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`U5005135757A
`_
`I
`United States Patent
`[19]
`[11] Patent Number:
`5,135,757
`
`Baichwal et a].
`[45] Date of Patent:
`Aug. 4, 1992
`
`[75]
`
`.
`[73] Asmgnee:
`
`[54] COMPRESSIBLE SUSTAINED RELEASE
`SOLID DOSAGE FORMS
`Inventors: Anand R. Buichwal, Poughkeepsie,
`NY' John N Staniforth Bath
`’
`England
`'
`’
`Edward Mendel] 00., Inc., Carmel,
`N~Y-
`[21] Anal. N0-= 642,070
`[22] Filed:
`Jun. 16, 1991
`_
`,
`Rem“ U-S- Application Data
`Division of Ser. No. 246,368, Sep. 19, 1988, Rat. No.
`4,994,276.
`Int. 01.5 .......................... A61K9/16;A61K 9/22
`[51]
`.
`.
`.
`........
`,
`,
`
`[52] U 5 Cl
`424/465' 424/440
`424/468; 424/469; 424/470; 424/488; 424/499;
`424/500; 514/960; 514/955
`[58] Field of Search ............... 424/440, 464, 465, 468,
`424/469
`
`[62]
`
`[56]
`
`Raferenm Cited
`U.S. PATENT DOCUMENTS
`
`.
`y
`2993 836
`7/1961
`167/82
`1/1963 Mayron
`3,074,852
`167/82
`3,079,303
`2/1963 Raff et al
`167/82
`3,133,863
`5/1964 Tansey ..
`.. 424/465
`3,147,187 9/1964 Playfair .
`.. 167/182
`3’388’041
`6/1968 Gus 6‘ 31'
`167/182
`
`3,456,049
`7/1969 . Hotko et a].
`..
`424/22
`3,627,583 12/1971 Troy et a1.
`127/29
`
`3,629,393 12/ 1971 Nakamoto .
`. 424/22
`..
`3,639,169 ”/1971 Bmeg et a].
`167/82
`
`3,726,690 4/1973 schuppnflY Jr
`99/139
`
`3,728,445 11/1973 Bardani .........
`424/22
`
`3,232,221; 11/1972 ls‘lakamoto e1 81.
`2241(1)?
`tevens .........
`,
`,
`9/197
`
`3,864,469
`2/1975 Reiser e1 31.
`. 424/22
`3,950,508 4/1976 Mony eta].
`.424/19
`
`3,963,832 6/1976 Hashimoto et al.
`424/49
`4,072,535
`8/1977 Short e131.
`. 424/22
`
`4,167,558
`9/1979 Shcth et a1.
`. 424/22
`
`4,199,560 4/1980 Gyarmati ..
`424/459
`4,259,314
`3/1981 Lowey ......
`. 424/19
`
`4,308,251 12/1981 Dunn et a1.
`. 424/19
`4.361.333 16/13:: are“ et :11 .
`. 3:23
`
`01' C' a ,
`4, 39»
`-
`
`4,424,235
`1/1984 Sheth et al.
`. 424/72
`4,439,453 6/1934 Vogel ..................... 424/22
`
`
`
`424/22
`4,525,345
`6/1985 Dunn et al.
`.
`
`424/16
`4,542,011 9/1985 Gleixner .-
`
`- 514/652
`415561678 ”/1985 Hm"
`
`.. 424/19
`4,590,062
`5/1986 Jung ........
`
`4,623,394 11/1986 Nakamura eta].
`.
`. 106/122
`4,692,337
`9/1987 Ukigaya et al. .
`. 424/469
`
`4,695,463
`9/1987 Yang et 1L ..
`‘ 424/440
`4,695,467
`9/1987 Uemura 61 al.
`.
`. 424/502
`4,698,101 10/1987 Koivurinta ..
`. 424/453
`
`. 424/408
`4,698,264 10/1987 Steinke
`
`. 424/468
`4,704,285 11/1987 Alderman
`
`4,717,713
`1/1988 Zatz et 31.
`
`
`-
`417551339
`1/1988 Jones ct 81-
`8/1988 Gergely et 3.1.
`.
`.
`4,762,702
`
`-424/475
`417921452 ”“933 “Ward --------
`4,803,077 2/1989 Mitsuhashl et al.
`. 424/440
`
`235332 323:: 5:33;"""
`‘ 3142;:
`'424/468
`4855143 8/1989 Lo‘ivey
`'
`‘
`"""""""
`FOREIGN PATENT DOCUMENTS
`8400104 6/1984 PCT lnt‘l App].
`.
`3700044 V1937 PCT Int’l'Appl.
`-
`1m
`in
`cm .
`53:22:; 1313:; 31111:: E11830!“ '
`8
`OTHER PUBLICATIONS
`.
`_
`.
`:23:me F°°d 6”“ xantha" Gm“ ”"13th by
`Hydrocolloids a publication by Mero Rousselot Satia.
`1
`1
`1 B'
`1
`Kant?“ Gum/K9119] Kc 28" a Nam”
`“’90 Ysac'
`chande for Scrennfic Water Control.
`.
`,
`Formulating for Controlled Release w1th Methocel
`Cellulose Ethers, the Dow Chemlcal Company, 1987.
`H. M. Ingam et 31., 6th Pharmaceuncal Technology
`fgoggfereuce, vol. II, pp. 459—460, Canterbury, England
`.
`Primary Examiner—Thurman K. Page
`Amman, Examiner—James M. 519,,lr
`Attorney, Agent, or Firm—Steinberg & Raskin
`
`A free-flowing directly compressible granulation useful
`as a slow release pharmaceutical excipient is disclosed.
`The excipicnt includes a hydrodrophilic matrix which
`includes hetero
`lysaccharide and a
`Iysaccharide
`material capablepgf cross-linking 1he hetgfopolysaccha-
`ride, and an inert diluent.
`7 Cllims, 3 Drawing Sheets
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`IPR2014-00360
`
`

`

`US. Patent
`
`Aug. 4, 1992
`
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`5,135,757
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`US. Patent
`
`Aug. 4, 1992
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`Sheet 2 of 3
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`5,135,757
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`

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`US. Patent
`
`.
`
`Aug.4, 1992
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`_
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`Sheet3 of3
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`5,135,757
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`%0/55041/50
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`

`1
`
`5,135,757
`
`COMPRESSIBLE SUSTAINED RELEASE SOLID
`DOSAGE FORMS
`
`This is a divisionof application Serial No. 246,368
`filed Sep. 19, 1988, now U.S. Pat. No. 4,994,275.
`FIELD OF THE INVENTION
`
`The present invention relates to a free flowing, di-
`rectly compressible granulation forming a sustained
`release pharmaceutical excipient product which can be
`blended with a wide range of therapeutically active
`medicaments and tableted.
`
`BACKGROUND OF THE INVENTION
`
`Many attempts have been made in the pharmaceutical
`art to provide a method by which therapeutically active
`medicaments can be directly tableted or mixed with a
`direct compression vehicle and thereafter directly tab-
`leted.
`
`Very few therapeutically active medicaments can be
`directly tableted due to unacceptable flow characteris-
`tics and compressibility factors of the crystalline or
`powdered medicament, and also due to the small
`amounts of medicament needed to provide the desired
`effect. Therefore, it is a common practice to use an inert
`ingrediate, i.e., excipients, diluents, fillers, binders and
`the like, such that combination of the same with the
`medicament provides a material which can be directly
`compressed into tablets. In order to provide a directly
`compressible product, these excipients must have cer-
`tain physical properties, including flowability, sufficient
`particle size distribution , binding ability, acceptable
`bulk and tap densities, and acceptable dissolution prop-
`erties in order to release the medicament upon oral
`administration.
`‘
`U.S. Pat. No. 3,639,169 (Broeg et a1.) discloses one
`such direct compression vehicle for a therapeutically
`active medicament which consists of an insoluble or
`soluble diluent such as lactose dispersed in a matrix of a
`hydrophilic hydratable high polymer such as hydro-
`philic polysaccharides,hydrocolloids or proteinaceous
`materials. The polymer, diluent and water are mixed
`and the resulting dispersion is dried, forming a film. The
`cooled film is fragmented, ground to the desired parti-
`cle size and then blended with a desired medicament.
`In another method disclosed in U.S. Pat. No.
`3,079,303 (Raff et al.), a granular excipient for making
`tablets is prepared by spray drying a slurry of 50-98%
`filler, 1—50% disintegrant, and 1—50% binder. A medi-
`cament is then added to the excipient and the finished
`product is tableted.
`It has become desirable to provide pharmaceutical
`formulations which utilize slow release profiles, an ob-
`jective not contemplated in Broeg et al., Raff et a1. or
`other similar prior art. The advantages of slow release,
`products are well known in the pharmaceutical field
`and include the ability to maintain a desired blood level
`over a longer period of time while increasing patient
`compliance by reducing the number of administrations
`necessary to achieve the same.
`Slow release excipients have been developed which
`attain their goals by a wide variety of methods. For
`instance, U.S. Pat. No. 3,629,393 (Nakamoto) utilizes a
`three-component system to provide slow release tablets
`in which granules of an active ingredient with a hydro-
`phobic salt of a fatty acid and a polymer are combined
`with granules of a hydrocolloid and a carrier and gran-
`
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`ules of a carrier and an active or a buffering agent and
`then directly compressed into tablets. U.S. Pat. No.
`3,728,445 (Bardani) discloses
`slow release tablets
`formed by mixing an active ingredient with a solid
`sugar excipient, granulating the same by moistening
`with a cellulose acetate phthalate solution, evaporating
`the solvent, recovering the granules and compressing
`under high pressure. These disclosures concentrate
`their attention to the type and combination of polymers
`and/or gums used, and processes for mixing the same,
`and therefore have not provided a directly compressible
`form of gums/polymers and adjuvants which can be
`used for a wide range of medicaments.
`Other slow release excipients are disclosed in the
`prior art which are directed to particular therapeuti-
`cally active medicaments.
`In one such disclosure, U.S. Pat. No. 3,456,049
`(Hotko et al.), a slow release benzothiadiazine diuretic
`tablets are prepared by mixing a fatty substance such as
`hydrogenated vegetable oil, alginic acid, a granulating
`liquid, a potassium salt and the benzothiadiazine. The
`wet mass is screened, dried, and then compressed into
`tablets. Similarly, U.S. Pat. No. 4,692,337 (Ukigaya et
`a1.) provides a slow release excipient for theophylline
`which utilizes 5-200 parts of ethyl cellulose for each 100
`parts theophylline, and optionally contains a filler such
`as lactose or a lubricant. The ingredients are mixed and
`compression molded'into tablets. In yet another exam-
`ple, U.S. Pat. No. 4,308,251 (Dunn et al.), a sustained"
`release aspirin formulation in which 0.8-1.6 percent of a
`release controlling aqent (cellulose acetate phthalate)
`and 1.0.7.5 percent of an erosion-promoting agent (corn
`starch) by .weight per tablet. A wet granular mass is
`formed, dried, reduced in particle size and compressed
`into tablets.
`
`More recently, a great deal of attention in the phar-
`maceutical field has turned to the use of various hydro-
`colloid materials such as hydroxypropylmethyl cellu-
`lose in providing a slow release matrix for a variety of
`medicaments.
`
`For example, U.S. Pat. No. 4,389.393 (Schor et al.)
`describes a slow release carrier base material of one or
`more hydroxypropylmethyl celluloses and up to 30%
`by weight of a mixture of m'ethylcellulose, sodium car-
`boxymethylcellulose and/or cellulose either which can
`be mixed with a medicament and other needed ingredi-
`ents such as binders, lubricants, etc. and then tableted.
`At least one of the hydroxypropylmethyl celluloses
`must have a methoxy content of 16-24% by weight, a
`hydroxypropyl content of 4—32% by weight, and a
`number average molecular weight of at least 50,000.
`The carrier base constitutes less than about 'one third of
`the weight of the solid unit dosage form.
`It is acknowledged in Schor et al. that in order to
`make tablets using this carrier base, other ingredients
`which are conventional in tablet making must necessar-
`ily be included, such as binders, fillers, disinteqratinq
`agents and the like. Only the completed mixture, which
`includes these additional ingredients, possess sufficient
`properties to produce tablets having the necessary hard-
`ness and low level of friability. Thus, the carrier base of
`the Schor et al. disclosure is not directed to the tableting
`aspects.
`U.S. Pat. No. 4,704,285 (Alderman) discloses solid
`slow release tablets containing 590% hydroxypropyl
`cellulose ether, 5-75% of an optional additional hydro-
`philic colloid such as hydroxypropylmethyl cellulose,
`an effective amount of an active medicament, and op-
`
`

`

`5,135,757
`
`4
`which can be used ‘with both relatively soluble and
`relatively insoluble therapeutically active medicaments.
`It is a further object of the present invention to pro- .
`vide a free-flowing directly compressible slow release
`excipient which is relatively inexpensive to manufac-
`ture due to the lack of coatings and expensive equip-
`ment.
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`tional binders, lubricants, glidants fillers, etc. The hy-
`droxypropyl cellulose ether is in the for of a finely sized
`powder and provides a longer release pattern than iden-
`tical compositions having coarser particles. However
`Alderman acknowledges the necessity of the additional
`excipients in order to form an acCeptable solid tablet,
`(i.e. fillers, binders,
`lubricants and glidants). In pre-
`ferred embodiments,
`these excipients comprise from
`63.5—94% of the tablet.
`The carrier bases which provide the slow release
`profiles in these disclosures can only be compressed into
`a tablet or a solid dosage form with the aid of other
`conventional tableting adjuvants such as binders and
`the like, and therefore contribute only to the slow re-
`lease aspect of the final solid unit dosage‘form and not
`to the tableting aspects. In other words, in each of these
`disclosures it is necessary for to first determine the
`physical properties of the active medicament to be tab-
`leted and thereafter proceed through a series of trial and
`error experiments in order to determine the optimal
`amount of gums/polymers and other adjuvants to pro-
`duce the right formulation which is free flowing and
`which can be compressed to a slow release solid dosage
`unit. This procedure is time intensive and costly.
`Similarly, slow release excipients disclosed to date
`which incorporate virtually any synthetic polymer such
`as hydroxypropylmethylcellulose, methyl cellulose,
`polyvinylpyrollidone, and any natural gum such as
`accacia, tragacanth, alginates, chitosan, xanthan, pectin
`and others to date have been mainly directed to the
`slow release aspect and do not satisfactorily address the
`tableting aspect. This is because these materials are not
`available in the necessary physical form that is essential
`for forming a solid unit dosage form.
`The failure of slow release excipients such of the
`above to be regarded as to their tableting properties is
`due, for instance, to their necessarily very fine particle
`size, which property does not lend itself well to flow-
`ability. Also, hydroxypropylmethyl cellulose polymers
`and the like are not particularly good binding agents, a
`problem which is amplified when other poorly binding
`excipients or medicaments are included in a formula-
`tion. Thus, at higher percentages of such polymers in '
`the final mixture, it becomes difficult if not impossible to
`provide a good flowing tablet formulation for direct
`compression without the use of further excipients, and
`experimentation.
`The tableting aspect has been addressed, albeit unsat-
`isfactorily, in US. Pat. No. 4,590,062 (Jang). Jang dis-
`closes a dry direct compressed slow release tablet con-
`taining from 0.01 to 95 parts by weight of an active
`ingredient combined with a matrix blend of 1—96 parts
`of a hydrophobic carbohydrate polymer and 4—99 parts
`of a wax, and a fatty acid material or neutral lipid. The
`tablets can be made by dry blending the active ingredi-
`ent with the matrix blend and compressing. However,
`while this combination of ingredients can provide a
`directly compressible tablet, the formulator is still re-
`nuired to perform a great 'deal of experimentation to
`provide the correct release profile for the chose medica-
`ment, given the wide range of wax (used for its binding
`and compacting properties) which can be included.
`It is therefore an object of the present invention to
`provide a free-flowing directly compressible slow re-
`lease excipient which can be used for a wide variety of 65
`therapeutically active medicaments.
`It is another object of the present invention to pro-
`vide an excipient having the properties set forth above
`
`SUMMARY OF THE INVENTION
`
`In accordance with the above-mentioned objectives,
`the present invention provides a directly compressible,
`free-flowing slow release granulation for use as a phar-
`maceutical excipient comprising from about 20 to about
`70 percent or more by weight of a hydrophilic material
`comprising a heteropolysaccharide and a polysaccha-
`ride material capable of cross-linking the heteropoly-
`saccharide in the presence of aqueous solutions, and
`from about 30 to about 80 percent by weight of an inert
`pharmaceutical filler. This excipient can be mixed with
`a wide ranqe of therapeutically active medicaments and
`then directly compressed into solid dosage forms such
`as tablets. The tablets thus formed slowly release the
`medicament when ingested and exposed to gastric flu-
`ids. By varying the amount of excipient relative to the
`medicament, a slow release profile can be attained.
`The heteropolysaccharide comprises from about 10
`to about 90 percent and the polysaccharide material
`comprises from about 90m about 10 percent by weight
`of the hydrophilic matrix. Preferably, the ratio of heter-
`opolysaccharide to polysaccharide material is about 1:1.
`In preferred embodiments, the heteropolysaccharide
`COmprises xanthan gum or a derivative thereof.
`In another preferred embodiment, the polysaccharide
`material comprises one or more galactomannans. Most
`preferably, the polysaccharide material comprises 10-
`cust bean gum.
`In yet another preferred embodiment, the inert phar-
`maceutical filler comprises lactose, dextrose, sucrose,
`sorbitol, xylitol, fructose or mixtures thereof.
`The present invention also provides a slow release
`granulation for use as a directly compressible pharma-
`ceutical excipient, comprising a heteropolysaccharide
`or a gum having similar properties and a polysaccharide
`material capable of cross-linking the heteropolysaccha-
`ride in the presence of water, the ratio of the hetero-
`polysaccharide to the polysaccharide material being
`from about 1:1 to about 4:1.
`The present invention also provides a slow release
`tablet for oral administration comprising (I)_a hydro-
`phillic material comprising (a) a heteropolysaccharide;
`or (b) a heteropolysaccharide and a cross~linking agent
`capable of cross-linking said heteropolysaccharide; or
`(c) a mixture of (a), (b) and a polysaccharide qum; and
`(11) an inert pharmaceutical filler comprising up to
`about 80 percent by weight of the tablet; and (III) an
`effective amount of a therapeutically active ingredient.
`In addition, the present invention provides a method
`for providing a universal tableting excipient for con-
`trolled release of therapeutically active medicaments
`having varied solubilities in water, comprising deter-
`mining the solubility of a therapeutically active medica-
`ment which is to be tableted; mixing an effective
`amount of said therapeutically active medicament with
`a premanufactured granulated slow release excipient
`comprising from about 20 to about 70 percent by weight
`of a hydrophilic material comprising a heteropoly-
`saccharide and a polysaccharide capable of cross-link-
`ing said heteropolysaccharide in the presence of aque-
`
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`'5
`ous solutions, and up to 80 percent by weight of an inert
`pharmaceutical filler; providing a final mixed product
`having a ratio of said therapeutically active medicament
`to said hydrophilic material of about 1:3-7 depending
`upon the relative solubility of the medicament, amount
`of medicament needed (dose), the desired total weight
`of the tablet,
`the compression force used, etc.; and
`thereafter directly compressing the resulting blend to
`form a tablet. Generally, the more soluble the medica—
`ment, the greater the amount of hydrophilic material
`needed to produce a slow release of the medicament.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`10
`
`The following drawings are illustrative of embodi-
`ments of the invention and are not meant to limit the
`
`15
`
`scope of the invention as encompassed by the claims.
`FIG. 1 is a graphical representation of the dissolution
`curves provided by Examples 3—6;
`FIG. 2 is a graphical representation of the dissolution
`curves provided by Examples 16—19;
`FIG. 3 is a graphical representation of the dissolution
`curves provided by Examples 18,20 and 28;
`FIG. 4 is a graphical representation of the dissolution
`curve provided by Example 18 as compared to Compar-
`ative Example C;
`FIG. 5 is a graphical representation of the dissolution
`curve provided by Examples 29—31 (in different pH,s);
`and
`
`20
`
`25
`
`FIG. 6 is a graphical representation of the viscosities
`of Examples 32—36.
`
`30
`
`DETAILED DESCRIPTION
`The excipients of the present invention have been
`preoptimized by providing an excipient product which
`may be mixed with a wide range of medicaments and
`directly compressed into solid dosage forms, without
`the aid of the usual pharmaceutical dry or wet binders,
`fillers, disintegrants, glidants etc. which must be added
`in prior art compositions to obtain an acceptable solid
`dosage form. Thus, the excipients of the present inven-
`tion substantially overcome the need for conducting
`further experimentation needed to optimize release
`characteristics and tableting properties for a particular
`therapeutically active medicament.
`In other words,
`the present invention provides a
`novel slow release excipient product which contains a
`combination of ingredients in preselected proportions to
`each other which provides a desired slow release profile
`for a wide variety of drugs. Thus, once the excipient
`prcduct is admixed with an active medicament (and
`optional lubricant) in a ratio to the hydrophilic matrix in
`accordance 'with the present invention, the resulting
`mixture may be directly compressed into solid dosage
`forms.
`Xanthan gum, the preferred heteropolysaccharide, is
`produced by microorganisms, for instance, by fermenta-
`tion with the organism xanthomonas compestris. Most
`preferred is xanthan gum which is a high molecular
`weight (>106) heteropolysaccharide. Xanthan gum
`contains D-glucose, D-mannose, D-glucuronate in the
`molar ratio of 2.8:2.0:2.0, and is partially acetylated
`with about 4.7% acetyl. Xanthan gum also includes.
`about 3% pyruvate, which is attached to a single unit
`D-glucopyromosyl side chain as a ketal. It dissolves in
`hot or cold water and the viscosity of aqueous solutions
`of xanthan gum is only slightly affected by changes in
`the pH of a solution between 1 and 11.
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`5,135,757
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`6
`Other preferred heteropolysaccharides include deriv-
`atives of xanthan gum, such as deacylated xanthan gum,
`the carboxymethyl ether, and the propylene glycol
`ester.
`
`The polysaccharide materials used in, the present
`invention which are capable of cross-linking with the
`heteropolysaccharide include the galactomannans, i.e.,
`polysaccharides which are composed solely of mannose
`and galactose. A possible mechanism for the interaction
`between the galactomannan and the heteropolysaccha-
`ride involves the interaction between the helical regions
`of the heteropolysaccharide and the unsubstituted man-
`nose regions of the galactomannan. Galactomannans
`which have higher proportions of unsubstituted man-
`nose regions have been found to achieve more interac-
`tion with the heteropolysaccharide. Hence, locust bean
`gum, which has a hiqher ratio of mannose to galactose,
`is especially preferred as compared to other galacto-
`mannans such as guar and hydroxypropyl guar.
`Other polysaccharide gums may also be added to the
`hydrophilic material in addition to the above-mentioned
`ingredients. These additional
`ingredients comprise
`other polysaccharide gums which may or may not
`cross-link with the heteropolysaccharides such as the
`alginates,
`tragacanth, accacia, karaya, agar, pectins,
`carrageenan, hydroxypropylmethyl cellulose, hydroxy-
`propyl cellulose, carboxymethyl cellulose, polyvinyl
`pyrrolidone, mixtures thereof, and the like.
`Two steps which are generally required for gelation
`are the fast hydration of the macromolecules which
`comprise the hydrophilic material and thereafter the
`association of the molecules to form gels. Thus, two
`important properties of a hydrophilic gel matrix which
`are needed for application in a slow release system are
`the fast hydration of the system and a matrix having a
`high gel strength. These two important properties
`which are necessary to achieve a slow release hydro-
`philic matrix are maximized in the present invention by
`the particular combination of materials. In particular,
`heteropolysaccharides such as xanthan gum have excel-
`lent water wicking properties which provide fast hydra-
`tion. On the other hand, the combination of xanthan
`gum with polysaccharides materials and the like which
`are capable of cross-linking the rigid helical ordered
`structure of the xanthan gum (i.e. with unsubstituted
`mannose regions in galactomannans) thereby act syner-
`gistically to provide a higher than expected viscosity
`(i.e., hiqh gel strenqth) of the matrix.
`Certain other polysaccharide gums, including alginic
`acid derivatives, hydrocolloids, etc. also are believed to
`act synergistically with xanthan gum to produce matri-
`ces having high gel strength. The combination of xan-
`than gum with locust bean gum with or without the
`other polysaccharide gums is especially preferred.
`However, the combination of any polysaccharide gums
`known to produce a synergistic effect when exposed to
`aqueous solutions may be used in accordance with the
`‘ present invention. By synergistic effect it is meant that
`the combination of two or more polysaccharide gums
`produce a higher viscosity and/or faster hydration than
`that which would be expected by either of the gums
`alone. One example of a combination of polysaccharide
`gums which has been reported to exhibit such syner-
`gism in food products is kappa carrageenan and a galac-
`tomannan such as guar gum and/or locust bean gum.
`Additionally, the combination of propylene glycol algi-
`nate and sodium carboxymethylcellulose has also been
`reported to exhibit a synergistic effect as a stabilizer in
`
`

`

`7
`fruit juices in US. Pat. No. 4,433,000. This list is not
`meant to be exclusive, and many other synergistic com»
`binations will be readily apparent to those skilled in the
`art.
`
`5,135,757
`
`Mixtures of xanthan gum and locust bean gum in a
`ratio from about 20:1 to about 1:10 are disclosed in US.
`Pat. No. 3,726,690 (Schuppner) as being useful to mini—
`mize serum separation in amounts of 02—06% by
`weight of acidified food products. In addition, mixtures
`of xanthan gum/locust bean gum are commercially
`available as Lygomme H96 from Satia and are recom-
`mended for uses such as syrup thickening, suspension of
`active components and emulsion stabilization. How-
`ever, there has been no recognition in the art that granu-
`lations of xanthan gum, locust bean gum and an inert
`diluent can be mixed with an active medicament and
`thereafter directly compressed to form slow release
`tablets.
`
`In the present invention it has been discovered that
`the slow release properties of the tablets are optimized
`when the ratio of xanthan gum to polysaccharide mate-
`rial (i.e., locust bean gum, etc.),is about 1:1, although
`xanthan gum in an amount of from about 10 to about 90
`percent or more by weight of the hydrophilic material
`provides an acceptable slow release product.
`Upon oral ingestion and contact with gastric fluid,
`the slow release tablets prepared according to the pres-
`ent invention swell and gel to form a hydrophilic gel
`matrix from which the drug is released. The swelling of
`the matrix causes a reduction in the bulk density of the
`tablet and provides the buoyancy necessary to allow the
`gel mass to float on the stomach contents to provide a
`slow delivery of the medicament. The matrix, the size of
`which is dependent upon the size of the original tablet,
`can swell considerably and become obstructed near the
`opening to the pylorus. Since the medicament is dis-
`persed throughout
`the tablet
`(and consequently
`throughout the gel matrix), a constant amount of drug
`can be released per unit time in vivo by dispersion or
`erosion of the outer portions of the matrix. This phe-
`nomenon is commonly referred to as a zero order re-
`lease proflle or zero order kinetics. The process continc
`ues, with the matrix remaining buoyant in the stomach,
`until substantially all of the medicament is released.
`The chemistry of certain of the ingredients compris-
`ing the excipients of the present invention such as xan-
`than gum is such that the excipients are considered to be
`self-buffering agents which are substantially insensitive
`to the solubility of the medicament and likewise insensi-
`tive to the pH changes alone the length of the gastroin-
`testinal tract. Moreover, the chemistry of the ingredi-
`ents comprising the excipients of the present invention
`is believed to be similar to certain known muco adhe-
`sive substances such as polycarbophil. Muco adhesive
`properties are desirable for buccal delivery systems.
`Thus, it may be possible that the gel system could po-
`tentially loosely interact with the mucin in the gastroin-
`testinal tract and thereby provide another mode by
`which a constant rate of delivery of the medicament is
`achieved. The above hypothesis is included for discus-
`sion purposes only and is not intended to limit the scope
`of the present invention.
`‘
`These two phenomenons, i.e., buoyancy of the gel
`matrix and the mucoadhesive properties discussed
`above, are possible mechanisms by which the gel matrix
`of the present invention could interact with the mucin
`and fluids of the gastrointestinal tract and provide a
`constant rate of delivery of the medicament. Other
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`-
`
`8
`mechanisms are possible and therefore this hypothesis is
`not meant to limit the scope of the present invention.
`Any generally accepted soluble or insoluble inert
`pharmaceutical filler (diluent) material can be used,
`including sucrose, dextrose,
`lactose, microcrystalline
`cellulose, xylitol, fructose, sorbitol, mixtures thereof
`and the like. However,
`it is preferred that a soluble
`pharmaceutical filler such as lactose, dextrose, sucrose,
`or mixtures thereof be used.
`An effective amount of any generally accepted phar—
`maceutical lubricant, including the calcium or magne»
`sium soaps may be added to the above-mentioned ingre-
`dients of the excipient be added at the time the medica-
`ment is added, or in any event prior to compression into
`a solid dosage form. Most preferred is magnesium stea—
`rate in an amount of about 0.5-3% by weight of the
`solid dosage form.
`The combination of the hydrophilic material (i.e., a
`mixture of xanthan gum and locust bean gum) with the
`inert diluent provides a ready to use product in which a
`formulator need only blend the desired active medica-
`ment and an optional lubricant with the excipient and
`then compress the mixture to form slow release tablets.
`The excipient may comprise a physical admix of the
`gums along with a soluble excipient such as compress-
`ible sucrose, lactose or dextrose, although it is preferred
`to granulate or agglomerate the gums with plain (i.e,
`crystalline) sucrose, lactose, dextrose, etc. to form an
`excipient. The granulate form has certain advantages
`including the fact that it can be optimized for flow and
`compressibility; it can be tableted, formulated in a cap-
`sule, extruded and spheronized with an active medica-
`ment to form pellets, etc.
`The pharmaceutical excipients prepared in accor-
`dance with the present invention are preferably sub-
`jected to wet granulation before the medicament is
`added, although the ingredients of the present excipient
`can be held together by any agglomeration technique to
`yield an acceptable excipient product. In this technique,
`the desired amounts of the heteropolysaccharide, the
`polysaccharide material, and the inert filler are mixed
`together and thereafter a moistening agent such as wa-
`ter, propylene glycol, glycerol, alcohol or the like is
`added to prepare a moistened mass. Next, the moistened
`mass is dryed. The dried mass is then milled with con-
`ventional equipment into granules.
`Thereafter, the excipient product is ready to use. The
`excipient is mixed in the desired proportion with a ther-
`apeutically active medicament and optional lubricant.
`The complete mixture, in an amount sufficient to make
`a uniform batch of tablets, is then subjected to tableting
`in a conventional production scale tableting machine at
`normal compression pressures,
`i.e about 2000~16(X)0
`lbs/sq. in. However, the mixture should not be com-
`pressed to such a degree that there is subsequent diffi-
`culty in its hydration when exposed to gastric fluid.
`The average particle size of the granulated excipient
`of the present invention ranges from about 50 micrcns
`to about 400 microns and preferably from about 185
`microns to about 265 microns. The particle size of the
`granulation is not narrowly critical, the important pa-
`rameter being that the average particle size of the gran-
`ules, must permit the formation of a directly compress-
`ible excipient which forms pharmaceutically acceptable
`tablets. The desired tap and bulk densities of the granu-
`lation of the present invention are normally between
`from about 0.3 to about 0.8 g/ml, with an average den-
`sity of from about 0.5 to about 0.7 g/ml. For best results,
`
`

`

`5,135,757
`
`9
`the tablets formed from the granulations of the present
`invention are from about 6 to about 8 kg hardness. The
`average flow of the granulations prepared in accor-
`dance with the present invention are from about 25 to
`about 40’ g/sec.
`.
`The ratio of medicament to the hydrophilic material
`is based in part upon the relatively solubility of the
`medicament and the desired rate of release. For in-
`stance, the ratio of medicament to hydrophilic material
`can be adjusted