PCT
`
`won
`
`Doc Ref. FP14
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`App1.NO. 11/273,575
`l
`_.. . eaomnou
`International Bureau
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`
`
`WTERNATIONAL APPLICATION PUBLISHED UNDER THE PA'I'ENT COOPERATION TREATY (PCT)
`
`(51) Intermtional Patent Classification 6 :
`(11) International Publication Number:
`WO 96/31197
`A61K 9/48, 31/19
`
`(43) International Publication Date:
`
`10 October I996 (10.10.96)
`
`(21) International Application Number:
`
`PCI'IUS96/04513
`
`(22) International “ling Data:
`
`2 April 1996 (02.04.96)
`
`(81) Designated States: CA. JP. MX. European patent (AT, BE.
`CH, DE. DK, ES, Fl, FR. GB, GR. IE. IT. LU, MC. NL,
`PT. SE)-
`
`Published
`With international search report:
`Before the expiration of the time limit for amending the
`claim: and to be republished in the event of the receipt of
`amendments.
`
`(30) Priority Data:
`08/415,401'
`
`‘
`
`3 April 1995 (03.04.95)
`
`US
`
`(71) Applicant: ABBUl'I' LABORATORIES [US/US]; CHAD
`0377/AP6D-2, 100 Abbott Park Road. Abbott Park,
`IL
`60064-3500 (US).
`
`(72) Inventors: CHESKIN. Howard; 893 Valley Road, Glencoe. IL
`60022 (US). HALE. Thomas. 1.; 2053 N. Howe. Chicago,
`IL 60614 (US). VAN SCOIK. Kurt. G.; 672 W. Trail North.
`Grayslalte. IL 60030 (US). ZHOU. 1i; 270 Cambridge
`Drive. Grayslake, IL 60030 (US).
`
`(74) Agents: WARD. Michael, I. et al.; Abbott Laboratories. CHAD
`0377/AP6D—2, 100 Abbott Park Road, Abbott Park,
`IL
`60064-3500 (US).
`
`
`
`(54) Title: HOMOGENEOUS MIXTURES OF LOW TEMPERATURE-MEETING DRUGS AND ADDITIVES FOR CONTROLLED
`RELEASE
`
`(57) Abstract
`
`A controlled-release formulation comprising, in combination a therapeutically-effective dosage of drug which melts at low temperature
`and an additive selected from the group consisting of ethyl cellulose. rnetllyleellulose. hydmxypropyl cellulose. polyacrylamide, ethylene
`vinyl acetate copolymer. polymelhylmetlmcrylate, polyhydroxyethyl medmcrylate and waxes. and the like. such that the additive and the drug
`form a homogeneous drug-additive composite with a 92-to-97 '5 weight/weight of said drug, wherein said drug is selected from the group
`consisting of: sodium hydrogen divalproex, ibuprofen. ramipril. dibcnzyline. crylhrityl retranitrate. isosorbide dinitrate. methosuximide.
`ketoprofen, gemfibrozil. paroxetine hydrochloride. and trimipramine maleate.
`
`

`

`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.
`
`MW
`MX
`NE
`NI.
`NO
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`56
`SI
`SK
`SN
`52
`TD
`TG
`TJ
`1T
`UA
`UG
`US
`UZ
`VN
`
`Democratic People'a Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`lauxernbourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`AM
`AT
`AU
`3!!
`BE
`BF
`BG
`3.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`
`Amalia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canda
`Central African Republic
`Congo
`Switzerland
`Cate d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`
`Vier Nam
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Pomrgal
`Romania
`Rmian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`U l
`l
`.
`
`

`

`WO 96131197
`
`PCTIUS96104513
`
`Homogeneous Mixtures of Low Temperature-Melting
`Drugs and Additives For Controlled Release
`
`W
`
`The present invention provides novel compositions and
`methods of manufacturing controlled-release therapeutics
`comprising dmgs which melt at low temperatures and an
`additive. such that the homogeneous composite contains 92-97%
`drug weight/weight
`(w/w).
`
`WWW
`
`Some medical conditions are best treated by
`administration of a pharmaceutical which is formulated to allow
`the active substance or ingredient to act as quickly as possible.
`Such a formulation may comprise an injectable solution or a
`readily-dissolvable tablet or capsule. This type of forrnuiation
`is useful, for instance, for treating acute pain, such as
`headaches. or pain associated with sudden trauma resulting from
`an accident.
`
`Other medical conditions are best treated by
`administration of a pharmaceutical
`in such a way as to sustain
`its action over an extended period of time. This type of
`administration is useful. for example. for treating chronic pain.
`such as that associated with rheumatic or arthritic conditions.
`or for the treatment of a chronic cardiovascular condition.
`It
`can be achieved by repeated administration of an immediate-
`release tablet or capsule at frequent intervals. for instance,
`every four to six hours. However, this is generally inconvenient.
`especially during the night, when it
`is often necessary to awaken
`a patient to administer the tablet or capsule.
`in addition, such
`multiple dosing may lead to undesirable fluctuations in the
`plasma concentration of the active substance.
`I
`
`'
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`

`

`WO 96/31197
`
`PCT/0596104513
`
`it has previously been proposed to produce a formulation
`which will release the active substance therein at a controlled
`
`rate. such that the amount available in the body to treat the
`condition is maintained at a relatively constant level over an
`extended period of time.
`Particularly suitable periods are
`twelve hours and twenty-four hours, since such formulations
`
`need only be taken once or twice a day to maintain an effective
`treatment-of the condition.
`Such formulations are generally
`known as 'controlled-release forrnulations.‘
`
`Many controlled-release formulations are already known,
`but there is no generally-applicable method by which such
`formulations can be designed. Each formulation is dependent on
`the particular active substance incorporated therein.
`In designing a formulation,
`it
`is generally necessary to
`take into account many- factors,
`including the rates of absorption
`and clearance of the active substance by the patient, the
`interaction of the active substance with the excipients and/or
`coatings to be used in the formulation. the solubility of the
`active substance and of the excipients and/or coatings, and the
`effects on the bioavailability of the active substance which may
`be caused by the excipients and/or coatings.
`it is. however. not
`readily possible to predict whether any particular formulation
`will provide the desired controlled-release, and it
`is generally
`found necessary to carry out substantial experimentation to
`produce a controlled-release formulation having the desired
`properties.
`Over the years. considerable effort has been directed
`
`toward the preparation of such controlled-release formulations
`in the pharmaceutical
`industry.
`Specifically, controlled-release
`compositions have been sought to deliver a controlled dmg
`release over a long time without fragmentation of the
`composition in vivo.
`
`WO 92/02145 to Warner-Lambert Corporation teaches a
`flavor delivery system by combining a flavor, resin and a
`polyalkylene wax in a liquid mixture. The resin and the wax
`
`protect. hold and mask the aroma of the flavor component.
`
`it is
`
`5
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`

`W0 9601197
`
`PC17US96I04513
`
`unclear what effect of mixing the wax with the resin has on the
`retention of the aroma of the flavor component.
`US Patent 4.885.175 to Zibell teaches a chewing gum with
`delayed release which comprises macroscopic flavorer or
`sweetener mixed with a molten wax to produce a damp mix. The
`wax comprises 10-50% weight of the damp mix.
`WO 92/01446 to APS Research Limited discloses
`application of a subcoat of a drug migration controlling agent
`(DMCA) to drug granules. The DMCA is a wax or wax-like
`material and is typically a long chain alcohol. acid or ester.
`paraffin wax. or a silicone wax. The DMCA is applied as a
`surface treatment on macroscopic drug granules.
`US Patent 4.483.847 to Augart teaches using a high-
`melting and a low-melting lipid or Iipoid material
`to produce a
`retarded liberation of active material. The solid active material
`and the high-melting lipid are embedded in the low-melting lipid
`at a temperature sufficient
`to melt
`the low-melting lipid but not
`the high-melting lipid. The mixture after cooling is ground to
`give a granulate which is then pressed into a tablet.
`Pharmaceutical compositions comprising low-melting
`drugs are one such example wherein controlled-release
`formulations are already known, but there is no generally-
`applicable method by which such formulations can be designed.
`In US 5.017.613 to Aubert ef 8]..
`liquid valproic acid (VPA)
`and solid ethyl cellulose are added slowly to a powdered sodium
`valproate to form a granular agglomeration.
`Precipitated silica
`is added to the granulate and compressed to tablets. The tablets
`are then lacquered.
`The use of additives, particularly waxes. with' low-melting
`drugs has had limited success in producing controlled-release
`formulations. An example of a low-melting drug is sodium
`hydrogen divalproex. an active ingredient
`in anti-epileptic drugs.
`In formulations, VPA is a liquid at room temperature,
`thereby making it difficult to formulate a tablet. One way to
`tablet a form of VPA is to mix VPA with an equimolar amount of
`
`10
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`W0 96131 197
`
`PCT/US96I04513
`
`sodium to form sodium valproate. However, sodium valproate is
`
`difficult
`
`to work with due to its hygroscopic characteristics.
`
`US Patent 4,913,906 to Friedman et al.. discloses
`
`controlled-release formulations of VPA combined with an
`
`additive. such as carboxymethylcellulose, ethylcellulose or
`Waxes, such as paraffin. The additives are added as solids and
`
`are used to granulate the VPA which is then pressed to a tablet.
`
`The active ingredient comprises 10-80% weight of the dosage
`
`form. The additives are formulated with VPA as solids.
`
`10
`
`What the prior art fails to teach is formulations of
`
`therapeutics where a liquid active ingredient is combined with a
`
`liquid additive to provide a homogeneous mixture which provides
`
`controlled-release of the active substance. The present
`
`invention relates to dmg/additive compositions which give
`
`15
`
`controlled-release of drug over a long time period after oral
`
`dosing.
`
`B
`
`FD
`
`FTHE DR WIN
`
`20
`
`Figure 1 depicts the results from a dissolution study. A sodium
`
`hydrogen divalproex and polyethylene wax mixture comprise a
`controlled-release capsule.
`Sodium hydrogen divalproex
`
`comprises 95.2% w/w of the drug-additive composite.
`
`Figure 2 depicts the results from a dissolution study with 93%
`
`w/w drug loaded composite capsules and 96.5% w/w drug loaded
`
`composite capsules.
`
`Figure 3 depicts in vivo studies in dogs with three separate
`
`formulations including a sodium valproate solution. a drug-
`
`additive composite comprising 93% w/w drug. and a drug-wax
`
`composite comprising 96.5% w/w drug.
`
`

`

`wo 96131197
`
`'
`
`PCT/11896104513
`
`W
`
`The present invention relates to compositions of
`controlled-release therapeutics.
`The controlled-release
`therapeutics of the present
`invention comprise low temperature-
`melting drugs that are melted and mixed with a molten additive
`to give a homogeneous. liquid mlxture. The drug comprises 92-
`97% w/w of the drug-additive composite.
`The present invention also relates to methods of
`manufacturing controlled-release therapeutics comprising
`melting low temperature-melting drugs and an additive by
`mixing the drug and additive to provide a homogeneous drug-
`additive mixture. and allowing them to harden to form a drug-
`wax composite.
`
`s a
`
`10
`
`15
`
`W
`
`The present invention is directed to compositions of and
`methods of manufacturing controlled-release orally
`administered drugs. The compositions are in a drug-additive
`composite, which show sustained release of the drug over time.
`One embodiment of the present invention includes melting
`a low temperature-melting drug (a drug which melts below
`150°Centigrade (C)) and combining it
`in a liquid state with a
`molten additive. More preferably.
`the low temperature-melting
`drugs melt at 125°C or below. Examples of drugs which melt at
`low temperatures include. but are not intended to be limited to,
`sodium hydrogen divalproex.
`ibuprofen,
`ramipril. dibenzyline.
`erythrityl
`tetranitrate.
`isosorbide dinitrate. methosuximide,
`ketoprofen. gemtibrozil. paroxetine hydrochloride, and
`tn‘mipramine maleate. Sodium hydrogen divalproex has a melting
`point of approximately 100°C while ibuprofen has a melting
`point between 75° and 77°C.
`
`The additives may be melted with the .low temperature-
`melting drugs or they may be melted separately and later
`
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`

`WO 96/31197
`
`PCT/0896104513
`
`if the additive is
`combined in liquid form with the molten drug.
`the additive
`melted with the low temperature-melting drug,
`must have a melting point at or below the melting point of the
`drug.
`if the melting point temperature of the additive is higher
`than the melting point temperature of the drug, themelting point
`
`of the additive must be such that the higher temperature would
`
`not cause drug degradation.
`
`Similarly.
`
`if the additive is melted
`
`separately from the drug it must be at a temperature such that
`
`when combined with the molten drug.
`
`it does not cause drug
`
`10
`
`degradation.
`
`Additives that are acceptable for use with the present
`
`invention include derivatives of cellulose. such as ethyl
`
`cellulose, methylcellulose, hydroxypropyl cellulose,
`polyacrylamide, ethylene vinyl acetate copolymer.
`polymethylmethacrylate. polyhydroxyethyi methacrylate and
`waxes. Preferably. the waxes are polyalkylene waxes, which can
`be natural or synthetic. such as polyethylene wax. Polyethylene
`wax has a melting point of approximately 97.8°C and when
`molten. forms a homogeneous mixture with the molten drug
`
`Polyethylene wax will
`without adversely affecting the drug.
`also remain a solid in vivo
`thereby providing a matrix through
`which drug can diffuse.
`It is to be understood by those skilled in
`the art that the additives used in the drug-additive composite
`
`must be pharrnaceutically acceptable for its intended use.
`The additives must also not adversely affect the ability of
`
`the low-melting drug and the additive to form a homogeneous
`drug-additive composite. The homogenous drug-additive
`composite provides for a more intimate mixture of drug and
`additive molecules. as opposed to simply dispersing solid drug
`
`particles in a liquid additive. For purposes of the present
`invention. the term 'composite' refers to the homogeneous drug-
`
`additive mixture after it has solidified and is not meant to
`
`include the capsule which in some embodiments of the present
`invention contains the composite. Generally. the molten.
`
`homogeneous mixture may be added to a capsule wherein it cools
`and hardens. Cooling times can be from a few seconds minutes.
`
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`

`WO 96/31197
`
`PCT/USWMSB
`
`However. the cooling time is fast enough so that a homogeneous
`drug-additive composite is produced. Other vehicles. which
`provide the same functions of the capsule. such as containment
`of and a site for cooling of the molten, homogeneous mixture, can
`be used as well.
`In addition, the molten. homogeneous mixture
`may be poured into molds where upon hardening the drug-additive
`composite may be removed from the mold and further processed
`or used.
`
`The homogeneous drug with additive composite allows for
`controlled-release over time. The additive in the drug-additive
`composite provides a matrix structure. due to its ability to
`remain a solid in viva, which allows drug to diffuse through the
`matrix over time.
`
`Different types of capsules may be utilized with the formulations
`of the present invention. For example. CapillTM capsules are an
`injection-molded. starch-based hard shell which may be filled and
`sealed manually or by using specialized manufacturing equipment.
`Another example of a capsule that may be used with the formulations of
`the present
`invention are Vegicapm. a hydroxypropylmethylcellulose
`hard shell that is similar in size and shape with standard gelatin
`capsules and may be filled using standard capsule-filling equipment.
`addition, soft or hard shell capsules may be used provided that the
`molten, homogenous mixture does not melt the capsule. The compositior
`of a soft elastic gelatin capsule typically comprises from about 30%-to
`about-50% by weight of gelatin, from about 20%-to-about-30% by
`weight of a plasticizer. and from about 25%-to-about-40% by weight of
`water.
`
`In
`
`Various methods may be used for manufacturing and filling the
`capsules. For example, seamless capsule methods, rotary methods.
`methods using a Liner machine or an Accogel machine. and the like. may
`be used. Also various manufacturing machines may be used for
`manufacturing the capsules. The target filling volume/weight depends
`on the potency of the molten filling solution in combination with the
`desired dosage strength.
`
`It is to be understood by those skilled in the art that a
`particular capsule is not a critical part of the present invention
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`WO 96131197
`
`PCT/11896104513
`
`is a vehicle-for delivering a homogeneous drug-additive
`but
`composite. However,
`if a capsule is used to deliver the drug-
`addltive composite.
`it
`is necessary that the capsule maintain its
`
`structural
`
`integrity while the molten drug-additive mixture
`
`hardens.
`
`It
`
`is also necessary that the capsule dissolves after it
`
`is administered in vivo thereby facilitating drug release from
`
`the drug-additive composite.
`Several advantages result from the present invention.
`
`First. complicated coatings of the drug-additive composite are
`
`10
`
`not needed for a controlled-release of drug. Molten.
`
`homogeneous drug-additive mixture can be added to a capsule and
`allowed to harden by cooling. The capsule containing the drug-
`
`additive composite may then be capped.
`
`Another advantage is there is no need for expensive
`
`15
`
`tabletting equipment because the molten. homogeneous drug-
`additive mixtures may be added directly to a preformed capsule.
`
`Yet another advantage of the present invention is that the
`
`drug-additive composite allows slow. regular diffusion of drug
`
`out of the drug-additive composite due to the solid matrix from
`
`20
`
`which diffusion of drug can occur over time.
`
`Still yet another advantage of the present invention is that
`
`since both the drug and additive are mixed as liquids to form a
`
`homogenous mixture. the drug and additive molecules are in a
`
`more intimate. uniform contact with each other. as opposed to
`
`25
`
`where relatively large macroscopic drug particles are merely
`
`dispersed in a liquid additive. Macroscopic drug particles are
`relatively large particles which have their surfaces coated with
`liquid additive. The more intimate nature of the molten,
`homogeneous drug-additive mixture ensures a more uniform
`matrix upon cooling from which diffusion of drug can oc’cur.
`‘ Still yet another advantage of the present invention is that
`the present invention allows for high drug loading with the
`
`additive. Drug loading of the drug-additive composite can
`
`comprise 92-97% drug (w/w).
`Once the molten drug and molten additive are mixed it is
`
`added to a capsule. mold. or other suitable vehicle. The
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`

`WO 96131197
`
`PCT/US96104513
`
`homogeneous mixture can be added by pipet, poured or added by
`more sophisticated instrumentation. Once the homogeneous
`mixture has hardened. it can be capped and sealed as the final
`product. Capping and sealing the final product may include using
`
`solvents such as ethanol.
`
`The additive used in the method of the present invention
`are generally polyalkylene waxes.
`Preferably, polyethylene wax
`is used in the drug-'wax composite.
`The following Examples are used to illustrate the scope of
`the present invention and is not intended to be limited to the
`Examples themselves.
`
`ExamniLI
`
`A dissolution test was carried out to determine the
`quantity of sodium hydrogen divalproex which went
`into solution
`in an artificial medium with a phosphate buffer at pH 7.5. The
`quantity of VPA was determined by measuring VPA
`concentrations in samples taken from the dissolution medium.
`A 25 gram (gm) sample of sodium hydrogen divalproex
`(Abbott Laboratories. Abbott Park.
`IL 60064) containing sodium
`hydrogen divalproex was melted in a beaker on a hot plate with
`1.25 gm of polyethylene wax (8-390 C, Shamrock Technologies
`Inc.. Newark. N.J. 07114) at approximately 115°C. The resulting
`sodium hydrogen divalproex-wax melt was mixed to town a
`sodium hydrogen divalproex-wax”composite. Size 00 CapillTM
`capsules (Capsugel Corp., Greenwood, 8.0. 29646), were filled
`with the molten sodium hydrogen divalproex-wax mixture by
`transferring the molten mixture using glass Pasteur pipets. The
`tip and of the plpets were shortened to increase the flow of the
`molten mixture. The molten mixture was allowed to' solidify by
`cooling for approximately 30 seconds. The CapillTM capsules
`were then capped and sealed with a 20% ethanol in water
`solution.
`Individual capsules were tested in USP Dissolution
`Apparatus II with a rotating paddle (VanKel Industries. Edison,
`N.J. 08820) for four hours in simulated gastric fluid without
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`WO 96131197
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`PCT/0896104513
`
`10
`
`pepsin and then‘ in simulated intestinal fluid without pancreatin.
`pH of 7.5. The gastric fluid without pepsin was made by
`dissolving 2.0 gm of sodium chloride (Sigma Chemical Co.. St.
`Louis, MO. 63178) in 7.0 milliliters (ml) of hydrochloric acid
`(Sigma) and adding water to 1000 ml. The simulated intestinal
`fluid without pancreatin was made by dissolving 6.8 gm of
`monobasic potassium phosphate in 250 ml of water and mixed.
`Added to the solution was 190 ml of 0.2 N sodium hydroxideto a
`
`‘
`
`pH of 7.5. The solution was diluted with water to 1000 ml.
`Samples (2 ml) were removed at predetermined times and
`concentrations of VPA measured on the TDx® Analyzer (Abbott
`
`Laboratories. Abbott Park,
`
`IL. 60064). Results are shown in
`
`Table 1. Percentages in Table 1
`reflect the percent sodium
`hydrogen divalproex released from the composite based on VPA
`measurements. Figure 1
`is a graphic representation of the data
`showing controlled-release over 24 hours.
`‘
`The capsules showed controlled release of sodium hydrogen
`divalproex such that only approximately 60% ot the sodium
`hydrogen divalproex in the sodium hydrogen divalproex-wax
`composite was released over 24 hours.
`
`Table 1
`
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`
`—_
`
`
`
`
`
`
`
`
`
`
`
`
`6.90%
`
`12.30%
`
`2
`
`3.50%
`
`27.40%
`
`30 50%
`
`33 00%
`
`60.10%
`
`2
`
`3.60%
`
`27.60%
`
`31.00%
`
`33.60%
`
`62.60%
`
`
`
`-___ I
`— [
`—m
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`

`

`WO 96131197
`
`PCT/0896104513
`
`11
`
`Examnlaz
`
`A dissolution test was done as in Example 1. 25 gm
`.samples of sodium hydrogen divalproex (Abbott Laboratories),
`which were combined with 0.875 gm and 1.75 gm polyethylene
`wax (8-390 C. Shamrock Technologies Inc.). The sodium hydrogen
`divalproex and polyethylene wax were melted in a beaker on a hot
`plate at a temperature of approximately 115°C. The resultant
`sodium hydrogen divalproex-wax melt was mixed to form a
`homogeneous sodium hydrogen divalproex-wax mixture. The
`molten sodium hydrogen divalproex-wax composite was filled
`into CapillTM capsules. The molten mixture was transferred to
`the Caplllm capsules using glass Pasteur pipets which had been
`shortened at the tip end to increase flow of the molten mixture.
`The Capill‘m capsules were then capped and sealed with a 20%
`ethanol
`in water solution.
`
`The dissolution liquids were prepared as described in
`Example 1 and the procedure of Example 1 was followed.
`Samples (2 ml) were removed at predetermined times (0.5. 1, 2,
`4, 5.1, 6. 7. 9.8, and 24 hours) and concentrations of VPA
`measured on the TDx® Analyzer (Abbott Laboratories. Abbott
`Park.
`IL. 60064). Results are shown in Table 2 and Table 3.
`Percentages in Table 2 and Table 3 reflect the percent sodium
`hydrogen divalproex released from the composite based on VPA
`measurements. Figure 2 is a graphic representation of the data
`showing controlled-release over 24 hours.
`The capsules showed controlled release of sodium hydrogen
`divalproex such that only 55% of the sodium hydrogen divalproex
`in the sodium hydrogen divalproex-wax composite was released
`in the 93% w/w drug loaded capsule over 24 hours while only
`70% of the sodium hydrogen divalproex in the sodium hydrogen
`divalproex-wax composite was released in the 96.5% w/w drug
`loaded capsule tor the same time period.
`
`10
`
`15
`
`35
`
`

`

`W0 9631197
`
`PCP/089004513
`
`12
`
`Table 2- 96.5% Drug
`
`I'-
`Ca . sule 3
`
`-- _
`
`18.4%
`
`1.4%
`
`7.9%
`
`4.6%
`
`30.6%
`
`m-
`2!-
`
`5.
`
`34.4%
`
`35.0%
`
`45 9%
`70.7%
`
`_
`
`13.9%
`
`7.0
`
`
`
`CasuIe 3
`
`% Release
`
`2.0%
`
`5.5%
`
`5.1%
`
`9.9%
`
`5.0%
`
`28.0%
`
`30.7%
`
`37.9%
`
`54.1%
`
`
`
`
`
`
`20.4%
`
`24.6%
`
`
`
`___
`
`1 .4%
`
`4.6%
`
`% Release
`
`

`

`wo 96mm
`
`PCI‘IUS96I04513
`
`13
`
`EXAMELEE
`
`Nine beagle dogs were fasted overnight and fed prior to
`dosing. Each dog was tested with a capsule containing a 93%
`w/w sodium hydrogen divalproex-wax composite (approximately
`515 milligrams (mg) of VPA equivalents). 96.5% w/w sodium
`hydrogen divalproex-wax composite (approximately 534 mg VPA
`equivalents). and a sodium valproate solution (approximately 500
`mg of VPA equivalents). Each dog received each of the three
`formulations with a week between dosings for the drug to clear.
`Blood samples were drawn before dosing and at 30 minutes, 1. 2.
`3. 4, 5, 6, 8, 10, 12. and 15 hours post dosing. EDTA was used as
`an anticoagulant in the blood tubes. The plasma was isolated and
`frozen prior to measurement. Plasma VPA concentrations were
`measured with the TDx® Analyzer (Abbott Laboratories. Abbott
`Park,
`IL. 60064). The results are shown in Figure 3. All
`determinations at each time point are the average of 9
`measurements. As shown in Figure 3, the sodium valproate
`solution peaks directly after administration and then shows a
`rapid decline of plasma VPA over time while the sodium
`hydrogen divalproex-wax composite formulations showed a
`delayed peak between 2-3 hours and consistently higher plasma
`VPA levels than the sodium valproate solution after 3 hours.
`Capsules were made by taking 25 gm samples of sodium
`hydrogen divalproex (Abbott Laboratories) which were combined
`with 0.875 gm'and 1.75 gm polyethylene wax (8-390 C, Shamrock
`Technologies Inc.). The sodium hydrogen divalproex and
`polyethylene wax were melted in a beaker on a hot plate at a
`temperature of approximately 115°C. The resultant sodium
`hydrogen divalproex-wax melt was mixed to form a homogeneous
`sodium hydrogen divalproex-wax mixture. The molten sodium
`hydrogen divalproex-wax composite was filled into Capillm
`capsules. The molten mixture was transferred to the Capillm
`capsules using glass Pasteur pipets which had been shortened at
`the tip and to decrease resistance to flow. After the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`W0 96I31 I97
`
`PCT/USWMSB
`
`14
`
`homogeneous mixture had hardened, the Capillm capsules were
`
`‘filled again with more of the homogeneous sodium hydrogen
`
`divalproex-wax mixture to a total of approximately 596 mg of
`
`sodium hydrogen divalproex-wax composite. The Capillm
`
`5
`
`capsules were then capped and sealed witha 20% ethanol in
`' water solution.
`
`

`

`we 96131197
`
`Permsmsn
`
`15
`
`We claim:
`
`in
`A controlled-release formulation comprising.
`1.
`combination a therapeutically-effective dosage of drug which
`melts at low temperature and an additive selected from the
`group consisting of ethyl cellulose, methylcellulose.
`hydroxypropyl cellulose, polyacrylamide. ethylene vinyl‘ acetate
`copolymer, polymethylmethacrylate, polyhydroxyethyl
`methacrylate and waxes, and the like, such that the additive and
`the drug form a homogeneous drug-additive composite with a 92-
`to-97% weight/weight of said drug.
`
`The controlled-release formulation of Claim 1 wherein
`2.
`said drug is selected from the group consisting of: sodium
`hydrogen divalproex,
`ibuprofen.
`ramipril. dibenzyline. erythrityl
`tetranitrate,
`isosorbide dinitrate. methosuximide, ketoprofen.
`gemfibrozil. paroxetine hydrochloride. and trimipramine maleate.
`
`The controlled-release formulation of Claim 1 wherein
`3.
`said additive is a polyalkylene wax.
`
`The controlled-release formulation of Claim 3 wherein
`4.
`said polyalkylene wax is polyethylene wax.
`
`The controlled-release formulation of claim 1 wherein said
`5.
`homogeneous drug-additive composite is formed in a capsule.
`
`A method for manufacturing a controlled-release
`6.
`formulation comprising:
`
`10
`
`15
`
`20
`
`30
`
`35
`
`

`

`WO 96131197
`
`PCIIUS96/04513
`
`16
`
`a) melting a drug an additive at a temperature below
`
`150°Centigrade, mixing said drug and said additive to produce a
`homogeneous mixture. said drug comprising 92-97% w/w of said
`said homogeneous mixture; and
`
`allowing said homogeneous mixture to harden to produce
`b)
`a drug-additive composite.
`.
`
`10
`
`7
`
`The method of Claim 6, wherein said additive is selected
`
`from the group consisting of ethyl cellulose. methylcellulose,
`hydroxypropyl cellulose. polyacrylamide. ethylene vinyl acetate
`copolymer, polymethylmethacrylate. polyhydroxyethyl
`methacrylate and waxes.
`
`15
`
`20
`
`25
`
`30
`
`8.
`
`The method of Claim 7 wherein said additive is a
`
`polyalkylene wax.
`
`The method of Claim 6, wherein said drug and said additive
`9.
`are melted separately and then combined together in liquid form.
`mixing said drug and said additive to form said homogeneous
`mixture.
`
`10.
`
`The method Claim 6 wherein said drug is selected from the
`
`ibuprofen.
`group consisting of sodium hydrogen divalproex,
`ramipril. dibenzyline. erythrityl
`'tetranitrate.
`isosorbide
`dinitrate. methosuximide, ketoprolen, gemfibrozil. paroxetine
`hydrochloride, and trimipramine maleate.
`
`11.
`
`A method for manufacturing a controlled-release
`
`35
`
`formulation comprising,
`
`in combination:
`
`

`

`WO 96131197
`
`PCP/0896104513
`
`17
`
`a) melting a drug an additive at a temperature below
`150°Centigrade. mixing said drug and said additive to produce a
`homogeneous mixture, said drug comprising 92-97% w/w of said
`said homogeneous mixture:
`
`b)
`
`adding said homogenous mixture to a capsule;
`
`allowing said homogeneous mixture to harden to produce
`c)
`a dmg-additive composite; and
`
`d) capping said capsule.
`
`12. The method of Claim 11 wherein said additive is selected
`from the group consisting of ethyl cellulose. methylcellulose.
`hydroxypropyl cellulose. polyacrylamide. ethylene vinyl acetate
`copoiymer, polymethylmethacrylate. polyhydroxyethyl
`methacrylate and waxes.
`
`13.
`
`wax.
`
`The method of Claim 12 wherein said wax is a polyalkylene
`
`5
`
`I
`
`10
`
`15
`
`20
`
`25
`
`14. The method of Claim 13 wherein said polyalkylene wax is
`polyethylene wax.
`
`15. The method of Claim 11 wherein said drug is selected
`from the group consisting of sodium hydrogen divalproex,
`ibuprofen,
`ramipril. dibenzyline, erythrityl
`tetranitrate,
`isosorbide dinitrate. methosuximide. ketoproien. gemfibrozil,
`paroxetine hydrochloride, and trimipramine maleate.
`
`30
`
`35
`
`

`

`W0 9GB] 197
`
`PCT/0596104513
`
`1/3
`
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`
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`
`

`

`WO 96/31197
`
`PCT/1596104513
`
`2/3
`
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`
`
`
`
`

`

`WO 9631197
`
`PCTIU896104513
`
`3/3
`
`9
`
`
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`285%
`
`

`

` INTERNATIONAL SEARCH REPORT
`Ink .uonal Application No
`
`PCT/US 96/04513
`
`
`,
`TI N 0F SUBJECT M TI'ER
`lPE‘J‘sss'F'CK61‘lc9/48
`A31K31/19
`
`
`
`
`a. FIELDS SEARCHED
`
`'
`
`Minimum manna searched (classification lynch {aloud by classification symbols)
`IPC 6
`A61K
`
`
` Am; no humans! Plum Clnn‘ficu'on (IPC) or to both national elimination and IPC
`
`
`
`
`
`
`Dmemmmmmmummmmmmdmmaterialism“
`
`
`
`
`
`
`
`
`
`
` FR.A,2 549 371 (SANOFI SA) 25 January 1985
`
`
`* see the whole document,
`in particular
`claims 1,2, and 4 *
`
`
`
`
`
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`C. DOCUMEN'IS CONSIDERED TO BE RELEVANT
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`EP,A,0 299 668 (BOOTS C0 PLC) 18 January
`1989
`*see the whole document.
`claims 1,2,9 and 10*
`
`in particular
`
`HO.A,92 05774 (SANOL ARZNEI SCHNARZ GHBH)
`16 April 1992
`*see claims 1,2,4-6 *
`
`FR,A,2 682 677 (SANOFI ELF) 23 April 1993
`* see claims 1,4 and page 3,
`lines 27-35*
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`
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`
`
`
`
`
`
`
`2 July 1996
`
`01.08.96
`
`NmuflmflingmdmeISA
`Em Pam Office. P3. sun Pm 2
`
`NL - 2280 HV hunk
`
`
`
`Tel. (+ Ill-70) mm 1!. ll 6.“ eye nl.
`Fa: («v 31-10) 360-1016
`
`
`Isert, B
`
`
`
`Fm ”TAM-Ill) (“I cum) "fly um)
`
`AM OH?”
`
`
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`lnfomuum on pun: [umly aunts:
`
`Patent document
`cited in search upon
`
`Publiulion
`dug
`
`
`
`In!
`Jun! Agitation No
`
`PCT/US 96/04513
`.
`Pub