United States Patent
`Rudnic et a1.
`
`[19]
`
`[54]
`
`ADVANCED DRUG DELIVERY SYSTEM
`AND METHOD OF TREATING
`PSYCHIATRIC, NEUROLOGICAL AND
`OTHER DISORDERS WITH
`CARBAMAZEPINE
`
`[75]
`
`Inventors: Edward M. Rudnic, Gaithersburg;
`George W. Belendiuk, Potomac, both
`of Md.
`
`[73]
`
`Assignee:
`
`Pharmavene, Inc., Gaithcrsburg, Md.
`
`[21]
`
`App1.No.: 734,541
`
`[22]
`
`Filed:
`
`Jul. 23, 1991
`
`[5 1]
`[52]
`
`[58]
`
`Int. Cl.5 ................................................ -A61K 9/54
`
`US. Cl. ..
`.
`.
`.
`.. .. 424/458; 424/451;
`424/452; 424/457; 424/459; 424/465; 424/468;
`424/469; 424/489; 424/490
`Field of Search ............... 424/451, 465, 457, 489,
`424/459, 458, 468, 469, 490, 452; 544/152
`
`IlllllHIIIIIIIIIIIIIIIIIIIHIIIllllllllllHlllllIIIIIIIIIIIIIIIIIIIIIIII
`
`USOOS32657OA
`
`[11] Patent Number:
`
`5,326,570
`
`[45] Date of Patent:
`
`Jul. 5, 1994
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,606,909 8/ 1986 Bechgaard ct al. ................. 424/481
`......
`,. 424/457
`4,794,001 12/1988 Mchta et a1.
`
`.. 424/465
`4,801,460 1/ 1989 Goertz ct al.
`.
`
`.. 424/486
`4,857,336
`8/1989 Khanna et a1.
`
`4,942,182
`7/1990 Weiss et al.
`424/10
`
`4,980,170 12/1990 Schneider ct a].
`.. 424/451
`5,009,894 4/1991 Hsiao .....
`.. 424/451
`5,023,272
`6/1991 Burch ct
`.. 544/152
`
`
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—James M. Spear
`Attorney, Agent, or Firm—Elliot M. Olstein; Susan A.
`Capello
`
`ABSTRACT
`[57]
`The present invention relates to a composition and
`method of treating a patient by administering carbamaz-
`epine in a pharmaceutical dosage form capable of main-
`taining the patient’s blood concentration at from about
`4 ug/xnl to about 12 ug/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
`
`COATING
`
`#
`
`I
`
`COATING _#2
`
`IR PELLET
`WITH
`
`WITH
`
`WITH
`pH-CONTROLLED
`EROSION i. DISS
`
`DISSOLUT ION SR PELLET
`ENHANCEMEN
`DISSOLUTION SR PELLET
`
`F’ELLET A
`
`FELLET B
`
`PELLET C
`
`0 PERCE NT DISSOLVED
`PELLET A
`
`ELLET B
`
`PELLET C
`
`100
`
`6 P
`
`O
`
`2
`
`4
`
`8
`(HOURS)
`
`TIME
`
`IO
`
`12
`
`14
`
`DOSAGE FORM COMPONENTS
`AND TARGET DISSOLUTION
`
`KVK-TECH EXHIBIT 1016
`
`KVK-TECH EXHIBIT 1016
`
`

`

`US. Patent
`
`July 5,1994 '
`
`5,326,570
`
`COATING #1
`
`COATING #2
`
`
`
`IR PELLET
`
`WITH
`
`DISSOLUTION
`
`ENHANCEMENT
`
`
`
`
`SR PELLET
`WITH
`DISSOLUTION
`ENHANCEMENT
`
`SR PELLET
`WITH
`pH-CONTROLLED
`EROSION 8. DISS
`
`ENHANCEMEN
`~ --
`
`PELLET A
`
`PELLET B
`
`.
`
`PELLET C
`
`PERCENT. DISSOLVED
`
`I20
`
`IOO
`
`PELLET A
`
`PELLET B
`
`PELLET c
`
`,
`
`,
`
`o
`
`2
`
`4
`
`6
`
`8
`
`IO'
`
`12
`
`:4
`
`TIME
`(HOURS)
`FIG.|
`DOSAGE FORM COMPONENTS
`
`AND TARGET DISSOLUTION
`
`

`

`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 carbamazepine. The blood levels
`of carbamazepine are within a therapeutic range re-
`quired for the treatment of epilepsy as well as other
`psychiatric, neurological and other disorders.
`7
`Carbamazepine is an iminostilbene 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 ug/ml to about 12 ug/ml of carbamaze-
`pine over a period of time. Blood levels of carbamaze-
`pine of less than 4 lag/ml have been found to be ineffec-
`tive in treating clinical disorders and blood levels
`greater than 12 ug/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
`Cmax/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
`0.8 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 butare 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 carbamazepine within thera-
`peutic range of from about 4 ug/ml to about 12 ug/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,
`transmucosal,
`transdermal,
`parenteral and preferably oral. Parenteral administra-
`tion would require an amount of carbamazepine of from
`about 100 mg to about 1000 mg per 12 hours. The dos-
`age forrns 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
`
`10
`
`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 ug/ml to about 12 ug/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-
`iod 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 carbamazepine, 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 carbamazepine.
`Since carbamazepine 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-
`
`

`

`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, hydroxypropylmethylcellulose
`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 1.0% (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), as 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
`
`3
`ate, polyoxyethylene sorbitan monooleate, glyceryl
`monostearate, glyceryl monooleate, glyceryl 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 due to mixing and de-mixing
`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 carboxymethylated starch,
`sodium carboxymethylated 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 carboxymethylcellulose (Ac-Di-Sol),
`cross-
`linked sodium carboxymethyl starch (Explotab, Primo-
`jel), cross-linked PVP (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
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`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-
`60 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-
`
`65
`
`

`

`5,326,570
`
`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.
`____________._—————-—-—-—-
`Pellet A: Immediate Release Comgnent
`Percent
`
`Kilograms
`
`ML.
`Microcrystalline Cellulose, N.F. (MCC)
`(Avicel PH-101/102, Emcocel, etc.)
`Hydroxypropylmethylcellulose (HPMC)
`(Methocel ESIESO/KS/KSO)
`‘ Croscarmellose, Type A, N.F.
`(Ac-Di-Sol)
`Sodium Lauryl Sulfate (81.5)
`Carbamazepine
`
`Total
`
`Example 2:
`MCC
`HPMC
`Sodium Starch Glycolate, N.F.
`(Explotab, Primojel)
`SLS
`Carbamazepine
`
`Total
`
`40.0
`
`2.5
`
`2.0
`
`0.1
`55.4
`100.0
`
`40.0
`5.0
`8.0
`
`0.3
`46.7
`100.0
`
`0.4
`
`0.025
`
`0.02
`
`0.001
`0.554
`1.000
`
`0.4
`0.05
`0.08
`
`0.003
`0.467
`1.000
`
`-continued
`
`Sodium bis-(2-ethylhexyl)sulfo-
`succinate (Aerosol OT)
`Carbamazepine
`
`MEL
`MCC
`HPMC
`Mono/Di/l‘ri-glyceride Mixture
`(Atmul-845)
`SLS
`Carbamazepine
`Exam 1e 10:
`MCC
`Polyvinylpyrrolidone (PVP)
`(Plasdone)
`Sodium Monoglycerate
`(MyvaPICX)
`SLS
`Carbamazepine
`
`Exam 1e 11:
`MCC
`HPMC
`Sodium Monoglycerate
`Tartaric Acid
`SLS
`Carbamazepine
`
`Coating:
`Ethacrylic/Methacrylic Acid Esters
`(Eudragit R5100)
`Ethacrylic/Methacrylic Acid Esters
`(Eudragit RLIOO)
`Propylene Glycol
`Talc
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1.5
`
`0.015
`
`Total
`
`__5_6_.0__
`100.0
`
`__0_5_6_Q
`1.000
`
`25.0
`5.0
`10.0
`
`0.25
`0.05
`0.1
`
`0.005
`0.5
`_25_ fl
`100.0
`1.000
`
`Total
`
`25.0
`8.0
`
`8.0
`
`0.35
`58.65
`100.0
`
`30.0
`5.0
`8.0
`5.0
`0.2
`51.8
`100.0
`
`45.0
`
`45.0
`
`9.0
`1.0
`100.0
`
`Total
`
`Total
`
`Total
`
`0.25
`0.08
`
`0.08
`
`0.0035
`0.5865
`1.0000
`
`0.3
`0.05
`0.08
`0.05
`0.002
`
`0.518
`1.000
`
`0.45
`
`0.45
`
`
`0.09
`0.01
`1.00
`
`Example 3:
`MCC
`Pre-gelatinized Starch
`(STARCH 1500, National 1551)
`Croscarmellose
`Corn Starch, U.S.P. (as paste)
`Dioctyl Sodium Sulfosuccinate (DDS)
`Carbamazepine
`
`Total
`
`Example 4:
`MCC
`MCC/Carboxymethyl Cellulose (CMC)
`(Avicel RC Grade)
`Croscarmellose
`SLS
`Carbamazepine
`
`Total
`
`20.0
`15.0
`
`5.0
`5.0
`0.5
`54.5
`100.0
`
`15.0
`15.0
`
`5.0
`0.5
`64.5
`100.0
`
`20.0
`3.0
`5.0
`8.0
`0.5
`63.5
`100.0
`
`10.0
`10.0
`5.0
`0.5
`74.5
`100.0
`
`25.0
`10.0
`
`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
`0.005
`0.635
`1.000
`
`0.10
`0.10
`0.05
`0.005
`0.745
`1.000
`
`0.25
`0.1
`
`0.002
`0.075
`0.573
`1.000
`
`0.30
`0.075
`0.05
`
`35
`
`92%.”;
`Same core pellet as in example 11
`Coating:
`HPMC (Methocel E50)
`Ethylcellulose (Ethocel)
`Polyethylene Glycol 400 (PEG400)
`
`45
`
`50
`
`55
`
`Example 13:
`Same core pellet as in example 11
`Coating:
`HPMC
`Ethylcellulose
`PEG400
`
`Example 14:
`MCC
`MCC/CMC Mixture
`Citric Acid
`DSS
`Carbamazepine
`
`Coating:
`HPMC (Methocel KSM)
`HPMC (Methocel E50)
`Ethylcellulose
`PEG400
`
`Exam le 15:
`Core pellet from example 14
`Coating from example 11
`Exam 1e 16:
`
`Core pellet from example 14
`Coating from example 12
`Exam 1e 16:
`
`65
`
`Core pellet from example 14
`Coating from example 13
`Example 17:
`MCC
`PVP
`Mono/Diffri-Glyceride Mixture
`
`45.0
`45.0
`10.0
`100.0
`
`20.0
`70.0
`10.0
`100.0
`
`15.0
`15.0
`6.0
`0.8
`63.2
`100.0
`
`10.0
`14.0
`66.0
`10.0
`100.0
`
`Total
`
`Total
`
`Total
`
`Total
`
`0.45
`0.45
`0.10
`100
`
`0.20
`0.70
`0.10
`1.00
`
`'
`
`0.15
`0.15
`0.06
`0.008
`0.632
`1.000
`
`0.10
`0.14
`0.66
`0.10
`1.00
`
`30.0
`8.0
`8.0
`
`0.3
`0.08
`0.08
`
`Example 5:
`MCC/CMC
`Croscarmellose
`Sodium Starch Glycolate
`HPMC
`DDS
`Carbamazepine
`
`Example 6:
`MCC
`MCC/CMC
`Croscarmellose
`DDS
`Carbamazepine _
`
`Example 7:
`MCC/CMC
`Polyacrylic Acid
`(Carbomer)
`SLS
`Sodium Starch Glycolate
`Carbamazepine
`
`Example 8:
`MCC
`HPMC
`Croscarmellose
`
`Total
`
`Total
`
`0.2
`7.5
`
`57.3
`100.0
`
`Total
`
`30.0
`7.5
`5.0
`
`

`

`5,326,570
`
`flk
`SLS
`0.3
`0.003
`7.5
`Tartan'c Acid
`0.075
`
`46.2
`Carbarnazepine
`_0;46_2
`100.0
`1.000
`
`Total
`
`Coating:
`Coating from example 11
`Exam le 18:
`Core pellet from example 17
`Coating from example 12
`Example 19:
`Core pellet from example 17
`Coating from example 13
`Core pellet from example 17
`Coating from example 14
`Pellet C: Delayed Release Comanent
`
`Exam le 21:
`Core Pellet:
` Percent Kilogram
`
`
`MCC
`25.0
`0.25
`Hydroxypropylmethylcellulose
`10.0
`0.10
`Phthalate (HPMCP)
`Tartaric Acid
`10.0
`0.10
`Sodium Monoglycerate
`7.5
`0.075
`0.5
`0.005
`DSS
`
`47.0
`0.470
`Carbamazepine
`100.0
`1.000
`
`Total
`
`Coating:
`Cellulose Acetate Phthalate (CAP)
`Ethylcellulose
`PEG400
`
`Exam 1e 22:
`Core pellet from example 21
`Coating:
`Ethacrylic/Methacrylic Acid Esters
`(Eudragit line of enteric polymers)
`Propylene Glycol
`Talc
`
`Exam 1e 23:
`Core pellet from example 21
`Coating:
`CAP
`HPMCP
`PEG 400
`PEG 8000
`
`Core Pellet:
`MCC
`Mono/Di/Triglyceride Mixture
`Tartan’c Acid
`CAP
`DSS
`Carbamazepine
`
`60.0
`0.60
`25.0
`0.25
`
`15.0
`0.15
`100.0
`1.00
`
`Total
`
`85.0
`
`0.85
`
`14.0
`0.14
`
`1.0
`0.01
`100.0
`1.00
`
`Total
`
`0.65
`65.0
`15.0
`0.15
`10.0
`0.10
`
`10.0
`0.10
`100.0
`1.00
`
`0.25
`25.0
`0.15
`15.0
`0.10
`10.0
`10.0
`0.10
`0.8
`0.8
`
`39.2
`0.392
`100.0
`1.000
`
`Total
`
`Total
`
`Coating as in example 21
`Exam le 25:
`
`Core pellet as in example 24
`Coating as in example 22
`Example 26:
`Core Pellet as in example 24
`Coating as in example 23
`Example 27:
`Core pellet as in example 24
`Coating:
`Shellac
`Mineral Oil
`51.5
`Talc
`
`0.85
`85.0
`13.0
`0.13
`0.5
`0.005
`
`1.5
`0.015
`100.0
`1.000
`
`Total
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Example 28:
`Core pellet as in example 21
`Coating as in example 27
`
`'
`
`65
`
`What is claimed is:
`
`8
`1. A drug delivery system for the oral administration
`of carbamazepine, comprising:
`(a) a sustained release unit containing carbamazepine;
`(b) an immediate release unit containing carbamaze-
`pine; and
`(c) an enteric release unit containing carbamazepine,
`said combination of components (a), (b), and (c)
`containing a therapeutically effective amount of
`carbamazepine.
`2. A method for treating a patient with carbamaze-
`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 claim 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 form.
`7. The system of claim 6 wherein the single dosage
`form is a capsule.
`8. The system of claim 1 wherein said system pro-
`vides a therapeutically effective amount over a 12 hour
`period.
`'
`9. The system of claim 1 wherein said system com-
`prising components (a), (b) and (c) contains carbamaze-
`pine in an amount from about 400 mg to about 600 mg.
`10. The system of claim 1 wherein the system pro-
`vides blood dosage levels of carbamazepine which do
`not vary by more than 60% over a 12 hour period.
`11. The system of claim 10 wherein the blood dosage
`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
`organic acid to maintain an acidic environment in the
`units.
`
`14. A system as in claim 12, wherein said surfactant is
`sodium lauryl sulfate.
`15. A system as in claim 1, wherein said sustained
`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 in an amount ranging from about 10.0% to about
`50.0% (w/w).
`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
`material in an amount ranging from about 1.0% to about
`15.0% (w/w).
`17. A system as in claim 1, wherein the carbamaze-
`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 carbamaze-
`pine comprising: orally administering to said patient a
`composition which contains,
`(a) an immediate release unit containing carbamaze-
`pine;
`(b) a sustained release unit containing carbamazepine;
`(c) an enteric release unit containing carbamazepine;
`said components (a), (b), and (c) containing a thera-
`peutically effective amount of carbamazepine.
`
`

`

`9
`19. A method as in claim 18, wherein said compo-
`nents (a), (b), (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 12 hours.
`20. A method as in claim 18, wherein the components
`being administered contain a combined amount of car-
`bamazepine of from about 400 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.
`3
`t
`t
`t
`I
`
`5,326,570
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`