CA2796884A1 - Improved controlled release oral dosage form - Google Patents
Improved controlled release oral dosage form Download PDFInfo
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- CA2796884A1 CA2796884A1 CA2796884A CA2796884A CA2796884A1 CA 2796884 A1 CA2796884 A1 CA 2796884A1 CA 2796884 A CA2796884 A CA 2796884A CA 2796884 A CA2796884 A CA 2796884A CA 2796884 A1 CA2796884 A1 CA 2796884A1
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- Prior art keywords
- bupropion
- pellet
- pharmaceutically acceptable
- acceptable salt
- sustained release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
Abstract
A pharmaceutical composition designed for once daily dosing of bupropion comprising: (A) a sustained release form of bupropion comprising: (i) a core comprising bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, and (ii) a sustained release component, and (B) an immediate release form of bupropion or a pharmaceutically acceptable salt or stereoisomer thereof.
Description
IMPROVED CONTROLLED RELEASE ORAL DOSAGE FORM
FIELD OF THE INVENTION
The present invention relates to oral controlled release dosage formulations containing bupropion hydrochloride.
BACKGROUND OF THE INVENTION
The compound designated bupropion hydrochloride is described in United States Patent Nos. 3,819,706 and 3,885,046. It is marketed as an anti-depressant and an aid to smoking cessation. Bupropion is an aminoketone-derivative chemically unrelated to other currently available antidepressants (e.g., selective serotonin-reuptake inhibitors, tricyclics, tetracyclics).
While the neurochemical mechanisms of the antidepressant and smoking cessation effects are unknown, noradrenergic pathways and/or dopaminergic effects appear to be primarily involved. Bupropion does not inhibit monoamine oxidase and is a weak blocker of serotonin and norepinephrine uptake.
The drug is useful in the treatment of depressive affective disorders (e.g., major depression) at dosages of 75 to 600 mg daily. Bupropion may be preferable to other agents because of its minimal anticholinergic, cardiovascular, and antihistaminic effects or in those patients who have experienced weight gain or sexual dysfunction with another antidepressant. Bupropion, as extended-release tablets, is used in the cessation of smoking at dosages of 100-300 mg daily. Withdrawal symptamns and cigarette craving are reduced with bupropion. Other uses include patients with b.polar depression, attention-deficit hyperactivity in both adult and pediatric patients, and panic symptoms superimposed on depression.
Immediate release bupropion tablets pro vide more than 75% of bupropion release into the dissolution media in 45 minutes. In studies to date, the risk of seizures appears to be strongly associated, in part, with the use of instant release tablets.
Numerous techniques exist in the prior art for preparing sustained or controlled release pharmaceutical formulations. One common technique involves surrounding an osmotically active drug core with a semipermeable membrane. The drug is released from the core over time by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the drug so the dissolved drug can permeate through the membrane. In some cases a hvdrogel is employed to push the active ingredient through the passageway of the membrane.
Another common technique for preparing controlled-release pharmaceutical formulations is to encapsulate a plurality of beads, pellets or tablets that are coated with varying levels of diffusion barriers. The barriers can be of the same or different chemical composition. Release of the pharmaceutical may occur by leaching, erosion, rupture, diffusion or similar actions depending on the nature and WO 02/062299 PCTiU, S02/03523 thickness of the coating material. These products require multi-layered coating, sometimes as much as 30 to 90 coats.
Film coating techniques are characterized by the deposition of a uniform film onto the surface of a substrate. Because of the capability of depositing a variety of coating materials onto solid cores, this process has been used to make controlled release dosage forms starring from different formulations, such as tablets, granules, pellets and capsules. Cores are usually prepared using one of the following processes. compaction, surface layering, or agglomeration.
One limitation associated with these dosage forms consists in their failure o delay drug delivery. Many o the m ilti-walled preparations described above do not provide prolonged delayed release of the drag prior to initiation of sustained release, which. is important when biphasic release profiles are desired. Other systems are essentially "delayed releases mechanisms. There is delay of drug release in the stomach. but once the coated drug reaches the i~rtestines, the release of medication is rapid. There is no sustained release in the intestines.
Bupropion hydrochloride is highly soluble in water with a high permeability characterized by rapid and almost complete absorption. Peak plasma concentrations occur within 2 hours for bupropion and 3 hours for bupropion sustained-release. Its biphasic pharniacokinetics is characterized by a two-compartment model; the distributive phase has a mean half-life of 3 to 4 hours with a biphasic decline and a terminal T Vz of about 14 hours following single doses.
A
major drawback is extensive first-pass metabolism. It appears that only a small portion of any oral dosage reaches the systemic circulation intact. Immediate-release tablets are dosed three times a day, preferably with 6 or more hours separating the doses. For those patients requiring doses greater than 300 mg daily, each divided WO 02/062299 PCTiUS02/03523 dose should not exceed 150 mg each. This necessitates administration of the tablets 4 times daily with at least 4 hours between successive doses. Commercially available sustained-release products are available in film-coated tablets marketed by Glaxo Wellcome under the tradenames Welibutrin SR and Zyban . These are dosed Mice daily. For those patients requiring above 300 mg daily, the regimen remains twice daily dosing. No currently available product provides a sustained release profile suitable for once daily dosing.
Patient compiiance is especially problematic in depressed patients.
There is a need for improved patient compliance. One of the means employed clinica'I_- to improve p tint adherence _ .
o , s es r; simplification or the dosing regi~ Een. Thus, need exists for a once daily bupropion formulation.
Sustained release tablet fours of bupropion are described in United States Patent No. 5,427,798. comprising a . ustained release tablet which provides peals bupropion blood levels at approximately 2-3 hours, thereby requiring twice daily dosing. Controlled release is achieved by combining bupropion particles with microcrvstalline cellulose and hy-drogel-forming hydroxv~propyl methyicelluiose.
Another sustained release bupropion tablet or caplet formulation disclosed in united States 4,687,660, comprises a difficult manufacturing process and limited shelf life. United States Patent No. 5,358,970 discloses a formulation of bupropion hydrochloride that contains an acid stabilizer.
United States Reissue Patent No. 33,994 discloses a tablet formulation of a water insoluble, water-permeable film coating surrounding the drug core and a particulate, water-soluble, pore-forming material dispersed within the film coating;
this osmotic gradient and channel forming system is applicable for tablet dosage forms. However, here also at least twice daily dosing is necessitated by the release profile of 25-70% of bupropion within 4 hours, and 40-90% within 6 hours.
Wellbutrin SR is a commercially available twice a day dosage form of bupropion which contains carnauba wax, cy steire hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.
There is no capsule form of bupropion commercially available.
Capsules are advantageous in those patients who have difficulty swallowing where the contents of the capsule may be sprinkled on food.
Immediate release tablets must be stored at a temperature above 15-C a _d protected from light and moist ere. Extendeu release tablets should be stored in tight, light-resistant containers at a temperature of 20-25 C.
The need exists for a relayed, sustained release pharmaceutical preparation that provides a longer delay of drag dissolution thereby allowing greater fiexibili in designing sustained release profiles, provides improved plasma levels wherein the maximum plasma concentration (Caw,) can be substantially reduced without a concomitant reduction in A1. C, and is simply and economically produced.
Such a delayed delivery dosage form has a practical application, and it represents a valuable contribution to the medical arts. The present invention provides such a composition and offers an efficient and cost effective method of preparation.
Accordingly, it is an object of this invention to provide a sustained release formulation of bupropion suitable for once daily administration.
Another object of the present invention is to provide a capsule dosage form comprising means for delaying delivery of the drug in gastric fluids for 6 hours up to 12 hours, usually 4 hours to 8 hours.
It is also an object of this invention to provide a controlled and extended release bupropion capsule formulation that is easy to manufacture and can be used to prepare a range of dosing levels suitable for once daily administration.
It is a further object of the present invention to provide 24-hour control of symptoms of depression or tobacco dependence withdrawal.
Seizures result more commonly by single dosages of bupropion over 150, mg, hence the need for twice to four times dally dosing regimens. Another object of this i vention is to provide simplified once daily dosing regimen with the potential to prevent or reduce the incidence of seizures caused by bupropion.
The present in v'ention also relates to a new sustained release bupropion pharmaceutical composition producing novel blood plasma levels after ingestion over 24 ` o r^ t n n or rep tss ho hat is not disclosed; ; nc_ . dead obvious by, the prior art. Other abJec f L-tunes and advantages of the invention are not taught in the prior art but will be more apparent to those versed in the art from the follo~. ng specification;
taken in conjunction with the d_rawirigs.
SUNENIARY OF THE PRESENT INVENTION
The present invention meets the unfulfilled needs of the pharmaceutical industry.
The current invention involves a new pelletization process, typified by the application of a bupropioncellulose ether suspension to inert spheres and two unique formulations of sustained release coatings that are applied to separate active pellets. The formulation functions by membrane-controlled extended-release in a pH
dependent manner. The bupropion release rate has been improved by the introduction of two types of film coated active pellets that release the drug at different pH resulting in novel dissolution profiles.
Inert spheres are initially coated with bupropion and hydroxypropyl methylceilulose. T% -e active pellets containing bupropion comprise 70-75 weight % of the dosage form. An enteric coating, applied to about one third of the active drug pellets, is comprised of a film insoluble at low pH, such as hydroX'Vpropyl .methylceilulose phthalate. The second coating applied to the other two thirds of active drug pellets is comprised of a combination of a hydrophobic coating agent and methyl acrylic acid copolymer. The two pellet types are then combined in a capsule.
Ge nerail= , -1__ eig _ratio of the airs' pellet to the second pellet will be from about .
9E:1 0 to about 10:90 y;; atho ugl'i a ~~~ elg__. ratio of from about 71v:70 to about -10-1:30 is preferred- Especially prof rred is a weight ratio of about 33.3:66.7.
This formulation can provide 24-hour efficacy with once daily dosing, with less than 50% of the drug released at 10 hours. Therapeutic plasma levels are maintained from 12 to 24 hours. The usual dosage range is 75-450 mg.
In another embodiment of the present, an uncoated bupropion component is also employed. In this embodiment, bupropion powder or granules, or the uncoated active pellets (bupropion and hydroxypropyl methylcellulose sprayed onto an ine sphere.) may be used directly (first co(mponent). The bupropion release rate is further modified and improved by the introduction of uncoated bupropion and the two types of film coated active pellets that release the drug at different pH
resulting in further novel dissolution profiles.
In. this embodiment, the enteric coating (hydroxypropyl methylceilulose phthalate) is applied to from about 10 to about 90 weight percent of the active drug pellets (second component). The second coating (hydrophobic and methyl acrylic acid copolymer) is applied to from about 90 to about 10 weight percent of active drug pellets (third component). The three components are then combined in a capsule. Generally, the weight ratio of the first component to the second component may vary from about 1: 50 to about 50: 1, the weight ratio of the first component to the third component may vary from about 1: 50 to about 50: 1, and the weight ratio of the second component to the third component may vary from about 10: 90 to about 90: 10, although a weight ratio of from about 30: 70 to about 70:30 is preferred. Especially preferred is a weight ratio of three components of about 10: 30 : 60.
In a broad aspect, the present invention relates to a pharmaceutical composition comprising: (A) at least one pellet consisting of. (i) a core which comprises an inert carrier, wherein said inert carrier is coated with bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, and (ii) a sustained release coating surrounding said core wherein said sustained release coating comprises at least one controlled release polymer for controlled release delivery of said bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, (B) said pharmaceutical composition further comprising bupropion or a pharmaceutically acceptable salt or stereoisomer thereof in an immediate release form, and wherein the pharmaceutical composition is designed for once daily dosing.
In another broad aspect, the present invention relates to a pharmaceutical composition comprising: (A) at least one pellet comprising: (i) a core which comprises an inert carrier.
wherein said inert carrier is coated with bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, and (ii) a sustained release coating surrounding said core wherein said sustained release coating comprises at least one controlled release polymer for controlled release delivery of said bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, (B) said pharmaceutical composition further comprising bupropion or a pharmaceutically acceptable salt or stereoisomer thereof in an immediate release form, and wherein the composition provides therapeutic plasma levels of bupropion for 12 to 24 hours with once daily dosing and less than 50% of the bupropion released at 10 hours.
R
In another broad aspect, the present invention relates to a once-a-day composition comprising: (a) an immediate release component comprising bupropion or a pharmaceutically acceptable salt thereof; (b) a first pellet comprising an enteric release component comprising bupropion or a pharmaceutically acceptable salt thereof and a pH dependent coating polymer; and (c) a second pellet comprising a sustained release component comprising bupropion or a pharmaceutically acceptable salt thereof and a water insoluble coating polymer, wherein said composition contains 75 to 450 mg of bupropion or a pharmaceutically acceptable salt thereof and provides an in vivo plasma profile selected from: (a) a mean Cmar of at least 50.0 ng/ml; (b) a mean AUCo_;,,f of greater than approximately 500.0 ng=hr/ml; and (c) a mean Tmax of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
BREW DESCRIPTION OF THE DRAWINGS
FIG. I is a graph depicting the dissolution profile in a pH 7.5 buffer of the formulations as described in Examples 1 and 3 versus the dissolution of the commercially available sustained release form of bupropion (Wallbutrin(k SR).
FIG. 2 is a graph depicting the dissolution profile in simulated gastric fluid (pH 1.5) of the formulations as described in Examples 1 and 3 versus the dissolution of the commercially available sustained release form of bupropion (Wellbutrin SR).
FIG. 3 is a graph depicting the mean plasma concentration-time profiles of bupropion in seven healthy subjects (smokers) following a single oral dose of the formulation in Example 2 versus 150 mg of the commercially available sustained release product (Zyban ).
FIG. 4 is a graph depicting the mean plasma concentration-time profiles of bupropion in seven healthy subjects (smokers) following a single oral dose of the formulation in Example 4 versus 150 mg of the commercially available sustained release product (Zyban(k).
da WO 02/062299 PCT/ S02i03523 DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention, in a first embodiment provides a two component controlled release bupropion formulation for oral administration the formulation comprising:
(1) a first pellet comprising:
(i) a core comprising:
(a) bupropion and its salts, isomers, or a pharmaceuticall acceptable aminoketone antidepressant agent;
(b} an inert pellet as a stating material; and (c) a binder; and;
(ii) a coating comprising:
(a) a pH dependent coating agent;
(b) a plasticizer; and (c) a lubricant; and (2) a second pellet comprising:
(i) a core comprising:
(a) bupropion and its salts, isomers, or a pharmaceutically acceptable aminoketone antidepressant agent;
(b) an inert pellet as a starting material; and (c) a binder; and (ii) a coating comprising:
(a) a methyl acrylic acid copolymer;
(b) a water insoluble polymer;
(c) a plasticizer; and WO 02/062299 PCT! tS02,'03523 (d) an antisticking agent.
In other embodiments of the present invention, there may also be present another component, a form of immediate release bupropion.
The immediate release bupropion component may comprise any form of immediate release bupropion. This may take the form of uncoated bupropion granules or powders, may comprise bupropion active pellets (as described hereinbelow), may include bupropion granules or active pellets coated with a highly soluble immediate r such as 2I' ad '^ r. n ; ?' t , ui at.elease coa_ r.~, s L Op y tyke coating, as are ko.
those skilled in the art (see generally, United States Patent No. 5,098,715), or a combination of any tof the Ibregoing t The active pellets of bupropion hydro-6 ,lori'de usef=ul in the practice of the present invention are preferably bas d on active pellets having a core formic g inert col ponent that may comprise any type of comm- on ' known pellet sta. in material, which may be water insoluble, such as, but not limited to, cellulose spheres or silicon dioxide. or may be water soluble, such as, but not limited to, starch or sugar spheres having a diameter ranging from about 15 to. about 50 mesh, preferably ranging from about 30 to about 35 mesh. The preferred pellet starting material is sugar spheres, NF, containing not less than about 62.5 percent and not more than about 91.5 percent of sucrose. The spheres should have consistent bulk density, low friability, and low dust generation properties.
The inert core is preferably coated with an aminoketone antidepressant agent or a pharmaceutically acceptable salt or stereoisomer thereof Most preferably;
the core drug is bupropion hydrochloride.
The core forming inert component is coated with a formulation that comprises bupropion hydrochloride and a binding agent. The binding agent should be Iv WO 02/062299 PCTitJS02/03523 water soluble, and should possess high adhesivity and an appropriate viscosity, to guarantee good adhesion between the sugar cores and bupropion particles, resulting in a high concentration of drug in the pellets. The binding agents employed can be any type of binding agent commonly known in the art such as polyvinyl pyrrolidone hydroxyethyI cellulose, hydroxypropyl cellulose, low molecular weight hydroxyprop,'I methylcellulose (HPMC}, polyinethacrylate or ethyl cellulose-In a preferred embodiment of the present invention, the binding agent is a ,rater-soluble polymer such as Iiydroxypr=opyl metylcei!uiose having a viscosity in the range o 2-12 cps at 20 C, preferably= 4-6 cps, such as the material sold as MIethocel E5. A
preferred ocn~.posltion of the binder for b?uproplo_ is about 2-10"=10 ev.W
and most preferably 3-5'%, The active pellets of the present invention will preferably comprise the following ingredients:
E GREDIENT PREFERRED MOST
PREFERRED
Bupropion HCI 40-80%% 60-%{0 %
HPIC 2-1 03% 2.5-5ilo starting pellets 10-35% 15-30%
All the percentages in the above-table are based on the total weight of the core.
The active pellets for use in the practice of the present invention that comprise the bupropion are typically prepared by forming a suspension of the binder and the drag and then layering the suspension onto the starting pellet using any of the layering techniques known in the industry, such as fluidized bed coating, rotor granulation or pan coating. The suspension medium may comprise any low viscosity solvent, such as isopropyl alcohol, ethanol, water, mixtures thereof and the like. A
II
sufficient amount of coating is applied to provide the desired level of bupropion.
These active pellets may be used directly as the first component of the three component formulations of the present invention.
The active pellets are also useful in preparing the other two components of the present invention (both the two component and three component formulations). The active pellets intended for such use are divided into two groups, each group receiving a film coax ng that releases the drug at a different pH.
One group of là is coated to release d tg at a pH correspond a 1 St nd ~
r r _ in-lower. about ~. an lower, which is likely to occur the upper gastrointestinal (GI) tract; the other group E pellets is Pcoated release drug a pH o_ 47 7 and above, which is likely to occur _ the lower Gi ii act. Thus, the entire does is released from this product for an -x-ended Period of time its transition through the GI tract.
n e re~ embodiment, one oup of pellets (enteric component) is coated v h a .91m comprising a pH dependent coating polymer, a plasticizer and a lubricant. This group of pellets preferably comprises from about 10 to about weight percent of the total pellets, preferably from about 30 to about 70 weight percent, and most preferably from about 33 to about 60 weight percent.
The pH dependent coating polymer may be selected from those enteric coatings known to those skilled in the art. Preferably, the pH dependent coating is selected from the group consisting of shellac; methacrylic acid copolymers (such as, but not limited to Eudragit E100 (a cationic copolymer of dimethyl aminoethyl methacrviate and neutral methacrylic acid esters)), cellulose acetate phthalate, hydroxypropyl methyleellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof Hvdroxypropyl methyicefulose phthalate (HP ICP) is preferred. The preferred concentration is 2-10% -'AV of the total dosage form, and most preferably 3-5%_ The coating preferably also contains plasticizers. Plasticizers that may be used in the practice of the present invention include any of those known to those skilled in the art, including, but not limited to, acetyltributyl citrate, triacetin, acetylated monoglyceride, rage oil, olive oil, sesame oil, acetyltriethyl citrate, ply ceri sorbitol, d_et'_esvloxalate, diet _yimalate, diethylfi r Brate, dibutylsuccinate, diethylmalo <a e. dioc :lphthai :e. dibutylphthaiate, d'sbut isebaCate.
ietliyi citrate tribuE Gitrate_ gl;-:cerohribut rate, polyethylene glycol propylene glycol and I es .}_ L T'he preferre cize_ i ace - 5ributYl citrate in an amount .g .g ^ r a ^ f . 4 t au~ u: out i_ercent based or, t i., t Glat -LO rar.~In P
a~ _: iC t weight Ci tlse final coating or D. -3 % `,v.., of the totad dosage forrn T bly includes a lubricant Such as, t::.t not limited to. hoe selected from the group consisting of giycer;-l m~onostearate;
Myvap ex 600P , ca ci 3tearate or stearic acid. The preferred lubricant giyceryl mono tearare in an amount ranging from about 1 to about 15 percent, and most preferably 1-2.5 ,9 based on the total weight of the coating.
A preferred enteric coating for use in the present invention therefore comprises the following ingredients:
INGREDIENT PREFERRED OS T
PREFERRED
HPMCP 2-10% 3-5%
Acetyltributyl citrate 0.1-3% 0.5-1%
Glyceryl monostearate 1-3% 1-2.5%
Additional active drug pellets for forming the second coated component of Cite present invention, preferably from about 90 to about 10 weight percent of the total pellets, more preferably from about 70 to about 30 weight percent, and most preferably from about 67 to about 40 weight percent, are coated with a coating that comprises a polymer such as a methacrylic copolymer, water insoluble polymer, a plasticizer and an anti-sticking agent.
The methacrylic acid copolymer is selected from the known group of meth acrylic acid cot ivrers, preferably' Eudragt' S (methacrylic acid copolymer Type B). and most preferably Eudragit' , 5100. The preferred concentration is 1-15%
in"
of the no-sal wig=___ of ' dosage form, preferably. 4-7%%.
The water insoluble polymer in the preferred embodiments y of the presen Invent it s formed from a cellulose ester, or a cellulose esLe-, et+her.
Represei_ta e r _aterials include a member selected from the group consisting of ethyl cellulose, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, mono-, di-and t -cellulose aryiates, and the like. Preferred is ethyl cellulose in a concentration ranging from about 1 to about 20%, preferably from about 2 to about 13%.
The preferred plasticizer additive for the second coating may be selected from a :y of those mentioned above. Acetyltributyl citrate is preferred.
The anti-sticking agents can be chosen from any of the known agents, such as, but not limited to, those selected from the group consisting of an alkaline earth metal stearate, such as magnesium stearate or calcium stearate, or talc.
The anti-sticking agents can be used alone or in combination in effective amounts. The preferred anti-sticking agent is talc.
WO 021062299 PCTrUS02103523 The coating for the active pellet for this (second coated) component of the present invention is applied to the active pellets by forming a solution of the respective coating components in a solvent or a mixture of solvents, such as, but not limited to, acetone and isopropyl alcohol, and employing any of the application techniques known to those skilled in the art, such as fluidized bed coating, rotor granulation or pan coating.
The components. either the two coated or the two coated and the re ease, of tine present invert ion are blended together in the desired ratio and placed in gelatin capsule to obtain a finished product. By va~-ing the ratio of the used of t e i tL le io n -onToren. rzc: .~ L_~ rease at 0 o, novel ,iss ilut :._ _.
pro riles and p asrna profiles may be obtained in acco rdanc with he pre-sent i- ret t_õ__. lter~a`iveiy, the dosage formulation may be made into tablets by firs..
t 'id pharrliaLeuticair ly acceptable tablet leet adding ~d from 25 " percent of a 5~o_ ... 40 0 _ [-ei?
excipient that w -ill form a compressible mixture without crushing the pellets, and then tabletting the mixture in a suitable tablet press.
The f =llovt-ing examples are intended to illustrate the present invention but are not intended to limit the scope of the appended claims.
A batch of controlled release bupropion was manufacture using all materials that comply with the current USP NF compendia specifications.
A controlled release 150 mg oral bupropion dosage form is prepared by forming active core pellets having the following composition:
1. ACTIVE CORE PELLETS
Bupropion HCI 70.0%
Sugar sphere 30!35 26.5%
Methocel ES 3.5%
Active pellets of bupropion are formed by dissolving 2.8 kg of bupropion HCI and 0.140 kg of hydroxypropyl methylcellulose (Methocel E5) in a mixture of water and isopropyl alcohol. The active drug solution is then sprayed onto 1.06 kg of sugar spheres 30135 in a fluidized bed processor with a W 'urster insert. The active core pellets are then dried in a fluidized bed processor until the loss on drying is below 1`',= . The bupropion pellets are than passed through a 16 mesh screen and a 3(j! mesh screen and pellets are colectedd that are smaller than 16 mesh and larger than 30 mesh.
11 EtiTEPJC COATED PELLETS
Bupropion active peflez 75.0%
HPMCP 50 16.9%
Acetvltrfbutvl citrate 2.5%
It vaplex 600P 5.6%
one-third , tJ_ 0.270 k,., of For a group of about one-third of the pe1le , hydroxvpropyl methylcellulose phthalate and 0.040 kg of acetyltributyl citrate are dissolved in a mixture of purified water and isopropyl alcohol, USP. Then 0.090 kg of glyceryI monostearate (1vIyvaplex 600P) is dissolved into the solution above. The solution is then sprayed onto 1.2 kg of the bupropion core pellets in a fluidized bed processor with a `I'urster insert. The pellets are then dried until the loss on drying (LOD) is less than 1%. The pellets are then mixed with 2% (w'w) talk for 10 minutes in a V"-blender. The pellets are then passed through a 14 mesh screen and a 24 mesh screen and pellets that are smaller than 14 mesh and larger than 24 mesh are collected.
III. SUSTAINED RELEASE (SR) COATED ACTIVE PELLETS
Bupropion active pellets 80.0%
Eudragit .DR S100 12.6%
Ethocel 10 cps 1.4%
WO 02/062299 PCTitS02103523 Acetyltributyi citrate 2.0%
Talc 4.0%
For another group of about two-thirds of the pellets, a coating is prepared where the ratio of the methacrylic acid copolymer to ethylcellulose is about 9:1. The coating is made as follows: 0.378 kg of methacrylic acid copolymer (Eudragit S 100), 0.42 kg of ethylcellulose (Ethocel 10 cps), and 0.060 kg of acet yltributvl citrate are dissolved in a i ixture of 0.690 kg acetone and 6.210 kg isopropsi alcohol. 0. 12 kv of talcl is then dispersed into to the solution above.
.. _0 y~ The suspension is then sprayed onto 2.40 kg of the active bupropion core pellets in a fluidized bed v r p rocessor with a W!-{ "t uster insert. The bupropion pellets are is ar: cried in a fluidized met pr'_essor unt the LOD is less than 1%. The pe lets are mixed With k4rw) talc for 10 m mutes in a V-blender and passed through a 14 mesh screen and -2-L
mesh sCr _>_ --- Pe, iet.. . rt ah. 1.=r t mesh larger t aan 24 mesh are Ci..
ected _ . -- i ?a.ll and iar, than ~:s_., ct4 .
These pellets have the following coating composition.
INGREDIENT MG`CAPSULE % TOTAL
WEIGHT
Eu agity S,100 22. 5 6.4 Ethocel 10 cps 2.5 0.7 Acetyltributyl citrate 3.6 1.0 Talc 2.0 The enteric coated pellets and the SR pellets are mixed after loading each group into dosators. The strength of the final product is 150 mg of bupropion with 50 mg of active drug in the first group of pellets and 100 mg of active in the second group. The pellets are then encapsulated into size "1" light turquoise blue/light turquoise blue capsules. The total weight of the formulation (capsule +
pellets) is 350 mg.
1%VO 02/062299 PCT/US02/03523 The resulting bupropion capsules of Example I were then tested according to the USP XXIII dissolution test (type 2, basket) at 50 rpm, at 37 C in pH
7.5 buffer and found to have the following release profile:
TABLE I
Time (hours) % Released y6 88 1v 93 YT
The release profile of the controlled release product shown in thus Example is sho n in FIG I by the line filled with circles.
The bupropicn capsules of Example 1 were then tested according to the liSP XXIII dissolution test (type 2, basket), at 50 rpm, at 3', C in SGF
(pH 1.5) to determine the percentage of drug dissolved versus time-Time (hours) % Released WO 02/062299 PCT,I IS02/03523 G' 60 The release profile of the controlled release product shown: in ti s Example sn -ri sin FIG 2 by the line -,nh the tilled circles.
T e bupr_pion capsules of Example I were ten evaluated in seven patients us in.- Ãa dard techniques mown in the art. Buprortv pion was 1 ~~ s frstL detected .
the plasma at about ~''. hours after adstTutioi_, and showed sustained G` ur 2=1 hours.
Two panels of seven patients were randomly assigned to receive either tae bupropion formulation described herein or ZS1B AN 3) an open; randomized single dose study. Blood samples were collected over a ?2-hour period and anal, zed for bupropion concentrations with a LCIMSiNIS method.
For the blood levels carried out Cam,:; is the maximum blood level concentration of bupropion, Tm., is the time at which the maximum blood level concentration occurs, Tt,g is the sampling point preceding the one at which concentrations first become quantifiable. AUC is the "area under the curve" of time versus blood concentration. The results provided are given in Table 3 and FIG.
show that the mean plasma concentration time profiles of bupropion were different for the Example I formulation and ZybanS. Following oral administration, the I
VVO 021062299 PCTfUS02J03523 Example 1 formulation had a delayed absorption with a Tig value of 1.9 hours.
The mean Coax value of the Example 1 bupropion formulation was about one-half of that for Zybar: The time to reach (T,.,,, ) maximum plasma concentration occurred about 8 hours after administration of the Example 1 formulation. The relative bioavailability of the Example 1 formL:lation to Zyban was 40% o in terms of C, and 80 r% in terms of ALTCO_;f ratio.
Variable Example I Mean Zvban Mean G-Mean Ratio i - 1 - C129. 0.40 AL Ce _; ,n g-h~r nu1 321. 0- 998.0 0.8=
(lir) 1 9 T,ax(lrj 8.1 3_a T112 thr) 17.0 20.3 Thus. it can be seen from the data above that although the Cma of Example I is significantly lower than, the C a of the. Zyban formulation, the AUK
has only been slightly reduced.
The pellets from Example 1 are taken as the second and third components. These pellets are loaded into the dosator along with active pellets and are filled into capsules in a ratio of 10:30:60 while maintaining the dosage at 150 mg.
The blood profiles from this example will show a Cna,, that is the same as shown in Table 3. but will show a slightly increase AUC, thereby rendering the G-Mean ratio at about 1.00. The amount of active pellets may be adjusted as is known in the an pellets are xmixed with 2`9% (wtw) talc for 10 minutes in a V-blender and passed through a 14 mesh screen and a 24 mesh screen. Pellets smaller than 14 mesh and larger than 24 mesh are collected.
The pellets have the following coating composi on:
Ingredient mg Capsule % Total Wt.
Methacrylic acid copolymer 12.5 3.6 Ethocel 10 cps 12.5 3.6 Acet sltrihutti-l citrate 3.6 1.0 Talc 7.1 2.0 The {-. an d r^e `:1 flu Tr )t group of pellets the 1 above pellets are nosed a r load-n In-Lo o v: ch group cos~xtoy- Tir Fe stI..a x. e~'gt v t e f -h- G ii r 3 _ ~l i prGc:. s 150 ~g of ~iupropi` n with mg. of-act-i-iie drug in the first group of pelts and 1 00 ling of active =1;. bl drug inn to se-fond groupThe pellet.. a:-- then aps:l enc ateu .7 lns.i, t"
Size aF
:
r ~~
opaque'light blue opaque capsules. The :oral weight of the formulation (capsule pellets) is 352 ME
The resulting bumropion capsules were then tested according - the raccording to U SP Xix1i dissolution test (tvp e 2. ba ket), at 50 rpm. at 3 7 C; in pH ?. ~
buf far and found to have the following release profile:
Time (hours) % Released %N O (121062299 PCT/US012103523 The release profile of the con rolled release product of Example 3 is shown r by the line ~zith the filled in squares, I'll. FIB. . '' The resulting bupropion capsules were then tested according to USP
II st e 2. :: :at 50 rpm at 37cC. i SG ip 1-1) an d f and to have the following release Times hours) % Released BYO 021062299 PCTfUS02,03523 The release profile of the controlled release product shown in Example 3 is shown in FIG. 2 by the line with the filled in squares.
The bupropion capsules of Example 3 were then analyzed in a seven patient test using techniques known in the art. Bupropion was first detected in the plasma about 1.4 hours after administration and showed a sustained release over 24 hours.
The testing procedure is as described in Example 1. The results provided are given in Table 4 and FIG. 4 and show that the mean plasma time profile of the bupropion formulation differs om that of Zyban . Bupropion had a delayed absorption, the relative 'ahabili-tv abill 0 bupropior2 to ZY can S was 48%
and 55` in tern's Cma, and AUC Values, respectivei . The terminal elimination ha:11-lives were similar TABLE _4 Parameter Example 3 Zvban G-Mean Ratio Cmax (ng rn) `6.9 114.8 0.48 -ALLFC2 - (ng=heml) 531.7 8895 0.59 Ti.. Chr: 1.4 0.1 Tura. (hr) 5.1 4.1 Ti,2 (hr) 12.6 14.1 Thus, again, the C,,,a, of the Example 3 product was reduced significantly more than the AUC compared to the reference product, demonstrating that an effective once-a-day product has been provided.
The pellets from Ex- le 3 are taken as the second and third componen hose pellets are loaded into the dosator along with active pellets and are filled into capsules in a ratio of 10:30:60 while maintaining the dosage at 150 tug bjsprcpion. The blood profiles from this example will show a C the same as in Table 3, but wil= show a slightly increased AUC, thereby rendering the G-mean ratio at about LOO_ The amount of active pellets may be adjusted as is known in the art ithcut undue expenme :tom on based on ne teachings of the present disclosure in c- suos_ar_ ah pr_ iae a C- 'eai for AL or approximately _ O.
FIELD OF THE INVENTION
The present invention relates to oral controlled release dosage formulations containing bupropion hydrochloride.
BACKGROUND OF THE INVENTION
The compound designated bupropion hydrochloride is described in United States Patent Nos. 3,819,706 and 3,885,046. It is marketed as an anti-depressant and an aid to smoking cessation. Bupropion is an aminoketone-derivative chemically unrelated to other currently available antidepressants (e.g., selective serotonin-reuptake inhibitors, tricyclics, tetracyclics).
While the neurochemical mechanisms of the antidepressant and smoking cessation effects are unknown, noradrenergic pathways and/or dopaminergic effects appear to be primarily involved. Bupropion does not inhibit monoamine oxidase and is a weak blocker of serotonin and norepinephrine uptake.
The drug is useful in the treatment of depressive affective disorders (e.g., major depression) at dosages of 75 to 600 mg daily. Bupropion may be preferable to other agents because of its minimal anticholinergic, cardiovascular, and antihistaminic effects or in those patients who have experienced weight gain or sexual dysfunction with another antidepressant. Bupropion, as extended-release tablets, is used in the cessation of smoking at dosages of 100-300 mg daily. Withdrawal symptamns and cigarette craving are reduced with bupropion. Other uses include patients with b.polar depression, attention-deficit hyperactivity in both adult and pediatric patients, and panic symptoms superimposed on depression.
Immediate release bupropion tablets pro vide more than 75% of bupropion release into the dissolution media in 45 minutes. In studies to date, the risk of seizures appears to be strongly associated, in part, with the use of instant release tablets.
Numerous techniques exist in the prior art for preparing sustained or controlled release pharmaceutical formulations. One common technique involves surrounding an osmotically active drug core with a semipermeable membrane. The drug is released from the core over time by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the drug so the dissolved drug can permeate through the membrane. In some cases a hvdrogel is employed to push the active ingredient through the passageway of the membrane.
Another common technique for preparing controlled-release pharmaceutical formulations is to encapsulate a plurality of beads, pellets or tablets that are coated with varying levels of diffusion barriers. The barriers can be of the same or different chemical composition. Release of the pharmaceutical may occur by leaching, erosion, rupture, diffusion or similar actions depending on the nature and WO 02/062299 PCTiU, S02/03523 thickness of the coating material. These products require multi-layered coating, sometimes as much as 30 to 90 coats.
Film coating techniques are characterized by the deposition of a uniform film onto the surface of a substrate. Because of the capability of depositing a variety of coating materials onto solid cores, this process has been used to make controlled release dosage forms starring from different formulations, such as tablets, granules, pellets and capsules. Cores are usually prepared using one of the following processes. compaction, surface layering, or agglomeration.
One limitation associated with these dosage forms consists in their failure o delay drug delivery. Many o the m ilti-walled preparations described above do not provide prolonged delayed release of the drag prior to initiation of sustained release, which. is important when biphasic release profiles are desired. Other systems are essentially "delayed releases mechanisms. There is delay of drug release in the stomach. but once the coated drug reaches the i~rtestines, the release of medication is rapid. There is no sustained release in the intestines.
Bupropion hydrochloride is highly soluble in water with a high permeability characterized by rapid and almost complete absorption. Peak plasma concentrations occur within 2 hours for bupropion and 3 hours for bupropion sustained-release. Its biphasic pharniacokinetics is characterized by a two-compartment model; the distributive phase has a mean half-life of 3 to 4 hours with a biphasic decline and a terminal T Vz of about 14 hours following single doses.
A
major drawback is extensive first-pass metabolism. It appears that only a small portion of any oral dosage reaches the systemic circulation intact. Immediate-release tablets are dosed three times a day, preferably with 6 or more hours separating the doses. For those patients requiring doses greater than 300 mg daily, each divided WO 02/062299 PCTiUS02/03523 dose should not exceed 150 mg each. This necessitates administration of the tablets 4 times daily with at least 4 hours between successive doses. Commercially available sustained-release products are available in film-coated tablets marketed by Glaxo Wellcome under the tradenames Welibutrin SR and Zyban . These are dosed Mice daily. For those patients requiring above 300 mg daily, the regimen remains twice daily dosing. No currently available product provides a sustained release profile suitable for once daily dosing.
Patient compiiance is especially problematic in depressed patients.
There is a need for improved patient compliance. One of the means employed clinica'I_- to improve p tint adherence _ .
o , s es r; simplification or the dosing regi~ Een. Thus, need exists for a once daily bupropion formulation.
Sustained release tablet fours of bupropion are described in United States Patent No. 5,427,798. comprising a . ustained release tablet which provides peals bupropion blood levels at approximately 2-3 hours, thereby requiring twice daily dosing. Controlled release is achieved by combining bupropion particles with microcrvstalline cellulose and hy-drogel-forming hydroxv~propyl methyicelluiose.
Another sustained release bupropion tablet or caplet formulation disclosed in united States 4,687,660, comprises a difficult manufacturing process and limited shelf life. United States Patent No. 5,358,970 discloses a formulation of bupropion hydrochloride that contains an acid stabilizer.
United States Reissue Patent No. 33,994 discloses a tablet formulation of a water insoluble, water-permeable film coating surrounding the drug core and a particulate, water-soluble, pore-forming material dispersed within the film coating;
this osmotic gradient and channel forming system is applicable for tablet dosage forms. However, here also at least twice daily dosing is necessitated by the release profile of 25-70% of bupropion within 4 hours, and 40-90% within 6 hours.
Wellbutrin SR is a commercially available twice a day dosage form of bupropion which contains carnauba wax, cy steire hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.
There is no capsule form of bupropion commercially available.
Capsules are advantageous in those patients who have difficulty swallowing where the contents of the capsule may be sprinkled on food.
Immediate release tablets must be stored at a temperature above 15-C a _d protected from light and moist ere. Extendeu release tablets should be stored in tight, light-resistant containers at a temperature of 20-25 C.
The need exists for a relayed, sustained release pharmaceutical preparation that provides a longer delay of drag dissolution thereby allowing greater fiexibili in designing sustained release profiles, provides improved plasma levels wherein the maximum plasma concentration (Caw,) can be substantially reduced without a concomitant reduction in A1. C, and is simply and economically produced.
Such a delayed delivery dosage form has a practical application, and it represents a valuable contribution to the medical arts. The present invention provides such a composition and offers an efficient and cost effective method of preparation.
Accordingly, it is an object of this invention to provide a sustained release formulation of bupropion suitable for once daily administration.
Another object of the present invention is to provide a capsule dosage form comprising means for delaying delivery of the drug in gastric fluids for 6 hours up to 12 hours, usually 4 hours to 8 hours.
It is also an object of this invention to provide a controlled and extended release bupropion capsule formulation that is easy to manufacture and can be used to prepare a range of dosing levels suitable for once daily administration.
It is a further object of the present invention to provide 24-hour control of symptoms of depression or tobacco dependence withdrawal.
Seizures result more commonly by single dosages of bupropion over 150, mg, hence the need for twice to four times dally dosing regimens. Another object of this i vention is to provide simplified once daily dosing regimen with the potential to prevent or reduce the incidence of seizures caused by bupropion.
The present in v'ention also relates to a new sustained release bupropion pharmaceutical composition producing novel blood plasma levels after ingestion over 24 ` o r^ t n n or rep tss ho hat is not disclosed; ; nc_ . dead obvious by, the prior art. Other abJec f L-tunes and advantages of the invention are not taught in the prior art but will be more apparent to those versed in the art from the follo~. ng specification;
taken in conjunction with the d_rawirigs.
SUNENIARY OF THE PRESENT INVENTION
The present invention meets the unfulfilled needs of the pharmaceutical industry.
The current invention involves a new pelletization process, typified by the application of a bupropioncellulose ether suspension to inert spheres and two unique formulations of sustained release coatings that are applied to separate active pellets. The formulation functions by membrane-controlled extended-release in a pH
dependent manner. The bupropion release rate has been improved by the introduction of two types of film coated active pellets that release the drug at different pH resulting in novel dissolution profiles.
Inert spheres are initially coated with bupropion and hydroxypropyl methylceilulose. T% -e active pellets containing bupropion comprise 70-75 weight % of the dosage form. An enteric coating, applied to about one third of the active drug pellets, is comprised of a film insoluble at low pH, such as hydroX'Vpropyl .methylceilulose phthalate. The second coating applied to the other two thirds of active drug pellets is comprised of a combination of a hydrophobic coating agent and methyl acrylic acid copolymer. The two pellet types are then combined in a capsule.
Ge nerail= , -1__ eig _ratio of the airs' pellet to the second pellet will be from about .
9E:1 0 to about 10:90 y;; atho ugl'i a ~~~ elg__. ratio of from about 71v:70 to about -10-1:30 is preferred- Especially prof rred is a weight ratio of about 33.3:66.7.
This formulation can provide 24-hour efficacy with once daily dosing, with less than 50% of the drug released at 10 hours. Therapeutic plasma levels are maintained from 12 to 24 hours. The usual dosage range is 75-450 mg.
In another embodiment of the present, an uncoated bupropion component is also employed. In this embodiment, bupropion powder or granules, or the uncoated active pellets (bupropion and hydroxypropyl methylcellulose sprayed onto an ine sphere.) may be used directly (first co(mponent). The bupropion release rate is further modified and improved by the introduction of uncoated bupropion and the two types of film coated active pellets that release the drug at different pH
resulting in further novel dissolution profiles.
In. this embodiment, the enteric coating (hydroxypropyl methylceilulose phthalate) is applied to from about 10 to about 90 weight percent of the active drug pellets (second component). The second coating (hydrophobic and methyl acrylic acid copolymer) is applied to from about 90 to about 10 weight percent of active drug pellets (third component). The three components are then combined in a capsule. Generally, the weight ratio of the first component to the second component may vary from about 1: 50 to about 50: 1, the weight ratio of the first component to the third component may vary from about 1: 50 to about 50: 1, and the weight ratio of the second component to the third component may vary from about 10: 90 to about 90: 10, although a weight ratio of from about 30: 70 to about 70:30 is preferred. Especially preferred is a weight ratio of three components of about 10: 30 : 60.
In a broad aspect, the present invention relates to a pharmaceutical composition comprising: (A) at least one pellet consisting of. (i) a core which comprises an inert carrier, wherein said inert carrier is coated with bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, and (ii) a sustained release coating surrounding said core wherein said sustained release coating comprises at least one controlled release polymer for controlled release delivery of said bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, (B) said pharmaceutical composition further comprising bupropion or a pharmaceutically acceptable salt or stereoisomer thereof in an immediate release form, and wherein the pharmaceutical composition is designed for once daily dosing.
In another broad aspect, the present invention relates to a pharmaceutical composition comprising: (A) at least one pellet comprising: (i) a core which comprises an inert carrier.
wherein said inert carrier is coated with bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, and (ii) a sustained release coating surrounding said core wherein said sustained release coating comprises at least one controlled release polymer for controlled release delivery of said bupropion or a pharmaceutically acceptable salt or stereoisomer thereof, (B) said pharmaceutical composition further comprising bupropion or a pharmaceutically acceptable salt or stereoisomer thereof in an immediate release form, and wherein the composition provides therapeutic plasma levels of bupropion for 12 to 24 hours with once daily dosing and less than 50% of the bupropion released at 10 hours.
R
In another broad aspect, the present invention relates to a once-a-day composition comprising: (a) an immediate release component comprising bupropion or a pharmaceutically acceptable salt thereof; (b) a first pellet comprising an enteric release component comprising bupropion or a pharmaceutically acceptable salt thereof and a pH dependent coating polymer; and (c) a second pellet comprising a sustained release component comprising bupropion or a pharmaceutically acceptable salt thereof and a water insoluble coating polymer, wherein said composition contains 75 to 450 mg of bupropion or a pharmaceutically acceptable salt thereof and provides an in vivo plasma profile selected from: (a) a mean Cmar of at least 50.0 ng/ml; (b) a mean AUCo_;,,f of greater than approximately 500.0 ng=hr/ml; and (c) a mean Tmax of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
BREW DESCRIPTION OF THE DRAWINGS
FIG. I is a graph depicting the dissolution profile in a pH 7.5 buffer of the formulations as described in Examples 1 and 3 versus the dissolution of the commercially available sustained release form of bupropion (Wallbutrin(k SR).
FIG. 2 is a graph depicting the dissolution profile in simulated gastric fluid (pH 1.5) of the formulations as described in Examples 1 and 3 versus the dissolution of the commercially available sustained release form of bupropion (Wellbutrin SR).
FIG. 3 is a graph depicting the mean plasma concentration-time profiles of bupropion in seven healthy subjects (smokers) following a single oral dose of the formulation in Example 2 versus 150 mg of the commercially available sustained release product (Zyban ).
FIG. 4 is a graph depicting the mean plasma concentration-time profiles of bupropion in seven healthy subjects (smokers) following a single oral dose of the formulation in Example 4 versus 150 mg of the commercially available sustained release product (Zyban(k).
da WO 02/062299 PCT/ S02i03523 DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention, in a first embodiment provides a two component controlled release bupropion formulation for oral administration the formulation comprising:
(1) a first pellet comprising:
(i) a core comprising:
(a) bupropion and its salts, isomers, or a pharmaceuticall acceptable aminoketone antidepressant agent;
(b} an inert pellet as a stating material; and (c) a binder; and;
(ii) a coating comprising:
(a) a pH dependent coating agent;
(b) a plasticizer; and (c) a lubricant; and (2) a second pellet comprising:
(i) a core comprising:
(a) bupropion and its salts, isomers, or a pharmaceutically acceptable aminoketone antidepressant agent;
(b) an inert pellet as a starting material; and (c) a binder; and (ii) a coating comprising:
(a) a methyl acrylic acid copolymer;
(b) a water insoluble polymer;
(c) a plasticizer; and WO 02/062299 PCT! tS02,'03523 (d) an antisticking agent.
In other embodiments of the present invention, there may also be present another component, a form of immediate release bupropion.
The immediate release bupropion component may comprise any form of immediate release bupropion. This may take the form of uncoated bupropion granules or powders, may comprise bupropion active pellets (as described hereinbelow), may include bupropion granules or active pellets coated with a highly soluble immediate r such as 2I' ad '^ r. n ; ?' t , ui at.elease coa_ r.~, s L Op y tyke coating, as are ko.
those skilled in the art (see generally, United States Patent No. 5,098,715), or a combination of any tof the Ibregoing t The active pellets of bupropion hydro-6 ,lori'de usef=ul in the practice of the present invention are preferably bas d on active pellets having a core formic g inert col ponent that may comprise any type of comm- on ' known pellet sta. in material, which may be water insoluble, such as, but not limited to, cellulose spheres or silicon dioxide. or may be water soluble, such as, but not limited to, starch or sugar spheres having a diameter ranging from about 15 to. about 50 mesh, preferably ranging from about 30 to about 35 mesh. The preferred pellet starting material is sugar spheres, NF, containing not less than about 62.5 percent and not more than about 91.5 percent of sucrose. The spheres should have consistent bulk density, low friability, and low dust generation properties.
The inert core is preferably coated with an aminoketone antidepressant agent or a pharmaceutically acceptable salt or stereoisomer thereof Most preferably;
the core drug is bupropion hydrochloride.
The core forming inert component is coated with a formulation that comprises bupropion hydrochloride and a binding agent. The binding agent should be Iv WO 02/062299 PCTitJS02/03523 water soluble, and should possess high adhesivity and an appropriate viscosity, to guarantee good adhesion between the sugar cores and bupropion particles, resulting in a high concentration of drug in the pellets. The binding agents employed can be any type of binding agent commonly known in the art such as polyvinyl pyrrolidone hydroxyethyI cellulose, hydroxypropyl cellulose, low molecular weight hydroxyprop,'I methylcellulose (HPMC}, polyinethacrylate or ethyl cellulose-In a preferred embodiment of the present invention, the binding agent is a ,rater-soluble polymer such as Iiydroxypr=opyl metylcei!uiose having a viscosity in the range o 2-12 cps at 20 C, preferably= 4-6 cps, such as the material sold as MIethocel E5. A
preferred ocn~.posltion of the binder for b?uproplo_ is about 2-10"=10 ev.W
and most preferably 3-5'%, The active pellets of the present invention will preferably comprise the following ingredients:
E GREDIENT PREFERRED MOST
PREFERRED
Bupropion HCI 40-80%% 60-%{0 %
HPIC 2-1 03% 2.5-5ilo starting pellets 10-35% 15-30%
All the percentages in the above-table are based on the total weight of the core.
The active pellets for use in the practice of the present invention that comprise the bupropion are typically prepared by forming a suspension of the binder and the drag and then layering the suspension onto the starting pellet using any of the layering techniques known in the industry, such as fluidized bed coating, rotor granulation or pan coating. The suspension medium may comprise any low viscosity solvent, such as isopropyl alcohol, ethanol, water, mixtures thereof and the like. A
II
sufficient amount of coating is applied to provide the desired level of bupropion.
These active pellets may be used directly as the first component of the three component formulations of the present invention.
The active pellets are also useful in preparing the other two components of the present invention (both the two component and three component formulations). The active pellets intended for such use are divided into two groups, each group receiving a film coax ng that releases the drug at a different pH.
One group of là is coated to release d tg at a pH correspond a 1 St nd ~
r r _ in-lower. about ~. an lower, which is likely to occur the upper gastrointestinal (GI) tract; the other group E pellets is Pcoated release drug a pH o_ 47 7 and above, which is likely to occur _ the lower Gi ii act. Thus, the entire does is released from this product for an -x-ended Period of time its transition through the GI tract.
n e re~ embodiment, one oup of pellets (enteric component) is coated v h a .91m comprising a pH dependent coating polymer, a plasticizer and a lubricant. This group of pellets preferably comprises from about 10 to about weight percent of the total pellets, preferably from about 30 to about 70 weight percent, and most preferably from about 33 to about 60 weight percent.
The pH dependent coating polymer may be selected from those enteric coatings known to those skilled in the art. Preferably, the pH dependent coating is selected from the group consisting of shellac; methacrylic acid copolymers (such as, but not limited to Eudragit E100 (a cationic copolymer of dimethyl aminoethyl methacrviate and neutral methacrylic acid esters)), cellulose acetate phthalate, hydroxypropyl methyleellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof Hvdroxypropyl methyicefulose phthalate (HP ICP) is preferred. The preferred concentration is 2-10% -'AV of the total dosage form, and most preferably 3-5%_ The coating preferably also contains plasticizers. Plasticizers that may be used in the practice of the present invention include any of those known to those skilled in the art, including, but not limited to, acetyltributyl citrate, triacetin, acetylated monoglyceride, rage oil, olive oil, sesame oil, acetyltriethyl citrate, ply ceri sorbitol, d_et'_esvloxalate, diet _yimalate, diethylfi r Brate, dibutylsuccinate, diethylmalo <a e. dioc :lphthai :e. dibutylphthaiate, d'sbut isebaCate.
ietliyi citrate tribuE Gitrate_ gl;-:cerohribut rate, polyethylene glycol propylene glycol and I es .}_ L T'he preferre cize_ i ace - 5ributYl citrate in an amount .g .g ^ r a ^ f . 4 t au~ u: out i_ercent based or, t i., t Glat -LO rar.~In P
a~ _: iC t weight Ci tlse final coating or D. -3 % `,v.., of the totad dosage forrn T bly includes a lubricant Such as, t::.t not limited to. hoe selected from the group consisting of giycer;-l m~onostearate;
Myvap ex 600P , ca ci 3tearate or stearic acid. The preferred lubricant giyceryl mono tearare in an amount ranging from about 1 to about 15 percent, and most preferably 1-2.5 ,9 based on the total weight of the coating.
A preferred enteric coating for use in the present invention therefore comprises the following ingredients:
INGREDIENT PREFERRED OS T
PREFERRED
HPMCP 2-10% 3-5%
Acetyltributyl citrate 0.1-3% 0.5-1%
Glyceryl monostearate 1-3% 1-2.5%
Additional active drug pellets for forming the second coated component of Cite present invention, preferably from about 90 to about 10 weight percent of the total pellets, more preferably from about 70 to about 30 weight percent, and most preferably from about 67 to about 40 weight percent, are coated with a coating that comprises a polymer such as a methacrylic copolymer, water insoluble polymer, a plasticizer and an anti-sticking agent.
The methacrylic acid copolymer is selected from the known group of meth acrylic acid cot ivrers, preferably' Eudragt' S (methacrylic acid copolymer Type B). and most preferably Eudragit' , 5100. The preferred concentration is 1-15%
in"
of the no-sal wig=___ of ' dosage form, preferably. 4-7%%.
The water insoluble polymer in the preferred embodiments y of the presen Invent it s formed from a cellulose ester, or a cellulose esLe-, et+her.
Represei_ta e r _aterials include a member selected from the group consisting of ethyl cellulose, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, mono-, di-and t -cellulose aryiates, and the like. Preferred is ethyl cellulose in a concentration ranging from about 1 to about 20%, preferably from about 2 to about 13%.
The preferred plasticizer additive for the second coating may be selected from a :y of those mentioned above. Acetyltributyl citrate is preferred.
The anti-sticking agents can be chosen from any of the known agents, such as, but not limited to, those selected from the group consisting of an alkaline earth metal stearate, such as magnesium stearate or calcium stearate, or talc.
The anti-sticking agents can be used alone or in combination in effective amounts. The preferred anti-sticking agent is talc.
WO 021062299 PCTrUS02103523 The coating for the active pellet for this (second coated) component of the present invention is applied to the active pellets by forming a solution of the respective coating components in a solvent or a mixture of solvents, such as, but not limited to, acetone and isopropyl alcohol, and employing any of the application techniques known to those skilled in the art, such as fluidized bed coating, rotor granulation or pan coating.
The components. either the two coated or the two coated and the re ease, of tine present invert ion are blended together in the desired ratio and placed in gelatin capsule to obtain a finished product. By va~-ing the ratio of the used of t e i tL le io n -onToren. rzc: .~ L_~ rease at 0 o, novel ,iss ilut :._ _.
pro riles and p asrna profiles may be obtained in acco rdanc with he pre-sent i- ret t_õ__. lter~a`iveiy, the dosage formulation may be made into tablets by firs..
t 'id pharrliaLeuticair ly acceptable tablet leet adding ~d from 25 " percent of a 5~o_ ... 40 0 _ [-ei?
excipient that w -ill form a compressible mixture without crushing the pellets, and then tabletting the mixture in a suitable tablet press.
The f =llovt-ing examples are intended to illustrate the present invention but are not intended to limit the scope of the appended claims.
A batch of controlled release bupropion was manufacture using all materials that comply with the current USP NF compendia specifications.
A controlled release 150 mg oral bupropion dosage form is prepared by forming active core pellets having the following composition:
1. ACTIVE CORE PELLETS
Bupropion HCI 70.0%
Sugar sphere 30!35 26.5%
Methocel ES 3.5%
Active pellets of bupropion are formed by dissolving 2.8 kg of bupropion HCI and 0.140 kg of hydroxypropyl methylcellulose (Methocel E5) in a mixture of water and isopropyl alcohol. The active drug solution is then sprayed onto 1.06 kg of sugar spheres 30135 in a fluidized bed processor with a W 'urster insert. The active core pellets are then dried in a fluidized bed processor until the loss on drying is below 1`',= . The bupropion pellets are than passed through a 16 mesh screen and a 3(j! mesh screen and pellets are colectedd that are smaller than 16 mesh and larger than 30 mesh.
11 EtiTEPJC COATED PELLETS
Bupropion active peflez 75.0%
HPMCP 50 16.9%
Acetvltrfbutvl citrate 2.5%
It vaplex 600P 5.6%
one-third , tJ_ 0.270 k,., of For a group of about one-third of the pe1le , hydroxvpropyl methylcellulose phthalate and 0.040 kg of acetyltributyl citrate are dissolved in a mixture of purified water and isopropyl alcohol, USP. Then 0.090 kg of glyceryI monostearate (1vIyvaplex 600P) is dissolved into the solution above. The solution is then sprayed onto 1.2 kg of the bupropion core pellets in a fluidized bed processor with a `I'urster insert. The pellets are then dried until the loss on drying (LOD) is less than 1%. The pellets are then mixed with 2% (w'w) talk for 10 minutes in a V"-blender. The pellets are then passed through a 14 mesh screen and a 24 mesh screen and pellets that are smaller than 14 mesh and larger than 24 mesh are collected.
III. SUSTAINED RELEASE (SR) COATED ACTIVE PELLETS
Bupropion active pellets 80.0%
Eudragit .DR S100 12.6%
Ethocel 10 cps 1.4%
WO 02/062299 PCTitS02103523 Acetyltributyi citrate 2.0%
Talc 4.0%
For another group of about two-thirds of the pellets, a coating is prepared where the ratio of the methacrylic acid copolymer to ethylcellulose is about 9:1. The coating is made as follows: 0.378 kg of methacrylic acid copolymer (Eudragit S 100), 0.42 kg of ethylcellulose (Ethocel 10 cps), and 0.060 kg of acet yltributvl citrate are dissolved in a i ixture of 0.690 kg acetone and 6.210 kg isopropsi alcohol. 0. 12 kv of talcl is then dispersed into to the solution above.
.. _0 y~ The suspension is then sprayed onto 2.40 kg of the active bupropion core pellets in a fluidized bed v r p rocessor with a W!-{ "t uster insert. The bupropion pellets are is ar: cried in a fluidized met pr'_essor unt the LOD is less than 1%. The pe lets are mixed With k4rw) talc for 10 m mutes in a V-blender and passed through a 14 mesh screen and -2-L
mesh sCr _>_ --- Pe, iet.. . rt ah. 1.=r t mesh larger t aan 24 mesh are Ci..
ected _ . -- i ?a.ll and iar, than ~:s_., ct4 .
These pellets have the following coating composition.
INGREDIENT MG`CAPSULE % TOTAL
WEIGHT
Eu agity S,100 22. 5 6.4 Ethocel 10 cps 2.5 0.7 Acetyltributyl citrate 3.6 1.0 Talc 2.0 The enteric coated pellets and the SR pellets are mixed after loading each group into dosators. The strength of the final product is 150 mg of bupropion with 50 mg of active drug in the first group of pellets and 100 mg of active in the second group. The pellets are then encapsulated into size "1" light turquoise blue/light turquoise blue capsules. The total weight of the formulation (capsule +
pellets) is 350 mg.
1%VO 02/062299 PCT/US02/03523 The resulting bupropion capsules of Example I were then tested according to the USP XXIII dissolution test (type 2, basket) at 50 rpm, at 37 C in pH
7.5 buffer and found to have the following release profile:
TABLE I
Time (hours) % Released y6 88 1v 93 YT
The release profile of the controlled release product shown in thus Example is sho n in FIG I by the line filled with circles.
The bupropicn capsules of Example 1 were then tested according to the liSP XXIII dissolution test (type 2, basket), at 50 rpm, at 3', C in SGF
(pH 1.5) to determine the percentage of drug dissolved versus time-Time (hours) % Released WO 02/062299 PCT,I IS02/03523 G' 60 The release profile of the controlled release product shown: in ti s Example sn -ri sin FIG 2 by the line -,nh the tilled circles.
T e bupr_pion capsules of Example I were ten evaluated in seven patients us in.- Ãa dard techniques mown in the art. Buprortv pion was 1 ~~ s frstL detected .
the plasma at about ~''. hours after adstTutioi_, and showed sustained G` ur 2=1 hours.
Two panels of seven patients were randomly assigned to receive either tae bupropion formulation described herein or ZS1B AN 3) an open; randomized single dose study. Blood samples were collected over a ?2-hour period and anal, zed for bupropion concentrations with a LCIMSiNIS method.
For the blood levels carried out Cam,:; is the maximum blood level concentration of bupropion, Tm., is the time at which the maximum blood level concentration occurs, Tt,g is the sampling point preceding the one at which concentrations first become quantifiable. AUC is the "area under the curve" of time versus blood concentration. The results provided are given in Table 3 and FIG.
show that the mean plasma concentration time profiles of bupropion were different for the Example I formulation and ZybanS. Following oral administration, the I
VVO 021062299 PCTfUS02J03523 Example 1 formulation had a delayed absorption with a Tig value of 1.9 hours.
The mean Coax value of the Example 1 bupropion formulation was about one-half of that for Zybar: The time to reach (T,.,,, ) maximum plasma concentration occurred about 8 hours after administration of the Example 1 formulation. The relative bioavailability of the Example 1 formL:lation to Zyban was 40% o in terms of C, and 80 r% in terms of ALTCO_;f ratio.
Variable Example I Mean Zvban Mean G-Mean Ratio i - 1 - C129. 0.40 AL Ce _; ,n g-h~r nu1 321. 0- 998.0 0.8=
(lir) 1 9 T,ax(lrj 8.1 3_a T112 thr) 17.0 20.3 Thus. it can be seen from the data above that although the Cma of Example I is significantly lower than, the C a of the. Zyban formulation, the AUK
has only been slightly reduced.
The pellets from Example 1 are taken as the second and third components. These pellets are loaded into the dosator along with active pellets and are filled into capsules in a ratio of 10:30:60 while maintaining the dosage at 150 mg.
The blood profiles from this example will show a Cna,, that is the same as shown in Table 3. but will show a slightly increase AUC, thereby rendering the G-Mean ratio at about 1.00. The amount of active pellets may be adjusted as is known in the an pellets are xmixed with 2`9% (wtw) talc for 10 minutes in a V-blender and passed through a 14 mesh screen and a 24 mesh screen. Pellets smaller than 14 mesh and larger than 24 mesh are collected.
The pellets have the following coating composi on:
Ingredient mg Capsule % Total Wt.
Methacrylic acid copolymer 12.5 3.6 Ethocel 10 cps 12.5 3.6 Acet sltrihutti-l citrate 3.6 1.0 Talc 7.1 2.0 The {-. an d r^e `:1 flu Tr )t group of pellets the 1 above pellets are nosed a r load-n In-Lo o v: ch group cos~xtoy- Tir Fe stI..a x. e~'gt v t e f -h- G ii r 3 _ ~l i prGc:. s 150 ~g of ~iupropi` n with mg. of-act-i-iie drug in the first group of pelts and 1 00 ling of active =1;. bl drug inn to se-fond groupThe pellet.. a:-- then aps:l enc ateu .7 lns.i, t"
Size aF
:
r ~~
opaque'light blue opaque capsules. The :oral weight of the formulation (capsule pellets) is 352 ME
The resulting bumropion capsules were then tested according - the raccording to U SP Xix1i dissolution test (tvp e 2. ba ket), at 50 rpm. at 3 7 C; in pH ?. ~
buf far and found to have the following release profile:
Time (hours) % Released %N O (121062299 PCT/US012103523 The release profile of the con rolled release product of Example 3 is shown r by the line ~zith the filled in squares, I'll. FIB. . '' The resulting bupropion capsules were then tested according to USP
II st e 2. :: :at 50 rpm at 37cC. i SG ip 1-1) an d f and to have the following release Times hours) % Released BYO 021062299 PCTfUS02,03523 The release profile of the controlled release product shown in Example 3 is shown in FIG. 2 by the line with the filled in squares.
The bupropion capsules of Example 3 were then analyzed in a seven patient test using techniques known in the art. Bupropion was first detected in the plasma about 1.4 hours after administration and showed a sustained release over 24 hours.
The testing procedure is as described in Example 1. The results provided are given in Table 4 and FIG. 4 and show that the mean plasma time profile of the bupropion formulation differs om that of Zyban . Bupropion had a delayed absorption, the relative 'ahabili-tv abill 0 bupropior2 to ZY can S was 48%
and 55` in tern's Cma, and AUC Values, respectivei . The terminal elimination ha:11-lives were similar TABLE _4 Parameter Example 3 Zvban G-Mean Ratio Cmax (ng rn) `6.9 114.8 0.48 -ALLFC2 - (ng=heml) 531.7 8895 0.59 Ti.. Chr: 1.4 0.1 Tura. (hr) 5.1 4.1 Ti,2 (hr) 12.6 14.1 Thus, again, the C,,,a, of the Example 3 product was reduced significantly more than the AUC compared to the reference product, demonstrating that an effective once-a-day product has been provided.
The pellets from Ex- le 3 are taken as the second and third componen hose pellets are loaded into the dosator along with active pellets and are filled into capsules in a ratio of 10:30:60 while maintaining the dosage at 150 tug bjsprcpion. The blood profiles from this example will show a C the same as in Table 3, but wil= show a slightly increased AUC, thereby rendering the G-mean ratio at about LOO_ The amount of active pellets may be adjusted as is known in the art ithcut undue expenme :tom on based on ne teachings of the present disclosure in c- suos_ar_ ah pr_ iae a C- 'eai for AL or approximately _ O.
Claims (25)
1. A sustained release oral dosage form comprising:
a) a core comprising 75-450 mg of bupropion or a pharmaceutically acceptable salt thereof and 2-10% of a water soluble binder; and b) a single membrane-controlled extended-release coating surrounding the core comprising 1-20% of ethylcellulose based upon the total weight of the dosage form and a plasticizer;
wherein the sustained release oral dosage form is administered once a day and provides a Tmax of about 5 or more hours and wherein less than 50% of the bupropion or pharmaceutically acceptable salt thereof is released at 10 hours when measured by the USP 23 dissolution test (type 2, basket), at 50 rpm, at 37°C in SGF (pH 1.5).
a) a core comprising 75-450 mg of bupropion or a pharmaceutically acceptable salt thereof and 2-10% of a water soluble binder; and b) a single membrane-controlled extended-release coating surrounding the core comprising 1-20% of ethylcellulose based upon the total weight of the dosage form and a plasticizer;
wherein the sustained release oral dosage form is administered once a day and provides a Tmax of about 5 or more hours and wherein less than 50% of the bupropion or pharmaceutically acceptable salt thereof is released at 10 hours when measured by the USP 23 dissolution test (type 2, basket), at 50 rpm, at 37°C in SGF (pH 1.5).
2. The sustained release oral dosage form as defined in claim 1 wherein the Tmax is about 8 hours.
3. The sustained release oral dosage form as defined in claim 1 wherein the Tmax is about 5.1 hours.
4. A use of the sustained release oral dosage form as defined in claim 1, administered orally once a day for treating depression.
5. A use of the sustained release oral dosage form as defined in claim 1, administered orally once a day for treating tobacco dependence withdrawal.
6. The sustained release oral dosage form as defined in claim 1 wherein the plasticizer is selected from the group consisting of acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate, triethyl citrate, tributyl citrate, glyceroltributyrate, polyethylene glycol, propylene glycol and mixtures thereof.
7. The sustained release oral dosage form as defined in claim 6 wherein the plasticizer is acetyltributyl citrate.
8. The sustained release oral dosage form as defined in claim 1 wherein the water soluble binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose.
9. The sustained release oral dosage form as defined in claim 8 wherein the water soluble binder is hydroxypropyl methylcellulose.
10. The sustained release oral dosage form as defined in claim 1 wherein the single membrane-controlled extended-release coating further comprises 2-10% of a pH dependent polymer based upon the total weight of the dosage form wherein the pH dependent polymer is selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.
11. A sustained release oral dosage form comprising:
a) a core comprising 75-450 mg of bupropion or a pharmaceutically acceptable salt thereof and 2-10% of a water soluble binder wherein the water soluble binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose; and b) a single membrane-controlled extended-release coating surrounding the core comprising:
(i) 1-20% of ethylcellulose based upon the total weight of the dosage form, (ii) 2-10% of a pH dependent polymer based upon the total weight of the dosage form, wherein the pH dependent polymer is selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof, and (iii) a plasticizer;
wherein the sustained release oral dosage form is administered once a day and provides a Tmax of about 5 or more hours and wherein less than 50% of the bupropion or pharmaceutically acceptable salt thereof is released at 10 hours when measured by the USP 23 dissolution test (type 2, basket), at 50 rpm, at 37°C in SGF (pH 1.5).
a) a core comprising 75-450 mg of bupropion or a pharmaceutically acceptable salt thereof and 2-10% of a water soluble binder wherein the water soluble binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose; and b) a single membrane-controlled extended-release coating surrounding the core comprising:
(i) 1-20% of ethylcellulose based upon the total weight of the dosage form, (ii) 2-10% of a pH dependent polymer based upon the total weight of the dosage form, wherein the pH dependent polymer is selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof, and (iii) a plasticizer;
wherein the sustained release oral dosage form is administered once a day and provides a Tmax of about 5 or more hours and wherein less than 50% of the bupropion or pharmaceutically acceptable salt thereof is released at 10 hours when measured by the USP 23 dissolution test (type 2, basket), at 50 rpm, at 37°C in SGF (pH 1.5).
12. A once-a-day composition comprising:
(a) an immediate release component comprising bupropion or a pharmaceutically acceptable salt thereof wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(b) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly-vinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases bupropion in the upper gastrointestinal tract of a human patient; and (c) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of :
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases bupropion in the lower gastrointestinal tract of a human patient, wherein said composition is a tablet or capsule that contains 75 to 450 mg of bupropion or a pharmaceutically acceptable salt thereof, and the ratio of first pellet to second pellet is about 30:70 to about 70:30 and provides an in vivo plasma profile selected from:
(a) a mean C max of at least 50.0 ng/ml;
(b) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and (c) a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
(a) an immediate release component comprising bupropion or a pharmaceutically acceptable salt thereof wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(b) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly-vinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases bupropion in the upper gastrointestinal tract of a human patient; and (c) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of :
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases bupropion in the lower gastrointestinal tract of a human patient, wherein said composition is a tablet or capsule that contains 75 to 450 mg of bupropion or a pharmaceutically acceptable salt thereof, and the ratio of first pellet to second pellet is about 30:70 to about 70:30 and provides an in vivo plasma profile selected from:
(a) a mean C max of at least 50.0 ng/ml;
(b) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and (c) a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
13. The composition of claim 12 wherein the immediate release component is an uncoated active pellet.
14. The composition of claim 12 wherein said water insoluble coating polymer is selected from the group consisting of ethyl cellulose, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate and mono-, di- and tri-cellulose arylates.
15. The composition of claim 12 wherein the composition is a tablet.
16. The composition of claim 12 wherein the composition is a capsule.
17. The composition of claim 12 wherein the mean C max is less than 90 ng/ml.
18. The composition of claim 17 wherein the mean C max is less than 80 ng/ml.
19. The composition of claim 17 wherein the mean C max is less than 70 ng/ml.
20. The composition of claim 12 wherein the mean T max is 5.1 hours to 8.1 hours.
21. A once-a-day bupropion capsule consisting of:
(d) an immediate release component comprising a pharmaceutically acceptable salt of bupropion wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(e) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases bupropion in the upper gastrointestinal tract of a human patient; and (f) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of:
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases bupropion in the lower gastrointestinal tract of a human patient;
wherein said capsule contains 75 to 450 mg of bupropion, the ratio of first pellet to second pellet in the capsule is about 30:70 to about 70:30 and administration of the capsule to a patient provides an in vivo plasma profile selected from:
(d) a mean C max of at least 50.0 ng/ml;
(e) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and (a) a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
(d) an immediate release component comprising a pharmaceutically acceptable salt of bupropion wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(e) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases bupropion in the upper gastrointestinal tract of a human patient; and (f) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of:
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases bupropion in the lower gastrointestinal tract of a human patient;
wherein said capsule contains 75 to 450 mg of bupropion, the ratio of first pellet to second pellet in the capsule is about 30:70 to about 70:30 and administration of the capsule to a patient provides an in vivo plasma profile selected from:
(d) a mean C max of at least 50.0 ng/ml;
(e) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and (a) a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
22. A once-a-day bupropion tablet consisting of:
(a) an immediate release component comprising a pharmaceutically acceptable salt of bupropion wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(b) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases the bupropion in the upper gastrointestinal tract of a human patient;
(c) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of:
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases the bupropion in the lower gastrointestinal tract of a human patient; and (d) 25-40 weight percent of a solid pharmaceutically acceptable tablet excipient;
wherein said tablet contains 75 to 450 mg of bupropion, the ratio of first pellet to second pellet in the tablet is about 30:70 to about 70:30 and administration of the tablet to a patient provides an in vivo plasma profile selected from:
(a) a mean C max of at least 50.0 ng/ml;
(b) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
(a) an immediate release component comprising a pharmaceutically acceptable salt of bupropion wherein the immediate release component is a powder, a granule or an uncoated active pellet;
(b) a first pellet comprising a first core containing a pharmaceutically acceptable salt of bupropion and an enteric coating applied to the first core wherein the enteric coating consists of:
(i) a pH dependent coating polymer selected from the group consisting of shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and mixtures thereof;
(ii) a plasticizer; and (iii) a lubricant;
and wherein the first pellet releases the bupropion in the upper gastrointestinal tract of a human patient;
(c) a second pellet comprising a second core containing a pharmaceutically acceptable salt of bupropion and a sustained release coating applied to the second core wherein the sustained release coating comprises a mixture of:
(i) a water insoluble polymer;
(ii) a methyl acrylic acid copolymer;
(iii) a plasticizer; and (iv) an antisticking agent and wherein the second pellet releases the bupropion in the lower gastrointestinal tract of a human patient; and (d) 25-40 weight percent of a solid pharmaceutically acceptable tablet excipient;
wherein said tablet contains 75 to 450 mg of bupropion, the ratio of first pellet to second pellet in the tablet is about 30:70 to about 70:30 and administration of the tablet to a patient provides an in vivo plasma profile selected from:
(a) a mean C max of at least 50.0 ng/ml;
(b) a mean AUC0-inf of greater than approximately 500.0 ng.cndot.hr/ml; and a mean T max of between approximately 5.0 hours and 8.5 hours based upon a single dose administration of a composition containing 150 mg of bupropion or a pharmaceutically acceptable salt.
23. The composition of claim 12 wherein the first pellet releases the bupropion or pharmaceutically acceptable salt thereof at a pH corresponding to about 4.8 or lower and the second pellet releases the bupropion or pharmaceutically acceptable salt thereof at a pH
corresponding to about 7 and above.
corresponding to about 7 and above.
24. The composition of claim 21 wherein the first pellet releases the bupropion at a pH
corresponding to about 4.8 or lower and the second pellet releases the bupropion at a pH
corresponding to about 7 and above.
corresponding to about 4.8 or lower and the second pellet releases the bupropion at a pH
corresponding to about 7 and above.
25. The composition of claim 22 wherein the first pellet releases the bupropion at a pH
corresponding to about 4.8 or lower and the second pellet releases the bupropion at a pH
corresponding to about 7 and above.
corresponding to about 4.8 or lower and the second pellet releases the bupropion at a pH
corresponding to about 7 and above.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26745701P | 2001-02-08 | 2001-02-08 | |
| US26745601P | 2001-02-08 | 2001-02-08 | |
| US60/267,456 | 2001-02-08 | ||
| US60/267,457 | 2001-02-08 | ||
| CA2685214A CA2685214C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2685214A Division CA2685214C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2796884A1 true CA2796884A1 (en) | 2002-08-15 |
Family
ID=26952450
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2796884A Abandoned CA2796884A1 (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
| CA2685214A Expired - Fee Related CA2685214C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
| CA2433915A Expired - Fee Related CA2433915C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2685214A Expired - Fee Related CA2685214C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
| CA2433915A Expired - Fee Related CA2433915C (en) | 2001-02-08 | 2002-02-08 | Improved controlled release oral dosage form |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1357898A4 (en) |
| CA (3) | CA2796884A1 (en) |
| WO (1) | WO2002062299A2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8545880B2 (en) | 1999-02-26 | 2013-10-01 | Andrx Pharmaceuticals, Llc | Controlled release oral dosage form |
| WO2006123364A2 (en) * | 2005-03-14 | 2006-11-23 | Sun Pharmaceutical Industries Limited | Oral drug delivery system providing a coating comprising both a cellulose and a methacrylic acid derivative |
| US8394415B2 (en) | 2006-11-21 | 2013-03-12 | Mcneil-Ppc, Inc | Modified release analgesic suspensions |
| US9833510B2 (en) | 2007-06-12 | 2017-12-05 | Johnson & Johnson Consumer Inc. | Modified release solid or semi-solid dosage forms |
| EP2437733A4 (en) * | 2009-06-02 | 2014-01-08 | Dow Global Technologies Llc | Sustained release dosage form |
| CN110200947A (en) * | 2019-06-27 | 2019-09-06 | 深圳市泛谷药业股份有限公司 | A kind of Bupropion enteric sustained-release pellet capsule and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG42869A1 (en) * | 1992-08-05 | 1997-10-17 | Faulding F H & Co Ltd | Pelletised pharmaceutical composition |
| GB9217295D0 (en) * | 1992-08-14 | 1992-09-30 | Wellcome Found | Controlled released tablets |
| US6270805B1 (en) * | 1998-11-06 | 2001-08-07 | Andrx Pharmaceuticals, Inc. | Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate |
| US6210716B1 (en) * | 1999-02-26 | 2001-04-03 | Andrx Pharmaceuticals, Inc. | Controlled release bupropion formulation |
-
2002
- 2002-02-08 CA CA2796884A patent/CA2796884A1/en not_active Abandoned
- 2002-02-08 CA CA2685214A patent/CA2685214C/en not_active Expired - Fee Related
- 2002-02-08 EP EP02723104A patent/EP1357898A4/en not_active Withdrawn
- 2002-02-08 WO PCT/US2002/003523 patent/WO2002062299A2/en not_active Application Discontinuation
- 2002-02-08 CA CA2433915A patent/CA2433915C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2433915C (en) | 2010-04-20 |
| EP1357898A4 (en) | 2005-07-13 |
| EP1357898A2 (en) | 2003-11-05 |
| CA2685214A1 (en) | 2002-08-15 |
| CA2685214C (en) | 2013-01-22 |
| WO2002062299A2 (en) | 2002-08-15 |
| CA2433915A1 (en) | 2002-08-15 |
| WO2002062299A3 (en) | 2003-04-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20121127 |
|
| FZDE | Dead |
Effective date: 20151126 |