(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0157173 A1
`(43) Pub. Date:
`Aug. 21, 2003
`Percel et al.
`
`US 2003O157173A1
`
`(54) TIMED, SUSTAINED RELEASE SYSTEMS
`FOR PROPRANOLOL
`(76) Inventors: Phillip J. Percel, Troy, OH (US);
`Krishna S. Vishnupad, Dayton, OH
`(US); Gopi M. Venkatesh, Vandalia,
`OH (US)
`Correspondence Address:
`THOMPSON HINE L.L.P.
`2000 COURTHOUSE PLAZA, N.E.
`10 WEST SECOND STREET
`DAYTON, OH 45402 (US)
`(21) Appl. No.:
`10/334,052
`(22) Filed:
`Dec. 30, 2002
`Related U.S. Application Data
`(63) Continuation of application No. 09/971,167, filed on
`Oct. 4, 2001, now Pat. No. 6,500,454.
`
`Publication Classification
`
`(51) Int. Cl." ....................................................... A61K 9/24
`(52) U.S. Cl. .............................................................. 424/473
`
`
`
`(57)
`
`ABSTRACT
`
`A unit dosage form, Such as a capsule or the like for
`delivering drugs into the body in a circadian release fashion,
`is comprising of one or more populations of propranolol
`containing particles (beads, pellets, granules, etc.). Each
`bead population exhibits a pre-designed rapid or Sustained
`release profile with or without a predetermined lag time of
`3 to 5 hours. Such a circadian rhythm release cardiovascular
`drug delivery System is designed to provide a plasma
`concentration-time profile, which varies according to
`physiological need during the day, i.e., mimicking the cir
`cadian rhythm and Severity/manifestation of a cardiovascu
`lar disease, predicted based on pharmaco-kinetic and phar
`maco-dynamic considerations and in vitro/in vivo
`correlations.
`
`Page 1
`
`SHIRE EX. 2050
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`Patent Application Publication Aug. 21, 2003 Sheet 1 of 2
`
`US 2003/0157173 A1
`
`Serum Levels of Propranolol after 8:00 PM daily dose of Propranolol Hydrochloride
`MTSR Capsules, 160 mg (Simulated) and Systolic Blood Pressure
`
`w
`
`50
`
`|
`
`45 |
`
`4 O
`
`--
`
`35 |
`
`3 O --
`
`25
`
`20
`
`-- 170
`
`--
`
`8 O
`
`--1 50
`
`| 1.
`
`s
`
`11
`
`1 s - -
`2
`
`3
`
`4.
`
`8
`
`B
`
`-
`9
`
`-- -
`-
`h
`5 1 6 18 20 21 22 24
`1 2 14
`1 0
`Time hours )
`Serum Levels of Pro p r a no lo -O-Sys to lic Blood Pressure
`
`-
`
`-
`
`O O
`
`Fig. 1
`
`Page 2
`
`

`

`Patent Application Publication Aug. 21, 2003 Sheet 2 of 2
`
`US 2003/0157173 A1
`
`Propranolol HCl TSR Capsules, 160 mg vs. Inderal LA 160 mg
`
`140 - -run-immorum.rumour-mour.no
`
`100 - ||
`
`--
`
`80
`
`f
`
`60 - -
`
`
`
`-- TSR 160
`
`-A Inderal
`160 mg
`
`2 4 6 8 10 2 14 16 18 20 22 24
`ours post dose
`
`Fig. 2
`
`Page 3
`
`

`

`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`TIMED, SUSTAINED RELEASE SYSTEMS FOR
`PROPRANOLOL
`
`TECHNICAL FIELD
`0001. A major objective of chronotherapy for cardiovas
`cular diseases is to deliver the drug in higher concentrations
`during the time of greatest need, typically during the early
`morning hours, and in lesser concentrations when the need
`is less, Such as during the late evening and early Sleep hours.
`This can be accomplished by administration of the release
`dosage form of the present invention, which relates to a
`controlled absorption of propranolol from dosage forms. In
`particular, the present invention relates to a unit dosage form
`of an assembly of one or more bead populations, each of
`which is designed to release one or more therapeutic agents
`as a rapid or Sustained release pulse after a predetermined
`delay (“time-controlled” drug delivery instead of “rate
`controlled”) with resulting plasma concentration(s) of pro
`pranolol varying in a circadian rhythm fashion following
`administration of a single dosage form at bedtime, thereby
`minimizing potential risks of a stroke and/or heart attack and
`enhancing patient compliance and therapeutic efficacy,
`while reducing cost of treatment.
`
`BACKGROUND OF THE INVENTION
`0002 Many therapeutic agents are most effective when
`made available at a constant rate at or near the absorption
`Site. The absorption of therapeutic agents thus made avail
`able generally results in desired plasma concentrations lead
`ing to maximum efficacy and minimum toxic side effects.
`Much effort has been devoted to developing Sophisticated
`drug delivery Systems, Such as OSmotic devices, for oral
`application. However, there are instances where maintaining
`a constant blood level of a drug is not desirable. For
`example, a "position-controlled” drug delivery System (e.g.,
`treatment of colon disease or use of colon as an absorption
`Site for peptide and protein based products) may prove to be
`more efficacious. A pulsatile delivery System is capable of
`providing one or more immediate release pulses at prede
`termined time points after a controlled lag time or at Specific
`Sites. However, there are only a few Such orally applicable
`pulsatile release Systems due to the potential limitation of
`the Size or materials used for dosage forms. Ishino et al.
`disclose a dry-coated tablet form in Chemical Pharm. Bull.
`Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851,229 to
`Magruder et al., U.S. Pat. No. 5,011,692 to Fujioka et al.,
`U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No.
`5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to
`Bai disclose preparation of pulsatile release Systems. Some
`other devices are disclosed in U.S. Pat. No. 4,871,549 to
`Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and
`5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441
`both to Chen disclose a pulsatile release System consisting of
`pellets coated with delayed release or water insoluble poly
`meric membranes incorporating hydrophobic water
`insoluble agents or enteric polymers to alter membrane
`permeability. U.S. Pat. No. 5,837.284 to Mehta et al. dis
`closes a dosage form which provides an immediate release
`dose of methylphenidate upon oral administration, followed
`by one or more additional doses spread over Several hours.
`0003. The incidence of many cardiovascular diseases
`varies predictably in time over 24 hours, i.e., in a circadian
`rhythm fashion (See, e.g., Y. A. Anwar and W. B. White,
`
`Chronotherapeutics for Cardiovascular Disease, Drugs
`1998, 55, pp 631-643, which is incorporated herein by
`reference). For example, a rapid increase in both acute
`myocardial infarction and Systolic blood preSSure has been
`reported in the well controlled Studies on actual patients. In
`Such cases, administration of a different kind of unit dosage
`form which delivers the drug in higher concentrations during
`the time of greatest need, typically during the early morning
`hours, and in lesser concentrations when the need is less,
`Such as during late evening and early Sleep hours. Com
`monly assigned and co-pending U.S. application Ser. No.
`09/778,645, filed Feb. 7, 2001, which is incorporated in its
`entirety, discloses a pulsatile release System which includes
`a combination of two or three pellet populations, each with
`a well defined release profile. In accordance with the present
`invention, a plasma profile is obtained which varies in a
`circadian rhythm fashion following administration of the
`novel dosage form.
`0004 Propranolol (1-(isopropyl amino)-3-(1-naphthy
`loxy)-2-propanol is a beta-adrenergic blocking agent and as
`such is a competitive inhibitor of the effects of catechola
`mines at beta-adrenergic receptor Sites. The principal effect
`of propranolol is to reduce cardiac activity by diminishing or
`preventing beta-adrenergic Stimulation. By reducing the rate
`and force of contraction of the heart, and decreasing the rate
`of conduction of impulses through the conducting System,
`the response of the heart to StreSS and exercise is reduced.
`These properties are used in the treatment of angina in an
`effort to reduce the oxygen consumption and increase the
`exercise tolerance of the heart. Propranolol is also used in
`the treatment of cardiac arrhythmias to block adrenergic
`Stimulation of cardiac pacemaker potentials. Propranolol is
`also beneficial in the long term treatment of hypertension.
`Other uses of propranolol are in the treatment of migraine
`and anxiety.
`0005 Propranolol is normally administered as propra
`nolol hydrochloride tablets.
`SUMMARY OF THE INVENTION
`0006 The present invention provides a timed, Sustained
`release multi-particulate dosage form comprising a propra
`nolol core having a first membrane of a Sustained release
`polymer and a Second membrane of a mixture of water
`insoluble polymer and an enteric polymer (2" or outer
`coating), wherein the water insoluble polymer and the
`enteric polymer may be present at a weight ratio of from
`10:1 to 1:2,and the total weight of the coatings is 10 to 60
`weight % based on the total weight of the coated beads. In
`Some cases depending on the type of drug release profile
`needed, an immediate release component may be included to
`provide a modified, timed, Sustained release dosage form.
`When administered at bedtime, the dosage form comprising
`one or more bead populations delivers the drug in lesser
`concentrations during the time of least need, for example,
`during late evening and early sleep hours, and in higher
`concentrations during the time of greatest need, for example,
`during the early morning hours.
`BRIEF DESCRIPTION OF THE FIGURES
`0007. The invention will be described in further detail
`with reference to the accompanying figures wherein:
`0008 FIG. 1 shows simulated plasma level of propra
`nolol hydrochloride following oral administration at about
`
`Page 4
`
`

`

`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`8:00 PM of one 160 mg modified, timed, sustained release
`(20 mg immediate release (IR) Beads/140 mg timed, sus
`tained release (TSR) Beads) capsule versus systolic blood
`preSSure.
`0009 FIG. 2 shows plasma levels of propranolol follow
`ing oral dosing at about 10:00 PM of one timed, Sustained
`release (TSR) capsule, 160 mg versus one Inderal LA 160
`mg.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0.010 The active core of the novel dosage form of the
`present invention may comprise an inert particle or an acidic
`or alkaline buffer crystal, which is coated with a propra
`nolol-containing film-forming formulation and preferably a
`water-Soluble film forming composition to form a water
`Soluble/dispersible particle. Alternatively, the active core
`may be prepared by granulating and milling and/or by
`extrusion and Spheronization of a polymer composition
`containing propranolol. Generally, the individual polymeric
`coating on the active core will be from 1 to 50% based on
`the weight of the coated particle. Those skilled in the art will
`be able to Select an appropriate amount of propranolol for
`coating onto or incorporating into the core to achieve the
`desired dosage. In one embodiment, the inactive core may
`be a Sugar Sphere, a buffer crystal or an encapsulated buffer
`crystal, Such as calcium carbonate, Sodium bicarbonate,
`fumaric acid, tartaric acid, etc. Buffer crystals are useful to
`alter the microenvironment.
`0011. In accordance with one embodiment of the present
`invention, the water Soluble/dispersible drug-containing par
`ticle is first coated with a water insoluble polymer (1 or
`inner coating), and further coated with a mixture of a water
`insoluble polymer and an enteric polymer (2" or outer
`coating). The water insoluble polymer and enteric polymer
`may be present at a weight ratio of from 10:1 to 1:2, more
`preferably 2:1 to 1:1, and the total weight of the coatings is
`10 to 60 weight % based on the total weight of the coated
`beads. The polymeric coatings typically contain plasticizers
`and may be applied from aqueous and/or Solvent based
`Systems.
`0012. The composition of the outer layer and the indi
`vidual weights of the inner and outer layers of the polymeric
`membrane are optimized for achieving desired drug release
`profiles. The unit dosage form according to certain embodi
`ments of the present invention may comprise an immediate
`release bead population which provides an immediate
`release component of propranolol to act as a bolus dose.
`0013 The invention also provides a method of making a
`timed, Sustained release dosage form comprising the Steps
`of:
`
`0014) 1. preparing an active-containing core by
`coating an inert particle Such as a non-pareil Seed, an
`acidic buffer crystal or an alkaline buffer crystal,
`with propranolol and polymeric binder or by granu
`lation and milling or by extrusion/spheronization to
`form an immediate release (IR) bead;
`0015 2. coating the core with a plasticized solution
`or Suspension of a water insoluble polymer to form
`Sustained release (SR) coated drug particle;
`
`0016 3. coating the SR coated particle with a mix
`ture of plasticized water insoluble and enteric poly
`mers to form a Timed Sustained Release (TSR)
`coated drug particle; and filling capsules with TSR
`particles to produce Timed, Sustained Release (TSR)
`capsules.
`0017. The release profile for TSR beads can be deter
`mined according to the following procedure:
`0018 Dissolution testing is conducted with a USP Appa
`ratus 2 (Paddles at 50 rpm) using a two-stage dissolution
`medium (first 2 hours in 700 mL 0.1N HCl at 37° C.
`followed by dissolution at pH=6.8 obtained by the addition
`of 200 mL of pH modifier). Drug release with time is
`determined by HPLC on samples pulled at selected inter
`vals.
`0019. The TSR Beads prepared in accordance with
`present invention release not more than 20%, more prefer
`ably not more than 10%, and most preferably not more than
`5% in 2 hours, about 5-35%, more preferably about 5-25%,
`and most preferably about 5-15% in 4 hours, about 10-60%,
`more preferably about 20-45%, and most preferably about
`25-35% in 6 hours, about 40-90%, more preferable about
`50-80%, and most preferably about 55-70% in 10 hours, and
`not less than 60%, more preferably not less than 70%, and
`most preferably not less than 75% in 16 hours.
`0020. In accordance with the present invention, the
`desired release properties are obtained as a result of the
`different characteristics of the two coating layers. The inner
`layer membrane provides Sustained or extended drug release
`over Several hours, while the Second or outer membrane
`provides a lag time of three to four hours. Typical release
`profiles for SR beads (ethylcellulose coated drug particle)
`and TSR beads when tested by the two-stage dissolution
`medium are provided in the following table:
`
`% Propanolol Released
`
`SR Beads
`
`TSR Beads
`
`11.2
`32.1
`39.8
`52.3
`62.3
`69.2
`79.4
`846
`90.O
`95.6
`
`O.O
`O1
`1.1
`8.6
`18.3
`27.4
`44.5
`58.4
`68.8
`9O.O
`
`Time
`
`1 hr
`2 hr
`3 hr
`4 hr
`5 hr
`6 hr
`8 hr
`10 hr
`12 hr
`16 hr
`
`0021. It is also possible that the TSR Capsule may
`optionally also contain a population of Immediate Release
`(IR) beads or particles to provide an immediate release
`component of active to act as a bolus dose in addition to the
`timed, sustained release of active provided by the TSR
`beads. These dosage forms provide a Modified Timed Sus
`tained Release (MTSR) profile.
`0022. An aqueous or a pharmaceutically acceptable Sol
`vent medium may be used for preparing drug containing
`core particles. The type of film forming binder that is used
`to bind propranolol to the inert Sugar Sphere is not critical
`but usually water-Soluble, alcohol-Soluble or acetone/water
`
`Page 5
`
`

`

`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`soluble binders are used. Binders such as polyvinylpyrroli
`done (PVP), polyethylene oxide, hydroxypropyl methylcel
`lulose (HPMC), hydroxypropylcellulose (BPC), polysac
`charides, Such as dextran, and corn Starch may be used at
`concentrations of from about 0.5 to 10 weight 9%. Propra
`nolol may be present in the coating formulation in Solution
`form or may be Suspended at a Solids content up to about 35
`weight % depending on the Viscosity of the coating formu
`lation.
`0023 Dissolution rate controlling polymers suitable for
`incorporating in the formulation for producing granules by
`high shear or fluid bed granulation or by dry granulation
`include high molecular weight hydroxypropyl methylcellu
`lose, hydroxypropyl cellulose, ethyl cellulose, Sodium car
`boxymethyl cellulose, alginic acid, polymethylmethacrylate
`copolymers and polyvinyl acetate/crotonic acid copolymer
`or combinations thereof Acidic buffers, which help maintain
`an acidic microenvironment within drug containing par
`ticles, include fumaric acid, tartaric acid, maleic acid, Suc
`cinic acid and mixtures thereof. An acidic microenvironment
`helps dissolve basic drugs with poor Solubility at the intes
`tinal pHs and become available for absorption. Examples of
`alkaline buffers include Sodium bicarbonate, calcium car
`bonate, and Sodium dihydrogen phosphate.
`0024 Propranolol, a binder such as PVP, a buffer, a
`dissolution rate controlling polymer (if used), and optionally
`other pharmaceutically acceptable excipients are blended
`together in a high shear granulator Such as Fielder or a fluid
`bed granulator Such as Glatt GPCG 5 and granulated to form
`agglomerates by adding/spraying a granulating fluid Such as
`water or alcohol and dried. The wet mass can be extruded
`and spheronized to produce spherical particles (beads) using
`an extruder/marumerizer. In these embodiments, the drug
`load could be as high as 90% by weight based on the total
`weight of the extruded/spheronized core. The blend can also
`be used to produce dry granules by Slugging in a tablet preSS
`or a chilSonator, without the addition of any granulating
`fluid.
`0025 The active containing cores (beads, pellets or
`granular particles) thus obtained may be coated with one or
`two layers of polymers to obtain desired release profiles with
`or without a lag time. The inner layer membrane, which
`largely controls the rate of release following imbibition of
`water or body fluids into the core, comprises a water
`insoluble polymer, Such as ethylcellulose, at a thickness of
`from 1 weight % up to 6 weight %, preferably from 1.5 to
`4% and most preferably about 2%, depending on the solvent
`or lateX Suspension based coating formulation used.
`0026. The outer membrane, which largely controls the
`lag time of up to 6 hours, comprises an enteric polymer and
`a water insoluble polymer at a thickness of 10 to 60,
`preferably from 10 to 56 weight 9% based on the total weight
`of the coated beads. The ratio of water insoluble polymer to
`enteric polymer may vary from 10:1 to 1:2, preferably from
`2:1 to 1:1.
`0.027
`Representative examples of enteric polymers use
`ful in the invention include esters of cellulose and its
`derivatives (cellulose acetate phthalate, hydroxypropyl
`methylcellulose phthalate, hydroxypropyl methylcellulose
`acetate Succinate), polyvinyl acetate phthalate, pH-sensitive
`methacrylic acid-methamethacrylate copolymers and shel
`lac. These polymers may be used as a dry powder or an
`
`aqueous dispersion. Some commercially available materials
`that may be used are methacrylic acid copolymerS Sold
`under the trademark Eudragit (L100, S100, L30D) manu
`factured by Rhom Pharma, Cellacefate (cellulose acetate
`phthalate) from Eastman Chemical Co., Aquateric (cellulose
`acetate phthalate aqueous dispersion) from FMC Corp. and
`Aqoat (hydroxypropyl methylcellulose acetate Succinate
`aqueous dispersion) from Shin Etsu K.K.
`0028 Both enteric and water insoluble polymers used in
`forming the membranes are usually plasticized. Represen
`tative examples of plasticizers that may be used to plasticize
`the membranes include triacetin, tributyl citrate, triethyl
`citrate, acetyl tri-n-butyl citrate diethyl phthalate, castor oil,
`dibutyl Sebacate, acetylated monoglycerides and the like or
`mixtures thereof. The plasticizer may comprise about 3 to 30
`wt.% and more typically about 10 to 25 wt.% based on the
`polymer. The type of plasticizer and its content depends on
`the polymer or polymers, nature of the coating System (e.g.,
`aqueous or Solvent based, Solution or dispersion based and
`the total solids).
`0029. In general, it is desirable to prime the surface of the
`particle before applying the pulsatile release membrane
`coatings or to Separate the different membrane layerS by
`applying a thin hydroxypropyl methylcellulose (HPMC)
`(Opadry Clear) film. While HPMC is typically used, other
`primers such as hydroxypropylcellulose (HPC) can also be
`used.
`0030 The membrane coatings can be applied to the core
`using any of the coating techniques commonly used in the
`pharmaceutical industry, but fluid bed coating is particularly
`useful.
`0031. The present invention is applied to multi-dose
`forms, i.e., drug products in the form of multi-particulate
`dosage forms (pellets, beads, granules or mini-tablets) or in
`other forms Suitable for oral administration.
`0032. The following non-limiting examples illustrate the
`capsule dosage forms manufactured in accordance with the
`invention, which exhibit in vitro drug release profiles, Simi
`lar to that predicted by performing modeling exercises, and
`in Vivo plasma concentrations following circadian rhythm
`pharmaco-dynamic profile of angina attackS. Such dosage
`forms when administered at bed time, would enable main
`taining drug plasma concentration at a level potentially
`beneficial in minimizing the occurrence of heart attacks in
`the early hours of the morning.
`
`EXAMPLES 1 TO 3
`0033) Modified Timed, Sustained Release (MTSR) cap
`Sules of Propranolol Hydrochloride may contain a mixture
`of two sets of beads: The first set is referred to as immediate
`release (IR) Beads and are designed to provide a loading
`dose by releasing all of the drug within the first hour,
`preferably within the first 30 minutes. The second set is
`referred to as Timed Sustained Release (TSR) Beads and are
`designed to release the remainder of the dose slowly over a
`period of 12-15 hours after a 3-5-hour lag time. The TSR
`Beads are produced by applying an inner layer of Sustained
`release coating (with a dissolution rate controlling polymer
`Such as ethylcellulose) (producing IntR Beads, intennediate
`release beads) and then an outer layer of pulse coating (with
`a blend of an enteric polymer such as HPMCP and a
`
`Page 6
`
`

`

`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`water-insoluble polymer such as ethylcellulose) on IR
`Beads. The two sets of beads (IR and TSR) when filled into
`capsule shells at an appropriate ratio will produce the target
`circadian rhythm release profile required for maintaining
`drug plasma concentrations at potentially beneficial levels in
`minimizing the occurrence of heart attacks. Alternatively,
`the capsules may comprise only the TSR Beads. It is well
`known that the blood pressure begins to drop as the night
`advances, and consequently, only the TSR beads may be
`orally administrated in certain cases.
`
`EXAMPLE 1.
`0034) Propranolol HCl (560 g) was slowly added to an
`aqueous Solution of polyvinylpyrrolidone (29 g PoVidone
`K-30) and mixed well. 25-30 mesh Sugar spheres (391 g)
`were coated with the drug solution in a Glatt fluid bed
`granulator. The drug containing pellets were dried, and a Seal
`coat of Opadry Clear (2% w/w) was first applied. The inner
`polymer coating was applied to the active particles (982 g)
`by spraying a Solution of ethylcellulose (16.36 g) and diethyl
`phthalate (1.64 g) in 98/2 acetone/water. The outer coating
`of 1:1 blend of ethylcellulose (68.25 g) and HPMCP (60 g)
`plasticized with diethyl phthalate (21.75 g) was sprayed onto
`the active particles having the inner coating (850 g) to
`produce TSR Beads. TSR Beads prepared in accordance
`with the Example 1 are characterized by the following
`properties:
`0035) Drug loading: 56% w/w based on core com
`position (corresponds to 45.7% drug based on final
`TSR bead).
`0036) EC Coating: 1.8% w/w based on ethylcellu
`lose coated (SR) beads (corresponds to 1.53% coat
`ing on final TSR bead weight).
`0037 TSR Coating: 15% w/w based on final TSR
`bead weight.
`0038. Two lots of finished TSR Beads with identical drug
`contents but coated with the aqueous and Solvent based
`coating at formulations were tested for in vitro dissolution
`properties using USP Dissolution Apparatus 2 at a paddle
`speed of 50 rpm. The beads were dissoluted using a three
`stage dissolution medium, i.e., first 2 hours in 0.1N HCl,
`next 2 hours at pH 4.0 and then at pH 6.8 for additional 14
`hours, the pH of the medium being changed by adding a pH
`modifier. The results obtained are presented in Table 1. The
`dissolution results show that there is a lag time of about four
`hours followed by Sustained release occurring over a period
`of 14-18 hours.
`
`TABLE 1.
`
`Dissolution Data for Example 1
`% Propranolol Released
`Organic Coating System
`1 Coating (1.8% w/w)/
`2" Coating (15% w/w)
`
`Time in
`hours
`
`1.O
`2.0
`3.0
`4.0
`5.0
`6.O
`8.0
`
`O
`O
`0.5
`0.4
`1O
`24
`47
`
`TABLE 1-continued
`
`Dissolution Data for Example 1
`% Propranolol Released
`Organic Coating System
`1 Coating (1.8% w/w)/
`2" Coating (15% w/w)
`
`62
`72
`78
`86
`
`Time in
`hours
`
`1.O.O
`12.0
`14.O
`16.0
`
`EXAMPLE 2
`0039 The pharmacokinetic modeling parameters for use
`in the computer Simulation of propranolol HCl plasma drug
`concentrations were Selected after reviewing the available
`literature (T. Shiga, A. Fujimura, T. Tateishi, K. Ohashi, and
`A. Ebihara, “Differences in Chronopharmacokinetic Profiles
`between Propranolol and Atenolol in Hypertensive Sub
`jects” in Journal of Clinical Pharmacology, Vol. 33, page
`756-761 (1993) and G. S. Rekhi and S. S. Jambhekar,
`“Bioavailability and In-vitro/In-vivo Correlation for Propra
`nolol HCl Extended Release Bead Products Prepared Using
`Aqueous Polymeric Dispersions” in Journal of Pharm. Phar
`macology, Vol. 34, page 1276-1284 (1996); both of these
`articles are hereby incorporated in their entirety). The fol
`lowing pharmaco-kinetic parameters fitted well a linear
`one-compartment model:
`
`0.7 hr'
`K,
`K: 0.18 hr'
`V/ 837.1 L, where Vd is Volume Distribution and F is a constant
`given a value of 1.0
`
`0040 and 0.7 for immediate release and extended release
`dosage forms, respectively.
`0041) Using these parameters, the initial attempts focused
`on optimizing the required IR (immediate release) portion of
`the maximum dose of 160 mg. From the Simulation plasma
`levels following oral administration of one 160 mg capsule
`consisting of 10, 20, and 30 mg IR Beads/balance TSR
`Beads and steady State plasma levels (plasma levels follow
`ing administration of one IR/TSR capsule every 24 hrs),
`incorporation of 20 mg IR Beads portion was judged to
`result in efficacious in vivo profiles to provide relief from the
`circadian rhythm variations. FIG. 1 compares the simulated
`plasma level following oral administration of one 160 mg
`MTSR capsule (20 mg IR Beads/140 mg TSR Beads) at
`about 8:00 PM and the observed systolic blood pressure as
`a function of time in patients as reported in the Anwar and
`Whites article.
`0042 Pilot clinical Supplies consisting of IR and TSR
`Beads were manufactured following Example 1, and hard
`gelatin capsules were filled with 20 mg IR/60 mg TSR and
`20 mg IR/140 mg TSR Beads to produce 80 and 160 mg
`propranolol HCI MTSR Capsules. Table 2 shows the disso
`lution data for these 80 and 160 mg capsules tested using the
`3-Stage dissolution method.
`
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`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`TABLE 2
`
`Dissolution Profiles of 80 and 160 mg MTSR Capsules of Example 2
`% Propanolol Released
`160 mg Capsules (Size 1)
`80 mg Capsules (Size 3)
`(20 mg IR + 140 mg TSR
`(20 mg IR + 60 mg TSR
`Beads)
`Beads)
`
`Time,
`hours
`
`1.O
`3.0
`4.0
`5.0
`6.O
`8.0
`1O.O
`12.O
`16.O
`18.0
`
`25
`25
`25
`34
`46
`65
`75
`82
`89
`92
`
`13
`13
`14
`24
`38
`60
`73
`82
`91
`95
`
`EXAMPLE 3
`0043 Propranolol HCl (45.2 kg) was slowly added to an
`aqueous Solution of polyvinylpyrrolidone (2.34 kg PoVidone
`K-30) and mixed well. #25-30 mesh sugar spheres (31.6 kg)
`were coated with the drug solution in a Glatt fluid bed
`granulator. The drug containing pellets were dried, and a Seal
`coat of Opadry Clear (2% w/w) was first applied (batch size:
`80.75 kg). The inner Sustained release coating was applied
`to the active particles (73.7 kg) by spraying a Solution of
`ethylcellulose and diethyl phthalate in 98/2 acetone/water.
`The outer coating of a blend of ethylcellulose and HPMCP
`plasticized with diethyl phthalate was sprayed onto the
`active particles having the inner coating to produce TSR
`Beads (batch size:82.5 kg). These TSR Beads were filled
`into hard gelatin capsules using an MG capsule filling
`equipment to produce Propranolol hydrochloride TSR Cap
`Sules, 80, 120, and 160 mg.
`0044) These Propranolol TSR Capsules were also tested
`for drug release profiles by a two-stage dissolution method,
`wherein capsules were dissoluted at pH 1.5 in 700 mL 0.1N
`HCl for two hours followed by testing at pH 6.8 in 900 mL
`obtained by adding 200 mL of concentrated buffer modifier.
`0045 Propranolol HCl TSR Capsules, 160 mg and
`Inderal E LA, 160 mg, a once a day extended release capsule
`dosage form from American Home Products were orally
`administrated to healthy volunteers at about 10:00 PM. The
`results from these clinical Studies demonstrated distinctly
`different pharmaco-kinetic profiles for the two formulations
`as shown in FIG. 2. Blood levels for InderalE LA achieved
`Ta at approximately 6 hours post-dosing while for pro
`pranolol TSR following a 2-4 hour lag time, blood levels
`rose progressively for 4-12 hours post-dosing, achieving
`T at about 12 hours, demonstrating the desired character
`isties of a TSR dosage form.
`
`What is claimed is:
`1. A pharmaceutical dosage form comprising timed, Sus
`tained release (TSR) beads, wherein said TSR beads com
`prise:
`a. a core particle comprising propranolol or a pharmaceu
`tically acceptable Salt thereof;
`b. a first membrane comprising ethylcellulose Surround
`ing Said core to Sustain drug release; and
`
`c. a Second outer membrane comprising a mixture of
`ethylcellulose and an enteric polymer, Said Second
`membrane providing a lag time before drug release,
`d. wherein said TSR beads when tested in a USP type II
`apparatus at 50 rpm using a 2-stage dissolution medium
`(first two hours in 700 ml 0.1N HCl at 37° C. followed
`by dissolution in a pH of 6.8 obtained by the addition
`of 200 ML of pH modifier) exhibit a dissolution profile
`Substantially corresponding to the following pattern:
`after 2 hours, 0-20% of the total propranolol is released;
`after 4 hours, 5-35% of the total propranolol is released;
`after 6 hours, 10-60% of the total propranolol is
`released;
`after 10 hours, 40-90% of the total propranolol is
`released; and
`after 16 hours, not less than 60% of the total propanolol
`is released.
`2. A pharmaceutical dosage form as defined in claim 1,
`wherein Said dissolution profile Substantially corresponds to
`the following pattern:
`after 2 hours, 0-10% of the total propranolol is released;
`after 4 hours, 5-25% of the total propranolol is released;
`after 6 hours, 20-45% of the total propranolol is released;
`after 10 hours, 50-80% of the total propranolol is released;
`and
`after 16 hours, not less than 70% of the total propranolol
`is released.
`3. A pharmaceutical dosage form as defined in claim 2,
`wherein the dissolution profile Substantially corresponds to
`the following pattern:
`after 2 hours, 0-5% of the total propanolol is released;
`after 4 hours, 5-15% of the total propranolol is released;
`after 6 hours, 25-35% of the total propranolol is released;
`after 10 hours, 55-70% of the total propranolol is released;
`and
`after 16 hours, not less than 75% of the total propranolol
`is released.
`4. A pharmaceutical dosage form as defined in claim 1,
`wherein the core particle is a non-pareil Sugar Seed coated
`with propranolol in a polymeric binder or the core particle
`is particle prepared by granulation and milling or extrusion/
`Spheronization to form a core particle containing propra
`nolol.
`5. A pharmaceutical dosage form as defined in claim 1
`wherein Said enteric polymer is Selected from the group
`consisting of esters of cellulose, polyvinyl acetate phthalate,
`pH-sensitive methacrylic acid-methylmethacrylate copoly
`mers, shellac and derivatives thereof.
`6. A pharmaceutical dosage form as defined in claim 5
`wherein Said enteric polymer is Selected from the group
`consisting of cellulose acetate phthalate, hydroxypropyl
`methylcellulose phthalate, hydroxypropyl methylcellulose
`Succinate and combinations thereof.
`7. A pharmaceutical dosage form as defined in claim 1
`wherein at least one of Said first and Second membranes
`further comprises a plasticizer.
`
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`US 2003/O157173 A1
`
`Aug. 21, 2003
`
`8. A pharmaceutical dosage form as defined in claim 7
`wherein Said plasticizer is