l|llIllI|||||||||||||||I|I|Illllllllllllllllilllllllllllllllllillllllllllll
`
`US005326570A
`_
`5,326,570
`[11] Patent Number:
`Umted States Patent
`Rudnic et al.
`[45] Date of Patent:
`Jul. 5, 1994
`
`
`[19]
`
`[54] ADVANCED DRUG DELIVERY SYSTEM
`AND METHOD or TREATING
`PSYCHIATRIC, NEUROLOGICAL AND
`cm. W
`C
`PINE
`
`[56]
`
`vs:
`
`Edw-rd =~s-we
`Gfififie W‘ 3°'°’“"“k’ P°‘°"“‘°‘b°“‘
`°
`-
`
`_
`[73] Asmgnee:
`
`_
`Pharmavene, Inc., Gauhersburg, Md.
`
`[211 Appl. No.: 734,541
`
`[223
`
`,
`«
`filed’
`
`Ju]° 23’ 1991
`
`[51]
`1nt_ c1_s _____________________________________,.A61K 9/54
`
`[52] U.S. Cl. .................................... 424/458; 424/451;
`424/452; 424/-$57; 424/459; 424/465; 424/463;
`424/469; 424/439; 424/490
`[58] Field of Search ............. .. 424/451, 465. 457, 489,
`424/459, 453, 468, 469, 490, 452; 544/ 152
`
`References Cited
`"'5' PATENT DOCUMENTS
`1:222:
`:°°::“::.°‘“-
`e
`e
`.
`,
`,
`1/1939 Goertz etel.
`4,801,460
`8/1989 Kl'u-Inna at a].
`4.857.336
`:’::3»:::1;:::%.3
`5.009.394 4/1991 Hsiac
`5,023,272 5/1991 Burch em.
`
`..
`
`
`
`31:12;
`424/455
`424/436
`:::-~4;:::;‘:
`424/451
`544/152
`
`Primary Examiner-—T11urman K. Page
`,4m'5;am Emmfflm-_Jamc3 M_ spur
`Attorney. Agent, or F£rm—I-Elliot M. 0lstei.n_; Susan A.
`C“"°"°
`[57]
`
`ABSTRACT
`
`resent invention relates to a composition and
`The
`methgd of treating a patient by administering carbamaz-
`epine in a pharmaceutical dosage form capable ofn1air1-
`taining the patient‘s blood concentration at from about
`4 pg/ml to about 12 pg/ml over at least a 12 hour per-
`iod, where the blood concentration of carbamazepine
`does not vary by more than 60 percent.
`
`_
`
`25 Claims, 1 Drawing Sheet
`
`IR PELLET
`WITH
`DISSOLU TION
`
`coxscrmc. #2
`
`SR PELLET
`WITH
`pi-I-CONTROLLE
`EROSION '1'. D155
`ENHANCEMEN
`
`
`
`
`PELLET A
`
`FELLET B
`
`PELLET C
`
`PERCENT DISSOLVED
`
`I20
`
`FELLET A
`I00 -'--'
`
`PELLET B
`
`FELLET C
`
`TIME
`
`(HOURS)
`
`DOSAGE FORM COMPONENTS
`AND TARGET DISSOLUTION
`
`Amerigen Ex. 1030, p. 1
`Amerigen Ex. 1030, p. 1
`
`

`
`U.S. Patent
`
`July 5,1994
`
`5,326,570
`
`
`
`IR PELLET
`
`WITH
`DISSOLUTION
`
`SR PELLET
`WITH
`
`DISSOLUTION
`
`COATING #2
`
`SR PELLET
`
`EROSION S DISS
`ENHANCEMEN
`
`PELLET A
`
`PELLET B
`
`_
`
`PELLET C
`
`PERCENT. DISSOLVED
`
`I20
`
`PELLET A
`
`PELLET B
`
`PELLET C
`
`I00 — - - - —
`
`— ——S - — — — - — — - - *-
`
`8O
`
`..__..._ _._.._. — — . _ — : — — j ¢ ——- —
`
`— — * m :1
`
`50
`
`_ _ * _ _ _ _ _ _ _.._
`
`.._. _ . _ . _ _ _._
`
`TIME
`(HOURS)
`F!G.|
`DOSAGE FORM COMPONENTS
`
`AND TARGET DISSOLUTION
`
`Amerigen Ex. 1030, p. 2
`Amerigen Ex. 1030, p. 2
`
`

`
`1
`
`5,326,570
`
`ADVANCED DRUG DELIVERY SYSTEM AND
`METHOD OF TREATING PSYCHIATRIC,
`NEUROLOGICAL AND OTHER DISORDERS
`WITH CARBAMAZEPINE
`
`The present invention relates to a method of delivery
`for carbamazepine which will provide steady and con-
`sistent blood levels of carbarnazepine. The bloo_d levels
`of carbarnazepine are within a therapeutic range re-
`quired for the treatment of epilepsy as well as other
`psychiatric, neurological and other disorders.
`Carbamazepine is an irninostilbene derivative that is
`used clinically to treat seizure disorders, trigeninal neu-
`ralgia, and most recently, manic depressive illness.
`The present invention provides a method and compo-
`sition for delivery of carbamazepine which provides
`steady and consistent blood levels of carbamazepine
`within a therapeutic range. The therapeutic range is
`from about 6 pg/ml to about 12 pg/ml of carbarnaze-
`pine over a period of time. Blood levels of carbanraze-
`pine of less than 4 pg/ml have been found to be ineffec-
`tive in treating clinical disorders and blood levels
`greater than 12 pg/ml have been found to be likely to
`result in undesirable side effects such as neuromuscular
`disturbances, cardiovascular and gastrointestinal ef-
`fects.
`The present invention provides for the maintenance
`of blood levels of carbamazepine (C) so as to minimize
`Cmart/Cmin variation or fluctuation. An acceptable
`fluctuation in the blood level Cmin/Cmax ratio would
`be a range of from about 0.6 to about 1.0. Most prefera-
`bly, the variation or fluctuation would range from about
`0.3 to about 1.0.
`The present invention maintains a therapeutic range
`of blood levels of carbamazepine effective for the treat-
`ment of disorders which include but -are not limited to
`depression, trigeminal; neuralgia; chronic pain states;
`headaches; addictive states for: cocaine, alcohol. opiates
`and nicotine; other obsessive compulsive disorders and
`cardiovascular disease.
`An embodiment of the present invention provides for
`a sustained release method of delivery of carbamazepine
`which is to be administered at least once a day, prefera-
`bly twice a day; therefore, in accordance with an aspect
`of the present invention there is provided a steady and
`consistent blood level of carbarnazepine within thera-
`peutic range of from about 4 pg/ml to about 12 pg/ml,
`over a time period of at least 12 hours. In accordance
`with the present
`invention, within the hereinabove
`noted therapeutic range,
`the blood concentration of
`carbamazepine varies by not more than 60 percent and
`preferably by not more than 4-0 percent and most prefer-
`ably by not more than 20% over a period of at least
`twelve hours.
`The method of delivery of carbamazepine of the
`present invention provides for the following routes of
`administration sublingual,
`transmucosai,
`transdermal,
`parenteral and preferably oral. Parenteral administra-
`tion would require an amount of carhamazepine of from
`about 100 mg to about 1000 mg per 12 hours. The dos-
`age forms may include but are not limited to liquids,
`tablets, capsules, sprinkle dosage forms, chewable tab-
`lets and transdermal patches.
`The sustained-release method of delivery of the pres-
`ent invention may be accomplished by administering
`multiple single unit dosage forms of equal or varying
`concentration of carbamazepine. Each such unit would
`
`I0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`2
`be designated to release its contents at varying times
`over at least a twelve hour time period so as to maintain
`a carbamazepine blood level within the therapeutic
`range previously described.
`A preferred embodiment of the present invention
`provides for that the patient to be treated, ingest at a
`single point in time a dosage form containing carbamaz-
`epine capable of maintaining the patient’s blood concen-
`tration at from about 4 pg/ml to about 12 pg/ml over at
`least a 12 hour time period, where the blood concentra-
`tion of carbamazepine does not vary by more than 20%.
`Such a dosage form may consist of one or more units.
`having the same or varying concentrations of carbam-
`azepine, designed to release its contents at varying times
`so as to maintain a carbamazepine blood concentration
`level within the therapeutic range and for the time per-
`io-d previously described.
`One preferred embodiment may comprise one single
`dosage form which contains multiple units within it,
`which are capable of releasing their contents at varying
`times. A second embodiment of the single dosage form,
`may also be to consist of one unit capable of immedi-
`ately releasing a concentration of carbarnazepine, then
`sustained-releasing carbamazepine at other time points
`as necessary to maintain blood levels within the thera-
`peutic range. A third embodiment may be for the dos-
`age form to be in multiple separate units capable of
`releasing carbamazepine at varying times, the separate
`multiple units as described above would all be ingested
`by the patient to be treated at the same time point.
`Another embodiment of the present invention pro-
`vides for a composition for treating a patient comprising
`an effective amount of carbamazepine and a pharmaceu-
`tically acceptable carrier which are sufficient for main-
`taining a blood concentration of carbamazepine within
`the therapeutic range and as described above.
`Using either dosage form it is preferred that the dose
`of carbamazepine administered each 24 hour period is
`from about 800 mg to about 1200 mm. The dose is ad-
`justed by the administering physician based upon the
`age, sex and weight of the patient to maintain therapeu-
`tic blood levels of carbamazepirre.
`Since carbarnazepine is needed to be absorbed into
`the bloodstream over at least a twelve-hour period, it is
`preferred that the drug be administered in a dosage
`form that will reliably remain in the GI tract, in a suffi-
`ciently high region as to favor absorption.
`_
`To achieve and maintain the therapeutic range, a dose
`of from about 400 to about 600 mg per 12 hour period of
`carbamazepine makes it necessary to have a reasonably
`high loading of drug in the pellets. Because of this, it is
`preferred to have greater than 30% (W/W) of the pellet
`content as carbamazepine. It is preferable to have as
`great a concentration as possible, and therefore ideally
`as much as 95% (W/W) of each pellet would consist of
`the drug. It may not be practical to obtain this high
`loading of carbamazepine for all combinations of ingre-
`dients identified this application.
`The term W/W as used herein is representative of a
`weight to weight ratio of the material specified to the
`weight of the unit dosage form as a whole.
`For carbamazepine. it is preferred to have three dif-
`ferent types of units in a single form multiple-unit dos-
`age form. The first unit is an immediate release dosage
`form, preferably in pellet form. This component can
`also be a powder if necessary. In either case, the pellet
`should have a surface-active agent such as sodium lau-
`ryl sulfate, sodium monoglycerate, sorbitan monoole-
`
`Amerigen Ex. 1030, p. 3
`Amerigen Ex. 1030, p. 3
`
`

`
`3
`ate. polyoxyethylene sorbitan rnonooleate. glyceryl
`monostearate, glyceryl monooleate, glyccryl monobu—
`tyrate. any one of the Pluronic line of surface-active
`polymers. or any other suitable material with surface
`active properties or any combination of the above. Pref-
`erably the surface-active agent would be a combination
`of sodium monoglycerate and sodium lauryl sulfate.
`The concentration of these materials in this component
`can range from about 0.05 to about 10.0% (W/W).
`The pellet should be made via a suitable process
`which makes the dosage form into a reasonably round
`unit. This process can be. for example. simple granula-
`tion, followed by seiving; extrusion and marumeriza-
`tion; rotogranulation; or any agglomeration process
`which results in a pellet of reasonable size and robust-
`ness. As stated earlier. it is also possible to have this
`immediate release component as a powder, although the
`preferred form is a pellet clue to mixing and de-misting
`considerations.
`The materials to be admixed along with the drug and
`surfactant for this first pellet should possess sufficient
`binding properties to allow agglomeration to occur.
`These materials can be. but are not limited to. micro-
`crystalline cellulose (such as Avicel). corn starch. pre-
`gelatinized starch (such as Starch 1500 or National
`1551), potato starch, sodium carboxyrnethylated starch,
`sodium carboxymetltylated cellulose, hydroxypropyl-
`methyl cellulose, hydroxypropylcellulose. hydroxyeth-
`ylcellulose, ethylcellulose. as well as any cellulose
`ether. In addition, any binder material such as gums (ex.
`Guar Gum) natural binders and derivatives such as
`alginates. chitosan. gelatin and gelatin derivatives. are
`also useful. Synthetic polymers such as polyvinylpyr-
`rolidone (PVP). acrylic acid derivatives (Eudragit. Car-
`bopol. etc.) and polyethylene glycol (PEG) are also
`useful as binders and matrix formers for the purpose of
`this invention. It may be useful to have these materials
`present in the range of from about 1.0 to about 60.0%
`(W/W) either in total. or individually in combination
`with one another. Preferably. these materials should be
`present in the range of from about 30 to about 50 per-
`cent (W/W).
`It may also be necessary to incorporate a disintegrant
`into these pellets in order to facilitate dissolution of the
`active ingredient. For this purpose. any suitable tablet
`disintegrant can be utilized here. such as cross-linked
`sodium carbortymethylcellulose (Ac-Di-Sol), cross-
`linked sodium carboxymethyl starch (Explotab. Primo-
`jel), cross-linked FVP (Plasdone XL) or any other ma-
`terial possessing tablet disintegrant properties.
`The second pellet should have a sustained release
`profile, and needs to be able to address the changing pH
`of the GI tract. and its effect on the absorption of car-
`bamazepine. This pellet should have all of the ingredi-
`ents as mentioned for pellet A. as well as some organic
`acid which will be useful to reduce the pH of the micro-
`environment of the pellet. and thus facilitate dissolution.
`These materials are. but not limitd to, citric acid, lactic
`acid. tartaric acid. or other suitable organic acids. These
`materials should be present in concentrations of from
`about 0 to about 15.0% (W/W). preferably these materi-
`als would be present in concentrations of from about 5.0
`to about 10.0 percent (W/W). The process for manufac-
`turing these pellets is consistent to the process described
`above for the previous pellet.‘
`In addition to the pellet. this component should have
`a controlling coat applied to the surface of the pellet
`such that the release of the drug from the pellet is con-
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5,326,570
`
`4
`trolled and released over a 6-10 hour period. The mate-
`rials used for this purpose can be, but are not limited to.
`ethylcellulose. hydroxypropylmethylcellulose. hydrox-
`ypropylcellulose, hydroxyethylcellulose, methylcellu-
`lose, nitrocellulose, carboxymethylcellulose. and any
`other cellulose ether. as well as copolymers of ethacry-
`lic acid and methacrylic acid (Eudragit), or any other
`acrylic acid derivative (Carbopol, etc.) can be used. In
`addition. an enteric coating material can also be em-
`ployed. either singularly, or in combination to the above
`non-pH sensitive coatings. These materials include, but
`are not
`limited to, hydroxypropylrnethylcellttlose
`phthalate and the phthalate esters of all the cellulose
`ethers. In addition, phthalate esters of the acrylic acid
`derivatives (Eudragit), or cellulose acetate phthalate.
`These coating materials can be employed in coating the
`surfaces in a range of from about l.0% (W/W} to about
`25% (W/W). Preferably these coating materials should
`be in a range of from about 8.0 to about 12.0 percent
`(W/W).
`The third component in this system should be qualita-
`tively similar to pellet B,
`in that the manufacturing
`process for producing this pellet is consistent with that
`of the first two pellets. and the microenvironment inside
`the pellet should be consistent with that of pellet B.
`However, this pellet should have some internal compo-
`nent for breaking down in the pH of the lower GI tract.
`Thus, it will be necessary to include some enteric or pH
`sensitive material into the pellet to facilitate erosion and
`breakdown in the lower GI tract. This material can be,
`but is not limited to, cellulose acetate phthalate, hydrox-
`ypropylmethylcellulose phthalate, any additional cellu-
`lose ether phthalates, any of the acrylic acid derivative
`phthalates (Eudragit). 3 well as any enteric coating
`material. such as shellac. zein. or others. The concentra-
`tion of these materials in the pellet should be from about
`1.0 to about 15.0% (W/W). Preferably the concentra-
`tion of amterials should be from about 5.0 to about 10.0
`percent (W/W).
`The coating of this third pellet should be similar to
`the coating for pellet B, except that it should have a
`considerable pH sensitivity associated with it. There-
`fore. it would be desirable to coat pellet C with any of
`the pH sensitive. or enteric coating materials listed
`above, either singularly, or in combination with any
`coating material mentioned above. The coating level of
`this pellet should range from about 1.0 to about 15.0%
`(W/W). preferably the concentration of materials
`should be from about 5.0 to about 12.0 percent (W/W).
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Each pellet should have its own dissolution profile
`associated with the formulation assigned to it. The tar-
`get dissolution curves for the three pellets can be seen in
`FIG. 1.
`This FIGURE shows a schematic of the three pellets,
`as well as the target dissolution for the materials. De-
`pending on the formulation chosen in this invention, the
`exact ratios of each of the pellets may need to be ad-
`justed. The amount of pellet A in the formulation
`should preferably range from about 5.0 to about 25.0%.
`The amount of Pellet B in the dosage form should range
`from about 15.0 to about 70.0%. The dosage form for
`Pellet C should be in a range of from about 10.0 to about
`50.0%.
`
`While the present invention has been described in
`conjunction with specific embodiments thereof,
`it
`is
`evident that many alternatives. modifications and varia-
`
`Amerigen Ex. 1030, p. 4
`Amerigen Ex. 1030, p. 4
`
`

`
`5,326,570
`
`6
`-continued
`
`5
`tions will be apparent to those skilled in the art in view
`of the foregoing description. Accordingly, the plenary
`invention in intended to embrace all such alternatives,
`modifications and variations as falling within the broad-
`est scope and spirit of the described invention.
`The following examples illustrate the invention in
`more detail without limiting the scope thereof.
`EXAMPLES
`
`The examples are presented in three groups, one for
`each pellet type as described above.
` ._m_
`Pellet :4: Immediate Release Oommnent
`Percent
`
`Kilograms
`
`Example 1:
`Microcrysulline Cellulose, N.F. (MCC)
`(Avioel ‘PH-101/I02, Emcocel. etc.)
`Hydroxypmpylmethyloelluloee (HPMC)
`(Methooel E5/E50/K5/K50)
`Croscarmellose. Type A, N.F.
`(Ac-Di-Sol)
`Sodium Lauryl Sulfate (SL5)
`Carbamazepine
`
`Total
`
`Example 1:
`MCC
`HI-‘MC
`Sodium Starch Glycolate. N.F.
`(Bxplotah, Ptimojel)
`SL5
`Clrbamnzepine
`
`Total
`
`40.0
`
`2.5
`
`2.0
`
`0.1
`55.4
`100.0
`
`40.0
`5.0
`8.0
`
`0.3
`46.1
`103.0
`
`0.4
`
`0.025
`
`0.02
`
`0.001
`0.554
`1.003
`
`0.4
`0.05
`0.08
`
`0.003
`0.467
`1.030
`
`Sodium |:is-(2~ethylhexyl)sull'o-
`stlccinate (Aeroso10T)
`Carbarnazepine
`
`Example 9:
`MISC
`I-I1‘-‘MC
`Mono/Diffri-glyceride Mixture
`(Atmul~E4S)
`SL5
`Carbamsupine
`
`Example 10:
`MCC
`Folyvinylpyrrolidone (PVP)
`(Plasdone)
`Sodium Moaoglycerate
`Mwaplexl
`SLS
`Cnrbatnazepine
`
`Example 1!:
`MCC
`!'l.PMC
`Sodium Monoglycerate
`Tlnarlc Acid
`31.5
`Carhamazepine
`
`Coating:
`Ethaerylic/Methaerylic Acid Esters
`('E1.Idragi1 RS100)
`Ethacrylicflltlelhacrylic Acid Esters
`(Eudragit RL100)
`Propylene Glycol
`Talc
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Total
`
`Total
`
`Total
`
`Total
`
`1.5
`
`55.0
`1120.0
`
`25.0
`5.0
`10.0
`
`0.5
`59.5
`113.0
`
`25.0
`8.0
`
`0.0
`
`0.35
`58.65
`100.0
`
`30.0
`5.0
`8.0
`5.0
`0.1
`51.8
`100.0
`
`45.0
`
`45.0
`
`0.015
`
`0.560
`1.0:!)
`
`0.25
`0.05
`0.1
`
`0.035
`
`0.595
`1.029
`
`0.25
`0.03
`
`0.08
`
`0.11135
`0.5365
`1.0000
`
`0.3
`0.05
`0.08
`0.05
`0.002
`
`0.518
`1.1110
`
`0.45
`
`0.45
`
`Example 3:
`MOC
`Pre-gelatirtized Starch
`(STARCH 1503, National 1551)
`Croscarmellose
`Corn Starch, U.S.P. (as paste)
`Dioctyl Sodium Sulfosuccinate (DDS)
`Carbamazepine
`
`Total
`
`Example 4:
`MCC
`MCC/Cuboxymethyl Cellulose (Cl:-IC}
`{fivicel RC Grade)
`Croscarmellose
`51.5
`Carbamazepine
`
`Total
`
`Example 5:
`MCCKCMC
`Croscarmellose
`Sodium Starch Glycolate
`HFMC
`DDS
`Carbamazepine
`
`Example 6:
`MCC
`MCCICMC
`Crosearmelloee
`DDS
`Cnrliamazepine _
`
`‘Example 7:
`MCCKCMC
`Polyacryfic Acid
`(Carbomer)
`SL5
`Sodium Starch Glycolate
`Carbamazepine
`
`Example 8:
`MCC
`HPMC
`Croscannellose
`
`Total
`
`Total
`
`Total
`
`20.0
`15.0
`5.0
`5.0
`0.5
`54.5
`lI'..‘l'.l.0
`
`15.0
`15.0
`
`5.0
`0.5
`64.5
`l(.‘I'J.0
`
`20.0
`3.0
`5.0
`8.0
`0.5
`63.5
`100.0
`
`10.0
`10.0
`5.0
`0.5
`14.5
`100.0
`
`25.0
`100
`
`0.2
`7.5
`513
`103.0
`
`30.0
`1.5
`5.0
`
`0.2
`0.15
`0.05
`0.05
`0.005
`
`0.545
`1.000
`
`0.15
`0.15
`
`0.05
`0.005
`0.645
`1.000
`
`0.2
`0.03
`0.05
`0.08
`0.035
`0.635
`1.000
`
`0.10
`0.10
`0.05
`0.005
`0.145
`1.033
`
`0.25
`0.1
`
`0.002
`0.035
`0.573
`1.000
`
`0.30
`0.0?5
`0-05
`
`35
`
`Example 12:
`Same core pellet as in example ll
`Coating:
`HPMC (Methocel E50)
`Ethylcellulose (Etliocel)
`Polyethylene Glycol 400 (PEG400)
`
`Example 13.-
`Same core pellet as in example 11
`Cflflllflg:
`I-IPMC
`Ethylcellulose
`PEG400
`
`45
`
`Example 14:
`MCC
`MCC/CMC Mixture
`Citric Acid
`D55
`Carhamazepine
`
`Coating:
`HPMC (Methocel KSM)
`HPMC (Methocel E50)
`Ethylcellulose
`P156400
`
`55
`
`Example 15:
`Core pellet from example :4
`Coating from example 11
`Example 16:
`Core pellet from example 14
`Coating from example 12
`Example 16:
`Core pellet from example 14
`Coating from example 13
`Example 17:
`MCC
`PVP
`Monofbi/'1'ri~Gl)tce1'ide Mixture
`
`65
`
`9.0
`1.0
`100.0
`
`Total
`
`
`0.09
`0.01
`1.113
`
`45.0
`45.0
`10.0
`I00.0
`
`20.0
`10.0
`10.0
`103.0
`
`15.0
`15.0
`6.0
`03
`63.2
`I00.0
`
`10.0
`14.0
`66.0
`10.0
`1010
`
`Total
`
`Total
`
`Total
`
`Total
`
`0.45
`0.45
`0.10
`1.1!)
`
`0.20
`0.'l'0
`0.10
`1.1!]
`
`0.15
`0.15
`0.06
`0.003
`0.632
`LOCO
`
`0.10
`0.14
`0.66
`0.10
`1.00
`
`30.0
`8.0
`8.0
`
`0.3
`0.08
`0.00
`
`Amerigen Ex. 1030, p. 5
`Amerigen Ex. 1030, p. 5
`
`

`
`5,326,570
`
`Total
`
`30.0
`‘L5
`Q5
`61.0
`100.0
`60.0
`15.0
`no
`§m_n
`
`35.0
`
`14_o
`1-0
`I0-0.0
`
`Total
`
`1-ma.
`
`Total
`
`7°“!
`
`65,0
`15_o
`10.0
`“W
`'0“
`M
`15.0
`10.0
`1‘;-is’
`'
`39.2
`Tm! mm
`
`0.10
`0.0'i'5
`gm;
`0.410
`L000
`0.60
`025
`M5
`mg
`
`0.35
`
`0,14
`0-01
`1.00
`
`M5
`mg.
`0.10
`“-1”
`W“
`M5
`0.15
`0.10
`3:0
`'
`0.392
`mm
`
`5
`
`10
`
`15
`
`20
`
`2
`
`50
`
`65
`
`Coating:
`“film? 7'1? =“mP’° 11
`G
`C
`rflmelflm E
`cT5’—E"‘“’°|]l’f
`I H
`Coetirll); from ua.niplePl2
`Emmy; 19,
`cm perm {mm .,.mp1, 1-;
`coating from example 13
`cc::‘.'P°':" rm“ "“:“3‘i': 17
`"M "m "gates, Dela ed Mme Com m,
` :$_m
`Bum It 2.:
`cm Mm:
`
`Percent
`Kilogram
`MCC
`no
`N,
`Hydroxyprcpylmethyloeliulosc
`no.0
`0.10
`Phthalate (HPMCP)
`Tartaric Aliid
`Sodium Monoglyceriite
`D55
`car-bamazepine
`
`8
`7
`1. A drug delivery system for the oral administration
`_
`.
`1‘
` -T? of carbamazepiiie, comprising:
`gljmc Add
`2::
`$39,:
`(a) a sustained release unit containing carbainazepme;
`cubamugp,-1,,
`463
`M5;
`(13) an immediate release unit containing carbai:naze-
`100.0
`1.000
`pins; and
`_
`_
`_
`(c) an enteric release unit containing carbamazepme,
`said combination of components (0). (D). and (c)
`-
`containing a therapeutically effective amount of
`carbamazepme‘
`,
`_
`,
`2. A method for treating a patient with carban:iaze-
`pine, comprising: orally administering to the patient the
`system of claim 1.
`3. The system of claim 1 wherein said components
`(a), (b) and (c) are present in a tablet.
`.
`.
`.
`4. The system of clami 1 wherein said components
`(a), (b) and (c) are present in a capsule.
`5. The system of claim 1 wherein said components
`(a), (b) and (c) are present in a single dosage form.
`6. The system of claim 1 wherein said components
`(a), (b). and (c) are in a pellet form and are present in a
`single dosage roan
`.
`.
`.
`'
`7. The system of claim 6 wherein the snigle dosage
`form is a capsule.
`‘
`_
`.
`3. The system of claim 1 wherein said system pro-
`5 vides a therapeutically effective amount over a 12 hour
`-0‘!
`-
`Pm '
`_
`,
`.
`The system of claim 1 wherein said system com-
`prising components (a), (b) and (c) contains carbariia_ze-
`30 pine in an amount from about 4-00 mg to about 600 mg.
`10. The system of claim 1 wherein the system pro-
`vides blood dosage levels of carbainazepine which do
`-
`not vary by more than 00% over 1: _l2 hour period.
`11. The system of claim 10 wherein the blood dosage
`35 levels do not vary by more than 20% over a 12 period.
`12. A system as in claim 1, wherein each of the units
`includes a surfactant.
`13. A system as in claim 12, wherein the sustained
`release unit and the enteric release unit each contain an
`40 organic acid to maintain an acidic environment in the
`umts.
`14. A system as in claim 12. wherein said surfactant is
`sodium iauryl sulfate.
`15. A system as in claim 1. wherein said sustained
`45 release unit is present in an amount ranging from about
`5.0% to about 25.0% (w/w), said immediate release unit
`is present in an amount ranging from about 15.0% to
`about 70.0% (W/w) and said enteric release unit is pres-
`_
`_
`ent m an amount ranging from about 10.0% to about
`50 503% (W/“’)-
`I
`_
`_
`.
`_
`16. A system as in claim 15, wherein said sustained
`release unit is coated with a coating material in an
`amount ranging from about 1.0% to about 25% {W/w)
`and said enteric release unit is coated with a coating
`55 material in an amount ranging from about 1.0% to about
`15-093 (W/W)-
`‘ 17.‘A system as in claim 1, wherein the carba.n:laae-
`pine in said sustained release unit is released from said
`unit over a period from about 6 to about 10 hours.
`_ 18. A method of treating a patient with _carbainaze-
`pine compnsmgf orally adniinistenng to said patient a
`composition which contains,
`_
`.
`‘
`(a) an immediate release unit contaimng carbaniaze-
`pine;
`a sustained release unit containin carbamaze ine;
`.
`-
`v
`n g
`P:
`(c) an entenc release unit containing carbamazepine;
`said components (a), (b). and (c)cont.a1ru.ng a thera-
`peutically effective amount of carbamazepine.
`
`C0aIins=
`Cellulose Acetate Phlhalale (CAP)
`Etityicellirlose
`pggm
`
`Eilarngle 22:
`Core pellet from example 2!
`°°3“'"E¢
`Ethacrylie/Metiiacryiic Acid Esters
`(Baum?! mm of mm]: mime“)
`pmpyim glycol
`Talc
`
`1’-lI+*“=£!L*£.13_=
`C°’°,P°““ ‘mm *““'‘P'‘ 1‘
`Ef1§""'3'
`Hpil.-[Cp
`PEG 400
`955 59°”
`_
`P I
`fig °’°‘-
`Honoffliffri-glyoeride Mixture
`Tartaric Acid
`Cg:
`garb
`.
`amazeplne
`
`Costing as in example 21
`Example 25-.
`Core pellet asineiuimple 24
`‘3°°‘*"3 *5 i“ °W"?l' 33
` ‘ I
`gig‘ H.“ L“ mm” ° 24
`3 as In example 23
`Example ii:
`go... 9,3,1 ,5 -Ln “mpg, 34
`Coating:
`_
`5h_°"“°
`gem 0'1
`-1-,],_.
`
`Dig
`L5
`[mg
`
`3-?
`0:005
`gm;
`mm
`
`1-”;
`Example 28:
`‘
`Core pellet as in example 21
`
`°°“"'"‘E “-5 in mm??? 37
`
`what is claimed is:
`
`Amerigen Ex. 1030, p. 6
`Amerigen Ex. 1030, p. 6
`
`

`
`5,326,570
`
`9
`19. A method as in claim 18, wherein said compo-
`nents (a).
`(13). (C) being administered in a combined
`amount to maintain a blood dosage level of carbamaze-
`pine within a range of from about 4 pg/ml to about 12
`pg/ml for a period of at least l2 hours.
`20. A method as in claim 18. wherein the components
`being administered contain a combined amount of ca!-
`bamazepine of from about 4-00 mg to about 600 mg.
`21. A method as in claim 19, wherein the blood dos-
`age level of carbamazepine does not vary by more that
`60 percent per 12 hour period.
`
`10
`22. A method as in claim 20, wherein the blood dos-
`age level of carbamazepine within said range does not
`vary by more than 20 percent per 12 hour period.
`23. A method as in claim 18, wherein each of the units
`includes a surfactant.
`24. A method as in claim 22, wherein said surfactant
`is sodium lauryl sulfate.
`25. A method as in claim 23, wherein said sustained
`release unit and said enteric release unit each contain an
`organic acid to maintain an acidic environment in the
`units.
`I
`S
`Q
`I
`C
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`SD
`
`55
`
`65
`
`Amerigen Ex. 1030, p. 7
`Amerigen Ex. 1030, p. 7