|Title of Invention||
"AN ORALLY DELIVERABLE PHARMACEUTICAL COMPOSITION"
|Abstract||An orally deliverable pharmaceutical composition comprising: (a) from 0.05% to 5% by weight pramipexole or a pharmaceutically acceptable salt thereof, as herein described and (b) a release modifying Omeans; wherein said release-modifying means comprises from 20% to 70% by weight of a hydrophilic polymer, as herein described and from 25% to 75% by weight of a starch; as herein described.|
|Full Text||The present invention relates to orally deliverable pharmaceutical compositions .of the dopamine receptor agonist pramipexole, and more particularly to sustained-release dosage forms suitable for once-daily administration of pramipexole.
BACKGROUND OF THE INVENTION
 Pramipexole (I) is a dopamine D2 receptor agonist useful in treatment of Parkinson's disease Pramipexole as its dihydrochloride salt is commercially available as Mirapex® tablets of Pharmacia & Upjohn These are immediate-release tablets in 0.125 mg, 0 25 mg, 0 5 mg, 1 0 mg and 1.5 mg strengths, designed for oral administration of a single tablet three times per day to provide a daily dose of 0.375 to 4 5 mg. See Physicians' Desk Reference 57th edition (2003), 2768-2772. Doses herem are expressed in amounts of pramipexole dihydrochloride monohydrate unless otherwise specified; 1.0 mg pramipexole dihydrochloride monohydrate is equivalent to about 0 7 mg pramipexole base.
 A three times daily dosing regimen for immediate-release pramipexole dihydrochloride tablets is well tolerated, but patient compliance would be much improved if a once-daily regimen were possible. In this regard, it will be noted that the primary indication for the drug, Parkinson's disease, is an affliction that becomes more prevalent with advancing age and is often accompanied by decline in memory. A once-daily regimen would be especially useful in enhancing compliance among elderly patients  In common with other anti-Parkinson's disease drugs, pramipexole has potential to cause undesirable side effects. Side effects of pramipexole have been reported to include orthostatic hypotension, the incidence of which is dose-related. There are also reports of subjects on pranapexoie medication experiencing increased somnolence, in particular "sleep attacks'". Such attacks involve a subject falling asleep while engaged in activities of daily living, including operation of a motor vehicle, sometimes resultmg in accidents Development of a new once-daily dosage form of pramipexole must take into account the potential to cause such side effects, so that the
new dosage form, administered once daily, can be tolerated at least as well as the present immediate-release tablet formulation, administered three times daily.  It is an object of the present invention to provide aonce-daily dosage form of pramipexole suitable for oral administration It is a further object to provide such a dosage form having potential for side effects no greater than a three times daily regimen of pramipexole immediate release tablets. It is a still further object to identify an in vitro release profile that would be characteristic of a well tolerated once-daily dosage form of pramipexole. It is a still further object to identify an in vivo pharmacokinetic (PK) profile that would be consistent with good therapeutic efficacy while not causing an unacceptable incidence or severity of side effects It is a still further object to provide exemplary dosage forms exhibiting such an in vitro release and/or in vivo PK profile. 10006] Sustained release formulations of many drugs have been described in the literature. For example, U S. Patent No. 6,197.339 discloses a sustained-release tablet comprising (R)-5,6-dihydro-5-(methylammo)-4H-imidazo[4,5-ij]-qumolm-2(lH)-one (Z)-2-butenedioate (l'l) (the dopamine D3 receptor agonist sumamrole maleate) in a matrix comprismg hydroxypropyknethylcellulose (HPMC) and starch. The tablet is disclosed to be useful in treatment of Parkinson's disease. Starches disclosed to be suitable therein include pregelatnuzed starch
 U S Patent No. 5,458,887 discloses a controlled-release tablet comprising an osmotic core that consists of a drug in admixture with a water-swellable component such as HPMC or polyethylene oxide, and a coating that comprises a water-resistant polymer and a minor amount of a water-soluble compound that acts as a pore-former Upon formation of pores in the coating by dissolution of the water-soluble compound, the water-swellable agent is said to expand the core and provide a drug-rich surface in contact with gastrointestinal fluid
 U.S. Patent No 5,656,296 discloses a dual control sustained-release formulation comprismg a core that comprises a drug and a low melting point excipient, and a coating layer over the core that comprises a pH-independent water-insoluble polymer and a water-soluble film-forming polymer
 European Patent Application No EP 0 933 079 discloses a starch said to be suitable for preparing tablets having high hardness yet being capable of rapid disintegration in an aqueous medium. Tensile strength of the finished tablets is calculated from the hardness
 Hubble et al (1995), Clinical Neuropharmacology 18(4), 338-347, described efficacy, safety, tolerability and pharmacokinetics of pranupexole administered three limes a day in patients with early Parkinson's disease. A review of pranupexole use in management of early and advanced Parkinson's disease has been published by Dooley & Markharn (1998), Drugs & Aging 12(6), 495-514. No disclosure is made therein of once-daily administration or sustained-release formulation of pranupexole.  More recently, Biglan & Holloway (2002), Expert Opinion on Pharmacotherapy 3(2), 197-210, reviewed pranupexole and its clinical utility in Parkinson's disease and noted that daily dosing with Mirapex® tablets is recommended in patients with impaired renal function, as evidenced by creatine clearance of 15-34 ml/minute They also indicated that while dopamine receptor agonists generally have been associated with orthostatic hypotension, pranupexole does not appear to cause this complication any more than placebo in randomized controlled trials It is reported therein, however, that evidence from such trials supports increased incidence of somnolence in patients receiving pranupexole in early Parkinson's disease.  Steady-state PK properties of pranupexole, administered three tunes a day in the form of pranupexole dihydro chloride tablets, were reported by Wright et al. (1997), Journal of Cluneal Pharmacology 37, 520-525, who concluded that steady-state PK charactenstics were lmear up to a daily dose of 4.5 rng, for both men and women.  Patents and publications cited above are incorporated herein by reference
SUMMARY OF THE INVENTION
 There is now provided an orally deliverable pharmaceutical composition comprismg a therapeutically effective amount of pranupexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of (a) an m vitro release profile wherein on average no more than about 20% of the pranupexole is dissolved within 2 hours after placement of the composition m a standard dissolution test, and (b) an in vivo pranupexole absorption profile following single dose oral administration to healthy adult humans wherein the tune to reach a mean of 20% absorption is greater than about 2 hours and/or the tune to reach a mean of 40% absorption is greater than about 4 hours  There is further provided a method of treatment of a subject having a condition or disorder for which a dopamine receptor agonist is indicated, the method comprising orally administering to the subject, not more than once daily, an orally
deliverable pharmaceutical composition comprising a therapeutically effective amount of prarmpexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of (a) an in vitro release profile wherein no more than about 20% of the prarmpexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and (b) an m vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours
 There is still further provided a process for selecting a formulation of pramipexole or a pharmaceutically acceptable salt theieof suitable for sustained-release oral delivery of pramipexole According to a first embodiment, the process comprises placmg a candidate formulation m a dissolution medium under conditions of a standard in vitro dissolution test, wherein if on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the candidate formulation in the dissolution medium, the candidate formulation is deemed suitable for selection According to a second embodiment, the process comprises conducting a standard pharmacokinetic study following single dose oral administration of a candidate formulation to healthy adult humans and deriving an in vivo pramipexole absorption profile from said study, wherein if the time to reach a mean of 20% absorption is greater than about 2 hours and/or the trme to reach a mean of 40%> absorption is greater than about 4 hours, the candidate formulation is deemed suitable for selection
 The term "orally deliverable" herein means suitable for oral, including peroral and intra-oral (e g, sublingual or buccal) administration, but compositions of the present invention are adapted primarily for peroral administration, 7 e , for swallowing Where the composition is in the form of a discrete solid article such as a tablet or capsule, it is typically swallowed whole or broken, with the aid of water or other drinkable fluid  A "therapeutically effective amount" of pramipexole herein is a daily dosage amount that, when administered as part of a regimen, provides therapeutic benefit in treatment of a condition or disorder for which a dopamine receptor agonist is indicated Suitable amounts per dose are likely to be found in a range from about 0.1 to about 10 mg, preferably about 0 3 to about 5 mg, for example about 0.375, 0.5, 0.75, 1.0,1.5, 2.0, 3 0 or 4.5 mg, expressed as pramipexole dihydrochloride monohydrate equivalent
 A "standard dissolution test" herein is a test conducted according to United States Pharmacopeia 24th edition (2000) (USP 24), pp. 1941-1943, using Apparatus 1 described therein at a spmdle rotation speed of 100 rpm and a dissolution medium of 0 05M phosphate buffer, pH 6.8, at 37°C or other test conditions substantially equivalent thereto
 In vivo "absorption" herein refers to the percentage of prannpexole that enters the bloodstream, as conventionally calculated from data of a standard PK study involving oral administration of a single dose of prannpexole It will be understood that PK data are subject to the usual variation seen in biological data, thus the absorption percentages specified above are means from a population, typically at least about 8 in number, of individual healthy adults in accordance with standard statistical practice  A "subject"' herein is an animal of any species, preferably mammalian, most preferably human. Conditions and disorders in a subject for which a dopamine receptor agonist is said herein to be "indicated1' are not restricted to conditions and disorders for which a dopamine receptor agonist has been expressly approved by a regulator)' authority, but also include other conditions and disorders known or believed by a physician to be amenable to treatment with a dopamine receptor agonist. 'Treatment" herein embraces prophylactic treatment unless the context requires otherwise  Compositions of the invention exhibit a number of surprising and unexpected features and benefits
 First, sustained-release dosage forms are typically sought where it is desired to
enable longer time intervals between dosing of a drug having a short half-life in plasma,
due for example to rapid metabolism, excretion or other routes of depletion. Among
drugs used to treat Parkmson's disease, levodopa is a well-known example, having a short
ehmmation half-life (T1/2) of about 1 5 hours See Colosrmo & De Michele (1999),
European Journal of Neurology 6(1), 1-21 By contrast, pramipexole has a T1/2 of about
9 to about 14 hours, depending on the particular study, and Avould not on this ground be
expected to require special attention to formulation to enable once-daily dosing
 Second, pramipexole, at least in the form of its dihydrochlonde salt, has high solubility in water (about 200 mg/ml at 20-25 °C) Highly water-soluble drugs are typically difficult to formulate in sustained-release form because of the tendency of the drug to rapidly leach out of the dosage form upon exposure to an aqueous medium such as gastrointestinal fluid
(0025) Third, as demonstrated herein, prarnrpexole dosage forms having very similar in vitro release profiles, as characterized by standard parameters such as time to reach 50% or 80% dissolution, can, as demonstrated herem, have in vivo PK profiles that differ in very meaningful ways Differences in PK profile between dosage forms having similar 50% and 80% dissolution tunes in an in viti-o test can define the difference between a dosage form that meets the criteria of the present invention and one that does not.  This last finding is especially unexpected in light of a close m vitro/in vivo correlation that is evident for individual dosage forms, as demonstrated herein It is surprisingly found that data for early time points (up to about 2 hours) and/or initial dissolution rates (up to about 20% dissolution) in the in vitro test described herein are indicative of a PK profile consistent with the present invention. Thus a pramipexole composition exhibiting no more than about 20% dissolution at a 2 hour time point m the in vitro test is strongly indicative of a desirable in vivo PK profile, whereas one exhibiting faster early dissolution, even if 50% and 80% dissolution times are no different, is not so indicative
 These and other features, benefits and advantages of the invention will be apparent from the disclosure that follows
BRIEF DESCRIPTION OF THE DRAWINGS  Fig 1 is a graph showmg in vitro dissolution profiles of three different 0.375 mg sustained-release tablet formulations of pramipexole dihydro chloride monohydrate, as more fully described in Example 6
 Fig 2 is a graph from a human PK study showing time course of mean plasma pramipexole concentration following oral administration of 0.375 mg pramipexole dihydro chloride monohydrate, either as a 0 125 mg immediate-release tablets administered three times at 8-hour intervals or as a single 0 375 mg dose of each of three different sustained-release tablets, as more fully described in Example 7. 10030] Fig 3 shows in vitro/in vivo correlation for the pramipexole dihydrochlonde tablets of Example 1.
 Fig 4 shows in vitro/m vivo correlation for the pramipexole dihydrochlonde tablets of Example 2
 Fig 5 shows in vitrohn vivo correlation for the pramipexole dihydro chloride tablets of Example 5
DETAILED DESCRIPTION OF THE INVENTION
 In one embodiment, a pramipexole composition of the invention exhibits at least one of the following
(a) an in -vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and
(b) an m vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the tune to reach a mean of 40% absorption is gi eater than about 4 hours
 Accordingly, in a particular embodiment the composition satisfies at least the
772 vifro test set forth in (a) above
10035] In another particular embodiment the composition satisfies at least the m vivo
test set forth in (b) above
 To satisfy the 7/z vitro test, on average no more than about 20% of the
pramipexole initially contained in the composition must dissolve within 2 hours after
placement in a dissolution test conducted according to USP 24 usmg Apparatus 1 at a
spindle rotation speed of 100 ipm and a dissolution medium of 0 05M phosphate buffer,
pH 6 8, at 37°C, or in a substantially equivalent test Preferably no more than about 12%
of the pramipexole dissolves within 1 hour in such a test Time to reach 50% dissolution
is preferably at least about 4 hours, more preferably at least about 6 hours. Time to reach
80% dissolution is preferably at least about 8 hours, more preferably at least about 12
 To satisfy the in vivo test, a single-dose PK study in healthy adult human
subjects must provide data consistent with an absorption profile wherein, at a time point
about 2 hours after administration, mean absorption has not yet reached 20%, and/or at a
tune pouit about 4 hours after administration, mean absorption has not yet reached 40%
Preferably the time to reach a mean of 40% absorption is at least about 5 hours, more
preferably at least about 6 hours
 It is preferred that the composition, when administered once daily, exhibit a
bioavailability, as expressed conventionally by AUQMS or AUCo-^o, that is substantially
equivalent to the same daily dose of an immediate-release pramipexole dihydrochloride
reference formulation, for example Mirapex® tablets, administered three times a day In
the present context, "substantially equivalent" means that the bioavailability of such a preferred composition is about 0 8 to about 1 25 times that of the refeience formulation  It is preferred that the composition, following single dose administration of 0.375 rng (expressed as pramipexole dihydrochloride monohydrate equivalent), exhibit a maximum plasma concentration (Cmax) of pramipexole that is not greater than about 0.3 ng/ml Where a higher dose is admmistered, the preferred upper limit of Cmax is proportionately greater, it being known that pharmacokinetics of pramipexole are substantially linearly dose-related up to a daily dose of 4 5 mg Wright et al (1997), op at
 It is preferred that the composition, following single dose administration, exhibit a time to reach maximum plasma concentration (Tmax) of pramipexole that is at least about 6 hours, preferably at least about 8 hours
 It is especially preferred that the composition exhibit a PK profile consistent with steady-state plasma concentrations having a fluctuation ratio that is not substantially-greater than that of the reference formulation as defined above Fluctuation ratio (FR) is defined by the following equation
where Cmax, Cmin and Cavg are maximum, minimum and average plasma concentrations
 Preferably the PK study used to generate the parameters specified above for a
candidate composition is conducted according to a protocol that is generally accepted in
the art. Preferably at least 6, more preferably at least 8, most preferably at least 10
subjects are enrolled in the study and receive the candidate composition
 A composition having the in vitro release and/or in vivo PK parameters
specified above is advantageous m having reduced potential to cause undesirable side
effects that may be related to a combination of high Cmax and short Tmax, by comparison
with other once-daily dosage forms. Preferably the incidence of side effects is no greater
than with an immediate-release dosage form such as Mirapex® tablets administered in a
three tunes daily regimen. More preferably, the incidence of side effects is even lower
than with such an immediate-release regimen. It is contemplated that these advantages
become more pronounced with increase in daily dosage
 A composition of the invention comprises pramipexole or a pharmaceutically
acceptable salt thereof, in a therapeutically effective daily dosage amount. It will be
understood thai mention of pramipexole or another active pharmaceutical agent herein embraces racemates, enantiomers, polymorphs, hydrates and solvates thereof. Pramipexole is used preferably in the form of its S-enantiomer, (S)-2-amrno-4,5,6,7-tetrahydro-6-(propylamino)-benzotmazole.
 It is preferred to use a salt ofprarmpexole, especially a salt exhibiting moderate to high solubility in water Illustrative salts include those prepared using the following acids: hydrochloric, hydrobrormc, hydroiodic, phosphoric, sulfuric, methanesulfomc acid, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, j9-hydroxybenzoic, toluenesulfomc, formic, acetic, propionic, benzoic, anthramlic, tartaric, maleic, malic, citric, isocitnc, succinic, ascorbic, lactic, glycolic, gluconic, glucuronic, pyruvic, oxaloacetic, fumanc, aspartic, glutamic, stearic, salicylic, phenylacetic, mandelic, pamoic, pantothenic, sulfamlic, cyclohexyl amino sulfonic, algemc, p-hydroxybutync, galactanc and galacturomc acids
 A preferred salt ofprarmpexole is the dihydro chloride salt, most preferably in the form of the monohydrate
 Pramipexole and salts thereof, including the dihydro chloride salt, useful herein can be prepared by processes known/?er se, including processes disclosed in patents and other literature pertammg to pramipexole
 The composition can take any form suitable for oral administration, but is typically formulated as a discrete solid dosage unit such as a tablet or capsule, wherein the pramipexole or salt thereof is present as solid particles, and is formulated together with one or more pharmaceutically acceptable excipients The excipients are selected ID part to provide a release profile and/or PK profile consistent with those defined above.  The amount ofprarmpexole present m a composition of the invention is sufficient to provide a daily dose in one to a small plurality, for example one to about 4, of dosage units to be administered at one time. Preferably the full daily dose is delivered in a single dosage unit. An amount of about 0 1 to about 10 mg per dosage unit, or about 0 05% to about 5% by weight of the composition, will generally be suitable. Preferably an amount of about 0.2 to about 6 mg, more preferably an amount of about 0 3 to about 5 mg, pramipexole per dosage unit is present Specific amounts per tablet contemplated herein include 0 375, 0 5, 0.75,1 0, 1 5,3 0 and 4 5 mg pramipexole dihydrochloride monohydrate  The particular formulation selected for the pramipexole is not critical so long
as it achieves a release and/or PK profile as defined herein Such a profile can be achieved using one or more release-modifying means Illustratively, release-modifying means suitable for use in a composition of the invention include a polymer matrix wherein the pramipexole is dispersed, a release-controlling layer or coating surrounding the whole dosage unit or pramipexole-containmg particles, granules, beads or zones within the dosage unit: and an osmotic pump
 In one embodiment, the composition takes the form of a tablet comprising pramipexole or a salt thereof, dispersed in a matrix comprising a hydrophilic polymer and starch Preferably the starch has a tensile strength of at least about 0 ] 5 kN cm"" at a solid fraction lepresentative of the tablet, foi example about 0 75 to about 0 85. illustratively 0 8.
 Hydrophilic polymers useful according to the present embodiment are pharmaceutically acceptable polymeric materials having a sufficient number and distribution of hydrophilic substituents such as hydroxy and carboxy groups to impart hydrophilic properties to the polymer as a whole. Suitable hydrophilic polymers include, without limitation, methylcellulose, HPMC (hypromellose), carmellose sodium (sodium carboxymethylcellulose) and carbomer (polyacrylic acid) More than one such polymer can optionally be used
 HPMC is a preferred hydrophilic polymer Various types and grades of HPMC are available In one embodiment HPMC type 2208, preferably meeting specifications set forth in a standard pharmacopeia such as USP 24, is used HPMC type 2208 contanis 19-24% by weight methoxy and 4-12% by weight hydroxypropoxy substituents. Especially suitable HPMCs have nominal viscosity ranging from about 100 to about 10,000 mPa s, illustratively a suitable HPMC type 2208 is one having a nominal viscosity of about 4,000, with a measured viscosity of about 3,000 to about 5,600 mPa s Such an HPMC is available, for example, as Methocel® K4MP from Dow Chemical Co , and substantially equivalent products are available from other manufacturers  The amount of hydrophilic polymer in the composition depends on the particular polymer selected, on the active pharmaceutical agent and on the desired sustained release profile Typically, however, the hydrophilic polymer is included in an amount of about 20% to about 70%, preferably about 30% to about 60% and more preferably about 35% to about 50%, by weight of the composition. In the illustrative case of HPMC type 2208, a suitable amount will generally be found in the range from about
30% to about 60%, preferably about 35% to about 50%, for example about 40%, by
weight of the composition.
 It is believed, without being bound by theory, that the hydrophilic polymer
functions to provide extended or sustained release of the pramipexole, for example by
gradual dissolution or erosion of the polymer in the gastrointestinal tract
 Starches useful herem mclude starches from any suitable botanical source, for
example com, wheat, nee, tapioca, potato, etc Preferred starches have a relatively high
ratio of amylose to amylopectin, containing for example at least about 20%, more
preferably at least about 25%, amylose Especially preferred is pregelatmized starch,
which is a type of modified starch that has been processed to render the starch more
flowable and directly compressible. Partially or wholly pregelatrnrzed starches can be
 It is believed, without being bound by theory, that the primary function of the
starch in a composition of the present embodiment is as a binding agent. A starch
meeting the preferred tensile strength criterion defined herein is sometimes referred to
herein as a "super bmder"
 The amount of starch in a composition of the present embodiment is typically
higher than is conventionally present as a binder in tablet formulations Suitable amounts
will generally be found hi the range of about 25% to about 75% by weight Preferably the
amount of starch is about 40% to about 70%, more preferably about 45% to about 65%,
for example about 50%, by weight of the composition
 Tensile strength of a starch sample can be measured by any suitable test
Illustrative test procedures are described by Hiestand & Smith (1984), Powder
Technology 38, 145-159, and by Hiestand & Smith (1991), International Journal of
Phannaceutics 67, 231-246, these articles being incorporated herem by reference
10060] An example of a tensile strength test that can be used (herem referred to as a
"tnaxial tensile strength test*') requires preparation of a series of compacts of the starch
sample, followed by determination of tensile strength of the compacts using a
computerized multifunction tablet tester (MTT). The compacts are prepared with various
degrees of compression force to provide compacts having a range of solid fraction. As a
sustamed release tablet formulation typically has a solid fraction of about 0 8, it is useful
to prepare compacts approximating such a solid fraction
 Absolute density of the starch sample can be determined usmg a helium-air
 A computer-controlled tnaxial tablet press is used to prepare the compacts Voltage output from the punch and die load cells of the tablet press are first zeroed The punch and die are lubricated with magnesium stearate powder and the die assembly is placed in the press Compression and decompression parameters are selected on the computer The desired amount of starch to be compacted is weighed and poured into the die cavity. The resultmg powder bed is leveled with a spatula The punch is mserted into the die and the computer-controlled compression/decompression cycle is started,  Just prior to the end of the compression phase, thickness of the compact as measured by LVDT is recorded At the end of the compression phase, the final compression force as measured by voltage of the punch load cell is recorded.  At the end of the decompression phase, the punch and die rams are retracted The compact is removed from the die and inspected for defects, such as cracking or • sticking Cracking can be reduced by increasing decompression time If the compact zs free of defects, its length, width, thickness and weight are measured to enable calculation of appaient density Solid fraction is calculated by dividing absolute density by apparent density
 In preparation of the MTT for tensile strength determination, a suitable software program is run The platen is screwed to the load cell of the MTT and the tensile strength assembly is slid into the MTT opposite the platen The load cell signal is monitored via the computer and the zero offset on the signal conditioner is adjusted to provide a positive baseline voltage as close as possible to zero. A forward velocity is selected that will generate a time constant of approximately 15 seconds (usually the velocity selected will be about 0.8 to about 1.2 mm s"1)
 The compact to be tested is placed in the holder of the tensile strength assembly The motor is initiated via the computer, driving the platen toward the compact until the surface of the compact is detected, and stopping the platen a few millimeters from the compact The oscilloscope is triggered, to record the force applied to the compact, and the motor is restarted The platen is driven into the compact until a crack is detected, either by sight or by sound, and the motor is immediately reversed  Peak force is recorded from the oscilloscope trace Tensile strength is calculated from the peak force using appropriate computer software.  From several runs using compacts at a range of solid fractions around 0.8, data
are plotted and tensile strength at a sohd fraction of 0 8 is estimated. If the tensile strength at a sohd fraction of 0 8 is about 0 15 kN cm-2 or greater, the starch sample is deemed to be suitable for use in preparing a composition according to the present embodiment of the invention
 It has now surprisingly been discovered that a much simpler test, one that is more amenable to implementation in a manufacturing setting, can be used to estimate tensile strength of a starch sample, in particular to determone whether the starch sample has a tensile strength of at least about 0.15 kN cm"2 at a solid fraction representative of a desired sustained-release tablet
 According to this test, compacts of the starch sample are prepared on a standard automated tablet press under a range of compression forces. For example, a Carver press (e.g, Model 3S88 1DT0000) fitted with fat-faced tooling of suitable diameter (e g, 10/32 inch or about 0.7 cm for a 300 mg compact), operated at compression forces of about 4 to about 16 kN (about 900 to about 3600 Ibf) for a dwell time of at least about 4 seconds has been found to give satisfactory results Illustratively, such compacts can be prepared at 1000, 1500, 2000 and 3000 lbf (4 45, 6 67, 8.90 and 13 34 kN) Preferably a dwell time of at least about 10 seconds, more preferably at least about 30 seconds, still more preferably at least about 60 seconds, is used Illustratively, a dwell tune of 90 seconds has been found to give satisfactory results Weight, diameter and thickness of each compact are measured accurately (alternatively, diameter can be assumed to equal that of the tooling) to enable calculation of apparent density and hence solid fraction, absolute density havmg been measured as described above, for example by helmm-air pycnometry
 Hardness of each compact thus prepared is then determined by any suitable tablet hardness test, for example using a Key HT 500 hardness tester. Hardness is a measure of the force required to cause crushing of the compact, and is typically expressed in units such as kiloponds (kp) or Strong-Cobb units (SCU) A hardness of about 10 2 kp or about 14 4 SCU corresponds to a force of 0 1 kN
 For present purposes it is considered that crushing strength of the compact is equivalent to tensile strength Thus tensile strength (or, in kN cm"2) can be calculated from the equation
where F is the force required to cause crushing (in kN), D is diameter of the compact (in
cm) and H is thickness of the compact (in cm) For example, a compact of diameter 0.7 cm and thickness 0 4 cm having a hardness of 20 SCU (equivalent to a force of 0 139 kN) has a calculated tensile strength of 0.316 kN cm""
 The relationship between tensile strength and solid fraction is next established for the starch sample. This can be done by plotting data for tensile strength and solid fraction on a graph (solid fraction tends to increase with increasing compression force during preparation of the compact) or by performing a regression analysis From that relationship, tensile strength at a standardized value of solid fraction can be estimated The standardized value selected is one that is representative of the solid fraction of a desired sustained-release tablet, e g, 0 8
 Where the material of the compact is pregelatrmzed starch, it has been found that tensile strength as determined in a simple test as described immediately above is surprisingly close to a "true" tensile strength measurement as determined by the tnaxial tensile strength test method previously described, which in turn is essentially similar to methods known in the art such as that disclosed by Hiestand & Smith (1984), op. at  It has also been found that a longer dwell time (e g , 90 seconds) in the test method of the present invention gives a better correlation with tnaxial tensile strength than a very short dwell time (eg ,4 seconds) See Example 1 below and Figs 1 and 2.  An especially prefen ed starch has a tensile strength of at least about 0 175 kN cm'2, even more preferably at least about 0 2 kN cm"2, at a solid fraction representative of a desired sustained-release tablet
 Even among commercially available pregelatrmzed starches, the preferred type of starch for use m a composition of the present embodiment, considerable variation exists in tensile strength Pregelatinized starches not meeting the tensile strength criterion established herein are not readily identified without testing, for example by a method as disclosed above Such pregelatrmzed starches are generally unsuitable for commercial-scale manufacture of a sustained-release matrix tablet formulation of prarmpexole, because of a problem as set forth immediately below.
 An uncoated tablet, or a tablet core prior to coating, comprising starch and a hydrophihc polymer acting as a matrix for a water-soluble drug or prodrug requires to have a certain minimum hardness in order to be able to resist breakage and/or attrition due to mechanical stresses imposed during a high-speed tabletnxg operation (including all steps up to and including filling of the tablets into containers) The minimum acceptable
hardness will depend on a number of factors, including the seventy of the mechanical sti esses, but is typically at least about 20 SCU, preferably at least about 22 SCU, more preferably at least about 24 SCU (about 17 kp)
 Hardness can be increased by mcreasmg the compression force applied by the tablet press, but only up to a certain level At least in the case of tablets as described herein, above a certain compression force, further increases in compression force give little or no further increase in tablet hardness. There is, in other words, a maximum hardness achievable by compression of a particular starch/hydrophilic polymer/active agent composition A starch providing a maximum hardness inadequate to withstand the mechanical stresses of a high-speed tabletrng operation is unsuitable for the present purpose As shown m Fig 3, certain pregelatrnized starches have been found to provide a maximum hardness of 20 SCU or less, these are now identified as starches having low tensile strength (0 1 kN cm"2 or less accordmg to the test method of the invention utilizing a dwell time of 90 seconds)
 Even if a maximum hardness of at least about 20 SCU is achievable, with a starch of low tensile strength it may be achievable only by use of extremely high compression forces. A requirement for such forces reduces speed and efficiency and increases cost of a tabletrng operation and is undesirable for these reasons.  Where tablets are to be subjected to an additional process step after compression, in particular a coating step, exposure to mechanical stresses is greatly increased Accordmg to a preferred embodiment, therefore, the sustained-release tablet of the invention further comprises a coating
 Particularly for a highly water-soluble salt such as pramipexole dihydrochloride, a hydrophihc polymer matrix is often inadequate to provide sustained release of sufficiently long duration to permit once daily administration It is believed that such a salt is readily leached out of the hydrophihc matrix when contacted by an aqueous medium such as gastrointestinal fluid It is therefore desirable to further slow the process of drug release by providing a release-controlling coating around the tablet. Such a coating typically comprises a hydrophobic or water-msoluble polymer component such as ethyl cellulose together with a hydrophihc or water-soluble pore-forming component such as HPMC.
 Where a starch is used having a tensile strength of at least about 0.15 kN cm"2, preferably at least about 0.175 kN cm"2, more preferably at least about 0 2 kN cm"2, at a
solid fraction representative of the tablet (e g, about 0.75 to about 0.85), the composition is found to be especially suited to a high-speed tabletmg operation that includes a step of coating the tablet with a release-controlling layer
 Alternatives to ethylcellulose and HPMC as components of a release coating layer include other cellulosic polymers (e g , methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, cellulose esters such as cellulose acetate, etc ), polyvinyl acetate, polyvinyl pyrrolidone, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, polyethylene glycol, carrageenan and other gums, and the like
10085] A release-controlling layer, if present, typically constitutes about 1% to about 15%, preferably about 2 5% to about 10%, by weight of the tablet as a whole The hydrophobic or water-insoluble component, preferably comprising ethylcellulose, typically constitutes about 1% to about 10%, preferably about 2% to about 7%, by weight of the tablet as a whole The pore-forming component, preferably comprising HPMC, is typically present in an amount of about 5% to about 50%, preferably about 10% to about 40%, by weight of the water-insoluble or hydrophobic component  The coating, if present, can optionally contain additional pharmaceutically acceptable excipients such as plasticxzers, dyes, etc
 Illustratively, a reJease-controlhng layer in an amount of about 2.5% to about 5% by weight of the tablet core (i e , the tablet weight excluding the coating) comprises an ethylcellulose-based material (e g , Surelease® of Colorcon) and an HPMC-based pore-forming material (e g, Opadry® of Colorcon) m a weight ratio of about 3:1 to about 4:1
 A release-controlling layer or coating should be applied at as uniform a thickness as possible to provide optimum control of release rate of the pramipexole.  Alternatively or m addition, the sustamed-release tablet of the invention comprises a nonfunctional coating A nonfunctional coatmg can comprise a polymer component, for example HPMC, optionally with other ingredients, for example one or more plasticrzers, colorants, etc The term 'nonfunctional" in the present context means havmg substantially no effect on release properties of the tablet, and should not be read to imply that the coatmg serves no useful purpose For example, such a coating can impart a distinctive appearance to the tablet, provide protection against attrition during packaging and transportation, improve ease of swallowing, and/or have other benefits A
nonfunctional coating should be applied in an amount sufficient to provide complete coverage of the tablet. Typically an amount of about 1% to about 10%, more typically an amount of about 2 5% to about 5%, by weight of the tablet as a whole, will be found suitable.
 Uncoated tablets and cores of coated tablets of the present embodiment can optionally contain one or more pharmaceutically acceptable excipients in addition to the starch and hydrophihc polymer components described above Such excipients include without limitation glidants and lubricants Other conventional excipients known in the art can also be included
10091] A glidant can be used to improve powder flow properties prior to and during tableting and to reduce cakmg Suitable glidants include colloidal silicon dioxide, magnesium tnsihcate, powdered cellulose, starch, talc, tnbasic calcium phosphate and the like In one embodiment, colloidal silicon dioxide is included as a glidant in an amount up to about 2%, preferably about 0.2% to about 0.6%, by weight of the tablet  A lubricant can be used to enhance release of a tablet from apparatus on which it is formed, for example by preventmg adherence to the face of an upper punch ("pickmg") or lower punch ("stickmg") Suitable lubricants include magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of about 0.1% to about 1 5%, preferably about 0.3% to about 1%, by weight of the tablet.
 Tablets can be of any suitable size and shape, for example round, oval, polygonal or pillow-shaped, and optionally bear nonfunctional surface markings. Especially in the case of coated tablets they are preferably designed to be swallowed whole and are therefore typically not provided with a breaking score. Dosage unit compositions of the invention can be packaged in a contamer, accompanied by a package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug mteractions and adverse reactions  There is also provided a method of treatment of a subject having a condition or disorder for which a dopamine D2 receptor agonist is indicated, the method comprising orally administering to the subject, not more than once daily, an orally deliverable
pharmaceutical composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of:
(a) an m vitro release profile wherem no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test as defined herein, and
(b) an in vivo pramipexole absorption profile following single dose administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the tune to reach a mean of 40% absorption is greater than about 4 hours
 The method is particularly useful where the condition or disorder is Parkinson's disease or a complication associated therewith
 Suitable daily dosage amounts of pramipexole include 0 375, 0.5, 0.75, 1 0, 1.5, 3 0 and 4 5 rng, expressed as pramipexole dihydrochloride monohydrate
EXAMPLES Example 1
 Pramipexole dihydro chloride sustamed-release tablets were prepared having the compositions shown in Table 1.
Table 1. Composition of pramipexole dihydrochloride tablets of Example 1
 All ingredients except the lubricant (magnesium stearate) were screened to remove lumps and were blended thoroughly in a low-shear mixer operatmg at 24 rpm for 10-30 minutes. The lubricant was then screened into the mixer and the materials were blended for a further 2-5 minutes The resulting lubricated mixture was compressed into 350 mg pillow-shaped tablets using a Kilian S100 tableting machine
 Coated sustained-release tablets of pramipexole dihydrochloride were
prepared having the composition shown in Table 2
Table 2. Composition of coated tablets of Example 2
 Tablet cores were prepared exactly as in Example 1 A coating solution was prepared as follows Opadry® HPMC-based material in an amount of 6 004 g was added to 106 682 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 72 045 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
 The coatmg solution was applied to the tablet cores m an amount providing a 3% weight gam The resultmg coated tablets were cured using a 12 inch (about 30 cm) Vector LCDS or 24 inch (about 60 cm) Thomas Accela-Coata coatmg pan for about 15 minutes at a bed temperature of at least about 70°C After curing, temperature was ramped down over a period of about 8 minutes to an exhaust temperature of about 45°C.
 Coated sustained-release tablets of pramipexole dihydrochloride were
prepared having the composition shown in Table 3.
Table 3. Composition of coated tablets of Example 3
 Tablet cores were prepared exactly as in Example 1 A coatmg solution was prepared as follows. Opadry® HPMC-based material in an amount of 4 801 g was added to 103.041 g water and mixed for 45 minutes to provide an HPMC mixture Next, 76.819 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution
 Coatmg to a 3% weight gain and curing of the coated tablets were performed exactly as in Example 2.
 Coated sustained-release tablets of pramrpexole dihydrochloride were
prepared having the composition shown in Table 4
Table 4. Composition of coated tablets of Example 4
 Tablet cores were prepared exactly as m Example 1. A coatmg solution was prepared as follows. Opadry® HPMC-based material m an amount of 10 003 g was added to 177 737 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 120 03 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coatmg solution  Coatmg to a 3% weight gam and curmg of the coated tablets were performed exactly as in Example 2 After this first curing step, coatmg was repeated to provide a total tablet weight gam of about 5%, followed by curmg for about 15 minutes at a bed temperature of at least about 70°C After curmg. temperature was ramped down over a period of about 8 minutes to an exhaust temperature of about 45°C
 Coated sustained-release tablets of pramipexole dihydrochloride were
prepared having the composition shown in Table 5.
Table 5. Composition of coated tablets of Example 5
 Tablet cores were pi epared exactly as in Example 1. A coating solution was
prepared as follows Opadry® HPMC-based material m an amount of 8 002 g was added
to 171 735 g water and mixed for 45 minutes to provide an HPMC mixture. Next,
128 032 g Surelease® ethylcellulose-based material was added to the HPMC mixture and
mixed for an additional 30 rmnutes to provide a coating solution.
 Coating to a 5% total weight gain and curing of the coated tablets were
performed exactly as in Example 2
 Dissolution profiles of the pramipexole dihydrochloride tablets of each of Examples 1, 2 and 5 were evaluated in a standard in vitro USP dissolution assay under the following conditions. USP apparatus 1 was used to stir a dissolution medium (900 ml of 0.05M phosphate buffer at a pH of 6 8) at a spindle rotation speed of 100 rpm and a temperature of 37°C.
 Data are shown m Fig. 1. The uncoated tablet of Example 1 and the tablet of Example 2 having a 3% coating comprismg 25% pore-former exhibited very similar overall dissolution profiles On close mspection, however, it will be noticed that the uncoated tablet of Example 1 showed faster initial dissolution, such that at 1 hour and 2 hour sampling times the percent dissolved was greater, than in the case of the coated tablet of Example 2. For example, at 1 hour, the coated tablet of Example 2 showed only 11% dissolution, while the uncoated tablet of Example 1 showed 15% dissolution. Similarly, at 2 hours, the coated tablet of Example 2 showed no more than 20% dissolution, while the uncoated tablet of Example 1 showed 24% dissolution  Dissolution of the tablet of Example 5 having a 5% coating comprismg 20% pore-former exhibited a dissolution profile much slower than either the tablet of Example
or the tablet of Example 2
 An in vivo study was conducted in healthy human volunteers to assess bioavailability of pramipexole formulated as the sustained-release or extended-release (XR) tablets of Examples 1,2 and 5 by comparison with a reference treatment with immediate-release (IR) pramipexole dihydrochlonde tablets, and to evaluate safety of pramipexole when its absorption profile is altered as in these extended-release tablets.
Method  The study followed an open-label. 4-way, randomized crossover design and was conducted m healthy male and female subjects rangnig from 18 to 55 years of age The subjects received each of the four treatments during the course of the study, which was conducted at a smgle center A total of 12 subjects were enrolled The subjects were fasted overnight and then given a 0 375 mg oral dose of pramipexole dihydrochlonde monohydrate In the case of the IR formulation, which was provided as Mirapex® tablets, three equally divided doses of 0 125 mg each were given at 8-hour intervals, beginning in the morning In the case of the XR formulations of Examples 1, 2 and 5, a smgle 0.375 mg tablet was given in the morning Serial blood samples were taken over a 48-hour period for PK assessment. Adverse events were recorded during the same 48-hour period
|0116] Plasma pramipexole concentrations were quantitated by an HPLC-MS/MS method, validated over the assay range 0 05-15 ng/ml. All runs met bioanalytical acceptance criteria for calibration standards and quality control Samples were not diluted prior to analysis as all sample concentrations were within the limits of quantitation
 PK parameters for pramipexole were estimated by non-compartmental methods, usmg the nonlinear regression program Kmetica of Innaphase. Individual plasma concentration data and the actual time-points of blood sampling from each subject were used in the analysis. Plasma concentrations below the lower limit of quantitation at early time-points were set to zero, whereas those m the terminal phase were excluded from the analysis.
 In vivo pramipexole absorption data were derived by a deconvolution routine employing the Kmetica program To perform this analysis, a fit of the pramipexole data
from the reference treatment was first made to a one-compartment open PK disposition model with first order absorption. Based on this fit, plasma pramipexole concentrations were simulated for a 0 375 mg intravenous bolus dose of pramipexole. These simulated pramipexole concentrations were used in the deconvolution routme  In vitro/in vivo correlations for each of the pramipexole XR formulations were examined by evaluating a linear relationship of m vivo absorption as a function of in vifro dissolution
 Prediction of mean steady-state concentrations arising from repeated daily dosing was performed by interpolation of hourly concentrations from individual subjects' observed concentration/time data and then by the principle of superposition, estimating the concentrations durmg the 6th day of dosing Estimates of half-life obtained from this study, which were consistent with values reported previously, indicate that steady state would be achieved by the 4th day. The steady-state parameters Tmx, Cmax, Cmm, AUC0-x, Cavg (calculated as AUCo-24/x) and FR (fluctuation ratio, calculated as (Cmax-Cmin)/Cavg) were also estimated during this exercise
Results  Of the 12 subjects enrolled, 10 completed the study TAVO subjects were dropped prior to receiving the reference treatment, therefore their data were not included rn the PK analysis
 Mean plasma pramipexole concentrations over the 48-hour assessment period are shown in Fig 2 PK estimates derived from the individual subject data are provided in Table 6.
Table 6. PK parameters (mean ± standard deviation)
* reached after third 0 125 mg tablet
 Mean cumulative absorption data (up to 24 hours) for the XR tablets are shown in Table 7, together with corresponding in vitro dissolution data from Example 6
Table 7. In vitro dissolution and in vivo absorption data for XR tablets
|0124] In vitro/in vivo correlation plots derived from the data of Table 7 are shown m Figs 3-5 for the XR tablets of Examples 1, 2 and 5 respectively  Estimated PK parameters calculated from predicted steady-state concentrations are given in Table 8.
Table 8. Estimated steady-state PK parameters (mean ± standard deviation)
 The subjects dropped from the study experienced a non-serious adverse event, orthostatic hypotension Both subjects were receivmg treatment with the XR tablet of Example 1 when this adverse event occurred
 No senous adverse events were reported in the study. The most frequently reported event was orthostatic hypotension, all but two of which were considered transient in nature. The numbers of individual non-serious adverse events reported for each treatment are given in Table 9
Table 9. Numbers of non-serious adverse events reported
 The mean plasma pramipexole concentration profile shown m Fig 2 clearly shows the tablets of Examples 1, 2 and 5 effectively extended the release of pramipexole relative to the IR tablet The XR tablets of Examples 1 and 2 exhibit a delay of approximately 1 hour in onset of absorption, whereas quantifiable levels of pramipexole were not observed until about 3 hours after adrmnistration of the XR tablet of Example 5  The derived PK parameters given in Table 6, in particular the Cmax and Tmax data, indicate that of the XR tablets, the tablet of Example 1 exhibited the fastest and the tablet of Example 5 the slowest absorption, the tablet of Example 2 being intermediate in this regard
 The relatively high incidence of non-serious adverse events associated with the tablet of Example 1 suggests that the relatively rapid release of pramipexole from this formulation, leading to a relatively high Cmax, is detrimental to the safety profile of such a formulation On the other hand, the tablets of Examples 2 and 5 exhibit a safety profile that is at least as favorable as the IR tablet administered three times daily. As shown in Table 8, the predicted fluctuation ratio was also greatest for the tablet of Example 1.  As shown in Figs. 3-5, a strong in viiro/in vivo correlation was established within each formulation. Surprisingly, however, the in vifro dissolution data did not clearly distmguish the uncoated tablet of Example 1 from the coated tablet of Example 2, except, as pointed out above, at the earliest sampling trmes.
WE CLAIMS :-
1. An orally deliverable pharmaceutical composition comprising: (a) from 0.05% to 5% by weight pramipexole or a pharmaceutically acceptable salt thereof, as herein described and (b) a release modifying means; wherein said release-modifying means comprises from 20% to 70% by weight of a hydrophilic polymer, as herein described and from 25% to 75% by weight of a starch; as herein described.
2. The composition as claimed in claim 1, wherein said release-modifying means is selected from the group consisting of a polymer matrix wherein the pramipexole is dispersed; a release-controlling layer or coating.
3. The composition as claimed in any of the preceding claims wherein the pramipexole is in a form of a pharmaceutically acceptable salt thereof having moderate to high solubility in water.
4. The composition as claimed in Claim 3, wherein said salt is pramipexole dihydrochloride.
|Indian Patent Application Number||4138/DELNP/2004|
|PG Journal Number||39/2010|
|Date of Filing||27-Dec-2004|
|Name of Patentee||PHARMACIA CORPORATION|
|Applicant Address||700 CHESTERFIELD PARKWAY WEST, CHESTERFIELD, MISSOURI 63017-1732, U.S.A.|
|PCT International Classification Number||A61K 31/428|
|PCT International Application Number||PCT/US2003/023522|
|PCT International Filing date||2003-07-25|