CN101052382A - Methods and formulations for making pharmaceutical compositions containing bupropion - Google Patents
Methods and formulations for making pharmaceutical compositions containing bupropion Download PDFInfo
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Abstract
Embodiments of the invention generally provide pharmaceutical drug compositions, methods of preparing oral drug compositions, such as extended release dosage compositions, and methods for treating antidepressant or smoking cessation. In one aspect, the invention provides a pharmaceutical formulation comprising a core, including bupropion and its salt derivatives, and a coating. The coating may include from about 5% to about 99% by weight of the coating of a pharmaceutically acceptable pH-independent polymer. The coating may further include from about 0.001% to about 30% by weight of the coating of a surfactant. In another aspect, the invention provides methods for preparing and administering a pharmaceutical composition in oral dosage form, such as a tablet.
Description
Technical field
The present invention for example is the pharmaceutical formulation of solid dosage forms or peroral dosage form roughly about multiple pharmaceutical compositions.Clearer and more definite, the invention relates to the compositions of multiple long-acting lasting dosage form and supporting agent and the active component in these compositionss, for example, as the prolongation release of pharmaceutical compositions of the oral sustained release prescription that contains a medicine and supporting agent material.
Background technology
The research that makes medicine discharge at a predetermined velocity at present and make drug level keep effective treatment concentration of wanting in can be between a longer-term is quite paid close attention to.Multiple known solid chemicals prescription needs oral three to four times of every day.
Therefore, need a kind of less formula of oral of number of times of taking, for example took once in one day.In addition, non-desired drug release rate also can cause other problems, for example take in the quick-releasing type prescription medicament after, the drug level in blood plasma or the blood flow can raise at once and cause multiple side effect.
BUP (bupropion, or claim amfebutamone) use as resist melancholy agent usually, and many to prepare medicament such as the form of salt derivatives such as BUP hydrochlorate.For example, the rich meaningful (Wellbutrin of prestige
) be a kind of of commercially available BUP medicine.Yet, once had data to show that the BUP hydrochlorate of fast dissolving dosage form may cause such as some serious side effects such as spasm, hypertension and severe allergic reactions.Need prepare a kind of new sustained release forms at present, to reduce the problem of side effect.
Have multiple preparation at present and continue to obtain the method for sustained release pharmaceutical dosage form, for example be prepared into the various prolongation release formulations of lozenge or capsule form.For example, manufacturing delay discharges or the method that continues release formulation comprises and makes a lozenge scribble the coating that one deck can delay to discharge, or after making each granule all coat this kind coating those granules with coating is pressed into a lozenge.In United States Patent (USP) case 5,358,970 and 5,427, in No. 798, narrating the multiple relevant BUP hydrochlorate that will be included in the substrate and be prepared into the solid technology of sustained release forms.Yet, BUP hydrochlorate instability, and it is very not suitable to narrate the method for using stabilizing agent to stablize this medicine in above-mentioned two pieces of patent cases.
Another kind method is to use a kind of core and a kind of mixture coating with polymer, porogen (pore-forming agent) and other excipient that can form water-insoluble/water permeability thin film that contains the BUP hydrochlorate to prepare sustained release lozenge prescription, detailed content is consulted United States Patent (USP) case 4,687,660 with European patent case EP-A-0171457 in narration.Yet this porogen can make the coating of this core inhomogeneous, and makes the rate of release instability of this lozenge.In United States Patent (USP) case 6,096,341 and 6,143, the example of other sustained release lozenge of narration then uses a core and one first coating to prepare a delay release lozenge in No. 327, and this first coating has comprised a kind of polymer, plasticizer (plasticizer) and a water-soluble polymer that can form water-insoluble/water permeability thin film.Subsequently, postpone to discharge coating one second coating or a rapid release coating on the lozenge at this.
Therefore, the method that needs a kind of sustained release prescription of improvement at present and prepare this sustained release prescription.
Summary of the invention
The present invention roughly provides a kind of and makes the core granule shape and contain pharmaceutical compositions such as therapeutic activity medicines such as BUP and derivants thereof.This pharmaceutical compositions may coat a coating in this core appearance.This coating can comprise a pharmacy can accept a pH dependent/non-dependent polymer and a surfactant.
In a scheme, provide a kind of prolongation release pharmaceutical composition with a pharmaceutical mixture core and a coating.This pharmaceutical mixture can comprise BUP, and for example about 10 milligrams (mg) contain 150 milligrams to 300 milligrams BUP hydrochlorates according to appointment to 500 milligrams BUP hydrochlorate.This coating can comprise a pharmacy can accept pH dependent/non-dependent polymer, and for example this pharmacy can be accepted pH dependent/non-dependent polymer and account for 5% to 99% of this coating weight.This pharmacy can be accepted coating mixture also can comprise a surfactant, and for example this surfactant accounts for 0.01% to 30% of this coating weight.
For example, a pharmaceutical compositions can be included in BUP or its esters (for example hydrochlorate derivant) that accounts for 5% to 95% percentage by weight in the said composition weight.This pharmaceutical compositions also can comprise a kind of pharmacy that accounts for 0.01% to 50% percentage by weight in said composition weight can accept pH dependent/non-dependent polymer, and a kind of surfactant that accounts for 0.001% to 30% percentage by weight in said composition weight.
Another program of the present invention more provides a kind of method of preparation one pharmaceutical compositions.This method comprises: formation one contains the core of a pharmaceutical mixture; And, make this core can accept the coating of coating mixture coated with one deck pharmacy.This pharmacy can be accepted coating mixture and comprise a pharmacy and can accept a pH dependent/non-dependent polymer and a surfactant.
In addition, provide a kind of method of using a pharmaceutical compositions.This method comprises the pharmaceutical compositions that contains BUP to a kind of effective dose of an administration.
The specific embodiment
Pharmaceutical compositions of the present invention comprises a therapeutic activity medicine (composition), a pharmacy can be accepted a pH dependent/non-dependent polymer and a surfactant agent.This pharmaceutical compositions is prepared into substantially such as peroral dosage form or solid formulation shapes such as lozenge, capsule and medicated bag, acceptable medicine type in any treatment.
This therapeutic activity content of medicines can be adjusted according to therapeutic dose, and accounts for 5% to 95% percentage by weight in this pharmaceutical compositions, and is good with about 30% to 90% percentage by weight.The example of this therapeutic activity medicine comprises BUP and its esters or derivant, and for example concentration is about the BUP hydrochlorate (bupropion hydrochloride) of 45% to 85% percentage by weight.For example, the BUP hydrochlorate in the pharmaceutical compositions of the present invention is about 10 milligrams to 500 milligrams.Also can use other to have the medicine of therapeutic activity among the present invention.
This therapeutic activity medicine can be prepared into powdery, microgranule, granule, beadlet, little bulk and the acceptable size of other pharmacy.This therapeutic activity medicine is microminiaturization more in addition, and making its particle size is good less than 20 microns (microns).
In one embodiment, the invention provides the prolongation release formulation that is used for this therapeutic activity medicine.For example, pharmacy of the present invention makes up to comprise and is suitable for this therapeutic activity controlled delivery of pharmaceutical agents release formulation, prolongs release formulation or controls prescription (timed release dosage formulation) release time.Prolongation release formulation as described herein can be those mammals that need treat in cycle a period of time, the treatment concentration of lasting and continual therapeutic activity medicine is provided, for example in the time more than four hours or four hours, more than six hours or six hours, more than 12 hours or 12 hours, provides to continue and continual therapeutic activity drug level.This type of prolongs release, sustained release or timing release dosage form prescription and is to use a pharmaceutical mixture core and a coating.Contain this therapeutic activity medicine in this pharmaceutical mixture, BUP hydrochlorate for example, and contain a pharmacy in this coating and can accept a pH dependent/non-dependent polymer and a surfactant.
The core that contains this therapeutic activity medicine comprises 0.01% to 80% the pharmacy acceptable polymer that a therapeutic activity medicine and a kind of its concentration account for this pharmaceutical compositions weight usually.This pharmacy acceptable polymer can help the swelling or the colloidization of this therapeutic activity medicine.Pharmacy acceptable polymer in this pharmaceutical compositions core can be a water-soluble polymer or a gelatinate polymer, for example polyvinylpyrrolidone (polyvinylpyrrolidone), hydroxypropyl cellulose (hydroxypropyl cellulose (HPC; Klucel)), hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose (HPMC; Methocel)), nitrocellulose (nitrocellulose), Cellulose ethyl hydroxypropyl ether (hydroxypropyl ethylcellulose), hydroxypropyl butyl cellulose (hydroxypropyl butylcellulose), hydroxypropyl amyl cellulose (hydroxypropylpentylcellulose), methylcellulose (methyl cellulose), ethyl cellulose (Ethocel), hydroxyethyl-cellulose (hydroxyethyl cellulose), various alkylcelluloses and hydroxy alkyl cellulose (various alkylcelluloses and hydroxyalkyl celluloses), various cellulose etherses (various celluloseethers), cellulose acetate (cellulose acetate), carboxymethyl cellulose (carboxymethyl cellulose), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), carboxymethylcellulose calcium (calciumcarboxymethyl cellulose) or the like.
For example demonstration is desired to be included in pharmacy in this core and can be accepted macromolecule and can be polyvinylpyrrolidone, for example has about 55cps or more full-bodied polyvinylpyrrolidone.Polyvinylpyrrolidone (PVP) is the single polymers (monopolymer) of a linearity, or have at least 80%, be preferably 90% copolymer by the formed repetitive of 1-ethylene-2-Pyrrolidone monomer (1-vinyl-2-pyrrolidone monomers).This polymer can be any monomer that can carry out polyreaction with it with 95%, for example, and such as neutral monomer (neutral monomers) such as olefines or acrylate (salt) classes.Other synonym titles of polyvinylpyrrolidone comprise Pu Weilong (transliteration of povidone), polyvidone (transliteration of polyvidone), 1-ethylene-2-Pyrrolidone (1-vinyl-2-pyrolidinone) and l-vinyl-2-pyrrolidone (1-ethenyl-2-pyrolionone, its CAS accession designation number 9003-39-8).Have many companies to sell the polyvinylpyrrolidone polymeric material, the trade mark that comprises ISP Technologies company is PLASDONE
TMThe trade mark of the commodity of K-29/32 and BASF Aktiengesellschaf company is KOLLIDON
TMAmerican Pharmacopeia level polyvinylpyrrolidone commodity, KOLLIDON for example
TMK-30 or K-90 (BASF Corporation, NV Division, 3000 Continental, Mount Olive, N.J.07628-1234, USA).What need to understand is, the present invention is not limited to any specific polyvinylpyrrolidone, and any have the polyvinylpyrrolidone equipollent that can accept purity and all can be used among the present invention, and is good with the purity of pharmaceutical grade.For example, the content of Pu Weilong in gross weight is approximately between 0.001% to 80% percentage by weight, and for example it accounts for 0.02% to 50% in this pharmaceutical compositions weight.
The core of this pharmaceutical mixture more can comprise multiple pharmaceutical acceptable excipient, filler, bonding agent, intermixture etc., for example moisture or water-free lactose, starch, glucose, sucrose, mannitol (mannitol), sorbitol (sorbitol), silicic acid (silicic acid), microcrystalline Cellulose (microcrystalline celluloses), sodium carboxymethyl cellulose (sodium carboxymethylcelluloses), sodium starch glycol (sodium starchglycolate) and derivant or mixture.For example, can in core, add concentration be about this pharmaceutical compositions weight of 0.01% to 50% microcrystalline Cellulose (avicel), for example, add the microcrystalline Cellulose of about 0.05% to 40% percentage by weight.Core of the present invention more can comprise lubricant, homogeneous agent, anti-adhesive, fluidizer, wetting agent, dyestuff, pigment, adhesive, dispersant, coating material and composition thereof etc. are not desired and the bonded various compositions of this pharmaceutical mixture core.The example of lubricant including, but not limited to Pulvis Talci (talc), calcium stearate (calcium stearate), magnesium stearate (magnesium stearate), glyceryl monostearate (glycerol monostearate), Polyethylene Glycol (polyethylene glycols, PEG), inertia silex glass material (inert silicon glass materials), silica colloidal (colloidal silicon dioxide), a high carbon number acid-proof and alkali metal group and alkaline earth metal salt.In addition, be to be exposed in the Remington ' s Pharmaceutical Sciences document of nineteen ninety-five version such as various excipient such as diluent, lubricant, dyestuffs, and can be used to make pharmaceutical compositions of the present invention to reach optimization.
The content of those lubricants, anti-adhesive and other excipient accounts for 0.005% to 50%, for example about 0.005% to about 30% of this pharmaceutical compositions weight usually.The excipient that can sneak in this pharmaceutical compositions core comprises that magnesium stearate, commodity are called silica flour, microcrystalline Cellulose (avicel), glyceryl monostearate and the Pulvis Talci of cab-O-sil, and its ultimate density in this pharmaceutical compositions weight is about 1.0% to 20% percentage by weight.
That this pharmaceutical mixture core can be made into is microgranular, graininess, pearl, spherical shape, ball shape (pellets), film clothing pearl (coated beads), film clothing ball (coated pellets), film clothing granule (coated particles) and acceptable shape of other pharmacy and size.Can reach above-mentioned action by various pelletizes and additive method, for example can use wet type or dry pelletizing method.Wet granulation is that the composition with needs is mixed with multiple conventionally known solvent, to form microgranule.Perhaps, can use dry pelletizing method to prepare this pharmaceutical compositions.Subsequently, this pharmaceutical compositions core mixture is prepared into such as in lozenge or other solid dosage formss, and applies the optionally outer top coat of one deck.For making the compacting ingot, can use traditional Ingot pressing machine that various mixture of ingredients granules of the present invention are squeezed into ingot.
A plurality of embodiment of the present invention provides a kind of coating, and this coating is positioned at the appearance of the core that contains this therapeutic activity composition.This coating comprises a pharmacy can accept a pH dependent/non-dependent polymer and a surfactant.Pharmacy in the coating of this pharmaceutical compositions can be accepted pH dependent/non-dependent polymer content and account for 0.01% to 99% of this coating weight usually, for example accounts for 5% to 99% of this coating weight.For example, this pharmacy can be accepted the concentration of pH dependent/non-dependent polymer in this pharmaceutical compositions approximately between 0.001% to 50% percentage by weight, for example, is about 0.01% to 10% of this pharmaceutical compositions weight.
This pharmacy can be accepted pH dependent/non-dependent polymer including, but not limited to insoluble polymer, water solublity hydrophilic polymer (water-soluble hydrophilic polymers), maltodextrin (maltodextrin), natural gum (natural gums), arabic gum (arabic gum), guar gum (guar gum), xanthan gum (xanthan gum, be commonly called as Hydrargyri Oxydum Rubrum glue), Te Lakagan glue (tragacanth gum), agar-agar glue (agar is commonly called as Eucheuma gelatinosum), tie blue glue (gellan gum), POLY-karaya (kayara gum), alginic acid (alginic acids), pectin (pectins), gelatinized starch (pre-gelatinized starch), glucosan (dextrin), the mixing thing or the compositions of maltodextrin (maltodextrin) and above-mentioned polymer.The representative water insoluble polymer that can be used among the present invention comprises polyacrylic acid (polyacrylates), such as ethyl cellulose cellulose derivatives such as (ethylcellulose), be called Kollicoat SR30D (available from BASF Corporation such as commodity, Mount Olive, New Jersey) polyvinyl acetate (polyvinyl acetate), the neutral copolymer of ethyl acrylate and methacrylate ester (neutral copolymers based on ethyl acrylate andmethylmethacrylate), acrylate and methacrylate copolymer (copolymers of acrylateand methacrylates) and other analog etc.The example of water-soluble polymer comprises polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel), hydroxypropyl emthylcellulose (HPMC; Methocel), nitrocellulose, Cellulose ethyl hydroxypropyl ether, the hydroxypropyl butyl cellulose, the hydroxypropyl amyl cellulose, methylcellulose, ethyl cellulose (Ethocel), hydroxyethyl-cellulose, various alkylcelluloses and hydroxy alkyl cellulose, various cellulose etherses, cellulose acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, vinylacetate/butenoic acid copolymer (vinyl acetate/crotonic acid copolymers), polymethylacrylic acid hydroxyalkyl (poly-hydroxyalkyl methacrylate), hydroxy methyl methacrylate (hydroxymethylmethacrylate), methacrylic acid copolymer (methacrylic acid copolymers), polymethylacrylic acid (polymethacrylic acid), polymethyl methacrylate (polymethylmethacrylate), maleic anhydride/ethylene methacrylic ether copolymer (maleic anhydride/methyl vinyl ether copolymers), polyvinyl alcohol (poly vinyl alcohol), sodium polyacrylate and calcium (sodium and calcium polyacrylic acid), polyacrylic acid (polyacrylic acid), acid carboxyl polymer (acidic carboxy polymers), carboxyl gathers methene (carboxypolymethylene, or title carboxyl polymethylene), carboxy vinyl polymer (carboxyvinylpolymers), poly(ethylene oxide)-polyoxy propane copolymer (polyoxyethylene polyoxypropylenecopolymer), poly-ethylene methacrylic ether-altogether-maleic anhydride (polymethylvinylether co-maleicanhydride), carboxymethyl amide (carboxymethylamide), methacrylic acid potassium divinyl benzene copolymer (potassium methacrylate divinylbenzene co-polymer), hydroxyalkyl vinyl glyceride (polyoxyethyleneglycols), poly(ethylene oxide) (polyethylene oxide) and derivant thereof, salt and mixture.
Can accept pH dependent/non-dependent polymer for sustained release or the useful especially pharmacy of lasting release formulation is that those have low water permeability and can postpone the polymer of the rate of release of this therapeutic activity medicament, no matter make medicine or therapeutic activity composition be under the low ph environment in the stomach, or be under the environment in the intestines and stomach, all can be slowly and stably disengage.This pH dependent/non-dependent polymer can be made into granule, powder, aqueous liquid dispersion and other various ways.For example, such as Eudragit
RS or RS30D, NE, RL or RL30D etc. have the acrylic acid of level Four ammonium and methacrylic acid copolymer, and (R hm Amrica LLC) all is applicable to the prolongation release dosage form of preparation BUP.
The coating of this pharmaceutical compositions more comprises kinds of surface activating agent, emulsifying agent, dispersant, defoamer and composition thereof.Any suitable pharmacy can be accepted or medical science can be accepted surfactant, emulsifying agent, dispersant (dispersing agent), dispersant (dispersant) and all can be used among the present invention with defoamer, and surfactant can be any ionic, anionic property or nonionic surfactant.For example, be no more than 50% of gross weight such as sodium lauryl sulphate (sodium lauryl sulfate), Tween 80 (can available from Fisher Scientific International company), Tween 20, Tween 100 with the working concentration of other surfactants, for example be about 0.01% to 10% of gross weight.For example, the surfactant use amount in the coating of this pharmaceutical compositions accounts for 0.001% to 50% in this coating weight, for example account for 0.1% to 30% of this coating weight.And need not quote any theory and can understand surfactant in this pharmaceutical compositions and can improve this pharmacy and can accept the drainage of pH dependent/non-dependent polymer (channeling process), to reach the drug release pattern of wanting.
This coating can more comprise multiple aforesaid pharmaceutical acceptable excipient, filler, bonding agent, intermixture, and those excipient are exposed in document Remington ' s Pharmaceutical Sciences, in the nineteen ninety-five version.And be found to, not only can accept the rate of release that pH dependent/non-dependent polymer and surfactant are controlled this therapeutic activity medicine, also can control the rate of release of therapeutic activity medicine by the thickness of this coating that contains excipient by in this coating, including suitable pharmacy in.
In one embodiment, the invention provides a kind of prolongation release formulation, for example sustained release type or prolongation release formulation by the prepared BUP hydrochlorate that forms of pharmaceutical compositions of the present invention.In another embodiment, the invention provides a kind of by preparing a core and making this core apply one deck coating to make a method that prolongs release formulation.Subsequently, this core with coating is contained in such as in the solid dosage formss such as lozenge.
Pharmaceutical compositions of the present invention can have second an extra coating, and this coating contains a pharmacy can accept coating mixture.This pharmacy in this second coating can accept coating mixture including but not limited to an enteric polymer (enteric polymers), a salt, collapse the type coating material that looses, a pigment, a plasticiser, a water-soluble polymer, an insoluble polymer, a dyestuff, a pigment fast, multiple other collapse the compositions of powder (disintegrant) and above-mentioned substance.Commonly used to collapse the type coating material that looses fast be the commodity of OPADRY by name, and it can be available from Colorcon, Inc company.
The example of enteric polymer comprises methacrylic acid copolymer (Eudragit for example
TMS and Eudragit
TML; it can be available from R hm America, LLC), Hydroxypropyl Methylcellulose Phathalate (hydroxypropyl methylcellulose phthalate), hydroxypropylmethylcellulose acetate methylcellulose (hydroxypropyl methylcellulose acetate), succinic acid hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose succinate), carboxymethylethylcellulose (carboxymethylethylcellulose), acetyl group O-phthalic acid cellulose (celluloseacetophthalate).Generally speaking, enteric polymer fast land fall loose or be dissolved under the condition of pH5 or higher pH value.
Any pharmaceutically acceptable salt class commonly used all can be used in this second coating, for example sodium chloride, magnesium chloride and other similar salts.In addition, the example of plasticiser comprises Polyethylene Glycol, propylene glycol (propyleneglycol is PEG) with other analog.Moreover, water-soluble polymer and water or with have high swelling (swelling) such as becoming to grade in the stomach usually after aqueous medium contacts.The example of water-soluble polymer comprises hydroxypropyl emthylcellulose, hydroxypropyl cellulose, poly(ethylene oxide) or the like.This ground case coating more can comprise multiple pharmaceutical acceptable excipient, filler, bonding agent, intermixture etc., and it can consult document Remington ' sPharmaceutical Sciences, nineteen ninety-five version.
Usually, the second coating amount that is coating the lozenge of existing coating accounts for 0.001% to 5% of pharmaceutical compositions gross weight, for example is about 0.01% to 2% of this pharmaceutical compositions gross weight.And be found to, not only can also can control it by wrap up the rate of release that this core that contains BUP is controlled this therapeutic activity medicine with first coating by the thickness of this second coating.
In a scheme, the expection release mode that the prepared pharmaceutical compositions dosage form that forms can show and can be used as sustained release, continue to discharge or prolong release formulation according to the present invention.Herein, " discharge (release) " speech can be broadly defined as a chemical compound in vivo or absorption in the external environment or solute effect.Normally the plasma concentration by the therapeutic activity medicine in the cycle between measuring for the moment records trap in this body.The release in vitro pattern of this therapeutic activity medicine then can be in the American Pharmacopeia second class device (USP type 2 apparatus), in getting with the detecting rotational speed of 50rpm in the phosphate buffer (pH5) at 900 milliliters under 37 ℃.Also can use other buffer herein, for example acetate buffer solution (pH5).Any standard U.S. pharmacopeia test set and condition all can be used.For example, can use the American Pharmacopeia first kind to be installed in simulated intestinal fluid buffer (SIP) or the simulated gastric fluid buffer (SGF, low pH value, about pH1.5), discharge test with the rotating speed of about 75rpm.
In another program of the present invention, the a plurality of embodiment of the present invention can be under the condition of simulated intestinal fluid buffer (SIF), be provided at the release mode that discharges about 40% therapeutic activity medicine in initial 2 hours at the most, and the preferably shows the release mode that discharged about 5% to 40% therapeutic activity medicine in initial 2 hours.This pharmaceutical compositions more is provided in to discharge in 4 hours about 10% to 75% therapeutic activity medicine, discharged the release mode of about 30% to 90% therapeutic activity medicine in 6 hours, and is good with the release mode that discharges about 40% to 80% therapeutic activity medicine in 6 hours.In 12 hours, it is about 50% that the therapeutic activity release amount of medicine that this pharmaceutical compositions provided is not less than, and the preferably is for being not less than about 75%.
In addition, under the condition of simulated gastric fluid buffer (SGF), the a plurality of embodiment of the present invention are provided at the release mode that discharges 20% therapeutic activity medicine in initial 2 hours at the most, and the preferably shows the release mode that discharged about 2% to 20% therapeutic activity medicine in initial 2 hours.This pharmaceutical compositions more is provided in to discharge in 4 hours about 10% to 65% therapeutic activity medicine, discharged the release mode of about 30% to 75% therapeutic activity medicine in 6 hours, and is good with the release mode that discharges about 30% to 75% therapeutic activity medicine in 6 hours.In 12 hours, it is about 50% that the therapeutic activity release amount of medicine that this pharmaceutical compositions provided is not less than, and the preferably is for being not less than about 75%.
A kind of method of using a prolongation release pharmaceutical composition is provided among another embodiment.This method comprises the pharmaceutical compositions of the present invention that contains a therapeutic activity medicine to an administration one effective dose.For example, when being used for the treatment of, be about 150 milligrams of every days according to the effective dose of the prepared prolongation release type BUP hydrochlorate lozenge that forms of the embodiment of the invention such as melancholia such as heavy melancholia and craving for tobacco.And, can every day about 150 milligrams predose continue to use a couple of days.Under some situation, also can use about 300 milligrams higher dosage every day.
Example
Be to describe and prepare multiple exemplary sustained release dosage form prescription herein.Allocate and test multiple pharmaceutical compositions herein, contain in those pharmaceutical compositions: a therapeutic activity medicament, its concentration account for 40% to 80% of gross weight; One pH dependent/non-dependent pharmacy acceptable polymer, its concentration accounts for 0.1% to 5% of gross weight; And a surfactant, its concentration accounts for 0.1% to 4.9% of gross weight.Usually, be mixed with such as BUP hydrochlorate etc. that to prolong the BUP formula of oral that discharges lozenge be to test in external, with the release mode (release profile) of measuring those lozenge, and in some cases, can in healthy human body, carry out the live body test to make comparisons with contrast (reference) prescription.Control formula as used herein is the medicine (GlaxoSmithKline) of commodity Wellbutrin XL lozenge by name.
Embodiment 1
Embodiment 1 be preparation contain 150 milligrams with the prolongations of 300 milligrams BUP hydrochlorate release lozenge.Comprise about 150 milligrams or 300 milligrams BUP hydrochlorate, the Pu Weilong (Povidone, American Pharmacopeia level specification) of about 0.1% to 5% percentage by weight, the microcrystalline Cellulose (Avicel) of about 0.01% to 2% percentage by weight, the glyceryl monostearate of about 0.01% to 2% percentage by weight, the Pulvis Talci (talc) of about 0.001% to 1% percentage by weight, the magnesium stearate of about 0.001% to 1% percentage by weight, the Eudragit of about 0.01% to 2% percentage by weight in the lozenge respectively
The Eudragit of the sodium lauryl sulphate of RS, about 0.001% to 1% percentage by weight, about 0.01% to 2% percentage by weight
The sodium chloride of L, about 0.001% to 0.1% percentage by weight and optionally comprise an anti-adhesive and a pigment.
Pelletize:
At first, getting an amount of Pu Weilong is dissolved in the water.BUP hydrochlorate and microcrystalline Cellulose are placed vertical type comminutor and stir about 10 to 20 minutes in advance.In second time whipping process, the Pu Weilong spray solution is stirred on thing at this.And may need extra water or mixing time to reach the pelletize effect of uniformity.Subsequently, those granules are placed (or carrying out dry loss of weight 10 minutes under 105 ℃) is lower than 1.5% up to those particulate moistures under 40 ℃ the environment.After finishing drying, grind those granules at once, and in the V-type blender, mix silica flour, Pulvis Talci and magnesium stearate with glyceryl monostearate, trade name cab-O-sil.
The system ingot:
With diameter is that 11/32 inch standard Ingot pressing machine (standard concave punch) is pressed into the lozenge core with the resulting granules mixture, and the average hardness that makes those lozenge cores is between 7 system 13Kp.Wrap up those lozenge cores with a coating mixed liquor subsequently, with as first coating.
First coating:
At first with Eudragit RS
TMBe dissolved in water and the alcoholic acid mixed liquor, then add sodium lauryl sulphate, to prepare the coating mixed liquor of this first coating.Subsequently, under 47 ℃, in a coating pan (O ' Harra), should be coated with mixed liquor or dispersion liquid is sprayed on this lozenge core.
Second coating or color dress (color coating):
Use square position formula coating machine with Eudragit
L plus casing is coated on this lozenge that has had coating once more, and optionally contains sodium chloride, anti-adhesive and pigment in this casing.Usually, resulting theoretical film clothing degree (theoretical coating level) is near 1%.
Discharge test:
According to the described program of the American Pharmacopeia second class device, it is the acetate buffer solution of 5 (pH5) that resulting lozenge and matched group lozenge are together placed about 900 milliliters (ml) and pH-value, stir discharging test with the rotating speed of 75rpm, and obtain following release mode.These results demonstrate the prolongation releasing effect according to the prepared BUP that goes out of the method for embodiment 1 and prescription.
| Time (hour) | Matched group discharges percentage ratio % | Embodiment 1 discharges percentage ratio % |
| 0 | 0 | 0 |
| 2 | 32.82 | 24.10 |
| 4 | 56.49 | 53.40 |
| 8 | 80.27 | 84.18 |
| 14 | 90.05 | 90.85 |
Embodiment 2
The prolongation release dosage form lozenge that uses above-mentioned same procedure to prepare to contain 300 milligrams of BUP hydrochlorates.
Discharge test:
The program of being narrated according to the American Pharmacopeia second class device, with coexist about 900 milliliters and pH-value of resulting lozenge and matched group lozenge one is in the acidic buffer of 1.5 (pH1.5), stir discharging test with the rotating speed of 75rpm, and obtain following release mode.These results demonstrate the prolongation releasing effect according to the prepared BUP that comes out of the method for embodiment 2 and prescription.
| Time (hour) | Matched group discharges percentage ratio % | Embodiment 2 discharges percentage ratio % |
| 0 | 0 | 0 |
| 2 | 8.61 | 9.74 |
| 4 | 52.87 | 51.25 |
| 8 | 85.72 | 85.12 |
| 14 | 99.54 | 97.39 |
Foregoing relates to the description of a plurality of embodiment of the present invention.Yet, can design other or embodiment further under the elemental range of the present invention not departing from, and the scope of the invention is defined by the attached claim in back.
Claims (34)
1. pharmaceutical compositions, it comprises:
One contains the core of BUP (bupropion); And
One coating, it comprises an a pharmacy acceptable pH dependent/non-dependent polymer and a surfactant.
2. pharmaceutical compositions as claimed in claim 1 is characterized in that, described BUP comprise about 10 milligrams to about 500 milligrams BUP hydrochlorate.
3. pharmaceutical compositions as claimed in claim 1 is characterized in that, described pharmacy can be accepted pH dependent/non-dependent polymer and account for 5% to 99% percentage by weight in this coating weight.
4. pharmaceutical compositions as claimed in claim 1, it is characterized in that it is to be selected from the group that is made of following polymers that described pharmacy can be accepted pH dependent/non-dependent polymer: polyacrylate (polyacrylate), acrylate and methacrylate copolymer (copolymer of acrylate andmethacrylate), methacrylate polymers (methacrylate polymer), the methacrylate of tool ammonium and the copolymer of acrylate (copolymer of acrylate and methacrylate withammonium group), maleic anhydride and ethylene methacrylic ether copolymer (copolymer of maleicanhydride and methyl vinyl ether), hydroxypropyl emthylcellulose (hydroxy propyl methylcellulose), Cellulose ethyl hydroxypropyl ether (hydroxy propyl ethyl cellulose), hydroxypropyl cellulose (hydroxy propyl cellulose), hydroxyethyl-cellulose (hydroxy ethyl cellulose), methylcellulose (methyl cellulose), hydroxy methyl methacrylate (hydroxymethyl methacrylate), poly(ethylene oxide) (polyethylene oxide), maltodextrin (maltodextrin), natural gum (natural gum), the derivant and the compositions of xanthan gum (xanthan gum) and above-mentioned substance.
5. pharmaceutical compositions as claimed in claim 5 is characterized in that, it is one to be selected from by the polymer in Eudragit RS, Eudragit RL and the group that derivant and compositions constituted thereof that described pharmacy can be accepted pH dependent/non-dependent polymer.
6. pharmaceutical compositions as claimed in claim 1 is characterized in that, described surfactant accounts for 0.01% to 30% percentage by weight in this coating weight.
7. pharmaceutical compositions as claimed in claim 1 is characterized in that, described surfactant is in the group that compositions constituted that is selected from by ionic surfactant, anion surfactant, nonionic surfactant and above-mentioned surfactant.
8. pharmaceutical compositions as claimed in claim 1 is characterized in that, this surfactant is sodium lauryl sulphate (sodium lauryl sulfate).
9. pharmaceutical compositions as claimed in claim 1, said composition also comprises the acceptable excipient of one or more pharmacy, and described excipient is to be selected from by filler (filler), adulterant (extender), bonding agent (binder), intermixture (blending agent), emulsifying agent, dispersant, defoamer (defoamer), lubricant (lubricant), be not stained with glutinous agent (nonstick agent), homogeneous agent (blender), fluidizer (glidant), anti-adhesive (anti-sticking agent), pigment (colorant), diluent (diluent), dyestuff (dyes), pigment (pigment), dispersant (dispersant), in the group that derivant and compositions constituted of wetting agent (wetting agent) and above-mentioned excipient.
10. pharmaceutical compositions as claimed in claim 1 is characterized in that, described core also comprises a water-soluble glue fluidized polymer (gelling polymer).
11. pharmaceutical compositions as claimed in claim 1 is characterized in that, described pharmaceutical compositions comprises: a bupropion salt, about 5% to 95% percentage by weight of its content; One pH dependent/non-dependent polyacrylate polymers, about 0.01% to 50% percentage by weight of its content; And a surfactant, about 0.001% to 30% percentage by weight of its content.
12. pharmaceutical compositions as claimed in claim 1, said composition also comprise one second coating, this second coating contains an enteric polymer.
13. pharmaceutical compositions as claimed in claim 13, it is characterized in that described enteric polymer is one to be selected from the polymer in the group that is made of following material: cellulose acetate-phthalate (cellulose acetate phthalate), O-phthalic acid cellulose hydroxypropyl methyl ether (cellulose phthalatehydroxy propyl methyl ether), polyethylene acetic acid phthalic acid ester (polyvinyl acetatephthalate), acetic acid succinic acid hydroxypropyl emthylcellulose (hydroxy propyl methyl celluloseacetate succinate), trimellitic acid cellulose acetate (cellulose acetate trimellitate), Lac (shellac), acrylic acid polymer, Eudragit L, the derivant of Eudragit S and above-mentioned substance and compositions.
14. pharmaceutical compositions as claimed in claim 13 is characterized in that, described second coating also comprises a salt.
15. one kind prolongs release pharmaceutical composition, it comprises:
One contains the core of the pharmaceutical mixture of BUP; And
One coating, this coating comprises:
One pharmacy can be accepted pH dependent/non-dependent polymer; And
One surfactant.
16. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, described BUP comprises about 10 milligrams to 500 milligrams BUP hydrochlorate.
17. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, this pharmacy can be accepted pH dependent/non-dependent polymer and account for 5% to 99% percentage by weight in this coating weight.
18. prolongation release pharmaceutical composition as claimed in claim 16, it is characterized in that it is to be selected from the group that is made of following polymers that described pharmacy can be accepted pH dependent/non-dependent polymer: polyacrylate, acrylate and methacrylate copolymer, methylcellulose, methacrylate polymers, the acrylate of tool ammonium and methacrylate copolymer, maleic anhydride and ethylene methacrylic ether copolymer, hydroxy methyl methacrylate, poly(ethylene oxide), hydroxypropyl emthylcellulose, Cellulose ethyl hydroxypropyl ether, hydroxypropyl cellulose, hydroxyethyl-cellulose, maltodextrin, natural gum, the derivant of xanthan gum and above-mentioned substance and compositions.
19. prolongation release pharmaceutical composition as claimed in claim 19, it is characterized in that it is a polymer that is selected from by in Eudragit RS, Eudragit RL and the group that derivant and compositions constituted thereof that described pharmacy can be accepted pH dependent/non-dependent polymer.
20. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, described surfactant accounts for 0.01% to 30% percentage by weight in this coating weight.
21. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, described surfactant is to be selected from by in ionic surfactant, anion surfactant, nonionic surfactant and the group that compositions constituted thereof.
22. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that described surfactant is a sodium lauryl sulphate.
23. prolongation release pharmaceutical composition as claimed in claim 16, said composition also comprises one or more pharmaceutical acceptable excipients, and these excipient are to be selected from by filler, pigment, adulterant, bonding agent, intermixture, emulsifying agent, dispersant, defoamer, lubricant, not to be stained with in the group that derivant and compositions constituted of glutinous agent, homogeneous agent, fluidizer, anti-adhesive, diluent, dyestuff, pigment, dispersant, wetting agent and above-mentioned excipient.
24. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, described pharmaceutical mixture also comprises a water-soluble glue fluidized polymer.
25. prolongation release pharmaceutical composition as claimed in claim 16 is characterized in that, described pharmaceutical compositions comprises: a bupropion salt, about 5% to 95% percentage by weight of its content; One pH dependent/non-dependent polyacrylate polymers, about 0.01% to 50% percentage by weight of its content; And a surfactant, about 0.001% to 30% percentage by weight of its content.
26. prolongation release pharmaceutical composition as claimed in claim 16, said composition also comprise one second coating, and this second coating contains an enteric polymer.
27. prolongation release pharmaceutical composition as claimed in claim 27, it is characterized in that described enteric polymer is a kind of polymer that is selected from the group that is made of following material: the derivant and the compositions of cellulose acetate-phthalate, O-phthalic acid cellulose hydroxypropyl methyl ether, polyethylene acetic acid phthalic acid ester, acetic acid succinic acid hydroxypropyl emthylcellulose, trimellitic acid cellulose acetate, Lac, polyacrylate polymers, Eudragit L, Eudragit S and above-mentioned substance.
28. prolongation release pharmaceutical composition as claimed in claim 26 is characterized in that, this second coating also comprises a salt.
29. a method for preparing a pharmaceutical compositions, this method comprises:
Form a pharmaceutical compositions core, and this pharmaceutical compositions comprises BUP; And
Make this core apply a coating, this coating comprises:
One pharmacy can be accepted pH dependent/non-dependent polymer; And
One surfactant.
30. method as claimed in claim 30, this method also comprise this pharmaceutical compositions is squeezed into the dosage form that is selected from the following group, this group is made of peroral dosage form, solid dosage forms and combination thereof.
31. method as claimed in claim 30 is characterized in that, described core is formed by mixing this pharmaceutical mixture and this mixture being squeezed into ingot.
32. method as claimed in claim 30 is characterized in that, described core also comprises a water-soluble glue fluidized polymer.
33. method as claimed in claim 30 is characterized in that, described core is formed by a technology that is selected from the group that is made of dried granulating technique and wet granulating technique.
34. use a method that contains the pharmaceutical compositions of BUP for one kind, this method comprises:
To the described pharmaceutical compositions of an administration one effective dose, and described pharmaceutical compositions comprises:
One contains the core of the mixture of BUP; And
One contains the coating that a pharmacy can be accepted a pH dependent/non-dependent polymer and a surfactant.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62631704P | 2004-11-08 | 2004-11-08 | |
| US60/626,317 | 2004-11-08 | ||
| US11/265,918 | 2005-11-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101052382A true CN101052382A (en) | 2007-10-10 |
Family
ID=38783436
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580037819 Pending CN101052382A (en) | 2004-11-08 | 2005-11-08 | Methods and formulations for making pharmaceutical compositions containing bupropion |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101052382A (en) |
| TW (1) | TWI377957B (en) |
-
2005
- 2005-11-07 TW TW94139004A patent/TWI377957B/en not_active IP Right Cessation
- 2005-11-08 CN CN 200580037819 patent/CN101052382A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| TW200621314A (en) | 2006-07-01 |
| TWI377957B (en) | 2012-12-01 |
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Application publication date: 20071010 |