United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,662,933
`
`Baichwal et al.
`
`[45] Date of Patent:
`
`*Sep. 2, 1997
`
`US005662933A
`
`[54]
`
`[75]
`
`[73]
`
`CONTROLLED RELEASE FORMULATION
`(ALBUTEROL)
`
`Inventors: Anand Baichwal. Wappingers Falls,
`N.Y.; 'h‘oy W. McCall, New Milford,
`Conn.
`
`Assignee: Edward Mendel] Co., Inc., Patterson,
`N.Y.
`
`[*1
`
`Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5455046.
`
`[21]
`
`Appl. No.: 553,008
`
`[22]
`
`Filed:
`
`Nov. 3, 1995
`
`Related US. Application Data
`
`Continuation—impart of Ser. No. 118,924, Sep. 9, 1993, Pat
`No. 5,455,046.
`
`Int. 01.5 ................................ A61K 9/14; A61K 9/22
`US. Cl. .......................... 424/457; 424/468; 424/488;
`514/777; 514/778; 514/779; 514/780; 514/781;
`514/964; 514/965
`Field of Search ..................................... 424/457, 468,
`424/488; 514/777. 778, 779, 780, 781,
`964. 965
`
`References Cited
`
`[63]
`
`[5 1]
`[52]
`
`[5 8]
`
`[56]
`
`.............................. 424/479
`1/1990 Ohm et al.
`4,892,741
`2/1990 Bauer ................... 514/972
`4,904,699
`
`7/1990 Jenkins et al.
`......
`424/480
`4,940,587
`7/1990 Ragnarsson et a1.
`. 424/486
`4,942,040
`
`4,973,469 11/1990 Mulligan et a1.
`...........
`424/461
`4,994,276
`2/1991 Baichwal et al.
`424/440
`5,007,790
`4/1991 Shell .................... 424/451
`
`5,019,397
`5/1991 Wong et a1.
`424/473
`.
`5,051,263
`9/1991 Barry et al.
`. 424/490
`......
`5,071,642 12/1991 Lahr et al.
`. 424/474
`
`5,128,143
`7/1992 Baichwal et a1.
`. 424/464
`.....
`5,132,116
`7/1992 Sournac et a1.
`. 424/469
`
`5,133,974
`7/1992 Paradissis et a1.
`..
`. 424/480
`
`5,135,757
`8/1992 Baichwal et al.
`424/465
`5,145,683
`9/1992 Rhodes ..................... 424/451
`
`5,169,638 12/1992 Dennis et al.
`..
`..... 424/457
`6/1993 Krishnamurthy ............... 424/488
`5,215,758
`
`5,264,459 11/1993 Chelmicka—Schorr et al.
`514/646
`5,273,760 12/1993 Oshlack et al. .................. 424/480
`
`5,286,493
`2/1994 Oshlack et al.
`.....
`. 424/468
`5,356,467
`10/1994 Oshlack et al.
`.
`..... 106/153
`5,455,046 10/1995 Baichwal
`................................ 424/457
`
`FOREIGN PATENT DOCUMENTS
`
`1 288049
`0232155A2
`0357793A1
`W08902738
`WO9206680
`
`8/1991 Canada .
`8/1987 European Pat. Off. .
`3/1990 European Pat. Off. .
`4/1989 WIPO .
`4/1992 WIPO .
`
`Primary Examiner—Nathan M. Nutter
`Anomey, Agent, or Firm—Steinberg, Raskin & Davidson,
`RC.
`
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`11/1983 Kawata et a1.
`4,412,986
`............................ 424/80
`
`4,562,069 12/1985 Hegasy et al.
`. 424/80
`4,673,564
`6/1987 Kawata et al.
`424/494
`
`4,764,382
`8/1988 Kydonieus et al.
`.
`424/449
`4,765,990
`8/1988 Sugimoto et a1.
`424/494
`.
`4,792,450 12/1988 Kydonieus et al.
`424/449
`4,792,452 12/1988 Howard et a1.
`......
`424/475
`
`4,808,413
`2/1989 Joshi et a1.
`...........
`424/458
`
`4,851,229
`7/1989 Magruder et a1.
`424/457
`4,867,985
`9/1989 Heafield et al.
`........................ 424/461
`
`
`
`A sustained release pharmaceutical formulation and meth-
`ods of making and using the same are provided The
`sustained release pharmaceutical formulation includes a
`sustained release excipient including a gelling agent, an inert
`pharmaceutical diluent, an optional hydrophobic material
`and/or hydrophobic coating, and a medicament for sustained
`oral administration.
`
`48 Claims, 3 Drawing Sheets
`
`AMN EAL 1032
`
`1
`
`

`

`US. Patent
`
`Sep. 2, 1997
`
`Sheet 1 of 3
`
`5,662,933
`
`°/o DlSSOLVED
`
`I00
`
`80
`
`60
`
`4O
`
`20
`
`o
`
`,4
`
`8
`
`:2
`
`TIME ( hours)
`
`—0— TIMER x7“ -Albu terol
`
`F/6./
`
`2
`
`

`

`US. Patent
`
`Sep. 2, 1997
`
`Sheet 2 of 3
`
`5,662,933
`
`I00
`
`80
`
`60
`
`4o
`
`20
`
`°/oDlSSOLVED
`
`O
`
`4
`
`8
`
`l2
`
`TIME(hours)
`
`+T|MER xT"-Albuterol
`
`[-76.2
`
`3
`
`

`

`US. Patent
`
`Sep. 2, 1997
`
`Sheet 3 of 3
`
`5,662,933
`
`IZ
`
`l0
`
`8
`
`(ng/mL)
`
`PLASMA
`CONCENTRATDN
`
`6
`
`O
`
`6
`
`I2
`
`I8
`
`24
`
`TIME (hours)
`
`—o—- TIMERxm-AlbuierOIIfosted
`
`——o— TIMER xW-Albuteror fed
`
`F/6.3‘
`
`4
`
`

`

`1
`CONTROLLED RELEASE FORMULATION
`(ALBUTEROL)
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a continuation-in-part of US.
`application Ser. No. 08/118,924. filed on Sep. 9. 1993. and
`now US. Pat. No. 5.455.046 the disclosure of which is
`incorporated by reference herein in its entirety.
`
`FIELD OF THE INVENTION
`
`The present invention relates to controlled release formu-
`lations which may be blended with a wide range of thera-
`peutically active medicaments and made into controlled
`release solid dosage forms for oral administration.
`
`BACKGROUND OF THE INVENTION
`
`The advantages of controlled release products are well
`known in the pharmaceutical field and include the ability to
`maintain a desired blood level of a medicament over a
`comparatively longer period of time while increasing patient
`compliance by reducing the number administrations. These
`advantages have been attained by a wide variety of methods.
`For example. different hydrogels have been described for
`use in controlled release medicines. some of which are
`synthetic. but most of which are semi-synthetic or of natural
`origin. A few contain both synthetic and non—synthetic
`material. However. some of the systems require special
`process and production equipment. and in addition some of
`these systems are susceptible to variable drug release.
`Oral controlled release delivery systems should ideally be
`adaptable so that release rates and profiles can be matched
`to physiological and chronotherapeutic requirements. In
`US. Pat Nos. 4.994.276, 5,128,143. and 5.135.757, hereby
`incorporated by reference in their entireties. it is reported
`that a controlled release excipient which is comprised of a
`synergistic combination of heterodisperse polysaccharides
`(e.g., a heteropolysaccharide such as xanthan gum in com-
`bination with a polysaccharide gum capable of cross-linking
`with the heteropolysaccharide. such as locust bean gum, in
`an aqueous environment) is capable of being processed into
`oral solid dosage forms using either direct compression (i.e.,
`dry granulation), following addition of drug and lubricant
`powder, conventional wet granulation, or a combination of
`the two. The release of the medicament from the formula-
`tions therein proceeded according to zero-order or first-order
`mechanisms.
`
`The controlled release excipients disclosed in U.S. Pat.
`Nos. 4.994276, 5.128.143. and 5.135,757 are commercially
`available under the trade name TlMERx® from Edward
`Mendell Co., Inc., Patterson. N.Y.. which is the assignee of
`the present invention.
`European Pat. No. 234670 B describes a controlled-
`release pharmaceutical formulation containing xanthan gum
`wherein the xanthan gum comprises from about 7.5 to about
`28 percent, by weight, of the formulation except for a
`formulation wherein the controlled release carrier comprises
`a mixture of 15—50 parts by weight dimethylsiloxane.
`30—100 parts by weight silicic acid. 30—100 parts by weight
`mannans or galactans or a mixture thereof, 50—150 parts by
`weight xanthans and 5—75 parts by weight micronized
`seaweed.
`
`However, heretofore there has been no teaching of a
`controlled release formulation providing a novel and unex-
`pected combination of suitable proportions of a
`
`10
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`15
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`20
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`25
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`30
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`35
`
`40
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`4s
`
`50
`
`55
`
`65
`
`5,662,933
`
`2
`
`homopolysaccharide such as. e.g., xanthan gum. a
`heteropolysaccharide, such as. e.g.,
`locust bean gum.
`together with an inert diluent and a pharmacologically
`acceptable hydrophobic material, so as to provide an
`improvement in controlled release properties for such an
`active medicament
`
`OBJECTS AND SUIVIMARY OF THE
`INVENTION
`
`It is therefore an object of the present invention to provide
`a controlled release formulation for a therapeutically active
`medicament.
`
`It is a further object of the present invention to provide a
`method for preparing a controlled release formulation for a
`therapeutically active medicament.
`It is yet another object of the present invention to provide
`a controlled release excipient which may be used in the
`preparation of a sustained release oral solid dosage form of
`a therapeutically active medicament that provides an even
`rate of release of an active medicament.
`
`It is a further object of the present invention to provide a
`controlled release excipient which. when combined with an
`effective amount of a bronchodilator, such as albuterol, is
`suitable for providing a sustained release of that medicament
`so as to provide a therapeutically effective blood level of the
`medicament for e.g.. 12 or 24 hours. without allowing an
`excessive early release of medication, and where the release
`kinetics are unaffected by the contents of the patient’s
`gastrointestinal tract
`It is yet a further object of the present invention to provide
`a method for treating patients with an active medication in
`controlled release form.
`
`The above-mentioned objects and others are achieved by
`virtue of the present invention. which relates in—part to a
`controlled release formulation comprising a therapeutically
`effective amount of a medicament, and a controlled release
`excipient comprising a gelling agent and a swelling agent.
`such as, for example, a homopolysaccharide, a
`heteropolysaccharide. an inert diluent.
`In certain preferred embodiments of the invention, the
`ratio of the heteropolysaccharide gum to the homopolysac-
`charide gum is from about 1:3 to about 3:1. More preferably,
`the ratio is about 1:1. Preferably, the heteropolysaccharide
`gum includes xanthan gum and the homopolysaccharide
`gum includes locust bean gum.
`The present invention is also related to a sustained release
`oral solid dosage form for albuterol or' salts or derivatives
`thereof in an amount necessary to render a therapeutic effect
`in a human patient. The albuterol is present in an amount
`ranging from, e.g., about 2 through about 50% by weight of
`the total formulation. or preferably from about 1 through
`about 10% by weight or more preferably from about 1
`through about 6% by weight of the total formulation.
`The dosage form includes an inert pharmaceutical diluent
`so that the ratio of the inert diluent to the gelling agent is
`from about 1:8 to about 8:1. Preferably, the diluent is from
`the group consisting of a pharmaceutically acceptable
`saccharide. polyhydric alcohol, a pre-manufactured direct
`compression diluent, and mixtures of any of the foregoing.
`The diluent can also be a saccharide such as sucrose.
`dextrose.
`lactose. microcrystalline cellulose. fructose,
`xylitol. sorbitol. a starch. and mixtures thereof.
`The dosage form optionally includes a pharmaceutically
`acceptable hydrophobic material. Any pharmaceutically
`acceptable hydrophobic material may be suitably employed
`
`5
`
`

`

`5,662,933
`
`3
`include
`hydrophobic materials
`Suitable
`carboxymethylcellulose. cellulose acetate phthalate. polyvi-
`nyl acetate phthalate. hydroxypropyl-methylcellulose
`phthalate. ethylcellulose. a copolymer of acrylic and meth-
`acrylic and esters. waxes. shellac. zein. hydrogenated veg-
`etable oils. and mixtures of any of the foregoing. Preferably.
`the hydrophobic material selected from cellulose ether. a
`cellulose ester and an alkylcellulose. such as ethylcellulose
`and carboxymethylcellulose. The hydrophobic material may
`be included in the dosage form in an amount effective to
`slow the hydration of the gelling agent when exposed to an
`environmental fluid.
`
`is preferably present in an
`The hydrophobic material
`amount ranging from about 1 through about 90%. by weight.
`of the solid dosage form. and can also be present in an
`amount ranging from about 25% through about 50%. by
`weight. of the solid dosage form.
`The medicament can be any medicament for which an
`orally administered controlled release form is desired.
`Preferably. the formulation is prepared to include a phar-
`maceutically eflective amount of albuterol or a salt or
`derivative thereof.
`
`The controlled release solid dosage form can be prepared
`in any conventional orally administered dosage form.
`including a tablet. as a granular form and as a granular form
`administered in a gelatin capsule containing a sufficient
`amount of the granules to provide an effective dose of the
`included therapeutically active medicament. For a tablet
`dosage form. at least part of a surface of the tablet can
`optionally be coated with a hydrophobic material to a weight
`gain from about 1 to about 20 percent. by weight. Further.
`a granular dosage form can optionally be coated with a
`hydrophobic coating material to a weight gain that ranges
`from about 1% to about 20%. The hydrophobic material can
`be selected from. e.g.. a cellulose ether. a cellulose ester and
`an alkylcellulose. The hydrophobic material can optionally
`be applied before. during or after the process of tableting. In
`addition. if there is a need for an early release of the active
`medicament. the coating can optionally be formulated to
`include from about 10 to about 40 percent of the total
`amount of the active medicament in a quick release external
`layer.
`The invention also relates to methods for preparing a
`controlled release solid dosage form as described above for
`providing an active medicament in an amount effective for
`treating a patient for from 12 to about 24 hours. The method
`includes the steps of preparing a sustained release excipient
`comprising from about 10 to about 99 percent by weight of
`a gelling agent comprising a heteropolysaccharide gum and
`a homopolysaccharide gum capable of cross-linking said
`heteropolysaccharide gum when exposed to an environmen—
`tal fluid. the ratio of said heteropolysaccharide gum to said
`homopolysaccharide gum being from about 1:3 to about 3:1.
`and from about 0 to about 89 percent by weight of an inert
`pharmaceutical diluent. and optionally from about 1 to 90%
`by weight of a pharmaceutically acceptable hydrophobic
`material; and adding an effective amount of a medicament to
`provide a final product having a ratio of medicament to
`gelling agent from about 1:3 to about 128. so that a gel matrix
`is created.
`
`The medicament to be added is preferably albuterol or
`salts or derivatives thereof in an amount ranging from. e.g..
`about 2 to about 50% by weight of the total formulation. or
`preferably from about 1 to about 10% by weight or more
`preferably from about 1 to about 6% by weight of the total
`formulation.
`
`4
`The resulting mixture of the sustained release excipient
`preferably includes from about 10 to about 75 percent
`gelling agent. from about 0 to about 90% hydrophobic
`material and from about 30 to about 75 percent inert diluent.
`Thereafter. the dosage form can be tableted. granulated with
`a pharrnaceutically acceptable hydrophobic material or
`placed in gelatine capsules. Optionally the tablet can be
`coated with a hydrophobic coating to a weight gain from
`about 1% to about 20%.
`
`Preferably. the medicament is albuterol or a salt or deriva-
`tive thereof in an amount effective to provide therapeutically
`effective blood levels of said medicament for at least 24
`hours.
`
`The present invention is further related to a method of
`treating a patient comprising orally administering the sus-
`tained release albuterol tablets to a patient. thereby provid-
`ing therapeutically effective blood levels of the medicament
`for at least about 24 hours.
`
`By “sustained release” it is meant for purposes of the
`present invention that the therapeutically active medicament
`is released from the formulation at a controlled rate such that
`therapeutically beneficial blood levels (but below toxic
`levels) of the medicament are maintained over an extended
`period of time. e.g.. providing a 24 hour dosage form.
`The term “environmental fluid” is meant for purposes of
`the present
`invention to encompass. e.g.. an aqueous
`solution. such as that used for in-vitro dissolution testing. or
`gastrointestinal fluid.
`In one aspect the invention provides formulations having
`particular pharmacokinetic properties. Thus. simply by way
`of example. the invention provides formulations suitable for
`oral administration that. when orally administered to a
`patient. provide a medicament plasma concentration-time
`curve with an area under the curve-calculated to infinity
`(“AUCm”). ranging from about 89 to about 150 (ng-hours/
`ml) or even fiom about 112 to about 129 (ng-hours/ml).
`Further. the formulations according to the invention can
`provide. e.g.. an AUC... ranging from about 57 to about 157
`(ng-hours/ml) (fasting patient) or from about 75 to about 162
`(ng-hours/ml) (fed patient).
`In addition. for example. mean peak plasma concentra-
`tions (Cmax) ranging from about 7 to about 12 ng/ml or even
`from about. 9.5 to about 12 ng/ml. are provided. Further. the
`formulations according to the invention can provide. e.g.. a
`Cmax ranging from about 4.5 to about 19 ng/rnl (fasting
`patient) or from about 6 to about 16 ng/ml (fed patient).
`In another example. time to mean peak plasma concen-
`tration (Tmax) ranging from about 3 to about 10 hours or
`even from about 3.5 to about 8 hours are provided. Further.
`the formulations according to the invention can provide.
`e.g.. a Tmax ranging from about 3 to about 6 hours (fasting
`patient) or from about 3 to about 8 hours (fed patient).
`In a further example. the formulation according to the
`invention provides. for example. ratios of AUC.o (fasting
`patient) to AUCw (fed patient) that range from about 0.50 to
`about 0.70.
`
`Further still. the formulation provides. for example ranges
`of Cmax (fasting patient) divided by Cmax (fed patient)
`from about 0.90 to about 1.10.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
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`FIG. 1 shows a dissolution profile of an albuterol con-
`taining tablet formulated according to Table 14 and Table 15
`(Example 10) and conducted as a Type ]I dissolution with a
`pH change to simulate gastric passage and stirring at 50 rpm.
`
`6
`
`

`

`5,662,933
`
`5
`
`FIG. 2 shows a dissolution profile of an albuterol con—
`taining tablet formulated according to Table 14 and Table 15
`(Example 10) and conducted as a Type I[[ dissolution with
`a pH change to simulate gastric passage and stirring at 15
`rpm.
`FIG. 3 shows an albuterol plasma profile of provided by
`ingestion of an albuterol containing tablet formulated
`according to Table 14 and Table 15 (Example 10): solid
`circles mark curve of plasma profile in fed subject; open
`circles mark curve of plasma profile in fasted subject.
`DETAILED DESCRIPTION
`
`As reported in U.S. Pat. Nos. 4.994.276. 5,128,143, and
`5.135.757, the disclosures of which are hereby incorporated
`by reference herein in their entireties. the heterodisperse
`excipient comprises a gelling agent of both hetero- and
`homo—polysaccharides which exhibit synergism. e. g., the
`combination of two or more polysaccharide gums produce a
`higher viscosity and faster hydration than that which would
`be expected by either of the gums alone, the resultant gel
`being faster-forming and more rigid
`In the present invention, it has been found that a sustained
`release excipient comprising only the gelling agent
`(heterodisperse polysaccharides. e.g., xanthan gum and
`locust bean gum, may not be sufficient to provide a suitable
`sustained release of an active medicament to provide a 12 or
`24 hour formulation. when the formulation is exposed to a
`fluid in an environment of use. e.g. an aqueous solution or
`gastrointestinal fluid
`In certain embodiments. the present invention is related to
`the surprising discovery that by granulating the sustained
`release excipient with a solution or dispersion of a pharma-
`cologically acceptable hydrophobic material prior to admix-
`ture of the sustained release excipient with the medicament
`and tableting. the medicament may provide therapeutically
`effective blood levels for extended periods of time, e.g.,
`from about 12 to about 24 hours. The hydrophobic material
`is present in a range from about 0 to about 90%, by weight,
`of the sustained release excipient and in a preferred
`embodiment. is present in a range from about 1 to 20 percent
`of the sustained release excipient or from about 25 to about
`75 percent of the sustained release excipient.
`The sustained release excipient can be granulated with a
`pharmacologically acceptable hydrophobic material such as.
`for. example, an alkylcellulose. a cellulose ether. a cellulose
`ester. In particular, the hydrophobic material can be alkyl-
`cellulose such as carboxymethylcellulose (“CMC”), cellu-
`lose acetate phthalate (“CAP”). hydroxypropylmethylcellu-
`lose phthalate (“HPMCP”) or a polyvinyl acetate polymer
`such as polyvinyl acetate phthalate “PVAP”).
`In certain preferred embodiments of the present invention,
`the sustained release excipient is prepared by mixing the
`gelling agent and an inert diluent. The gelling agent prefer-
`ably ranges, e.g., from about 10 to about 75 percent of the
`sustained release excipient. Thereafter, the mixture is granu-
`lated with a solution or dispersion of a hydrophobic material
`in an amount effective to slow the hydration of the gelling
`agent without disrupting the hydrophilic matrix. Next, the
`medicament is added. and the resultant mixture is tableted
`In other preferred embodiments of the present invention.
`the tablets prepared as set forth above are then coated with
`a hydrophobic material to a weight gain from about 1 to
`about 20 percent by weight. The hydrophobic material can
`be an alkylcellulose such as, for example, an aqueous
`dispersion of ethylcellulose (commercially available. for
`example. as Aquacoat®. available from FMC or Surelease®.
`available from Colorcon).
`
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`
`6
`The term “heteropolysaccharide” as used in the present
`invention is defined as a water-soluble polysaccharide con-
`taining two or more kinds of sugar units. the heteropolysac-
`charide having a branched or helical configuration, and
`having excellent water-wicking properties and immense
`thickening properties.
`An especially preferred heteropolysaccharide is xanthan
`gum, which is a high molecular weight (>106) het-
`eropolysaccharide. Other preferred heteropolysaccharides
`include derivatives of xanthan gum. such as deacylated
`xanthan gum, the carboxymethyl ether. and the propylene
`glycol ester.
`The homopolysaccharide gums used in the present inven-
`tion which are capable of cross—linking with the het-
`eropolysaccharide include the galactomannans, i.e., polysac-
`charides which are composed solely of mannose and
`galactose. Galactomannans which have higher proportions
`of unsubstituted mannose regions have been found to
`achieve more interaction with the heteropolysaccharide.
`Locust bean gum. which has a higher ratio of mannose to
`galactose.
`is especially preferred as compared to other
`galactomannans such as guar and hydroxypropyl guar.
`The controlled release properties of the formulations of
`the present invention may be optimized when the ratio of
`heteropolysaccharide gum to homopolysaccharide material
`is about 1:1, although heteropolysaccharide gum in an
`amount of from about 20 to about 80 percent or more by
`weight of the heterodisperse polysaccharide material pro-
`vides an acceptable slow release product. The combination
`of any homopolysaccharide gums known to produce a
`synergistic effect when exposed to aqueous solutions may be
`used in accordance with the present invention. It is also
`possible that the type of synergism which is present with
`regard to the gum combination of the present invention
`could also occur between two homogeneous or two het-
`eropolysaccharides. Other acceptable gelling agents which
`may be used in the present invention include those gelling
`agents well—known in the art. Examples include vegetable
`gums such as alginates, carrageenan. pectin, guar gum.
`xanthan
`gum,
`modified
`starch,
`hydroxypropylmethylcellulose, methylcellulose, and other
`cellulosic materials such as sodium carboxymethylcellulose
`and hydroxypropylcellulose. This list is not meant to be
`exclusive.
`
`The combination of xanthan gum with locust bean gum
`with or without the other homopolysaccharide gums is an
`especially preferred gelling agent. The chemisz of certain
`of the ingredients comprising the excipients of the present
`invention such as xanthan gum is such that the excipients are
`considered to be self-bulfering agents which are substan-
`tially insensitive to the solubility of the medicament and
`likewise insensitive to the pH changes along the length of
`the gastrointestinal tract.
`The inert pharmaceutical diluent (i.e.. filler) of the sus-
`tained release excipient preferably comprises a pharrnaceu—
`tically acceptable saccharide. including a monosaccharide, a
`disaccharide, or a polyhydric alcohol, a pre-rnanufactured
`direct compression diluent. and/or mixtures of any of the
`foregoing. Examples of suitable inert pharmaceutical fillers
`include sucrose. dextrose,
`lactose, microcrystalline
`cellulose, fructose. xylitol, sorbitol, a starch, mixtures
`thereof and the like. However, it is preferred that a soluble
`pharmaceutical filler such as lactose, dextrose, sucrose. or
`mixtures thereof be used If the mixture is to be manufac-
`tured without a wet granulation step, and the final product is
`to be tableted. it is preferred that all or part of the inert
`
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`7
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`8
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`5,662,933
`
`diluent comprise a pre—manufactured direct compression
`diluent. Such direct compression diluents are widely used in
`the pharmaceutical arts. and may be obtained from a wide
`variety of commercial sources. Examples of such pre-
`manufactured direct compression excipients include Emco—
`cel® (microcrystalline cellulose. N.F.). Emdex® (dextrates.
`NR). and Tab-Fine® (a number of direct-compression sug—
`ars including sucrose. fructose. and dextrose). all of which
`are commercially available from Edward Mendell Co.. Inc..
`Patterson. N.Y.). Other direct compression diluents include
`Anhydrous lactose (Lactose N.F.. anhydrous direct
`tableting) from Sheffield Chemical. Union. NJ. 07083;
`Elcems® G-250 (Powdered cellulose. N.F.) from Degussa.
`D—600 Franldurt (Main) Germany; Maltrin® (Agglomerated
`maltodextrin) from Grain Processing Corp.. Muscatine. IA
`52761; Neosorb 60® (Sorbitol. N.F.. direct—compression)
`from Roquette Corp. 645 5th Ave.. New York. N.Y. 10022;
`Nu-Tab® (Compressible sugar. N.F.) from Ingredient
`Technology. Inc.. Pennsauken. NJ. 08110; Polyplasdone
`XL® (Crospovidone. N.F. .
`cross-linked
`polyvinylpyrrolidone) fi'om GAF Corp.. New York. N.Y.
`10020; Primojel® (Sodium starch glycolate. NF. car~
`boxymethyl starch) from Generichem Corp. Little Falls.
`NJ. 07424; Solka Floc® (Cellulose floc) from Edward
`Mendel] Co.. Carmel. N.Y. 10512; Fast-F10 Lactose®
`(Lactose N.F.. spray dried) from Foremost Whey Products.
`Baraboo. Wis. 53913 and DMV Corp.. Vehgel. Holland; and
`Sta-Rx 1500® (Starch 1500) (Pregelatinized starch. N.F..
`compressible) from Colorcon. Inc.. West Point. Pa. 19486.
`However. it is preferred that a soluble pharmaceutical filler
`such as lactose. dextrose. sucrose. or mixtures thereof be
`used.
`
`the
`In certain embodiments of the present invention.
`sustained release excipient comprises from about 10 to about
`99 percent by weight of a gelling agent comprising a
`heteropolysaccharide gum and a homopolysaccharide gum
`and from about 0 to about 89 percent by weight of an inert
`pharmaceutical diluent. In other embodiments. the sustained
`release excipient comprises from about 10 to about 75
`percent gelling agent. and from about 30 to about 75 percent
`inert diluent. In yet other embodiments. the sustained release
`excipient comprises from about 30 to about 75 percent
`gelling agent and from about 15 to about 65 percent inert
`diluent.
`
`The sustained release excipient of the present invention
`may be further modified by incorporation of a hydrophobic
`material which slows the hydration of the gums without
`disrupting the hydrophilic matrix. This is accomplished in
`preferred embodiments of the present invention by granu-
`lating the sustained release excipient with the solution or
`dispersion of a hydrophobic material prior to the incorpo-
`ration of the medicament. The hydrophobic material may be
`selected from an alkylcellulose such as ethylcellulose such
`as carboxyrnethyl—cellulose (“CMC”). other hydrophobic
`cellulosic materials. acrylic and/or methacrylic ester
`polymers. copolymers of acrylic and methacrylic esters.
`zein. waxes. other hydrophobic cellulosic materials. cellu-
`lose acetate phthalate (“CAP”). hydroxypropylmethylcellu-
`lose phthalate (“HPMCP”) or a polyvinyl acetate polymer
`such as polyvinyl acetate phthalate (“PVAP”). hydrogenated
`vegetable oils. and any other pharmaceutically acceptable
`hydrophobic material known to those skilled in the art. The
`amount of hydrophobic material incorporated into the sus—
`tained release excipient is that which is effective to slow the
`hydration of the gums without disrupting the hydrophilic
`matrix formed upon exposure to an environmental fluid.
`In certain preferred embodiments of the present invention.
`the hydrophobic material is included in the sustained release
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`excipient in an amount from about 1 to about 20 percent by
`weight. The solvent for the hydrophobic material may be an
`aqueous or organic solvent. or mixtures thereof.
`Examples of commercially available alkylcelluloses are
`Aquacoat® (aqueous dispersion of ethylcellulose available
`from FMC). Surelease® (aqueous dispersion of ethylcellu-
`lose available from Colorcon). Examples of commercially
`available acrylic polymers suitable for use as the hydropho-
`bic material include Eudragit® RS and RL (copolymers of
`acrylic and methacrylic acid esters having a low content
`(e.g. 1:20 or 1:40) of quaternary ammonium compounds).
`Once the sustained release excipient of the present inven-
`tion has been prepared. it is then possible to blend the same
`with the medicament. e.g.. in a high shear mixer. In one
`embodiment. the formulation is prepared by dry blending
`the components. e.g.. a heteropolysaccharide.
`a
`homopolysaccharide. an inert filler. and a hydrophobic
`material. optionally followed by the addition of a suitable
`amount of water. with continued blending. followed by dry
`granulation in a fluid bed dryer and then milling of the
`resulting granulation product.
`A wide variety of therapeutically active agents can be
`used in conjunction with the present invention. The thera-
`peutically active agents (e.g.. pharmaceutical agents) which
`may be used in the compositions of the present invention
`include drugs ranging in solubility from water soluble to
`water insoluble. Examples of such therapeutically active
`agents include antihistamines (e.g.. dimenhydrinate.
`diphenhydramine. chlorpheniramine and dexchlorphe-
`niramine maleate). analgesics (e.g.. aspirin. codeine.
`morphine. dihydromorphone. oxycodone. etc.). non-
`steroidal anti—inflammatory agents (e.g.. naproxyn.
`diclofenac. indomethacin. ibuprofen. sulindac). anti-emetics
`(e.g.. metoclopramide). anti-epileptics (e.g.. phenytoin.
`meprobamate and nitrazeparn). vasodilators (e.g..
`nifedipine. papaverine. diltiazem and nicardirine). anti-
`tussive agents and expectorants (e.g.. codeine phosphate).
`anti-asthmatics (e.g.
`theophylline). antacids. anti-
`spasmodics (e.g. atropine. scopolamine). antidiabetics (e.g..
`insulin). diuretics (e.g.. ethacrynic acid. bendrofluazide).
`anti-hypotensives (e.g.. propranolol. clonidine). antihyper-
`tensives (e.g.. clonidine. methyldopa). bronchodilators (e.g..
`albuterol). steroids (e.g.. hydrocortisone.
`triamcinolone.
`prednisone). antibiotics (e.g..
`tetracycline).
`antihemorrhoidals. hypnotics, psychotropics. antidiarrheals.
`mucolytics. sedatives. decongestants. laxatives. vitamins.
`stimulants (including appetite suppressants such as
`phenylpropanolamine). The above list is not meant to be
`exclusive.
`
`the therapeutically active
`In a preferred embodiment.
`agents are sympathomimetics such as. dobutamine
`hydrochloride. dopamine hydrochloride. ephedrine sulfate.
`epinephrine. fenfluramine hydrochloride.
`isoetharine.
`isoproterenol. mephentermine sulfate. metaproterenol
`sulfate. metaraminol bitartrate. methoxamine hydrochloride.
`norepinephrine bitartrate. phenylephrine hydrochloride.
`phenylpropanolamine hydrochloride. pseudoephedrine. rito-
`drine hydrochloride.
`terbutaline sulfate.
`tetrahydrozoline
`hydrochloride. triprolidine and pseudoephedrine. xylometa—
`zoline hydrochloride. isoproterenol and dobutamine as well
`as beta2 selective adrenergic agonists.
`including. for
`example. terbutaline. albuterol. isoetharine. pirbuterol and
`bitolterol (GOODMANAND GlLMAN’ S. THE PHARMA-
`COLOGICAL BASIS OF THERAPEUTICS. Eighth
`Edition. the disclosure of which is incorporated herein by
`reference in its entirety).
`Generally any flavoring or food additive such as those
`described in Chemicals Used in Food Processing, pub 1274
`
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`

`5,662,933
`
`9
`by the National Academy of Sciences, pages 63—258, incor-
`porated herein in its entirety, may be used. Generally, the
`final product may include fiom about 0.1% to about 5% by
`weight flavorant.
`The tablets of the present invention may also contain
`effective amounts of coloring agents, (e.g., titanium dioxide,
`ED.