CN1738608A - Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders - Google Patents
Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders Download PDFInfo
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- CN1738608A CN1738608A CNA2003801087750A CN200380108775A CN1738608A CN 1738608 A CN1738608 A CN 1738608A CN A2003801087750 A CNA2003801087750 A CN A2003801087750A CN 200380108775 A CN200380108775 A CN 200380108775A CN 1738608 A CN1738608 A CN 1738608A
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Abstract
A pharmaceutical composition comprising a first component comprising a short-acting hypnotic or a pharmaceutically acceptable salt thereof; a second component comprising at least one particle, wherein the at least one particle comprises a core and at least one coating over the core, the core comprising a short-acting hypnotic or a pharmaceutically acceptable salt thereof, and the at least one coating comprising at least one pharmaceutically acceptable polymer that is soluble at a pH greater than or equal to about 5.5, and optionally a third component comprising at least one particle, wherein the at least one particle comprises a core and at least one coating over the core, the core comprising a short-acting hypnotic or a pharmaceutically acceptable salt thereof, and the at least one coating comprising at least one pharmaceutically acceptable polymer that is soluble at a pH greater than or equal to about 6.0. Methods of treating sleep disorders, prolonging sleep, and inducing sleep using these compositions are also disclosed.
Description
The application requires in the U.S. Provisional Application No.60/426 of submission on November 15th, 2002,369 rights and interests.
The present invention relates to comprise modification release (modified release) compositions of fugitive (short acting) hypnotic.Especially, the present invention relates to implement the modified release composition that transmits short-acting hypnotic with pulse mode.The invention further relates to the solid oral dosage form that comprises this kind modified release composition.In addition, the invention further relates to the method for in the patient of this treatment of needs, treating sleep disorder by this kind compositions that gives effective dose.
The blood plasma characteristic relevant with the described administration of medical compounds can be described as " pulse characteristic (pulsatile profile) ", wherein observes the pulse of the high activity component concentration that a little is embroidered with the low concentration trough.Contain bimodal pulse characteristic and can be described as " bimodal distribution ".The pulse characteristic that contains three peaks can be described as " distribution of three peaks ".Similarly, compositions or the dosage form that produces this specific character after administration can be expressed as " pulsed discharges (pulsed release) " that shows this reactive compound.
Wherein the conventional multiple dose scheme with periodic intervals administration instant-free (IR) dosage form causes pulsed blood plasma characteristic usually.For example, behind each IR dosage of administration, observe the peak of plasma drug level, be accompanied by trough (the low drug level zone) development between successive administration time point.These dosages (and pulsed blood plasma characteristic of gained) have special pharmacological relevant with them and treatment effect.For example, the cleaning phase that reduction provided of the plasma concentration of active component (wash out period) is considered to reduce or prevents the contribution factor of patient to all kinds drug resistance between the peak.
The zero level (zeroorder) that the purpose of many controlled-release pharmaceutical formulations is to produce medical compounds discharges.Really, the specific purpose of these preparations usually is the crest that makes the medicine blood plasma level relevant with conventional multiple dose scheme-to-trough minimize variations.Yet, as discharge by zero level that medicine is that delivery system obtains constant or near the result of constant blood plasma level, inherent some treatment and pharmacological effect can be lost or reduce in pulse system.Therefore, the repeatedly release of IR dosage be need imitate substantially, modified release composition or preparation that multiple dosing needs reduced simultaneously.
Controlled release for example can be used for being used for the treatment of the short-acting hypnotic of sleep disorder.Short-acting hypnotic is the chemical compound that can induce the mammiferous tranquilizer, antianxiety drugs, muscle relaxant and the anticonvulsant drug effect that have been given them.These chemical compounds also can be used for inducing and prolonging the mammiferous sleep that has been given them.These examples for compounds comprise some Pyrazolopyrimidines type, cyclopyrrole ketone (cyclopyrrolones), benzodiazepine class, phenothiazines and Imidazopyridine class.
Zaleplon is also referred to as N-[3-(the 3-cyano pyrazole is [1,5-a] pyrimidin-7-yl also) phenyl]-the N-ethyl acetamide, be a kind of new pyrazolopyrimidine hypnotic, its selective binding is in GABA
ABenzodiazepine I type site on (γ-An Jidingsuan, A type) receptor complex.
Zaleplon
In animal model, it produces and similarly calmness of those commercially available benzodiazepine , anxiety, of flaccid muscles and convulsion effect.The clinical test results of zaleplon has shown that it will effectively shorten the sleep starting-up stage, has benzodiazepine and the more favourable security feature of non-benzodiazepine hypnotic than previous acquisition.Find that also zaleplon has minimum influence to learning and memory and second day remaining (" residual ") effect.At US and European, zaleplon go through with 5,10 and 20mg dosage be used for the insomnia.The U.S. it with trade mark Sonata
Go on the market, and be approved for the short term therapy of insomnia.Show that in the clinical research of contrast, it reduces the time in sleep starting-up stage, this effect was up to 28 days.It also can be used for providing sleep to those patients with insomnia anxiety.
In the mankind, zaleplon reaches the time (t of maximal plasma concentration
Max) be 0.8 hour, and have about 1 hour (terminal) half-life (t of end eventually
1/2).Startup that these dynamics data indications are very fast and short action period.Though proved zaleplon in the patient's who suffers from some sleep disorder treatment effectively, it shows the time that total length of one's sleep or reduction wake that increases consistently as yet.This mainly is because the rapid metabolism of this medicine is the metabolite of non-activity, causes 4-5 hour average effect persistent period.Therefore, what needs were obtained is the duration of effect that increases, and such as from 6-8 hour, is keeping the advantage of nothing " residual " effect simultaneously.
The modification delivery formulations that comprises short-acting hypnotic is disclosed in licensing to the EP 1064937A1 of Sanofi-Synthelabo.This file relates to the time control of short-acting hypnotic dual-release dosage form.Be described as " pulse " first heavily to discharge be instant-free, and second " pulse " is to prolong for a long time to discharge.This invention relates to piller, globule, particulate or the spheroid that is coated with medicine, the optional then polymer that is coated with, and its dissolubility is that pH relies on.Yet the product release characteristics of these preparations provides medication amount to increase continuously until its whole releases.The shortcoming of this release characteristics is: well-known short-acting hypnotic stands first-pass metabolism, and wherein the rapid metabolism of this medicine is the non-activity metabolite.Use the prolongation release characteristics of describing as the Sanofi-Synthelabo patent can reduce this bioavailability of medicament potentially, be used for metabolism because it is presented with constant relatively speed.
License to the U.S. Patent number the 6th of this assignee's Devane etc., 228,398 B1 have also described wherein active drug substance widely can be with the pulse mode transmission, so that the pharmaceutical preparation that has two or more distinct absorption phases after giving single dose.Different with the method for Sanofi-Synthelabo, this method has avoided causing slow, the constant release of the drug substance of above-mentioned metabolic problems.Yet Devane is unexposed to use its compositions with zaleplon.
At U.S. Patent number the 4th, 728, in 512,4,794,001 and 4,904,476 (licensing to American Home Products Corp. on the surface), the pharmaceutical preparation that three completely different releases of drug substance are provided from single dose is disclosed.Said preparation comprises three groups of spheroides that contain active pharmaceutical substance; First group of spheroid be coating not, and absorb the back rapidly disintegrate with the predose of release medicinal material.Second group of spheroid is that the coating with the pH-sensitivity comes coating, so that second dosage to be provided; The 3rd group of spheroid is to come coating with the coating that does not rely on pH, so that the 3rd dosage to be provided.
If use the plasma concentration of transmitting this medicine so that this medicine with pulse mode to experience the increase sharply preparation of (" pulse ") several times of needed time, people will give the short-acting hypnotic such as zaleplon, and discharging relevant shortcoming with the time-delay that can occur when using the coating that does not rely on pH among other things can be overcome.This release characteristics will have reduction by the advantage of metabolic medication amount, the opposite extended treatment effect that will consider single dose with existing preparation, and will be suitable for long term administration.In addition, give medicine with pilule or micro-tablet form and will have such advantage: for the patient who is impatient at existing tablet and capsular oral administration, administration easily.These pillers or micro-tablet can absorb with meals, for example by they are sprinkled upon on the food.
Therefore the inventor has developed preparation and has used the method for transmitting the multiparticulates modified release composition of short-acting hypnotic with pulse mode, to overcome above-mentioned and known relevant one or more problems of these compound compositions that contain at present.
Especially, the present invention relates to be used for the treatment of by the pharmaceutical composition that the patient to this treatment of needs gives effective dose the method for sleep disorder, described pharmaceutical composition comprises:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the pH that is greater than or equal to about 5.5, such as 6.0 or further such as 7.0 soluble pharmaceutically acceptable polymer; Randomly
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the pH that is greater than or equal to about 5.5, such as 6.0 or further such as 7.0 soluble pharmaceutically acceptable polymer.
In one embodiment, at first, short-acting hypnotic in second and optional the 3rd component is zaleplon.
Will further discuss as following, the character that does not rely on pH that is contained in the described at least a polymer in the coating makes described short-acting hypnotic, is controlled such as the release of zaleplon.
On the other hand, the present invention relates to pharmaceutical composition, described pharmaceutical composition comprises:
A) contain first component of short-acting hypnotic or its officinal salt; With
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the pH that is greater than or equal to about 5.5, such as 6.0 or further such as 7.0 soluble pharmaceutically acceptable polymer.
In one embodiment, the short-acting hypnotic in first and second component is a zaleplon.
On the other hand, the present invention relates to pharmaceutical composition, described pharmaceutical composition comprises:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0.The two selects a ground, and the 3rd component can comprise and contain at least at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
In one embodiment, the short-acting hypnotic in any one of described three components is a zaleplon.
On the other hand, the present invention relates to pharmaceutical composition, described pharmaceutical composition comprises:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at described extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
In one embodiment, the short-acting hypnotic in any one of described three components is a zaleplon.
In another embodiment, the invention provides the sleep disorder that needs the patient of this treatment by this preparation for treating that gives effective dose to described patient, induce its sleep and prolong the method for its sleep.
Brief description of drawings
Fig. 1 is the dissolution characteristic of globule in the 0.01N hydrochloric acid solution as preparation in embodiment 1 and 2.
Fig. 2 is the globule as preparation in embodiment 3,4 and 5, measures 2h measures other 4h afterwards by the phosphate buffer of pH7.2 dissolution characteristic in 0.01N hydrochloric acid.
Fig. 3 is the capsule as preparation in embodiment 6 and 7, measures 2h measures other 4h afterwards by the phosphate buffer of pH7.2 dissolution characteristic in 0.01N hydrochloric acid.
Fig. 4 is the dissolution characteristic of measuring in 0.01N hydrochloric acid as the tablet of preparation in embodiment 10 and 11.
Fig. 5 is the tablet as preparation in embodiment 12,13 and 14, measures 2h measures other 4h afterwards by the phosphate buffer of pH7.2 dissolution characteristic in 0.01N hydrochloric acid.
Fig. 6 is the capsule as preparation in embodiment 15 and 16, measures 2h measures other 4h afterwards by the phosphate buffer of pH7.2 dissolution characteristic in 0.01N hydrochloric acid.
Term used herein " short-acting hypnotic " refers to induce the compound of the mammiferous calmness that has been given them, antianxiety, of flaccid muscles and anticonvulsion effect. In the operable short-acting hypnotic according to the present invention, include, but are not limited to pyrazolo miazines (such as zaleplon), cyclopyrrole ketone (such as zopiclone and its enantiomer, such as (R)-zopiclone), benzodiazepine class (such as triazolam, Temazepam and brotizolam), phenothiazines (such as alimemazine or its tartrate) and imidazoles pyridine class (such as zolpidem).
The term used herein " zaleplon " that relates to composition of the present invention refers to N-[3-(3-cyano group pyrazolo [1,5-a] pyrimidine-7-yl) phenyl]-the N-ethyl acetamide, or its officinal salt.
The term used herein " zopiclone " that relates to composition of the present invention refers to 6-(5-Chloro-2-Pyridyle)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]-pyrazine-5-base-1-piperazinecarboxylic acid ester.
The term used herein " triazolam " that relates to composition of the present invention refers to 8-chloro-6-(ortho-, meta-or p-chlorphenyl)-1-methyl-4H-s-triazol-(4,3-α) (Isosorbide-5-Nitrae) benzodiazepine .
The term used herein " Temazepam " that relates to composition of the present invention refers to 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone.
The term used herein " brotizolam " that relates to composition of the present invention refers to 2-bromo-4-(ortho-, meta-or p-chlorphenyl)-9-methyl-6H-thieno [3,2-f]-s-triazol [4,3-a] [Isosorbide-5-Nitrae] diaza .
The term used herein " alimemazine " that relates to composition of the present invention refers to N, N-dimethyl-2-[(phenthazine-10-yl) methyl] propyl group amine half tartrate.
The term used herein " zolpidem " that relates to composition of the present invention refers to N, N, the p-tolyl-imidazo of 6 trimethyls-2-(1,2-a) pyridine-3-acetamide L-(+)-tartrate (2: 1).
Term used herein " multiparticle " refers to a large amount of particulate, globule, piller, particle, sheet or its mixtures discrete or that assemble, does not consider their size, shape or form.
Term used herein " sleep-disorder " refers to and enters sleep and keep the relevant obstacle of sleep, such as, for example chronic insomnia disease, scrambling sleep-recovery time table, can not keep rule length of one's sleep table rotating shift work, jet lag, be in depression and other mental disease states and upset other medical science states that sleep becomes problem. Term " insomnia " is used for description all states relevant with the patient's of insufficient or unpeaceful sleep perception. Sleep-disorder is one of common sympton of finding in common medical practice. Insomnia is common main suit, it was reported to account for 13% to 45% of adult's population. Symptom comprises frequent or continuous difficulty falling asleep in night, wake up night frequently and/or wake up early morning. Insomnia itself can have a lot of forms, but seems more closely related with the spiritual pathological state of age, sex and individuality, and special importance is arranged in the elderly and women. Therefore, the treatment of sleep-disorder can comprise the patient's who needs them the inducing and prolong of sleep.
Term used herein " is modified and is discharged " and refers to not to be instant-free and contain the release that controlled release, sustained release and delay discharge.
Term used herein " officinal salt " comprises by the salt of individual physiological tolerance. These salt are usually from the inorganic and/or organic acid that is fit to and the alkali compounds preparation that is fit to. The example of suitable inorganic acid includes but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid. Organic acid can be aliphatic acid, aromatic acid, carboxylic acid and/or sulfonic acid. Suitable organic acid includes but not limited to formic acid, acetic acid, propionic acid, butanedioic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, lactic acid, malic acid, glactaric acid, tartaric acid, p-toluenesulfonic acid, glycolic, Portugal (grape) uronic acid, maleic acid, furancarboxylic acid, glutamic acid, benzoic acid, ortho-aminobenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, piperazine acid (pamoic), methanesulfonic acid, ethyl sulfonic acid, pantothenic acid, benzene sulfonic acid (benzene sulfonate), stearic acid, sulfanilic acid, alginic acid, galacturonic acid, p-bromophenyl sulfonic acid, camphorsulfonic acid, carbonic acid, ethyl sulfonic acid, gluconic acid, isethionic acid, maleicmandelic, oxalic acid, pantothenic acid, p-toluenesulfonic acid etc. Therefore, the example of these officinal salts of zaleplon includes but not limited to acetate, benzoate, beta-hydroxy-butanoic acid salt, disulfate, acid sulphite, bromide, butine-1,4-diacid salt (butyne-1,4-dioate), caproate, chloride, chloro benzoate, citrate, dihydrogen orthophosphate, dinitro-benzoate, fumarate, glycollate, enanthate, hexin-1,6-diacid salt (hexyne-1,6-dioate), hydroxybenzoic acid salt, iodide, lactate, maleate, malonate, mandelate, metaphosphate, mesylate, methoxy benzoic acid salt, methyl benzoic acid salt, one hydrogen orthophosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, oxalates, PB, phenylpropionic acid salt, phosphate, phthalate, phylacetate, propane sulfonic acid salt, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulphite, sulfonate, tartrate, dimethylbenzene sulphur salt etc.
Term used herein " pharmaceutically acceptable excipient " comprise with pharmaceutical preparation in other compositions compatible and when with treatment effective dose administration, do not damage this individual compound.
Be included in the short-acting hypnotic as active component in each component, can be identical or different according to needed dosage such as the ratio of zaleplon. For example, in described dipulse preparation, each component can comprise this active component with about 30% quantity to about 70% scope, such as zaleplon. In described three pulse preparations, each component can comprise this active component with about 15% quantity to about 50% scope, such as zaleplon. Described active component can be united in the first component individually or with the active component (or a plurality of active component) in second component, to be enough to causing that any amount of therapeutic response exists.
The described short-acting hypnotic that is contained in any above-mentioned composition can exist with such quantity, so that the accumulated dose of institute's administration is to about 100mg from about 0.1mg. Selection according to the appropriate dose of short-acting hypnotic of the present invention will depend on the factor relevant with each individual patients, and optimal dosage can use knowledge well known by persons skilled in the art to select.
Zaleplon can be present in any above-mentioned composition so that the accumulated dose of institute's administration is the quantity from about 5mg to about 60mg, such as from about 1mg to 30mg, from about 5mg to about 30mg; For example, about 5mg, about 10mg, about 15mg, perhaps about 20mg. Selected dosage will depend on the factor relevant with each individual patients, and optimal dosage can use knowledge well known by persons skilled in the art to select. In any case zaleplon has the needed time of positive clinical effect so that the PC of zaleplon experiences therein at about 10ng/ml to the scope of 35ng/ml need to select dosage. In addition, when needs used with pharmaceutically acceptable polymer (its solubility is that the pH relies on) piller of dressing or the associating of tablet, being included in the quantity of the zaleplon in each globule and the number of these globules can determine by knowledge well known by persons skilled in the art.
Can utilize U.S. Patent No. 4,626, the 538 described methods of Dusza etc. to prepare zaleplon. Also can utilize method well known to those skilled in the art to prepare zaleplon.
In one embodiment, preparation of the present invention provides as the film controlling agent. The pH pauper character of the polymer that film or dressing comprise is so that the release of said preparation is controlled. Film controlling agent of the present invention can be by the rapid nuclear that discharges of preparation, and it can be monolithic type (for example tablet) or many units type (for example piller), and this examines to produce to come dressing with the dressing that comprises at least a aforesaid polymer.
In one embodiment, described short-acting hypnotic can provide in multiparticle film controlling agent. More specifically, have from about 0.4 average diameter to about 1.1mm scope by this medicine is coated on, such as the superfine product seed from about 0.71mm to about 0.85mm, described short-acting hypnotic can be prepared into active nuclear. Companion or do not accompany other excipient, described short-acting hypnotic can be coated on the inert core, and can utilize fluidized bed coating device (for example, Wurster dressing) or dish dressing system to spray from solution or suspension. Alternatively, use adhesive that short-acting hypnotic is bonded on the described nuclear, can with this short-acting hypnotic as power applications on described inert core. Push this nuclear by any other processing aid with suitable plasticizer (being described below) and needs and also can form active nucleus. Forming film described above, and other keep not dressing to some nuclears that contain this short-acting hypnotic with at least a pharmaceutically acceptable polymer coating. Therefore the dressing nuclear that contains short-acting hypnotic is not the example of the invention described above the first component, that is, and and the instant-free dosage form. The nuclear that contains short-acting hypnotic of described dressing is the example of the second of the present invention and the third component, namely, the dressing that described pH relies on allows the release of modifying so that discharge and modify when discharging component and uniting when instant in the present composition, can obtain dipulse and the three pulses release of the anticipation of this short-acting hypnotic.
In another embodiment, can in being called the multiparticle film controlling agent of microplate, provide this short-acting hypnotic, wherein for example by direct tablet compressing or granulation it is prepared into and contain this short-acting hypnotic and the active nucleus of other compositions, suitable excipient randomly. Then, this active nucleus can come dressing with suitable film dressing. As described, instant-free dosage microplate does not come dressing with the film dressing. These microplates can have about 1.5mm to the diameter of about 6mm scope.
The described at least a pharmaceutically acceptable polymer that is coated on the nuclear that contains medicine as the film dressing for example can be from following selection: polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, HYDROXY PROPYL METHYLCELLULOSE phthalic acid ester (comprising HPMCP50 and HPMCP55), polyethylene glycol, EUDRAGITTMPolymer and/or its mixture. EUDRAGITTMPolymer (available from Rohm Pharma) is based on the polymerism lacquer material of acrylates and/or methacrylate. Slight this active component of infiltration and water and the infiltrative suitable EUDRAGIT of demonstration pH dependenceTMPolymer includes but not limited to EUDRAGITML and EUDRAGITTMS。
Methacrylic acid copolymer is such as EUDRAGIT
TMS and EUDRAGIT
TML (Rohm Pharma) is particularly suitable for using in sustained release preparation of the present invention.These polymer are stomach tolerance and enteric polymer.Their thin polymer film is insoluble to the acid of pure water and dilution.When this thin polymer film becomes when solvable, it is subjected to the pH of environment and is used to produce the influence of carboxylic acid monomer's content of this polymer.EUDRAGIT
TMS and EUDRAGIT
TML can be used for polymer coating individually or unite with any ratio.By utilizing the associating of polymer, described polymeric material can be presented at EUDRAGIT
TML and EUDRAGIT
TMThe dissolubility of pH between the independent dissolved pH of S.
EUDRAGIT
TML is from methacrylic acid and the synthetic anionic polymer of methyl methacrylate.It is insoluble to acid and pure water.It is solvable in the weak basic condition in neutrality.EUDRAGIT
TMThe permeability of L is that pH relies on.Be suitable for EUDRAGIT of the present invention
TMAmong the L polymer is EUDRAGIT
TML 100-55, EUDRAGIT
TML 100, EUDRAGIT
TML 30D-55 and EUDRAGIT
TML 12.5.Contain EUDRAGIT
TML 100-55 and EUDRAGIT
TMThe film of L 30D-55 increases in the pH infiltration that is greater than or equal to about 5.5.Contain EUDRAGIT
TML 100 and EUDRAGIT
TMThe film of L 12.5 increases in the pH infiltration that is greater than or equal to about 6.0.
EUDRAGIT
TMS is from methacrylic acid and the synthetic anionic polymer of methyl methacrylate.It is insoluble to acid and pure water.It is solvable in the weak basic condition in neutrality.EUDRAGIT
TMThe permeability of S is that pH relies on.Be higher than pH7.0, this polymer penetration increases.Be suitable for EUDRAGIT of the present invention
TMAmong the S polymer is EUDRAGIT
TMS 100 and EUDRAGIT
TMS 12.5.
Described coating also can comprise one or more adjuvant such as filler, plasticizer and/or anti-foaming agent.Representative filler comprises Talcum, pyrogenic silica, glyceryl monostearate, magnesium stearate, calcium stearate, Kaolin, silica sol, Gypsum Fibrosum, fine silica powder and magnesium trisilicate.The common scope of the amount of used filler be from based on about 2 weight % of this polymer gross dry weight to about 300 weight %, and can from about 20 to about 100%.In one embodiment, Talcum is described filler.
Described coating membrane and functional coatings are same, also can comprise the raw material that improves this Polymer Processing.These raw materials are commonly referred to as plasticizer and comprise for example adipate, azelate, benzoate, citrate, isoebucates, phthalate, sebacate, stearate and glycols.Representational plasticizer comprises acetylated monoglyceride; glycolic butyl phthalyl butyl ester; tartaric acid dibutyl ester; the phthalic acid diethyl ester; the phthalic acid dimethyl esters; glycolic ethyl phthalyl ethyl ester; glycerol; ethylene glycol; propylene glycol; the glyceryl triacetate citrate; glyceryl triacetate; glyceryl tripropanoate; Glycerine 1,3-diacetate; phthalic acid dibutyl ester; the acetyl group monoglyceride; Polyethylene Glycol; Oleum Ricini; citric acid triethyl group ester; polyhydric alcohol; acetate; glycerol triacetate; the citric acid acetyl three ethyl ester; phthalic acid dibenzyl ester; phthalic acid dihexyl ester; phthalic acid butyl octyl ester; the phthalic acid diisononyl esters; phthalic acid butyl octyl ester; Azelaic Acid dioctyl ester; the epoxidation resinate; benzenetricarboxylic acid three isooctyl acrylate; phthalic acid diethylhexyl ester; phthalic acid di-n-octyl ester; phthalic acid diisooctyl ester; phthalic acid isodecyl ester; phthalic acid two n-undecane base esters; phthalic acid two n-tridecane base esters; benzenetricarboxylic acid three-2-ethyl hexyl ester; adipic acid two-2-ethyl hexyl ester; decanedioic acid two-2-ethyl hexyl ester; Azelaic Acid two-2-ethyl hexyl ester; decanedioic acid dibutyl ester; Monooctamoin; and monocaprin.In one embodiment, described plasticizer is a decanedioic acid dibutyl ester.The quantitative range that is used in the plasticizer in this polymer raw material normally from based on this anhydrous polymer weight about 10% to about 50%, for example, about 10,20,30,40 or 50%.
Also can comprise anti-foaming agent, for example simethicone.The quantity of used anti-foaming agent comprises usually from about 0% to about 0.5% of final preparation.
The amount of polymer that common adjusting is used for this film controlling agent comprises the quantity of the medicine that will be transmitted, speed and position, the time delay of drug release and the size of the multiparticle in the preparation of drug delivery to obtain needed drug delivery characteristic.Usually the amount of polymers of using provides the weight of this nuclear to increase about 2% to about 50%.In one embodiment, the weight increase scope from this polymer raw material is from about 3% to about 30%.
Described coating raw material comprises the associating of all solids component of copolymer, filler, plasticizer and excipient of choosing wantonly and processing aid, provides the weight of this nuclear to increase about 3% to about 60% usually.In one embodiment, described weight increases to from about 3% to about 45%.
Can utilize any known method to use described coating raw material, for example, by using fluidized bed coating device (for example, Wurster coating) or dish coating system to spray.Usually be dried by the nuclear of coating behind the polymer raw or solidify (cured) in coating.Solidify and to mean this multiparticle is remained in the time that controlled temperature continues to be enough to provide stabilized release rate.Solidify and for example can carry out at baking box or in fluidized bed dryer.Curing can be carried out in any temperature that is higher than room temperature.
Sealant or barrier layer also can be used for this polymer coating.Sealant or barrier layer also can be coated on this nuclear before this polymer raw material of coating.The release of short-acting hypnotic is not planned to modify in sealant or barrier layer.Suitable sealant or barrier layer are penetrating agent or solubilized agent such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Cellulose ethyl hydroxypropyl ether and xanthan gum.
Can add other reagent to improve the machinability on described sealant or barrier layer.These reagent comprise Talcum, silica sol, polyvinyl alcohol, titanium dioxide, fine silica powder, pyrogenic silica, glyceryl stearate, magnesium trisilicate and magnesium stearate, or its mixture.Described sealant layer or barrier layer can utilize any known method such as fluidized bed coating device (for example, Wurster coating) or dish coating system from solution (for example, aqueous) or suspension coating.Suitable sealant or barrier layer comprise for example OPADRY WHITE Y-1-7000 and OPADRYOY/B/28920 WHITE, and wherein each all derives from Colorcon Limited, England.
In one embodiment, provide two alleged pulse preparations, comprised zaleplon as the accumulated dose 20mg of the mixture administration of first and second pillers.First piller comprises the nuclear of 10mg zaleplon, and can choose wantonly further comprise proper additive or excipient on the superfine product seed.Second piller comprises the nuclear of the zaleplon of 10mg on the superfine product seed, and can choose wantonly and further comprise proper additive or excipient, and further comprises the EUDRAGITL coating.This preparation can be to comprise the capsule form oral administration of described first and second pillers.The ratio of first and second pillers to be administered in this preparation can be determined without over-drastic experiment by those skilled in the art.In this preparation, with respect to the nuclear of the drug loading of coating not, the weight of the coating of EUDRAGIT L can from about 1% in the scope of about 50 weight %, or from about 1% in the scope of about 30 weight %, or from about 1% in the scope of about 20 weight %, or, perhaps can be about 5 weight % from about 2% in the scope of about 10 weight %.The required weight of each coating will depend on required release and pharmacokinetic properties, and can be determined without over-drastic experiment by those skilled in the art.
In another embodiment, provide two pulse preparations, comprised zaleplon as the accumulated dose 20mg of the mixture administration of first and second micro-tablets.First micro-tablet comprises the nuclear of 10mg zaleplon, and can choose wantonly and further comprise any proper additive or excipient, and described micro-tablet is produced by zaleplon and other optional ingredients direct compressions or pelletize.Second micro-tablet comprises the nuclear of 10mg zaleplon, and can choose wantonly and further comprise any proper additive or excipient, and further comprises EUDRAGIT L coating.This preparation can be to comprise the capsule form oral administration of described first and second micro-tablets.The ratio of first and second micro-tablets to be administered in this preparation can be determined without over-drastic experiment by those skilled in the art.In this preparation, with respect to the nuclear of the drug loading of coating not, the weight of the coating of EUDRAGIT L can from about 1% in the scope of about 50 weight %, or from about 1% in the scope of about 30 weight %, or from about 1% in the scope of about 20 weight %, or can from about 2% in the scope of about 20 weight %.The required weight of each coating will depend on required release and pharmacokinetic properties, and can be determined without over-drastic experiment by those skilled in the art.
In another embodiment, provide three alleged pulse preparations, comprised zaleplon as the accumulated dose 20mg of the mixture administration of first, second and the 3rd piller.First piller comprises the nuclear of 6.7mg zaleplon, and can choose wantonly further comprise proper additive or excipient on the superfine product seed.Second piller comprises the nuclear of the zaleplon of 6.7mg on the superfine product seed, and can choose wantonly and further comprise proper additive or excipient, and further comprises EUDRAGIT L coating.The 3rd piller comprises the nuclear of the zaleplon of 6.7mg on the superfine product seed, and can choose wantonly and further comprise proper additive or excipient, and further comprises EUDRAGIT S coating.This preparation can be to comprise the capsule form oral administration of described first, second and the 3rd piller.To be administered first, second in this preparation and the ratio of the 3rd piller can be determined without over-drastic experiment by those skilled in the art.In this preparation, with respect to the nuclear of the drug loading of coating not, the weight of the coating of EUDRAGIT L and EUDRAGIT S independently can from about 1% in the scope of about 50 weight %, or from about 1% in the scope of about 30 weight %, or from about 1% in the scope of about 20 weight %, or can perhaps can be about 4% to about 5 weight % from about 2% in the scope of about 10 weight %.The required weight of each coating will depend on required release and pharmacokinetic properties, and can be determined without over-drastic experiment by those skilled in the art.
In another embodiment, provide three alleged pulse preparations, comprised zaleplon as the accumulated dose 20mg of the mixture administration of first, second and the 3rd micro-tablet.First micro-tablet comprises the nuclear of 6.7mg zaleplon, and can choose wantonly and further comprise proper additive or excipient, and described micro-tablet is produced by zaleplon and other optional ingredients direct compressions or pelletize.Second micro-tablet comprises the nuclear of 6.7mg zaleplon, and can choose wantonly and further comprise proper additive or excipient, and further comprises EUDRAGIT L coating.The 3rd micro-tablet comprises the nuclear of 6.7mg zaleplon, and can choose wantonly and further comprise proper additive or excipient, and further comprises EUDRAGIT S coating.This preparation can be to comprise the capsule form oral administration of described first, second and the 3rd micro-tablet.To be administered first, second in this preparation and the ratio of the 3rd micro-tablet can be determined without over-drastic experiment by those skilled in the art.In this preparation, with respect to the nuclear of the drug loading of coating not, the weight of the coating of EUDRAGIT L and EUDRAGIT S independently can from about 1% in the scope of about 50 weight %, or from about 1% in the scope of about 30 weight %, or from about 2% in the scope of about 20 weight %.The required weight of each coating will depend on required release and pharmacokinetic properties, and can be determined without over-drastic experiment by those skilled in the art.
Any pharmaceutical composition as herein described and dosage form can further comprise one or more pharmaceutical active compounds except that zaleplon.These chemical compounds are included treats the identical morbid state of prevention and/or control with zaleplon or different a kind of medicines with treatment, prevention and/or control.The chemical compound that is applicable to this purpose includes but not limited to zopiclone, triazolam, temazepam, brotizolam, alimemazine and zolpidem.Those skilled in the art are familiar with being used for other active component is mixed into the example of the technology of the compositions that contains zaleplon.The two selects a ground, and these other medical compoundss can provide and can be with zaleplon compositions co-administered of the present invention in individuality with preparation independently.These independently preparation can be before giving zaleplon compositions of the present invention, afterwards or administration simultaneously.
Embodiment
Following embodiment is used to illustrate and does not limit above-mentioned disclosing.
Embodiment 1: the instant-free globule that contains zaleplon
Suspension coating 1350g superfine product seed (0.71-0.85mm) with following composition.
| Zaleplon (micronization) | 20.0％ | 122.34g |
| Hydroxypropyl emthylcellulose 3cps | 7.4％ | 45.27g |
| Polysorbate80 | 0.2％ | 1.22g |
| Silica sol | 1.7％ | 10.40g |
| Water USP | 70.7％ | 432.47g |
(Glatt Protech, Leicester England) carry out with the Wurster application software coating at the Uniglatt fluid bed processor.The stripping of globule is measured with USP I (40 order) in the 100rpm mixing speed.Dissolution medium is 37 ± 0.5 ℃ 500ml 0.01M HCl.The quantity of dissolved zaleplon is measured by the UV spectrophotometry at 232nm.Stripping curve is seen Fig. 1.
Embodiment 2: the instant-free globule that contains zaleplon
Suspension coating 1250g superfine product seed (0.71-0.85mm) with following composition.
| Zaleplon (micronization) | 20.0％ | 182.00g |
| Hydroxypropyl emthylcellulose 3cps | 7.4％ | 67.34g |
| Polysorbate80 | 0.2％ | 1.82g |
| Silica sol | 1.7％ | 15.47g |
| Water USP | 70.7％ | 643.37g |
(Glatt Protech, Leicester England) carry out with the Wurster application software coating at the Uniglatt fluid bed processor.The stripping of globule is measured with USP I (40 order) in the 100rpm mixing speed.Dissolution medium is 37 ± 0.5 ℃ 900ml 0.01M HCl.The quantity of dissolved zaleplon is measured by the UV spectrophotometry at 232nm.Stripping curve is seen Fig. 1.
Embodiment 3: the globule of coating
Derive from the zaleplon instant-free globule of the 1000g of embodiment 1 with the polymer suspension coating of following composition.
| Methacrylic acid copolymer Type B * | 50.00％ | 320.0g |
| Decanedioic acid dibutyl ester | 1.25％ | 8.0g |
| The sterilized talc powder | 2.50％ | 16.0g |
| Isopropyl alcohol | 43.25％ | 276.8g |
| Water USP | 3.00％ | 19.2g |
*Eudragit S 12.5
(Glatt Protech, Leicester England) carry out with the Wurster program coating at Glatt GPCG3.The stripping of globule is measured with USP I (40 order) in the 100rpm mixing speed.The stripping test is carried out 2h in 37 ± 0.5 ℃ 500ml 0.01M HCl.Then described globule is transferred in the 500ml pH7.2 phosphate buffer, the stripping test continues other 4h.The quantity of dissolved zaleplon is measured by the UV spectrophotometry at 232nm.Stripping curve is seen Fig. 2.
Embodiment 4: the globule of coating
Derive from the zaleplon instant-free globule of the 1000g of embodiment 1 with the polymer suspension coating of following composition.
| Methacrylic acid copolymer C type * | 53.0％ | 166.4g |
| Citric acid triethyl group ester | 1.6％ | 5.0g |
| The sterilized talc powder | 3.2％ | 10.0g |
| Water USP | 42.2％ | 132.5g |
*Eudragit L 30D 55
(Glatt Protech, Leicester England) carry out with the Wurster program coating at Uniglatt.Measure the stripping of globule as described in example 3 above.Stripping curve is seen Fig. 2.
Embodiment 5: the globule of coating
Derive from the zaleplon instant-free globule of the 1000g of embodiment 2 with the polymer suspension coating of following composition.
| Methacrylic acid copolymer C type * | 53.0％ | 166.4g |
| Citric acid triethyl group ester | 1.6％ | 5.0g |
| The sterilized talc powder | 3.2％ | 10.0g |
| Water USP | 42.2％ | 132.5g |
*Eudragit L 30D 55
(Glatt Protech, Leicester England) carry out with the Wurster program coating at the Uniglatt fluid bed processor.The stripping of globule is measured with USPI (40 order) in the 100rpm mixing speed.The stripping test is carried out 2h in 37 ± 0.5 ℃ 900ml 0.01M HCl.Then described globule is transferred in the 900ml pH7.2 phosphate buffer, the stripping test continues other 4h.The quantity of dissolved zaleplon is measured by the UV spectrophotometry at 232nm.Stripping curve is seen Fig. 2.
Embodiment 6: prolong the capsule that discharges
(Germany) preparation contains instant-free globule, the 95mg that 85mg derives from embodiment 1 and derives from the coating globule of embodiment 4 and the capsule of the coating globule that 91mg derives from embodiment 3 for Robert Bosch GmbH, Waiblingen with the Bosch sealer.The accumulated dose of zaleplon is 20mg.Condition shown in this capsular stripping simulation embodiment 5.This simulation stripping curve sees Fig. 3.
Embodiment 7: prolong the capsule that discharges
(Robert Bosch GmbH, Waiblingen Germany) produce and to contain 83mg and derive from the instant-free globule of embodiment 2 and the capsule of the coating globule that 91mg derives from embodiment 5 with the Bosch sealer.The accumulated dose of zaleplon is 20mg.Condition shown in this capsular stripping simulation embodiment 5.This simulation stripping curve sees Fig. 3.
Embodiment 8: the instant-free granule
(Glatt Protech, Leicester prepare the instant-free granule by top spray pelletize in England) at Glatt GPCG3.The waterborne suspension that will contain polyvinylpyrrolidone (Kollidon K30) and sodium lauryl sulphate is coated in the mixture of zaleplon, sodium starch glycollate (Explotab) and microcrystalline Cellulose (Avicel PH101).This is particulate composed as follows:
| Zaleplon (micronization) | 9.71％ | 194.2g |
| Microcrystalline Cellulose | 77.70％ | 1554.0g |
| Sodium starch glycollate | 3.88％ | 77.6g |
| Polyvinylpyrrolidone | 7.46％ | 149.2g |
| Sodium lauryl sulphate | 1.26％ | 25.2g |
Embodiment 9: the instant-free granule
(Glatt Protech, Leicester prepare the instant-free granule by top spray pelletize in England) at Glatt GPCG3.The waterborne suspension that will contain polyvinylpyrrolidone (Kollidon K30) and sodium lauryl sulphate is coated in the mixture of zaleplon, sodium starch glycollate (Explotab) and microcrystalline Cellulose (Avicel PH101).This is particulate composed as follows:
| Zaleplon (micronization) | 15.14％ | 302.8g |
| Microcrystalline Cellulose | 74.93％ | 1498.5g |
| Sodium starch glycollate | 4.04％ | 80.8g |
| Polyvinylpyrrolidone | 5.03％ | 100.6g |
| Sodium lauryl sulphate | 0.84％ | 16.8g |
Embodiment 10: immediate release tablet
(Pharmatech Ltd., Warwicks mix in England) and prepare immediate release tablet at V taper Pharmatech blender for instant-free granule by will deriving from embodiment 8 and sodium starch glycollate, silica sol and magnesium stearate.(Riva S.A., Buenos Aires Argentina) suppress this tablet with 10 grades of PiccolaTablet Press.This tablet composed as follows:
| Zaleplon (micronization) | 9.13％ | 6.67mg |
| Microcrystalline Cellulose | 73.04％ | 53.36mg |
| Sodium starch glycollate | 7.65％ | 5.59mg |
| Polyvinylpyrrolidone | 7.01％ | 5.12mg |
| Sodium lauryl sulphate | 1.18％ | 0.86mg |
| Silica sol | 1.00％ | 0.73mg |
| Magnesium stearate | 1.00％ | 0.73mg |
Stripping as embodiment 1 this tablet of measurement.Stripping curve sees Fig. 4.
Embodiment 11: immediate release tablet
(Pharmatech Ltd., Warwicks mix in England) and prepare immediate release tablet at V taper Pharmatech blender for instant-free granule by will deriving from embodiment 9 and sodium starch glycollate, silica sol and magnesium stearate.(Riva S.A., Buenos Aires Argentina) suppress this tablet with 10 grades of PiccolaTablet Press.This tablet composed as follows:
| Zaleplon (micronization) | 14.24％ | 10.00mg |
| Microcrystalline Cellulose | 70.43％ | 49.46mg |
| Sodium starch glycollate | 7.80％ | 5.48mg |
| Polyvinylpyrrolidone | 4.73％ | 3.32mg |
| Sodium lauryl sulphate | 0.79％ | 0.55mg |
| Silica sol | 1.00％ | 0.70mg |
| Magnesium stearate | 1.00％ | 0.70mg |
Stripping as embodiment 2 these tablets of measurement.Stripping curve sees Fig. 4.
Embodiment 12: the tablet of coating
Use polymer suspension coating in Vector LCDS-3 Coater of following composition to derive from the immediate release tablet of the 600g of embodiment 10.
| Methacrylic acid copolymer Type B * | 50.00％ | 192.00g |
| Decanedioic acid dibutyl ester | 1.25％ | 4.80g |
| The sterilized talc powder | 2.50％ | 9.60g |
| Isopropyl alcohol | 43.25％ | 166.08g |
| Water USP | 3.00％ | 11.52g |
*Eudragit S 12.5
Stripping as embodiment 3 these tablets of measurement.Stripping curve sees Fig. 5.
Embodiment 13: the tablet of coating
The polymer suspension that uses following composition Vector LCDS-3 Coater (VectorCorporation, Marion, Iowa, USA) in coating derive from the immediate release tablet of the 600g of embodiment 10.
| Methacrylic acid copolymer A type * | 50.00％ | 288.00g |
| Decanedioic acid dibutyl ester | 1.25％ | 7.20g |
| The sterilized talc powder | 2.50％ | 14.40g |
| Isopropyl alcohol | 43.25％ | 249.12g |
| Water USP | 3.00％ | 17.28g |
*Eudragit S 12.5
The stripping of this tablet of simulation under the condition shown in embodiment 3.This mimic stripping curve sees Fig. 5.
Embodiment 14: the tablet of coating
The polymer suspension that uses following composition Vector LCDS-3 Coater (VectorCorporation, Marion, Iowa, USA) in coating derive from the immediate release tablet of the 600g of embodiment 11.
| Methacrylic acid copolymer A type * | 50.00％ | 288.00g |
| Decanedioic acid dibutyl ester | 1.25％ | 7.20g |
| The sterilized talc powder | 2.50％ | 14.40g |
| Isopropyl alcohol | 43.25％ | 249.12g |
| Water USP | 3.00％ | 17.28g |
*Eudragit S 12.5
The stripping of this tablet of simulation under the condition shown in embodiment 5.This mimic stripping curve sees Fig. 5.
Embodiment 15: prolong release capsule
Manual preparation contains the capsule of the coated tablet of the coated tablet of immediate release tablet, a kind of embodiment of deriving from 12 of a kind of embodiment of deriving from 10 and a kind of embodiment of deriving from 13.Accumulated dose is each capsule 20mg zaleplon.This capsular stripping of simulation under the condition shown in embodiment 5.This mimic stripping curve sees Fig. 6.
Embodiment 16: prolong release capsule
Manual preparation contains the capsule of the coated tablet of the immediate release tablet of a kind of embodiment of deriving from 11 and a kind of embodiment of deriving from 14.Accumulated dose is each capsule 20mg zaleplon.This capsular stripping of simulation under the condition shown in embodiment 5.This mimic stripping curve sees Fig. 6.
Embodiment 17: to patient's administered over prolonged release capsule
To deliver medicine to the non-aged patient who has a rest in the length of one's sleep as the prolongation release capsule of preparation in embodiment 6.Observe the time range that causes sleep and arrive about 30 minutes about 20.Observe be not disturbed the length of one's sleep scope at about 6 hours to about 8 hours.
Embodiment 18: to patient's administered over prolonged release capsule
To deliver medicine to the non-aged patient who has a rest in the length of one's sleep as the prolongation release capsule of preparation in embodiment 15.Observe the time range that causes sleep and arrive about 30 minutes about 20.Observe be not disturbed the length of one's sleep scope at about 6 hours to about 8 hours.
Consider description of the present invention disclosed herein and practice, other embodiments of the present invention are conspicuous for those skilled in the art.Mean that it only is illustrative that this description and embodiment should be considered to, essential scope of the present invention and spirit are pointed out by following claims.
Claims (37)
1. pharmaceutical composition contains:
A) contain first component of zaleplon or its officinal salt; With
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5.
2. the pharmaceutical composition of claim 1, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 6.0.
3. the pharmaceutical composition of claim 1, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 7.0.
4. the pharmaceutical composition of claim 1, wherein said zaleplon be selected from 10,15,20 and the accumulated dose of 25mg exist.
5. the pharmaceutical composition of claim 1, wherein the quantitative range of the zaleplon that exists in each component from about 30% to about 70%.
6. pharmaceutical composition, wherein:
A) contain first component of zaleplon or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0.
7. the pharmaceutical composition of claim 6, wherein the quantitative range of the zaleplon that exists in each component from about 15% to about 50%.
8. pharmaceutical composition, wherein:
A) contain first component of zaleplon or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
9. the pharmaceutical composition of claim 8, wherein the quantitative range of the zaleplon that exists in each component from about 15% to about 50%.
10. pharmaceutical composition, wherein:
A) contain first component of zaleplon or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
11. the pharmaceutical composition of claim 10, wherein the quantitative range of the zaleplon that exists in each component from about 15% to about 50%.
12. a pharmaceutical composition, wherein:
A) contain first component of short-acting hypnotic or its officinal salt; With
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5.
13. the pharmaceutical composition of claim 12, wherein said short-acting hypnotic are selected from zaleplon, zopiclone, triazolam, temazepam, brotizolam, alimemazine or zolpidem and its associating.
14. the pharmaceutical composition of claim 12, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 6.0.
15. the pharmaceutical composition of claim 12, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 7.0.
16. a pharmaceutical composition, wherein:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0.
17. the pharmaceutical composition of claim 16, wherein said short-acting hypnotic are selected from zaleplon, zopiclone, triazolam, temazepam, brotizolam, alimemazine or zolpidem and its associating.
18. a pharmaceutical composition, wherein:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
19. the pharmaceutical composition of claim 18, wherein said short-acting hypnotic are selected from zaleplon, zopiclone, triazolam, temazepam, brotizolam, alimemazine or zolpidem and its associating.
20. a pharmaceutical composition, wherein:
A) contain first component of short-acting hypnotic or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains short-acting hypnotic or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 7.0.
21. the pharmaceutical composition of claim 20, wherein said short-acting hypnotic are selected from zaleplon, zopiclone, triazolam, temazepam, brotizolam, alimemazine or zolpidem and its associating.
22. the pharmaceutical composition of claim 12, wherein said short-acting hypnotic be selected from 1,5,10,15,20 and the accumulated dose of 25mg exist.
23. be used for the treatment of the method for sleep disorder, comprise that the patient to this treatment of needs gives the pharmaceutical composition of effective dose, described pharmaceutical composition contains:
A) contain first component of zaleplon or its officinal salt; With
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5.
24. the method for claim 23, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 6.0.
25. the method for claim 23, wherein said at least a polymer is soluble at the pH that is greater than or equal to about 7.0.
26. the method for the treatment sleep disorder of claim 23, wherein said sleep disorder is acute.
27. the method for the treatment sleep disorder of claim 23, wherein said sleep disorder is chronic.
28. be used for the treatment of the method for sleep disorder, comprise that the patient to this treatment of needs gives the pharmaceutical composition of effective dose, described pharmaceutical composition contains:
A) contain first component of zaleplon or its officinal salt;
B) contain second component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 5.5; With
C) contain the 3rd component of at least a particle, wherein said at least a particle comprise nuclear and at this extranuclear at least a coating, described nuclear contains zaleplon or its officinal salt, and described at least a coating contains at least a at the soluble pharmaceutically acceptable polymer of the pH that is greater than or equal to about 6.0.
29. the method for the treatment sleep disorder of claim 28, the described at least a pharmaceutically acceptable polymer of wherein said second component is being soluble at the pH that is greater than or equal to about 6.0, and the described at least a pharmaceutically acceptable polymer of described the 3rd component is being soluble at the pH that is greater than or equal to about 7.0.
30. the method for the treatment sleep disorder of claim 28, wherein said sleep disorder is acute.
31. the method for the treatment sleep disorder of claim 23, wherein said sleep disorder is chronic.
32. the method for inducing the patient to sleep contains the compositions that gives the claim 1 of sleep derivation effective dose to described patient.
33. prolong the method for patient's sleep, contain the sleep compositions of the claim 1 that prolongs effective dose to described patient.
34. the method for the treatment sleep disorder of claim 23, wherein said compositions are such forms: it can be sprayed onto on described patient's the food and by described patient and absorb.
35. the method for inducing the patient to sleep contains the compositions that gives the claim 12 of sleep derivation effective dose to described patient.
36. prolong the method for patient's sleep, contain the sleep compositions of the claim 12 that prolongs effective dose to described patient.
37. the method for claim 23, wherein said patient does not experience residual effect.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42636902P | 2002-11-15 | 2002-11-15 | |
| US60/426,369 | 2002-11-15 | ||
| US10/704,633 | 2003-11-12 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101028409A Division CN101156855A (en) | 2002-11-15 | 2003-11-14 | Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1738608A true CN1738608A (en) | 2006-02-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007101028409A Pending CN101156855A (en) | 2002-11-15 | 2003-11-14 | Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders |
| CNA2003801087750A Pending CN1738608A (en) | 2002-11-15 | 2003-11-14 | Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101028409A Pending CN101156855A (en) | 2002-11-15 | 2003-11-14 | Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824331A (en) * | 2012-09-28 | 2012-12-19 | 河南中帅医药科技发展有限公司 | Zaleplon double-release capsule and preparation method thereof |
-
2003
- 2003-11-14 CN CNA2007101028409A patent/CN101156855A/en active Pending
- 2003-11-14 CN CNA2003801087750A patent/CN1738608A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824331A (en) * | 2012-09-28 | 2012-12-19 | 河南中帅医药科技发展有限公司 | Zaleplon double-release capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101156855A (en) | 2008-04-09 |
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