111111111111111111111111111111111111111111111111111111111111111111111111111
`US005128143A
`Patent Number:
`Date of Patent:
`
`[II]
`
`[45]
`
`5,128,143
`* Jul. 7, 1992
`
`United States Patent fi9J
`Baicbwal et al.
`
`[54] SUSTAlSED RELEASE EXCIPIEJ'Iol AND
`TABLET FORMULATIOJ\
`
`[75]
`
`Inventors: Anand R. Baichwal, Poughkeepsie,
`N.Y.; John N. Staniforth, Bath,
`England
`
`[73] Assignee: Edward Mendell Co., Inc., Patterson,
`N.Y.
`
`[.] Notice:
`
`The portion of the term of this patent
`subsequent to Feb. 19, 2008 has been
`disclaimed.
`
`[21] Appl. No.: 491,189
`
`[22] Filed:
`
`Mar. 9, 1990
`
`[63]
`
`Related U.S. Application Data
`Continuation-in-pan of Ser. No. 246,368, Sep. 19, 1988,
`Pat. No. 4,994,276.
`
`[51]
`
`Int. Cl.s ......................... A61K 9/16; A61K 9/20;
`A61K 9/26
`[52] u.s. Cl. ···································· 424/464; 424/439;
`424/440;424/465; 424/468; 424/469; 424/470;
`424/488;424/499; 424/500; 469/470; 469/488;
`469/499; 469/555; 514/960; 514/965
`[58) Field of Search ............... 424/464, 465, 468, 469,
`424/470, 484, 488, 4&5
`
`[56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`2,993,836 7/1961 Nash et al. ............................ 167/82
`3,074,852 1/1963 Mayron ................................. 167/g2
`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
`3,456,049 7/1969 Hotko et al. .......................... 424/22
`3,388,041 6/1968 Gans et al. .......................... 167/182
`3,627,583 12/1971 Troy et al. ............................ 127/29
`3,629,393 12!1971 Nakamoto ............................. 424/22
`3,639,169 12/1971 Broeg et al. .......................... 167/82
`3,726,690 4/1973 Schuppner, Jr ...................... 99/139
`3,728,445 511973 Bardani ................................. 424/22
`3,773,920 11/1973 Nakamoto et asl. .................. 424/19
`3,836,618 9/1974 Stevens ............................... 264/101
`3,864,469 2/1975 Reiser et al. .......................... 424/22
`3,950,508 4/1976 Mony et al. ........................... 424/19
`
`-··-·- EXG
`---·-t!X5
`------EX ..If
`--E)(.3
`
`/37
`
`3,963,832 6/1976 Hashimoto et al ................... 424/49
`4,013,820 3/1977 Farhadieh et al. .................... 536/64
`4,072,535 8/1977 Shon et al. ........................... 424/22
`4,167,558 9/1979 Sheth et al. ........................... 424/22
`4,259,314 3/1981 Lowey .................................. 424/19
`4,308,251 12/1981 Dunn et al. ........................... 424/19
`4,361,545 11/1982 Powell et al. ......................... 424/19
`4,389,393 10/1983 Schor et al. ........................... 424/19
`4,424,235 1/1984 Sheth et al. ........................... 424/72
`4,439,453 6/1984 Vogel .................................... 424/22
`4,525,345 6/1985 Dunn et al. ........................... 424/22
`4,542,011 9/1985 Gleixner ................................ 424/16
`4,556,678 12/1985 Hsiao ................................... 514/652
`4,590.062 5/1986 Jang ...................................... 424/19
`4,623,394 11/1986 Nakamura et al. ................. 106/122
`4,692,337 9/1987 Ukigaya et al. ..................... 424/469
`4,695,463 9/1987 Yang et al. .......................... 424/488
`4,695,467 9/1987 Uemura et al. ..................... 424/502
`4,698,101 10/1987 Koivurinta ........................ :. 424/453
`4,704,285 11/1987 Alderman ........................... 424/468
`4,717,713 1/1988 Zatz et al. ............................... 514/2
`4,755,389 1/1988 Jones et al. ............................. 514/2
`4,762,702 8/1988 Gergely et al. ..................... 424/300
`4,803,077 1/1989 Mitsuhashi et al. ................. 424/440
`4,829,056 5/1989 Sugden ................................ 424/464
`
`FOREIGN PATENT DOCUMENTS
`0180364 5/1986 ·European Pat. Off ..
`0234670 9/1987 European Pat. Off ..
`(List continued on next page.)
`
`OTHER PUBLICATIONS
`
`Satiaxane Food-Grade Xanthan Gum published by
`Satia.
`
`(List continued on next page.)
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-James M. Spear
`Attorney. Agent, or Firm-Steinberg & Raskin
`
`ABSTRACT
`[57]
`A slow release pharmaceutical excipient of an inert
`diluent and a hydrodrophilic material including xanthan
`gum and a galactomannan gum capable of cross-linking
`the xanthan gum in the presence of aqueous solutions.
`
`24 Claims, 9 Drawing Sheets
`
`dL--dL---~2--~4~--6~--8~--~£7=-~,2~-­
`l/AIE (Ht/VRS)
`
`1
`
`

`

`5,128,143
`
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`8400104 1/1984 PCT lnt'1 Appl. .
`8700044 1/1987 PCT lnt'1 Appl. .
`8705212 9/1987 PCT Int'l Appl. .
`1097807 12/1967 United Kingdom .
`2178658 2/1987 United Kingdom .
`2188843 10/1987 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Hydrocolloids a Publication by Mero Rousselot Satia.
`
`Xanthan Gum/Keltrol Kaltan a Natural Biopolysac(cid:173)
`charide for Scientific Water Control.
`Formulating for Controlled Release With Methocel
`Cellulose Ethers, the Dow Chemical Company, 1987.
`H. M. Ingani et al., 6th Pharmaceutical Technology
`Conference, Volume II, pp. 459-460, Canterbury, En(cid:173)
`gland 1987.
`Pharm. Ind., vol. 42, No. 6, 1980, Georgakopoulos et
`al., "Locust Bean Gum as Granulating and Binding
`Agent for Tablets".
`
`2
`
`

`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 1 of 9
`
`5,128,143
`
`--·-·· E.X ~
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`8
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`FIG. I
`
`3
`
`

`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 2 of 9
`
`5,128,143
`
`.....•.•• EX 16
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`__ £XIS
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`
`4
`
`

`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 3 of 9
`
`5,128,143
`
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`U.S. Patent
`
`July 7, 1992
`
`Sheet 4 of 9
`
`5,128,143
`
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`

`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 5 of 9
`
`5,128,143
`
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`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 6 of 9
`
`5,128,143
`
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`U.S. Patent
`
`July 7, 1992
`
`Sheet 7 of 9
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`5,128,143
`
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`

`

`U.S. Patent
`
`July 7, 1992
`
`Sheet 8 of 9
`
`5,128,143
`
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`U.S. Patent
`
`July 7, 1992
`
`Sheet 9 of 9
`
`5,128,143
`
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`

`

`SUSTAINED RELEASE EXOPIE:!\T AND TABLET
`FORMULATIO~
`
`This application is a continuation-in-part of U.S. ap- 5
`plication Ser. No. 246,368, filed Sep. 19, 1988, nov.· U.S.
`Pat. No. 4,994,276.
`
`1
`
`5,128,143
`
`FIELD OF THE INVENTION
`The present invention relates to a sustained release
`pharmaceutical excipient product which can be blended
`with a wide range of therapeutically active medica(cid:173)
`ments and tableted.
`
`2
`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 moisteni~g
`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
`10 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
`BACKGROUND OF THE INVENTION
`15 prior art which are directed to particular therapeuti-
`cally active medicaments.
`Many attempts have been made in the pharmaceutical
`art to provide a method by which therapeutically active
`In one such disclosure, U.S. Pat. No, 3,456,049
`(Hotko et al.), a slow release benzothiadiazine diuretic
`medicaments can be directly tableted or mixed with a
`tablets are prepared by mixing a fatty substance such as
`direct compression vehicle and thereafter directly tab-
`leted.
`20 hydrogenated vegetable oil, alginic acid, a granulating
`liquid, a potassium salt and the benzothiadiazine. The
`Very few therapeutically active medicaments can be
`wet mass is screened, dried, and then compressed into
`directly tableted due to unacceptable flow characteris-
`tics and compressibility factors of the crystalline or
`tablets. Similarly, U.S. Pat. No. 4,692,337 (Ukigaya et
`al.) provides a slow release excipient for theophylline
`powdered medicament. and also due to the small
`amounts of medicament needed to provide the desired 25 which utilizes 5-200 parts of ethyl cellulose for each 100
`effect. Therefore, it is a common practice to use an inert
`parts theophylline, and optionally contains a filler such
`ingredient, i.e., excipients, diluents, fillers, binders and
`as lactose or a lubricant. The ingredients are mixed and
`the like, such that the combination of the same with the
`compression !l!Olded into tablets. In yet another exam-
`medicament provides a material which can be directly
`pie. U.S. Pat. No. 4,308,251 (Dunn et al.), a sustained
`compressed into tablets. In order to provide a directly 30 release aspirin formulation in which 0.8-1.6 percent of a
`compressible product, these excipients must have cer-
`release controlling agent (cellulose acetate phthalate)
`tain physical properties, including flowability, sufficient
`and 1.0-7.5 percent of an erosion-promoting agent
`particle size distribution, binding ability, acceptable
`(corn starch) by weight per tablet. A wet granular mass
`bulk and tap densities, and acceptable dissolution prop-
`is formed, dried, reduced in particle size and com-
`erties in order to release the medicament upon oral 35 pressed into tablets.
`administration.
`More recently, a great deal of attention in the phar-
`U.S. Pat. No. 3.639,169 (Broeg et al.) discloses one
`maceutical field has turned to the use of various hydro-
`such direct compression vehicle for a therapeutically
`colloid materials such as hydroxypropylmethyl cellu-
`active medicament which consists of an insoluble or
`Jose in providing a slow release matrix for a variety of
`soluble diluent such as lactose dispersed in a matrix of a 40 medicaments.
`For example, U.S. Pat. No. 4,389.393 (Schor et al.)
`hydrophilic hydratable high polymer such as hydro-
`philic polysaccharides, hydrocolloids or proteinaceous
`describes a slow release carrier base material of one. or
`materials. The polymer, diluent and water are mixed
`more hydroxypropylmethyl celluloses and up to 30%
`and the resulting dispersion is dried, forming a film. The
`by weight of a mixture of methylcellulose, sodium car-
`cooled film is fragmented, ground to the desired parti- 45 boxymethylcellulose and/or cellulose ether which can
`cle size and then blended with a desired medicament.
`be mixed with a medicament and other needed ingredi-
`In another method disclosed
`in U.S. Pat. No.
`ents such as binders, lubricants, etc. and then tableted.
`3,079,303 (Raff et al.), a granular excipient for making
`At least one of the hydroxypropylmethyl celluloses
`tablets
`is prepared by spray drying a slurry of
`must have a methoxy content of 16%-24% by weight,
`50%-98% filler, 1%-50% disintegrant, and 1%-50% 50 a hydroxypropyl content of 4%-32% by weight, and a
`binder. A medicament is then added to the excipient and
`number average molecular weight of at least 50,000.
`the finished product is tableted.
`The carrier base constitutes Jess than about one third of
`It has become desirable to provide pharmaceutical
`the weight of the solid unit dosage form.
`It is acknowledged in Schor et al. that in order to
`formulations which utilize slow release profiles, an ob-
`jective not contemplated in Broeg et al., Raff et al. or 55 make tablets using this carrier base, other ingredients
`other similar prior art. The advantages of slow release
`which are conventional in tablet making must necessar-
`products are well known in the pharmaceutical field
`ily be included, such as binders, fillers, disintegrating
`and include the ability to maintain a desired blood level
`agents and the like. Only the completed mixture, which
`over a longer period of time while increasing patient
`includes these additional ingredients, possess sufficient
`compliance by reducing the number of administrations 60 properties to produce tablets having the necessary hard-
`necessary to achieve the same.
`ness and low level of friability. Thus, the carrier base of
`Slow release excipients have been developed which
`the Schor et al. disclosure is not directed to the tableting
`attain their goals by a wide variety of methods. For
`aspects.
`instance. U.S. Pat. No. 3,629,393 (Nakamoto) utilizes a
`U S. Pat. No. 4,704,285 (Alderman) discloses solid
`three-component system to provide slow release tablets 65 slow release tablets containing 5%-90% hydroxypro-
`in which granules of an active ingredient with a hydro-
`pyl cellulose ether, 5%-75% of an optional additional
`phobic salt of a fatty acid and a polymer are combined
`hydrophilic colloid such as hydroxypropylmethyl eel-
`with granules of a hydrocolloid and a carrier and gran-
`lulose, an effective amount of an active medicament,
`
`12
`
`

`

`15
`
`35
`
`3
`and optional binders, lubricants, glidants, fillers, etc.
`The hydroxypropyl cellulose ether is in the form of a
`finely sized powder and provides a longer release pat(cid:173)
`tern than identical compositions having coarser parti(cid:173)
`cles. However, Alderman acknowledges the necessity 5
`of the additional excipients in order to form an accept(cid:173)
`able solid tablet, (i.e. fillers, binders, lubricants and gli(cid:173)
`dants). In preferred embodiments, these excipients com(cid:173)
`prise from 63.5%-94% of the tablet.
`The carrier bases which provide the slow release IO
`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(cid:173)
`leted and thereafter proceed through a series of trial and 20
`error experiments in order to determine the optimal
`amount of gums/polymers and other adjuvants to pro(cid:173)
`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
`acacia tragacanth, alginates, chitosan, xanthan, pectin 30
`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(cid:173)
`ability. Also. hydroxypropylmethyl cellulose polymers 40
`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(cid:173)
`tion. Thus, at higher percentages of such polymers in
`the final mixture, it becomes difficult if not impossible to 45
`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 U.S. Pat. No. 4,590,062 (Jang). Jang dis(cid:173)
`closes a dry direct compressed slow release tablet con(cid:173)
`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 55
`of a wax, and a fatty acid material or neutral lipid. The
`tablets can be made by dry blending the active ingredi(cid:173)
`ent with the matrix blend and compressing. However,
`while this combination of ingredients can provide a
`directly compressible tablet, the formulator is still re- 60
`quired to perform a great deal of experimentation to
`provide the correct release profile for the chosen medi(cid:173)
`cament, given the wide range of wax (used for its bind(cid:173)
`ing and compacting properties) which can be included.
`It is therefore an object of the present invention to 65
`provide a free-flowing directly compressible slow re(cid:173)
`lease excipient which can be used for a wide variety of
`therapeutically active medicaments.
`
`50
`
`5,128,143
`
`4
`It is another object of the present invention to pro(cid:173)
`vide an excipient which can be prepared by wet granu(cid:173)
`lation to form controlled release tablets.
`It is a further object of the present invention to pro(cid:173)
`vide an excipient having the properties set forth above
`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(cid:173)
`vide a free-flowing directly compressible slow release
`excipient which is relatively inexpensive to manufac(cid:173)
`ture due to the Jack of coatings and expensive equip(cid:173)
`ment.
`
`SUMMARY OF THE INVENTION
`In accordance with the above-mentioned objectives,
`the present invention provides a slow release pharma(cid:173)
`ceutical excipient comprising from about 20 to about 70
`percent or more by weight of a hydrophilic material
`comprising a heteropolysaccharide and a polysaccha(cid:173)
`ride material capable of cross-linking the heteropoly(cid:173)
`saccharide in the presence of aqueous solutions, and
`from about 30 to about 80 percent by weight of an inert
`pharmaceutical tiller. This excipient can be mixed with
`a wide range of therapeutically active medicaments and
`25 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(cid:173)
`ids. By varyin,g the amount of excipient relative to the
`medicament, a slow release profile can be attained.
`The heteropolysaccharide comprises from about 20
`to about 80 percent and the polysaccharide material
`comprises from about 80 to about 20 percent by weight
`of the hydrophilic matrix. Preferably, the ratio ofheter(cid:173)
`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 lo(cid:173)
`cust bean gum.
`In yet another preferred embodiment, the inert phar(cid:173)
`maceutical tiller 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(cid:173)
`ceutical excipient, comprising a heteropolysaccharide
`or a gum having similar properties and a polysaccharide
`material capable of cross-linking the heteropolysaccha(cid:173)
`ride in the presence of water, the ratio of the hetero-
`polysaccharide to the polysaccharide material being
`from about 1:1 to about 4: I.
`The present invention also provides a slow release
`tablet for oral administration comprising (I) a hydro(cid:173)
`phillic material comprising (a) a heteropolysaccharide;
`or (b) a heteropolysaccharide and a cross-linking agent
`capable of cross-linking said heteropo1ysaccharide; or
`(c) a mixture of (a), (b) and a polysaccharide gum; and
`(II) an inert pharmaceutical tiller comprising up to
`about 80 percent by weight of the tablet; and (Ill) an
`effective amount of a therapeutically active ingredient.
`In addition, the present invention provides a method
`for providing a universal tableting excipient for con(cid:173)
`trolled release of therapeutically active medicaments
`having varied solubilities in water, comprising deter(cid:173)
`mining the solubility of a therapeutically active medica(cid:173)
`ment which is to be tableted; mixing an effective
`amount of said therapeutically active medicament with
`a premanufactured granulated slow release excipient
`
`13
`
`

`

`5,128,143
`
`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 60
`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(cid:173)
`tion substantially overcome the need for conducting 65
`further experimentation needed to optimize release
`characteristics and tableting properties for a particular
`therapeutically active medicament.
`
`5
`comprising from about 20 to about 70 percent by weight
`of a hydrophilic material comprising a heteropoly(cid:173)
`saccharide and a polysaccharide capable of cross-link(cid:173)
`ing said heteropolysaccharide in the presence of aque(cid:173)
`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 I :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(cid:173)
`ment, the greater the amount of hydrophilic material
`needed to produce a slow release of the medicament.
`
`6
`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
`5 for a wide variety of drugs. Thus, once the excipient
`product 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
`10 forms.
`Xanthan gum, the preferred heteropolysaccharide, is
`produced by microorganisms, for instance, by fermenta(cid:173)
`tion with the organism xanthomonas compestris. Most
`preferred is xanthan gum which is a high molecular
`IS weight (> 106) heteropolysaccharide. Xanthan gum
`contains D-glucose, D-mannose, D-glucuronate in the
`BRIEF DESCRIPTION OF THE DRAWINGS
`molar ratio of 2.8:2.0:2.0, and is partially acetylated
`with about 4.7% acetyl. Xanthan gum also includes
`The following drawings are illustrative of embodi-
`about 3% pyruvate, which is attached to a single unit
`ments of the invention and are not meant to limit the
`20 D-glucopyromosyl side chain as a ketal. It dissolves in
`scope of the invention as encompassed by the claims.
`hot or cold water and the viscosity of aqueous solutions
`FIG. 1 is a graphical representation of the dissolution
`curves provided by Examples 3-6;
`of xanthan gum is only slightly affected by changes in
`the pH of a solution between 1 and 11.
`FIG. 2 is a graphical representation of the dissolution
`Other preferred heteropolysaccharides include deriv-
`curves provided by Examples 16-19;
`FIG. 3 is a graphical representation of the dissolution 25 atives of xanthan gum, such as deacylated xanthan gum,
`curves provided by Examples 18,20 and 28;
`the carboxymethyl ether, and the propylene glycol
`FIG. 4 is a graphical representation of the dissolution
`ester.
`curve provided by Example 18 as compared to Compar-
`The polysaccharide materials used in the present
`ative Example C;
`invention which are capable of cross-linking with the
`FIG. 5 is a graphical representation of the dissolution 30 heteropolysaccharide include the galactomannans, i.e.,
`curve provided by Examples 29-31 (in different pH's);
`polysaccharides which are composed solely of mannose
`and
`and galactose. A possible mechanism for the interaction
`FIG. 6 is a graphical representation of the viscosities
`between the galactomannan and the heteropolysaccha-
`of Examples 32-36.
`ride involves the interaction between the helical regions
`FIG. 7 is a graphical representation of the dissolution 35 of the heteropolysaccharide and the unsubstituted man-
`curves provided by Examples 41-43;
`nose regions of the galactomannan. Galactomannans
`FIG. 8 is a graphical representation of the dissolution
`which have higher proportions of unsubstituted man-
`curves provided by Examples 44-46;
`nose regions have been found to achieve more interac-
`FIG. 9 is a graphical representation of the dissolution
`tion with the heteropolysaccharide. Hence, locust bean
`40 gum, which has a higher ratio of mannose to galactose,
`curves provided by Examples 47-50;
`FIG. 10 is a graphical representation of the dissolu-
`is especially preferred as compared to other galacto-
`tion curves provided by Examples 51-53;
`mannans such as guar and hydroxypropyl guar.
`FIG. 11 is a graphical representation of the dissolu-
`Other polysaccharide gums may also be added to the
`tion curves provided by Example 54 and Calan ® SR;
`hydrophilic material in addition to the above-mentioned
`FIG. 12 is a graphical representation of the dissolu- 45 ingredients. These additional
`ingredients comprise
`tion curves provided by Example 55 and Inderal ®LA;
`other polysaccharide gums which may or may not
`FIG. 13 is a graphical representation of the dissolu-
`cross-link with the heteropolysaccharides such as the
`tion curves provided by Example 56 and Chlor-
`alginates, tragacanth, acacia, karaya, agar, pectins, car-
`trimeton @;
`rageenan, hydroxypropylmethyl cellulose, hydroxypro-
`FIG. 14 is a graphical representation of the dissolu- 50 pyl cellulose, carboxymethyl cellulose, polyvinyl pyr-
`tion curves provided by Example 57 and Acutrim @;
`rolidone, mixtures thereof, and the like.
`Two steps which are generally required for gelation
`and
`FIG. 15 is a graphical representation of the bioavaila-
`are the fast hydration of the macromolecules which
`bility of Example 57 as compared to Acutrim @.
`comprise the hydrophilic material and thereafter the
`55 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(cid:173)
`philic matrix are maximized in the present invention by
`the particular combination of materials. In particular,
`heteropolysaccharides such as xanthan gum have excel(cid:173)
`lent water wicking properties which provide fast hydra(cid:173)
`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
`
`14
`
`

`

`5,128,143
`
`7
`8
`tract. Moreover, the chemistry of the ingredients com-
`mannose regions in galactomannans) thereby act syner-
`prising the excipients of the present invention is be-
`gistically to provide a higher than expected viscosity
`(i.e., high gel strength) of the matrix.
`lieved to be similar to certain known muco adhesive
`substances such as polycarbophil. Muco adhesive prop-
`Certain other polysaccharide gums, including alginic
`acid derivatives, hydrocolloids, etc. also are believed to 5 erties are desirable for buccal delivery systems. Thus, it
`act synergistically with xanthan gum to produce matri-
`may be possible that the gel system could potentially
`ces having high gel strength. The combination of xan-
`loosely interact with the mucin in the gastrointestinal
`than gum with locust bean gum with or without the
`tract and thereby provide another mode by which a
`other polysaccharide gums is especially preferred.
`constant rate of delivery of the medicament is achieved.
`However, the combination of any polysaccharide gums 10 The above hypothesis is included for discussion pur-
`known to produce a synergistic effect when exposed to
`poses only and is not intended to limit the scope of the
`aqueous solutions may be used in accordance with the
`present invention.
`present invention. By synergistic effect it is meant that
`These two phenomenons, i.e., buoyancy of the gel
`the combination of two or more polysaccharide gums
`matrix and the mucoadhesive properties discussed
`produce a higher viscosity and/or faster hydration than 15 above, are possible mechanisms by which the gel matrix
`that which would be expected by either of the gums
`of the present invention could interact with the mucin
`alone. One example of a combination of polysaccharide
`and fluids of the gastrointestinal tract and provide a
`gums which has been reported to exhibit such syner-
`constant rate of delivery of the medicament. Other
`gism in food products is kappa carrageenan and a galac-
`mechanisms are possible and therefore this hypothesis is
`tomannan such as guar gum and/or locust bean gum. 20 not meant to limit the scope of the present invention.
`Any generally accepted soluble or insoluble inert
`Additionally. the combination of propylene glycol algi-
`pharmaceutical filler (diluent) material can be, used,
`nate and sodium carboxymethylcellulose has also been
`reported to exhibit a synergistic effect as a stabilizer in
`including sucrose, dextrose, lactose, microcrystalline
`fruit juices in U.S. Pat. No. 4,433,000. This list is not
`cellulose, xylitol, fructose, sorbitol, mixtures thereof
`meant to be exclusive, and many other synergistic com- 25 and the like. However, it is preferred that a soluble
`binations will be readily apparent to those skilled in the
`pharmaceutical filler such as lactose, dextrose, sucrose,
`or mixtures thereof be