_
`
`United States Patent [191
`Amidon et al.
`
`[54] PULSATILE DRUG DELIVERY SYSTEM
`
`[75] Inventors: Gordon L. Amidon; Glen D. Leesman,
`both of Ann Arbor, Mich.
`_
`_
`D
`_
`
`3
`
`_
`
`[7 ] Asslgnee‘ ?lilgirsny of Mlchlgan’ Ann Arbor’
`
`[21] Appl. No.: 771,895
`,
`[22] Filed:
`
`Oct‘ 7’ 1991
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 475,644, Feb. 5, 1990, aban- .
`cloned
`
`Illt. CLS .............................................. ..
`US. Cl. .................................. ..
`
`48
`
`424/ 473; 424/480
`Of Search ...................... .. 424/473, 451,
`.
`References cued
`U.$- PATENT DOCUMENTS
`4,773,907 9/1988 Urquhart ........................... .. 424/467
`
`[56]
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`
`USOO5229131A
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,229,131
`Jul. 20, 1993
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-D. Gabrielle Phelan
`Attorney’ Agent, or Firm_Rohm & Monsanto
`
`[57]
`
`ABSTRACT
`
`A drug delivery system for administering a drug in
`controlled pulse doses to an aqueous environment in the
`body of a living- being has one or more, and preferably
`less than ten, individual drug-containing subunits in a
`unitary drug depot, such as a tablet or capsule. The
`individual subunits are designed to dissolve at different
`sites and/or times in the gastrointestinal tract to release
`P111Se d°ses °f drug mm the P°m1 sys‘em 1", a“ “910'
`gous manner to the rate of release from an immediate
`release dosage form administered according to an ap
`propriate dosing sehedule The dissolution time of the
`subunits can be controlled by Several meth
`ods including the provision of pH-sensitive enteric coat
`ings and permeability-controlled cgatingg The drug
`delivery system has signi?cant advantages for the oral
`administration of ?rst-pass metabolized drugs which
`exhibit a non-linear relationship between input rate of
`the drug into the Portad System and bioa"aila‘bility
`
`
`
`4,777,049 10/1988 Magruder 4,783,337 8/1988 Wong ................................ .. 424/468
`
`18 Claims, 5 Drawing Sheets
`
`.
`IN VIVO DOG STUDY
`80 MG 19 PLUS 80 MG PULSE DOSE
`
`20o -
`
`10o -
`
`so -
`
`CONCENTRATION 2° ‘
`lng/ml)
`1o
`
`2
`
`0
`
`I
`
`2
`
`I
`
`4
`
`I
`
`I
`
`T
`
`10
`8
`5
`TIME (HOLES)
`
`I
`
`i2
`
`I
`
`14
`
`Page 1
`
`SHIRE EX. 2006
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`US. Patent
`
`July 20, 1993
`
`Sheet 1 of 5
`
`5,229,131
`
`FIG '
`
`1
`
`RESPONSE SURFACE
`EROSION OEPENOENT SYSTEM
`
`m .M m Tl m @
`
`TEMPERATURE (DEB K)
`
`FIG' 2
`
`,
`IN VIVO DOG STUDY,
`80 HS IR PLUS 80 MG PULSE DOSE
`
`FIG.
`
`3
`
`TIME (HOURS)
`
`RESPONSE SURFACE
`PERMEABILITY CONTROLLED SYSTEM
`
`Page 2
`
`

`

`US. Patent
`
`July 20, 1993
`
`Sheet 2 of 5
`
`5,229,131
`
`FIG. 4
`
`D06 #1
`
`<-~ E i
`E ;
`
`+
`.++ + + '
`
`'I1
`
`'1‘
`
`El
`
`E
`+ %
`
`w
`
`+
`
`i
`
`+
`
`+ +
`
`+
`
`+
`
`102Mé
`
`PLASMA
`cons.
`(NB/ML)
`
`j
`
`'
`
`101';
`E
`
`-
`
`I
`
`100
`
`I
`
`200
`
`I
`
`I
`
`400
`300
`TIME (MIN)
`
`I
`
`500
`
`I
`
`500
`
`I
`
`700
`
`F I 6. 8
`
`0m
`
`cm
`
`E73:
`6:
`5
`pH 4
`
`3
`
`2_
`1-1
`
`GET
`
`_
`
`250
`
`260
`TIME (MIN)
`
`zéq
`
`360
`
`Page 3
`
`

`

`US. Patent
`
`July 20, 1993
`
`Sheet 3 of 5
`
`5,229,131
`
`FIG. 5
`
`2-
`10 5E.
`
`— E4
`_
`E‘
`_
`'5‘ E1 E1
`
`DOG #2
`.
`
`PLASMA
`couc.
`(NB/ML)
`
`1
`
`101-:
`:
`I
`
`5*
`E? §r+ ++++ +
`+ +% i
`%
`
`+
`
`+
`
`+
`
`1
`
`100
`
`I
`
`200
`
`I
`
`I
`
`400
`300
`TIME (MIN)
`
`|
`
`500
`
`I
`
`600
`
`I
`
`700
`
`FIG. 9
`
`um
`
`BE 7_
`g-
`n 4‘
`p 3'
`2: GET
`1'
`
`cm
`
`1%5
`
`26o
`
`2é5
`TIME (MIN)
`
`250
`
`2%
`
`Page 4
`
`

`

`US. Patent
`
`July 20, 1993
`
`Sheet 4 of 5
`
`5,229,131
`
`FIG. 6
`
`876543211
`
`
`
`__-__ -____
`
`GET
`
`CDT
`
`TIME (MIN)
`
`FIG. 10
`
`DDT
`
`TIME (MIN)
`
`Page 5
`
`

`

`US. Patent
`
`July 20, 1993
`
`Sheet 5 of 5
`
`5,229,131
`
`F I G . 7
`
`D06 #4
`
`++
`+
`+_ +
`
`% %
`
`+ +
`
`102-2-
`:
`#
`_
`
`l
`
`PLASMA
`CONE .
`(NB/ML)
`
`I
`
`I
`
`400
`300
`TIME (MIN)
`
`T
`
`500
`
`I
`
`500
`
`I
`
`700
`
`F I G .
`
`1 1
`
`GET
`
`DDT
`
`I
`
`‘D I
`
`8 I
`7 -l
`
`6 an
`
`5 -
`4
`
`3
`2
`I
`
`210
`
`150
`TIME (MIN)
`
`250
`
`Page 6
`
`

`

`1
`
`5,229,131
`
`PULSATILE DRUG DELIVERY SYSTEM
`
`This invention was sponsored, in part, by the Depart
`ment of Health and Human Services under Small Busi
`ness Innovation Research Program Grant No. 1 R43
`GM 37856-01, and therefore, the government of the
`United States of America may have certain rights in this
`invention.
`This application is a continuation of application Ser.
`No. 07/475,644 ?led Feb. 5, 1990, now abandoned.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`2
`minimize the effect of the release rate on the bioavaila
`bility.
`Propranolol is a ?rst-pass metabolized drug which
`exhibits non-linearity, or dose dependent bioavailability
`in the normal therapeutic dosage range. Propranolol
`hydrochloride, which is available commercially from
`Ayerst Laboratories, New York, N.Y. under the trade
`mark INDERAL, was the ?rst beta-adrenergic block
`ing agent to have widespread clinical usage in treating
`angina and hypertension. The biological half-life of
`propranolol in man is between two to six hours, and the
`dosage range is from about 40 to 2000 mg/day typically
`administered in two to four divided doses.
`In order to extend the dosing interval, a controlled
`release form of propranolol was developed and sold by
`Ayerst Laboratories under the trademark INDERAL
`LA. However, reports indicate that INDERAL-LA
`performs unsatisfactorily with respect to bioavailability.
`Although blood levels of propranolol are sustained for
`a period of 24 hours, the bioavailability is compromised
`by about 50% as compared to the immediate release
`dosage form administered in divided doses. It has been
`determined that such differences in bioavailability are
`caused by a higher degree of metabolism on ?rst-pass
`through the liver for the lower release rate, and not
`incomplete absorption. Since patients on beta-adrener
`gic blockers are titrated to a particular dosage level
`given in divided doses, the bene?t of once-a-day ther
`apy is offset by possible changes in dosage needed to
`achieve ef?cacy.
`It is evident from the foregoing that drugs which are
`eliminated by metabolism and exhibit a non-linear ?rst
`pass effect will have drug-to-metabolite level ratios
`which are dose rate dependent. Consequently, the kinet
`ics of the parent compound and the metabolite are al
`tered by dose rate leading to potentially different clini
`cal responses to the drug. Propranolol, for example, has
`a bioavailability which varies from 20% to 80% due to
`dose rate differences. These differences were observed
`in humans where, for example, the bioavailability of a
`controlled release form of propranolol was 60% that of
`the immediate release dosage form, and the peak plasma
`levels were three-fold lower with the controlled release
`form leading to potential reduced clinical ef?cacy. As a
`result of these de?ciencies, INDERAL-LA was re~
`quired to be the subject of clinical studies to establish
`ef?cacy.
`In addition to propranolol, other highly metabolized
`therapeutic agents are suitable for use with the drug
`dosage delivery system of the present invention. Some
`commercially available ones of such agents include
`other beta-adrenergic blockers such as metoprolol and
`timolol, calcium channel blockers such as verapamil,
`diltiazem and the anti-epileptic drug phenytoin. Given
`the large number of drugs which are eliminated by
`metabolism, there is a great need for an oral dosage
`form which reduces the relative extent of metabolism.
`There are several signi?cant goals which are desired
`to be realized with the use of a pulsed drug dosage
`delivery system which delivers doses of a drug at inter
`vals timed to correspond to the administration of a
`plurality of immediate release doses at predetermined
`intervals. These include realization of: plasma level time
`curves equivalent to the immediate release dosage form;
`clinical efficacy, established through bioavailability,
`equivalent to the immediate release dosage form; in
`crease in patient compliance as a result of a reduced or
`simpli?ed dosing schedule; pharmacodynamic equiva
`
`BACKGROUND OF THE INVENTION
`This invention relates generally to drug delivery
`systems, and more particularly, to a controlled release
`drug delivery system which is particularly suited for use
`with ?rst-pass metabolized drugs and which delivers
`pulsed doses at predetermined time intervals to achieve
`a bioavailability which is equivalent to immediate re
`lease dosage forms administered in divided doses.
`A known approach toward effecting the controlled
`release of orally administered drugs endeavors to
`achieve a zero order release pro?le whereby a substan
`tially constant plasma level of the drug is maintained
`over a predetermined period of time. Although this
`known approach is suitable for many drugs, it is bur
`dened with several signi?cant disadvantages, and there
`fore is inappropriate particularly when used with ?rst
`pass metabolized drugs and others which are character
`ized by idiosyncratic pharmacokinetics or pharmacody
`namics resulting in reduced bioavailability, altered
`drug-to-metabolite ratios, altered steady state levels of
`drug and metabolite, potential food-drug interactions,
`and altered pharmacodynamic response.
`Strategies for reducing the dosing interval of orally
`administered drugs typically rely on changing the re
`lease pattern of the drug from a delivery system, or
`dosage form, such that the blood level pro?le of the
`drug falls within the therapeutic window of the dosing
`interval. Factoring into this strategy are the pharmaco
`kinetics of the drug and the absorption rate of the drug
`in the gastrointestinal tract at the site of, and at the time
`when, the drug is released from the dosage form. The
`bene?ts of extended release delivery systems include a
`decrease in the frequency of dosing and a reduction in
`45
`the variability of plasma levels of the administered drug
`over an immediate release dosage form.
`In the case of drugs which do not exhibit ?rst pass
`metabolism, the relationship between the extent of ab
`sorption and the bioavailability is linear. Accordingly,
`changes in bioavailability can be attributed to changes
`in the extent of absorption. However, in the case of
`drugs which exhibit ?rst-pass metabolism, the relation
`ship between extent of absorption (or input rate of drug
`into the portal system) and bioavailability is nonlinear,
`thereby leading to reduced bioavailability when drugs
`are administered at very low rates into the gastrointesti
`nal tract.
`There is therefore a need for a drug delivery system
`which yields a reduction in the oral dosing interval of
`60
`drugs exhibiting ?rst-pass metabolism while simulta
`neously maintaining bioavailability equivalent to the
`immediate release dosage form.
`In conventional sustained release dosage forms, the
`bioavailability is compromised by the decreasing release
`rate. There is therefore a need for a drug dosage deliv
`ery system which will release fractions of the total dose
`at speci?ed times and sites in the GI tract, and thereby
`
`50
`
`55
`
`65
`
`Page 7
`
`

`

`20
`
`5,229,131
`3
`lence to that of the immediate release dosage form;
`metabolic rate equivalence to that obtained by conven
`tional dosing schedules so that no unusual accumulation
`of metabolites or altered metabolic pro?le will result;
`accurate programmability of the pulse delay and deter
`mination of the fraction of the total dose at each pulse to
`achieve a variety of predeterminable dosing schedules
`and permit allowance for circadian rhythms to optimize
`plasma level time pro?les throughout the day and night;
`and oral delivery of drugs which undergo particularly
`extensive ?rst-pass metabolism (both gastro-intestinal
`and hepatic).
`In order to accomplish these objectives with a con
`trolled release dosage form, the dosage form must be
`reproducible, precise, and programmable. However, as
`a result of the complexity of developing such a system,
`there is not presently available a drug dosage delivery
`system of this type. In fact, at the present time, the '
`operating principles of available controlled release dos
`age forms for oral delivery are based on relatively sim
`ple transport models which do not take into account
`many of the critical factors required to achieve repro
`ducibility and precise programming, such as the physi
`cal properties of enteric coating ?lms, including water
`diffusion into and plasticizer diffusion out of the poly
`meric coating ?lms, and the consequent time dependent
`changes in the diffusion coef?cient and permeability of
`the coating; and the time dependent mechanical proper
`ties of the coating and its polymer-plasticizer combina
`tion such as modulus of elasticity, tensile strength, type
`of failure (brittle, ductile, necking) or critical strain at
`failure. In addition, the composition of the core and the
`conditions under which the coatings are applied to the
`core can signi?cantly alter the time rate of change of
`the properties of the coating. Such core variables as
`osmotic pressure inducing agents, viscosity inducing
`agents, disintegrants and the presence or absence of
`lipid materials can in?uence the swelling rate of the
`core and therefore the time for failure of the coating.
`It is, therefore, an object of this invention to provide
`a drug delivery system for ?rst-pass metabolized drugs,
`or other drugs wherein the relationship between extent
`of absorption and bioavailability is nonlinear, which
`drug delivery system will have bioavailability equiva
`lent to the immediate release dosage form administered
`in divided doses.
`It is another object of this invention to provide a drug
`delivery system which reduces oral dosing intervals for
`?rst-pass metabolized drugs, and hence improves pa
`tient compliance, while maintaining bioavailability
`equivalent to the immediate release dosage form admin
`istered in divided doses.
`It is also an object of this invention to provide a drug
`delivery system for ?rst-pass metabolized drugs which
`maintains higher plasma levels of drug, and reduces
`variability in the plasma levels, than currently available
`controlled release dosage forms.
`It is a further object of this invention to provide a
`drug delivery system for ?rst-pass metabolized drugs
`which will release an individual dose of drug at speci
`?ed sites and time in the gastro-intestinal tract so that
`bioavailability will not be compromised by the de
`creased release rate of conventional controlled or sus
`tained release dosage forms.
`It is additionally an object of this invention to provide
`a drug delivery system which will provide pulse doses
`of drugs at precise and reproducible times which corre
`spond to immediate release dosing intervals.
`
`4
`It is yet a further object of this invention to provide a
`drug delivery system which permits efficacious oral
`delivery of nonlinear ?rst-pass drugs of the type which
`are extensively metabolized both gastro-intestinally and
`hepatically.
`It is yet an additional object of this invention to pro
`vide a drug delivery system wherein the delivery rate
`into the portal system is increased, with a correspond
`ing decrease in ?rst pass metabolism.
`It is also another object of this invention to provide a
`method for making a drug delivery device which reli
`ably and precisely programs delivery of pulse doses of
`drug.
`'
`It is a yet further object of this invention to provide a
`drug delivery system which facilitates accommodation
`for circadian rhythms in order to optimize plasma level
`time pro?les throughout the day and night.
`It is still another object of this invention to provide a
`method of making a drug delivery system wherein opti
`mal dosing schedules for two, or more drugs, can be
`achieved by tailoring pulse delivery of each drug to its
`individual pharmacokinetic and pharmacodynamic
`properties.
`It is also a further object of this invention to provide
`a drug delivery system which yields a reduction in the
`oral dosing interval of drugs exhibiting ?rst-pass metab
`olism while simultaneously maintaining bioavailability
`equivalent to the immediate release dosage form.
`A still further object of this invention is to provide a
`drug delivery system for oral administration of a drug
`which reduces the relative extent of metabolism of the
`administered drug.
`
`SUMMARY OF THE INVENTION
`The foregoing and other objects are achieved by this
`invention which provides, in a system aspect thereof, a
`drug delivery system for administering a drug in con
`trolled pulse doses in an aqueous environment in the
`body of a living being, over a predetermined dosage
`period of time. In accordance with this aspect of the
`invention, a unitary body, which is con?gured for ad
`ministration to the body of the living being, contains a
`plurality of subunits. Each of the subunits has a core
`portion which contains an individual dose of the drug.
`The core is surrounded by a respectively associated
`coating portion which is formed of a selectable one of
`?rst and second polymer materials, in a speci?c embodi
`ment of the invention. The coating portion is arranged
`to surround the core portion impermeably, with respect
`to the drug contained therein. Ones of the coating por
`tions formed of the ?rst polymer material are character
`ized by a respective predetermined period of core pro
`tection time which is different from that of the second
`polymer material. During the core protection time,
`release of the drug from its associated core portion is
`prevented after communication with the aqueous envi
`ronment. Moreover, the period of core protection time
`is shorter than the predeterminable dosage time period.
`In one embodiment of the invention, the ?rst and
`second polymer materials are each formed of respective
`water-permeable polymers having respective tensile
`strengths and maximum elongations, such that the cohe
`sive strength of the associated coating portions is ex
`ceeded after the respective predetermined periods of
`insolubility. In this manner, water which is obtained
`from the aqueous environment penetrates the coating
`portions and travels in an inward direction so as to
`create a pressurizing force in the core portion which ~
`
`25
`
`35
`
`45
`
`50
`
`55
`
`65
`
`Page 8
`
`

`

`20
`
`5,229,131
`5
`causes the coating portion to rupture after expiration of
`the core protection time period. Thus, release of the
`drug to the aqueous environment is effected.
`In a speci?c illustrative embodiment of the invention,
`the water-permeable polymer is cellulose acetate. Alter
`natively, the water-permeable polymer is selected from
`the group of water-permeable polymers consisting of
`cellulose acetate, ethyl acetate latexes, ethyl cellulose,
`cellulose butyrate, and Eudragit RS and Eudragit R 30
`D (available from Rohm Pharma, W. Germany). In
`addition, there may be provided, in certain embodi
`ments, a plasticizer, which is selected from the group of
`polyethylene glycol (PEG 200, PEG 1000), diethyl
`phthalate, and dibutyl phthalate.
`In addition to a drug, or other therapeutic or diagnos
`tic agent, viscosity enhancers, disintegrants, and other
`excipients may also be provided in the core portion.
`In another speci?c embodiment of the invention, the
`aqueous environment has predetermined pH character
`istics which cooperate with the coating portion which is
`provided with ?rst and second polymer materials which
`are each pH-responsive. The pH-responsive polymer
`_ materials are soluble in the aqueous environment in
`response to the pH characteristic of the environment
`over a predetermined pI-I-responsive period of solubil
`ity to release drug to the environment. In such an em
`bodiment, the pH-responsive material is selected from
`the group consisting of cellulose acetate phthalate,
`methyl cellulose phthalate, hydroxyethyl cellulose,
`cellulose acetate tetrahydrophthalate, cellulose acetate
`hexahydrophthalate, methyl-methacrylate, methacrylic
`acid and combinations thereof. Additionally, the pH
`responsive material may be formed from a layered com
`bination of cellulose acetate phthalate and a mixture of
`methyl-methacrylate and methylacrylic acid.
`35
`In the practice of the invention, the unitary body may
`be configured as a capsule, or as a tablet, and may con
`tain illustratively ten subunits therein. Additionally, the
`drug to be administered may be a ?rst-pass metabolized
`drug, which may, for example, be propranolol.
`In accordance with a method aspect, the invention
`prdvides a method of producing a drug delivery device
`for administering a drug over a predetermined period of
`time to an aqueous region in the body of a living being.
`The method includes the steps of: forming ?rst and
`second core units, each core unit containing a predeter
`mined dosage of the drug; applying a ?rst-type protec
`tive coating to the ?rst core unit; and applying a second
`type protective coating to the second core unit, the
`?rst-type and second-type protective coatings being
`formed of respective polymeric materials having differ
`ent protective aspects from one another, whereby their
`respectively associated core units are exposed to the
`aqueous region after different periods of exposure
`thereto.
`In accordance with a further method aspect, the in
`vention provides a method of making a drug delivery
`device for administering drugs in a controlled dose at a
`time T,, to an aqueous living body environment. This
`method aspect includes the steps of: forming a drug
`containing core; coating the drug-containing core with
`a pH-sensitive polymeric material dissolved in a sol
`vent, the pH-sensitive material being of the type which
`will dissolve in response to the pH of the aqueous living
`body environment, the pH-sensitive polymeric material
`comprising a weight percentage E of the solution; and
`curing the coating at a temperature T for a given time
`period, Tp being described by the equation:
`
`BRIEF DESCRIPTION OF THE DRAWING
`Comprehension of the invention is facilitated by read
`ing the following detailed description, in conjunction
`with the annexed drawing, in which:
`FIG. 1 is a response surface plot for a drug delivery
`system of the present invention of a pH-sensitive em
`bodiment showing pulse time (Tp) as a function of per
`cent enteric coating and curing temperature;
`FIG. 2 is a graphical depiction of plasma level time
`curves for the oral administration of propranolol in a
`drug delivery system of the present invention for two
`dogs;
`FIG. 3 is a response surface plot for a permeability
`controlled embodiment of a drug delivery system of the
`present invention showing pulse time (Tp) as a function
`of percent viscosity enhancer (NaCMC) in a drug-con
`taining core and percent plasticizer (PEG 200) in a
`coating formulation;
`FIGS. 4, 5, 6 and 7 are graphical plots of plasma level
`time curves for respective individual dogs representing
`the amount of free propranolol in blood specimens
`(ng/ml) over time (minutes) following administration of
`propranolol by IV and orally in an immediate release
`form (INDERAL 80mg) and a permeability-controlled
`drug delivery system embodiment of the present inven
`tion; and
`FIGS. 8, 9, 10 and 11 are tracings of the pH-time
`profile in the gastrointestinal tract of the respective
`individual dogs (FIGS. 4 to 7) after administration of
`the permeability-controlled drug delivery system of the
`present invention.
`
`45
`
`50
`
`55
`
`where T is in K.
`In a still further method aspect of the invention, a
`method of making a drug delivery device for adminis
`tering drugs in a controlled dose at a time Tp to an
`aqueous living body environment is provided with the
`steps of: forming a drug-containing core, the core con
`taining a viscosity enhancing agent in concentration N;
`coating the drug-containing core with at least one poly
`meric material of the type which is water-permeable to
`permit water from the aqueous living body environ
`ment to penetrate the drug-containing core at a con
`trolled rate in an inward direction, for creating a pres
`sure which causes the coating to rupture at the prede
`’ termined release‘time, thereby releasing the drug to the
`aqueous environment at time Tp, the coating further
`containing a plasticizer in concentration P; and curing
`the coating at a temperature for a given time period, Tp
`being described by the equation:
`
`25
`
`DETAILED DESCRIPTION
`The drug delivery system, or dosage form, of the
`present invention has one or more, preferably less than
`10, individual drug-containing units (also referred to
`herein as “subunits”) in a unitary drug depot which
`dissolve at different sites and/or times in the gastroin
`testinal tract to release “pulse doses.” The drug delivery
`system of the present invention is an extended interval
`dosage form as compared to a conventional sustained
`release dosage form which provides a slow, steady
`release of drug over a long period of time. The term
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`7
`pulse dose is used herein to describe the rapid delivery
`of a dose of drug (F1, F2, . . . , F,,) at speci?c respective
`times (T1, T2, . . . , T,,) into the portal system which is
`analogous to the rate of release from an immediate re
`lease dosage form administered according to an appro
`priate dosing schedule.
`This drug delivery system has signi?cant advantages
`for the oral administration of ?rst-pass metabolized
`drugs which exhibit a non-linear relationship between
`input rate of the drug into the portal system and bi
`oavailability. By devising a drug dosage delivery form
`which will release pulsed doses at rates comparable to
`immediate release forms, bioavailability will not be
`compromised by a decreased release rate as has been
`observed in conventional sustained release dosage
`forms for these drugs (e.g., INDERAL-LA).
`The dissolution time of the individual subunits can be
`controlled by several methods to be discussed hereinbe
`low. Two illustrative means of controlling dissolution
`are (1) pH-sensitive enteric coatings which are eroded
`in response to the pH of the aqueous environment in the
`gastrointestinal tract and (2) permeability-controlled
`systems which are subject to disruption in response to
`absorption of water from the environment which cre
`ates a pressure as the core contents expand. Variation of 25
`process variables and coating and core compositions, in
`manners to be discussed hereinbelow, enables precise
`tailoring of the dissolution, or pulse, time of the individ
`ual unit cores. The individual units are combined into a
`unitary depot which may be single tablet or a gelatin
`capsule or any other form known in the art.
`Illustratively, a two unit system may comprise an
`immediate release form (uncoated in some embodi
`ments) and a polymeric coated form which would dis
`solve 6 to 12 hours later to provide a second dose of 35
`drug. A three unit system, for example, could provide
`an immediate release form, a 4-12 hour release form,
`and an 8-16 hour release form. The subunits may be
`combined into a single unitary body, such as a tablet or
`hard gelatin capsule, in any manner known in the art. Of 40
`course, these examples are only illustrative of the many
`speci?c embodiments which can be devised in accor
`dance with the principles of the invention depending
`upon the desired dosing schedule of any particular
`drug.
`
`10
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`15
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`30
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`45
`
`Erosion-Dependent Systems
`Enteric coatings of pH-sensitive polymers are em
`ployed to control the time of delivery of a drug-contain
`ing core composition to the small intestine of a living
`mammal.
`Characteristics of suitable enteric coatings include:
`insolubility in the stomach, solubility in the intestines,
`no toxicity, moisture permeability resistance, stability,
`and good coating capability. A widely used enteric
`coating, and one which is used in the examples set forth
`herein, is cellulose acetate phthalate. Other well known
`cellulose ethers and ether derivatives including methyl
`cellulose phthalate, hydroxyethylcellulose phthalate,
`cellulose acetate tetrahydrophthalate, and cellulose
`acetate hexahydrophthalate, are among the many poly
`meric materials which could be employed in the prac
`tice of the invention.
`In illustrative embodiments, cellulose acetate phthal
`ate (CAP) and/or methyl-methacrylate/methacrylic
`acid are suitable materials for the enteric coatings con
`templated by the invention. These coatings delay re
`lease of the drug until the dosage form has passed from
`
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`65
`
`5,229,131 .
`
`8
`the stomach to the small intestine. In particular, the
`methyl-methacrylate/methacrylic acid coatings dis
`solve at a higher pH than CAP and are capable of ex
`tending the time of dissolution to four to eight hours in
`vitro in simulated intestinal ?uid of pH 6.8. Methyl
`methacrylate is sold commercially by Rohm Pharma,
`W. Germany under the trademark Eudragit S100 and
`methacrylic acid is sold under the trademark Eudragit
`L100.
`Although the core composition may comprise any
`drug, combination of drugs and therapeutic agents,
`including excipients and pharmacologically inert ?llers
`as are known in the art, the invention is particularly
`suited to first-pass metabolized drugs which are not
`readily adaptable to conventional controlled release
`dosage forms. The examples herein are directed to the
`beta-adrenergic blocking agent propranolol as an exem
`plary ?rst-pass metabolized drug. However, it is to be
`understood that any other drug or therapeutic/diagnos
`tic agent can be formulated into the drug delivery sys
`tem of the present invention. Moreover, more than one
`drug can be simultaneously administered in the dosage
`form of the present invention and each subunit, or pulse
`dose, can be tailored to compensate for the individual
`pharrnacokinetics and phannacodynamics of each.
`Core Composition for Erosion-Dependent
`Embodiment
`An illustrative core formulation for administration of
`propranolol is as follows:
`
`Propranolol HCl
`Citric acid, anhydrous
`Avicel PH 102
`AcDiSol
`Lactose qs
`
`20 mg
`60 mg
`120 mg
`.12 mg
`300 mg
`
`Avicel pH 102 (a form of microcrystalline cellulose
`distributed by FMC Corporation, Philadelphia, Pa.) and
`AcDiSo] (FMC Corporation, Philadelphia, Pa) are dis
`integrants. Lactose is an inert ?ller which, in certain
`permeability-controlled embodiments, affects the os
`motic pressure. All components will affect the pulse
`time (T p)- In this particular formulation, citric acid has
`been added for the purpose of creating a drastic pH
`change upon release of the core contents to facilitate
`tracking by a Heidelberg capsule in the in vivo studies.
`In this particular embodiment, the unit cores were
`compressed on a Carver Press with a 2th inch die and
`deep-cut concave punches, at a pressure of 1600 psi for
`60 seconds. Of course, other pressures and dwell times
`may be employed in the practice of the invention.
`Changes to the pressure and dwell time may affect the
`hardness and disintegration time of the unit core. An
`illustrative, and preferred, range for pressure is from
`about 500-3000 psi and for dwell time is from about
`10-120 seconds. It is to be understood that any tech
`nique or device, conventional or otherwise, for produc
`ing compressed tablets may be employed in the fabrica
`tion of the individual unit cores and/or drug delivery
`system from a plurality of such unit cores. Another
`exemplary method is by use of a conventional rotary
`tablet press.
`The unit cores are next coated with a solution of the
`desired coating polymer(s) in a solvent. The solvent
`may be organic, such as acetone, or in some embodi
`ments, aqueous. Suitable machinery for coating include
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`5,229,131
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`10
`TABLE 2
`
`a rotating pan apparatus with a Sigma glass spray unit,
`a Uni-Glatt suspension coater or any other known ?uid
`ized bed equipment or pan coating technique typically
`used in the pharmaceutical industry. Next, the coated
`unit core is dried or cured for a predetermined time
`period at a predetermined temperature. The process
`variables, including spray rate, spray distance, atomiza
`tion pressure, drying temperature and rate, and pan
`rotation speed, may effect the physical and mechanical
`properties of polymer coated drug cores.
`Coating Formulations For Erosion-Dependent
`Embodiment
`
`In an advantageous embodiment, the unit cores de
`scribed hereinabove were pre-coated with a 3% ?lm of
`CAP in order to reduce water permeability of a subse
`quently deposited coating of 5% Eudragit(s). This was
`necessary since the Eudragits were observed to immedi
`ately fail in simulated gastric ?uid (pH 1.2).
`Illustrative formulas for Eudragit and CAP coatings
`are as follows:
`
`s
`
`Eudragit Coating Formula;
`Eudragit L100
`Eudragit S100
`Polyethyl