Herein disclosed is controlled release preparation, it comprises: contain the core of core activating agent and wax excipient, substantially around core and contain delay release coating material delay to discharge coating; The release of activating agent is undertaken by zero level substantially in the wherein said preparation.The particular combinations of having found wax-matrix core and controlled release coat makes activating agent substantial linear from core discharge.Use wax-matrix or controlled release coat then not to provide zero level to discharge separately.

This paper also discloses preparation, and it comprises: contain the core of core activating agent and wax excipient, be centered around around this core substantially and contain delay release coating material delay to discharge coating; The basic unable to take food thing influence of wherein said preparation.By selecting suitable core material and coating material, the gained preparation has enough intensity preventing breaking or obviously destroying of dosage form, this break or destruction can make releasing properties suffer damage.The core of having found particular stiffness (" intensity ", for example about 10 to about 15 kPas (kPa)) can provide enough support effects for the coating of controlled release, to guarantee the integrity of coating when preparation is taken in food.

In another embodiment, described preparation comprises controlled release part and the instant-free part that is coated core form.The activating agent that exists in described controlled release part and the instant-free part can be identical or different.

Term " one ", " a kind of " do not represent the logarithm quantitative limitation, but there be in the mentioned project at least one in expression.Term " or " expression " and/or ".Term " comprises ", " having " and " comprising " is considered as open-ended term (i.e. expression " including but not limited to ").All comprise end points and can make up independently about the end points of all scopes of same composition or character.

" activating agent " expression is when it is combined when being administered to the patient direct or indirect chemical compound, element or the mixture that the patient is produced physiological action separately or with other chemical compound, element or mixture.Indirect physiological action can take place by metabolite or other indirect mechanism.When activating agent was chemical compound, crystal form, amorphous form and any polymorphic of the solvate (comprising hydrate) of salt, this free cpds or salt, this chemical compound all comprised in the present invention so.Chemical compound can comprise one or more asymmetric factors such as three-dimensional center, three-dimensional axle etc., asymmetric carbon atom for example, thus chemical compound can exist with different stereoisomeric forms in any ratio.These chemical compounds can be for example racemic modification or optically-active form.For the chemical compound with two or more asymmetric factors, these chemical compounds can also be the mixture of diastereomer.For chemical compound, comprise optical isomer of all pure forms and composition thereof with asymmetric center.In addition, the chemical compound with carbon-carbon double bond can exist with Z-formula and E-formula, comprises all isomeric forms of this chemical compound.In these cases, single enantiomer, i.e. optically-active form can be by asymmetric synthesis, synthetic or split by racemic modification and to obtain by optically pure precursor.Racemic modification split also can be for example by conventional method as crystallization in the presence of resolving agent or for example utilize chirality HPLC post to carry out chromatography and realize.No matter the method that is used to obtain them how, form of ownership is included among the present invention.

" pharmaceutically acceptable salt " comprises the derivant of activating agent, and wherein said activating agent is modified because of preparing its acid or base addition salts; This term also refers to pharmacy acceptable solvent thing, comprises hydrate, crystal form, amorphous form and the polymorphic of these salt.The example of pharmaceutically acceptable salt includes but not limited to that basic species (basic residue) is as the alkali of the mineral acid of amine or organic acid addition salt, acid (acidic residue) or organic addition salts etc. and the combination that comprises at least a aforementioned salt.Pharmaceutically acceptable salt comprises the salt and the quaternary ammonium salt of activating agent.For example, hydrochlorate comprises those that are obtained by mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc.; Other can be accepted inorganic salt and comprise slaine such as sodium salt, potassium salt, cesium salt etc.; Alkali salt such as calcium salt, magnesium salt etc., and the combination that comprises at least a aforementioned salt.Pharmacy can be accepted organic salt and comprise by organic acid such as acetic acid, propanoic acid, succinic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pounce on acid (pamoic acid), maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethyl sulfonic acid (esylic acid), benzenesulfonic acid, p-anilinesulfonic acid., the 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethionic acid, oxalic acid, hydroxyethylsulfonic acid., HOOC-(CH₂)_nThe salt that-COOH (wherein n is 0-4) etc. makes, organic amine salt such as triethylamine salt, pyridiniujm, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt etc., amino acid salts such as arginine salt, aspartate, glutamate, Glu etc., and the combination that comprises at least a aforementioned salt.

Except as otherwise noted, " fexofenadine " refers to fexofenadine free alkali or the acceptable fexofenadine salt of pharmacy, comprises its any solvate, hydrate, crystal form and amorphous form.

" dosage form " (" dosage form " or " dosage formulation ") refers to the activating agent unit of using.The example of dosage form comprises tablet, capsule, injection, suspensoid, liquid, Emulsion, emulsifiable paste, ointment, suppository, inhalable formulations, percutaneous preparation etc.Except as otherwise noted, " dosage form " and " preparation " can exchange use.

" peroral dosage form " is intended to comprise and is used for oral unit dosage forms.Peroral dosage form can randomly comprise a plurality of subunits such as microcapsule or microplate.Can pack a plurality of subunits uses being used for single agent.

" subunit " is intended to comprise can be separately or provide the compositions, mixture, granule, pill etc. of peroral dosage form with other subunit combination.

" bioavailability " refers to that activating agent is absorbed and enters in the live body system or in available degree in physiologically active position or speed.For being intended to absorb the activating agent that enters in the blood flow, can provide institute's application dosage to be absorbed for the biological utilisation degrees of data of customization agent to enter the relative mark estimated value of systemic circulation." bioavailability " can characterize with one or more pharmacokinetic parameters.

" pharmacokinetic parameter " describes activating agent (or surrogate markers thing of activating agent) body internal characteristic in time, for example plasma concentration (C), C_Max, C_n, C₂₄, T_MaxAnd AUC." C_Max" be activating agent measured concentration during maximum concentration site in blood plasma." C_n" be the measurement concentration of activating agent in the blood plasma about n hour time the after using." C₂₄" be the measurement concentration of activating agent in the blood plasma about 24 hours time the after using.Term " T_Max" refer to the time when the measurement concentration of activating agent is the highest in the blood plasma after the administering active agents." AUC " be in measurement concentration (normally plasma concentration) curve chart in time at activating agent from a time point to the measured area under curve of another time point.For example, AUC_0-tBe to be carved into t area under curve constantly in the plasma concentration versus time curve from 0 o'clock.AUC_0-∞Or AUC_0-INFBe to be carved into the infinitely great area under curve of constantly being calculated in the plasma concentration versus time curve from 0 o'clock.

" food " is often referred to has enough volumes and fat content and can be under one's belt by food that dissolves fast and absorb or solid/liquid mixed food.In one embodiment, food refers to canteen, as breakfast, lunch or dinner.Term " is taken with food ", " feed " and " not fasting " is equal to, and the implication that provides with FDA guide and standard is identical.In one embodiment, " with food " referred to before the patient is having a dinner about 30 minutes to form of administration in about 2 hours after the meal.In another embodiment, " with food " refers to form of administration when having a dinner basically.

Term " does not have food ", " fasting " and " on an empty stomach " is equal to, and the implication that provides with FDA guide and standard is identical.In one embodiment, " fasting " state of being illustrated in before the form of administration in 1 hour or form of administration after, not having in 2 hours to take food.In another embodiment, " fasting " be illustrated in before the form of administration 1 hour to the state that form of administration after, does not have within 2 hours to take food.

" basic unable to take food thing influence " is illustrated in the pharmacokinetics of oral administered formulation feed state (" not fasting ") under and is basic identical when using under fasting state.For example, the C of single administered formulation and single administration same preparation under fasting state under the state on the feed_MaxOr the comparative result between the AUC is C_MaxOr 90% confidence interval that has of AUC percentage ratio be the upper limit be less than or equal to 125% or lower limit more than or equal to 80%.This information can be based on the logarithm data converted.Exemplary research Consideration is found in the guide and the standard of federal drug administration (FDA), comprise and to obtain in " the Guidance for Industry; Food-Effect Bioavailability and Fed Bioeq uivalence Studies " of in December, 2002 formulation from U.S. HHS (DHHS), Food and Drug Administration (FDA), CDER (CDER) that its full content is incorporated herein.

Stripping curve is the cumulant function curve in time of the activating agent that discharges from preparation.Stripping curve can utilize drug release test＜724〉(comprising code test USP 26 (test＜711 〉)) record.Temperature, volume and the pH value of selected test condition of curve negotiating such as type of device, axle speed, dissolve medium characterize.Can measure more than one stripping curve.For example, first stripping curve can record under the pH level near stomach, and second stripping curve can be near intestinal records under a plurality of pH levels of a plurality of points under certain any pH level or near intestinal.

Peracidity pH can be used for simulating stomach, and weaker acid can be used for simulating intestinal to the pH of alkalescence.Term " peracidity pH " refers to about 1 to about 4 pH.For example about 1.2 pH can be used for simulating the pH of stomach.Term " weaker acid to alkalescence pH " refers to greater than about 4 to about 7.5, about 6 to about 7.5 pH particularly.About 6 to about pH of 7.5, particularly about 6.8 can be used for simulating the pH of intestinal.

" instant-free " refers to routine or not improved release, wherein more than or equal in after using 2 hours of about 75% activating agent, particularly discharge in 1 hour after using.

" controlled release " refers to the controlled or dosage form that changes in the certain hour section that is released in of activating agent wherein.Controlled can represent for example to delay, continue, postpone to discharge or when special time pulse discharge.As selection, controlledly can represent that the release of activating agent is extended, and for example prolongs some hrs at least in the instant-free dosage form.

Dosage form can not only have the instant-free characteristic but also have controlled release characteristics, for example the combination of instant-free pill and controlled release pill; The combination of instant-free coating and controlled release core (comprising the tablet core) etc.The instant-free part of combination dosage forms can be called load doses (loading dose).

24 HOUR are sold and are delayed to discharge fexofenadine hydrochloride (180mg)/pseudoephedrine hydrochloride (240mg) oral tablet product by new drug application No.021704 approval by Sanofi-Aventis.

12 HOUR are sold and are delayed to discharge fexofenadine hydrochloride (60mg)/pseudoephedrine hydrochloride (120mg) oral tablet product by new drug application No.020786 approval by Sanofi-Aventis.

Disclosed herein is to show the fexofenadine of basic unable to take food thing influence and the combination dosage forms of pseudoephedrine.

This paper also discloses the combination dosage forms of fexofenadine and pseudoephedrine, wherein pseudoephedrine discharges by zero level or near zero level substantially and discharges from dosage form, promptly as draw that activating agent release profiles in time measures, the rate of release of pseudoephedrine is constant substantially in time.In specific embodiments, described being released at least 8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 or 24 hours undertaken by zero level.

Described core can be forms such as granule, pill, beadlet, tablet, particularly as tablet.

In certain embodiments, preparation as herein described show with street drug as

24 HOUR or

The bioequivalence of 12 HOUR.

" bioequivalence " refers to that when using, activating agent in medicine equivalent or the medicine succedaneum or activating agent surrogate markers thing can not have notable difference for speed and the degree utilized at site of action in the research of suitably design.

In one embodiment, bioequivalence is any definition by the issue of any adoption of U.S. food and drug administration or its mechanism.In a particular, bioequivalence is determined according to the guide and the standard of federal drug administration (FDA), comprising can be from U.S. HHS (DHHS), the revised edition 1 of working out in March, 2003 that Food and Drug Administration (FDA) and CDER (CDER) obtain " about the industrial bioavailability of oral drug and bioequivalence Journal of Sex Research guideline-general Consideration (GUIDANCE FORINDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIESFOR ORALLY ADMINISTERED DRUG PRODUCTS-GENERALCONSIDERATIONS) ", and DHHS, FDA, CDER determines that in " about determining the industrial statistics method guideline (GUIDANCE FORINDUSTRY STATISTIC ALAPPROACHES TO ESTABLISHINGBIOEQUIVALENCE) of bioequivalence " that work out January calendar year 2001 these two guidelines all are incorporated herein in full.

In one embodiment, the compositions pharmacokinetic parameter of determining surfactant composition by interior medicine dynamics than the bioequivalence of reference medicine is determined.Particularly, bioequivalence can by in the pharmacokinetic study in vivo relatively the pharmacokinetic parameter of these two kinds of compositionss determine.The pharmacokinetic parameter of surfactant composition or reference medicine can utilize repetition or non-design iterations to measure in single dose or multiple dose bioequivalence Journal of Sex Research.For example, the pharmacokinetic parameter of surfactant composition of the present invention and reference medicine can utilize binary cycle two order cross-over design to measure in the single dose of drug dynamics research.As selection, phase design iterations crossing research around also can utilizing.Use the test composition and the reference medicine of single dose, and measure the blood levels or the blood plasma level of activating agent in time.Statistical evaluation characterizes the speed of activating agent absorption and the pharmacokinetic parameter of degree.

But can measure the measurement moment (AUC from 0 moment to last quantitative concentrations in plasma concentration-time graph according to standard technique_0-t) and to infinitely great (AUC_0-∞) area under curve, C_MaxAnd T_MaxThe statistical analysis of pharmacokinetic data is at logarithm data converted (AUC for example_0-t, AUC_0-∞Or C_MaxData) utilize variance analysis (ANOVA) to carry out.

According to the U.S. FDA guideline, if two kinds of products (Fexofenadine customization agent for example of the present invention and

24Hour) or two kinds of methods (for example not administration under administration and the fasted conditions under the fasted conditions) to number conversion AUC_0-∞, AUC_0-tAnd C_Max90% confidence interval (CI) limit of ratio of geometrical mean be about 0.80 to about 1.25, then these two kinds of products or method are bioequivalent.

In another embodiment, according to can (European Medicines Agency, EMEA) the EMEA file of publishing the July 26 calendar year 2001 that obtains " Note for Guidance onthe Investigation of Bioavailability and Bioequivalence " be determined bioequivalence from Europe medicine office.

For showing according to the bioequivalence between two kinds of chemical compounds of European EMEA guide or the application conditions, two kinds of products or method to number conversion AUC_0-∞And AUC_0-tThe 90% CI limit of ratio of geometrical mean be about 0.80 to about 1.25.When the Consideration from safety and effectiveness proves, two kinds of products or method to number conversion C_MaxThe 90% CI limit of ratio of geometrical mean can have wideer allowed band.For example, allowed band can be about 0.70 to about 1.43, particularly about 0.75 to about 1.33, more particularly about 0.80 to about 1.25.

In one embodiment, in given experiment, if to number conversion AUC_0-∞, AUC_0-tOr C_MaxThe corresponding 90% CI bound of ratio of test/reference of geometrical mean in the scope of about 0.8 lower limit and about 1.25 upper limits, then surfactant composition is considered as and reference product bioequivalence.Therefore, for direct relatively surfactant composition of the present invention and reference product, can be in same pharmacokinetic study the pharmacokinetic parameter of the described surfactant composition of parallel assay and reference product.

In certain embodiments, single-dose bioequivalence Journal of Sex Research is not carrying out under fasting or the fasted conditions.

In other embodiments, the specification that adopts FDA to stipulate in APPROVED DRUG PRODUCTSWITH THERAPEUTIC EQUIVALENCE EVALUATIONS (orange paper) is carried out single dose bioequivalence Journal of Sex Research between surfactant composition and listed reference medicine.

In certain embodiments, carry out bioequivalence Journal of Sex Research in the body, relatively to have all surfactant compositions of the corresponding specification of reference product (for example 60,120 or 180mg activating agent).In other embodiments, only surfactant composition of the present invention is carried out body in bioequivalence Journal of Sex Research under the lower or high gauge in the specification of listed reference medicine (for example approval high standard) down with at other, compositions of the present invention meets the dissolution test of reference product.

In one embodiment, controlled release preparation comprises fexofenadine and pseudoephedrine, wherein said preparation show controlled release preparation to number conversion AUC_0-∞Geometrical mean with press fexofenadine/pseudoephedrine reference medicine that new drug application No.021704 ratifies to number conversion AUC_0-∞The ratio of geometrical mean be about 0.80 to about 1.25.

In another embodiment, controlled release preparation comprises fexofenadine and pseudoephedrine, wherein said preparation show controlled release preparation to number conversion AUC_0-tGeometrical mean with press fexofenadine/pseudoephedrine reference medicine that new drug application No.021704 ratifies to number conversion AUC_0-tThe ratio of geometrical mean be about 0.80 to about 1.25.

In another embodiment, controlled release preparation comprises fexofenadine, wherein said preparation show controlled release preparation to number conversion C_MaxGeometrical mean with press fexofenadine/pseudoephedrine reference medicine that new drug application No.021704 ratifies to number conversion C_MaxThe ratio of geometrical mean be about 0.70 to about 1.43.

In another embodiment, controlled release preparation comprises fexofenadine and pseudoephedrine, wherein said preparation show controlled release preparation to number conversion C_MaxGeometrical mean with press fexofenadine/pseudoephedrine reference medicine that new drug application No.021704 ratifies to number conversion C_MaxThe ratio of geometrical mean be about 0.80 to about 1.25.

The suitable activity agent that is used for core or instant-free coating can comprise for example α 2 adrenergic agents, analgesics, angiotensin converting enzyme (ACE) inhibitor, antianxiety drug, anti-arrhythmic, antibacterial, antibiotic, antidepressant, the treatment Rezulin, antiemetic, antuepileptic, antifungal, vermifuge, hydryllin, antihyperlipidemic, hypotensive agent, anti-infective, antimalarial, antimicrobial, the migraine agent, muscarine antagonist, antineoplastic agent, antiprotozoal drug, psychosis, spasmolytic, antiviral agent, attention deficit moves obstacle (ADHD) agent more, beta blocker, calcium channel blocker, chemotherapeutics, cholinesterase inhibitor, the Cox-2 inhibitor, alleviate congested agent, diuretic, histamine-2 receptor antagonist, sleeping pill, depressor, immunosuppressant, lipotropic, psychosis, opioid analgesic, peripheral vasodilation agent/vasoconstrictor, tranquilizer, the 5-hydroxytryptamine receptor agonist, sympathomimetic, and their pharmaceutically-acceptable salts, solvate, hydrate, stereoisomer (racemic modification, single enantiomer or diastereomer, or their combination in any) or polymorphic, or the medicine that comprises at least a aforementioned activating agent can accept combination etc.

Exemplary pharmaceutically active agents comprises amphetamine, brompheniramine, cetirizine, chlorphenamine, clemastine, Desloratadine, dextro-amphetamine, the diltiazem leather, diphenhydramine, fexofenadine, fluvastatin, guaifenesin, hydromorphone, loratadine (loratidine), morphine, oxibutynin, oxycodone, paroxetine, Propranolol, pseudoephedrine, teldane (terphenadine), tolterodine, venlafaxine, Sulfamethoxazole, trimethoprim and their pharmaceutically-acceptable salts, solvate, hydrate, stereoisomer (racemic modification, single enantiomer or diastereomer, or their combination in any) or polymorphic, or the medicine that comprises at least a aforementioned activating agent can accept combination.

Especially, described activating agent is pseudoephedrine ([S-(R^*, R^*)]-α-[1-(methylamino) ethyl]-benzyl alcohol), pseudoephedrine salt (for example hydrochlorate), fexofenadine ((±)-4-[1-hydroxyl-4-[4-(hydroxyl diphenyl methyl)-piperidino]-butyl]-α, alpha-alpha-dimethyl phenyl acetic acid, fexofenadine salt (for example hydrochlorate) and their combination.Known fexofenadine (comprising fexofenadine hydrochloride) exists with many different polymorphics, and the character that the unexpected polymorphic of finding specific fexofenadine of the inventor can appreciable impact fexofenadine dosage form, for example stripping character.Suitable fexofenadine free alkali and salt comprise United States Patent (USP) and the open No.6613906 of patent application, 2002193603 (anhydrous hydrochloric acid Fexofenadine definite form I and form III, and hydration fexofenadine hydrochloride form II and form IV), US2002193601, US2005090528 (fexofenadine free alkali), US20020177608, US2003021849, US20040044038, US2004058955, US2004167168, US2004077683, US2004248935, US2005090528, US20050165056, US20050256163, those disclosed among open WO2005019175 of US20050282860 and US20060025444 and PCT and the WO2006037042, the full content of every piece of document all is incorporated herein by reference.

Preparation disclosed herein comprises the core that contains activating agent, wax excipient and optional other core excipient.

Be used in wax excipient in the described core and can be the solid wax under the room temperature, for example solid hydrophobic material (promptly water insoluble) or solid hydrophilic material (for example Polyethylene Glycol is water miscible), but solid hydrophobic material especially.

Exemplary wax excipient comprises wax and wax shape excipient, for example Brazil wax (obtaining), vegetable wax (vegetable wax), wax for waxing fruits, microwax (" pertroleum wax "), Cera Flava from palm Copernicia Cerifera (white or bleached and xanchromatic), chloroflo, paraffin, cetyl esters wax, nonionic emulsifing wax, anionic emulsifing wax, candelilla wax or comprise the combination of at least a aforementioned wax.Other suitable wax excipient comprises that for example aliphatic alcohol (for example lauryl alcohol, myristyl alcohol, stearyl alcohol, spermol or particularly cetearyl alcohol), hydrogenated vegetable oil, castor oil hydrogenated, fatty acid such as stearic acid, fatty acid ester comprise fatty glyceride (monoglyceride, diglyceride and triglyceride ester), number-average molecular weight M_nPolyethylene Glycol greater than about 3000 (PEG, for example PEG 3350, PEG 4000, PEG 4600, PEG 6000 and PEG 8000) or comprise the combination of at least a aforementioned wax excipient.In the combination in any of wax excipient is also included within.

The fusing point of wax excipient is the above temperature of room temperature, especially about 30 to about 150 ℃, and more particularly about 75 to about 100 ℃, more particularly about 75 to about 90 ℃.

The amount of wax excipient in core can based on selected specific wax or wax makes up and the desired target release characteristics of gained preparation is determined.Wax examples of excipients amount comprise based on except that the gross weight meter that delays to discharge the core the coating about 5 to about 60wt%, especially about 10 to about 50wt%, more particularly about 15 to about 40wt%.

Described core also comprises core activating agent such as pseudoephedrine.In the core amount of activating agent for example comprise based on except that the gross weight meter that delays to discharge the core the coating about 30 to about 60wt%, especially about 35 to about 50wt%, more particularly about 40 to about 45wt%.

Described core is chosen wantonly and is also comprised the extra releasable material that delays.The described extra releasable material that delays comprises that for example acrylic polymer, alkylcellulose comprise that substituted alkyl cellulose, Lac, zein, polyvinylpyrrolidine comprise crospolyvinylpyrrolidone, vinyl acetate copolymer, polyoxyethylene, polyvinyl alcohol and the combination that comprises at least a previous materials.

Comprise for example acrylic acid and methacrylic acid copolymer as the suitable acrylic polymer that additionally delays releasable material, methylmethacrylate copolymer, the methacrylic acid ethoxy ethyl ester, methacrylic acid cyano group ethyl ester, the amino alkyl methacrylate copolymer, poly-(acrylic acid), poly-(methacrylic acid), methacrylic acid alkylamide copolymer, poly-(methyl methacrylate), poly-(methacrylic anhydride), methyl methacrylate, polymethacrylates, poly-(methyl methacrylate) copolymer, polyacrylamide, the amino alkyl methacrylate copolymer, methyl propenoic acid glycidyl base ester copolymer, perhaps comprise the combination of at least a aforementioned polymer.Acrylic polymer can comprise the methacrylate copolymer of the full polymerization copolymer of acrylate that contains a small amount of quaternary ammonium group described in the NF XXIV and methacrylate.

Suitable alkylcellulose and substituted alkyl cellulose comprise the alkyl-alkylcellulose (as hydroxypropyl emthylcellulose) of for example alkylcellulose of methylcellulose, ethyl cellulose, hydroxyl or carboxyl substituted (for example hydroxy propyl cellulose, crosslinked hydroxypropyl cellulose, carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose), hydroxyl replacement or comprise the cellulosic combination of at least a aforesaid alkyl.

Described extra other delay releasable material with based on the coregross weight 0 to about 65wt%, especially about 0.1 to about 50wt%, more particularly about 10 to about 45wt%, more particularly about amount of 15 to about 30wt% is present in the core.Except extra delaying the releasable material, optional binding agent, filler, disintegrating agent, lubricant, the fluidizer etc. of comprising of other core excipient.

Optional disintegrating agent is used for promoting core to decompose at fluid environment (particularly aqueous environment).The selection of disintegrating agent and amount are arranged to guarantee to obtain desired preparation stripping curve or are provided desired body inner control to discharge.Can swelling or expansible material when exemplary disintegrating agent comprises in being exposed to fluid environment (particularly aqueous environment).Exemplary disintegrating agent comprises alkylcellulose (for example hydroxypropyl cellulose), the starch that hydroxyl replaces, the pregelatinized Starch (Starch that can obtain from Colorcon for example

), (for example " croscarmellosesodium " can be from FMC BioPolymer of Philadelphia, and PA obtains for cross-linking sodium carboxymethyl cellulose

), the cross-linked homopolymer of N-vinyl-2-Pyrrolidone (as " crospovidone ", for example can be from International Specialty Products, Wayne NJ obtains

XL,

XL-10 and

INF-10), modified starch such as carboxymethyl starch sodium, Explotab (as

) etc., alginate, or comprise the combination of at least a aforementioned disintegrating agent.

The consumption of disintegrating agent depends on the target release characteristics of selected disintegrating agent or disintegrating agent combination and gained preparation.Exemplary amount comprise based on the core gross weight about 0 to about 10wt%, especially about 0.5 to about 7.0wt%, more particularly about 0.1 to about 5.0wt%.

Exemplary lubricants comprises stearic acid, stearate (as calcium stearate, magnesium stearate and zinc stearate), stearyl fumarate, behenic acid glyceride, mineral oil, Polyethylene Glycol, Talcum, hydrogenated vegetable oil, based on the fatty acid (vegetable based fattyacid) of plant or comprise the combination of at least a aforementioned substances.Fluidizer comprises for example silicon dioxide (as aerosil (fumedsilicon dioxide) or silica sol).Generally acknowledge that some material can not only can serve as fluidizer but also can serve as lubricant.

Lubricant or fluidizer with the core gross weight about 0.1 to about 15wt%, especially about 0.5 to about 5wt%, more particularly about amount of 0.75 to about 3wt% is used.

Described core prepares by methods known in the art, comprise pelletize (dry method or wet method) and compacting, round as a ball, melt extrude, hot melt etc.

In case core forms, just it is coated with the coating that delays to discharge.Basically being centered around delaying around the core discharges coating and comprises coating material and optional other component such as plasticizer, the porogen etc. that delay to discharge.

The coating that delays to discharge with the gross weight that discharges coating based on core and time-delay about 0.1 to about 30wt%, especially about 3.0 to about 25wt%, more particularly about 4.0 to about 20wt%, particularly about amount of 5.0 to about 20wt% is present in the preparation.

Utilize known coating method (as simple or complicated cohesion, interfacial polymerization, liquid dried, Thermogelling and ionic gelization, spray drying, spray cooling, fluidized bed coating, pan coating, electrostatic precipitation, pressed coated, dry polymeric powder coating etc.) that the coating that delays to discharge is provided on core.

The coating material that delays to discharge for example is the form that comprises the film coating of hydrophobic polymer dispersion.The solvent that is used to apply controlled release coat comprises medicine acceptable solvent such as water, methanol, ethanol, dichloromethane and the combination that comprises at least a aforementioned solvents.

What can for example change activating agent by the following method delays release characteristics (body in or external): the release coating material that delays that uses more than one, change the thickness that delays release coating material, change the used release coating material that specifically delays, change the relative quantity that delays release coating material, use plasticizer, change the adding mode when obtaining (for example when delay to discharge the aqueous dispersion of coating) of plasticizer by hydrophobic polymer, change plasticizer with respect to the amount that delays release coating material, add other coating excipient, change preparation method etc.

The exemplary release coating material that delays comprises film forming polymer, for example alkylcellulose comprises methylcellulose or ethyl cellulose, hydroxy alkyl cellulose such as hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose, hydroxyalkyl alkylcellulose such as hydroxyethylmethyl-cellulose and hydroxypropyl emthylcellulose, carboxyl alkyl cellulose such as carboxymethyl cellulose, the alkali metal salt of carboxyl alkyl cellulose such as sodium carboxymethyl cellulose, carboxyalkyl alkylcellulose such as carboxymethylethylcellulose, the carboxyl alkyl cellulose ester, starch, pectin such as carboxymethyl amylopectin, chitin (chitine) derivant such as chitosan, polysaccharide such as alginic acid, their alkali metal salt and ammonium salt, carrageenin, galactomannan, traganth (traganth), agar, arabic gum, guar gum and xanthan gum, polyacrylic acid and salt thereof, polymethylacrylic acid and salt thereof, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxide such as poly(ethylene oxide), poly(propylene oxide), and the copolymer of oxirane and expoxy propane, or comprise the combination of at least a aforementioned substances.

The optional combination that comprises plasticizer, other film former, porogen or comprise at least a aforementioned substances of controlled release coat.

The also optional non-functional coating that comprises of described preparation." functional coatings " is intended to comprise the coating that changes total preparation releasing properties, the controlled release coat that continues release for example is provided." non-functional coating " is intended to comprise the coating that does not significantly change total preparation releasing properties, and the decoration that for example is used for separation function coating and other component of preparation is with coating or interlayer coating.The non-functional coating can produce some influence because of the initial stripping of coating, hydration, perforation etc. discharge activating agent, but does not think to produce coated composition not and significantly depart from.

Randomly the pore material is added in the controlled release coat to promote that activating agent disengages from core.The pore material is an organic or inorganic, the material that it is can stripping from coating in environment for use, extract or leach, and perhaps it can have the dissolution properties that relies on pH value etc.Exemplary pore material comprises hydrophilic polymer such as hydroxyalkyl-alkylcellulose (as hydroxypropyl emthylcellulose etc.), hydroxy alkyl cellulose (as hydroxypropyl cellulose etc.) or polyvidone, saccharide (as lactose etc.), Metallic stearates, inorganic salt is (as calcium hydrogen phosphate, sodium chloride etc.), Polyethylene Glycol (as Polyethylene Glycol (PEG) 1450 etc.), sugar alcohol is (as sorbitol, mannitol etc.), alkylsurfuric acid alkali metal salt (as sodium lauryl sulfate), polyoxyethylene sorbitan fatty acid esters (as polysorbate (Polysorbate)), methacrylate copolymer is (as EUDRAGIT

RL), perhaps comprise the combination of at least a aforementioned pore material.

Specific delay release coating material comprise ethyl cellulose and randomly with the combination of hydroxypropyl emthylcellulose.

In one embodiment, ethyl cellulose is about 90:10 with the ratio of hydroxypropyl emthylcellulose, especially about 60:40, more particularly about 50:50.

In one embodiment, described controlled release core is at about 6 hours to about 24 hours, especially disengages the core activating agent in about 12 hours or about 24 hours time period.

In one embodiment, described preparation comprises the controlled release part of coating core form and is arranged on instant-free part at least a portion of described controlled release core.Said preparation is made into for example double-layer tablet, coated tablet, compression coated tablets or any other suitable form.In one embodiment, described instant-free partly is the coating core coating form on every side that is centered around substantially of for example utilizing spray coating, pressed coated or other suitable technique to use.The activating agent that exists in controlled release part and the instant-free part can be identical or different.In one embodiment, the activating agent in the controlled release part is a pseudoephedrine, and the activating agent in the instant-free part is a fexofenadine.The amount of pseudoephedrine in preparation is 80-300mg, especially 60-240mg, more particularly 120 or 240mg.The amount that Fexofenadine fixes in the preparation is 40-250mg, especially 60-180mg, more particularly 60 or 180mg.

In one embodiment, the instant-free of described preparation partly is the coating form that comprises activating agent (as fexofenadine) and one or more following compositions: excipient such as disintegrating agent (as polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch), binding agent (as polyvidone), lubricant (as magnesium stearate, Polyethylene Glycol), filler (as microcrystalline Cellulose, silica sol), solubilizing agent and/or wetting agent (as polysorbate 80) and the combination that comprises one or more aforementioned excipients.

The inventor is surprised to find that the character that fexofenadine hydrochloride discharges is subjected to the hydration status and/or polymorphous influence of fexofenadine hydrochloride from the instant-free compositions.In one embodiment, fexofenadine hydrochloride is substantially free of the form I of anhydrous hydrochloric acid fexofenadine." be substantially free of the form I of anhydrous hydrochloric acid fexofenadine " and represent that this fexofenadine hydrochloride lacks at least one following main x ray diffraction peaks: 11.8,7.3,6.3,5.9,5.0,4.8,4.4,3.9,3.8 and 3.7 dusts.In another embodiment, fexofenadine hydrochloride is substantially free of the form I or the form II of anhydrous hydrochloric acid fexofenadine." be substantially free of the form II of anhydrous hydrochloric acid fexofenadine " and represent that this fexofenadine hydrochloride lacks at least one following main x ray diffraction peaks: 7.8,6.4,5.2,4.9,4.7,4.4,4.2,4.1,3.7,3.6 and 3.5 dusts.

In one embodiment, fexofenadine hydrochloride is the fexofenadine hydrochloride of the type of C basically described in the WO2005019175, and the full content of the document is incorporated herein by reference." fexofenadine hydrochloride of C type basically " represents that this fexofenadine hydrochloride has the characteristic peak that is positioned at following place: at 9.85,5.97,5.52,5.19,4.83,4.59,4.49,4.20,4.13,3.85 and 3.73 dust places, perhaps 2 θ values are 8.9712,14.8293,16.0514,17.0775,18.3418,19.3099,19.7703,21.1340,21.5207,23.0743 and 23.8286 degree.

In one embodiment, described fexofenadine hydrochloride is the fexofenadine hydrochloride of the type of X basically described in US 20040077683 and the US20040058955, and the full content of these two pieces of documents is incorporated herein by reference." fexofenadine hydrochloride of X type basically " represents that this fexofenadine hydrochloride has the characteristic peak that is positioned at following place: at 16.05,12.98,8.29,8.06,6.25,5.97,5.54,5.41,4.89,4.70,4.55,4.37,4.32,4.15,4.03,3.80,3.67,3.57 and 3.42 dust places, perhaps 2 θ values are 4.2,8.0,9.3,14.2,16.0,16.8,17.2,17.6,18.8,20.0,20.6,21.7,22.9,23.8,24.2 and 24.4 degree.

In another embodiment, fexofenadine and one or more excipient deposition (for example spraying) are arrived tablet core in the heart to form successive basically coating.In a specific embodiment, described fexofenadine is the fexofenadine hydrochloride of anhydrous form, and this anhydrous hydrochloric acid fexofenadine and one or more excipient are deposited on the core with the solution that contains non-aqueous solvent (as isopropyl alcohol) or the form of suspension.

In one embodiment, the polymorphic fexofenadine hydrochloride before depositing on the core is basic identical with the polymorphic fexofenadine hydrochloride after depositing on the core.That is to say that depositing operation does not change the polymorphic of described fexofenadine hydrochloride substantially." basic identical " expression is less than 5%, be less than 2%, be less than 1% or be less than 0.5% Fexofenadine and fix on deposition and the time changed its polymorphic.

When in desired dissolution medium, testing, pseudoephedrine disclosed herein/Fexofenadine customization agent can show basically with

Stripping curve in the similar body of stripping curve of 24 HOUR products (NDA No.021704).

This paper also comprises medicine box, and it comprises one or more containers that comprise controlled release preparation, and wherein said preparation comprises the core that contains activating agent and wax excipient and contains and delays release coating material and be centered around substantially to delay to discharge coating around the described core.Described medicine box can also comprise one or more conventional kit components, operation instructions of for example one or more containers that help lend some impetus to concrete dosage regimen compliance, one or more carriers, printing (put into medicine box or as the amount of label with the explanation composition of being used) or use guidance.Exemplary medicine box can be the form of bubble-cap or blister plate, can randomly settle with desired sequence for concrete dosage regimen.Can settle in every way with the suitable blister that adapts to concrete dosage regimen be this area as everyone knows or determined by those of ordinary skills easily.

Embodiment

The preparation of embodiment 1 pseudoephedrine hydrochloride delayed release tablets core (240mg)

What preparation had following table 1 a listed component delays to discharge Sudanyl core (drug core and delay to discharge coating).

Table 1

^*In final products, do not find

This tablet core is by pelletize in blender/comminutor made in 5 minutes with pseudoephedrine hydrochloride and Brazil wax.Under mixing and mild heat, stearic acid is dissolved in the denatured alcohol.Add described stearic acid mixture in described activating agent/wax mixture and mix and form granule.With gained particle drying and grinding.Granule through grinding is installed in the Gemco blender, and will join in the described Gemco blender and mixing through the hydroxypropyl cellulose and the silicon dioxide of screening.The magnesium stearate and the mixing that then add through screening form mixture.Then in flakes with the compacting of gained mixture.Use by

The sheet that the core coating enrobed compacted that the suspension of Clear and water makes becomes, the Defed core that delays to discharge with formation.

Utilization is according to the method for testing rules of USP 26,711, use 37 ℃ ± 0.5 ℃ of 900ml down dissolution medium and the oar speed of per minute 50 commentaries on classics (rpm), the external stripping situation of the delayed release tablets core of preparation A-D in the analytical table 1.The result of stripping analysis is summarized among following table 2a and the 2b, comprise embodiment 1 not coating core and

The test result of 24HOUR sample.

Table 2a

Table 2b

As show shown in the stripping result of 2a and Fig. 1-2, the delaying of preparation A-C discharges that the Defed core shows basic zero level or near the release profiles of zero level.

Table 2b comprises the stripping result of preparation D in multiple dissolution medium.As indicated in the result, the release of activating agent pH value basic and medium is irrelevant, and is zero level basically.

Embodiment 2 fexofenadine hydrochlorides/pseudoephedrine hydrochloride delayed release tablets (180mg/240mg):

Preparation is delaying to discharge the release dosage form that delays that has instant-free fexofenadine hydrochloride coating on the Sudanyl core.

Preparation has the fexofenadine hydrochloride spray coating preparation of the component of following table 3:

Table 3

^*In final products, do not find

With the Defed core according to the fexofenadine coated preparation spray coating embodiment 1 of table 3, the gained amount is enough to the fexofenadine that makes every to contain about 180mg amount.Can use suitable spray coating technology well known by persons skilled in the art.

Embodiment 3 fexofenadine hydrochlorides/pseudoephedrine hydrochloride delayed release tablets (180mg/240mg):

Preparation is delaying to discharge the release dosage form that delays that has instant-free fexofenadine hydrochloride pressed coated on the Sudanyl core.

Preparation has the fexofenadine hydrochloride pressed coated preparation of the component of following table 4:

Table 4

With the pseudoephedrine core tablet according to the fexofenadine coated preparation pressed coated embodiment 1 of table 4, the gained amount is enough to the fexofenadine that makes every to contain about 180mg amount.

Randomly, pressed coated is not a dry mixture used in the table 4, but can comprise water, isopropyl alcohol (anhydrous), ethanol (anhydrous) or other medicines acceptable liquid, to form the wet mixture of granulating before pressed coated, convenient preparation.Can use suitable pressed coated technology well known by persons skilled in the art.Granulation liquid is not present in the final dosage form.

Embodiment 4 fexofenadine hydrochlorides/pseudoephedrine hydrochloride delayed release tablets (180mg/240mg):

Preparation delay to discharge have instant-free fexofenadine hydrochloride coating on the Sudanyl core delay release dosage form (preparation N).The pseudoephedrine core is made by embodiment 1, and the fexofenadine coating deposits by spray drying in coating pan.

Table 5: pseudoephedrine core

Table 6: fexofenadine coating

^*In final products, do not find

Use non-functional coating 3wt% according to appointment then

Clear or about 3wt.%

White coats the tablet that contains pseudoephedrine and fexofenadine.

According to USP 26,711, use 900ml in the oar speed of dissolution medium 37 ℃ ± 0.5 ℃ under and per minute 50 commentaries on classics (rpm) in the acetate buffer of 0.1N HCl or pH 4.5, the release of measuring fexofenadine in this exemplary formulation.The result provides in table 11 and 12, and and ALLEGRA

24hour compares.

Table 7:0.1N HCl

Table 8:pH 4.5 acetate buffers

From table 7 and 8, can see, on the fexofenadine coating, add the release of fexofenadine from dosage form afterwards in first 10-20 minute that the non-functional coating can obviously not change in stripping.

Research inembodiment 5 bodies, fasting

The preparation of pseudoephedrine hydrochloride delayed release tablets core (240mg): what preparation had a listed component in the following table 9 delays to discharge Sudanyl core (drug core and delay to discharge coating).

Table 9

According to above embodiment 1 preparation tablet core.The core coating enrobed compacted tablet of using the suspension by Surelease, Opadry Clear and water to make forms and delays to discharge the Defed core.

The healthy volunteer is studied, measure preparation E AUC (0-24 hour and 0-INF) and the C afterwards that contains the 240mg pseudoephedrine hydrochloride in the delayed release tablets of under fasting state, using single oral dose_MaxThis research is carried out 12 experimenters.After application dosage, in the 1st hour per 1/3 hour, per then half an hour was until 3rd hour, extracted experimenter's blood sample at last at the 12nd, 16,24,36 and 48 hour until 10th hour in per then 1 hour.The result is calculated as the least square meansigma methods of Ln translation data, geometrical mean and unconverted data.Geometrical mean is based on the least square meansigma methods of Ln conversion value.The result is provided in the following table 10.Preparation F is carried out similar experiment, and the result is provided in the following table 11.

Table 10 preparation E, fasting

Table 11 preparation F, fasting

Shown in result in the table 10, under fasted conditions, for the AUC geometrical mean (AUC of natural logrithm conversion_0-tAnd AUC_0-INF) and C_Max, preparation E provides the pharmacokinetic parameter that is similar to the reference medicine substantially.During administration, preparation E and reference medicine be bioequivalence (AUC of preparation E and C basically under fasted conditions_Max90% confidence interval be 80-125%).Under fasted conditions during administration, preparation F and reference medicine basically bioequivalence (when with reference relatively the time, the AUC90% confidence interval of preparation F is 80-125%, just at C_MaxThis scope beyond).

Research in embodiment 6 bodies, not fasting

The healthy volunteer is studied, measure AUC (0-24 hour and 0-INF) and C after the preparation E that contains the 240mg pseudoephedrine hydrochloride in the delayed release tablets of under fasting state not, using single oral dose_MaxThis research is carried out 12 experimenters.Provide higher fatty acid breakfast preceding 30 minutes of administration to the experimenter.After application dosage, in the 1st hour per 1/3 hour, followed per 1 hour until 10th hour until 3rd hour per then half an hour, extracted experimenter's blood sample at last at the 12nd, 16,24,36 and 48 hour.The result is calculated as the least square meansigma methods of Ln translation data, geometrical mean and unconverted data.Geometrical mean is based on the least square meansigma methods of Ln conversion value.The result is provided in the following table 12.Preparation F is carried out similar experiment, and the result is provided in the following table 13.

Table 12 preparation E, not fasting

Table 13 preparation F, not fasting

Shown in result in the table 12, under fasted conditions not, preparation E provides the pharmacokinetic parameter that is similar to the reference medicine substantially, particularly the AUC geometrical mean (AUC of natural logrithm conversion_0-tAnd AUC_0-INF).Under fasted conditions not during administration, (when with reference relatively the time, 90% confidence interval of the AUC of preparation E is 80-125%, just at C for preparation E and the basic bioequivalence of reference medicine_MaxThis scope beyond).

Embodiment 7: the stripping of exemplary fexofenadine IR formulation

For determining of the influence of various fexofenadine hydrochloride polymorphics, multi-form fexofenadine hydrochloride is pressed into the immediate release tablet of table 14 to the stripping of Fexofenadine customization agent.The various polymorphics of being tested in table 15, have been provided.

Table 14

Table 15

The tablet code	Polymorphic
The tablet code	Polymorphic	G	Form
16 and 20 is mixed, and does not grind		G	Form
16 and 20 is mixed, and does not grind	H	Form 16 andform 20 are mixed, through grinding
I	H	Form 16 andform 20 are mixed, through grinding	Form I
I	J	Form X	Form I
K	J	Form X	Unknown polymorphic
K	L	Amorphous	Unknown polymorphic
M	L	Amorphous	Form A

According to USP 26,711, use 900ml to change oar speed test tablet A-G in the acetate buffer of 0.1N HCl or pH 4.5 of (rpm) at dissolution medium under 37 ℃ ± 0.5 ℃ and per minute 50.The result provides in table 16 and 17, and and ALLEGRAWith

180mg relatively.

Table 16:0.1N HCl

Table 17:pH 4.5 acetate buffers

Can see that from table 16 and 17 fexofenadine hydrochloride form A (tablet M) and fexofenadine hydrochloride form X (tablet J) have (tablet I, ALLEGRA with fexofenadine hydrochloride form IWith

180mg) similar instant-free curve.

This paper has described embodiment of the present invention, comprises the known enforcement of inventor best mode of the present invention.The version of these preferred embodiments can become clear after those skilled in the art read the description of front.The inventor estimates that the technical staff can adopt these variation schemes as required, and the inventor estimates that the present invention can be different from the concrete described mode of this paper and implement.Therefore, allow, the present invention includes all modifications and the equivalent of theme described in the claims according to applicable law.And, unless this paper have in addition explanation or with the obvious contradiction of context, the present invention contain its might the variation scheme in the combination in any of above-mentioned key element.

Claims

1. controlled release preparation comprises:

Core, it comprises core activating agent and wax excipient;

Delay to discharge coating, it is centered around around the described core substantially and contains and delays release coating material; And

The instant-free part, it comprises the instant-free activating agent;

The release of core activating agent described in the wherein said preparation is zero level basically, and described core activating agent and described instant-free activating agent are identical or different.

2. the preparation of claim 1, wherein said core activating agent and described instant-free activating agent are α 2 adrenergic activating agents independently of one another, analgesics, angiotensin converting enzyme (ACE) inhibitor, antianxiety drug, anti-arrhythmic, antibacterial, antibiotic, antidepressant, the treatment Rezulin, antiemetic, antuepileptic, antifungal, vermifuge, hydryllin, antihyperlipidemic, hypotensive agent, anti-infective, antimalarial, antimicrobial, the migraine agent, muscarine antagonist, antineoplastic agent, antiprotozoal drug, psychosis, spasmolytic, antiviral agent, attention deficit moves obstacle (ADHD) medicament more, beta blocker, calcium channel blocker, chemotherapeutics, cholinesterase inhibitor, the Cox-2 inhibitor, alleviate congested agent, diuretic, histamine-2 receptor antagonist, sleeping pill, depressor, immunosuppressant, lipotropic, psychosis, opioid analgesic, peripheral vasodilation agent/vasoconstrictor, tranquilizer, 5-hydroxytryptamine receptor analeptic, sympathomimetic, and their pharmaceutically-acceptable salts, solvate, hydrate, stereoisomer or polymorphic, the pharmacy that perhaps comprises at least a aforementioned activating agent can be accepted combination etc.

3. the preparation of claim 1, wherein said core activating agent is pseudoephedrine or its pharmaceutically-acceptable salts, solvate, hydrate, stereoisomer or polymorphic.

4. the preparation of claim 1, wherein said wax excipient is that fusion temperature is higher than 20 ℃ wax.

5. the preparation of claim 1, wherein said wax excipient is Brazil wax, vegetable wax, wax for waxing fruits, microwax, Cera Flava, chloroflo, paraffin, cetyl esters wax, nonionic emulsifing wax, anionic emulsifing wax, candelilla wax, stearyl alcohol, spermol, cetearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oil, castor oil hydrogenated, fatty acid, fatty acid ester, fatty glyceride, M_nPolyethylene Glycol greater than about 3000 or comprise the combination of at least a aforementioned wax excipient.

6. the preparation of claim 1, wherein said wax excipient is to exist based on about 5 to about 60wt% the amount of described core gross weight.

7. the preparation of claim 1, wherein said core also comprises the extra material that delays to discharge.

8. the preparation of claim 7, the wherein said extra material that delays to discharge are alkylcellulose, Lac, zein, polyvinylpyrrolidine, crospolyvinylpyrrolidone, vinyl acetate copolymer, polyoxyethylene, the polyvinyl alcohol of acrylic polymer, alkylcellulose, replacement or comprise at least a aforementioned extra combination that delays releasable material.

9. the preparation of claim 1, the wherein said release coating material that delays comprises film forming polymer, wherein said film forming polymer is an alkylcellulose, hydroxy alkyl cellulose, the hydroxyalkyl alkylcellulose, carboxyl alkyl cellulose, the alkali metal salt of carboxyl alkyl cellulose, the carboxyalkyl alkylcellulose, the carboxyl alkyl cellulose ester, starch, pectin, chitin derivative, polysaccharide, carrageenin, galactomannan, traganth, agar, arabic gum, guar gum, xanthan gum, polyacrylic acid, polymethylacrylic acid, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxide, the copolymer of oxirane and expoxy propane, or comprise the combination of at least a aforementioned film forming polymer.

10. the preparation of claim 9, wherein said film forming polymer be methylcellulose, ethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylethylcellulose, carboxymethyl cellulose ester, carboxymethyl amylopectin sodium, chitosan, alginic acid, alginic acid alkali metal salt, alginic acid ammonium salt or comprise the combination of at least a aforementioned film forming polymer.

11. the preparation of claim 1 wherein saidly delays to discharge coating with based on described core with delay to discharge about 0.1 to about 30wt% of coating gross weight and exist.

12. the preparation of claim 1 wherein saidly delays to discharge coating with based on described core with delay to discharge about 5.0 to about 20wt% of coating gross weight and exist.

13. the preparation of claim 1, wherein said instant-free partly are the layer form at least a portion that is arranged on described core.

14. the preparation of claim 1, wherein said instant-free partly delay to discharge coating form around the coating for what be centered around described core substantially.

15. the preparation of claim 1, wherein said core comprise pseudoephedrine or its pharmaceutically-acceptable salts, Brazil wax and hydroxypropyl cellulose;

Wherein saidly delay to discharge coating and comprise ethyl cellulose and hydroxypropyl emthylcellulose; And

Wherein said instant-free partly comprises fexofenadine or its pharmaceutically-acceptable salts.

16. a controlled release preparation, it comprises:

The tablet core, it comprises pseudoephedrine or its pharmaceutically-acceptable salts and wax excipient;

Delay to discharge coating, it is centered around around the described tablet core substantially and contains and delays release coating material; And

The instant-free part, it comprises hydryllin as the instant-free activating agent;

The basic unable to take food thing influence of wherein said preparation.

17. the preparation of claim 16, wherein said wax excipient are that fusion temperature is higher than 20 ℃ wax.

18. the preparation of claim 16, wherein said wax excipient are Brazil wax, vegetable wax, wax for waxing fruits, microwax, Cera Flava, chloroflo, paraffin, cetyl esters wax, nonionic emulsifing wax, anionic emulsifing wax, candelilla wax, stearyl alcohol, spermol, cetearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oil, castor oil hydrogenated, fatty acid, fatty acid ester, fatty glyceride, M_nPolyethylene Glycol greater than about 3000 or comprise the combination of at least a aforementioned wax excipient.

19. the preparation of claim 16, wherein said wax excipient is to exist based on about 5 to about 60wt% the amount of described core gross weight.

20. the preparation of claim 16, wherein said core also comprise the extra releasable material that delays.

21. the preparation of claim 20, wherein said extra delaying alkylcellulose, Lac, zein, polyvinylpyrrolidine, crospolyvinylpyrrolidone, vinyl acetate copolymer, polyoxyethylene, the polyvinyl alcohol that releasable material is acrylic polymer, alkylcellulose, replacement or comprise at least a aforementioned extra combination that delays releasable material.

22. the preparation of claim 16, the wherein said release coating material that delays comprises film forming polymer, wherein said film forming polymer is an alkylcellulose, hydroxy alkyl cellulose, the hydroxyalkyl alkylcellulose, carboxyl alkyl cellulose, the alkali metal salt of carboxyl alkyl cellulose, the carboxyalkyl alkylcellulose, the carboxyl alkyl cellulose ester, starch, pectin, chitin derivative, polysaccharide, carrageenin, galactomannan, traganth, agar, arabic gum, guar gum, xanthan gum, polyacrylic acid, polymethylacrylic acid, methacrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxide, the copolymer of oxirane and expoxy propane, or comprise the combination of at least a aforementioned film forming polymer.

23. the preparation of claim 22, wherein said film forming polymer be methylcellulose, ethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylethylcellulose, carboxymethyl cellulose ester, carboxymethyl amylopectin sodium, chitosan, alginic acid, alginic acid alkali metal salt, alginic acid ammonium salt or comprise the combination of at least a aforementioned film forming polymer.

24. the preparation of claim 16 wherein saidly delays to discharge coating with based on described core with delay to discharge about 0.1 to about 30wt% of coating gross weight and exist.

25. the preparation of claim 16 wherein saidly delays to discharge coating with based on described core with delay to discharge about 5.0 to about 20wt% of coating gross weight and exist.

26. the preparation of claim 16, wherein said instant-free partly are the layer form at least a portion that is arranged on described core.

27. the preparation of claim 16, wherein said instant-free are partly for substantially delaying to discharge coating form around the coating in described core.

28. the preparation of claim 16, wherein said core comprise pseudoephedrine or its pharmaceutically-acceptable salts, Brazil wax and hydroxypropyl cellulose;

29. the preparation of claim 28, wherein said preparation provide about 11 to about 13 hours pseudoephedrine T_MaxWith about 1.6 to about 2.2 hours fexofenadine T_Max

30. the preparation of claim 28, wherein after the described preparation of single administration, described preparation provides about 360ng/mL pseudoephedrine C to about 430ng/mL_MaxWith the fexofenadine C of about 600ng/mL to about 660ng/mL_Max

31. the preparation of claim 28 is wherein being used 5 doses or more after the described preparation of multi-agent, described preparation provides about 450ng/mL pseudoephedrine C to about 550ng/mL_MaxWith the fexofenadine C of about 640ng/mL to about 710ng/mL_Max

32. a controlled release preparation, it comprises:

The instant-free part, it comprises fexofenadine or its pharmaceutically-acceptable salts;

Wherein said preparation with according to the reference medicine bioequivalence of new drug application No.021704.

33. the preparation of claim 32, wherein said preparation show said composition to number conversion AUC_0-tOr AUC_0-∞Geometrical mean with according to the reference medicine of new drug application No.021704 to number conversion AUC_0-tOr AUC_0-∞The ratio of geometrical mean be about 0.80 to about 1.25.

34. the preparation of claim 33,90% confidence interval of wherein said ratio are about 0.80 to about 1.25.

35. the preparation of claim 32, wherein said preparation show said preparation to number conversion C_MaxGeometrical mean with according to the reference medicine of new drug application No.021704 to number conversion C_MaxThe ratio of geometrical mean be about 0.80 to about 1.25.

36. the preparation of claim 35,90% confidence interval of wherein said ratio are about 0.80 to about 1.25.

37. the preparation of claim 32, wherein said preparation show said preparation to number conversion C_MaxGeometrical mean with according to the reference medicine of new drug application No.021704 to number conversion C_MaxThe ratio of geometrical mean be about 0.70 to about 1.43.

38. the preparation of claim 32, wherein bioequivalence is measured under fasted conditions.

39. the preparation of claim 32, wherein bioequivalence is not being measured under the fasted conditions.

40. the preparation of claim 32, wherein when according to USP28＜711〉use under the condition of method of testing 2 (oar) the 900ml purified water at 37 ℃ ± 0.5 ℃ down and during the test of 50rpm oar speed, the stripping curve of described preparation with etc. the stripping curve according to the reference medicine of new drug application No.021704 of same specification basic identical.

41. a controlled release preparation, it comprises:

The tablet core, it comprises pseudoephedrine or its pharmaceutically-acceptable salts and wax excipient; With

Delay to discharge coating, it is centered around around the described tablet core substantially and contains and delays release coating material;

Wherein said preparation shows following dissolution characteristic: according to USP28＜711〉method of testing 2 (oar) makes described preparation and 900ml dissolution medium after mixing 5 hours under 37 ℃ ± 0.5 ℃ with 50rpm oar speed, and the about 25wt.% that discharges the activating agent total amount is to about 50wt.%.

42. the preparation of claim 41, wherein after 3 hours, discharge pseudoephedrine or its pharmaceutically-acceptable salts total amount about 15 to about 35wt%.

43. the preparation of claim 41, wherein after 7 hours, discharge pseudoephedrine or its pharmaceutically-acceptable salts total amount about 35 to about 65wt%.

44. the preparation of claim 41, wherein after 9 hours, discharge pseudoephedrine or its pharmaceutically-acceptable salts total amount about 45wt% or more than.

45. the preparation of claim 41, wherein said dissolution medium are the acetate buffer of purified water, 0.1N HCl, pH4.5 or the phosphate buffer of pH6.8.

46. a controlled release preparation, it comprises:

Core, it comprises core activating agent or its pharmaceutically-acceptable salts and wax excipient; With

Delay to discharge coating, it is centered around around the described core substantially and contains and delays release coating material;

Wherein said preparation shows following dissolution characteristic: according to USP28＜711〉method of testing 2 (oar) makes described preparation and 900ml purified water after mixing under 37 ℃ ± 0.5 ℃ with 50rpm oar speed,

The about 13wt.% that wherein discharged described core activating agent total amount after 3 hours is to about 40wt.%;

The about 20wt.% that discharged described core activating agent total amount after 5 hours is to about 60wt.%; And

The about 40wt.% that discharged described core activating agent total amount after 7 hours is to about 80wt.%.

47. a controlled release preparation, it comprises:

Wherein said preparation shows following dissolution characteristic: according to USP28＜711〉method of testing 2 (oar) makes described preparation and 900ml dissolution medium after mixing under 37 ℃ ± 0.5 ℃ with 50rpm oar speed,

The about 15wt.% that discharged described core activating agent total amount after 3 hours is to about 35wt.%;

The about 25wt.% that discharged described core activating agent total amount after 5 hours is to about 50wt.%;

The about 35wt.% that discharged described core activating agent total amount after 7 hours is to about 65wt.%; And

The about 45wt.% that discharged described core activating agent total amount after 9 hours is to about 75wt.%.

48. the preparation of claim 47, wherein said dissolution medium are the acetate buffer of purified water, 0.1N HCl, pH4.5 or the phosphate buffer of pH6.8.

49. a controlled release preparation, it comprises:

Wherein said preparation with according to the reference medicine bioequivalence of new drug application No.020786.

50. a medicine box wherein comprises the multiple medicine of the preparation that contains claim 1.

51. a method for the treatment of the patient comprises the preparation of using claim 1 to the patient.