CN1155242A - Liquid pharmaceutical composition for controlled release of moguisteine - Google Patents

Abstract

Disclosed are compositions and dosage forms containing moguisteine and having controlled release properties, methods for using such compositions and dosage forms and methods for making them.

Description

The sustained release moguisteine pharmaceutical composition of liquid form

The present invention relates to the liquid dosage form of sustained release moguisteine (moguisteine) pharmaceutical composition.

Moguisteine, (R, S)-2-[(2-methoxyl group phenoxy group) methyl-3-ethoxy carbonyl-1-acetyl group]-1,3-thiazoles alkane, being that a kind of effective periphery described in the European patent EP 169,581 is anti-organizes agent.

By suppressing neural coughre flex or can the pharmacological relieving cough by mucous amount or denseness in the minimizing respiratory tract.Be called that some of the first kind of " opiate " are anti-organizes agent to suppress coughing centre and work by concentrating.An example codeine of opiate is to use the most anti-agent of organizing, but it has and causes addicted shortcoming.So, organize agent that a kind of demand is arranged to non-narcotic is anti-in this area.

Moguisteine is a kind of the same effective anti-agent of organizing with codeine, dextro-methorphan and zipeprol (zipripol), and than (D, L)-the effective 3-4 of dropropizine is doubly.Importantly, it does not cause addiction, and than codeine or dextro-methorphan better toleration is arranged when it uses heavy dose for bringing out calmness and reducing anxiety.Moguisteine is a kind of the have R (+) of identical anti-tissue activity and racemic mixture of S (-) enantiomer.

The research of the mechanism of action of moguisteine has been shown that it does not work by opioid receptor.Its site of action be periphery and it can be called " quick adjustment costimulatory receptor " and (RARs) react (Sampson, S.R. etc., Adv.Exp.Med.Biol.99:281-290,1979).

Moguisteine has the prodrug characteristic.Behind oral or intravenous administration, but in biological fluid, only can find its active metabolite (R, S)-2-[(methoxyl group phenoxy group) methyl of measured quantity]-3-carboxyl-acetyl group]-the 1,3-thiazoles alkanoic acid.But because this active metabolite than the absorption of moguisteine slow 5 times, so that it is not suitable for is oral.

Up to the present known moguisteine oral formulations comprises the bag agent of tablet and 200mg dosage and conventional 2% suspension.Every day dosage 100 to 800mg range and when the child takes dosage lower.

A limitation using moguisteine be after the administration its half-life shorter, the half-life is less than 1 hour concerning the people.Before the present invention, this just mean often administration promptly keep for one day at least 3 to 4 times fixed blood drug level (Castoldi D. etc., (1990), Pharmacol.Res., 22:102).

People have known that the requirement of multiple dosing every day is unfavorable to the toleration that influences the patient.Once the average toleration of taking medicine in one day is 87% but four times the toleration of taking medicine in a day has just dropped to 39%; So the preparation of obviously preferably can every day taking for twice or even be more preferably and be administered once every day (Kramer, J.A. etc., (1989) JAMA, 1:601).

Use agent for slow releasing type such as tablet, pill etc. can realize reducing the dosage number of times.But it is preferred dosage form that agent, liquid preparation are organized in antagonism.

U.S. Pat 5,296,236 (hereinafter being called " 236 patent "), described the liquid preparation of sustained release pharmaceutical composition, and it comprises the microparticle of making good use of several polymeric layer coatings.In these compositionss some make the active component in the preparation to be used in a period of time by the release from microparticle, and a part is present in the outer composition of granule and take after can be at once by biological utilisation.But, provide the comparatively ideal solution of specific question that administration is produced to moguisteine liquid in the compositions described in the patent of ' 236.

First consideration is the very uncomfortable taste of moguisteine.This just makes and utilizes suspension preparation or solution undesirable; So, as described in the patent of ' 236, can not comprise rapidly by the outer moguisteine of the granule of biological utilisation.

For the moguisteine preparation that obtains to be suspended easily, the diameter of the microparticle behind the coating must be less than 500 μ m.Greater than the diameter of 500 μ m because it is easy to rapid subsidence, so thereby be not easy to be caused the uneven distribution of active component on the preparation by suspending.But, compare with tablet or pill, use microparticle to increase surface area significantly, thereby make the sustained release active component and remain unchanged more difficult in the time behind this suspension of reprovision less than 500 μ m.Concerning moguisteine, difficulty is bigger like this, because the lacking to have increased and disperse gradient and discharge the speed of medicine in the surrounding from granule of the outer medicine of granule.

The low melting point that second kind of consideration using the instruction design of ' 236 patent to be fit to the dosage form of moguisteine is this molecule be about 65 ℃ (Drugs of the Future, (1991), 16:618).Be particularly conducive to the microparticle that parcel contains moguisteine and hide their bitterness effectively because resemble wax sample lipophilic substances such as cera alba, spermol, glyceryl monostearate (instruction is as the material of coating in the patent of ' 236), but problem occurred.These materials will be with dissolving of toxic and environment-conscious chlorinated solvent and coating, perhaps they with molten condition be coated on the microparticle (Pharm.Res., (1990), 7:1119).But, use chlorating solvent to have toxicity and environmental problem.A kind of method in back must use the compressed air of heating to make this wax remain on temperature on its fusing point, and this is can not make film forming matter by reuse because of the easy curing of cryogenic wax.But the low melting point active substance that uses high relatively temperature can liquefy and resemble moguisteine so just causes the failure of coating steps, and only the remaining chlorating solvent of use (shortcoming is arranged) is as unique a kind of selectable method.

In a word, to moguisteine and medicine, need a kind of liquid dosage form of sustained release, this dosage form with similar characteristic:

1) measures easily and eat;

2) have the time-dependent that compensates this active component half-life, property release does not need multiple dose like this;

3) in liquid-carrier, has satisfied stability after the suspension;

4) enough good to eat to guarantee patient's toleration; With

5) do not need to use chlorating solvent and other to environment undesirable or toxic material.

So one object of the present invention just provides a kind of sustained release compositions of form of suspension, it can be administered once or guarantee the therapeutic activity haemoconcentration of moguisteine (or its biologically active metabolite product) more precisely for twice in every day.Preferred said composition has fabulous palatability and water is prepared the back has good stable along with the time characteristics again.

Another object of the present invention provides a kind of pharmaceutical composition that comprises the microparticle that contains moguisteine, and microparticle wherein is not dissolved and promote it to discharge at gastral distal site with protection moguisteine when preparing again in suspension (or in case) in the oral cavity with three layers of successive rete coating at least.

A further object of the invention provides a kind ofly gives the method contain the microparticle coating that the low melting point active component if you would Wei Tanni with Wax, has avoided making the active component fusion simultaneously or has used chlorination

Have now found that to use and contain moguisteine and make the compound microparticle of active component and can realize being suitable for the sustained release pharmaceutical dosage form of moguisteine with the form of suspension administration, this granule alternately contains hydrophilic and the continuous coating of the coatings lipophilic film with three kinds at least, is made into preparation with the medicine acceptable carrier then.This microparticle core can also comprise at least a plasticizer except moguisteine, preferred Polyethylene Glycol, and other optional excipient, and size is 50-500 μ m, has slick surface and is suitable for polymer or Wax coating.This coating can prevent that moguisteine from discharging and then guarantee the release profiles that the distal site of moguisteine in digestive tract is predetermined and keep this release profiles in a period of time in the oral cavity.At least a coating should make the compositions that contains moguisteine have the sustained release feature.These carriers are optional to contain one or more suspending agents, plasticizer, surfactant, sweetener, buffer agent, antiseptic and flavoring agent, and these are all in those of ordinary skills' known range.This dosage form can water (or mixture of water and water solublity cosolvent) be mixed with the suspension dosage form or the dry powder doses of water and/or other solvent reprovisions in use.

In a preferred version, the microparticle that contains moguisteine and account for the Polyethylene Glycol of mixture weight 0.5-1% has used to contain cellulosic one deck of acetic acid-phthalic acid or two-layered coating or use to contain in addition and has resembled C ₆-C ₃₆The one deck or the two-layered coating of the Wax of single, double or triglyceride, Brazil wax, candelilla wax, alcohols, fatty acid and the compositions thereof of fatty acid.Preferably using wax class coating heated compressed air to make spraying substrate under the condition that does not melt this microparticle core with molten condition (promptly not using solvent) is coated with.

Moguisteine preparation of the present invention not only has the sustained release characteristic of the required medicining times of moguisteine haemoconcentration that reduction need remain unchanged, and has good palatability and in case the stability when being made into suspension again.This is because active component is retained in the microparticle of coating after the digestion of carrying out subsequently, is easy to like this pass through upper digestive tract and insipidness with quick at once.

On the other hand, present invention includes a kind of method for the treatment of the cough symptom, it comprises the above-mentioned dosage form of taking treatment cough effective dose.

Aspect another, the invention provides a kind of method for preparing good to eat sustained release moguisteine pharmaceutical dosage form with the form of suspension administration, it comprises uses heated compressed air to make spraying substrate, gives the microparticle coating that contains moguisteine with the Wax of molten condition.This method is suitable for the microparticle coating that contains active constituents of medicine to any, but is particularly suitable for to the microparticle coating that contains the low melting point active component.

Brief description of drawings

Fig. 1 is that a width of cloth describes in detail with a kind of conventional suspension or with the figure of the moguisteine concentration in patient's blood plasma of sustained release preparation of the present invention administration.

Fig. 2 is that a width of cloth describes the illustraton of model of taking the conventional suspension of twice moguisteine or taking the moguisteine blood content that produces behind the sustained release preparation of a moguisteine of the present invention in detail.

All patents as referred to herein, patent application and bibliographic reference data are with them all as a reference at this. When inconsistent, the restriction of this specification of definition will be comprised.

The present composition comprises a kind of microparticle of compound dressing, it contains moguisteine and one or more optional binder and excipient, be coated with the pantostrat of at least three kinds of polymer coatings on it, at least a dressing makes the preparation that contains the dressing microparticle have the characteristic that control discharges. Three kinds of continuous coatings preferably contain respectively (i) acetic acid-O-phthalic acid cellulose and forming agent; (ii) one or more waxes; (iii) acetic acid-O-phthalic acid cellulose. (dressing (iii) is consistent with dressing (i)) then is mixed with the liquid suspension liquid formulation to the microparticle of dressing.

These preparations have kept the release characteristics of contained microparticle formulation. Can they be designed to have two-and-a-half years at least decline stable liquid dosage form of the easy use of phase and time or when needed water again prepare and during treating, keep stable dry powder doses.

The invention provides a kind of pharmaceutical composition of controlling release, it comprises that control discharges the coated granule of moguisteine, and its size is the preferred 90-300 μ of 50-500 μ m m, and it is retained in the suspension in can be for a long time at an easy rate. This microparticle comprises:

A) moguisteine and one or more optional binders and the core of excipient are made into particle diameter less than 500 μ m; surface uniform; substantially spherical; the about 500-600g/l of superficial density also has the particle of very low fragility; the mixture of its available water or water and other solvents adopts temperature to pinch method micronize moguisteine (if present, and binder and excipient) and makes. The microparticle of making does not so have the control release characteristics before dressing, but has the physical characteristic of guaranteeing to produce and be uniformly distributed in the continuous coating layer.

B) have the ground floor dressing of water-wet behavior, it separates with this microparticle.

C) has the second layer dressing of lipophilic characteristic at the ground floor dressing.

D) have the 3rd layer of dressing of water-wet behavior.

The present invention also provides a kind of carrier system that is suitable for above-mentioned sustained release dosage form; it comprise can with the blended dry mixture that adds agent of the drug microparticles of long-term storage; the aqueous solution that perhaps has selective additives, wherein containing the moguisteine microparticle can and keep the long time at best release conditions low suspension.The example of the additive of indefiniteness given below.

The basic step that comprises pharmaceutical preparation of the present invention has below been described, but not as limiting: the microparticle core

Pinch the microparticle mixture that contains moguisteine by temperature and make that to have a moguisteine high-load and guarantee the microparticle of the suitable physical characteristic (comprising particle diameter, shape, density and fragility) of even coating and suspension.At US 5,296,236 or in common unsettled Application No. 08/188,193 (" 193 application " now go through), described blend step.

In a preferred scheme; in this microparticle mixture, add before the kneading and account for the Polyethylene Glycol of the about 0.3-1% of this mixture weight preferred 0.6% (from BASF Corp.; Parsippany, NJ obtains Carbowax) impel by the coating microparticle desirable sphere and slick surface are arranged.PEG highly water-soluble (being that concentration is greater than 10%W/V) is so make the moguisteine of water insoluble relatively liquid moistening easily.Even being surprised to find PEG, we when being lower than 1% concentration, also can impel the spheric formation of microparticle.In enforcement of the present invention, can use the PEG preparation of any 200-8000 of containing polydispersity polymer, preferred PEG 5000-7000, the best is PEG 6000 (CARBOWAX ^6000).

The microparticle core that contains moguisteine also can comprise optional excipient, this excipient comprises filler and binding agent, they are selected from but are not limited to that wet-mixed uses always, as copolymer of lactose, calcium hydrogen phosphate, microcrystalline Cellulose, starch, Pulvis Talci, sugar, polyvinylpyrrolidone, gelatin, polyvinylpyrrolidone and vinyl-acetic ester etc.This microparticle preferably includes lactose and makes binding agent (PVP content is (by weight) in the 5-20% scope) as filler (lactose content is (by weight) in the 10-50% scope) and polyvinylpyrrolidone.

Described in ' 236 patent that blend step can be or ' 193 applications described in.The mixing material that for example is used for wet granular in high-speed mixing granulating machine can be a water; Or other alcohols that for example use in ethanol or the pharmaceuticals industry with the miscible solvent of water; Or the mixture of water and at least a other solvents.

Thereby the operating condition of kneading and granulation step is to cause having the condition that ideal physical characteristic can produce the microparticle of effective coating.For example, the technological parameter that uses the acceptable and preferable range of flash mixer and grinder has been described in ' 193 applications, for example mixed liquor is added to relative scale in the dried microparticle mixture; The speed of atomizing of liquids; Expulsion pressure; The kneading time; Speed with independent blender and grinder.Then the mixture of kneading being dried to humidity is the preferred 5-8% of 1-10%, and is filtered into the granule of required particle size range.At last, the following properties of assessment gained microparticle: particle size distribution, density (ventilation, packing and surface), Ka Er index (coefficient of compressibility) and composed view.At last, as described below, give this microparticle coating with the film of different compositionss.Coating

Have two purposes at least for the microparticle coating that contains moguisteine according to the present invention.At first, this coating has prevented the release of moguisteine in the oral cavity, has hidden the bitterness of moguisteine thus and has increased the palatability that contains the moguisteine liquid preparation.Secondly.This coating has guaranteed that moguisteine arrives the sustained release curve of moguisteine behind the harmonization of the stomach intestinal environment.The coated granule that contains moguisteine should contain the anti-pH of one deck (being intestinal) coatings but it needs not to be the ground floor that is coated with at least three layers of coating.

Give the microparticle coating that contains moguisteine with at least three layers of alternative hydrophilic and lipophilic coatings as described below like this.Preferably hydrophilic the helping of the last coating that is coated with dissolved and suspended.Preferred packaging technique is the liquid bed technology in the Wuster technology (Jones, D., DrugDev.Indus.Pharm.20:3175-3206,1994) concerning following all coatings.

The material that is suitable for the ground floor coating comprises but is not defined as hydrophilic substance such as cellulosic derivant (as acetic acid-O-phthalic acid cellulose, Hydroxypropyl Methylcellulose Phathalate, ethyl cellulose, acetic acid carbonyl methyl cellulose ester etc.) and acrylate copolymer (as methacrylate and acrylic acid copolymer, methyl methacrylate etc.).Preferred acetic acid-O-phthalic acid cellulose and the Hydroxypropyl Methylcellulose Phathalate that use.These polymer can be arbitrarily mix with plasticizer such as diethyl phthalate, dibutyl sebacate and the vegetable oil known in the sustained release formulation art.

Being suitable for the lipophilic material of having of the second class coatings comprises but is not defined as fatty material such as C ₆-C ₃₆Single, double or triglyceride, Brazil wax, Cera Flava, candelilla wax, alcohols, fatty acid and the compositions thereof of fatty acid.These coatings can spray under chlorinated solvent is assisted.But, preferably under molten condition, do not use solvent to spray Wax.Because the fusing point lower (65 ℃) of moguisteine, use can coating and not make the condition of the moguisteine fusing in the core be important.We have found that the use coaxial nozzle now, wherein spraying liquid is a compressed air, its be heated so that Wax remain on always liquid again can be enough warm the temperature of coating chamber, make Wax be wrapped in to contain on the microparticle of moguisteine and do not make the moguisteine fusing.

Concerning the 3rd coatings, also can use the same substance that constitutes first coatings.As mentioned above, the under any circumstance all preferred last coating that sprays is hydrophilic.Carrier

In enforcement of the present invention, the microparticle that contains moguisteine according to the above-mentioned steps coating is mixed dry mixture or a kind of standby liquid suspension of formation interim suspension during a kind of the needs with a kind of carrier.

Be added in the coated granule of the sustained release dosage form that contains moguisteine, the component of carrier can comprise but not be defined as:

-suspending agent or structure agent are as cellulose esters, microcrystalline Cellulose, alginate derivatives and polyvinylpyrrolidone derivant;

-surfactant (preferred ion type or nonionic) is as Span20, Span80, polysorbas20 and sodium laurylsulfate;

-saccharide such as sucrose, Sorbitol, xylitol, dextrose etc.;

-buffer substance such as citric acid and sodium citrate, glycerol and hydrochloric acid, sodium phosphate and potassium phosphate;

-antiseptic and antibacterial such as p-Hydroxybenzoate; With

Various flavoring agents and the sweeting agent used always in-the pharmacy.

We are understood that with regard to the concrete component in the property quality and quantity preparation of composition adding and will change according to the difference of concrete purposes.Referring to as Wade and Weller, Handbook ofPharmaceutical Excipients (second edition), medicine publishing house, London, 1994.

Except mentioned component, standby preparation also comprises the mixture of the acceptable water solublity cosolvent of water or water and medicine well known in the prior art such as glycols, alcohols and glycerol.

The present composition comprises the form that they are different, comprises as (i) multiple dose granular preparation the particulate not commensurability dosage that obtains adapting to of resuspending when wherein needing by mensuration; The (ii) single dose dosage form of the accurate metering of medicine bag form; The interim bottle of preparation again that is used for of preserving lid is (iii) arranged; And known other forms of prior art.Concerning department of pediatrics was used, the present invention also comprised and contains and concentrate and drip the preparation of (as contain dripping of 10%w/v moguisteine, every about 5mg active component works), has wherein suspended and has contained the granule of moguisteine.The therapeutic administration

Pharmaceutical preparation of the present invention be with once a day or twice administration discharge the moguisteine of effective dose.The amount that is provided for patient's relieving cough is provided the moguisteine of effective dose.Should be understood that effective dose is by digesting the next release of single dose or multiple dose in one period set time.Generally, effectively to treat and/or prevent dosage every day of cough be about 5 to the 15mg/kg weight in patients to moguisteine.Mean dose is 9mg/kg.So the anti-administration of organizing the moguisteine of effective dose comprises that be administered once every day or twice, contain the about 30ml of about 2-of the final preparation (described in following embodiment 8A, preparing) of 30mg/ml moguisteine, preferably 10ml at every turn.

Benefit of the present invention comprises the remarkable patient's of improvement adaptability, and this is based on and reduces the palatability that the number of times of taking medicine every day is become reconciled.Because easily administration and swallowing can be expected other benefit in department of pediatrics enforcement.Further, in preferred scheme,, therefore can produce better treatment response because said preparation just can be regulated required dosage by the volume of measuring required suspension.

The following example is in order to describe preferred version of the present invention better in detail and to confirm its advantage and practicality, but is not to limit scope of the present invention.Embodiment 1: the preparation of moguisteine microparticle

In a Diosna P25 mixer-granulator the mixture mixing of forming by the 450 order lactose of moguisteine, 10% (w/w) polyvinylpyrrolidone (PVP K30) of 79% (w/w) and 10% (w/w) 10 minutes.In the speed of the pressure use 0.8mm of 2 crust nozzle 1% (w/w) PEG 6000 as aqueous solution is added in the stirred mixture with 25ml/ minute.In moistening step process, the speed of mixer is 175rpm, and the speed of mill is 3000rpm.Adding the required time of solution is 20 minutes.After moistening, the speed of mixer and mill is kept carrying out in 15 minutes kneading and rounding step with constant speed.Resulting microparticle drying, to screen up to obtaining particle size distribution be the microparticle of 0.593g/ml and real density 1.36g/ml at 90-300 mu m range, sphere, tap density to the sieve by 225 order/square centimeters then in the artificial draft couveuse.Embodiment 2:

Mix and kneading as 1 mixture of forming by the PEG 6000 of the PVP K30 and 0.6% (w/w) of the lactose, 10% (w/w) of the moguisteine, 10% (w/w) of 79.4% (w/w) of embodiment.Embodiment 3:

Moistening with the water of 500ml (adding time-consuming 15 minutes with 25ml/ minute speed) the mixture that the PEG 6000 by 450 purpose lactose of the moguisteine, 10% (w/w) of 79.4% (w/w), 10% (w/w) PVP K30 and 0.6% (w/w) forms.The PEG that adds is 5% solution as above-mentioned embodiment 1.The mixing speed of mixer is 175rpm, and the speed of mill is 3000rpm.The resulting microparticle in dry back has 4% residue humidity, non-tap density be 0.584g/ml, tap density be 0.669g/ml, Ka Er coefficient be 18.08% and actual density be 1.38g/ml.At Ellis Horwood, (1988), Pharmaceutical Preformulation, 209-214 page or leaf, Chichester, England; With Advances in PharmaceuticalScience; 2:181-220 describes above-mentioned parameter in detail in 1967.Owing to have PEG6000, so each granule in the microparticle that obtains like this has special surface smoothness.4: the first retes (Cellacefate) of embodiment

(Buizen Lorrach stirs the microparticle that makes among the 2g embodiment 31 minute in fluidizer Germany) for Glad, GmbH, is blown into the air that is heated to 40 to 45 ℃ to the speed with 40 cubic metres/hour wherein at Glatt GPCG3.Under 2 bar pressures, give this microparticle spraying with 400 milliliters of solution with following percentage by weight component with 10 to 13 gram/minute speed:

Acetic acid-O-phthalic acid cellulose 4%

Diethyl phthalate 1%

Acetone 71%

5: the second retes (Wax) of isopropyl alcohol 24% embodiment

The solution that preparation has following percentage by weight component:

Glyceryl monostearate 4.50%

Cera alba 0.40%

Spermol 0.05%

Chloroform 90.60%

Methanol 4.40%

On the microparticle with ground floor coating of this solution spraying of 1.152g described in 2000g the foregoing description 4.When the spraying second layer, use as embodiment 4 identical operations conditions.Embodiment 6:

The wax class mixture that preparation has following percentage by weight component:

Glyceryl monostearate 90%

Cera alba 8%

Spermol 1%

Octadecanol 1%

Under molten condition, this mixture is sprayed to as on the described microparticle with ground floor coating of embodiment 4.In this case, at first this Wax is melted with about 110 ℃ couveuse.Then, under about 80 ℃ of temperature, it is sprayed on the 2kg microparticle with molten condition.Use is preheating to 125 ℃ and the air that is compressed to 3 bar pressures and adopts the coaxial nozzle of mixed melting wax and hot compressed air to finish above-mentioned steps.In Glatt equipment with 7 " the Wurster plug sprays step.Equal the wax (with respect to the microparticle weight of coating not) of 3.8% (weight) with the spraying of the speed of about 1.5 gram/minute.7: the three layers of coatings of embodiment

Last coating is become to use identical component and the step described in the embodiment 4 that is suitable for first coatings.Embodiment 8: contain the pharmaceutical preparation of moguisteine

A) suspension of multi-dose vials

To containing 6.2% microcrystalline Cellulose, 0.8% carbonyl methyl cellulose sodium, 0.5% sodium citrate, 0.8% citric acid, 0.2% methyl butex, 0.05% propylparaben, 2% Tragacanth, 0.05%Span 20 surfactants, 0.2% dimethyl propylene radical siloxane, 0.01%, the fragrant flavoring agent of 0.025% crocus-uva and being added to add in the mixture of 100% powder sugar as among the embodiment 3 preparation and use embodiment 4, the microparticle of three layers of continuous coating described in 5 and 7 is 12.5% (w/w) up to final ratio.(above-mentioned all percent value by weight) is added to the water of 80g in the 33g slurry compositions, obtains the moguisteine suspension that 100ml contains 30mg/ml.Oxybenzene formic acid in above-mentioned preparation is as antiseptic; The many siloxanes of dimethyl are as foam reducing composition.

B) suspension of unit dose package

The slurry compositions that makes among the 3.3 gram A is divided into independent five equilibrium, and every part of moguisteine that contains the 300mg single dose is in the paper/aluminum of packing into/polyethylene packaging.The content of each packing can resuspending in half bottle of water.

C) suspension of single dose vial

Also putting into the microparticle of three layers of continuous coating described in embodiment 4,5 and 7 of preparation among the 1.25 gram embodiment 3 had the single dose vial of preserving lid and the contained liquid of itself and single dose vial is separated.The mixture of single dose is 3, the citric acid of 70% sorbitol of 500mg, the Fructus Ananadis comosi of 15mg-Fructus Citri Limoniae flavoring agent, 15mg, the sodium benzoate of 10mg and be added to the pure water of 8ml.Before the use, extruding preserve lid make the content preserved in the lid with bottle in liquid contact.Every bottle of moguisteine that contains 300mg is as the single dose suspension.

D) standby suspension

The liquid carrier that also has following component with the slow adding of the microparticle of three layers of continuous coating described in embodiment 4,5 and 7 respectively in following 4g embodiment of vacuum 3 preparations:

Cellulose (crystallite) 0.85g

Carbonyl methyl cellulose sodium 0.15g

Sodium laurylsulfate 0.10g

Potassium sorbate 0.15g

Sorbitol (70% solution) 67.50g

Glycerol 11.80g

Xanthan gum 0.12g

Titanium dioxide 0.50g

Many siloxanes of dimethyl 0.10g

Citric acid monohydrate 0.10g

Xylitol 0.40g

Flavoring agent 0.15g

Purified water is to 100ml

This solution does not need to prepare again, and the patient can directly use.Embodiment 9: extracorporeal releasing test

Use the apparatus II (paddle wheel leaf) described in the American Pharmacopeia XXII 37 ℃ under 75rpm operational testing from embodiment 3,4,5 and 7 in the prepared coated granule moguisteine discharge.The moguisteine of 300mg uses the dissolved matrix of 900ml.The 1st hour, dissolved matrix was the hydrochloric acid of 0.1N, and the 2nd to the 12nd hour is the phosphate buffer of pH7.4.Decide the active principle that is discharged in the solution with the absorption value of spectrophotometric determination solution at 275 μ m places.By the time (hour) the active component percentage ratio that discharges from microparticle is as follows: 21% (1 hour), 46% (2 hours), 78% (4 hours), 93% (8 hours) and 98% (12 hours).Embodiment 10: steady dissolution in time

A) measure embodiment 8, the stability of the sustained release suspension that the A part is prepared with following manner.Beginning, the 3rd month and prepared the microparticle of coating in 6th month again and the mixture of pharmaceutical carrier component, and with the release in vitro of the step measurements moguisteine described in the embodiment 9.The results are shown in Table 1:

Table 1

Steady-state conditions	The release of % moguisteine
						1 hour	2 hours	4 hours	8 hours	12 hours
	Beginning	????22	????50	????77	????94						????95
25 ℃, 3 months						????21	????52	????82	????97	????98
	25 ℃, 6 months	????22	????52	????80	????95						????96
35 ℃, 6 months						????22	????50	????76	????89	????90

Even these data acknowledgement samples 35 ℃ deposit 6 months after the release profiles of moguisteine also constant substantially.

In another test that comprises same recipe, water is prepared and was estimated this suspension solubility curve in back 15 days.The results are shown in Table 2.

Table 2

Steady-state conditions	The release % of moguisteine
						1 hour	2 hours	4 hours	8 hours	12 hours
	Beginning	????22	????50	????77	????94						????95
25 ℃, 3 months						????21	????48	????79	????93	????95

Even water is prepared the back solubility curve that did not also change moguisteine in 15 days again, so in general therapeutic process, guaranteed good steady dissolution.

B) as mentioned above, by measure beginning and 18 months afterwards the release percentage ratio of moguisteine decide embodiment 8, the stability of the standby suspension of sustained release that the D part is prepared.The results are shown in Table 3.

Table 3

Dissolving	The release % of moguisteine
						1 hour	2 hours	4 hours	8 hours	12 hours
	Beginning	????18	????48	????76	????97						????100
After 18 months						????19	????50	????76	????93	????98

In standby preparation, the solubility curve of moguisteine is constant after 18 months; The chances are for this because the ratio relatively low (about 30%) of water in the preparation.Embodiment 11: the physical characteristic of moguisteine preparation

The suspension that makes among the embodiment 8 to 33 grams adds water to 100 milliliter.Measure following parameters then: 1) factor in precipitation F, it is precipitation height and the ratio that stirs and place the height of 3 days rear suspension liquids; 2) pH; 3) denseness, usefulness Brookkfield DVII Instrument measuring; 4) density.The result is as follows: F=0.6, pH=4.3, denseness (cps)=226 and density (g/ml)=1.1.Embodiment 12: bioavailability

The dynamics research that carries out single dose with preparation of the present invention is estimated the bioavailability of moguisteine.Six healthy premenopausal volunteers have once been taken sustained release liquid preparation prepared among the embodiment 8 of 10ml dosage (moguisteine that is equivalent to 300mg).Take a blood sample and measure the concentration of moguisteine in the blood plasma with the HPLC method at different time.In test for the second time, the volunteer taking dose is conventional 2% suspension (moguisteine that is equivalent to 200mg).Table 4 has compared the main pharmacodynamics parameter that obtains from two kinds of preparations.

Table 4

Moguisteine	????C Maximum????(ug/ml?)	??T Maximum(h)	??AUC(ug ????h/ml)
				C.R. suspension	????1.79	????2.83	????7.05
Conventional suspension	????3.05	????0.73	????4.01

C _Maximum=(peak concentration): the highest blood drug level that medicine reaches after the administration; T _Maximum=(time-concentration): reach C _MaxBe worth the required time; AUC _0-∞The overall area of=(zone under the curve) time-concentration curve is also represented the measured value of bioavailability.

These data show in sustained release preparation of the present invention:

(a) T _MaximumBe extended and C _MaximumDescended with respect to conventional suspension, as desired to the sustained release preparation;

(b) half-life (t _1/2) and the average residence time (MRT) of calculating increased by three times than conventional suspension; With

(c) so AUC is similar to conventional formulation with relative bioavailability.

These data show that the prepared suspension of the present invention has the sustained release preparation characteristic of good bioavailability.

Fig. 1 has shown that the back difference between the initial moguisteine dosage of sustained release and conventional formulation of moguisteine blood content normalization makes.This figure vertical coordinate is the dose concentration value, and abscissa is the time.Data show that taking moguisteine of the present invention has avoided initial maximum effect and reduced every day taking medicine number, have guaranteed the treatment blood drug level of satisfied moguisteine simultaneously in the time of an elongated segment.

Fig. 2 has shown the simulation of moguisteine blood drug level after taking conventional suspension for twice or once taking the sustained release suspension.The sustained release suspension has avoided using the viewed initial maximum effect of conventional suspension (having reduced relevant side effect like this).And this sustained release suspension can use with the mode of twice administration every day rather than four times mode every day of conventional formulation.

Claims (44)

1. one kind is suitable for the sustained release pharmaceutical dosage form of moguisteine with the form administration of liquid suspension, and it comprises:

Contain the microparticle of moguisteine as active component and optional plasticizer and excipient, this microparticle before the coating has slick surface and basic for spherical, but does not have the performance of sustained release,

Contain at least three kinds of coatings on this microparticle, at least a this microparticle that can make has the sustained release performance in these coatings,

Described at least three kinds of coatings alternately contain the hydrophilic and hydrophilic layer that is useful on this microparticle, and these coatings are in case prevented this moguisteine and sapid dissolving occurs and guarantee the slow release profiles that moguisteine is predetermined and can keep this release profiles in a period of time in the digestion.

2. according to the dosage form of claim 1, it also contains a kind of carrier that is useful on this coating microparticle administration.

3. according to the dosage form of claim 1, plasticizer wherein comprises Polyethylene Glycol.

4. according to the dosage form of claim 3, excipient wherein comprises a kind of following chemical compound that is selected from: the copolymer and the gelatin of polyvinylpyrrolidone, lactose, dalcium biphosphate, microcrystalline Cellulose, starch, Pulvis Talci, saccharide, polyvinylidene ketopyrrolidine/ethyl acetate.

5. according to the dosage form of claim 3, Polyethylene Glycol wherein is that 0.5 to 1% content with this microparticle gross dry weight is present in the microparticle.

6. according to the dosage form of claim 1, hydrophilic coating wherein comprises the polymer that is selected from acetic acid-O-phthalic acid cellulose and the Hydroxypropyl Methylcellulose Phathalate.

7. according to the dosage form of claim 6, hydrophilic coating wherein also comprises a kind of plasticizer that is selected from diethyl phthalate, dibutyl sebacate and the vegetable oil.

8. according to the dosage form of claim 7, plasticizer content wherein is the 10-30% (by weight) of this hydrophilic layer gross weight.

9. according to the dosage form of claim 1, lipophilic coating wherein comprises a kind of waxy substance in the single, double or triglyceride that are selected from the C6-C36 fatty acid, Brazil wax, candelilla wax, alcohols, fatty acid and composition thereof.

10. according to the dosage form of claim 9, wax wherein is to use the compressed air do spraying substrate of heating to be coated with under molten condition.

11. according to the dosage form of claim 2, carrier wherein contains the reagent in one or more mixture that are selected from suspending agent, structure agent, surfactant, sweetener, buffer agent, antiseptic and flavoring agent and at least two kinds.

12. according to the dosage form of claim 2, carrier wherein also contains water or water and is selected from the mixture of the pharmaceutically acceptable water solublity cosolvent of glycols, alcohols and glycerol.

13. a method for the treatment of the cough symptom, it comprises takes the anti-dosage form of organizing the claim 1 of effective dose.

14. one kind is suitable for the sustained release dosage form of moguisteine with the liquid suspension form administration, it comprises:

Contain moguisteine as active component and the Polyethylene Glycol microparticle as plasticizer, this microparticle before the coating has slick surface and basic for spherical, but does not have the performance of sustained release,

On this microparticle, contain at least three kinds of coatings, at least a this microparticle that can make in these coatings has the sustained release performance, wherein first coating contains acetic acid-O-phthalic acid cellulose, second coating that is coated in subsequently on first coating comprises glyceryl monostearate and mellisic mixture, the 3rd coating that is coated in subsequently on second coating comprises acetic acid-O-phthalic acid cellulose

These coatings are in case can prevent in the digestion that sapid dissolving from appearring in this moguisteine and the moguisteine guaranteeing to be scheduled to continues release profiles and keep this release profiles.

15., also contain the carrier that is useful on described coated granules administration according to the dosage form of claim 14.

16. according to the dosage form of claim 14, wherein this Polyethylene Glycol is PEG 6000.

17. preparation is suitable for the method for moguisteine with the good to eat sustained release dosage form of liquid suspension form administration, it comprises:

(a) moguisteine and at least a plasticizer are mixed and made into microparticle; With

(b) give the microparticle coating with containing the first hydrophilic coatings that is selected from polymer in acetic acid-O-phthalic acid cellulose and the Hydroxypropyl Methylcellulose Phathalate;

(c) be selected from C with containing ₆-C ₃₆The second lipophilic coating of the waxy substance of the single, double or triglyceride of fatty acid, Brazil wax, candelilla wax, alcohols, fatty acid and composition thereof is given the microparticle coating of making in (b), and wax wherein is to use the compressed air do spraying substrate of heating to be coated with under molten condition; With

(d) give the microparticle coating of making in (c) with the 3rd hydrophilic coatings that contains the polymer that is selected from acetic acid-O-phthalic acid cellulose and Hydroxypropyl Methylcellulose Phathalate.

18. a compositions that is used for the treatment of the symptom of coughing, said composition comprises:

Contain the microparticle of moguisteine as active component and any plasticizer and excipient, this microparticle before the coating has slick surface and is sphere substantially, but does not have the performance of sustained release;

Contain at least three kinds of coatings on this microparticle, at least a this microparticle that can make in these coatings has the sustained release performance;

At least three kinds of such coatings alternately contain the hydrophilic and hydrophilic layer that is useful on this microparticle, and these coatings are in case prevented in the digestion that sapid dissolving from appearring in this moguisteine and the lasting release profiles of the moguisteine guaranteeing to be scheduled to and keep this release profiles.

19., also contain the carrier that is useful on this coated granule administration according to the compositions of claim 18.

20. according to the compositions of claim 18, wherein this plasticizer contains Polyethylene Glycol.

21. according to the compositions of claim 18, wherein this excipient comprises the chemical compound that is selected from polyvinylpyrrolidone, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, starch, sugar, polyvinylpyrrolidone/vinyl acetate copolymer and the gelatin.

22. according to the compositions of claim 20, Polyethylene Glycol wherein is that 0.5 to 1% content with this microparticle gross dry weight is present in wherein.

23. according to the compositions of claim 18, wherein said hydrophilic coating comprises the polymer that is selected from acetic acid-O-phthalic acid cellulose and the Hydroxypropyl Methylcellulose Phathalate.

24. according to the compositions of claim 23, wherein said hydrophilic coating also comprises the plasticizer that is selected from diethyl phthalate, dibutyl sebacate and vegetable oil.

25. according to the compositions of claim 24, plasticizer wherein accounts for 10 to 30% of this hydrophilic layer gross weight.

26. according to the compositions of claim 18, lipophilic coating wherein comprises and is selected from C ₆-C ₃₆Waxy substance in the single, double or triglyceride of fatty acid, Brazil wax, candelilla wax, alcohols, fatty acid and composition thereof.

27. according to the compositions of claim 26, wax wherein is to use the compressed air do spraying substrate of heating to be coated with under molten condition.

28. according to the compositions of claim 19, carrier wherein contains the reagent in one or more mixture that are selected from suspending agent, structure agent, surfactant, sweeting agent, buffer agent, antiseptic and flavoring agent and at least two kinds.

29. according to the compositions of claim 28, carrier wherein also contains water or water and is selected from the mixture of the pharmaceutically acceptable water solublity cosolvent in glycols, alcohols and the glycerol.

30. a compositions that is used for the treatment of the symptom of coughing, said composition comprises:

Contain moguisteine as active component and the Polyethylene Glycol microparticle as plasticizer, this microparticle before the coating has slick surface and basic for spherical, but does not have the performance of sustained release,

Contain at least three kinds of coatings on this microparticle, at least a this microparticle that can make in these coatings has the sustained release performance;

First coating comprises acetic acid-O-phthalic acid cellulose, and second coating that is coated in subsequently on first coating contains glyceryl monostearate and mellisic mixture, and the 3rd coating that is coated in subsequently on second coating contains acetic acid-O-phthalic acid cellulose,

These coatings are in case can prevent in the digestion that sapid dissolving from appearring in this moguisteine and the lasting release profiles of the moguisteine guaranteeing to be scheduled to and keep this release profiles; With

A kind of carrier that is suitable for this coating microparticle administration.

31. according to the compositions of claim 30, Polyethylene Glycol wherein is PEG 6000.

32. the purposes of the sustained release dosage form of moguisteine in the cough symptom treatment, wherein this dosage form comprises:

Contain moguisteine as active component and the optional microparticle that plasticizer and excipient are arranged, this microparticle before the coating has slick surface and basic for spherical, but does not have the performance of sustained release;

Contain at least three kinds of coatings on this microparticle, at least a this microparticle that can make in these coatings has the sustained release performance;

At least three kinds of such coatings alternately contain the hydrophilic and hydrophilic layer that is useful on this microparticle, and these coatings are in case prevent in the digestion that sapid dissolving from appearring in this moguisteine and the slow release profiles of the moguisteine guaranteeing to be scheduled to and keep this release profiles.

33. according to the purposes of claim 32, dosage form wherein also contains the carrier that is useful on the microparticle administration that this coating crosses.

34. according to the purposes of claim 32, wherein this plasticizer contains Polyethylene Glycol.

35. according to the purposes of claim 34, wherein this excipient contains the chemical compound that is selected from polyvinylpyrrolidone, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, starch, sugar, polyvinylpyrrolidone/vinyl acetate copolymer and the gelatin.

36. according to the purposes of claim 34, Polyethylene Glycol wherein is that 0.5 to 1% content with this microparticle gross dry weight is present in wherein.

37. according to the purposes of claim 32, hydrophilic coating wherein comprises the polymer that is selected from acetic acid-O-phthalic acid cellulose and the Hydroxypropyl Methylcellulose Phathalate.

38. according to the purposes of claim 37, hydrophilic coating wherein also comprises the plasticizer that is selected from diethyl phthalate, dibutyl sebacate and the vegetable oil.

39. according to the purposes of claim 38, plasticizer wherein accounts for 10 to 30% of this hydrophilic layer gross weight.

40. according to the purposes of claim 32, lipophilic coating wherein comprises and is selected from C ₆-C ₃₆Waxy substance in single, double or triglyceride, Brazil wax, candelilla wax, alcohols, fatty acid and the compositions thereof of fatty acid.

41. according to the purposes of claim 40, wax wherein is to use the compressed air do spraying substrate of heating to be coated with under molten condition.

42. according to the purposes of claim 33, carrier wherein contains one or more reagent that is selected from suspending agent, structure agent, surfactant, sweeting agent, buffer agent, antiseptic and flavoring agent and at least two kinds of mixture thereof.

43. according to the purposes of claim 42, carrier wherein also contains water or water and is selected from the mixture of the pharmaceutically acceptable water solublity cosolvent of glycols, alcohols and glycerol.

44. the purposes of the sustained release dosage form of moguisteine in the cough symptom treatment, wherein this dosage form comprises:

Contain moguisteine as active component and the Polyethylene Glycol microparticle as plasticizer, this microparticle before the coating has slick surface and basic for spherical, but does not have the performance of sustained release,

Contain at least three kinds of coatings on this microparticle, at least a this microparticle that can make in these coatings has the sustained release performance,

First coating contains acetic acid-O-phthalic acid cellulose, and second coating that is coated in subsequently on first coating contains a kind of glyceryl monostearate and mellisic mixture, and the 3rd layer of coating that is coated in subsequently on the second layer coating contains acetic acid-O-phthalic acid cellulose;

These coatings are in case can prevent in the digestion that sapid dissolving from appearring in this moguisteine and the lasting release profiles of the moguisteine guaranteeing to be scheduled to and keep this release profiles; With

A kind of carrier that is suitable for this coated granule administration.

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