Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-02-26
2001-04-03
Dees, Jose′ G. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S490000
Reexamination Certificate
active
06210716
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a controlled release formulation of bupropion hydrochloride. The compound bupropion hydrochloride is described in U.S. Pat. No. 3,819,706 as an antidepressant.
U.S. Pat. No. 5,427,798 describes a controlled release formulation of bupropion which based on a ratio of hydroxypropyl methylcellulose which is 1 part of bupropion to 0.19 to 1.1 parts of hydroxypropyl methylcellulose. U.S. Pat. No. 5,358,970 discloses a formulation of bupropion hydrochloride which is stabilized with a stabilizer which has specific acid properties under particular test conditions. RE 33,994 is limited to a bupropion hydrochloride controlled release formulation which releases 10-45% of bupropion hydrochloride within two hours; 25-70% bupropion hydrochloride within 4 hours and 40-90% of bupropion hydrochloride within six hours. Wellbutrin SR is a commercially available twice a day dosage form of bupropion hydrochloride which contains carnauba wax, cysteine hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.
The applicants have discovered that a two pellet controlled release formulation may be employed to provide a dosage formulation which has a controlled release profile which is bioequivalent to Wellbutrin SR but has a distinctly different in vitro release profile than Wellbutrin SR.
SUMMARY OF THE INVENTION
The present invention provides a novel dosage form of bupropion hydrochloride which comprises:
(a) a first pellet having a core which comprises bupropion hydrochloride and hydroxypropyl methylcellulose at a weight ratio of 10:1 to 30:1 and a coating which comprises a mixture of an acrylic resin which is soluble in acidic media and ethyl cellulose;
(b) a second pellet having a core which comprises bupropion hydrochloride and hydroxypropyl methylcellulose at a ratio of 10:1 to 30:1, preferably 20:1; an inner coating which comprises a mixture of an acrylic resin which is soluble in acidic media and a water insoluble polymer and an outer coating which comprises an enteric coating polymer.
Generally, the weight ratio of the first pellet to the second pellet will be from 90:10 to 30:70 although a weight ratio of 80:20 is preferred.
Accordingly, it is a primary object of this invention to provide a pharmaceutical dosage formulation of bupropion which is suitable for twice a day administration.
It is also an object of this invention to provide a hydrogel-free pharmaceutical dosage form of bupropion hydrochloride which is bioequivalent to dosage forms of bupropion hydrochloride which have a hydrogel component.
It is also an object of this invention to provide a stable dosage form of bupropion hydrochloride which is based on a two pellet-membrane coated dosage form.
These and other objects of the invention will become apparent from a review of the appended specification.
DETAILED DESCRIPTION OF THE INVENTION
The bupropion hydrochloride formulation of the invention is preferably based on active pellets having a core forming inert component which may comprise non-pareil sugar seeds (sugar spheres, USP XXII) having an average size of from 14 to 35 mesh, preferably about 30 to 35 mesh. The core forming inert component is coated with a formulation which comprises bupropion hydrochloride and hydroxypropyl methylcellulose. A sufficient amount of the coating is applied to provide the dosage of bupropion hydrochloride, i.e. 50 mg to 300 mg.
To form pellet A, the active pellet is then coated with a seal coat which may comprise a mixture of hydroxypropyl methylcellulose and polyethylene glycol. The hydroxypropyl methylcellulose may have a viscosity of 5 mPa's at a 2 wt % conc. in water at 20° C. The polyethylene glycol may have a number average molecular weight of from 200 to 2000 although a number average molecular weight of 400 is preferred. Generally a ratio of 2:1 to 6:1 of hydroxypropyl methylcellulose to polyethylene glycol may be applied as a 3 to 7 wt % solution in a solvent such as ethanol, isporopyl alcohol, water, mixtures therof and the like.
The seal coat is then coated with a release modifying coating which comprises a mixture of an acrylic resin which is soluble in acidic media and a water insoluble polymer. The water insoluble polymer may comprise a cellulosic polymer such as ethylcellulose, cellulose acetate and the like. The release modifying seal coating may comprise a weight ratio of acrylic resin which is soluble in acidic media to water insoluble polymer of about 1:4 which is applied from a 3 to 7 wt % solution of isopropyl alcohol, ethanol, acetone, mixtures therof and the like to form a coating.
A useful acrylic resin which is soluble in acidic media is Eudragit E which is a cationic copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid esters having a mean weight average molecular weight of 150,000.
If desired a seal coat of a film forming polymer such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or the like may be applied to form a coating.
To form pellet B, pellet A is coated with a first coating of hydroxypropyl methylcellulose which is applied from a 5 wt % solution of ethanol, water or mixtures thereof to form a coating. An enteric coating is then placed on the coating of the hydroxypropyl methylcellulose. The enteric coating polymer may be selected from the group consisting of shellac, methacrylic acid copolymers, (Eudragit S or L) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof. Cellulose acetate phthalate is preferred. The thickness of the coating is selected to provide the desired release rate depending on the thickness of the coating and the particular coating. The enteric coating may be applied as a 3 to 7 wt % solution of the enteric polymer in acetone, ethanol, isopropyl alcohol or mixtures thereof.
Other auxiliary coating aids such as a minor amount (1-5 wt % based on the active core component and the total weight of the final coating) of a plasticizer such as acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol (molecular weight of from 380 to 420), propylene glycol and mixtures thereof in combination with an antisticking agent which is selected from the group consisting of an alkaline earth metal stearate, such as magnesium stearate or calcium stearate, or talc. The antisticking agents can be used alone or in combination.
The cores are formed by spraying the non-pareil seeds with an aqueous or non-aqueous suspension which contains the bupropion hydrochloride and the hydroxypropyl methylcellulose. The suspension medium may comprise any low viscosity solvent such as isopropyl alcohol, ethanol, water, mixtures thereof and the like. When fluids such as water are employed, this will usually require a weight of fluid which is about seven times the weight of the dry components of the coating composition.
It is preferred to dry each coating before applying a second coating. A color imparting agent may be added to the enteric coating mixture or a rapidly dissolving seal coat containing color may be coated over the enteric coating layer provided that the seal coat is compatible with and does nor affect the dissolution of the enteric coating layer.
Pellets A and pellets B are blended together to obtain a finished product having the following in vitro release profile:
50 to 80 wt % released after 2 hours in SGF (pH 1.5);
70 to 95 wt % released after 4 hours in SGF (pH 1.5);
not less than 80 wt % released after 6 hours in SGF (pH 1.5);
as determined in a USPXXII Type 2 apparatus, at 37° C. and 50 rpm.
The pellets may be placed in a gelatin capsule or they may be made into t
Chen Chih-Ming
Jan Steve
Xie Jianbo
Andrx Pharmaceuticals Inc.
Dees Jose′ G.
George Konata M.
Hedman & Costigan ,P.C.
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