WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intematlonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 =
`A61K 9/24
`
`(11) International Publication Number:
`
`WO 99/47128
`
`(43) International Publication Date:
`
`23 September 1999 (23.09.99)
`
`(21) International Application Number:
`
`PCT/US99/05233
`
`(22) International Filing Date:
`
`10 March 1999 (10.03.99)
`
`(30) Priority Data:
`09/044,446
`
`19 March 1998 (19.03.98)
`
`US
`
`SQUIBB COMPANY
`BRISTOL—MYERS
`(71) Applicant:
`[US/US]; PO. Box 4000, Princeton, NJ 08543—4000 (US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ,
`TM, TR, 'I'I‘, UA, UG, UZ, VN, YU, ZW, ARIPO patent
`(GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`release delivery system for treating diabetes are also provided.
`
`Irby,
`5 Heathbank Avenue,
`(72) Inventors: TIMMINS, Peter;
`Merseyside L61 4XD (GB). DENNIS, Andrew, B.; 7 Pear Published
`Tree Close, Bamston, Merseyside L60 lYD (GB). VYAS,
`With international search report.
`Kiren, A.; 34 Adisham Green, Sittingboume, Kent ME10
`23R (GB).
`
`(74) Agents: RODNEY, Burton et al.; Bristol—Myers Squibb Com-
`pany, PO. Box 4000, Princeton, NJ 085434000 (US).
`
`(54) Title: BIPHASIC CONTROLLED RELEASE DELIVERY SYSTEM FOR HIGH SOLUBILITY PHARMACEUTICALS AND
`METHOD
`
`(57) Abstract
`
`A biphasic controlled release delivery system for pharmaceuticals which have high water solubility, such as the antidiabetic metforrnin
`HCl salt, is provided which provides a dosage form that has prolonged gastric residence and includes ( 1) an inner solid particulate phase
`formed of substantially uniform granules containing a pharmaceutical having a high water solubility, and one or more hydrophilic polymers,
`one or more hydrophobic polymers and/or one or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid
`esters, and (2) an outer solid continuous phase in which the above granules of inner solid particulate phase are embedded and dispersed
`throughout, the outer solid continuous phase including one or more hydrophilic polymers, one or more hydrophobic polymers and/or one
`or more hydrophobic materials such as one or more waxes, fatty alcohols and/or fatty acid esters, which may be compressed into tablets or
`filled into capsules. Methods for forming the so—described biphasic controlled release delivery system and using such biphasic controlled
`
`AUROBINDO EX. 1013, ‘l
`
`AUROBINDO EX. 1013, 1
`
`

`

`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`I-IU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`AUROBINDO EX. 1013, 2
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`AUROBINDO EX. 1013, 2
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`

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`WO 99/47128
`
`PCT/US99/05233
`
`BIPHASIC CONTROLLED RELEASE DELIVERY SYSTEM
`
`FOR HIGH SOLUBILITY PHARMACEUTICALS AND METHOD
`
`Field of the Invention
`
`The present invention relates to a new dosage form
`
`for highly water soluble medicaments, such as the
`
`antidiabetic metformin, which provides for extended release
`
`of the drug and also for prolonged gastric residence which
`
`enables efficient delivery of drugs normally absorbed in
`
`the upper gastrointestinal tract, and to a method for
`
`preparing such dosage form.
`
`Background of the Invention
`
`Metformin is an antihyperglycemic agent of the
`
`biguanide class used in the treatment of non—insulin
`
`dependent diabetes mellitus
`
`(NIDDM).
`
`It is usually
`
`marketed in the form of its hydrochloride salt as
`
`Glucophage® (TM~BMS).
`
`Metformin hydrochloride has intrinsically poor
`
`permeability in the lower portion of the gastrointestinal
`
`tract leading to absorption almost exclusively in the upper
`
`part of the gastrointestinal tract.
`
`Its oral
`
`bioavailability is in the range of 40 to 60% decreasing
`
`with increasing dosage which suggests some kind of
`
`saturable absorption process, or permeability/transit time
`
`limited absorption.
`
`It also has a very high water
`
`solubility (>300 mg/ml at 25°C). This can lead to
`
`difficulty in providing a slow release rate from a
`
`formulation and problems in controlling the initial burst
`
`of drug from such a formulation. These two difficulties
`
`are further compounded by the high unit dose, 500 mg per
`
`tablet, usually required for metformin hydrochloride (1997—
`PDR) .
`
`Drugs that have absorption limited to the upper
`
`gastrointestinal tract coupled with poor absorption in the
`
`distal small intestine,
`
`large intestine and colon are
`
`usually regarded as inappropriate candidates for
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`AUROBINDO EX. 1013, 3
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`AUROBINDO EX. 1013, 3
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`WO 99/47128
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`
`formulation into oral controlled delivery systems. This
`
`limitation on absorption (for example,
`
`in the upper
`
`gastrointestinal tract) is referred to as the "absorption
`window".
`
`The gastrointestinal tract functions to propel
`
`ingested material from the stomach (where digestion takes
`
`place)
`
`into the small intestine (where absorption
`
`principally occurs) and on to the large intestine (where
`
`water is absorbed/secreted as part of body fluid regulation
`
`processes). Residence time for non—digestible materials in
`
`the stomach depends on whether one is dealing with a fed or
`
`a fasted subject. Typical gastric emptying times for
`
`particulate material (greater than a few millimeters in
`
`diameter) varies from a few tens of minutes in the fasted
`
`state to a few hours in the fed state. Transit times
`
`through the small intestine are consistently of the order
`of 3 to 4 hours.
`
`Oral controlled release delivery systems function by
`
`releasing their payload of drug over an extended period of
`
`time following administration. Thus,
`
`controlled release
`
`dosage forms may only spend a relatively short period in
`
`the regions of the gastrointestinal tract where good
`
`absorption of certain drugs can occur.
`
`The dosage form
`
`will pass on to regions of the intestine where absorption
`
`of certain drugs is poor or non—existent, still releasing
`
`its contained drug albeit with a significant percentage of
`
`its payload still to be delivered. Drug when released from
`
`the dosage form in the circumstances described will not be
`
`absorbed. Thus, administration of a drug subject to a
`
`window of absorption in a conventional controlled release
`
`delivery system can lead to subtherapeutic blood levels and
`
`ineffective treatment of the disease state for which the
`
`drug was intended.
`
`Drugs with very high solubility in water (for
`
`example,
`
`greater than 100 mg/ml)
`
`can be difficult to
`
`formulate into a controlled release oral dosage form.
`
`Solubility is a driving force for a drug substance to
`
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`AUROBINDO EX. 1013, 4
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`
`dissolve in water;
`
`the greater the solubility the greater
`
`the rate of dissolution when all other factors are
`
`maintained constant.
`
`In a controlled release dosage form,
`
`the formulator
`
`tries to reduce the rate of dissolution by,
`
`for example,
`
`embedding the drug in a polymeric matrix or surrounding it
`
`with a polymeric barrier membrane through which drug must
`
`diffuse to be released for absorption.
`
`To reduce the rate
`
`of release of drug from the dosage form to an appropriate
`
`level consistent with the blood level profile desired for a
`
`drug possessing very high water solubility, very large
`
`amounts of polymer would be required for the matrix or
`
`barrier membrane.
`
`If the total daily dose of drug to be
`
`delivered is of the order of only a few milligrams this may
`
`be feasible, but many drugs having the solubility
`
`properties described require total daily doses of the order
`
`of many hundreds of milligrams. Whilst it is possible to
`
`create oral controlled release dosage forms for such
`
`products by use of large amounts of polymer, an
`
`unacceptably large dosage form may result.
`
`A further problem with highly water soluble drugs
`
`formulated into a controlled release dosage form is that a
`
`significant and variable "burst" of drug can occur from
`
`these systems.
`
`The burst of highly water soluble drug is
`
`the initial rapid release of drug that occurs from oral
`
`controlled release dosage forms when first contacting
`
`fluid, such as gastric fluids, prior to release controlling
`
`mechanisms of the dosage form establishing themselves and a
`
`stable release rate being provided. Hydration of any
`
`polymer matrix used to formulate the dosage form is a pre—
`
`requirement of establishing a stable release rate. Thus, a
`
`readily hydrating polymer is required to establish the
`
`desired stable release rate. However,
`
`if the polymer used
`
`10
`
`15
`
`20
`
`25
`
`30
`
`is slow to hydrate,
`occur.
`
`35
`
`then an undesireable variable burst can
`
`Studies by Vidon et a1 (1)
`
`strongly suggest that
`
`there is permeability limited absorption of metformin.
`
`AUROBINDO EX. 1013, 5
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`
`Perfusing drug into the jejunum via an intubation technique
`
`showed a 2.5 fold greater area under the plasma
`
`concentration—time profile (a measure of the quantity of
`
`drug absorbed) compared with similar introduction of drug
`
`into the ileum. Drug was not detectable in plasma when
`
`drug was perfused into the colon. Drug will transit down
`
`the small intestine following dissolution from an ingested
`
`dosage form and, if absorption rate is slow, it is possible
`
`that drug can reach regions of poor permeability before
`
`absorption of a given dose is complete.
`
`In such a case,
`
`increasing the given dose may be predicted to result in a
`
`reduction in the percentage of administered dose absorbed.
`
`Improvements in the therapeutic regimes employing
`
`metformin might be achieved by a dosage form that allows a
`
`reduction in dosing frequency, providing patient
`
`convenience that would probably improve compliance.
`
`Conventional extended release formulations have been
`
`demonstrated to invariably compromise the availability of
`
`metformin (2). This is probably because the dosage form
`
`carries a significant proportion of the drug content
`
`remaining to be released, as the dosage form is carried to
`
`regions of the gastrointestinal tract with very poor
`
`permeability to the drug.
`
`To reduce dosing frequency,
`
`the
`
`rate of release from the dosage form must be such as to
`
`extend effective plasma levels, but the potential for
`
`effective delivery at this rate is compromised by the
`
`combined influences of the significant reduction in
`
`permeability to the drug in passing from the proximal small
`
`intestine down to the colon and the limited residence time
`
`in the regions of the gastrointestinal tract where the drug
`
`is well absorbed. That transit time down the "useful"
`
`region of the gastrointestinal tract is only likely to be
`
`of the order of a few hours.
`
`Maintained or even improved bioavailability from an
`
`extended release dosage form that releases metformin at a
`
`rate likely to provide the desired plasma levels of drug
`
`for an extended time period might, however, be possible
`
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`15
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`
`AUROBINDO EX. 1013, 6
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`AUROBINDO EX. 1013, 6
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`WO 99/47128
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`
`from a dosage form that has extended residence time in the
`
`upper gastrointestinal tract, resisting mechanisms that
`
`promote normal transit time for solid materials.
`
`That this
`
`principle might work in practice was demonstrated in an in—
`
`house study where metformin was co—administered with
`
`propantheline, an agent that reduces gastrointestinal
`
`motility. Compared with giving metformin alone,
`
`the
`
`combination provided an increased AUC, a delayed tmax and
`
`an extended time period over which therapeutically
`
`beneficial plasma levels of drug were maintained.
`
`Giving a drug such as metformin for the treatment of
`
`diabetes with a further drug, such as propantheline, not
`
`used for the treatment of diabetes and where the sole
`
`intent of using the second agent is to achieve extended
`
`residence time in the upper GI tract, has many
`
`disadvantages although it is likely to allow effective
`
`extended delivery of metformin to an optimal absorption
`
`site.
`
`The co—administered drug may have other undesirable
`
`pharmacological effects or side effects deleterious to the
`
`patients well being and detract from the improved quality
`
`of life offered by the treatment for their diabetes.
`
`Furthermore, it may be difficult or impossible to
`
`appropriately co—formulate the two agents
`
`due to chemical
`
`compatibility issues or solubility differences,
`
`the latter
`
`preventing the required release rate of agent influencing
`
`residence time in the upper GI tract.
`
`Thus,
`
`the patient
`
`could be required to take separate, multiple medications to
`
`achieve the desired effect.
`
`The timing of taking the two
`
`medications would be critical to effective delivery of the
`
`drug with the limited window of absorption and many
`
`patients may thus fail to take their medication correctly
`
`resulting in ineffective treatment of their diabetes.
`
`Prior Art Gastro—Retentive Systems
`
`It would be desirable to provide a dosage form that
`
`inherently has the property of extended gastric residence,
`
`possessing some resistance to the pattern of waves of
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`AUROBINDO EX. 1013, 7
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`AUROBINDO EX. 1013, 7
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`WO 99/47128
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`PCT/US99/05233
`
`motility present in the gastrointestinal tract that serve
`
`to propel material through it. There have been many
`
`attempts to provide for this, with varying degrees of
`success .
`
`Possible approaches described in prior art include:
`
`Floating or buoyant systems:
`
`These are designed to have a low density and thus
`
`should float on gastric contents after
`
`administration until the system either disintegrates
`
`(and presumably the resultant particles empty from
`
`the stomach) or the device absorbs fluid to the
`
`point where its density is such that it loses
`
`buoyancy and can pass more easily from the stomach
`
`with a wave of motility responsible for gastric
`
`emptying.
`
`Bioadhesive systems:
`
`These are designed to imbibe fluid following
`
`administration such that the outer layer becomes a
`
`viscous,
`
`tacky material that adheres to the gastric
`
`mucosa/mucus layer. This should encourage gastric
`
`retention until the adhesive forces are weakened for
`
`example by continuing hydration of the outer layer
`
`of the device or by the persistent application of
`
`shear.
`
`Swelling and expanding systems:
`
`These are designed to be sufficiently small on
`
`administration so as not to make ingestion of the
`
`dosage form difficult (for example,
`
`less than
`
`approximately 23 mm long and less than ll mm wide
`
`for an oval or capsule-shaped tablet).
`
`On ingestion
`
`they rapidly swell or unfold to a size that
`
`precludes passage through the pylorus until after
`
`drug release has progressed to a required degree.
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`AUROBINDO EX. 1013, 8
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`AUROBINDO EX. 1013, 8
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`PCT/US99/05233
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`Gradual erosion of the system or its breakdown into
`
`smaller particles enables it to leave the stomach.
`
`Re :
`
`l
`
`Buo ant floatin svstems
`
`Buoyant systems designed to float on the gastric
`
`contents have been designed where buoyancy is created by
`
`low density of the formulation components.
`
`For example,
`
`Watanabe et al
`
`(3) used low density shells such as
`
`spherical polystyrene foam particles in which polymer and
`
`drug layers were loaded.
`
`Such a system has the required
`
`low density and will not need to disintegrate into small
`
`pieces to empty from the stomach, but may not have a
`
`controlled loss of density alternatively required for it to
`
`eventually exit from the stomach.
`
`It also has limited
`
`capacity for loading with drug in the thin layers that can
`
`be applied around the polystyrene shells.
`
`It would be
`
`difficult to also layer large amounts of polymer on such a
`
`system to retard the release of very water soluble drugs.
`
`Sheth described hydrodynamically balanced systems
`
`including both capsules and tablets
`
`(4,5,6) which had low
`
`density to enable floating on the stomach contents and
`
`which slowly eroded after administration,
`
`losing buoyancy
`
`and being expelled from the stomach.
`
`Buoyancy can also be combined with control of drug
`
`release at different pH values to make for a device with
`
`better control in case of drugs with very marked dependency
`
`of solubility on pH (7); hence dissolution of contained
`
`drug depending on environment pH.
`
`These approaches may be applicable to many drugs
`
`dosed in doses of up to a maximum of a few hundred
`
`milligrams per day but may not be applicable to similar or
`
`higher dose levels of highly water soluble drugs.
`
`Where
`
`large amounts of polymer are needed to retard drug release
`
`as in the case of use of high water soluble drugs a capsule
`
`dosage form may not be possible on grounds of size.
`
`Furthermore,
`
`the relatively homogenous distribution of drug
`
`in the tablet versions of this technology would not readily
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`AUROBINDO EX. 1013, 9
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`AUROBINDO EX. 1013, 9
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`WO 99/47128
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`control the burst effect seen with a very water soluble
`
`drug.
`
`A bilayer tablet approach (8) where the buoyancy
`
`generation comes from a separate layer to the drug
`
`containing layer having a release rate controlling property
`
`might overcome some of the problems seen with the
`
`hydrodynamically balanced systems, but this type of system
`
`would probably only be able to carry low drug payloads due
`
`to size constraints.
`
`Approaches involving ig sitg gas generation within
`
`the system, where the gas is trapped within the dosage form
`
`on generation, encouraging buoyancy, might offer improved
`
`control over degree, onset time and persistence of
`
`buoyancy.
`
`Ichikawa (9) described such a device with a drug
`
`loaded core surrounded by the gas generating layer, which
`
`in turn was surrounded by a polymeric layer responsible for
`
`controlling drug release from the system.
`
`Such floating or buoyant dosage forms seem to have
`
`met with limited clinical success due to the requirement
`
`that such dosage forms be taken with a suitable amount of
`
`fluid
`
`(normal gastric contents could be as little as a few
`
`tens of milliliters so that the total amount of fluid thus
`
`10
`
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`
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`
`available would not be conducive to performance of such
`
`systems even when taken with a draught of water). Davis et
`
`25
`
`al
`
`(10)
`
`found no benefit of floating formulations over non—
`
`floating formulations when studied in vivo.
`
`Their
`
`performance may also be posture dependent.
`
`A patient
`
`sitting upright may ensure prolonged gastric residence of a
`
`buoyant dosage form, whereas a supine patient might allow
`
`30
`
`35
`
`ready presentation of the floating dosage form to the
`
`pylorus and thus allow rapid exit of the dosage form from
`
`the stomach
`
`(ll).
`
`The physical size of such dosage forms
`
`seems to be as important if not more important as ability
`
`to float in encouraging prolonged gastric residence.
`
`Hence,
`
`floating/buoyant dosage forms might be expected to
`
`only have limited applications.
`
`AUROBINDO EX. 1013, 10
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`AUROBINDO EX. 1013, 10
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`WO 99/47128
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`Re:
`
`2
`
`Bioadhesive s stems
`
`Polycarbophil has been identified as a suitable
`
`polymer for encouraging adhesion of orally administered
`
`dosage forms to the gastric mucosa,
`
`thereby prolonging
`
`residence time for a system designed to slowly deliver drug
`
`to absorptive sites in the proximal small intestine (Longer
`
`et al, J. Pharm. Sci., 74, 406—411 (1985)).
`
`The success
`
`seen in animal models with such systems has been found not
`
`to translate to human subjects due to differences in mucous
`
`amounts, consistency and turnover between animals and
`
`humans. Bioadhesive systems allow dosage forms to adhere
`
`to mucous, not mucosa.
`
`The mucous layer in humans would
`
`appear to slough off readily, carrying any dosage form with
`
`it. Therefore, bioadhesive dosage forms would not appear
`
`to offer a solution for extended delivery of drug over a
`
`period of more than a few hours to the upper small
`
`intestine in humans.
`
`Re:
`
`3
`
`Swellin e
`
`andin
`
`s stems
`
`Other solutions to encouraging prolonged gastric
`
`residence have included dosage forms that unfold rapidly
`
`within the stomach to a size that resists gastric emptying.
`
`Such systems retain their integrity for an extended period
`
`and will not empty from the stomach at all until breakdown
`
`into small pieces occurs.
`
`Caldwell
`
`(12)
`
`describes a cross
`
`shaped device made of erodible polymer and loaded with drug
`
`which is folded and inserted into a hard gelatin capsule.
`
`Following oral administration the gelatin shell
`
`disintegrates and the folded device opens out.
`
`With a
`
`minimum size of l.6cm and a maximum size of 5cm it will not
`
`pass from the stomach through the pylorus until the polymer
`
`erodes to the point where the system is sufficiently small
`
`that it can be passed from the stomach.
`
`Such a system may
`
`in fact obstruct the pylorus or even open earlier or later
`
`than intended possibly causing obstruction in the esophagus
`
`or small intestine. As such, it may represent a potential
`
`hazard to the patient.
`
`10
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`15
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`WO 99/47128
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`PCT/US99/05233
`
`An alternate approach to using size to modulate
`
`gastric residence of a dosage form is to use a hydrophilic
`
`erodible polymer system that is of a convenient size for
`
`administration to humans.
`
`On imbibing fluid the system
`
`swells over a short period of time to a size that will
`
`encourage prolonged gastric retention, allowing sustained
`
`delivery of contained drug to absorption sites in the upper
`
`gastrointestinal tract. Because these systems are made of
`
`an erodible and hydrophilic polymer or polymer mixture,
`
`they readily erode over a reasonable time period to pass
`
`from the stomach.
`
`The time period of expansion is such
`
`that this will not occur in the esophagus and if the system
`
`passes into the intestine in a partially swollen state,
`
`the
`
`erodibility and elastic nature of the hydrated polymer will
`
`eliminate the chance of intestinal obstruction by the
`device.
`
`Mamajek et al, U.S. Patent No. 4,207,890,
`
`describes
`
`a system wherein a drug release rate controlling (metering)
`
`Component and a swelling component are mixed with drug
`
`enclosed within a membrane.
`
`The swelling component draws
`
`in fluid through the membrane, which maintains system
`
`integrity during its functioning, and the drug metering
`
`component controls the rate of drug release through the
`
`membrane.
`
`Urquart
`
`(13) describes a different approach which
`
`consists of a matrix of hydrogel that imbibes fluid to
`
`swell the system so that it reaches a size encouraging
`
`prolonged gastric retention. This matrix surrounds a
`
`plurality of tiny pills consisting of drug with a release
`
`rate controlling wall of fatty acid and wax surrounding
`
`each of the pills.
`
`Shell
`
`(14,15,16) has described systems for
`
`delivering drugs for the treatment of diseases of the upper
`
`gastrointestinal tract or for delivering drugs that might
`
`be irritating or injurious to the gastrointestinal mucosa.
`
`A swelling hydrogel polymer has embedded within it drug
`
`particles that dissolve once the hydrogel matrix is
`
`-10-
`
`10
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`WO 99/47128
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`PCT/US99/05233
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`hydrated.
`
`The swollen matrix is of a size to encourage
`
`gastric retention but only dissolved drug reaches the
`
`mucosa and this can be delivered in a sustained manner.
`
`Such a system thus does not insult the mucosa with solid
`
`particles of irritant drug and is suitable for delivering
`
`drug to upper gastrointestinal tract. These systems only
`
`apply in case of drugs of limited water solubility.
`
`In the case of metformin, it is desirable to provide
`
`a dosage form that allows extended delivery of the drug and
`
`has a prolonged gastric residence via swelling of the
`
`system rather than unfolding or expanding of a folded
`
`device, and that may be manufactured on a commercial scale.
`
`The prolonged gastric residence time is required due to the
`
`window of absorption seen with metformin.
`
`Another problem for extended delivery of metformin
`
`is its very high water solubility. High levels of polymer
`
`would be needed if many prior art approaches to provide the
`
`required release rate are employed. This could result in a
`
`rapid and variable initial release
`
`(burst)
`
`of drug from an
`
`extended release dosage form.
`
`The latter will thus give
`
`rise to difficulty in providing a true control of drug
`
`release and minimal inter—patient variability in drug
`
`plasma levels (arising from the possibility of variable
`
`burst of drug from tablets given to different patients).
`
`Prior Art gontrolled Release Systems for Very Soluble Drugs
`
`Typical prior art techniques for creating a
`
`controlled release oral dosage form would involve either
`
`matrix systems or multi particulate systems. Matrix
`
`systems may be formulated by homogeneously mixing drug with
`
`hydrophilic polymers, such as hydroxypropylmethylcellulose,
`
`hydroxypropylcellulose, polyethylene oxide, carbomer,
`
`certain methacrylic acid derived polymers,
`
`sodium alginate,
`
`or mixtures of components selected from these, and
`
`compressing the resultant mixture into tablets (employing
`
`some other excipients where needed). Hydrophobic polymers,
`
`-11-
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`WO 99/47128
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`PCT/US99/05233
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`such as ethyl cellulose, certain polymeric methacrylic acid
`
`esters, cellulose acetate butyrate, poly(ethylene-co—vinyl—
`
`acetate) may be uniformly incorporated with the above
`
`materials to give additional control of release.
`
`A further
`
`alternative involves embedding drug within a wax based
`
`tablet, by granulation or simply mixing of drug with a wax,
`
`such as carnauba wax, microcrystalline wax or commercially
`
`available purified fatty acid esters. As noted above, it
`
`may not be possible to use these approaches with very
`
`highly water soluble drugs.
`
`Multi particulate systems consist of a dosage form
`
`based on a plurality of drug loaded spheres, prepared by
`
`layering drug onto a core, usually a sugar~starch mixture
`
`sphere of around 0.8mm diameter, until a sufficient level
`
`is reached, and then providing a drug release barrier
`
`around the drug—loaded sphere. Drug—loaded spheres can
`
`also be made by wet massing a mixture of drug and
`
`excipients,
`
`forcing the wet mass through a perforated
`
`screen to form short strands which are rounded in a
`
`spheronisation apparatus before drying and having the drug
`
`release barrier applied.
`
`The drug release barrier can be a
`
`wax, such as carnauba wax or glyceryl fatty acid esters, or
`
`a polymeric barrier, such as a mixture of ethyl cellulose
`
`and hydroxypropylmethylcellulose. These work well for
`
`moderately soluble drugs with doses in the units of
`
`milligrams to less than a few hundred milligrams per day.
`
`In several examples, prior art systems seem to
`
`provide a controlled release formulation of a very water
`
`soluble drug by improving the multi particulate system
`
`approach. Fisher discloses a multi particulate system for
`
`highly soluble drugs especially opiate agonists (17) based
`
`on drug containing cores surrounded by a drug release
`
`controlling barrier which has the property of being
`
`partially soluble at a highly acidic pH.
`
`Hansraj
`
`(18)
`
`coats drug loaded cores with
`
`methacrylic or acrylic acid derived polymers whose
`
`properties are modified by inclusion of at least one
`
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`WO 99/47128
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`PCT/US99/05233
`
`anionic surfactant.
`
`In such a system, drug release of
`
`highly water soluble drugs is controlled without having to
`
`resort to the use of thick coatings on the release rate
`
`controlling layer.
`
`Rollet
`
`(l9) achieves prolonged release of a drug
`
`from a multi particulate formulation based on fine
`
`particles of hydrophilic and hydrophobic silicas or
`silicates.
`
`this system would function for
`
`Presumably,
`
`drugs of high water solubility.
`
`10
`
`15
`
`Multi particulate systems are usually filled into
`
`capsules to provide unit dose forms because of the damage
`
`caused to such particles in trying to compress them into
`
`tablets. Total dose contained in a single unit is
`
`constrained by the loading possible in a hard gelatin
`
`capsule of easily swallowable size and is usually not more
`
`than a few hundred milligrams.
`
`Single unit controlled release systems applicable to
`
`highly water soluble drugs include the application of
`
`multiple layers around a dose form as described by Howard
`
`20
`
`(20).
`
`Where coating is not employed, special mixtures of
`
`polymers or formation of a complex with the drug have been
`used.
`
`Macrae (21) uses mixtures of polyethylene oxide and
`
`hydroxypropylmethylcellulose with optional enteric polymers
`
`to produce a constant release rate for highly water soluble
`
`drugs. Belenduik (22) combines the highly water soluble
`
`drug with a hydrophilic polymer based on acrylic acid and
`
`disperses this in a hydrophobic matrix.
`
`Variations of Alza osmotic systems have been
`
`described suitable for highly water soluble drugs such as
`
`venlafaxine hydrochloride
`
`(23).
`
`These systems need two
`
`layers, a drug layer and an osmotically driven displacement
`
`layer all surrounded by a water permeable/drug impermeable
`
`membrane with an exit passage in this membrane for the
`
`drug.
`
`Granules of highly water soluble clavulanate were
`
`prepared (24) having to employ a barrier layer of a
`
`hydrophobic waxy material in order to provide for
`
`25
`
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`
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`WO 99/47128
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`PCT/US99/05233
`
`controlled release of this material when co—formulated with
`
`controlled release amoxycillin trihydrate granules in
`
`capsule or compressed tablet.
`
`5
`
`Description of the Invention
`
`In accordance with the present invention, a novel
`
`way has been found of formulating drug with high water
`
`solubility and a limited window of absorption such as
`
`metformin or a salt thereof which has a window of
`
`10
`
`absorption in the upper gastrointestinal tract,
`
`to provide
`
`a dosage form that inherently has prolonged gastric
`
`residence. This is accomplished (a) without need for co—
`
`administration of a drug such as propantheline,and (b)
`
`without need for low density formulation or gas generation
`
`15 within the formulation, The formulation of the invention
`
`(a) achieves extended gastric residence by virtue of size
`
`but will degrade in yiyg so as not to have potential for
`
`causing gastric or intestinal obstruction, and (b) controls
`
`drug release adequately where the initial burst of drug is
`
`20
`
`under control.
`
`The formulations of the invention will
`
`provide for an extended release formulation of drug with
`
`minimal interpatient variability in pharmacokinetic
`
`parameters.
`
`The invention is applicable to all drugs having high
`
`25 water solubility and a limited window of absorption.
`
`The biphasic controlled release delivery system of
`
`the invention is a heterogeneous two phase system which
`
`includes (1) an inner solid particulate phase in the form
`
`of individual granules or particles containing (a) drug
`
`30 which has a high water solubility and a limited window of
`
`absorption (such as in the upper gastrointestinal tract),
`
`and (b) an extended release material formed of one or more
`
`hydrophilic polymers, and/or one or more hydrophobic
`
`polymers, and/or one or more other type hydrophobic
`
`35
`
`compounds
`
`(such as one or more waxes, fatty alcohols and/or
`
`fatty acid esters), and (2) an outer solid continuous phase
`
`in which granules or par