(12) United States Patent
`(10) Patent N0.:
`US 6,475,521 B1
`
`Timmins et al.
`(45) Date of Patent:
`Nov. 5, 2002
`
`USOO6475521B1
`
`(54) BIPHASIC CONTROLLED RELEASE
`DELIVERY SYSTEM FOR HIGH
`SOLUBILITY PHARMACEUTICALS AND
`METHOD
`
`(75)
`
`Inventors: Peter Timmins, Irby; Andrew B.
`Dennis, Barnston; Kiren A. Vyas,
`Canterbury, all of (GB)
`.
`.
`.
`.
`(73) ASSignee: Bristol-Myers Squibb C0., Princeton,
`NJ (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U S C 154(b) by 0 days
`'
`'
`'
`'
`09/398 10
`,
`
`7
`
`Sep. 16’ 1999
`
`(
`
`21
`
`)
`
`(22)
`
`1
`App . No.:
`.
`.
`Flled’
`
`(63)
`
`51
`()
`
`.
`.
`Related U'S' Application Data
`.
`.
`.
`.
`.
`Continuation—in—part of application No. 09/044,446, filed on
`Man 19’ 1998’ now abandoned
`Int. Cl.
`............................ A61K 9 22’ A61K 9 26’
`7
`/,
`/,
`A61K 9/52
`....................... 424/469; 424/468; 424/457,
`(52) us. Cl.
`424/470, 424/484; 424/485; 424/486; 424/488;
`514/7723; 514/779; 514/781; 514/951
`(58) Field Of Search ................................. 424/464, 465,
`424/468> 469, 470, 457, 484, 485, 486,
`488, 472, 473
`
`EP
`E11:
`W0
`W0
`WO
`W0
`W0
`‘ZVAD
`ZA
`
`502642 A1
`£3223; A1
`WO93/18755
`WO94/27557
`94/27589
`W0 96/031996
`WOW/£814
`W0 93437733
`957670
`
`*
`
`9/1992
`3433‘;
`9/1993
`12/1994
`12/1994
`3/1996
`5/1997
`1341332
`9/1995
`
`OTHER PUBLICATIONS
`
`Chem. Ab’ 126229547 MP Gouldson et al*. 1991*
`Chem. Ab’“13.2’83528 Je Pinko et al. 1999’
`.
`Noel, M., Kinetic study.of normal and sustained release
`dosage forms of metformin in normal subjects”, Journal of
`International Biomedicl Information and Data, 1980, pp.
`9_20.
`Karttunen, P. et al, “The pharmacokinetics of metformin: a
`comparison of the properties of a rapid—release and a
`sustained—release preparation”, Int. J. Clin. Pharmacology,
`Therapy & Toxicology, vol. 21, No. 1, pp. 31—36.
`Vidon, N. et al, “Metformin in the digestive tract”, Diabetes
`Research and Clinical Practice, 4 (1988) 223_229.
`Pentikainen, P.J., “Bioavailability of metformin. Compari-
`son 0 50 HUGH, Pa 1
`1550 VH1
`ta eta an t Pee SUStalne
`fl'
`p'dlyd'
`l'gbl
`dh
`'d
`release products”, Int’l Journal of Clin. Pharm., Therapy and
`E0X1C01°fy>124j> N°~ 11> 19151? 213—2?” 1 S .
`1 74
`’
`Ngnfierp; 1562333; lgeggnaceu lea
`Clences’ V0 ‘
`Davis’et al., Pharmaceutical Research, vol. 3, No. 4, pp.
`208—213, 1986.
`Timmermans et al., Journal of Pharmaceutical Sciences, vol.
`83, No. 1, pp. 18—24, Jan. 1994.
`
`(56)
`
`References Cited
`
`* cited by examiner
`
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`5,645,858 A
`3,3??ng 2
`6:099:859 A
`6,099,862 A
`6,340,475 B2
`2001/0018070 A1
`
`U.S. PATENT DOCUMENTS
`.
`8/1976 Sumio et 211.
`11/1978 Sheth et a1.
`2/1979 Sheth et 211.
`9/1979 Sheth .et a1~
`6/1980 Mamalek etal’
`11/1982 Schor
`1/1983 Schor et a1.
`2/1984 Urquart et a1.
`11/1987 Alderman
`12/1987 Okada et a1.
`8/1988 Caldwell et a1.
`5/1989 Elger 6t a1~
`7/1989 IChikawa 6t a1~
`9/1990 Yamamom et al‘
`4/1991 Shell
`12/1992 Dennis et 211.
`8/1993 Franz et a1.
`12/1994 Newton et a1.
`1/1996 Rudnic et a1.
`11/1996 Kamei et a1.
`12/1996 Shell
`7/1997 K0twa1 6t a1~
`134333 iiiglfie‘i’teilél
`8/2000 Cheng et a1.
`8/2000 Chen et a1.
`1/2002 Shell et a1.
`8/2001 Shell et 211.
`
`............... 424/464
`................. 424/473
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`
`4414544 C2
`
`11/1994
`
`Primary Examiner—James M. Spear
`(74) Attorney, Agent, or Firm—Stephen B. Davis
`
`(57)
`
`ABSTRACT
`
`A biphasic controlled release delivery system for pharma-
`ceuticals Which have high water solubility such as the
`t.d. b t.
`tf
`. HCl
`11
`.
`.d d ’h. h
`.d
`ani ia e ic me ormin
`sa ,is prov1 e w ic prov1 es
`a dosage form that has prolonged gastric reSidence so that a
`dosmg regimen of at least one gram metformin, once daily,
`may be achieved While providing effective control of plasma
`glucose. The delivery system 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 hydro:
`hobic ol mers and/or one or more h, dro hobic materials
`P
`P y
`y
`P
`.
`such as one or more waxes, fatty alcohols and/or fatty ac1d
`esters, and (2) an outer solid continuous phase in Which the
`above granules of inner solid particulate phase are embed-
`ded and dispersed throughout, the outer solid continuous
`phase including one or more hydrophilic polymers, one or
`more hydrophobic polymers and/or one or more hydropho-
`bic materials such as one or more waxes, fatty alcohols
`“El/0r fatt3f’ilf1‘3d.65ters’ “1mm 191121111? iomlf’reSSPd mg"
`ta as or
`e
`“”0 caPsu es
`et 0 5 0r ormmg t 6
`so-described biphasic controlled release delivery system and
`using such biphasic controlled release delivery system for
`treating diabetes are also provided.
`
`50 Claims, N0 Drawings
`
`AUROBINDO EX. 1014, 1
`
`AUROBINDO EX. 1014, 1
`
`

`

`US 6,475,521 B1
`
`1
`BIPHASIC CONTROLLED RELEASE
`DELIVERY SYSTEM FOR HIGH
`SOLUBILITY PHARMACEUTICALS AND
`METHOD
`
`REFERENCE TO OTHER APPLICATIONS
`
`This is a continuation-in-part of US. application Ser. No.
`09/044,446 filed Mar. 19, 1998, now abandoned.
`
`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, so that a dosing
`regimen of at least one gram metformin once daily, may be
`achieved while providing effective control of plasma
`glucose, and to a method for treating diabetes employing
`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 perme-
`ability 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 gas-
`trointestinal tract coupled with poor absorption in the distal
`small
`intestine,
`large intestine and colon are usually
`regarded as inappropriate candidates for formulation into
`oral controlled delivery systems. This limitation on absorp-
`tion (for example,
`in the upper gastrointestinal
`tract) is
`referred to as the “absorption window”.
`ingested
`The gastrointestinal
`tract functions to propel
`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 dos-
`age 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
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`to be
`with a significant percentage of its payload still
`delivered. Drug when released from the dosage form in the
`circumstances described will not be absorbed. Thus, admin-
`istration 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 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 dif-
`fuse 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 mem-
`brane. 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 for-
`mulated 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 formu-
`late 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 is slow to hydrate, then an
`undesireable variable burst can occur.
`
`Studies by Vidon et al (1) strongly suggest that there is
`permeability limited absorption of metformin. 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) com-
`pared 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 fol-
`lowing 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 met-
`formin might be achieved by a dosage form that allows a
`reduction in dosing frequency, providing patient conve-
`nience that would probably improve compliance. Conven-
`tional extended release formulations have been demon-
`
`strated to invariably compromise the availability of
`metformin (2), (2A), and (2B). This is probably because the
`dosage form carries a significant proportion of the drug
`
`AUROBINDO EX. 1014, 2
`
`AUROBINDO EX. 1014, 2
`
`

`

`US 6,475,521 B1
`
`3
`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 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 motil-
`ity. 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 pre-
`venting the required release rate of agent influencing resi-
`dence 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
`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:
`(1) 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 result-
`ant 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.
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`(2) Bioadhesive systems:
`These are designed to imbibe fluid following administra-
`tion 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 continu-
`ing hydration of the outer layer of the device or by the
`persistent application of shear.
`(3) Swelling and expanding systems:
`These are designed to be sufficiently small on adminis-
`tration so as not to make ingestion of the dosage form
`difficult (for example, less than approximately 23 mm
`long and less than 11 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. Gradual erosion of the system or its
`breakdown into smaller particles enables it to leave the
`stomach.
`
`Re: (1) Buoyant/floating Systems
`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 rela-
`tively homogenous distribution of drug in the tablet versions
`of this technology would not readily control the burst effect
`seen with a very water soluble drug.
`A bilayer tablet approach (8) where the buoyancy gen-
`eration comes from a separate layer to the drug containing
`layer having a release rate controlling property might over-
`come 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 con-
`straints.
`
`Approaches involving in situ 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
`
`AUROBINDO EX. 1014, 3
`
`AUROBINDO EX. 1014, 3
`
`

`

`US 6,475,521 B1
`
`5
`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 available
`
`would not be conducive to performance of such systems
`even when taken with a draught of water). Davis et 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 ready presenta-
`tion of the floating dosage form to the pylorus and thus allow
`rapid exit of the dosage form from the stomach (11). 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.
`Re: (2) Bioadhesive Systems
`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 absorp-
`tive 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) Swelling/Expanding Systems
`Other solutions to encouraging prolonged gastric resi-
`dence 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 1.6 cm and
`a maximum size of 5 cm 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.
`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 administra-
`tion 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 hydro-
`philic 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
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`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, US. Pat. 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 meter-
`ing 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 gastrointes-
`tinal tract or for delivering drugs that might be irritating or
`injurious to the gastrointestinal mucosa. Aswelling hydrogel
`polymer has embedded within it drug particles that dissolve
`once the hydrogel matrix is 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 sys-
`tems 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 diffi-
`culty 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 Controlled Release Systems for Very
`Soluble Drugs
`techniques for creating a controlled
`Typical prior art
`release oral dosage form would involve either matrix sys-
`tems or multi particulate systems. Matrix systems may be
`formulated by homogeneously mixing drug with hydrophilic
`polymers, such as hydroxypropylmethylcellulose,
`hydroxypropylcellulose, polyethylene oxide, carbomer, cer-
`tain methacrylic acid derived polymers, sodium alginate, or
`mixtures of components selected from these, and compress-
`ing the resultant mixture into tablets (employing some other
`excipients where needed). Hydrophobic polymers, 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 avail-
`able purified fatty acid esters. As noted above, it may not be
`possible to use these approaches with very highly water
`soluble drugs.
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`AUROBINDO EX. 1014, 4
`
`AUROBINDO EX. 1014, 4
`
`

`

`US 6,475,521 B1
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`7
`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 0.8 mm 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 hydroxypropylmethylcellu-
`lose. 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 anionic surfactant. In such a
`system, drug release of highly water soluble drugs is con-
`trolled without having to resort to the use of thick coatings
`on the release rate controlling layer.
`Rollet (19) achieves prolonged release of a drug from a
`multi particulate formulation based on fine particles of
`hydrophilic and hydrophobic silicas or silicates.
`Presumably, this system would function for drugs of high
`water solubility.
`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).
`Where coating is not employed, special mixtures of poly-
`mers or formation of a complex with the drug have been
`used. Macrae (21) uses mixtures of polyethylene oxide and
`hydroxypropylmethylcellulose with optional enteric poly-
`mers 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 mem-
`brane with an exit passage in this membrane for the drug.
`Granules of highly water soluble clavulanate were pre-
`pared (24) having to employ a barrier layer of a hydrophobic
`waxy material in order to provide for controlled release of
`this material when co-formulated with controlled release
`
`amoxycillin trihydrate granules in capsule or compressed
`tablet.
`
`DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, a novel way has
`been found of formulating drug with high water solubility
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`and a limited window of absorption such as metformin or a
`salt thereof which has a window of absorption in the upper
`gastrointestinal tract, to provide a dosage form that inher-
`ently 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 formu-
`lation or gas generation within the formulation. The formu-
`lation of the invention (a) achieves extended gastric resi-
`dence by virtue of size but will degrade in vivo 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 under control. The formulations of the
`invention will provide for an extended release formulation
`of drug with minimal interpatient variability in pharmaco-
`kinetic parameters.
`In the case of metformin, the formulation of the invention
`allows a patient a dosing regimen of at least one gram
`metformin, once-daily, preferably from about 1 to about 3
`grams, once daily, in the form of one or more tablets and/or
`one or more capsules, while providing effective control of
`plasma glucose. The metformin formulations of the inven-
`tion may be administered once daily at the above dosages to
`effectively treat diabetes while avoiding problems which
`may be associated with high plasma metformin levels as
`may be encountered with conventional metformin
`formulations, while providing optimum therapeutic control.
`The invention is applicable to all drugs having high 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 which
`has a high water solubility, preferably, metformin or a salt
`thereof, 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 ma