United States Patent (19)
`Oshlack et al.
`
`US005639476A
`Patent Number:
`11
`45 Date of Patent:
`
`5,639,476
`*Jun. 17, 1997
`
`54 CONTROLLED RELEASE FORMULATIONS
`COATED WITH AQUEOUS DISPERSIONS OF
`ACRYLC POLYMERS
`
`4,837,004 6/1989 Wu et al. ................................ 424/438
`4,853,230 8/1989 Lovgren et al. ........................ 424/466
`4,891.230
`1/1990 Geogheogan et al. .
`... 424/461
`4,954,350 9/1990 Jones et al. ............................. 424/493
`5,008,118 4/1991 Iwanami et al. ........................ 424/498
`8
`tE.S.S. 5,019,397 5/1991 Wong et al. ............................ 424/468
`Pedi, Jr., Yorktown Heights, N.Y.
`(List continued on next page.)
`73) Assignee: Euro-Celtique, S.A., Luxembourg
`FOREIGN PATENT DOCUMENTS
`
`B
`75 Inventors:
`
`8
`
`*) Notice:
`
`The term of this patent shall not extend
`3. expiration date of Pat. No.
`286,493.
`21 Appl. No.: 459,110
`22 Filed:
`Jun. 2, 1995
`Related U.S. Application Data
`60 Division of Ser. No. 97.558, Jul. 27, 1993, Pat No. 5,580,
`578, which is a continuation-in-part of Ser. No. 826,084,
`Jan. 27, 1992, Pat No. 5286,493.
`Int. Cl.
`A61K9/62
`(51
`52 U.S c so as a woo
`424/468; 424/486. 424/482
`soooooo in
`58 rida fsearch.
`424As
`(58
`0 Sert .....................................
`424/482
`
`E.8: AG, Patoff so see wwww. A61K 3/55
`0327295 1/1989 European Pat. Off..
`0377517 1/1990 European Pat. Off..
`0377518 1/1990 European Pat. Of..
`0463877 6/1991 European Pat. Off...
`0166608 8/1985 Japan ..................................... 424/472
`2178313 2/1987 United Kingdom.
`OTHER PUBLICATIONS
`D.L. Munday, A.R. Fassihi, 5th Congr. Int. Tech. Pharm. vol.
`2, pp. 55–60 Changes in Drug Release Rate, Effect of
`Temperature and Relative Humidity on Polymeric Film
`Coating, 1989, Assoc. Pharm. Galenique Ind., Chatenay
`Malabry, FR.
`U.S. Set No. 07-102567 as filed inconnection with Euro
`pean Patent Application No. 921083614.
`Primary Examiner-Peter F. Kulkosky
`0
`Attorney, Agent, or Firm-Steinberg, Raskin & Davidson,
`References Cited
`PC.
`U.S. PATENT DOCUMENTS
`ABSTRACT
`57
`3,901.968 8/1975 Cohen et al. ............................. 424/22
`3,901.969 8/1975 Cohen et al. ............................. 424/22
`A stable solid controlled release formulation having a coat
`was
`ing derived from an aqueous dispersion of a hydrophobic
`E. E; Eric - O - O
`OO .5.
`acrylic polymer includes a substrate including an active
`427/3
`4,088,798 5/1978 Michealis ................
`26 agent selected from the group consisting of a systemically
`4,443,497 4/1984 Sameima et al. .
`52.5/369
`active therapeutic agent, a locally active therapeutic agent, a
`4,520,172 5/1985 Lehmann et al. ...
`... 525/123
`disinfecting and sanitizing agent, a cleansing agent, a fra
`4,548,990 10/1985 Mueller et al. .............
`... 424/482
`grance agent and a fertilizing agent, overcoated with an
`4,600,645 7/1986 Ghebre-Sellassie et al.
`4,705,695 11/1987 Lehmann et al. ........................ 427/22
`aqueous dispersion of the plasticized water-insoluble acrylic
`4,728,513 3/1988 Ventouras...........................
`2
`polymer. The formulation provides a stable dissolution of
`4,766,012 8/1988 Valenti .......
`427/213.36
`the active agent which is unchanged after exposure to
`4,784,858 11/1988 Ventouras ................................ 424/468
`4,786,505 11/1988 Lovgren et al.
`"E: accelerated storage conditions.
`4,786,506 11/1988 Fontanelli.............................. 424/470
`4,798,724 1/1989 Khanna ................................... 424/480
`13 Claims, 8 Drawing Sheets
`
`56)
`
`
`
`DS9kDRONE
`by it
`
`ORP808
`is a
`
`i
`
`B
`
`is a 24 as
`tEARS
`
`32
`
`is 40
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`5,639,476
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`U.S. PATENT DOCUMENTS
`6/1991 Edgren et al. .......................... 424/472
`5,024,842
`5,047,258 9/1991 Belanger et al. .
`... 427/3
`5,068,110 11/1991 Fawzi et al. ..
`... 424/462
`5,084.278
`1/1992 Mehta ...........
`... 424/441
`5,085,866 2/1992 Cowsar et al.
`... 424/481
`5,091,175 2/1992 Imondi et al.
`... 424/486
`5,096,717 3/1992 Wirth et al........
`... 424/490
`5,112,384 5/1992 Paradissis et al.
`... 424/451
`5,112,621
`5/1992 Stevens et al. ......................
`424/497
`
`5,130,171 7/1992 Prud’Homme et al. ........... 427/213.36
`5,133,974 7/1992 Paradissis et al. ...................... 424/480
`5,158,777 10/1992 Abramowitz et al
`... 424/458
`5,160,742 11/1992 Mazer et all
`424/469
`sr. ww.
`re -
`-
`-
`O - OOOOO------
`5,171,580 12/1992 Iamartino et al. ...................... 424/490
`5,178.866 1/1993 Wright et al. ...
`... 424/473
`5,202,128 4/1993 Morella et al. ......................... 424/469
`5202,159 4/1993 Chen et al. .....
`427/213.31
`5,219,621
`6/1993 Geoghegan et al..................... 424/462
`5,286,493 2/1994 Oshlack et al. ......................... 424/468
`
`
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`U.S. Patent
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`Sheet 1 of 8
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`Jun. 17, 1997
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`1.
`CONTROLLED RELEASE FORMULATIONS
`COATED WITH AQUEOUS DISPERSIONS OF
`ACRYLC POLYMERS
`
`5,639,476
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`2
`controlled release coatings have a low solubility in water,
`they are usually applied by dissolving the polymer in an
`organic solvent and spraying the solution onto the individual
`drug forms (such as beads or tablets) and evaporating of the
`solvent,
`Aqueous dispersions of hydrophobic polymers have been
`used in the prior art to coat pharmaceutical dosage forms for
`aesthetic reasons such as film coating tablets or beads or for
`taste-masking. However, these dosage forms are used for
`immediate release administration of the active drug con
`tained in the dosage form.
`The use of organic solvents in the preparation of hydro
`phobic coatings is considered undesirable because of inher
`ent problems with regard to flammability, carcinogenicity,
`environmental concerns, cost, and safety in general. It is
`considered very desirable in the art, however, to provide a
`controlled release coating derived from aqueous dispersions
`of a hydrophobic material, such as an acrylic polymer.
`While many formulations have been experimentally pre
`pared which rely upon a hydrophobic coating derived from
`an aqueous dispersion to provide controlled release of an
`active agent, such formulations have not proven to be
`commercially viable because of stability problems. Aqueous
`polymeric dispersions have been used to produce stable
`controlled release dosage forms, but this has only been
`possible by other methods such as incorporation of the same
`into the matrix of the dosage form, rather than via the use of
`a coating of the aqueous polymeric dispersion to obtain
`retardant properties.
`When coating using aqueous polymeric dispersions to
`obtain a desired release profile of the active agent(s) over
`several hours, or longer, it is known in the art that the
`dissolution release profile changes on ageing, e.g. when the
`final coated product is stored for a period of time, during
`which time it may be exposed to elevated temperature and/or
`humidity above ambient conditions.
`This was recently demonstrated by Munday, et al., Drug
`Devel. and Indus. Phar, 17 (15) 2135-2143 (1991), which
`reported the effect of storing theophylline mini-tablets film
`coated with ethyl cellulose with PEG (2:1 ratio; total
`coating=3% whv), ethyl cellulose with Eudragité L. (2:1
`ratio; total coating=3% w/w); and Eudragit(8) RL (amount of
`coating=1.5% whv) at varying temperatures and relative
`humidities upon the rate of drug release. Samples were
`subjected to isothermal storage at 28°C., 35° C. and 45° C.
`with the relative humidity (RH) maintained between
`55-60%, under cyclic conditions of 45° C. at 55% RHfor 24
`hours, then at 28°C. and 20% RH for 24 hours, and then at
`5° C. and 10% RH for 24 hours, after which the cycle was
`repeated, and alternating conditions every 24 hours between
`45° C. and 55% RH and 28° C. and 0% RH. The aging
`process brought about by storage under the above stress
`conditions impeded dissolution, irrespective of the nature of
`the polymeric film. The greatest reduction in release rate was
`said to occur in the first 21 days (isothermal storage) after
`coating.
`While this instability problem is known not to exist when
`the polymers are applied from organic solvent solution, it
`has not been possible to obtain a controlled release formu
`lation utilizing coatings prepared from such aqueous acrylic
`polymer dispersions which is stable under various storage
`conditions.
`In particular, it is known that controlled release coatings
`of commercially available acrylic polymers such as those
`sold under the tradename Eudragit(8) by Rohm Pharma
`GmbH are not stable when cured according to recommended
`curing conditions of 45° C. for 2 hours.
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`5
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`This is a divisional of application Ser. No. 08/097.558,
`filed Jul. 27, 1993, now U.S. Pat. No. 5,580,578 which is a
`continuation-in-part of U.S. application Ser. No. 07/826,084
`filed Jan. 27, 1992, now U.S. Pat. No. 5,286,493.
`BACKGROUND OF THE INVENTON
`An important aspect of the manufacture, regulatory
`review and approval of all dosage forms concerns their
`stability over extended periods of time. The stability data
`obtained with regard to a particular dosage form directly
`affects its shelf-life. The stability of a pharmaceutical dosage
`form is related to maintaining its physical, chemical,
`microbiological, therapeutic, and toxicological properties
`when stored, i.e., in a particular container and environment.
`Stability study requirements are covered, e.g., in the Good
`20
`Manufacturing Practices (GMPs), the U.S.P., as well as in
`the regulatory requirements of the country where approval to
`market a dosage form is being sought. In the United States,
`a request to test, and eventually market, a drug or a drug
`formulation may be made via a New Drug Application
`(NDA), an Abbreviated New Drug Application (ANDA) or
`an Investigational New Drug Applications (IND).
`The agents used in sustained release dosage formulations
`often present special problems with regard to their physical
`stability during storage. For example, waxes which have
`been used in such formulations are known to undergo
`physical alterations on prolonged standing, thus precautions
`are taken to stabilize them at the time of manufacture or to
`prevent the change from occurring. Fats and waxy materials
`when used in purified states are known to crystallize in
`unstable forms, causing unpredictable variations availability
`rates during stability testing at the time of manufacture and
`during later storage.
`It is known that certain strategies can be undertaken to
`obtain stabilized controlled release formulations in many
`cases, such as insuring that the individual agents are in a
`stable form before they are incorporated into the product,
`and that processing does not change this condition, retarding
`the instability by including additional additives, and induc
`ing the individual agents of the dosage form to reach a stable
`state before the product is finally completed.
`It is also recognized that the moisture content of the
`product can also influence the stability of the product.
`Changes in the hydration level of a polymeric film, such as
`the ethyl celluloses, can alter the rate of water permeation
`and drug availability. Also, binders such as acacia are known
`to become less soluble when exposed to moisture and heat.
`However, moisture content of a product can be controlled
`fairly successfully by controls in the processing method and
`proper packaging of the product.
`Hydrophobic polymers such as certain cellulose
`derivatives, zein, acrylic resins, waxes, higher aliphatic
`alcohols, and polylactic and polyglycolic acids have been
`used in the prior art to develop controlled release dosage
`forms. Methods of using these polymers to develop con
`trolled release dosage forms such as tablets, capsules,
`suppositories, spheroids, beads or microspheres include
`incorporating these agents into a controlled release matrix or
`using certain of these agents in a controlled release coating
`of the dosage form. It is known in the prior art that
`hydrophobic coatings can be applied either from a solution,
`suspension or dry. Since most of the polymers used in
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`3.
`OBJECTS AND SUMMARY OF THE
`INVENTION
`It is therefore an object of the present invention to provide
`a controlled release formulation of a substrate comprising an
`active agent, e.g. a therapeutically active agent, a disinfect
`ing agent, a cleansing agent, a Sanitizing agent and a
`fertilizing agent, coated with an aqueous dispersion of a
`hydrophobic acrylic polymer such that there is a stable
`dissolution or other release profile of the active agent when
`placed in an environment of use, despite exposure to a
`variety of storage conditions, including accelerated storage
`conditions.
`It is another object of the present invention to provide a
`controlled release formulation comprising a plurality of inert
`beads comprising an active agent, and a controlled release
`tablet comprising a core containing an active agent, the
`beads or tablet core being coated with an aqueous dispersion
`of a hydrophobic polymer and providing a reproducible,
`stable dissolution despite exposure to accelerated storage
`conditions, as well as a method of preparing the same.
`Still another object of the present invention is to provide
`a controlled release formulation comprising a substrate
`containing an active agent coated with an aqueous disper
`sion of a hydrophobic polymer which upon dissolution
`in-vitro provides a band range, when comparing the disso
`lution profile of the formulation after exposure to a variety
`of storage conditions including "stressed” or accelerated
`storage conditions, which is not wider than about 15% of the
`total active agent released at any point of time during the
`dissolution.
`A further object of the present invention is to provide a
`controlled release formulation wherein the controlled
`release is caused by a coating on the formulation of an
`aqueous dispersion of a hydrophobic polymer Such as an
`acrylic polymer which coating provides a stable dissolution
`of an active agent contained in the formulation, despite
`exposure to accelerated storage conditions such that the
`dissolution would be deemed acceptable by a governmental
`regulatory agency such as the U.S. FDA for purposes of
`according expiration dating.
`These objects and others have been accomplished by the
`present invention, which relates in part to a controlled
`release formulation comprising a substrate comprising an
`active agent in an amount sufficient to provide a desired
`effect in an environment of use, the substrate being coated
`with an aqueous dispersion of plasticized pharmaceutically
`acceptable hydrophobic acrylic polymer in an amount suf
`ficient to obtain a controlled release of said active agent
`when said formulation is exposed to an environmental fluid,
`and cured at a temperature greater than the glass transition
`temperature of the aqueous dispersion of plasticized acrylic
`polymer for a sufficient period of time until a curing end
`point is reached at which the coated Substrate provides a
`stable dissolution of the active agent which is unchanged
`after exposure to accelerated storage conditions. The end
`point may be determined, e.g., by comparing the dissolution
`profile of the formulation immediately after curing to the
`dissolution profile of the formulation after exposure to
`accelerated storage conditions such as one to three months
`at a temperature of 37° C. and at a relative humidity of 80%,
`or at a temperature of 40° C. and at a relative humidity of
`75%. In certain preferred embodiments, the substrate is
`coated to a weight gain from about 2% to about 25%.
`In other preferred embodiments, the coated substrate
`when subjected to in-vitro dissolution, releases said active
`agent in amounts which do not vary at any time point along
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`the dissolution curve by more than about 15% of the total
`amount of active agent released, when compared to the
`in-vitro dissolution of said coated substrate after curing.
`In yet other embodiments of the invention, the cured
`formulation provides a stabilized dissolution of said active
`agent which is unchanged after exposure to accelerated
`storage conditions, the stabilized dissolution being deemed
`appropriate by the United States Food & Drug Administra
`tion for the purpose of according expiration dating for said
`formulation.
`Other preferred embodiments relate to controlled release
`dosage formulation comprising a substrate coated with an
`effective amount of an aqueous dispersion of acrylic poly
`mer to obtain a controlled release of an active agent which
`formulation, after exposure to accelerated Storage
`conditions, releases an amount of therapeutically active
`agent which does not vary at any given dissolution time
`point by more than about 20% of the total amount of
`therapeutically active agent released, when compared to
`in-vitro dissolution conducted prior to storage. The acrylic
`polymer preferably has a permeability which is unaffected
`by the pH conditions prevailing in the gastrointestinal tract.
`In other embodiments, the coated Substrate, upon in-vitro
`dissolution testing, provides a band range after exposure to
`accelerated point of time when compared to the dissolution
`profile prior to exposure to the accelerated storage condi
`tions.
`The active agent may be chosen for a wide variety of uses,
`including but not limited to systemically active therapeutic
`agents, locally active therapeutic agents, disinfectants,
`cleansing agents, fragrances, fertilizers, deodorants, dyes,
`animal repellents, insect repellents, pesticides, herbicides,
`fungicides, and plant growth stimulants.
`The present invention is further related to a solid con
`trolled release oral dosage formulation, comprising a sub
`strate containing a systemically active therapeutic agent in
`an amount sufficient to provide a desired therapeutic effect
`when said formulation is orally administered. The substrate
`is coated with an aqueous dispersion of plasticized acrylic
`polymer and cured at a temperature greater than the glass
`transition temperature Of the aqueous dispersion of plasti
`cized acrylic polymerfor a period of time sufficient to obtain
`a controlled release of said active agent when measured by
`the USP Paddle or Basket Method at 100 rpm at 900 ml
`aqueous buffer (pH between 1.6 and 7.2) at 37° C. from
`about 0% to about 42.5% (by wt) active agent released after
`1 hour, from about 5% to about 60% (by wt) active agent
`released after 2 hours, from about 15% to about 75% (by wt)
`active agent released after 4 hours, and from about 20% to
`about 90% (by wt) active agent released after 8 hours. The
`coated substrate has a stable release when comparing the
`rate of release of the active agent after exposing the coated
`Substrate to accelerated conditions, to the release rate
`obtained immediately after curing. The dosage form prefer
`ably provides a therapeutic effect for about 24 hours. The
`present invention further relates to a method of preparing the
`dosage form.
`The present invention is also related to a method for
`obtaining a controlled release formulation of an active agent,
`comprising preparing a solid substrate comprising an active
`agent, coating the substrate with a sufficient amount an
`aqueous dispersion of plasticized acrylic polymer to obtain
`a predetermined controlled release of the active agent when
`the coated substrate is exposed to an environmental fluid,
`and curing the coated substrate at a temperature greater than
`the glass transition temperature of the aqueous dispersion of
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`plasticized acrylic polymer until a curing endpoint is
`reached at which said coated substrate provides a stabilized
`dissolution of said active agent which is unchanged after
`exposure to accelerated storage conditions.
`The present invention is further related to a method of
`treating a patient with an oral solid dosage form described
`above. In this method, present invention further comprises
`administering the oral solid dosage form comprising the
`cured, coated substrate to the patient to thereby obtain the
`desired therapeutic effect for about 12 to about 24 hours or
`more. In especially preferred embodiments, the oral solid
`dosage forms of the present invention provide a desired
`therapeutic effect for about 24 hours.
`In certain preferred embodiments of the presentinvention,
`the hydrophobic acrylic polymer is comprised of copoly
`merizates of acrylic and methacrylic acid esters having a
`permeability which is unaffected by the pH conditions
`prevailing in the gastrointestinal tract. Preferably, these
`copolymerizates further include a low content of quaternary
`ammonium groups, which occur as salts and are responsible
`for the permeability of the lacquer substances.
`The present invention provides many benefits over prior
`art coatings, including, but not limited to, avoidance of
`organic solvents which have inherent safety concerns
`(flammability, carcinogenicity, environmental concerns,
`cost, safety in general), and extended stability which may
`result in extended shelf life and expiration dating.
`BRIEF DESCRIPTION OF THE DRAWINGS
`The following drawings are illustrative of embodiments
`of the invention and are not meant to limit the scope of the
`invention as encompassed by the claims.
`FIG. 1 is a graphical representation of the dissolution
`results of Comparative Example 13A;
`FIG. 2 is a graphical representation of the dissolution
`results of Example 5;
`FIG. 3 is a graphical representation comparing the plasma
`levels obtained by Example 13 against the plasma levels
`obtained by comparative Example 13A;
`FIG. 4 is a graphical representation of the plasma levels
`obtained for Examples 14A and 15A;
`FIG. 5 is a graphical representation of the plasma levels
`obtained for Examples 14 and 15;
`FIG. 6 is a graphical representation of the plasma levels
`obtained for Examples 16 and 17;
`FIG. 7 is a graphical representation of the trough levels
`obtained for Example 16A versus the results obtained for
`Examples 16 and 17; and
`FIG. 8 is a graphical representation of the plasma levels
`obtained for Examples 19 and 20 versus the plasma levels of
`Comparative Example 19A.
`DETALED DESCRIPTION
`The aqueous dispersions of hydrophobic acrylic polymers
`used as coatings in the present invention may be used to coat
`substrates such as tablets, spheroids (or beads),
`microspheres, seeds, pellets, ion-exchange resin beads, and
`other multi-particulate systems in order to obtain a desired
`controlled release of the active agent. Granules, spheroids,
`or pellets, etc., prepared in accordance with the present
`invention can be presented in a capsule or in any other
`suitable dosage form. The tablets of the present invention
`may be any suitable shape, such as round, oval, biconcave,
`hemispherical, any polygonal shape such as square,
`rectangular, and pentagonal, and the like.
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`In order to obtain a controlled release formulation, it is
`usually necessary to overcoat the substrate comprising the
`active agent with a sufficient amount of the aqueous disper
`sion of hydrophobic acrylic polymer to obtain a weight gain
`level from about 2 to about 25 percent, although the overcoat
`may be lesser or greater depending upon the physical
`properties of the active agent and the desired release rate, the
`inclusion of plasticizer in the aqueous dispersion and the
`manner of incorporation of the same, for example. In certain
`embodiments of the invention, the controlled release coat
`ings may be applied to the substrate up to, e.g., a 50% weight
`gain.
`The cured, coated substrates of the present invention
`provide a stable dissolution profile (e.g., release of the active
`agent in the environment of use) when stored for extended
`periods of time at room temperature and ambient humidity
`(e.g., long term (real time) testing), and when tested under
`accelerated storage conditions.
`The terms "stable dissolution profile” and "curing end
`point” are defined for purposes of the present invention as
`meaning that the cured, coated substrate reproducibly pro
`vides a release of the active agent when placed in an
`environment of use which is unchanged, even after exposing
`the cured, coated substrate to accelerated storage conditions.
`Those skilled in the art will recognize that by "unchanged”
`it is meant that any change in the release of the active agent
`from the cured, coated formulation would be deemed insig
`nificant in terms of the desired effect. For pharmaceutical
`formulations, stability is evaluated by, e.g., a regulatory
`agency such as the Food & Drug Administration (FDA) in
`the U.S., for the purpose of according an expiration date for
`the formulation.
`By the phrase “accelerated storage conditions” it is meant,
`e.g., storage conditions of elevated temperature and/or
`elevated relative humidity. Preferably, the phrase "acceler
`ated storage conditions” refers to storage conditions to
`which the final drug formulation is subjected for the purpose
`of obtaining regulatory approval (e.g., FDA approval in the
`U.S.) and an expiration date.
`The term "expiration date” is defined for purposes of the
`present invention as the date designating the time during
`which a packaged batch of the, product (e.g., the cured,
`coated substrate) is expected to remain within specification
`if stored under defined conditions, and after which it should
`not be used.
`By "environmental fluid", it is meant that the formulation
`is placed in an aqueous solution (e.g., in-vitro dissolution),
`in simulated gastric fluid (e.g., in accordance with the USP
`Basket Method (i.e., 37° C., 100 RPM, first hour 700 ml
`gastric fluid with or without enzymes at pH 1.2, then
`changed to 900 ml at pH 7.5), or in gastrointestinal fluid
`(in-vivo).
`The term "band range” or "band width” for purposes of
`the present invention is defined as the difference in in-vitro
`dissolution measurements of the controlled release formu
`lations when comparing the dissolution profile (curve)
`obtained by the formulation upon completion of the manu
`facturing of the coated product (prior to storage) and the
`dissolution profile obtained after the coated product is
`exposed to accelerated storage conditions, expressed as the
`total (absolute) change in percent of the active agent
`released from the coated product at any dissolution time
`point along the dissolution curves.
`In general, the length of the studies and the storage test
`conditions required by regulatory agencies such as the FDA
`for pharmaceutical formulations are sufficient to cover
`
`KASHIV1051
`IPR of Patent No. 9,492,393
`
`

`

`5,639,476
`
`7
`storage, shipment, and subsequent use. Allowable storage
`test conditions may vary depending upon the particulars of
`the product. For example, temperature sensitive drug sub
`stances should be stored under an alternative, lower tem
`perature condition, which is then deemed to be the long term
`testing storage temperature. In such cases, it is generally
`accepted that the accelerated testing should be carried out at
`a temperature at least 15° C. above this designated long term
`storage temperature, together with appropriate relative
`humidity conditions for that temperature.
`10
`A generally accepted accelerated test employed in FDA
`guidelines relates to the storage of a drug product (e.g., in its
`container and package) at 80% Relative Humidity (RH) and
`37° C. (1985 FDA guidelines). If the product holds up for,
`e.g., three months under these conditions (chemical stability,
`dissolution, and physical characteristics), then the drug
`product will be accorded, e.g., a two year expiration date.
`This accelerated test is also now also considered to be
`acceptable if conducted at 75% RH and 40° C. (FDA 1987
`guidelines). It has recently been proposed that long-term
`storage testing be conducted for pharmaceutical formula
`tions at 25 C-2 c at not less than 60% RH-5% for a
`minimum time period of 12 months. It has been further
`proposed that accelerated testing be conducted for pharma
`ceutical formulations at 40° C.2° C. at 75% RH-5% for a
`minimum time period of 6 months. All of the above
`mentioned accelerated testing criteria and others are deemed
`equivalent for purposes of the present invention, with regard
`to the determination of stability and the determination of the
`curing endpoint. All of the above-mentioned accelerated
`testing conditions, as well as others known to those skilled
`in the art, provide an acceptable basis for determining the
`curing (stability) endpoint of the controlled release formu
`lations of the present invention.
`The controlled release coatings of the present invention
`comprise aqueous dispersions of hydrophobic (water
`in soluble) acrylic polymers. In certain preferred
`embodiments, the hydrophobic acrylic polymer coatings of
`the present invention have a solubility and permeability
`independent of the pH of the fluid present in the environment
`of use. In the case of oral solid dosage forms, the hydro
`phobic acrylic polymers of the present invention have a
`solubility and permeability independent of physiological pH
`values. Hydrophobic acrylic polymers which may be used in
`the formulations of the present invention are derived from
`acrylic acid or derivatives thereof. Acrylic acid derivatives
`include, for example, the esters of acrylic acid and meth
`acrylic acid, and the alkyl esters of acrylic acid and meth
`acrylic acid. In certain preferred embodiments, the alkyl
`esters of acrylic acid and methacrylic acid have from about
`1 to about 8 carbon atoms in the alkyl group. The monomers
`which may be used in the polymer coatings of the present
`invention also include styrene and its homologs, vinyl esters
`such as vinyl acetate, and vinyl chloride. Generally, mono
`mers forming hydrophobic water-insoluble polymers are
`55
`nonionic. The term "nonionic monomers" for purposes of
`the present invention is meant to include not only monomers
`which have no ionic groups (such as alkalimetal carboxylate
`or sulfonate or tertammonium groups) in the molecule, but
`also monomers which are unable to form such groups with
`bases or acids. In many cases, the composition of the
`hydrophobic acrylic polymer coating may include other
`OOCS.
`One skilled in the art will appreciate that the hardness and
`extensibility of the coating film and the lowest temperature
`at which film formation from the aqueous dispersion is
`possible are influenced by the particular monomers included
`
`8
`in the hydrophobic acrylic polymer used in the present
`invention. Lower alkyl esters of methacrylic acid are known
`to form relatively harder homopolymers, which acrylic acid
`esters and the higher alkyl esters of methacrylic acid provide
`relatively softer homopolymers. Alkyl groups having greater
`than 4 carbon atoms or aryl groups have a hydrophobizing
`effect and thereby reduce the swelling capacity and diffusion
`permeability.
`In certain preferred embodiments of the present invention,
`the acrylic polymer also includes one or more polymerizable
`permeability-enhancing compounds which will allow the
`active agent enclosed within the coating to be released at a
`desired diffusion rate, regardless of the prevailing pH value.
`In the case of oral solid dosage forms, the permeability
`enhancing compound allows the