`
`
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(22) International Filing Date:
`
`11 June 1999 (11.06.99)
`
`(30) Priority Data:
`60/088,855
`
`11 June 1998 (11.06.98)
`
`US
`
`(71) Applicant (for all designated States except US): EM INDUS-
`TRIES, INC. [US/US]; 7 Skyline Drive, Hawthorne, NY
`10532 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): TALLAVAKHALA, Siva,
`Narayan [-/US]; 8 Langhans Court, Dix Hills, NY 11746
`(US).
`
`(74) Agents: JOYCE, Catherine, M.et al.; Millen, White, Zelano
`& Branigan, P.C., Arlington Courthouse Plaza 1, 2200
`Clarendon Boulevard, Arlington, VA 22201 (US).
`
`
`
`
`PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`
`
`(51) International Patent Classification 6;
`WO 99/63971
`(11) International Publication Number:
`
`A61K 9/20, 9/50
`
`16 December 1999 (16.12.99)
`(43) International Publication Date:
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`(21) International Application Number:
`PCT/US99/13223
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, Fl, GB,
`GD, GE, GH, GM, HR, HU,iD, IL, IN, 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, TT, UA, UG, US, UZ, VN, YU, ZA,
`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).
`
`
`Y SYSTEMS
`
`(54) Title: MICRO-OSMOTIC CONTROLLED DRUG DELIVER
`
`(57) Abstract
`
`armaceutical compositions that employ a micro-osmotic core for the
`Disclosed herein are compositions and methodsrelated to phi
`controlled delivery of a therapeutic agent. The invention particularly relates to therapeutic agents which are present in some portion in a
`solid state solution in the composition.
`
`
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`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.
`
`
`
`Albania
`AL
`Armenia
`AM
`Austria
`AT
`Australia
`AU
`Azerbaijan
`AZ
`Bosnia and Herzegovina
`BA
`Barbados
`BB
`Belgium
`BE
`Burkina Faso
`BF
`Bulgaria
`BG
`Benin
`BJ
`Brazil
`BR
`Belarus
`BY
`Canada
`CA
`Central African Republic
`CF
`Congo
`CG
`Switzerland
`CH
`Cote d'Ivoire
`CI
`Cameroon
`CM
`China
`CN
`Cuba
`cu
`CZ .. Czech Republic
`DE
`Germany
`DK
`Denmark
`FE
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`1S
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`L¢
`Ll
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`sD
`SE
`SG
`
`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
`Singapore
`
`Slovenia
`SI
`Slovakia
`SK
`Senegal
`SN
`Swaziland
`S87.
`Chad
`TD
`Togo
`TG
`Tajikistan
`TJ
`™ Turkmenistan
`TR
`Turkey
`TT
`Trinidad and Tobago
`VA
`Ukraine
`UG
`Uganda
`Us
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`YU
`Yugoslavia
`ZW
`Zimbabwe
`
`
`
`Co
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`WO 99/63971
`
`.
`
` PCT/US99/13223
`
`MICRO-OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS
`
`BACKGROUNDOF THE INVENTION
`
`The inventionrelates to the field of osmotic release systems for the controlled
`
`release of a therapeutic agent. Osmotic release systemsfacilitate the controlled release of
`
`a medicament from a dosage form based on a change in osmotic pressure in the dosage
`
`form. Osmotic release systemsare usefulfor the delivery of both poorly soluble and
`
`highly soluble therapeutic agents.
`
`SUMMARY OF THE INVENTION
`
`10
`
`In accordance with the current invention, a micro-osmotic controlled drug
`
`delivery system has been developed. The micro-osmotic system contains the following
`
`components: a micro-osmotic core, a drug component, and, optionally, a controlled
`
`release matrix and/or coating.
`
`The micro-osmotic core contains at least one osmotic agent and, optionally,a
`
`15
`
`swelling agent and/or a gelling agent. Osmotic agents facilitate the penetration of
`
`aqueousbiological fluids into the micro-osmotic core. Osmotic agents include, for
`
`example, sorbitol, mannitol, xylitol, sodium chloride or any other such highly soluble and
`
`pharmaceutically acceptable excipient. Preferred osmotic agents include, for example,
`
`the following osmotic agents: spray dried sorbitol, particularly Sorbitol Instant (EM
`
`20
`
`Industries, Hawthorne, New York), which has a surface area of ~1m?*/g; spray dried
`
`mannitol; mannitol with a polymorphic composition (dry state) that contains not less than
`
`about 85% ofthe “5” form of mannitol; a combination of sorbitol-mannitol-xylitol,
`
`preferably with sorbitol = 90%, mannitol > 4%, and xylitol 24%, such as described in DE
`
`196 47 282 Al, P96 47 282 - DE and WO 44 39 858, PCT/EP95/04059.
`
`25
`
`The micro-osmotic core may also optionally comprise a swelling agent. The
`
`swelling agent expands in volume when contacted by aqueousbiological fluids, thereby
`changing the volume ofthe micro-osmotic core. A swelling agent preferably is capable
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`of swelling to a volumethat is many times its volumein the dry state. Preferred swelling
`agents include, for example, sodium starch glycollate, crosscarmellose sodium,cellulose,
`
`and microcrystalline cellulose.
`The micro-osmotic core may also optionally comprise a gelling agent. The
`gelling agent functions to maintain the integrity of the swelling agent and thereby
`functions to maintain the integrity of the micro-osmotic core. The gelling agent is
`
`preferably a water soluble polymer. Preferred gelling agents include, for example,
`hydroxypropyl! methy! cellulose (HPMC), hydroxypropyl cellulose (HPC),
`polyvinylpyrrolidone (PVP)andits derivatives, gums- tragacanth, accacia, guar,
`carageenan, and other carbohydrate derived gums, alginic acid andits derivatives, and
`
`carbomers.
`
`The micro-osmotic coreis in the form of small particles, with diameter ranges of
`
`between about 2 zm to about 3000 um,preferably 200 um about to about 3000 um, and
`more preferably about 200 wm to about 1500 zm. Theparticles may be miniature tablets
`suchas, for example, may be formed using a water soluble lubricant such as PEG 8000.
`The micro-osmotic core may also be extruded and spheronized into small spheres and/ or
`spray agglomerated into particles. The osmotic agent/swelling agent/gelling agent may
`be combinedin weightratios ranging from 100/0/0 to 0.05/99.9/0.05 to 99.9/0.05/0.05 to
`0.05/0.05/99.9. Preferred ratios of osmotic agent/swelling agent/gelling agent are the
`
`following: 1/8/1, 2/7/1, 3/6/1, 4/5/1, 6/2/2, 7/1/2, 8/1/1, 9/0.5/0.5, and 5/4/1.
`The micro-osmotic cores of the invention are coated with a drug componentto
`
`obtain loaded cores. Coated, as used herein, refers to any physical contact between the
`
`drug component and the micro-osmotic core. For example, micro-osmotic cores may be
`fully coated with the drug component, partially coated with the drug component, or
`impregnated with the drug component. Loaded cores preferably have diameter ranges of
`between about 2 m to about 3000 wm, more preferably about 200 wm to about 3000 um,
`and mostpreferably about 200 jzm to about 1500 wm. The drug component comprises at
`least one therapeutic agent. The therapeutic agent in the drug component maybe, for
`example,in the form ofasolid, a solid-state solution, a solid-state solution-dispersion, a
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`microdisperse system, a solution-suspension(e.g. aqueous, alcoholic, or hydroalcoholic),
`or any combination thereof. The therapeutic agents may be combined with select
`excipients and/or binders. The solution-suspension form ofthe therapeutic agent may
`optionally include a hydrophilic agent such as HPMC, HPC, PVP,sorbitol, and/or natural
`gums (for example, accacia) in addition to water, alcohol, or a hydroalcoholic system.
`A solid-state solution, as used herein, refers to a solution of the therapeutic agent
`
`in solid form. A solid-state solution of the therapeutic agent is characterized by the lack
`of a melting point peak at the melting point ofthe therapeutic agent, indicating the
`absenceofthe solid state of the therapeutic agent. A solid state solution-dispersion, as
`
`10
`
`usedherein, is a system in which part of the therapeutic agent is in the form of a solid-
`
`15
`
`20
`
`25
`
`state solution and part of the therapeutic agent is in the form ofa finely dispersed solid.
`
`Preferably, greater than 1% of the total therapeutic agent content exists in solution in
`the system, in either the solid, semi-solid, or liquid phases. The system is also
`characterized in that at least one therapeutic agent can exist as a solid dispersion. Any
`
`portion of the therapeutic agent which exists as a solid dispersion preferably has a
`particle size distribution wherein the diameter of about 90% ofthe particles is less than
`
`about 10.
`
`For a solid-state solution-dispersion, the solubilized therapeutic agent/dispersed
`therapeutic agentratio is in a range from 1/99 to 100/0. Preferably, about 30% to
`about 100% ofthe therapeutic agent exists in solution, and more preferably, about 60%
`
`to about 90% of the therapeutic agent exists in solution. The ratio of the amount of
`therapeutic agent presentin the form ofa solid-state solution to the amountpresent in the
`form of solid dispersion can be easily ascertained by the use of techniques in thermal
`analysis such as Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis
`(TGA), and Differential Scanning Microcalorimetry. The crystallinity of the therapeutic
`agent is easily determined by X-ray diffraction.
`One exampleof a solid-state solution-dispersion system, particularly for
`
`therapeutic agents having poor water solubility, comprises a mixture of saturated
`polyglycolyzed glycerides (for example, Gelucire®, available from Gattefosse),
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`polyoxypropylene-polyoxyethylene block copolymer(for example, Pluronic®NF
`surfactants, available from BASF), and a therapeutic agent, as described, for example, in
`
`U.S. Patent Application No. 09/050913 and in U.S. Provisional Patent Application Nos.
`
`60/080163, 60/085417,60/085333, and 60/092767. The polyglycolyzed glycerides
`
`componentof the pharmaceutical carrier composition may include all grades of the
`saturated and unsaturated polyglycolyzed glycerides, preferably polyglycolyzed
`
`glycerides with a hydrophilic-lipophilic balance (HLB) > 10. Preferred
`polyglycolyzed glycerides include, for example, Gelucire ® 44/13 and Gelucire ®
`50/13. The mixture may also includeall grades of polyoxypropylene-polyoxyethylene
`
`10
`
`block co-polymer, preferably polyoxypropylene-polyoxyethylene block co-polymers
`
`15
`
`20
`
`with a HLB > 10. Preferred polyoxypropylene-polyoxyethylene block co-polymers
`
`include, for example, Pluronic® L44, Pluronic® F68, Pluronic® F108, and Pluronic®
`
`F127. The polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-
`
`polymer may be combined in weight ratios ranging from about 0.10/99.9 to about
`99.9/0.10. The preferred ratios are 1/9, 2/8, 3/7, 4/6, 6/4, 7/3, 8/2, 9/1 and 5/5. The
`combinationof saturated polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene
`
`block co-polymerpreferably has a melting point in the range of about 30°C to about
`70°C, and morepreferably about 50°C to about 70°C. When a polyglycolyzed
`
`glycerides/polyoxypropylene-polyoxyethylene block co-polymer combinationis
`employed, the combinationis presentin the final composition of the drug componentin
`an amount of about 0.10% to about 99.9%, and preferably about 5% to about 75%.
`
`Therapeutic agents are present in the final composition of the drug componentin an
`
`amount of about 0.10% to about 99.9%,preferably about 5% to about 75%.
`
`Examples of therapeutic agents that may be used in conjunction with this
`
`25
`
`invention include the following: dihydropyridine compounds, including for example,
`
`nifedepine, felodipine, nicardipine; cyclopeptides, including for example cyclosporine;
`omperazol; spironolactone; furosemide; terbutaline, riboflavin; gemfibrozi;
`indomethacin; ibuprofen; phenytoin; and glyburide. Additionally, any therapeutic
`
`agent with an intrinsic solubility of less than about 10.0 g/L and having therapeutic
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`activity in any of the following areas are contemplatedaspart of this invention: activity
`in the cardiovascular system; immunosuppressiveactivity; cholesterol lowering
`
`activity; anti-hypertensive activity; anti-epileptic activity; hormonal activity;
`hypoglycemicactivity; anti-viral activity; anti-histaminic activity; nasal decongestant
`activity; anti-microbial activity; anti-arrthrytic activity; analgesic activity, anti-
`mycobacterial, anti-canceractivity, diuretic activity, anti-fungal activity, anti-parasitic
`activity, activity as a central nervous system (CNS)stimulant, activity as a CNS
`depressant, activity as a 5-HT inhibitor, anti-schizophrenia activity, anti-alzheimer
`activity, anti-psoriatic activity, anti-ulcer activity, activity as a proton pumpinhibitor,
`
`10
`
`anti-asthmatic activity, activity as a bronchodialator, and thrombolytic activity. The
`
`therapeutic agent may be, for example, a protein, a peptide, a cyclopeptide, a steroid
`
`molecule, a vitamin, an oligonucleotide, or any small or large molecule, or any
`
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`
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`
`combination of the foregoing.
`
`In addition to the therapeutic agent or agents, the drug component may
`
`optionally comprise excipients. Excipients preferably comprise about 5% to about
`95% by weight of the final composition of the drug component, and more preferably
`about 10% to about 70%. Examples of suitable excipients include, but are not limited
`
`to, the following: ascorbyl palmitate; tocopheryl acetate; glycerol; glyceryl
`monooleate; glyceryl monosterate; glyceryl palmitosterate; triglycerides; diglycerides,
`monoglycerides; stearic acid; magnesium stearate, talc, diesters of polyethylene glycol
`(PEG); monoesters of PEG; polyethylene glycol; glyceryl polyoxyethylene fatty acid
`
`esters; glyceryl polyoxyethylene polyethylene glycol fatty acid esters and ethers;
`polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene
`sorbitan fatty acid esters; polyoxyethylene sterates; polyvinyl alcohol; sodium starch
`
`glycollate; sorbitan fatty acid esters; polyoxyl sterates; polyethylene glycol
`hydroxysterate; polyoxyethylene alcohols; anionic; cationic; amphiphilic compounds;
`lecithins; phospholipids; carbohydrates, including for example, lactose, maltodextrins,
`
`sucrose, and starch; polyols, including for example, sorbitol, mannitol, and xylitol,
`
`microcrystalline cellulose; vitamins, including for example, ascorbic acid and
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`niacinamide: bioflavonoids, including for example, quercetin, isoquercetin, naringin,
`
`rutin, etc.; and inorganic compounds, including for example, calcium carbonate,
`dicalcium phosphate, and any combinations of the above mentioned materials.
`The micro-osmotic cores that are coated with a drug component (loaded cores),
`
`can be either coated with a suitable polymeric coating and/or combined with a polymer
`
`matrix system. The polymercoating or the polymer matrix may serve to modify the.
`release profile of the therapeutic agent from the loaded cores. The polymer coating may
`comprise, for example, the following: hydrophilic polymers such as, for example HPMC,
`HPC,derivatives of cellulose, derivatives of starch, PVP and PVP derivatives, and
`
`10
`
`carbomers; water insoluble polymers such as, for example,ethyl cellulose, cellulose
`
`acetate, polymethacrylate polymers(for example, Eudragit® polymers, ) and pseudolatex
`dispersionsof the above; enteric polymers such as, for example, shellac, cellulose acetate
`phthalate; plasticizers such as, for example, dibutyl sebecate, triacetin, acetyl tributy!
`phthalate; and pearlescent pigments such as, for example, the Candurin™ line of
`pigments (EM Industries, Hawthome, New York). Coating of the loaded cores can be
`performed using pharmaceutical techniques that are well knownin theart, including
`techniques such as wurster coating, rotor coating, and/or pan coating.
`The polymer matrix comprisesat least one hydrophilic polymer such as, for
`example, cellulose and its derivatives, including, for example, HPMC, HEC, Carbomers
`(e.g. Carbopol P934, Carbopol P974), and alginic acid andits derivatives. The
`hydrophilic polymers of the polymermatrix preferably have molecular weights of
`between about 100 to about 4,000,000. The hydrophilic polymers are also preferably
`
`combined with at least one hydration enhancer which allows for faster hydration of the
`
`hydrophilic polymer. Hydration enhancers include, for example, sorbitol, mannitol,
`xylitol, and microcrystalline cellulose, and any combination thereof. A preferred
`hydrating enhanceris a specialized spray agglomerated form of sorbitol (commercially
`available as Sorbitol Instant, EM Industries, Hawthorne, New York) which has a surface
`
`area of 1m?/g. Hydrophilic polymers of different molecular weights and different
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`chemical natures may be combinedto achieve the desired release profile for the
`
`therapeutic agent.
`The loaded cores and the polymer matrix may be dry blended and then granulated
`by using a suitable solvent(e.g. aqueous and/or organic) and/or processed to form beads
`or spheres, or compressedinto tablets using suitable lubricants. Suitable lubricants for
`compressing the dry blended mixture of the loaded cores and the polymer matrix include,
`for example, sodium stearyl fumarate, magnesium sterate, PEG 8000. A flow promoter
`such as, colloidal silicon dioxide, may also be employed as part of the compressionstep.
`The product from the above processes, which comprises loaded cores, both coated
`and uncoated, optionally blended with a polymeric matrix to form a dry blend, and
`optionally further processed to form granules, beads, spheres or tablets, may be further
`processedinto final dosage formsas follows. As one example, granules, spheres, beads
`or the dry blend may be compressedintotablets, and the tablets may optionally be coated
`with a polymeric coating to modify the release profile of the therapeutic agent. The
`polymeric coating is essentially as described above. As another example, beads, spheres,
`or granules may be coated with a polymeric coating essentially as described above. The
`coated beads, spheres or granules may then be encapsulated into capsules or compressed
`into tablets, with the use of suitable pharmaceutical excipients.
`
`It is also contemplated as part of this invention that a final dosage form may
`comprise more than one type of loaded core. For example, loaded cores containing
`same therapeutic agent but having different release profiles may be incorporated into
`the final dosage formulation. Different release profiles for loaded cores containing the
`same therapeutic agent may be obtained, for example, by varying the content of the
`micro-osmotic core or the polymeric coating of the loaded cored. Alternatively, loaded
`cores having different therapeutic agents may also be incorporated into the same final
`
`dosage formulation.
`
`Theinvention also relates to a method of manufacturing a pharmaceutical
`
`composition. The method comprises the steps of providing a micro-osmotic core,
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`coating the micro-osmotic core with a drug componentto form loadedcores, and
`optionally, formulating the loaded coresinto final dosage forms as described above.
`Theinvention also relates to a method for delivering one or more therapeutic
`
`agents to a physiologic target site. The method comprises the steps of providing a
`pharmaceutical composition according to the invention and introducing a
`pharmaceutically effective amount of the pharmaceutical composition to a physiologic
`target site. The introduction of the pharmaceutical composition to the physiologic
`target site may be accomplished, for example, by administration topically,
`subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily, vaginally,
`rectally, aurally, orally or ocularly. A preferred method for delivering at least one
`therapeutic agent to a physiologictarget site that is contemplated by this inventionis
`
`through oral delivery.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 is a graph showingthein vitro release profile of felodipine from
`
`tablets formed according to example 17.
`Figure 2 is a graph showing the in vitro release profile of felodipine from
`
`tablets formed according to example 18.
`Figure 3 is a graph showing thein vitro release profile of felodipine from
`
`tablets formed according to example 19.
`Figure 4 is a graph showing thein vitro release profile of felodipine from
`
`tablets formed according to example 20.
`Figure 5 is a graph showing thein vitro release profile of felodipine from
`
`tablets formed according to example 21.
`Figure 6 is a graph showingthein vitro release profile of felodipine from
`
`tablets formed according to example 22.
`Figure 7 is a graph showing thein vitro release profile of felodipine from
`
`tablets formed according to example 23.
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`Without further elaboration, it is believed that one skilled in the art can, using the
`
`preceding description,utilize the present inventionto its fullest extent. The following
`preferred specific embodimentsare, therefore, to be construed as merelyillustrative, and
`not limitative of the remainder ofthe disclosure.
`
`EXAMPLES
`
`In the following examples, all parts and percentages are by weight unless
`
`otherwise indicated.
`
`For examples 17-23 below,the following components were employed.
`
`— . Pruv™- (sodium stearyl fumarate) (available from Mendell).
`
`10
`
`. Avicel™ PH200- (microcrystalline cellulose NF) (available from FMC).
`
`meWwN . Methocel™ E4M Premium CR- (hydroxypropylmethyl cellulose NF) (available from
`
`. Sorbitol Instant P300 - (Sorbitol NF) (available from Merck KGaA).
`
`Dow Chemical).
`
`5. Methocel™ K100 M - (hydroxypropylmethyl cellulose NF) (available from
`
`15
`
`Dow Chemical).
`
`6. Triacetin™- (glyceroltriacetate) (available from Spectrum Quality Products).
`7. Eudragit® NE 30 D - (30% aqueousdispersion of polyacrylate copolymers) (available
`
`from Roehm).
`Oo . Eudragit® L 30 D - (30% aqueousdispersion of methacrylic acid/methacrylate
`
`copolymers) (available from Roehm).
`9. PVP 30 - (polyvinylpyrrolidone, MW:44,000-54,000)(available as Kollidon® 30
`
`from BASF)
`10. Gelucire® 50/13 - (saturated polyglycolized glycerides of hydrogenated vegetable oil
`
`consisting glycerides and PEG-esters) (available from Gattefosse).
`11. Pluronic® F 68 - (polyoxy propylene-polyoxy ethylene block copolymers)(available
`
`20
`
`25
`
`from BASF)
`
`Example 1: Manufacture of the micro-osmotic cores.
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`

`WO 99/63971
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`-10-
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`Micro-osmotic cores may be manufactured by any number of techniques known
`in the art, using a variety of materials. A few of these techniques and materials are as
`
`follows:
`
`(1) crystalline or spray agglomerated sorbitol are employedas the micro-osmotic
`
`core;
`
`(2) sorbitol, sodium starch glycollate, and HPMCare combined and compressed
`into miniature tablets (for example, a diameter < 1 mm) using PEG 8000asa lubricant;
`(3) sorbitol powder and sodium starch glycollate are combined, and the mixture is
`
`extruded and spheronized into spheres;
`(4) sodium starch glycollate is spray agglomeratedonto sorbitol.
`Micro-osmotic cores may be made using any of the above methodsor using any
`
`other techniques that are well known in the art, including granulation.
`
`Example 2: Manufacture ofthe therapeutic agent componentasa solid state
`
`solution-dispersion.
`A mixture ofpolyglycolyzed glycerides and polyoxypropylene-polyoxyethylene
`block copolymerare heated to 20°C above the melting point (~50°C). The therapeutic
`agent is added gradually to the molten mixture. The therapeutic agentis preferably
`milled to a particle size range such that the diameter ofat least about 90% ofthe particles
`is less than about 75 microns. The mixture is maintained at 20°C above the melting point
`
`of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer
`mixture. Theratio of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene
`block co-polymeris selectedto facilitate solubilization of > 1% and preferably 30-100%
`
`of the therapeutic agent in the mixture.
`
`Example 3: Controlled release tablets containing Nifedepine.
`Ingredients:
`Quantities (mg/Tab):
`Application
`Sorbitol Instant P300
`50
`osmotic core
`
`Nifedepine, USP '
`
`90
`
`active
`
`1.
`
`2.
`
`10
`
`15
`
`20
`
`25
`
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`

`WO 99/63971
`
`-ll-
`
`otanneY
`
`Gelucire 50/13
`
`Pluronic F68
`
`HPMC E4M CRGrade
`
`Sorbitol Instant P300
`
`Microcrystalline Cellulose
`
`Magnesium Stearate
`
`90
`
`90
`
`300
`
`75
`
`75
`
`6.8
`
`PCT/US99/13223
`
`excipient
`
`excipient
`
`hydrophillic polymer
`
`hydration enhancer
`
`hydration enhancer
`
`lubricant
`
`Sorbitol Instant was used as an osmotic core. Gelucire 50/13, Pluronic F68, and
`
`Nifedepine were processed together to yield a drug componenthaving Nifedepine as the
`therapeutic agentin a solid state solution-dispersion. The drug component wasthen
`spray congealed onto Sorbitol Instant. The loaded cores as manufactured above were
`blended with a polymeric matrix containing Sorbitol Instant P300, HPMC E4M CR
`Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets
`were obtained by compression ofthe mixture of the loaded cores with the polymeric
`
`formulation.
`
`Example 4: Controlled release tablets containing Felodipine.
`Application:
`
`Quantities (mg/Tab):
`
`Ingredients:
`
`—_
`
`woemNDHFYDS
`
`Sorbitol Instant P300
`
`Sodium starch glycollate
`
`Felodipine, USP
`
`Gelucire 50/13
`
`Pluronic F68
`
`HPMC E4M CRGrade
`
`Sorbitol Instant P300
`
`Microcrystalline Cellulose
`
`Magnesium Stearate
`
`50
`
`20
`
`90
`
`90
`
`90
`
`300
`
`75
`
`75
`
`6.8
`
`osmotic agent
`
`swelling agent
`
`active
`
`excipient
`
`excipient
`
`hydrophillic polymer
`
`hydration enhancer
`
`hydration enhancer
`
`lubricant
`
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`10
`
`15
`
`20
`
`25
`
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`

`0) 99/63971
`
`PCT/US99/13223
`
`-12-
`
`Sorbitol Instant P300 and sodium starch glycollate were combined into a micro-
`
`osmotic core. Gelucire 50/13, Pluronic F68, and felodipine were combinedto yield drug
`
`componenthaving felodipine in a solid-state solution. The drug component was then
`spray congealed onto the micro-osmotic core. The loaded cores as manufactured above
`were then blended with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline
`
`cellulose, and magnesium stearate. Controlled release tablets were obtained by
`compression of the mixture of the loaded cores with the polymeric formulation.
`
`Example 5: Controlled release tablets containing Phenytoin.
`
`Ingredients:
`
`Quantities (mg/Tab):
`
`1.
`
`2.
`
`3,
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Sorbitol Instant P300
`
`Sodium starch glycollate
`
`HPMC E4M
`
`Phenytoin, USP
`
`Gelucire 50/13
`
`Pluronic F68
`
`HPMC K100 Grade
`
`Sorbitol Instant P300
`
`Magnesium Stearate
`
`50
`
`20
`
`10
`
`95
`
`90
`
`90
`
`300
`
`150
`
`6.8
`
`Application:
`
`osmotic agent
`
`swelling agent
`
`gelling agent
`
`active
`
`excipient
`
`excipient
`
`hydrophillic polymer
`
`hydration enhancer
`
`lubricant
`
`Sorbitol Instant P300, HPMC E4M andsodium starch glycollate are processed
`
`together into a micro-osmotic core. Gelucire 50/13, Pluronic F68, and Phenytoin are
`processed togetherto yield a solid state solution of Phenytoin in the matrix. This drug
`system is spray congealed onto the micro-osmotic core. The drug system micro-osmotic
`cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M CR
`
`Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets are
`
`10
`
`15
`
`20
`
`25
`
`compressed with the above formulation.
`
`Example 6: Controlled release tablets containing indomethacin.
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`
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`

`wo 99/63971
`
`PCT/US99/13223
`
`-13-
`
`Ingredients:
`
`Quantities (mg/Tab):
`
`Application:
`
`eoNDPFLYDN
`
`Sorbitol Instant P300
`
`Sodium starch glycollate
`
`HPMC E4M
`
`Indomethacin, USP
`
`PVP
`
`HPMC K100 Grade
`
`Sorbitol Instant P300
`
`Magnesium Stearate
`
`50
`
`20
`
`10
`
`100
`
`90
`
`300
`
`150
`
`6.8
`
`osmotic agent
`
`swelling agent
`
`gelling agent
`
`active
`
`excipient, binder.
`
`hydrophillic polymer
`
`hydration enhancer
`
`lubricant
`
`10
`
`Sorbitol Instant P300, HPMC E4M and sodiumstarch glycollate are processed
`
`together into a micro-osmotic core. PVP, and Indomethacin are processed together to
`yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic
`core. The drug system micro-osmotic cores as manufactured above are blended with
`Sorbitol Instant P300, HPMC E4M CRGrade, microcrystalline cellulose, and magnesium
`
`15
`
`stearate. Controlled release tablets are compressed with the above formulation.
`
`Example 7: Controlled release tablets containing Chlorpheniramine maleate.
`Application:
`
`Quantities (mg/Tab):
`
`Ingredients:
`
`coIWDAARFYN
`
`Sorbitol Instant P300
`
`Sodium starch glycollate
`
`HPMC E4M
`
`Chlorpheniramine maleate
`
`PVP
`
`HPMC K100 Grade
`
`Sorbitol Instant P300
`
`Microcrystalline Stearate
`
`50
`
`20
`
`10
`
`10
`
`20
`
`300
`
`150
`
`6.8
`
`20
`
`25
`
`osmotic agent
`
`swelling agent
`
`gelling agent
`
`active
`
`excipient, binder
`
`hydrophillic polymer
`
`hydration enhancer
`
`lubricant
`
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`

`wo 99/63971
`
`PCT/US99/13223
`
`-14-
`
`Sorbitol Instant P300, HPMC E4M andsodium starch glycollate are processed
`together into a micro-osmotic core. PVP and chlorpheniramine maleate are processed
`together to yield a solution in water. This drug system is spray coated onto the micro-
`osmotic core. The drug system micro-osmotic cores as manufactured aboveare blended
`
`with Sorbitol Instant P300, HPMC E4M CRGrade, microcrystalline cellulose, and
`
`magnesium stearate. Controlled release tablets are compressed with the above
`
`formulation.
`
`Example 8: Controlled release tablets containing Diltiazem hydrochloride.
`Ingredients:
`Quantities (mg/Tab):
`Application:
`Sorbitol Instant P300
`160
`osmotic agent
`
`Sodium starch glycollate
`
`HPMC E4M
`
`Diltiazem hydrochloride
`PVP
`
`Ethyl Cellulose dispersion
`Dibutyl sebecate
`Talc
`
`40
`
`20
`
`300
`60
`
`_q.s.
`q.s.
`qs.
`
`swelling agent
`
`gelling agent
`
`active
`excipient, binder
`
`hydrophobic polymer
`plasticizer
`anti-caking agent
`
`1.
`
`2.
`
`3.
`
`4,
`5.
`
`6
`7.
`8.
`
`Sorbitol Instant P300, HPMC E4M and sodiumstarch glycollate are processed
`together into a micro-osmotic core. PVP and diltiazem hydrochloride are processed
`togetherto yield a solution in water. This drug system is spray coated onto the micro-
`osmotic core. The drug system micro-osmotic cores as manufactured aboveare coated
`with ethyl cellulose dispersion plasticized with dibutyl sebecate. Controlled release
`tablets are compressed with the above formulation.
`
`Example 9: Capsules containing controlled release pellets containing
`
`Chlorpheniramine maleate.
`Ingredients:
`
`Quantities (mg/Tab):
`
`Application:
`
`10
`
`15
`
`20
`
`25
`
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`

`WO 99/63971
`
`PCT/US99/13223
`
`-15-
`
`oNDwFYNY
`
`Sorbitol Instant P300
`
`Sodium s