(12) United States Patent
`Tyler et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006733780Bl
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6, 733, 780 Bl
`May 11, 2004
`
`(54) DIRECT COMPRESSION POLYMER TABLET
`CORE
`
`(75)
`
`Inventors: Joseph Tyler, Somerville, MA (US);
`John S. Petersen, Acton, MA (US)
`
`(73) Assignee: Genzyme Corporation, Cambridge,
`MA(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/691,429
`
`(22) Filed:
`
`Oct. 18, 2000
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/160,258, filed on Oct. 19,
`1999, and provisional application No. 60/174,227, filed on
`Jan. 3, 2000.
`Int. Cl.7 .................................................. A61K 9/20
`U.S. Cl. ..................... 424/464; 424/78.08; 424/474
`Field of Search ........................... 424/78.11, 78.16,
`424/78.08, 78.12, 426, 468
`
`(51)
`(52)
`(58)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,383,236 A
`3,431,138 A
`3,539,380 A
`4,115,537 A
`4,211,763 A
`4,302,440 A
`4,341,563 A
`4,543,370 A
`4,631,305 A
`4,849,227 A
`4,956,182 A
`4,983,398 A
`4,983,399 A
`5,073,380 A
`5,194,464 A
`5,262,167 A
`5,401,515 A
`5,447,726 A
`5,455,047 A
`5,487,888 A
`5,496,545 A *
`5,520,932 A
`5,607,669 A
`5,618,530 A
`5,624,963 A
`5,654,003 A
`5,667,775 A
`5,679,717 A
`5,686,106 A
`5,693,675 A
`5,702,696 A
`5,703,188 A
`
`5/1968
`3/1969
`11/1970
`9/1978
`7/1980
`* 11/1981
`7/1982
`9/1985
`12/1986
`7/1989
`9/1990
`1/1991
`1/1991
`12/1991
`3/1993
`11/1993
`3/1995
`9/1995
`10/1995
`1/1996
`3/1996
`5/1996
`3/1997
`4/1997
`4/1997
`8/1997
`9/1997
`10/1997
`11/1997
`12/1997
`12/1997
`12/1997
`
`Brindamour . . . . . . . . . . . . . . . . 117 /100
`Zingerman et al. . . . . . . . . . 117 /100
`Johnson et al. . ... ... ... ... 117 /100
`Driscoll et al. . ... ... ... ... ... 424/1
`Marshall et al. ... ... ... ... ... 424/1
`John et al. .................. 424/480
`Kurihara et al. ... ... ... ... 106/171
`Porter et al. ................ 523/100
`Guyer et al. ................ 523/400
`Cho ........................... 424/498
`Bequette et al. ............ 424/476
`Gaylord et al. ............. 424/465
`Maish ........................ 424/465
`Babu et al. ................. 424/472
`Itoh et al. ..................... 524/42
`Vegesna et al. ............. 424/439
`Woodard et al. ............ 424/475
`Nomura ...................... 424/464
`Bequette et al. ............ 424/476
`Mandeville et al.
`....... 424/78.1
`Holmes-Farley et al. 424/78.11
`McCurdy et al. ........... 424/501
`Mandeville et al.
`..... 424/78.12
`Mandeville et al.
`..... 424/78.12
`Mandeville et al.
`........ 514/789
`Fuisz et al. ................. 424/469
`Holmes-Farley et al. 424/78.11
`Mandeville et al.
`........ 514/742
`Kelm et al. ................. 424/463
`Mandeville et al.
`........ 514/742
`Mandeville et al.
`..... 424/78.12
`Mandeville et al.
`........ 526/290
`
`5,709,880 A
`5,718,920 A
`5,747,067 A
`5,750,148 A
`5,807,582 A
`5,814,336 A
`5,840,339 A
`5,840,766 A
`5,985,938 A
`6,034,129 A
`6,083,495 A
`6,264,937 Bl *
`
`1/1998
`2/1998
`5/1998
`5/1998
`9/1998
`9/1998
`11/1998
`11/1998
`11/1999
`3/2000
`7/2000
`7/2001
`
`Del Corral et al. ......... 424/464
`Notenbomber .............. 424/489
`Auguello et al.
`........... 424/464
`Maruyama et al. ......... 424/494
`Cha ........................... 424/489
`Kelm et al. ................. 424/463
`Kunin ........................ 424/489
`Mandeville et al.
`........ 514/742
`Holmes-Farley et al.
`... 514/789
`Mandeville et al.
`........ 514/549
`Holmes-Farley et al. 424/78.11
`Mandeville et al.
`... .. 424/78.35
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`WO
`WO
`WO
`
`0 997 148 Al
`WO 93/00915
`W098/29107
`WO 98/44933
`W099/22721
`WO 00/22008
`
`5/2000
`1/1993
`7/1998
`10/1998
`5/1999
`4/2000
`
`OTHER PUBLICATIONS
`Physicians Desk Reference "Renagel". *
`U.S. Ser. No.: 09/359,226, filed Jul. 22, 1999.
`U.S. Ser. No.: 09/668,874, filed Sep. 25, 2000.
`U.S. Ser. No.: 09/542,329, filed Apr. 04, 2000.
`U.S. Ser. No.: 08/956,572, filed Oct. 23, 1997.
`U.S. Ser. No.: 09/406,311, filed Sep. 27, 1999.
`U.S. Ser. No.: 09/655,998, filed Sep. 6, 2000.
`U.S. Ser. No.: 08/979,096, filed Nov. 26, 1997.
`U.S. Ser. No.: 09/359,226, filed Jul. 22, 1999.
`U.S. Ser. No.: 08/777,408, filed Dec. 30, 1996.
`U.S. Ser. No.: 08/964,498, filed Nov. 5, 1997.
`* cited by examiner
`Primary Examiner-Thurman K. Page
`Assistant Examiner-----Konata M. George
`(74) Attorney, Agent, or Firm-Hamilton, Brook, Smith &
`Reynolds, P.C.
`
`(57)
`
`ABSTRACT
`
`The present invention provides a tablet core which com(cid:173)
`prises at least about 95% by weight of an aliphatic amine
`polymer. The invention also provides a method of producing
`a tablet core comprising at least about 95% by weight of an
`aliphatic amine polymer resin. The method comprises the
`step of compressing the aliphatic amine polymer to form the
`tablet core. The tablet core can further include one or more
`excipients. In this embodiment the method of producing the
`tablet core comprises the steps of: (1) hydrating the aliphatic
`amine polymer to the desired moisture level; (2) blending
`the aliphatic amine polymer with the excipients in amounts
`such that the polymer comprises at least about 95% by
`weight of the resulting blend; and (3) compressing the blend
`to form the tablet core. The present invention further relates
`to a coated tablet comprising an aliphatic amine polymer
`core wherein the coating is a water based coating.
`
`19 Claims, 1 Drawing Sheet
`
`1
`
`EX 1009
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`d •
`\JJ.
`•
`~
`~ ......
`~ = ......
`
`~
`~
`'-<
`'"""'
`!""
`N c c
`
`.i;;..
`
`e
`rJ'J.
`-..a-..
`tj
`-..~
`""-l
`~
`Q
`~
`lo-"
`
`The Figure
`
`2
`
`

`
`US 6,733,780 Bl
`
`2
`polymer. In a preferred embodiment, the aliphatic amine
`polymer resin is a cross-linked polyallylamine resin. The
`aliphatic amine polymer is preferably hydrated. The
`hydrated polymer can, for example, comprise from about
`5 5% water by weight or greater.
`The invention also provides a method of producing a
`tablet core comprising at least about 95% by weight of an
`aliphatic amine polymer resin. The method comprises the
`step of compressing the aliphatic amine polymer to form the
`10 tablet core. The tablet core can further include one or more
`excipients. In this embodiment, the method of producing the
`tablet core comprises the steps of: (1) hydrating or drying the
`aliphatic amine polymer to the desired moisture level; (2)
`blending the aliphatic amine polymer with the excipients in
`15 amounts such that the polymer comprises at least about 95%
`by weight of the resulting blend; and (3) compressing the
`blend to form the tablet core. The present invention further
`relates to a coated tablet wherein the coating comprises a
`water based coating.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The FIGURE is a table comprising data showing formu(cid:173)
`lations and responses for sevelamer hydrochloride com-
`25 pressed tablet cores.
`
`1
`DIRECT COMPRESSION POLYMER TABLET
`CORE
`RELATED APPLICATION
`This application claims the benefit of U.S. Provisional
`Application No. 60/160,258, filed Oct. 19, 1999, and U.S.
`Provisional Application No. 60/174,227, filed Jan. 3, 2000.
`The entire teachings of which are incorporated herein by
`reference.
`BACKGROUND OF THE INVENTION
`A number of polymeric materials having useful therapeu-
`tic activity have been described for treatment of various
`conditions such as hyperlipidemia and hyperphosphatemia.
`Many of these polymeric materials function as non-absorbed
`ion exchange resins in the digestive tract. Such non(cid:173)
`absorbed polymeric materials bind or otherwise sequester a
`target molecule and facilitate its removal from the body via
`the gastrointestinal tract. Examples of such resins include:
`Colestipol and Cholestyramine useful as orally administered
`cholesterol lowering agents; a variety of aliphatic amine 20
`polymers disclosed U.S. Pat. Nos. 5,496,545 and 5,667,775
`useful as phosphate binders particularly for removing phos(cid:173)
`phate from patients suffering from renal failure; and other
`aliphatic amine polymers disclosed in U.S. Pat. No. 5,624,
`963, U.S. Pat. No. 5,679,717, W098/29107 and W099/
`22721 useful as cholesterol lowering agents.
`Non-absorbed polymer therapeutics have traditionally
`presented a number of formulation challenges as the dosages
`are generally very large (gram quantities), and the resins
`tend to be extremely hydrophilic. The most desirable for- 30
`mulation for oral delivery of a therapeutic is a direct
`compression tablet formulation. However, not all
`therapeutics, particularly given the high dose requirements
`of polymeric ion exchange therapeutics, lend themselves to
`a tablet formulation. Even if such materials could be ren- 35
`dered into a tablet, it is generally not possible without the
`significant addition of other materials which assist in the
`tableting process. Ultimately the addition of any materials
`other than the active ingredient is undesirable given the dose
`requirement of the active ingredient. Ideally the tablet 40
`should contain as much active ingredient as possible with
`little else in the way of additional materials such that the
`tablet is as small as possible and easy to administer to the
`patient.
`In addition, once the polymeric materials are compressed
`into a tablet, the tablet requires a coating for ease of
`administration to the patient. It has been discovered that the
`core polymeric material tends to be very hygroscopic, and
`thus will swell immediately upon contact with the inside of
`the mouth. Most coatings contain water, and thus it was
`believed that coating such tablets with a water-based coating
`would be impossible because the hygroscopic tablets would
`swell during the coating process. Thus providing a tablet
`core comprising a hygroscopic material such that a suitable
`coating may be used in conjunction with that core, is another
`significant challenge to providing the polymeric active
`ingredient in tablet form.
`There is a need to provide suitable dosage forms for
`polymeric ion exchange materials, particularly for hydro(cid:173)
`philic aliphatic amine polymers useful as therapeutic agents,
`which minimize the overall amount of material administered
`to the patient, which are easy to administer orally, and which
`are stable upon production and storage.
`
`SUMMARY OF THE INVENTION
`The present invention provides a tablet core which com(cid:173)
`prises at least about 95% by weight of an aliphatic amine
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`A number of polymeric materials having useful therapeu(cid:173)
`tic activity have been discussed above. In particular, ali(cid:173)
`phatic amine polymers have been disclosed which are useful
`in methods of lowering the serum phosphate level of a
`patient and lowering the serum cholesterol level of a patient.
`For example an epichorohydrin-cross-linked poly
`(allylamine hydrochloride) resin (U.S. Pat. Nos. 5,496,545
`and 5,667,775), also referred to as sevelamer hydrochloride
`or sevelamer and marketed as RENAGEL®, has been shown
`to be effective at removing phosphate from human patients
`suffering from renal failure. Therapeutically effective dos(cid:173)
`ages of sevelamer hydrochloride are large, typically on the
`order of 4 to 6 grams per day. Consequently, development of
`a dosage form of this and similar resins which minimizes the
`amount of excipient material is desirable.
`The present invention provides a tablet core comprising at
`45 least about 95% by weight of an aliphatic amine polymer.
`The aliphatic amine polymer resin can be any of the aliphatic
`amine resins described in U.S. Pat. Nos. 5,496,545; 5,667,
`775; 5,624,963; 5,703,188; 5,679,717; 5,693,675, 5,607,
`669; 5,618,530; 5,487,888; and 5,702,696, each of which is
`50 hereby incorporated herein by reference in its entirety. Other
`suitable aliphatic amine polymers are disclosed in U.S. Ser.
`Nos. 08/670,764; 08/959,471, and 08/979,096, each of
`which is hereby incorporated by reference herein in its
`entirety. In a particularly preferred embodiment, the ali-
`55 phatic amine polymer is polyallylamine, polyvinylamine,
`poly( diallylamine) or poly( ethyleneimine) or a salt thereof
`with a pharmaceutically acceptable acid. The aliphatic
`amine polymer is optionally substituted at one or more
`nitrogen atoms with an alkyl group or a substituted alkyl
`60 group such as a trialkylammonioalkyl group. The aliphatic
`amine polymer can optionally be cross-linked, for example
`via a multifunctional monomer or a bridging group which
`connects two amino nitrogen atoms from two different
`polymer strands. In a preferred embodiment, the aliphatic
`65 amine polymer resin is hydrated. For sevelamer
`hydrochloride, in particular, the compressibility is strongly
`dependent upon the degree of hydration (moisture content)
`
`3
`
`

`
`US 6,733,780 Bl
`
`10
`
`15
`
`3
`of the resin. Preferably, the resin has a moisture content of
`about 5% by weight or greater, more preferably, the moisture
`content is from about 5% to about 9% by weight, and most
`preferably about 7% by weight. It is to be understood that in
`embodiments in which the polymer resin is hydrated, the
`water of hydration is considered to be a component of the
`resin. Thus, in this embodiment, the tablet core comprises at
`least about 95%, preferably at least about 96%, and more
`preferably at least about 98% by weight of the hydrated
`polymer, including the water of hydration.
`The tablet can further comprise one or more excipients,
`such as hardeners, glidants and lubricants, which are well
`known in the art. Suitable excipients include colloidal sili(cid:173)
`con dioxide, stearic acid, magnesium silicate, calcium
`silicate, sucrose, calcium stearate, glyceryl behenate, mag-
`nesium stearate, talc, zinc stearate and sodium stearylfuma(cid:173)
`rate. The excipients can represent from 0 to about 5% of the
`tablet core by weight.
`The tablet core of the invention is prepared by a method
`comprising the steps of: (1) hydrating or drying the aliphatic
`amine polymer to the desired moisture level; (2) blending 20
`the aliphatic amine polymer with any excipients to be
`included in amounts such that the polymer comprises at least
`about 95% by weight of the resulting blend; and (3) com(cid:173)
`pressing the blend using conventional tableting technology.
`The invention also relates to a stable, swallowable coated 25
`tablet, particularly a tablet comprising a hydrophilic core,
`such as a tablet comprising an aliphatic amine polymer, as
`described above. In one embodiment, the coating composi(cid:173)
`tion comprises a cellulose derivative and a plasticizing
`agent. The cellulose derivative is, preferably, hydroxypro- 30
`pylmethylcellulose (HPMC). The cellulose derivative can be
`present as an aqueous solution. Suitable hydroxypropylm(cid:173)
`ethylcellulose solutions include those containing HPMC low
`viscosity and/or HPMC high viscosity. Additional suitable
`cellulose derivatives include cellulose ethers useful in film 35
`coating formulations. The plasticizing agent can be, for
`example, an acetylated monoglyceride such as diacetylated
`monoglyceride, The coating composition can further include
`a pigment selected to provide a tablet coating of the desired
`color. For example, to produce a white coating, a white
`pigment can be selected, such as titanium dioxide.
`In one embodiment, the coated tablet of the invention can
`be prepared by a method comprising the step of contacting
`a tablet core of the invention, as described above, with a
`coating solution comprising a solvent, at least one coating
`agent dissolved or suspended in the solvent and, optionally, 45
`one or more plasticizing agents. Preferably, the solvent is an
`aqueous solvent, such as water or an aqueous buffer, or a
`mixed aqueous/organic solvent. Preferred coating agents
`include cellulose derivatives, such as hydroxypropylmeth(cid:173)
`ylcellulose. Typically, the tablet core is contacted with the 50
`coating solution until the weight of the tablet core has
`increased by an amount ranging from about 4% to about 6%,
`indicating the deposition of a suitable coating on the tablet
`core to form a coated tablet.
`In one preferred embodiment, the solids composition of 55
`the coating solution is:
`
`4
`Astonishingly, it has been found that an aqueous coating
`dispersion is suitable as a coating solution for tablets com(cid:173)
`prising a hygroscopic, or water-swellable substance, such as
`an aliphatic amine polymer tablet. For example, the coating
`5 composition provides a strong, elastic and moisture(cid:173)
`permeable coating without causing significant concomitant
`swelling of the tablet core during the coating process. In a
`preferred embodiment, the coating composition provides a
`tablet coating which withstands the swelling and contraction
`of sevelamer hydrochloride tablets during exposure to vary(cid:173)
`ing humidity levels and other known stability tests. Further,
`the coating composition can be used to coat other aliphatic
`amine polymer tablets without excessive uptake by the tablet
`core of water from the coating solution during the coating
`process.
`The present invention also relates to the use of an aliphatic
`amine polymer as a disintegrant in a tablet. In general, in this
`embodiment the aliphatic amine polymer is not the active
`ingredient in the tablet, but is added to the tablet to enhance
`the rate of disintegration of the tablet following administra(cid:173)
`tion. This allows a more rapid release of the active agent or
`agents. The tablet will generally include the aliphatic amine
`polymer, one or more active ingredients, such as therapeutic
`agents (medicaments), and, optionally, one or more addi(cid:173)
`tional excipients.
`The aliphatic amine polymer can be one of the aliphatic
`amine polymers disclosed above, such as
`polyethyleneimine, polyvinylamine, polyallylamine, polydi(cid:173)
`allylamine or any of the aliphatic amine polymers disclosed
`in U.S. Pat. Nos. 5,496,545 and 5,667,775 and U.S. Ser. Nos.
`08/777,408 and 08/964,498, the teachings of each of which
`are incorporated herein by reference. In one embodiment,
`the aliphatic amine polymer is a cross-linked polyallylamine
`or a salt thereof with a pharmaceutically acceptable acid.
`Preferably, the aliphatic amine polymer is an
`epichlorohydrin-cross-linked polyallylamine or salt thereof
`with a pharmaceutically acceptable acid, such as sevelamer
`or sevelamer hydrochloride.
`The tablet which includes an aliphatic amine as a disin(cid:173)
`tegrant will, generally, include a sufficient amount of the
`aliphatic amine polymer to effectively enhance the rate of
`tablet disintegration under conditions of use. For example, if
`the tablet is an oral doseage form and it is desired that the
`tablet disintegrate in the stomach of the patient, the tablet
`should include a sufficient amount of the polymer to enhance
`the disintegration rate of the tablet under the conditions
`encountered in the stomach. The appropriate amount of the
`polymer to be included in the tablet can be determined by
`one skilled in the art using known methods. Typically, the
`polymer, the active ingredient or ingredients and any addi-
`tional fillers or excipients are combined by mixing, and the
`resulting mixture is compressed to form a tablet using
`conventional methods. The tablet core formed in this way
`can then be coated, for example, as described above, or by
`other methods and other coating compositions which are
`known in the art and suitable for the intended use of the
`tablet.
`In one embodiment, the tablet which includes an aliphatic
`amine polymer as a disintegrant is intended for administra(cid:173)
`tion in vivo, for example, to a patient, such as a human.
`60 Preferably, the tablet is intended to be administered orally. In
`this embodiment, the active ingredient or ingredients will be
`a therapeutic or diagnostic agent. The tablet can also be
`intended for use in vitro, for example, to deliver an active
`ingredient to an aqueous environment, such as a swimming
`pool.
`The invention will now be described in detail by reference
`to the following examples.
`
`40
`
`Material
`
`HPMC low viscosity Type 2910, cUSP
`HPMCE high viscosity Type 2910, cUSP
`diacetylated monoglyceride
`
`%W/W
`
`38.5%
`38.5%
`23.0%
`
`Tablets may be coated in a rotary pan coater as is known 65
`in the art or any other conventional coating apparatus such
`as a column coater or a continuous coater.
`
`4
`
`

`
`US 6,733,780 Bl
`
`6
`
`5
`EXAMPLES
`
`Example 1
`
`Material
`
`HPMC low viscosity Type 2910, cUSP
`HPMCE higb viscosity Type 2910, cUSP
`diacetylated monoglyceride
`
`%W/W
`
`38.5%
`38.5%
`23.0%
`
`The coating solution was applied to the compressed cores
`until a weight gain of approximately 4 to 6% was achieved.
`Stability studies-controlled room temperature, accelerated
`conditions, freeze/thaw and photosensitivity-for the coated
`sevelamer hydrochloride tablets were conducted in accor(cid:173)
`dance with those procedures known in the art and described
`in the following references: International Committee on
`Harmonization (ICH) guidance "QlA-Stability Testing of
`New Drug Substances and Products" (June 1997); ICH
`"QlB-Guidelines for the Photostability Testing of New
`Drug Substances and Products" (November 1996); and ICH
`guidance "QlC-Stability Testing for New Dosage Forms"
`(November 1996. The results (not shown) indicate that the
`coated tablets all met industry standard criteria.
`
`Example 3
`
`Factors Affecting the Processing and Performance
`Characteristics of Compressed Tablets (Prior to
`Coating)
`
`5
`
`Preparation and Characterization of 400 mg and
`800 mg Sevelamer Hydrochloride Direct
`Compression Tablet Cores
`Preparation of Tablet Cores 400 mg sevelamer hydrochlo(cid:173)
`ride tablet cores were prepared from a blend consisting of 10
`5000.0 g sevelamer hydrochloride, 50.0 g colloidal silicon
`dioxide, NF (Aerosil 200) and 50.0 g stearic acid. The
`sevelamer hydrochloride was hydrated to moisture content
`of 6% by weight. The blend was prepared by passing the
`sevelamer hydrochloride and colloidal silicon dioxide 15
`through a #20 mesh screen, transferring the mixture to a 16
`quart PK blender and blending for five minutes. The stearic
`acid was then passed through an oscillator equipped with a
`#30 mesh screen, transferred into the 16 quart PK blender
`and blended for five minutes with the sevelamer 20
`hydrochloride/colloidal silicon dioxide mixture. The result(cid:173)
`ing blend was discharged into a drum and weighed. The final
`blend was then compressed on a 16 station Manesty B3B at
`4 tons pressure using 0.280"x0.620" punches to give tablet
`cores with an average weight of 434 mg. The resulting 25
`tablets consisted of 425 mg 6% hydrated sevelamer hydro(cid:173)
`chloride (equivalent to 400 mg anhydrous sevelamer
`hydrochloride), 4.25 mg colloidal silicon dioxide and 4.25
`mg stearic acid.
`800 mg sevelamer hydrochloride tablet cores were pre- 30
`pared from 19.0 kg sevelamer hydrochloride, 0.19 kg col(cid:173)
`loidal silicon dioxide, and 0.19 kg stearic acid,. The seve(cid:173)
`lamer hydrochloride had a moisture content of 6% by
`weight. The blend was prepared by passing the sevelamer
`hydrochloride and colloidal silicon dioxide through a #20 35
`mesh screen, transferring the mixture to a PK blender and
`blending for five minutes. The stearic acid was then passed
`through an oscillator equipped with a #30 mesh screen,
`transferred into the PK blender and blended for five minutes
`with the sevelamer hydrochloride/colloidal silicon dioxide
`mixture. The resulting blend was then discharged into a
`drum and weighed. The final blend was then compressed in
`on a 16 station Manesty B3B at 4 tons pressure using
`0.3125"x0.750" punches to give tablets with an average
`weight of 866 mg. The resulting tablets consisted of 850 mg
`6% hydrated sevelamer hydrochloride (equivalent to 800 mg
`anhydrous sevelamer hydrochloride), 8.0 mg colloidal sili(cid:173)
`con dioxide and 8.0 mg stearic acid.
`Characterization of Tablet Cores
`The tablets prepared as described above were white to
`off-white, oval shaped, compressed tablets. The variation of
`the tablets prepared from each blend with respect to weight,
`thickness, friability, hardness, disintegration time and den(cid:173)
`sity was assessed. Standard methods in the art were 55
`employed for each of the measurements. The results, (not
`shown), indicate that the hardness, friability, thickness, and
`disintegration behavior of the sevelamer hydrochloride tab(cid:173)
`lets all met industry-standard criteria.
`
`Example 2
`
`Coating of Sevelamer Hydrochloride Tablet Cores
`
`Compressed core tablets prepared as described in
`Example 1 were coated in a coating pan with an aqueous
`coating solution having a solids composition comprising:
`
`In order to maintain consistently acceptable compressed
`tablet on a per batch basis, a number of correlative tests were
`performed in order to determine which factors most strongly
`impact the quality and integrity of the tablets. Studies such
`as weight variation, tablet hardness, friability, thickness,
`disintegration time, among others are known to those skilled
`in the art and are described in the United States Pharma-
`copeia. (U.S.P.). "Hardness" means the measure of the force
`(measured herein in Newtons) needed to fracture a tablet
`when such tablet is placed lengthwise on a Hardness Tester.
`40 "Friability" is the measure of the mechanical strength of the
`tablet needed to withstand the rolling action of a coating pan
`and packaging. It is measured using a friabiliator. "Thick(cid:173)
`ness" is the measure of the height of the tablet using a
`micrometer. "Disintegration Time" is the time necessary for
`45 the tablet to break apart in an appropriate solution at 37° C.
`and is measured in minutes.
`Attainment of appropriate hardness (150-170 N hardness
`range) and friability (no more than 0.8%) is important to the
`success of the formulation. Having tablets with high hard-
`50 ness and low friability is particularly important when the
`tablets are to be coated as is the case with sevelamer
`hydrochloride tablets.
`The FIGURE provides a table listing several different
`sevelamer hydrochloride tablet core formulations that vary
`by a number of factors including (actual) moisture content,
`and compression force used, excipient content among other
`variations. The data in
`The FIGURE indicates that the most important factor
`60 affecting the processing and performance characteristics of
`compressed tablets is the moisture content. All formulations
`provided good flow with little weight variation throughout
`the entire range of compositions. In addition, disintegration
`times were less than 5 minutes across the range of compo-
`65 sitions. Thus, it appears that moisture content and compres(cid:173)
`sion force provide the most appropriate factors on which to
`establish operating ranges for hardness and friability.
`
`5
`
`

`
`US 6,733,780 Bl
`
`7
`
`Equivalents
`While this invention has been particularly shown and
`described with references to preferred embodiments thereof
`it will be understood by those skilled in the art that variou~
`changes in form and details may be made therein without 5
`departing from the spirit and scope of the invention as
`defined by the appended claims.
`What is claimed is:
`1. A tablet comprising a core and a coating thereof,
`wherein at least about 95% by weight of the core is an 10
`aliphatic amine polymer selected from the group consisting
`of. unsubs~ituted and N-substituted poly(allylamine), poly
`(diallylamme), and poly(vinylamine).
`2. The tablet of claim 1 wherein the N-substituents are
`selected from the group consisting of substituted and unsub- 15
`stituted C1-C24-alkyl groups.
`3. The tablet of claim 2 wherein the alkyl substituents are
`trialkylammonioalkyl groups.
`4. The tablet of claim 1 wherein the aliphatic a polymer
`is cross-linked.
`5. The tablet of claim 1 comprising one or more excipi(cid:173)
`ents.
`6. A tablet comprising a core and a coating therefor
`wherein at least about 95% by weight of the core is a linea;
`or cross-linked poly(allylamine) or a pharmaceutically
`acceptable salt thereof.
`7. The tablet of claim 6 wherein the poly(allylamine) is
`hydrated.
`8. The tablet of claim 7 wherein the poly(allylamine)
`comprises from about 3% to about 10% water.
`9. The tablet of claim 8 wherein thee poly(allylamine)
`comprises from about 5% to about 8% water.
`10. The tablet of claim 9 wherein the polyallylamine is
`from about 1 % to about 10% cross-linked.
`
`30
`
`20
`
`25
`
`8
`11 . . A tablet comprising a core and a coating therefor,
`wherem at least about 95% by weight of the core is a
`hydrated cross-linked poly(allylamine hydrochloride).
`12. The tablet of claim 1 wherein the coating is a
`water-based coating.
`13. The tablet of claim 6 wherein the coating is a
`water-based coating.
`14. The tablet of claim 13 wherein said water-based
`coating comprises hydroxypropylmethylcellulose and a
`plasticizer.
`15. The tablet of claim 14 wherein said water-based
`coating comprises hydroxypropylmethylcellulose low
`v~scosity, hydroxypropylmethylcellulose high viscosity, and
`diacetylated monoglyceride.
`16. The tablet of claim 1 wherein said polymer is poly(cid:173)
`diallylamine.
`17. The tablet of claim 16 wherein said tablet further
`comprises a water-based coating.
`18 . . A tablet comprising a core and a coating therefor,
`wherem at least about 95% by weight of the core is a linear
`or cross-linked poly(allylamine) or a pharmaceutically
`acceptable salt thereof, wherein the moisture content of the
`poly(a.llylamine) is from about 5% to about 9% by weight,
`wherem the hardness of the tablet is at least about 150 N and
`wherein the friability of the tablet is no more than 0.8%.
`19 . . A tablet comprising a core and a coating therefor,
`wherem the core comprises 98% by weight sevelamer
`hydrochloride with a moisture content of 6% by weight, 1 %
`by weight colloidal silicon dioxide and 1 % by weight stearic
`acid, and wherein the coating is a mixture comprising 38.5%
`w/w low viscosity hydroxypropylmethylcellulose, 38.5%
`high viscosity hydroxypropylmethylcellulose and 23% w/w
`diacetylated monoglyceride.
`* * * * *
`
`6