparation.In such embodiments, the accumulated dose that is included in this dosage form discharges with pulse or continuation mode.In such embodiment, the part of accumulated dose discharges immediately, and beginning effect rapidly, the remainder of accumulated dose is after time delay or go through up to about 24 hours time and discharge.
In another embodiment, this dosage form is the injectable depot formulations that comprises the nanoparticle compositions, and wherein this nanoparticle compositions comprises Ziprasidone.This depot formulations is lentamente with medicine dissolution and be discharged in patient's the circulation.The single injection of said preparation can provide the Ziprasidone of the effective plasma concentration of treatment that reaches 3 months
The present invention also relates to the nanoparticle method for compositions that a kind of preparation comprises Ziprasidone.This method is included under the condition that is enough to provide the stable nanoparticle compositions that comprises Ziprasidone, and the nanoparticle granule that will comprise Ziprasidone contacts the step of a period of time with at least a surface stabilizer.
The invention further relates to the method that includes but not limited to prevent and treat schizophrenia and similar mental disorder for the treatment of.This method comprises the compositions to patient's administering therapeutic effective dose, for example comprises the step of the nanoparticle compositions of Ziprasidone.
Compositions of the present invention and dosage form are used to reduce required administration frequency, therefore strengthen patient's convenience and improved patient's compliance, therefore, having improved all needs the Ziprasidone treatment, includes but not limited to prevent and treat the therapeutic outcome of schizophrenia and similar psychiatric disturbance.This approach can substitute the Ziprasidone dosage form of repeatedly using conventional every day.
Above-mentioned generality is described and following detailed description is an illustrative and indicative, is to attempt to provide further explanation for the present invention for required protection.According to following detailed description of the present invention, other purpose, advantage and new feature will be conspicuous for those skilled in the art.
Detailed Description Of The Invention
Use several in this article as hereinafter describe the present invention with listed definition in full.
" pact " used herein one of ordinary skill in the art will appreciate that, have difference to a certain degree in the context of its use.If it is unclear providing for those of ordinary skills in its employed context, " pact " just is meant that being this particular term to the maximum adds deduct 10% so.
" Ziprasidone " used herein comprises Ziprasidone, the acceptable salt of its pharmacy, acid, ester, metabolite, complex or other derivants and they every kind of stereoisomer separately comprises the mixture, racemate of two or more stereoisomers or other.
The amount that the pharmacology that phrase used herein " Ziprasidone of treatment effective dose " is meant provides specific replys, Ziprasidone is applied to the patient who much needs associated treatment for this reason.What should emphasize is, always the particular patient that the Ziprasidone of treatment effective dose is applied to particular case under is not necessarily effective for treatment disease as herein described, although those skilled in the art think that this dosage is to treat effective dose.
Term used herein " granule " is meant a kind of state of material, it is characterized in that being discrete particle, piller, pearl or granule, no matter and its size, shape or form.
Term used herein " many granules " is meant a plurality of granule, piller, pearl, granule or its mixture that disperse or reunite, no matter and its size, shape or form.As herein describedly comprise granose compositions and be also referred to as " many particulate compositions ".
Term " nanoparticle " is meant a kind of many granules, and wherein this particulate effective mean diameter is that diameter is less than about 2000nm (2 microns).The compositions that comprises nanoparticle as herein described is also referred to as " nanoparticle compositions ".
Term used herein " effectively mean diameter " in order to describe many granules (for example, nanoparticle), is meant that its granule of at least 50% is specific size.Therefore, " effectively mean diameter be that diameter is less than about 2000nm " is meant that wherein at least 50% particulate diameter is less than about 2000nm." D50 " is meant in many granules that 50% granule is at this particle diameter below particle diameter.Similarly, " D90 " is meant in many granules that 90% granule is at this particle diameter below particle diameter.
As for stable particle in this article, " stablizing " is meant but is not limited to, one or more following parameters: (1) granule not can owing to captivation between granule or along with the time particle diameter increase significantly and slightly the flocculation or in bulk; (2) particulate physical arrangement can for example not change the crystal phase into by amorphous phase along with the time changes; (3) this granule is chemically stable; And/or (4) active component in the preparation of nanoparticle of the present invention does not carry out heating steps on particulate fusing point or fusing point.
" being insoluble in the medicine of water " used herein is meant dissolubility in water less than about 30mg/ml, less than about 20mg/ml, and less than about 10mg/ml, or less than the medicine of about 1mg/ml.
Term used herein " changes release " and comprises non-release immediately, and comprises that sustained release, prolongation discharge, continue release and delay release.
Term used herein " time delay " is meant is using the dosage form that comprises compositions of the present invention and the described active component time between discharging from specific components.
Term used herein " lag time " is meant and discharges the component from active component from compositions and the time of described active component between discharging from another component of compositions.
Term used herein " erodable " is meant can be by intravital material effect wearing and tearing, minimizing or rotten preparation.
Term used herein " DIFFUSION CONTROLLED " is meant as autonomic movement for example from the preparation of high concentration to result's diffusion of low concentration region motion.
Term used herein " infiltration control " is meant that wherein this infiltration can make the concentration balance of film both sides preparation as the preparation of result's diffusion of the solution motion that enters higher concentration by semipermeable membrane.
I. the nanoparticle compositions that comprises Ziprasidone
The invention provides a kind of particulate nanoparticle compositions that comprises, wherein this granule comprises: (A) Ziprasidone or its salt or derivant; (B) at least a surface stabilizer.In U.S. patent 5,145,684, describe the nanoparticle compositions first, in following document, also described the compositions of nanoparticle activating agent, for example, U.S. patent 5,298,262; 5,302,401; 5,318,767; 5,326,552; 5,328,404; 5,336,507; 5,340,564; 5,346,702; 5,349,957; 5,352,459; 5,399,363; 5,494,683; 5,401,492; 5,429,824; 5,447,710; 5,451,393; 5,466,440; 5,470,583; 5,472,683; 5,500,204; 5,518,738; 5,521,218; 5,525,328; 5,543,133; 5,552,160; 5,565,188; 5,569,448; 5,571,536; 5,573,749; 5,573,750; 5,573,783; 5,580,579; 5,585,108; 5,587,143; 5,591,456; 5,593,657; 5,622,938; 5,628,981; 5,643,552; 5,718,388; 5,718,919; 5,747,001; 5,834,025; 6,045,829; 6,068,858; 6,153,225; 6,165,506; 6,221,400; 6,264,922; 6,267,989; 6,270,806; 6,316,029; 6,375,986; 6,428,814; 6,431,478; 6,432,381; 6,582,285; 6,592,903; 6,656,504; 6,742,734; 6,745,962; 6,811,767; 6,908,626; 6,969,529; 6,976,647; With 6,991,191; With U.S. patent disclosure 20020012675; 20050276974; 20050238725; 20050233001; 20050147664; 20050063913; 20050042177; 20050031691; 20050019412; 20050004049; 20040258758; 20040258757; 20040229038; 20040208833; 20040195413; 20040156895; 20040156872; 20040141925; 20040115134; 20040105889; 20040105778; 20040101566; 20040057905; 20040033267; 20040033202; 20040018242; 20040015134; 20030232796; 20030215502; 20030185869; 20030181411; 20030137067; 20030108616; 20030095928; 20030087308; 20030023203; 20020179758; 20020012675; With 20010053664.Described unbodied granule compositions in the lower class document, for example the U.S. patent 4,783, and 484; 4,826,689; 4,997,454; 5,741,522; 5,776,496.
As mentioned above, particulate effective mean diameter is that diameter is less than about 2000nm (that is, 2 microns) in the nanoparticle compositions of the present invention.In embodiments of the invention, when passing through light scattering method, when microscopy or other suitable methods were measured, effectively mean diameter can be that diameter is for example less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 75nm or less than about 50nm.
This nanoparticle granule can be crystal phase, amorphous phase, hemihedral crystal bulk phase, half amorphous phase or its mixture.
Except solid dosage forms is less, compare with the nanoparticle compositions existing routine that comprises Ziprasidone, non-, nanoparticle compositions display of the present invention the bioavailability that increases and the Ziprasidone that needs smaller dose.In one embodiment of the invention, the bioavailability of nanoparticle compositions of the present invention is than the Ziprasidone of using in regular dosage form high about 50%.In other embodiments, the bioavailability of nanoparticle compositions of the present invention ratio Ziprasidone in regular dosage form high about 40%, high about 30%, high about 20% or height about 10%.
When measuring after using predose to mammalian subject, this nanoparticle compositions also can have the pharmacokinetic curve of expectation.The pharmacokinetic curve of the expectation of said composition includes but not limited to: (1) when using the blood plasma of post analysis mammalian subject, the C of preferred Ziprasidone MaxC greater than the non-nanoparticle compositions of the identical Ziprasidone of using same dose MaxAnd/or (2) when using the blood plasma of post analysis mammalian subject, and the AUC of preferred Ziprasidone is greater than the AUC of the non-nanoparticle compositions of the identical Ziprasidone of using same dose; And/or (3) when using the blood plasma of post analysis mammalian subject, the T of preferred Ziprasidone MaxT less than the non-nanoparticle compositions of the identical Ziprasidone of using same dose Max
In one embodiment of the invention, with respect to the T of the non-nanoparticle compositions of the identical Ziprasidone of same dose Max, nanoparticle compositions display of the present invention goes out, for example the T of its Ziprasidone that comprises MaxBe no more than its about 90%.In other embodiments of the present invention, with respect to the T of the non-nanoparticle compositions of the identical Ziprasidone of same dose Max, nanoparticle compositions display of the present invention goes out, for example the T of its Ziprasidone that comprises MaxBe no more than the about 80% of its, be no more than the about 70% of its, be no more than the about 60% of its, be no more than its about 50%, be no more than the about 30% of its, be no more than the about 25% of its, be no more than its about 20%, be no more than the about 15% of its, be no more than the about 10% of its, or be no more than its about 5%.In one embodiment of the invention, the T of Ziprasidone when analyzing the blood plasma of mammalian subject MaxBe to use the back less than about 6 to about 8 hours.In other embodiments of the present invention, the T of Ziprasidone MaxBe to use the back less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour or less than about 30 minutes.
In one embodiment of the invention, with respect to the C of the non-nanoparticle compositions of the identical Ziprasidone of same dose Max, nanoparticle compositions display of the present invention goes out, for example the C of its Ziprasidone that comprises MaxBe at least its about 50%.In other embodiments of the present invention, with respect to the C of the non-nanoparticle compositions of the identical Ziprasidone of same dose Max, nanoparticle compositions display of the present invention goes out, for example the C of its Ziprasidone that comprises MaxBigger than it at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, at least about 1900%.
In one embodiment of the invention, with respect to the AUC of the non-nanoparticle compositions of the identical Ziprasidone of same dose, nanoparticle compositions display of the present invention goes out, and for example the AUC of its Ziprasidone that comprises is bigger at least about 25% than it.In other embodiments of the present invention, with respect to the AUC of the non-nanoparticle compositions of the identical Ziprasidone of same dose, nanoparticle compositions display of the present invention goes out, for example the AUC of its Ziprasidone that comprises is bigger at least about 50% than it, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200%.
The present invention includes a kind of nanoparticle compositions, wherein, do not absorbed patient's the feed of said composition or the influence of fasting state substantially at the pharmacokinetic curve of using the back Ziprasidone.This means, when on the feed with fasting state under when using this nanoparticle compositions, the speed that amount that Ziprasidone absorbs or Ziprasidone absorb does not have difference basically.Ziprasidone formulations in routine is
Figure BSA00000156166500111
In, when using with food, the absorption of Ziprasidone increases.This absorption difference that observes in the ziprasidone formulations of routine does not want have.Ziprasidone formulations of the present invention has overcome this problem.
Basically the advantage of having eliminated the dosage form of food effect comprises that patient's convenience strengthens, and has therefore strengthened patient's compliance, because the patient does not need to guarantee that they take this dosage when taking food on the feed or not.This is very important, because follow patient's compliance relatively poor, observes the medical conditions enhancing that Ziprasidone will be treated.
The present invention also comprises the nanoparticle compositions that comprises Ziprasidone, wherein said composition is applied to patient's bioequivalence under the fasting state in compositions being applied to patient under the feed state.
When on the feed with fasting state under when using, the absorption difference of compositions of the present invention is preferably less than about 100%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.
In one embodiment of the invention, the present invention includes the compositions that comprises Ziprasidone, wherein said composition is applied to patient under the fasting state and is equivalent to compositions is applied to patient under the feed state, particularly according to the C of U.S. food and drug administration and corresponding European administrative organization (EMEA) guide MaxDefine with AUC.At the U.S. FDA guide, if AUC and C MaxThen two kinds of products or method are equivalent (for the purpose of regulating, T between 0.80 to 1.25 in 90% confidence interval (CI) MaxMeasured value and bioequivalence are irrelevant).According to the two kinds of chemical compounds of guide demonstration of European EMEA or the bioequivalence between the application conditions, the 90%CI of AUC must be between 0.80 to 1.25, C Max90%CI must be between 0.70 to 1.43.
Nanoparticle compositions of the present invention is to be intended to have beat all, noticeable solubility curve.Preferred Ziprasidone is rapidly-soluble, because dissolved fast more, it is rapid more generally to begin effect, and bioavailability is high more.For solubility curve and the bioavailability of improving Ziprasidone, the dissolving that strengthens Ziprasidone is useful, so that it can reach the level near 100%.
The solubility curve that compositions of the present invention preferably has is: the Ziprasidone at least about 20% in about 5 minutes dissolves.In other embodiments of the present invention, dissolve in about 5 minutes at least about 30% or about 40% Ziprasidone.In other embodiments of the present invention, preferably at least about 40%,,,, or in about 10 minutes, dissolve at least about 80% Ziprasidone at least about 70% at least about 60% at least about 50%.At last, in another embodiment of the invention,,,, or in about 20 minutes, dissolve at least about 100% Ziprasidone at least about 90% at least about 80% preferably at least about 70%.
Preferably in identifiable medium, measure dissolving.For two kinds of very different products of solubility curve in gastric juice, this dissolve medium will produce two very different solubility curves; That is, this dissolve medium can dissolve in the body of prediction group compound.A kind of exemplary dissolve medium is the aqueous medium that comprises the surfactant sodium laurylsulfate of 0.025M.Can carry out determining of meltage by spectrophotography.Can measure dissolving with pivoting leaf method (European Pharmacopoeia).
Another feature of nanoparticle combination of compositions thing of the present invention is, its granule can redispersion, so that this particulate effective mean diameter is that diameter is less than about 2000nm.This is very important, because if this granule can not redispersion so that effectively mean diameter be diameter less than about 2000nm, said composition will be lost owing to general's Ziprasidone wherein is mixed with the benefit that the nanoparticle form obtains so.This is that to comprise Ziprasidone alive particulate than small particle diameter because the nanoparticle compositions is benefited from.If this granule can not become smaller particle size by redispersion after using, because very high surface free energy and the thermodynamic driving force of nanoparticle system can cause free energy totally to reduce, so the granule of their meetings " in bulk " or formation reunion.When these agglomerated particles formed, the bioavailability of this dosage form can greatly be reduced to below the bioavailability that observes in the liquid dispersion form of nanoparticle compositions.
In other embodiments of the present invention, when passing through light scattering method, when microscopy or other suitable methods were measured, redispersion granule of the present invention was (at water, biological dependency medium or any other suitable liquid medium) effective mean diameter be that diameter is less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 75nm or less than about 50nm.These methods that are fit to the effective mean diameter of mensuration are that those of ordinary skills are known.
Can measure redispersibility with any proper method known in the art.Referring to the U.S. patent 6 that for example is entitled as " Solid Dose nanoparticle Compositions Comprising aSynergistic Combination of a Polymeric Surface Stabilizer andDioctyl Sodium Sulfosuccinate ", 375,986 embodiment part.
Nanoparticle compositions of the present invention has for example shown noticeable redispersibility behind the human or animal being applied to mammal, this can obtain proof by the reconstruction/redispersion in biological dependency aqueous medium, so that the particulate effective mean diameter of redispersion is that diameter is less than about 2000nm.This biology dependency aqueous medium can be to show the ionic strength of expectation and any aqueous medium of pH, and it has formed the basis of the biological dependency of medium.The pH of expectation and ionic strength be in the physiological condition in the human body representational those.These biological dependency aqueous mediums can be pH and for example aqueous electrolyte solution of ionic strength or aqueous solution or its combinations of any salt, acid or alkali that shows expectation.
Biological dependency pH is well known in the art.For example, the scope of pH is high to 4 or 5 from being slightly less than 2 (but usually greater than 1) under one's belt.In small intestinal, the scope of pH is 4 to 6, and in colon, its scope is 6 to 8.Biological dependency ionic strength also is well known in the art.Under the fasting state ionic strength of gastric juice be about 0.1M and under the fasting state ionic strength of intestinal juice be about 0.14.Referring to, people such as Lindahl for example, " Characterization of Fluidfrim the Stomach and Proximal Jejumum in Men andWomen ", Pharm.Res., 14 (4): 497-502 (1997).It is believed that pH and the ionic strength of being tried solution are more more crucial than concrete chemical contents.Therefore, can obtain suitable pH and ionic strength value by strong acid, highly basic, salt, single or multiple conjugation Acid-Base to a lot of combinations of (that is the corresponding salt of weak acid and this acid), monobasic and multicomponent electrolyte or the like.
Representational electrolyte solution can be, but be not limited to NaCl solution and its mixture of the HCl solution of concentration range about 0.001 to about 0.1N and concentration range about 0.001 to about 0.1M.For example, electrolyte solution can be, but be not limited to about 0.1N or littler HCl, about 0.01N or littler HCl, about 0.001N or littler HCl, about 0.1M or littler NaCl, about 0.01M or littler NaCl, about 0.001M or littler NaCl, and composition thereof.In these electrolyte solutions, because pH and ionic strength conditions be near gastrointestinal tract, 0.01NHCl and/or 0.1M NaCl are the most representative examples of human physiology condition of fasting.
0.001N the electrolyte concentration of HCl, 0.01N HCl and 0.1N HCl corresponds respectively to pH 3, pH 2 and pH 1.Therefore, the 0.01NHCl solutions simulate typical stomach acidity condition.0.1M the solution of NaCl reasonably is similar to whole body, comprises the ionic strength conditions of gastro-intestinal Fluid, although can use the feed condition that surpasses in the concentration of analog people GI road of 0.1M.
The solution of the pH of exemplary demonstration expectation and salt, acid, alkali or its combination of ionic strength includes but not limited to, the sodium of phosphoric acid/phosphate+chlorine, potassium and calcium salt, the sodium of acetic acid/acetate+chlorine, potassium and calcium salt, the sodium of carbonate+chlorine, potassium and calcium salt, and the sodium of citric acid/citrate+chlorine, potassium and calcium salt.
As mentioned above, said composition also comprises at least a surface stabilizer.This surface stabilizer can adsorb, or is attached to the particle surface that comprises Ziprasidone.Preferably, this surface stabilizer preferably adsorbs or is connected to particulate surface, rather than with granule or with other surface-stable agent molecule generation chemical reactions.The molecule of each absorption of this surface stabilizer does not have intermolecular interconnection basically.
It is extensively different being present in the Ziprasidone of combination species of the present invention and the relative quantity of surface stabilizer.The optional amount of each component can depend on, surface tension of for example selected among other things concrete medicine, hydrophilic-lipophilic balance (HLB), fusing point and stabilizing agent aqueous solution or the like.Based on total mixed weight of Ziprasidone and surface stabilizer, and do not comprise other excipient, ziprasidone concentration can be different, and from about 99.5% to about 0.001%, about 95% to about 0.1% or about 90% to about 0.5 weight %.Based on total mixing dry weight of Ziprasidone or its salt or derivant and surface stabilizer, and do not comprise other excipient, the concentration of surface stabilizer can be different, and from about 0.5% to about 99.999%, about 5.0% to about 99.9% or about 10% to about 99.5 weight %.
For Ziprasidone, the selection of surface stabilizer is not footy, requires to test widely to make required preparation.Therefore, the present invention relates to beat all discovery: can prepare the nanoparticle compositions that comprises Ziprasidone.
Can use the combination of more than one surface stabilizer in the present invention.The useful surface stabilizer that can use in the present invention includes but not limited to, known organic and inorganic drug excipient.These excipient comprise various polymer, low-molecular-weight oligomer, natural product and surfactant.Surface stabilizer comprises nonionic, anion, cation, ion and zwitterionic surfactant.
The representative example of surface stabilizer comprises hydroxypropyl emthylcellulose (now being called hypromellose), hydroxypropyl cellulose, polyvinylpyrrolidone, sodium laurylsulfate, the dioctyl sulfosuccinate, gelatin, casein, lecithin (phospholipid), glucosan, arabic gum, cholesterol, the tragakanta, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, the octadecanol hexadecanol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example, polyglycol ether is cetomacrogol 1000 for example), castor oil derivatives, polyoxyethylene sorbitan fatty acid ester is (for example, commercially available
Figure BSA00000156166500151
For example, Tween
Figure BSA00000156166500152
And Tween
Figure BSA00000156166500153
(ICI Speciality Chemicals)); Polyethylene Glycol (for example, Carbowaxs
Figure BSA00000156166500154
With
Figure BSA00000156166500155
(Union Carbide)), Myrj 45, silicon dioxide colloid, phosphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl methyl O-phthalic acid cellulose, non-microcrystalline Cellulose, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3, the 3-tetramethyl butyl)-polymer (being also referred to as tyloxapol, superione and triton), poloxamer (for example, the Pluronics of phenol and oxirane and formaldehyde
Figure BSA00000156166500156
With
Figure BSA00000156166500157
They are block copolymers of oxirane and expoxy propane); Poloxamines (for example, Tetronic
Figure BSA00000156166500158
Be also referred to as Poloxamine
Figure BSA00000156166500159
Be to add expoxy propane and oxirane continuously and the four-functional group block copolymer that obtains (BASF Wyandotte Corporation, Parsippany, NJ.)) to aminophylline; Teronic
Figure BSA00000156166500161
(T-1508) (BASF Wyandotte Corporation), Tritons X-
Figure BSA00000156166500162
It is alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F- It is the mixture (Croda Inc.) of sucrose stearate and sucrose distearate; Right-different Nonylphenoxy gathers-((+)-2,3-Epoxy-1-propanol), is also referred to as Olin- Or Surfactant 10-
Figure BSA00000156166500165
(OHn Chemicals, Stamford, CT); Crodestas SL- (Croda, Inc.); And SA9OHCO, it is C 18H 37CH 2(CON (CH 3)-CH 2(CHOH) 4(CH 2OH) 2(Eastman Kodak Co.); Capryl-N-methyl glucoside amine; Positive decyl β-D-pyranglucoside; Positive decyl β-D-pyrans maltoside; Positive lauryl β-D-pyranglucoside; Positive lauryl β-D-maltoside; Heptanoyl group-N-methyl glucoside amine; N-heptyl-β-D-pyranglucoside; N-heptyl β-D-thioglycoside; N-hexyl β-D-pyranglucoside; Pelargonyl group-N-methyl glucoside amine; Pelargonyl group β-D-pyranglucoside; Caprylyl-N-methyl glucoside amine; N-octyl-β-D-pyranglucoside; Octyl group β-D-pyrans thioglycoside; Randomcopolymer of PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, vinylpyrrolidone and vinyl acetate or the like.
The ion of useful cationic surface stabilizing agent includes but not limited to, polymer, biopolymer, polysaccharide, cellulose family, alginate, phospholipid and non-polymerization chemical compound, amphoteric ion type stabilizing agent for example, poly--the n-picoline, chlorination anthryl pyridine, cationic phospholipid, chitosan, polylysine, polyvinyl imidazole, polybrene, Diethylaminoethyl acrylic acid poly-methyl ester trimethylammonium bromide (PMMTMABr), hexyl desyl,a-phenyl phenacyl trimethylammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
Other useful cationic stabilized agent include but not limited to, cation lipid, sulfonium, Phosphonium and quaternary ammonium compound, for example stearyl trimethyl ammonium chloride, benzyl-two (2-chloroethyl) ethyl ammonium bromide, Cortex cocois radicis trimethyl chlorine or bromine ammonium, Cortex cocois radicis methyl dihydroxy ethyl chlorine or bromine ammonium, decyl triethyl ammonium chloride, decyl dimethyl hydroxyl ethyl chloride or ammonium bromide, C 12-15Dimethyl hydroxyl ethyl chloride or ammonium bromide, Cortex cocois radicis dimethyl hydroxyl ethyl chloride or ammonium bromide, myristyl trimethyl ammonium methylsulfuric acid ester, lauryl dimethyl benzyl chloride or ammonium bromide, lauryl dimethyl (ethyleneoxy) 4Chlorine or bromine ammonium, N-alkyl (C 12-18) dimethyl benzyl ammonium chloride, N-alkyl (C 14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide, alkyl-leptodactyline and dialkyl group-dimethyl ammonium, lauryl trimethyl ammonium chloride, ethoxylated alkyl amidoalkyl dialkyl ammonium salt and/or ethoxylation trialkyl ammonium salts, dialkyl benzene dialkylammonium chloride, N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride and lauryl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C 12, C 15, C 17Trimethylammonium bromide, lauryl benzyltriethylammoinium chloride, poly--diallyldimethylammonium chloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, hexatriacontane ylmethyl ammonium chloride, decyl trimethylammonium bromide, lauryl triethyl group ammonium bromide, four decyl trimethylammonium bromides, (ALIQUAT 336 for methyl trioctylphosphine ammonium chloride TM), POLYQUAT 10 TM, tetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester (for example cholinester of fatty acid), benzalkonium chloride, the stearic alkane ammonium compounds (for example stearoyl three monium chlorine and distearyl two monium chlorine) of chlorination, bromine or cetylpyridinium chloride, halogeno salt, the MIRAPOL of oxozone ethyl alkylamine TMWith ALKAQUA T TM(AlkarilChemical Company), Fixanol; Amine, for example alkylamine, dialkylamine, alkanoyl amine, polyethylenepolyamine, N, N-dialkyl amino alkyl acrylate and vinylpyridine, amine salt be acetic acid lauryl amine, stearylamine acetate, Fixanol and alkyl imidazole salt and amine oxide for example; Acid imide azolinium salt; Protonated tetrapropylene amide; Methylated tetravalence polymer, for example poly-[diallyldimethylammonium chloride] and poly--[N-ethylene methacrylic yl pyridines chlorine]; And cation guar gum.
These exemplary cationic surface stabilizing agents and other useful cationic surface stabilizing agents are at J.Cross and E.Singer, Cationic Surfactants:Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D.Rubingh (Editor), Cationic Surfactants:Physical Chemistry (MarcelDekker, 1991); And J.Richmond, Cationic Surfactants:OrganicChemistry is described in (Marcel Dekker, 1990).
The non-polymerization surface stabilizer is non-polymeric arbitrarily type chemical compound, for example the organic compound, phosphonium compounds of benzalkonium chloride, positively charged, oxygen compound, halogen compound, cation organo-metallic compound, tetravalence phosphorus compound, pyridine compounds, aniline compound, ammonium compounds, hydroxyl ammonium compounds, uncle's ammonium compounds, secondary ammonium compounds, tertiary amine chemical compound and structural formula NR 1R 2R 3R 4 (+)Quaternary ammonium compound.For structural formula NR 1R 2R 3R 4 (+)Chemical compound:
(i) R 1-R 4Not CH 3
(ii) R 1-R 4In one be CH 3
(iii) R 1-R 4In three be CH 3
(iv) R 1-R 4All be CH 3
(v) R 1-R 4In two be CH 3, R 1-R 4In one be C 6H 5CH 2, and R 1-R 4In one be 7 or the alkyl chain of carbon atom still less;
(vi) R 1-R 4In two be CH 3, R 1-R 4In one be C 6H 5CH 2, and R 1-R 4In one be the alkyl chain of 19 or more a plurality of carbon atoms;
(vii) R 1-R 4In two be CH 3, R 1-R 4In one be group C 6H 5(CH 2) n, n＞1 wherein;
(viii) R 1-R 4In two be CH 3, R 1-R 4In one be C 6H 5CH 2And R 1-R 4In one comprise at least one hetero atom;
(ix) R 1-R 4In two be CH 3, R 1-R 4In one be C 6H 5CH 2And R 1-R 4In one comprise at least one halogen;
(x) R 1-R 4In two be CH 3, R 1-R 4In one be C 6H 5CH 2And R 1-R 4In one comprise at least one ring plate section;
(xi) R 1-R 4In two be CH 3, R 1-R 4One among the x is phenyl ring; Or
(xii) R 1-R 4In two be CH 3, R 1-R 4In two be pure fatty fragment.
These chemical compounds include but not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride Yu chlorination triamine, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenaminechloride (Quateraium-15), distearyl trimethyl ammonium chloride (Quaternium-5), lauryl dimethyl ethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, hydrochloric acid dimethyl aminoethyl chlorine, cysteine hydrochloride, the oily ether phosphate of diethanol ammonium POE (10), the oily ether phosphate of diethanol ammonium POE (3), chlorination tallow benzene diformazan hydrocarbon ammonium, dimethyl two hot decyl ammonium bentonite, stearyl chloride, Bradosol Bromide, denatonium benzoate, the myristyl dimethyl benzyl ammonium chloride, Dodecyl trimethyl ammonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine hydrochloride, iofetamine hydrochloride, the hydrochloric acid meglumine, methylbenzethonium chloride, the myristyl trimethylammonium bromide, the oil base trimethyl ammonium chloride, polyquaternary ammonium salt-1, procaine hydrochloride, the Cortex cocois radicis betanin, the oronain bentonite draws in department, the oronain hectorite draws in department, two hydrofluorination stearoyl trihydroxy ethyl trimethylene diamines, Adeps Bovis seu Bubali base trimethyl ammonium chloride and six decyl trimethylammonium bromides.
Surface stabilizer is commercially available and/or can prepares by technology known in the art.Most surface stabilizer is the known drug excipient, and in the theHandbook of Pharmaceutical Excipients that the AmericanPharmaceutical Association and The Pharmaceutical Society ofGreat Britain (The Pharmaceutical Press, 2000) co-publicate, be described in detail.
Except Ziprasidone, compositions of the present invention can comprise one or more chemical compounds that is used for the treatment of schizophrenia or similar mental disorder and associated conditions.Said composition also can be co-administered with this chemical compound.These other reactive compounds preferably include be used for the treatment of the health disease for example have a headache, generate heat, painful or generally by schizophrenia and similar those chemical compounds of other similar conditions of causing of psychiatric disturbance.These reactive compounds should determine that it can not disturb the mode of the therapeutic effect of Ziprasidone to exist with those skilled in the art.
Compositions of the present invention also can comprise one or more binding agents, filler, diluent, lubricant, emulsifying agent and suspending agent, sweeting agent, flavoring agent, antiseptic, buffer agent, wetting agent, disintegrating agent, foaming agent, aromatic and other excipient.These excipient are known in the art.In addition, various antibiotic for example parabens, chlorobutanol, phenol, sorbic acid or the like can guarantee to stop microbial growth with antifungal by adding.When using in injectable formulation, said composition can comprise isotonic agent for example sugar, sodium chloride or the like, and postpones reagent that the injectable drug dosage form absorbs for example aluminum monostearate and gelatin.
The example of filler is lactose monohydrate, Lactis Anhydrous and various starch; The example of binding agent be various starch and crospolyvinylpyrrolidone, microcrystalline Cellulose for example
Figure BSA00000156166500191
PH101 and
Figure BSA00000156166500192
Microcrystalline Cellulose (the ProSolvSMCC of PH 102, microcrystalline Cellulose and silication TM).
Suitable lubricant comprises that influence wants the reagent of the flowability of pressed powder, be silicon dioxide for example
Figure BSA00000156166500193
200, Talcum, stearic acid, magnesium stearate, calcium stearate and silica gel.
The example of sweeting agent is any natural or synthetical sweeting agent, for example sucrose, xylitol, saccharin sodium, cyclamate, aspartame and acesulfame.The example of flavoring agent is
Figure BSA00000156166500201
(trade mark is MAFCO), bubble gum flavor, flavoring agent of fruit etc.
Examples of preservatives is other esters butoben, alcohol second or benzylalcohol, phenolic compound phenol for example for example for example of potassium sorbate, methyl hydroxybenzoate, propylparaben, benzoic acid and salt thereof, P-hydroxybenzoic acid, or quaternary ammonium compound benzalkonium chloride for example.
The suitable dilution agent comprises the acceptable inert filler of pharmacy, for example the mixture of microcrystalline Cellulose, lactose, Bibasic Calcium Phosphate, sugar and/or any above-mentioned substance.The example of diluent comprises that microcrystalline Cellulose for example
Figure BSA00000156166500202
PH101 and PH102; Lactose for example lactose monohydrate, Lactis Anhydrous and
Figure BSA00000156166500204
DCL21; Bibasic Calcium Phosphate for example
Figure BSA00000156166500205
Mannitol; Starch; Sorbitol; Sucrose; And glucose.
Suitable disintegrating agent comprises slight crosslinked polyvinylpyrrolidone, corn starch, potato starch, corn starch and modified starch, cross-linking sodium carboxymethyl cellulose, crospovidone, primojel and their mixture.
The example of foaming agent is that foaming is to for example organic acid plus carbonate or bicarbonate.Suitable organic acid comprises, for example lactic acid, tartaric acid, malic acid, Fumaric acid, adipic acid, succinic acid and alginic acid and anhydride and hydrochlorate.Suitable carbonate and bicarbonate comprise, for example sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate.Alternately, can only there be the right sodium bicarbonate component of foaming.
Compositions of the present invention can comprise carrier, adjuvant or inert matter (hereinafter, being referred to as " carrier ").
Can for example use, grinding, homogenize, precipitation, lyophilizing or plate emulsifying technology prepare this nanoparticle compositions.The illustrative methods of preparation nanoparticle compositions is described in ' 684 patents.The illustrative methods of preparation nanoparticle compositions has also been described: patent 5,518,187 in following document; 5,718,388; 5,862,999; 5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; 5,510,118; With 5,470,583.
In a method, the Dispersion of Particles that will comprise Ziprasidone is in the liquid dispersion medium of Ziprasidone indissoluble.In the presence of abrasive media, use mechanical means particle diameter to be decreased to the effective mean diameter that needs then.Disperse medium can be, for example, and water, safflower oil, ethanol, the tert-butyl alcohol, glycerol, Polyethylene Glycol (PEG), hexane or ethylene glycol.Preferred disperse medium is a water.Can in the presence of at least a surface stabilizer, reduce particulate size.The granule that can will comprise Ziprasidone after grinding contacts with one or more surface stabilizers.In reducing the process of its particle diameter, can in Ziprasidone/surface stabilizer compositions, add other chemical compounds, for example diluent.Can prepare dispersion continuously or in a batch mode.It will be understood to those of skill in the art that in this case after grinding, not every granule all can be decreased to the size that needs.In this case, can isolate the granule with required size and be used to implement the present invention.
The another kind of method that forms the nanoparticle compositions that needs is the microprecipitation method.This is a kind of method for preparing the stabilising dispersions of slightly solubility Ziprasidone in the presence of surface stabilizer and one or more colloid-stabilised enhancing surfactants and when not comprising the toxic solvents of any trace or soluble beavy metal impurity.This method comprises that for example: (1) is dissolved in Ziprasidone in the appropriate solvent; (2) in the solution that comprises at least a surface stabilizer, add the preparation of step (1); (3) with the preparation of suitable non-solvent settling step (2).If exist, can be after this method by dialysis or diafiltration and concentrate this dispersion by conventional method and remove formed whole salt.
Also can be equipped with the nanoparticle compositions by the homogenize legal system.Exemplary homogenize method is in U.S. patent 5,510,118, is entitled as in " Process of Preparing Therapeuticcompositions Containing Nanoparticles " to be described.This method comprises the Dispersion of Particles that will comprise Ziprasidone in liquid dispersion medium, and this dispersion of homogenize is decreased to described particle diameter the effective mean diameter that needs then.Can in the presence of at least a surface stabilizer, reduce particulate size.Can before or after grinding, this granule be contacted with one or more surface stabilizers.Reduce its particle diameter cross the Cheng Qian, in or after, can in said composition, add other chemical compounds, for example diluent.Can prepare dispersion continuously or in a batch mode.
The another kind of method that forms the nanoparticle compositions that needs is that spraying is lyophilized into liquid (SFL).This method comprises that the organic or organic aqueous solution with Ziprasidone and surface stabilizer is expelled in cooling liquid style such as the liquid nitrogen.To be enough to the making speed of crystallization and germination minimum freeze the microdroplet that this comprises ziprasidone solution, formed the granule of nano-architecture like this.According to selected solvent system and treatment conditions, this granule can have different particle shapes.In separating step, avoiding removing denitrification and solvent under particle aggregation or the sophisticated condition.
As the compensation process of SFL, also can form equivalent nano-architecture granule with ultrafast lyophilization (URF) with the surface area that extremely increases.URF comprise take Ziprasidone with mixable, anhydrous, organic or organic aqueous solution of water and surface stabilizer, on the substrate that is applied to lower the temperature.Remove by for example lyophilizing or atmosphere lyophilization then and desolvate the granule of remaining resulting nanoparticle structure.
The another kind of method that forms the nanoparticle compositions that needs is the plate emulsion process.The plate emulsion process is prepared the granule of the nano-architecture with controlled particle size distribution and quick dissolution properties.This method comprises prepares oil-in-water emulsion, then with the non-aqueous solution swelling that comprises Ziprasidone and surface stabilizer.This particle grain size distribution is the direct result of Emulsion droplet size before being written into the Emulsion that comprises medicine.This particle diameter is controlled and optimizes in this process.In addition, by selecting to use solvent and stabilizing agent, in the stability that does not have or suppress to have realized under the Ostwald ripening Emulsion.Subsequently, remove and desolvate and water, recover stable nano-architecture granule.Can realize different particle shapes by control treatment condition suitably.
The invention provides a kind of method, comprise the nanoparticle compositions that comprises Ziprasidone of using effective dose.
Compositions of the present invention (for example can be mixed with parenteral, vein, intramuscular or subcutaneous), oral (for example solid, liquid or aerosol form, vagina), in intranasal, rectum, ear, eye, part (for example, powder, ointment or drop), containing, the brain pond, intraperitoneal or local application etc.
This nanoparticle compositions can be used with solid or liquid dosage form, for example liquid dispersion, gel, aerosol, ointment, long-acting medicament, emulsifiable paste, sustained release preparation, fast melt preparation, lyophilized formulations, tablet, capsule, delayed release preparation, prolongation delivery formulations, pulsed delivery formulations, mixed type discharges immediately and sustained release preparation or the like.
The compositions that is fit to the parenteral injection can comprise the acceptable sterile aqueous of physiology or non-aqueous solution, dispersion liquid, suspension or Emulsion, with the sterilized powder that can remake into sterile injectable solution or dispersion liquid.The example of suitable aqueous or non-aqueous carrier, diluent, solvent or inert matter comprises for example ethyl oleate of water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol or the like), its suitable mixture, vegetable oil (for example olive oil) and injectable organic ester.Can be for example by using for example lecithin of coating, by in dispersion liquid, keeping the particle diameter that needs and by using surfactant to keep suitable flowability.
Oral solid dosage forms includes but not limited to, capsule, tablet, pill, powder and granule, this solid dosage forms can be for example melt preparation, sustained release preparation, lyophilized preparation, delayed release preparation, prolongation delivery formulations, pulsed delivery formulations fast, mixed type discharges immediately and sustained release preparation or its combination.Preferred solid tablet.In these solid dosage formss, activating agent mixes with at least a following material: (a) one or more inert excipients (or carrier), for example sodium citrate or dicalcium phosphate; (b) filler or extender, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (c) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (d) wetting agent, for example glycerol; (e) disintegrating agent, for example agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some composition silicate and sodium carbonate; (f) solution retarder paraffin for example; (g) absorption enhancer, for example quaternary ammonium compound; (h) wetting agent, for example hexadecanol and glyceryl monostearate; (i) adsorbent, for example Kaolin and bentonite; (j) lubricant, for example Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium laurylsulfate or its mixture.For capsule, tablet and pill, this dosage form also can comprise buffer agent.
Oral liquid dosage form comprises the acceptable Emulsion of pharmacy, solution, suspension, syrup and elixir.Except Ziprasidone, liquid dosage form can comprise this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent.Exemplary emulsifying agent is ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl formamide, oil is Oleum Gossypii semen for example, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, the fatty acid ester of Oleum Ricini and Oleum sesami, glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol, sorbitan or mixture of these materials or the like.
Those of ordinary skill will be understood that, can rule of thumb come to determine the treatment effective dose of Ziprasidone.The actual dose level of Ziprasidone can be different in nanoparticle compositions of the present invention, so that the amount of this medicine that obtains can be replied for the treatment that concrete compositions and application process need to obtain effectively.Therefore, selected dosage level depends on the effectiveness of the therapeutic effect, route of administration of needs, the Ziprasidone used, required treatment persistent period and other factors.
Units dosage composition can comprise Ziprasidone or its about quantity of this tittle, can be used to constitute dosage every day.But, should be understood that any concrete patient's concrete dosage level depends on various factors: the cell that reach or the type of physiologic response and degree; The concrete reagent of being used or the activity of compositions; Employed concrete reagent or compositions; Patient's age, body weight, general health, sex and diet; The time of using of Ziprasidone, route of administration and excretion rate; The persistent period of treatment; With Ziprasidone associating or the reactive compound that uses simultaneously; And the known similar factor of field of medicaments.
II. the sustained release compositions that comprises Ziprasidone
The effectiveness of pharmaceutical compound in prevention and treatment morbid state depends on several factors, comprises the speed and the persistent period of sending chemical compound from dosage form to the patient.Given dosage form shows in the patient delivery rate and the combination of persistent period can be described as release profiles in its body, and according to the pharmaceutical compound of being used, it is relevant with blood plasma Chinese materia medica compound concentrations and persistent period.Because the speed of pharmacokinetic property biological example availability, absorption and the elimination of pharmaceutical compound changes, so release profiles and resulting curve of blood plasma have become the factor of thinking very important to designed effective treatment.
The release profiles of dosage form can demonstrate different rates of release and persistent period, can be continuous or pulse.The release profiles that successive release profiles comprises is that wherein a certain amount of one or more pharmaceutical compounds discharge continuously with constant or variable speed during whole dosing interval.The release profiles that the pulse release curve comprises is, wherein one or more pharmaceutical compounds of at least two discontinuous quantities are with different speed and/or discharge in differing time frames.For any given pharmaceutical compound or these combination of compounds, the release profiles of given dosage form has produced relevant curve of blood plasma in the patient.When two or more components of dosage form had different release profiles, it was the combination of individual release profiles that the release profiles of this dosage form is done as a whole, can be described as " multimodal ".Wherein release profiles with two-component dosage form of different release profiles of every kind of component can be described as " bimodal ", and wherein release profiles with three-component dosage form of different release profiles of every kind of component can be described as " three peaks ".
With the variable class that can be applicable to release profiles seemingly, patient's relevant curve of blood plasma has shown the plasma concentration level that pharmaceutical compound is constant or variable in the persistent period of effect, can be continuously or pulse.Successive release profiles comprises that all show peaked speed of single plasma concentration and the curve of blood plasma of persistent period.The curve of blood plasma that the pulse curve of blood plasma comprises is that wherein at least two higher plasma concentration levels of pharmaceutical compound are separated by lower plasma concentration level, can be described as " multimodal ".The pulse curve of blood plasma that shows two peaks can be described as " bimodal ", shows that the pulse curve of blood plasma at three peaks can be described as " three peaks ".According to, to the release profiles of small part according to individual components in the pharmacokinetics of the pharmaceutical compound that comprises in the dosage form and the dosage form, multimodal discharges.
In one embodiment, the invention provides granose change release composition, the nanoparticle that it is sent Ziprasidone or comprise Ziprasidone with pulse mode.This nanoparticle is a above-mentioned type, and comprises at least a surface stabilizer simultaneously.
In another embodiment, the invention provides granose change release composition, the nanoparticle that it is sent Ziprasidone in a continuous manner or comprises Ziprasidone.This nanoparticle is a above-mentioned type, and comprises at least a surface stabilizer simultaneously.
In another embodiment, the invention provides a kind of granose change release composition, wherein the Ziprasidone of first or the nanoparticle that comprises Ziprasidone discharge after using immediately, and the Ziprasidone of one or more further parts or the nanoparticle that comprises Ziprasidone postpone the back at initial time and discharge.
In another embodiment, the invention provides and use a kind of every day 1 time or use 2 times solid oral dosage form every day, comprise granose change release composition of the present invention.
In another embodiment, the invention provides a kind of method that prevents and/or treats schizophrenia and similar psychiatric disturbance, comprise and use compositions of the present invention.
In one embodiment, the invention provides a kind of granose change release composition, wherein forming granose granule is the nanoparticle granule of the above-mentioned type.When needs, this nanoparticle granule comprises change and discharges coating and/or change the release matrix material.
According to an aspect of the present invention, a kind of pharmaceutical composition is provided, have and comprise particulate first component that contains active component and comprise particulate at least one subsequent component that contains active component, every kind of subsequent component has rate of release and/or the persistent period different with first component, and wherein at least a described component comprises the granule that contains Ziprasidone.In one embodiment of the invention, form the nanoparticle granule that the granose granule that comprises Ziprasidone itself comprises the above-mentioned type, wherein this nanoparticle granule comprises Ziprasidone and also comprises at least a surface stabilizer.In another embodiment of the invention, the nanoparticle granule that comprises Ziprasidone and also comprise the above-mentioned type of at least a surface stabilizer itself is the granose granule that comprises medicine.The granule that comprises medicine can wrap quilt with changing the coating that discharges.Alternately or additionally, the granule that comprises medicine can comprise and changes the stroma ground substance that discharges.Behind oral delivery, send Ziprasidone with pulse mode or comprise the nanoparticle of Ziprasidone in said composition.In one embodiment, first component provides Ziprasidone that discharges immediately or the nanoparticle that comprises Ziprasidone, and one or more subsequent component provide the nanoparticle that changes the Ziprasidone that discharges or comprise Ziprasidone.In these embodiments, immediate-release component has the shortlyest promoted effect by making from being administered to the time of treatment between the effective plasma concentration level, one or more subsequent component can be used to make the change minimum of plasma concentration level, and/or keep the effective plasma concentration of treatment in whole dosing interval.
Change to discharge coating and/or change that particulate active component that the release matrix material can cause first to comprise active component discharges and the particulate active component that comprises active component of further part has a lag time between discharging.When a granule that comprises active component more than the part provided change to discharge, change release coating and/or change release matrix material had caused between the release of the particulate active component that comprises active component of different piece a lag time being arranged.By regulating the composition that changes composition and/or the amount that discharges coating and/or change employed change release matrix material and/or measuring the persistence length that changes these lag times.Therefore, the persistence length of lag time can be designed for the required curve of blood plasma of simulation.
Because change curve of blood plasma that release composition produces and be substantially similar to twice of continuous administration or the curve of blood plasma that produces of IR dosage form repeatedly using the back, therefore change release composition of the present invention is useful especially for using Ziprasidone.
According to another aspect of the present invention, said composition can be designed for the generation curve of blood plasma, and it makes and twice of continuous administration or the repeatedly minimum or disappearance of change of the relevant plasma concentration level of IR dosage form.In these embodiments, said composition can have immediate-release component with by making from being administered to the time of treatment between the effective plasma concentration level the shortest and facilitation, and has at least a change and discharge component to keep the effective plasma concentration level of treatment in whole dosing interval.
Active component in every kind of component can be identical or different.For example, compositions can comprise and only contains Ziprasidone or contain the component of the nanoparticle of Ziprasidone as active component.Alternately, compositions can comprise first component that contains Ziprasidone or contain the nanoparticle of Ziprasidone, contain Ziprasidone or contain the subsequent component with the co-administered active component of Ziprasidone of being fit to beyond the nanoparticle of Ziprasidone with at least a, perhaps contain Ziprasidone or contain first component and at least a subsequent component that contains Ziprasidone or contain the nanoparticle of Ziprasidone of the active component beyond the nanoparticle of Ziprasidone.Really, when mutual when compatible between the active component, two or more active component can be incorporated in the same composition.The active component that exists in a component of said composition can be attended by, and for example enhancing chemical compound in another component of said composition or enhanced sensitivity chemical compound are to change its bioavailability or therapeutic effect.
Term used herein " reinforcing agent " be meant a kind of energy by promote animal for example among the people by the clean output of GIT the absorption of enhanced activity composition and/or the chemical compound of bioavailability.Reinforcing agent includes but not limited to medium-chain fatty acid; Its salt, ester, ether and derivant comprise glyceride and triglyceride; Nonionic surfactant is for example by those of oxirane and fatty acid, aliphatic alcohol, alkyl phenol or sorbitan or fatty acid glyceride prepared in reaction; Cytochrome P 450 inhibitors, P-glycoprotein inhibitors or the like; And two or more mixture in these reagent.
Exist therein in those embodiments of the component that comprises more than one medicines, dosage regimen as required, the ratio of the Ziprasidone that comprises in every kind of component can be identical or different.The Ziprasidone that exists in first component and subsequent component can be any amount that is enough to produce the effective plasma concentration level of treatment.But when the time spent, Ziprasidone can exist with optical voidness stereoisomer basically or as mixture, the racemic mixture of two or more stereoisomers.Ziprasidone preferred amount in compositions is about 0.1 to about 500mg.In another embodiment, Ziprasidone preferred amount in compositions is about 1 to about 100mg.In another embodiment, the amount of Ziprasidone in first component is about 0.5 to about 60mg; In another embodiment, the amount of Ziprasidone in first component preferably about 2.5 to about 30mg.If be present in the subsequent component, the amount of Ziprasidone with the described similar scope of first component in.
The time release characteristic of sending Ziprasidone from each component can change by the composition that changes every kind of component, comprises existing arbitrarily excipient of change and/or coating.Especially, if there is coating, can discharge the composition of coating and/or the release that amount is controlled Ziprasidone by the change that changes on the granule.If exist more than a kind of change to discharge component, the change of each in these components discharges coating can be identical or different.Similarly, bring about changes when discharging, can pass through the selection of the change release matrix material used and the release that amount is controlled active component when change the release matrix material by embedding.It can be to measure arbitrarily that the change that exists in every kind of component discharges coating, as long as it is enough to make every kind of concrete component to obtain the time delay of needs.It can be to measure arbitrarily that the change that exists in every kind of component discharges coating, as long as it is enough to make the lag time that obtains needs between the component.
The lag time and/or the time delay that discharge Ziprasidone from every kind of component also can change by the composition that changes every kind of component, comprise excipient and coating that change may exist arbitrarily.For example, first component can be an immediate-release component, and wherein Ziprasidone discharges immediately after using.Alternately, first component can be the immediate-release component of time delay for example, and wherein Ziprasidone all discharges immediately basically after postponing a period of time.Second and subsequent component can be the immediate-release component of described time delay for example as just, or alternately, the lasting release of time delay or prolong and discharge component, wherein Ziprasidone time of going through prolongation with controllable mode discharges.
It will be understood to those of skill in the art that the exact nature of plasma concentration curve can be subjected to the influence of the combination of all above-mentioned factors.Especially, each lag time of sending between (and therefore also beginning effect) that comprises the Ziprasidone in the component of Ziprasidone can be controlled by the composition and the coating (if existence) that change every kind of component.Therefore, the composition (amount and the character that comprise active component) by changing every kind of component and by changing lag time can obtain a lot of release and curve of blood plasma.According to from every kind of component, discharge the character (promptly discharge immediately, continue to discharge or the like) that lag time length between the Ziprasidone and Ziprasidone discharge from every kind of component, curve of blood plasma can be successive (promptly, have single maximum) or wherein can in curve of blood plasma, separate well and clear (for example the definition, when time delay than long time) or the pulse at the peak of high superposed (for example, when time delay more in short-term).
When not needing to use two or more dosage device, use the single dosage device that comprises compositions of the present invention and the curve of blood plasma that produces is favourable when the two or more pulses that need delivering active ingredients.
Can use in required mode and change any coating substance that Ziprasidone discharges.Especially, the coating substance that is adapted at implementing using when of the present invention includes but not limited to the polymeric coatings material, for example Cellacefate, acetic acid three maleic acid celluloses, hydroxypropyl methyl O-phthalic acid cellulose, Opaseal, ammonio methacrylate copolymer are for example with trade mark
Figure BSA00000156166500291
With RL sells those, polyacrylic acid and polyacrylate and methacrylate copolymer are for example with trade mark
Figure BSA00000156166500292
With L sells those, polyethylene acetal diethylamino acetas, hydroxypropyl methyl cellulose acetate succinate, Lac; Hydrogel with become the glue material; for example carboxy vinyl polymer, sodium alginate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, polyvinyl alcohol, hydroxy ethyl cellulose, methylcellulose, gelatin, starch and based on cellulosic cross linked polymer-wherein the degree of cross linking is so low so that can promote the absorption of water and the expansion of polymeric matrix, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline Cellulose, chitin, aminoacyl-methacrylic acid copolymer (
Figure BSA00000156166500293
-PM, Rohm ﹠amp; Haas), pullulan, collagen, casein, agar, arabic gum, sodium carboxymethyl cellulose, (swellable hydrophilic polymer) gather (hydroxyalkyl methacrylic acid) (the about 5k-5 of mol.wt., 000k), polyvinylpyrrolidone (the about 10k-360k of mol.wt.), anion and cationic water gel, polyvinyl alcohol with rudimentary acetic acid residue, the swellable mixture of agar and carboxymethyl cellulose, maleic anhydride and cinnamic copolymer, ethylene, propylene or isobutene., pectin (the about 30k-300k of mol.wt.), polysaccharide is agar for example, arabic gum, karaya, the tragakanta, algin and guar gum, polyacrylamide;
Figure BSA00000156166500294
Poly(ethylene oxide) (the about 100k-5 of mol.wt., 000k),
Figure BSA00000156166500295
The diester of acrylate polymer, glucosan, the pure and mild poly N-vinyl-2-Pyrrolidone of crosslinked polyethylene, glucoamylase sodium are (for example
Figure BSA00000156166500296
Edward Mandell C.Ltd.); Hydrophilic polymer, for example polysaccharide, methylcellulose, sodium carboxy methyl cellulose or calcium, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, NC Nitroncellulose, carboxy methyl cellulose, cellulose ether, poly(ethylene oxide) are (for example,
Figure BSA00000156166500297
UnionCarbide), the copolymer of methylethylcellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid glyceride, polyacrylamide, polyacrylic acid, methacrylic acid or methacrylic acid are (for example Rohm and Haas), other acrylic acid derivative, sorbitan ester, natural gum, lecithin, pectin, alginate, ammonium alginate, sodium alginate, calcium, potassium, alginic acid propylene glycol, agar and natural gum for example arabic gum, karaya, locust bean, tragakanta, carrageenin, guar gum, flavochrome, scleroglucan and their mixture and admixture.Those skilled in the art will appreciate that and in coating, to add excipient for example plasticizer, lubricant, solvent or the like.Suitable plasticizer comprises for example acetyl monoglyceride; Butyl phthalyl butyl glycolate; Dibutyl tartrate; Diethyl phthalate; The phthalic acid dimethyl esters; Glycolic ethyl ethyl phthalate; Glycerol; Propylene glycol; Glyceryl triacetate; Citrate; Tripropioin; Diacetine; Dibutyl phthalate; Acetoglyceride one ester; Polyethylene Glycol; Oleum Ricini; Triethyl citrate; Polyhydric alcohol, glycerol, acetas, glyceryl triacetate, citric acid acetyl triethyl, dibenzyl phthalate, dihexylphthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, the tall oil acid epoxy-ester, triisooctyl trimellitate, the hexyl diethyl phthalate, dinoctyl phthalate, diisooctyl phthalate, diisooctyl phthalate, phthalic acid two n-undecane base esters, phthalic acid two n-tridecane esters, hexyl tri trimellitate-2-ethyl ester, hexyl adipic acid two-2-ethyl ester, hexyl decanedioic acid two-2-ethyl ester, hexyl Azelaic Acid two-2-ethyl ester, dibutyl sebacate.
Comprising when changing the release matrix material when change discharging component, can use the combination of any suitable change release matrix material or suitable change release matrix material.These materials are well known by persons skilled in the art.Term used herein " change release matrix material " comprises can change the hydrophilic polymer that is dispersed in external or intravital Ziprasidone or its salt or derivant and discharges, hydrophobic polymer and composition thereof.Be fit to implement change release matrix material of the present invention and include but not limited to, microcrystalline Cellulose, sodium carboxy methyl cellulose, hydroxy alkyl cellulose be for example methylcellulose and ethyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate-butyrate, Cellacefate, Cellulose acetotrimellitate, phthalic acid polyvinylacetate, poly-alkylmethacrylate, polyvinyl acetate and composition thereof of hydroxypropyl emthylcellulose and hydroxypropyl cellulose, polyethylene glycol oxide, alkylcellulose for example.
Change release composition according to the present invention can be incorporated in any suitable dosage form, and wherein this dosage form promotes that active component discharges with pulse mode.In one embodiment, this dosage form comprises the particulate admixture that comprises active component of different piece, and it constitutes to discharge immediately and to change and discharges component, and this admixture is filled into suitable capsule, for example firmly or in the Perle.Alternately, the granule that comprises active component of different various pieces can be suppressed (choosing the excipient with other wantonly) and become tabloid, then it is filled in the capsule in the proper ratio.Another kind of suitable dosage form is a multilayer tablet.In this case, first component that changes release composition can be pressed into one deck, adds the second layer of second component as multilayer tablet subsequently.The granule that constitutes the each several part of compositions of the present invention may further include at rapid-dissolve dosage form, for example effervescent dosage form or melt in the dosage form fast.
In one embodiment, said composition comprises at least two kinds of components that comprise Ziprasidone: first component and one or more subsequent component.In this embodiment, first component of compositions can show different release profiles, comprise that the nearly all Ziprasidone that wherein comprises in first component discharges immediately behind form of administration, but after postponing a period of time, discharge (postponing to discharge) immediately, or slowly discharge in a period of time.In such embodiment, the Ziprasidone that comprises in first component after being applied to the patient discharges rapidly." discharging rapidly " used herein comprises such release profiles, wherein the active component at least about 80% is being used back release in about 1 hour in the component, term " postpones release " and comprises such release profiles, wherein the active component of component discharges (quick or slow) after postponing a period of time, term " sustained release " and " prolong and discharge " comprise such release profiles, and wherein contained active component slowly discharges at least about 80% in the component.
Second component of these embodiments also shows a lot of release profiles, comprises release profiles, delay release profiles and sustained release curve immediately.In such embodiment, the second component display delay release profiles, wherein Ziprasidone discharges after postponing a period of time.
Immediate-release component and at least a change that comprises the nanoparticle that contains Ziprasidone or contain Ziprasidone that dosage form of the present invention comprises the nanoparticle that contains Ziprasidone or comprise Ziprasidone discharge component, use curve of blood plasma that this dosage form produces and be substantially similar to twice of continuous administration or the curve of blood plasma that produces of I R dosage form repeatedly, or be similar to and use IR respectively and change the curve of blood plasma that release dosage form produces.Therefore, dosage form of the present invention for use need keep pharmacokinetic parameter but be that problematic Ziprasidone is useful especially.
In one embodiment, said composition discharges Ziprasidone with the solid oral dosage form that comprises said composition, so that the whole basically Ziprasidones that are included in before Ziprasidone discharges from least a subsequent component in first component all discharge.When first component comprises the IR component, after for example preferred hangover of Ziprasidone from least a subsequent component to the whole Ziprasidones in the IR component have basically all discharged.Such as detailed description, can postpone the release of Ziprasidone from least a subsequent component by use to change discharging coating and/or changing the release matrix material.
When needs make the patient to the dosage regimen toleration of the first dosage drug withdrawal of the promotion patient whole body Ziprasidone that provided hour, the hangover of Ziprasidone from subsequent component, whole basically Ziprasidones in first component all discharge, and further postpone, until from patient's whole body, removing to the small part Ziprasidone of from first component, discharging.In one embodiment, even the release of Ziprasidone from the subsequent component of compositions is not completely, also be to be delayed to basically to use after the said composition at least about 2 hours.In another embodiment, even the release of Ziprasidone from the subsequent component of compositions is not completely, also be to be delayed to basically to use after the said composition at least about 4 hours.
As described below, the present invention also comprises various types of change delivery systems, and Ziprasidone can discharge with pulse or continuation mode by this system.These systems include but not limited to: containing Ziprasidone or comprising the film (monolithic devices) of the nanoparticle of Ziprasidone in polymeric matrix; Ziprasidone or the nanoparticle that comprises Ziprasidone are included in the system's (storage medicine device) in the polymer; The polymerization micelle or the microcapsule (microgranule, microsphere or nanoparticle) of storage medicine and matrix device form; But Ziprasidone or the nanoparticle that comprises Ziprasidone are included in and contain for example system in the polymer of second polymer, surfactant or plasticizer etc. of hydrophilic and/or filtration additives, can be by the device (storing medicine and matrix device) of infiltration " control " to obtain Multiple-Aperture Device or its Chinese medicine; Enteric coating (ionizing is also suitably being dissolved under the pH); With Ziprasidone molecule (covalency) bonded (soluble) polymer that dangles; Device with dynamic sustained release speed: osmotic pumps for example.
Delivery mechanism of the present invention will be controlled the rate of release of Ziprasidone.Although some mechanism discharge Ziprasidone with constant speed, other then are different, are for example to change Concentraton gradient or filtration causes the function of the time of porous additive or the like according to various factors.
Continuing to discharge the polymer that uses in the coating must be biocompatibility, is biodegradable in theory.The example of natural polymer for example
Figure BSA00000156166500331
(FMC Corporation, Food ﹠amp; Pharmaceutical Products Division, Philadelphia, USA) (mechanical ball changes into the ethyl cellulose of sub-micron, water base, puppet-latex dispersion) and in for example poly-(acrylate, methacrylate) the copolymer scope of synthetic polymer
Figure BSA00000156166500332
(
Figure BSA00000156166500333
Pharma is known in the art Weiterstadt.).
The storage medicine device
A typical approach that change to discharge is to incapsulate or medicine (for example, as nuclear) is completely contained in (that is microcapsule or spraying ,/dish coating is examined) in polymeric film or the coating.
The various factors that can influence diffusion process can easily be applied to store medicine device (for example effect of additive, functional (with consequent infiltration-pH value of solution), the porosity of polymer, film casting condition or the like), must think better of when therefore, medicine device is store in the selective polymer development.The model of setting up the wherein transportation of Ziprasidone and be the releasing properties of the storage medicine device (with monolithic devices) by solution diffusion mechanism generally includes relevant boundary condition Fick Two laws(labile state condition; The concentration dependent flux) solution.When this device comprised dissolved activating agent, because the concentration (activity) (i.e. the driving force of Shi Fanging) of reagent descends (being that one-level discharges) in this device, rate of release is exponential type in time to be increased.But if activating agent in saturated suspension the time, the driving force that discharges keeps constant no longer saturated until this device so.Alternately, the kinetics of rate of release can be that desorption is controlled, and is the subduplicate function of time.
Compare with the thin film that does not contain polymer, owing to can form the closure property (permeability) of the coating nuclear of osmotic pressure (it plays a role then tablet is infiltrated) in inside, the transportation character of coated tablet can strengthen.
After deliberation the effect of deionized water for the saliniferous tablet of bag of poly-by comprising (ethylene glycol) silicone elastomer bag quilt (PEG), also studied the effect of water for free film.Find that the release of salt from tablet is the immixture in the hole that diffuses through the water filling that forms of hydration and osmotic pumps by coating.The KCl transportation can be ignored by the film that only comprises 10%PEG, although similarly observing expansion widely in the free film, show that porous is necessary for the release of KCl, strides the hole diffusion then.Find discous coating salt sheet swelling in deionized water, owing to the generation of interior hydrostatic pressure changes over oblate spherical: the change of shape provides the method for measuring the power that is produced.As expected, penetration is along with the level of PEG content improves and reduces.Lower PEG level can make the water infiltration by hydrated polymer, and simultaneously, the hole that the coating dissolving produces when PEG content is higher level (20 to 40%) makes can alleviate the mobile pressure of KCl.
Developed method and equation, can be used for calculating because salt discharges the osmotic pumps that produces and strides the dispersive relative value in hole from tablet by the release of monitoring (independently) two kinds of different salt (for example KCl and NaCl).When lower PEG level, owing to only produce lower hole count density, osmotic flow is much larger than striding the film diffusion: when load 20%, two kinds of mechanism are to equate generally for the effect that discharges.But the generation of hydrostatic pressure has reduced infiltration and has flowed into and osmotic pumps.When the PEG load was higher, the hole that contains moisture film was more, and is less to the effusive resistance of salt.Therefore, although osmotic pumps strengthens (with low load time compare), stride the film diffusion and remain main releasing mechanism.Reported that also the infiltration releasing mechanism can be used to comprise the microcapsule of water-soluble core.
Monolithic devices (matrix device)
Skeleton (substrate) device can be used to control the release of medicine.This may be that they are easy to make relatively owing to compare with the storage medicine device, does not also have the danger of the unexpected high dose that the film rupture of storing medicine device causes.In this device, activating agent exists with dispersion in polymeric matrix, and they form by compacting polymer mixture or by dissolving or fusing typically.The administration releasing properties of monolithic devices depends on the dissolubility of medicine in polymeric matrix, perhaps in the situation of porous matrix, the dissolubility of the percolating solution in particulate pore network and the curvature of this network (being greatly increased than permeability of the membrane) depend on whether medicine is dispersed in the polymer or is dissolved in the polymer.For the low load (0 to 5%W/V) of medicine, medicine discharges by solution dispersal mechanism (not having the hole).When higher load (5 to 10%W/V), because drug loss, the existence by near form the apparatus surface hole makes the releasing mechanism complexity: thus release rate of drugs has been improved with the liquid filling in the environment in these holes.
Usually, to matrix device (with the storage medicine device) add plasticizer (for example poly-(ethylene glycol)), surfactant or adjuvant (promptly increasing the composition of effectiveness) as strengthen infiltrative method (although, on the contrary, plasticizer can be temporary transient, just help film to form, therefore, reduced permeability-a kind of character that in polymer-coated coating, more needs usually).The effect that should be noted in the discussion above that leaching PEG makes that (ethyl cellulose) permeability of the membrane strengthens linearly, and by increasing hole, it is the function of PEG load, and still, this film has kept their shield property, does not allow the electrolyte transmission.Can inference, infiltrative enhancing is the result that thickness that the PEG leaching causes effectively reduces.When the PEG of load 50%W/W, what this showed as per unit area accumulates the chart of osmotic flow as the function of the inverse of time and film thickness: (Fick) solution diffusion type transport mechanism in homogeneous membrane as expected, this chart understand that between the inverse of infiltration rate and film thickness be linear relationship.The linear zone of this figure has obtained positive intercept to the extended line of time shaft on time shaft: along with reducing of film thickness, its size is reduced to 0.Help the time delay of these changes two kinds of diffusion flows (Ziprasidone stream and PEG stream) to take place, also help time delay more generally during the penetrating agent concentration in the establishment film at the commitment of experiment.When using caffeine, shown minus time delay as penetrating agent.Also can't make explanations to this, but it should be noted that caffeine has shown lower partition coefficient in this system, this also is the feature of aniline infiltration by polyethylene film, and it has shown similarly negative time delay.
After deliberation the effect of the surfactant that added for (hydrophobic) matrix device.It is believed that surfactant increases drug release rate by three kinds of possible mechanism: (i) solubilising, (ii) improve to " wettability " of dissolve medium with (iii) because the leaching surfactant has formed the hole.(plastifying for the system of being studied by Sorbitol
Figure BSA00000156166500351
100 and RS 100, flurbiprofen is as medicine, the surfactant of certain limit), the moistening that can infer tablet improves and causes drug release that improve (it is diffusion that hint discharges, rather than controllably dissolving) of part only arranged, although this effect is
Figure BSA00000156166500352
Greater than
Figure BSA00000156166500353
Be those surfactants to discharging maximum influence simultaneously, they are easier to dissolving owing to producing to break in substrate, and this makes dissolve medium be easy near in the substrate.Since opposite when not containing surfactant, can easily prepare polymer emulsion with surfactant, obviously be relevant therefore with the research of the latex film that is suitable as drug coating.Found the difference-have only between these two kinds of polymer
Figure BSA00000156166500354
Show the mutual relation between anion/cationic surfactant and the medicine.This is the level difference owing to quaternary ammonium ion on polymer.
Also there is the substrate composed set composite of polymer that is coated in the polymer that does not comprise medicine.This device is by aqueous
Figure BSA00000156166500361
Emulsion constitutes, and finds that medicine can produce release continuously by shell diffusion from examine.Similarly, also made the polymer core that comprises medicine, but examined by this with the erodible shell bag of gastric juice.Find that release rate of drugs is linear relatively (function of the speed by shell restriction diffusion process), inversely proportional with the thickness of shell, on the contrary only find that the release meeting was slowed down along with the time from nuclear.
Microsphere
The method for preparing tiny balloon has been described.The ethanol/dichloromethane solution that comprises medicine and polymer by preparation prepares tiny balloon.After in pouring water into, formed the particulate emulsifying agent that comprises dispersive polymer/solvent by cohesion type process, ethanol obtains sealing the duricrust granule of the medicine that is dissolved in the dichloromethane at the surperficial rapid diffusion precipitation polymers of microdroplet thus.In granule, produced the gas phase of dichloromethane then, by after the shell diffusion, observed to the surface of the water bubble of emerging.Under reduced pressure hollow ball has been filled water, can remove by the drying of a period of time and anhydrate.In water, do not find medicine.High porosity matrix type microsphere has also been described.By medicine and polymer dissolution are prepared the matrix type microsphere in ethanol.Except water, ethanol disperses from the Emulsion microdroplet, the granule of remaining high porosity.The purposes of a suggestion of described microsphere is the floating drug delivery apparatus that uses under one's belt.
Device dangles
Developed and a kind of ester chain of poly-(acrylic acid) ester latex particle by aqueous emulsion polymerization preparation to a certain extent and adhere to for example method of analgesic and antidepressants or the like of medicine.When by ion exchange resin so that polymer end groups is when being transformed into their strong acid form, these latexes can self-catalysis ground hydrolysis by the ester chain discharge medicine.
Medicine is attached on the polymer, also with the medicine synthon that dangles that adheres to.Prepared dosage form; its Chinese medicine is incorporated into by unsettled chemical bonded refractory on the polymer of biocompatibility, for example by the polyanhydride of the acid anhydride preparation that replaces (by the prepared in reaction itself of acid chloride and medicine: the sodium salt of methacrylic chloride and methoxybenzoic acid) can be used for and second polymer
Figure BSA00000156166500362
Form substrate, wherein the hydrolysis in gastric juice of second polymer discharges medicine.The purposes of the polymerization Schiff alkali of the carrier that is suitable as medicine amine has also been described.
Enteric film
Enteric coating comprises the pH sensitive polymer.Usually, polymer is carboxylated, and under low pH and the effect between the water very little, under high pH, polymer ionsization causes the swelling or the dissolving of polymer simultaneously.Therefore, coating can be designed in the sour environment of stomach be kept perfectly (the protection Ziprasidone is avoided this environment or protected stomach to avoid the destruction of this medicine), but can dissolve in the more alkaline environment of intestinal.
The infiltration control device
Osmotic pumps is similar to the storage medicine device, but comprises the penetrating agent (for example activating agent of salt form) that water is penetrated into surrounding medium by semipermeable membrane.The device of " basic osmotic pumps " has also been described this being called.In device, produced pressure, this device comes out activating agent by the aperture from device, the size design in aperture makes the solution diffusion minimum, has prevented the growth of hydrostatic pressure head simultaneously, and this hydrostatic pressure head has the effect of the big small size that reduces osmotic pressure and modifier.Simultaneously, it is constant that the inner volume of device keeps, and excessive solid or saturated solution are arranged in device, and rate of release keeps constant so, and the volume of sending equals the volume of the solvent that absorbed.
The releasing device of electricity irritation
Go out monolithic devices with the polyelectrolyte preparing gel, described gel swelling when for example using external electric to stimulate causes pH to change.Can come adjustment release by changing applied electric current, obtain constant or the pulsed release profiles.
Hydrogel
Except they are used for the drug matrices, find that hydrogel can be used for a lot of biochemical purposes, for example soft contact lens and various soft implants or the like.
III. use the method for the change release composition that comprises Ziprasidone
According to another aspect of the present invention, provide a kind of method for the treatment of the patient who suffers from schizophrenia or relevant psychiatric disturbance, comprise the step of compositions of the present invention of the solid oral dosage form form of administering therapeutic effective dose.The advantage of method of the present invention comprises and reduces the conventional repeatedly administration frequency of IR dosage regimen needs, and the while has still kept benefit or elimination that the pulsed curve of blood plasma obtains or the variation minimum that makes the plasma concentration level.The minimizing administration frequency is useful for patient's compliance, and the method for the application of the invention reduces administration frequency and may help to control the health care expense by the time that minimizing hygiene care personnel are spent after using Ziprasidone.
In following embodiment, all except as otherwise noted percentage ratio is percentage by weight.The term that uses in whole embodiment " pure water " is meant its water by the water filtering system purification.Should be understood that embodiment is only used for purpose of explanation, and should not be interpreted as the spirit and scope of the present invention are limited that described spirit and scope are as the scope definition of hereinafter claim.
Embodiment
Embodiment 1 to 4 provides exemplary Ziprasidone tablet.These embodiment are intended to where face restriction claim in office, and provide the exemplary Ziprasidone tablet that can be used for method of the present invention.These exemplary tablets also can comprise coating materials.
Embodiment 1
Figure BSA00000156166500381
Embodiment 2
Figure BSA00000156166500391
Embodiment 3
Figure BSA00000156166500392
Embodiment 4
Figure BSA00000156166500401
Embodiment 5
The many granules that comprise Ziprasidone change release composition
Be prepared as follows many granules according to the present invention and change release composition, it comprises the immediate-release component that contains Ziprasidone and changes the release component.
(a) discharge (IR) component immediately.
The solution of any formulation preparation Ziprasidone that provides according to table 1.For example use then Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) the fluidized bed coating device by to good seed, reaches about 16.9% solid weightening finish level with methylphenidate solution bag, has formed the IR granule of immediate-release component.
Table 1
Immediate-release component solution
Amount, % (w/w)
Composition (i) (ii)
Ziprasidone 13.0 13.0
Polyethylene glycol 6000 0.5 0.5
Polyvinylpyrrolidone 3.5
Pure water 83.5 86.5
(b) change the release component
Preparation comprises the delayed release granule of Ziprasidone, discharges coating solution bag by the release particles immediately according to the foregoing description 5 (a) preparation by being used in the change of describing in detail in the table 2.With fluidized bed plant for example with the varying level bag by this release particles immediately, be up to about 30% weightening finish.
Table 2
Change and discharge component coating solution
Amount, % (w/w)
Composition (i) (ii) (iii) (iv) (v) (vi) (vii) (viii)
Figure BSA00000156166500411
49.7 42.0 47.1 53.2 40.6 -- -- 25.0
RS?12.5
-- -- -- -- -- 54.35 46.5
S?12.5
Figure BSA00000156166500413
-- -- -- -- -- -- 25.0
L?12.5
Polyethylene pyrroles------0.35 0.3------
Alkane ketone
Phthalic acid 0.5 0.5 0.6 1.35 0.6 1.3 1.1--
Diethylester
Triethyl citrate--------------1.25
Isopropyl alcohol 39.8 33.1 37.2 45.1 33.8 44.35 49.6 46.5
Acetone 10.0 8.3 9.3--8.4------
Talcum 1--16.0 5.9--16.3--2.8 2.25
1At row (i), (iv) and (in the preparation vi), Talcum is to use in coating.
(c) discharge immediately and the capsule of delayed release granule
Use for example Bosch GKF 4000S encapsulation device, with No. 2 hard gelatin capsules will be according to embodiment 5 (a) and (b) preparation become 20mg dose intensity altogether with the delayed release granule encapsulation immediately.The accumulated dose intensity of 20mg Ziprasidone is included in the 10mg in the immediate-release component and is changing the 10mg that discharges in the component.
Embodiment 6
The many granules that comprise Ziprasidone change release composition
According to table 3 (a) and the formulation preparation (b) change the Ziprasidone compositions that discharges according to many granules according to the present invention, its change that has immediate-release component and contain the release matrix material that changes discharges component.
Table 3 (a)
Change with 100mg discharges the IR component encapsulation of (MR) component with 100mg, obtains the product % (w/w) of 20mg dose intensity
The IR component
Ziprasidone 10
Microcrystalline Cellulose 40
Lactose 45
Polyvidone 5
The MR component
Ziprasidone 10
Microcrystalline Cellulose 40
Figure BSA00000156166500431
45
Polyvidone 5
Table 3 (b)
Change with 50mg discharges the IR component encapsulation of (MR) component with 50mg, obtains the product % (w/w) of 20mg dose intensity
The IR component
Ziprasidone 20
Microcrystalline Cellulose 50
Lactose 28
Polyvidone 2
The MR component
Ziprasidone 20
Microcrystalline Cellulose 50
Figure BSA00000156166500432
28
Polyvidone 2
Embodiment 7
The purpose of present embodiment is to describe the Ziprasidone compositions that how to prepare nanoparticle.
For example hydroxypropyl cellulose (HPC-SL) and dioctylsulfosuccinat are combined in the aqueous dispersions of 5% (w/w) Ziprasidone and one or more surface stabilizers
Figure BSA00000156166500433
0.01 (NanoMill Systems, King of Prussia, PA; Referring to for example, U.S.6,431,478) the 10ml chamber in grind, wherein this lapping device has 500 microns
Figure BSA00000156166500434
Abrasive media (Dow Chemical) (for example, the medium of load 89%).In an exemplary process, this mixture was ground 60 minutes under the grinding rate of 2500rpm.
In the Ziprasidone particle grain size that can in deionized water, measure with Horiba LA-910 granularmetric analysis device after the grinding after grinding.For the compositions of success, expect that initial meansigma methods and/or D50 grind the particle diameter of back Ziprasidone less than 2000nm.
Those skilled in the art can make various changes and change, and not break away from the spirit and scope of the present invention apparently in method and composition of the present invention.Therefore, the present invention covers change of the present invention and change, as long as they are in the scope and their equivalent scope of appended claims.

Claims (91)

1. stable nanoparticle compositions, comprise: (A) comprise the granule of Ziprasidone, described particulate effective mean diameter is that diameter is less than about 2000nm; (B) at least a surface stabilizer.
2. the compositions of claim 1, wherein said granule is selected from crystal phase, amorphous phase, hemihedral crystal bulk phase, half amorphous phase and composition thereof.
3. the compositions of claim 1, wherein said particulate effective mean diameter is to be selected from diameter less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 100nm, less than about 75nm and the group formed less than about 50nm.
4. the compositions of claim 1, wherein said composition is mixed with
(A) be used for by be selected from parenteral, oral, vagina, nose, rectum, ear, eye, part, containing, the brain pond, intraperitoneal or local application;
(B) form a kind of dosage form, be selected from tablet, capsule, wafer, solution, dispersion, gel, aerosol, ointment, emulsifiable paste and its mixture;
(C) formed a kind of dosage form, be selected from the sustained release dosage form, fast melt dosage form, freeze-dried formulation, delayed release dosage forms, prolongation release dosage form, pulsed release dosage form, and discharge immediately and sustained release mixed type dosage form; Or
(D) (A), (B) or combination in any (C).
5. the compositions of claim 1 wherein further comprises the acceptable excipient of one or more pharmacy, carrier or its combination.
6. the compositions of claim 1, wherein:
(A) based on total mixing dry weight of Ziprasidone in the compositions and surface stabilizer, and do not comprise other excipient, the amount of described Ziprasidone in described compositions is from about 99.5% to about 0.001%, about 95% to about 0.1% or about 90% to about 0.5 weight %;
(B) based on total mixing dry weight of Ziprasidone in the compositions and surface stabilizer, and do not comprise other excipient, the amount of described one or more surface stabilizers in described compositions is from about 0.5% to about 99.999%, about 5.0% to about 99.9% or about 10% to about 99.5 weight %; Or
(C) combination (A) and (B).
7. the compositions of claim 1, wherein surface stabilizer is selected from the group that nonionic surface stabilizer, anionic surface stabilizing agent, cationic surface stabilizing agent, amphion surface stabilizer and ion-type surface stabilizer are formed.
8. the compositions of claim 1, wherein surface stabilizer is selected from cetylpyridinium chloride, gelatin, casein, phospholipid, glucosan, glycerol, arabic gum, cholesterol, the tragakanta, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, the octadecanol hexadecanol, cetomacrogol emulsifying wax, the sorbitan ester, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene Sorbitan acid anhydride fatty acid ester, Polyethylene Glycol, Dodecyl trimethyl ammonium chloride, Myrj 45, silica sol, phosphate ester, sodium laurylsulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl first O-phthalic acid cellulose, non-microcrystalline Cellulose, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethyl butyl)-polymer of phenol and oxirane and formaldehyde, poloxamer; The mixture of dialkyl, sodium laurylsulfate, alkyl aryl polyether sulfonate, sucrose stearate and the sucrose distearate of poloxamines, charged phospholipid, dioctyl sulfosuccinate, sodium sulfosuccinate, right-different Nonylphenoxy gather-((+)-2,3-Epoxy-1-propanol), capryl-N-methyl glucoside amine; Positive decyl β-D-pyranglucoside; Positive decyl β-D-pyrans maltoside; Positive lauryl β-D-pyranglucoside; Positive lauryl β-D-maltoside; Heptanoyl group-N-methyl glucoside amide; N-heptyl-β-D-pyranglucoside; N-heptyl β-D-thioglycoside; N-hexyl β-D-pyranglucoside; Pelargonyl group-N-methyl glucoside amide; Pelargonyl group β-D-pyranglucoside; Caprylyl-N-methyl glucoside amine; N-octyl-β-D-pyranglucoside; Octyl group β-D-pyrans thioglycoside; Lysozyme, PEG-phospholipid, the PEG-cholesterol, the PEG-cholesterol derivative, the PEG-vitamin A, the PEG-vitamin E, lysozyme, the randomcopolymer of vinyl acetate and vinylpyrrolidone, cationic polymer, cationic biopolymers, cationic polysaccharide, the cationic cellulose class, the cation alginate, cation non-polymerization chemical compound, cationic phospholipid, cation lipid, poly-methyl acrylic acid trimethylammonium bromide, sulfonium compound, polyvinylpyrrolidone-2-dimethyl aminoethyl dimethylaminoethyl acrylate methyl sulfuric ester, cetyl trimethyl ammonium bromide phosphonium compounds, quaternary ammonium compound, benzyl-two (2-chloroethyl) ethyl ammonium bromide, the Cortex cocois radicis trimethyl ammonium chloride, the Cortex cocois radicis trimethylammonium bromide, Cortex cocois radicis methyl dihydroxy ethyl ammonium chloride, Cortex cocois radicis methyl dihydroxy ethyl ammonium bromide, the decyl triethyl ammonium chloride, decyl dimethyl hydroxyl ethyl ammonium chloride, decyl dimethyl hydroxyl bromic ether ammonium chloride, C 12-15Dimethyl hydroxyl ethyl ammonium chloride, C 12-15Dimethyl hydroxyl bromic ether ammonium chloride, Cortex cocois radicis dimethyl hydroxyl ethyl ammonium chloride, Cortex cocois radicis dimethyl hydroxyl ethyl ammonium bromide, myristyl trimethyl ammonium methylsulfuric acid ester, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethyleneoxy) 4Ammonium chloride, lauryl dimethyl (ethyleneoxy) 4Ammonium bromide, N-alkyl (C 12-18) dimethyl benzyl ammonium chloride, N-alkyl (C 14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, trimethyl-ammonium halide, alkyl-leptodactyline, dialkyl group-dimethyl ammonium, lauryl trimethyl ammonium chloride, ethoxylated alkyl amidoalkyl dialkyl ammonium salt, ethoxylation trialkyl ammonium salts, dialkyl benzene dialkylammonium chloride, N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C 12-14) dimethyl 1-naphthyl methyl ammonium chloride, lauryl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C 12Trimethylammonium bromide, C 15Trimethylammonium bromide, C 17Trimethylammonium bromide, lauryl benzyltriethylammoinium chloride, poly--diallyldimethylammonium chloride (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three cetyl ammonio methacrylates, decyl trimethylammonium bromide, lauryl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, methyl trioctylphosphine ammonium chloride, POLYQUAT10 TM, tetrabutyl ammonium bromide, halogeno salt, the MIRAPOL of benzyltrimethylammonium bromide, cholinester, benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride, brocide, cetylpyridinium chloride, oxozone ethyl alkylamine TM, ALKAQUA T TM, Fixanol; Amine, amine salt, amine oxide, acid imide azolinium salt, protonated season acrylamide, methylated tetravalence polymer and cation guar gum.
9. the compositions of claim 1 is wherein compared with fasted conditions, and said composition can not produce significantly different absorption level when using under the condition on the feed.
10. the compositions of claim 1, the patient who wherein compositions is applied to fasting state is bioequivalent with the patient who is applied to the feed state.
11. the compositions of claim 1, wherein the pharmacokinetic curve of said composition can not be subjected to absorbing patient's the feed of described compositions or the appreciable impact of fasting state.
12. the compositions of claim 1, wherein give the described compositions of administration after, compositions has produced therapeutic effect under the dosage less than the non-nanoparticle dosage form of identical Ziprasidone.
13. the compositions of claim 1, it has:
(a) when using the blood plasma of post analysis mammalian subject, the C of Ziprasidone MaxC greater than the non-nanoparticle preparation of the identical Ziprasidone of using same dose Max
(b) when using the blood plasma of post analysis mammalian subject, the AUC of Ziprasidone is greater than the AUC of the non-nanoparticle preparation of the identical Ziprasidone of using same dose;
(c) when using the blood plasma of post analysis mammalian subject, the T of Ziprasidone MaxT less than the non-nanoparticle preparation of the identical Ziprasidone of using same dose MaxOr
(d) (a) and (b) and combination in any (c).
14. the compositions of claim 1 also comprises the reactive compound that one or more are used to prevent and treat schizophrenia and similar psychiatric disturbance.
15. the compositions of claim 14, wherein one or more chemical compounds are selected from the group of the chemical compound composition of the disease that is used for the treatment of the group that is selected from headache, misery, heating and its combination composition.
16. the compositions of claim 1, wherein said granule comprises the medicine storage device that contains Ziprasidone, and described medicine storage device seals the semipermeable membrane that water is drawn in the granule by permission, has therefore produced the pressure that described Ziprasidone is disengaged from described granule.
17. the compositions of claim 1, wherein said medicine storage device also comprises penetrating agent.
18. method for compositions for preparing claim 1, being included in is enough to provide that to have effective mean diameter be that the granule that will comprise described Ziprasidone contacts a period of time with at least a surface stabilizer under the condition of diameter less than the nanoparticle compositions that comprises Ziprasidone of about 2000nm.
19. the method for claim 18, wherein this contact comprises grinding, wet grinding, homogenize, precipitation, plate emulsifying or supercritical liq granule generating technique.
20. the method for claim 18, wherein the particulate effective mean diameter of this nanoparticle is to be selected from diameter less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 100nm, less than about 75nm with less than about 50nm.
21. a method that prevents and/or treats schizophrenia or similar psychiatric disturbance comprises the compositions of using according to claim 1.
22. the method for claim 21, wherein the particulate effective mean diameter of this nanoparticle is to be selected from diameter less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1000nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 100nm, less than about 75nm with less than about 50nm.
23. pharmaceutical composition, comprise the granule that comprises active component of first component and the granule that comprises active component of at least one subsequent component, wherein at least a described component comprises Ziprasidone, at least a described component further comprises and change to discharge coating, changes the release matrix material or both have concurrently, so that after giving patient's oral delivery, said composition is with bimodal or multimodal mode delivering active ingredients.
24. the compositions of claim 23, wherein every kind of component all comprises the granule that contains Ziprasidone.
25. the compositions of claim 23, wherein said composition comprises the granule that comprises Ziprasidone of first component and the granule that comprises Ziprasidone of a subsequent component.
26. the compositions of claim 25, wherein first component comprises immediate-release component, and second component comprises change and discharges component.
27. the compositions of claim 23, wherein this granule that comprises active component is an erodable.
28. further comprising to change, the compositions of claim 23, wherein at least a described component discharge coating.
29. further comprising, the compositions of claim 23, wherein at least a described component change the release matrix material.
30. the compositions of claim 29, wherein said change release matrix material are selected from the group that hydrophilic polymer, hydrophobic polymer, natural polymer, synthetic polymer and composition thereof are formed.
31. the compositions of claim 30, wherein said Ziprasidone is discharged in the surrounding by corrosion.
32. the compositions of claim 31, wherein said compositions further comprises reinforcing agent.
33. the compositions of claim 30 comprises the Ziprasidone of about 0.1mg to about 1g.
34. pharmaceutical composition, comprise the granule that comprises active component of first component and the granule that comprises active component of at least one subsequent component, wherein at least a described component comprises Ziprasidone, at least a described component further comprises and change to discharge coating, changes the release matrix material or both have concurrently, so that after giving patient's oral delivery, said composition is delivering active ingredients in a continuous manner.
35. the compositions of claim 34, wherein every kind of component all comprises the granule that contains Ziprasidone.
36. the compositions of claim 34, wherein said composition comprises the granule that comprises Ziprasidone of first component and the granule that comprises Ziprasidone of a subsequent component.
37. the compositions of claim 36, wherein first component comprises immediate-release component, and second component comprises change and discharges component.
38. the compositions of claim 34, wherein this granule that comprises active component is an erodable.
39. further comprising to change, the compositions of claim 34, wherein at least a described component discharge coating.
40. further comprising, the compositions of claim 34, wherein at least a described component change the release matrix material.
41. the compositions of claim 40, wherein said change release matrix material are selected from the group that hydrophilic polymer, hydrophobic polymer, natural polymer, synthetic polymer and composition thereof are formed.
42. the compositions of claim 41, wherein said Ziprasidone is discharged in the surrounding by corrosion.
43. the compositions of claim 42, wherein said compositions further comprises reinforcing agent.
44. the compositions of claim 41 comprises the Ziprasidone of about 0.1mg to about 1g.
45. a dosage form comprises the compositions of claim 23.
46. the dosage form of claim 45 comprises the particulate admixture that contains active component that is included in hard gelatin capsule or the Perle.
47. the dosage form of claim 46, the granule that wherein contains active component is the form of tabloid, and this capsule comprises the mixture of described tabloid.
48. the dosage form of the claim 47 of tablet form.
49. the dosage form of claim 48, the wherein said granule that contains Ziprasidone is a rapid-dissolve dosage form.
50. the dosage form of claim 48, wherein this tablet is to melt tablet fast.
51. a dosage form comprises the compositions of claim 34.
52. the dosage form of claim 51 comprises the particulate admixture that contains active component that is included in hard gelatin capsule or the Perle.
53. the dosage form of claim 52, the granule that wherein contains active component is the form of tabloid, and this capsule comprises the mixture of described tabloid.
54. the dosage form of the claim 53 of tablet form.
55. the dosage form of claim 54, the granule that wherein comprises Ziprasidone is a rapid-dissolve dosage form.
56. the dosage form of claim 54, wherein this tablet is to melt tablet fast.
57. one kind prevents and/or treats the schizophrenia or the similar method of psychiatric disturbance, comprises the step of compositions of the claim 23 of administering therapeutic effective dose.
58. one kind prevents and/or treats the schizophrenia or the similar method of psychiatric disturbance, comprises the step of compositions of the claim 34 of administering therapeutic effective dose.
59. the compositions of claim 28, wherein said change discharge coating and comprise pH-dependent polymers coating, are used for after described compositions is applied to described patient, discharge the pulse of active component after 6 to 12 hours in described patient in time delay.
60. the compositions of claim 59, wherein said polymer coating comprises methacrylate copolymer.
61. the compositions of claim 59, wherein said polymer coating comprise the mixture of methacrylate and quaternary amine ylmethyl acrylate copolymer, its ratio is enough to realize the pulse of active component after postponing at least about 6 hours time.
62. the compositions of claim 61, wherein the ratio of methacrylate and quaternary amine ylmethyl acrylate copolymer is about 1: 1.
63. the compositions of claim 39, wherein said change discharge coating and comprise pH-dependent polymers coating, are used for after described compositions is applied to described patient, discharge the pulse of active component after 6 to 12 hours in described patient in time delay.
64. the compositions of claim 63, wherein said polymer coating comprises methacrylate copolymer.
65. the compositions of claim 64, wherein said polymer coating comprise the mixture of methacrylate and quaternary amine ylmethyl acrylate copolymer, its ratio is enough to realize the pulse of active component after postponing at least about 6 hours time.
66. the compositions of claim 65, wherein the ratio of methacrylate and quaternary amine ylmethyl acrylate copolymer is about 1: 1.
67. a sustained release compositions comprises nanoparticle granule partly, it comprises: (A) Ziprasidone; (B) change to discharge coating or, alternatively or additionally, change the stroma ground substance that discharges; So that said composition is sent Ziprasidone with pulse or continuation mode after giving patient's oral delivery.
68. the compositions of claim 67 is wherein compared with fasted conditions, described compositions can not produce significantly different absorption level when using under the condition on the feed.
69. the compositions of claim 67, the pharmacokinetic curve of wherein said compositions can not be subjected to absorbing patient's the feed of described compositions or the appreciable impact of fasting state.
70. the compositions of claim 67, the patient who wherein described compositions is applied to fasting state is bioequivalent with the patient who is applied to the feed state.
71. the compositions of claim 67, wherein this part comprises the change release particles.
72. the compositions of claim 67, wherein this part is the preparation of erodable.
73. the compositions of claim 67, wherein said granule all are the forms of permeability apparatus.
74. the compositions of claim 71, wherein this change release particles comprises change release coating.
75. the compositions of claim 71, wherein this change release particles comprises change release matrix material.
76. the compositions of claim 71, wherein said change release particles are combined to by corrosion described Ziprasidone are discharged in the preparation in the surrounding.
77. the compositions of claim 71 further comprises reinforcing agent.
78. the compositions of claim 71, the amount of the active component that wherein comprises are that about 0.1mg is to about 1g.
79. a dosage form comprises the compositions of claim 67.
80. the dosage form of claim 79 comprises the particulate admixture that contains active component that is included in hard gelatin capsule or the Perle.
81. the dosage form of claim 80, the granule that wherein contains active component is the form of tabloid, and this capsule comprises the mixture of described tabloid.
82. the dosage form of the claim 81 of tablet form.
83. the dosage form of claim 82, the granule that wherein comprises Ziprasidone is a rapid-dissolve dosage form.
84. the dosage form of claim 82, wherein this tablet is to melt tablet fast.
85. one kind prevents and/or treats the schizophrenia or the similar method of psychiatric disturbance, comprises the compositions of the claim 67 of administering therapeutic effective dose.
86. the compositions of claim 71 wherein changes release particles and comprises pH-dependent polymers coating, it is discharging in the pulse release of active component after 6 to 12 hours in time delay be effective.
87. the compositions of claim 86, wherein this polymer coating comprises methacrylate copolymer.
88. the compositions of claim 86, wherein this polymer coating comprises the mixture of methacrylate and quaternary amine ylmethyl acrylate copolymer, and its ratio is enough to realize the pulse of active component after time delay.
89. the compositions of claim 88, wherein the ratio of methacrylate and quaternary amine ylmethyl acrylate copolymer is about 1: 1.
90. the compositions of claim 67, wherein said granule all are the forms of permeability apparatus.
91. the compositions of claim 1, wherein said composition is mixed with the bank dosage form.
CN2010102092071A 2005-06-20 2006-06-19 The nanoparticle and the sustained release compositions that comprise aryl-heterocyclic compounds Pending CN101879140A (en)

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US11/372,857 US20060240105A1 (en) 1998-11-02 2006-03-10 Multiparticulate modified release composition

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