United States Patent [19]
`Denton et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,911,921
`Mar.27, 1990
`
`[54] HIGH IBUPROFEN CONTENT
`GRANULATIONS
`
`[75]
`
`Inventors; Larry E. Denton, Collinsville, Ill.;
`Anil M. Salepkar, St. Louis, Mo.
`
`[73] Assignee; Mallinckrodt, Inc., St. Louis, Mo.
`
`[21] Appl. No.; 306,014
`
`[22] Filed;
`
`Feb. 2, 1989
`
`[51]
`Int. Cl,4 ..................... A61K 31/74; A61K 31/79;
`A61K 9/26; A61K 9/36
`[52] u.s. Cl •........................................ 424/80; 424/78;
`424/482; 424/479; 424/480; 424/470; 514/570
`[58] Field of Search ................... 424/80, 78, 482, 479,
`424/480,470; 514/570
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,108,046 10/1963 Harbit ................................. 514/165
`4,209,513 6/1980 Torode et al ....................... 424/228
`4,609,675 9/1986 Franz .................................. 514/568
`4,661,521 4/1987 Salpekar et al ..................... 514/613
`4,753,801 6/1988 Oren et al ............................. 424/80
`4,757,090 7/1988 Salepkar eta!. .................... 514/613
`4,806,359 2/1989 Radebaugh et al ................. 424/470
`
`FOREIGN PATENT DOCUMENTS
`0172014 2/1986 European Pat. Off ............. 514/570
`
`OTHER PUBLICATIONS
`GAF Corp. "Tableting with Plasdone ® Povidone
`USP" 1981.
`Primary Examiner-Joseph L. Schafer
`Assistant Examiner-Carmen Pili-Curtis
`Attorney, Agent, or Firm-Grace L. Bonner; Roy J.
`Klostermann
`. [57]
`ABSTRACf
`A granular pharmaceutical composition containing 85
`to 99 percent ibuprofen, 0.9 to 15.0 percent binder, and
`0.1 to 5.0 percent polyvinylpyrrolidone, wherein the
`polyvinylpyrrolidone forms a film with a portion of said
`binder to form agglomerates, is disclosed. Ibuprofen
`may be fluidized with a portion of the binder in a fluid
`bed apparatus and sprayed with an aqueous dispersion
`of polyvinylpyrrolidone and the remainder of the
`binder. This granulation may be subsequently blended
`with additional excipients and, optionally, additional
`active pharmaceutical ingredients for direct compres(cid:173)
`sion into tablets.
`
`8 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1010
`Page 001
`
`

`

`1
`
`4,911,921
`
`2
`pyrrolidone (PVP) in a film-forming amount, and (d)
`moisture up to 2.0 percent of the total weight. This
`granulation is in the form of agglomerates of ibuprofen
`and dry binder held together in some manner by the
`5 binder and PVP.
`Formulations of this granuation are capable of being
`used in a wide variety of dosage forms such as com(cid:173)
`pressed tablets and dosage sizes ranging from 100 to
`1200 mg per unit, and may contain other active ingredi(cid:173)
`ents. They are particularly suited for preparing tablets
`having 800 or more mg ibuprofen per unit.
`In another aspect, this invention provides for a
`method of preparing the granulation just described by a
`wet granulation method, i.e., fluid bed granulation. The
`method follows the steps of
`(a) charging the ibuprofen and a portion of the binder
`to a fluid bed granulator-dryer,
`(b) fluidizing the ibuprofen and binder until thor(cid:173)
`oughly blended,
`(c) dispersing the remaining binder and the PVP in
`water using a high shear mixer to form a slurry having
`from about 5 to 10 percent by weight solids,
`(d) spraying the binder/PVP dispersion onto the
`fluidized bed of ibuprofen and binder at a rate sufficient
`to maintain the powder bed moisture between about 5
`and about 20 percent by weight,
`(e) continuing drying until the moisture level of the
`bed is 2.0 percent or less, and
`(f) optionally, sizing the material to the desired parti(cid:173)
`cle size distribution.
`
`HIGH IBUPROFEN CONTENT GRANULATIONS
`
`FIELD OF THE INVENTION
`The present invention relates to pharmaceutical ibu(cid:173)
`profen compositions and wet granulation methods of
`preparing them. More particularly, the invention relates
`to new granular compositions containing high levels of
`ibuprofen which are eminently suitable for subsequent
`blending with lubricants, binders, disintegrants, and, 10
`optionally, additional pharmaceutical active ingredi(cid:173)
`ents, for tabletization.
`
`20
`
`BACKGROUND OF THE INVENTION
`Ibuprofen, the generic name for 2-(4-isobutylphenyl)- 15
`propionic acid, is a well known anti-inflammatory drug
`and is disclosed in U.S. Pat. Nos. 3,228,831 and
`3,385,886. Normally, ibuprofen is formulated for sale to
`the consumer in the form of compressed tablets or cap-
`sules.
`Previously known compositions produced by a wet
`granulation method have required relatively large per(cid:173)
`centages of excipients to produce a compressible formu(cid:173)
`lation. This lowers the maximum level of ibuprofen that
`can be contained in the formulation. This in tum in- 25
`creases the size of the tablet formed from such a formu(cid:173)
`lation, especially a problem for the higher dose level
`tablets, such as 800 or 1200 mg units. This increased size
`is undesirable both from a manufacturing and handling
`standpoint and a patient acceptability standpoint. There 30
`has been a need, therefore, for higher active ingredient
`levels in compressible formulations.
`U.S. Pat. No. 4,609,675 discloses a method of prepar(cid:173)
`ing a pharmaceutical ibuprofen-containing granulate
`composition suitable for preparing tablets of relatively 35
`high dosage. This is accomplished by dry mixing ibu(cid:173)
`profen with 1 to 15 percent by weight croscarmellose
`sodium NF (cross-linked sodium carboxymethylcellu(cid:173)
`lose). This dry granulation method meets this need
`described above, but uses a relatively expensive addi- 40
`tive to accomplish it. Croscarmellose sodium NF is used
`at levels up to 15 percent, preferably about 7 to 8 per(cid:173)
`cent. This contributes significantly to the cost of the
`formulation.
`It is an object of the present invention to provide an 45
`ibuprofen granulation formulation having a high level
`of active ingredient and which can be ultimately table-
`tized by direct compression.
`·
`It is a further object of the present invention to pro(cid:173)
`vide an ibuprofen granulation that can be formulated 50
`with additional excipients, and, optionally other active
`ingredients, and compressed into tablets having high
`hardness, short disintegration time, and fast dissolution
`rate without being unacceptably friable.
`It is a still further object of the invention to provide a 55
`wet granulation method that produces a granulation
`formulation having a high ibuprofen content.
`
`DESCRIPTION OF THE INVENTION
`Generally stated, the present invention provides a 60
`free-flowing, high-ibuprofen content granulation capa(cid:173)
`ble of being blended with external excipients to produce
`a formulation capable of being directly formed into a
`tablet having high hardness, short disintegration time
`and short dissolution time. This granulation has as com- 65
`ponents (a) ibuprofen in an amount of about 85 percent
`or more on a dry weight basis, (b) a pharmaceutically
`acceptable binder in a binding amount, (c) polyvinyl-
`
`DETAILED DESCRIPTION OF THE
`INVENTION AND THE MANNER AND
`PROCESS OF MAKING AND USING IT
`The binder used in the present granulation can be
`selected from those known in the art to be suitable for
`use in directly compressible pharmaceutical formula(cid:173)
`tions. Examples of these are starches, celluloses, and
`sugars. More specifically the binder may be pregelati(cid:173)
`nized starch, microcrystalline cellulose, lactose, or corn
`starch. Pregelatinized starch NF is preferred.
`Polyvinylpyrrolidone, also known as povidone or
`PVP, is available in various forms from various suppli(cid:173)
`ers. A wide range of molecular weights are available.
`The higher molecular weight products, 600,000 Daltons
`and above (K values of 90 or greater), are preferred for
`the present invention because eutectic formation during
`storage at elevated temperatures can be a problem with
`ibuprofen-PVP formulations. Higher molecular weight
`PVP products minirnize this undesirable property. Par(cid:173)
`ticular commercial products that be used in the present
`invention are Plasdone@ K-90 and K-120 (Povidone
`U.S.P.) from GAF Corporation.
`Ibuprofen and dry binder are powdery materials,
`which by themselves do not form satisfactory tablets by
`direct compression. The PVP-binder mixture or disper(cid:173)
`sion works in the presence of water to form a film that
`agglomerates these powdery materials to form granules.
`These granules are more free-flowing than the powders
`one starts with and their compressibility is greatly en(cid:173)
`hanced. PVP is used in a film-forming amount. This
`amount is generally from about 0.1 to about 5.0 percent
`of the granulation on a dry weight basis.
`The binder component, in addition to its binding
`properties during agglomeration or granulation, is also
`an aid to the disintegration and dissolution of tablets
`made with the present granulation. The balance be-
`
`Par Pharm., Inc.
`Exhibit 1010
`Page 002
`
`

`

`4,911,921
`
`9~:~
`~~~~:f!~i~ized Starch NF
`o.s
`PVP
`_______________ __:.;.;....____
`
`60
`
`90% IBUPROFEN GRANULATION
`CALCIUM STEARATE
`STEARIC ACID
`SILICON DIOXIDE
`SODIUM STARCH GLYCOLATE
`MICROCRYSTALLINE CELLULOSE
`LACTOSE
`
`3
`tween good compression properties and good disinte(cid:173)
`gration properties is achieved by using a portion of the
`binder in a dry form and a portion in a wetted form, the
`latter working with PVP for film formation and ag(cid:173)
`glomeration.
`Thus, the binder component of the present granula(cid:173)
`tion serves to impart good binding and disintegrant
`properties as well as a good balance thereof to the final
`dosage forms prepared from the granulation, i.e., tab(cid:173)
`lets. It is included in an amount effective for imparting 10
`to the granulation and formulations made therefrom,
`the capability of being formed into tablets having high
`hardness (e.g., about 8 kp or more), short disintegration
`time (e.g., about 10 minutes or less), and short dissolu(cid:173)
`tion time (e.g., about 20 minutes or less for 80 percent or 15
`more ibuprofen to dissolve). In general, such effective
`amount of total binder in the granulation is from about
`0.9 percent to about 15 percent on a dry weight basis,
`preferably, from about 5.0 to about 10.0 percent, and
`more preferably, about 9.5 percent. In general, about 20
`half, or more preferably, slightly less than half, of the
`amount of binder is used in a dry form to aid in dissolu(cid:173)
`tion and disintegration. The remainder, preferably
`slightly more than half of the total amount is used in a
`wetted form with PVP to bind the agglomerates, impart 25
`compressibility and enhance tablet hardness.
`A preferred embodiment includes the following com(cid:173)
`ponents in the amounts indicated with a moisture con(cid:173)
`tent of 0.8 to 1.8 percent of the total weight:
`
`4
`rate of the binder solution during the granulation phase
`and therefore are adjusted accordingly. The particle
`size of the bed material is influenced by the atomization
`pressure used to spray the granulating liquid as well as
`5 by the moisture level of the fluid bed during the granu(cid:173)
`lation phase. By adjusting operative parameters, the
`desired particle size distribution for the granulation can
`be obtained. A further sizing of the dry granulation (to
`obtain a narrow particle size distribution) may be
`achieved using a Glatt Quick Sieve or other suitable
`sizing equipment. A preferred particle size distribution
`is 100 percent from 20 to 200 mesh.
`The granulation thus produced could be directly
`compressed to form tablets. However, better tablets are
`produced by blending the granulation by known meth(cid:173)
`ods, such as using a double cone blender, with addi(cid:173)
`tional excipients that aid in the compression and provide
`improved properties such as hardness and disintegration
`time. These excipients may be selected from the whole
`range known in the art and are chosen based on the
`desired properties of the tablet produced.
`It is highly desirable to add a lubricant that aids in the
`production of the tablets. Examples of such lubricants
`are stearic acid, metal stearates, sodium Iaury! sulfate,
`polyethylene glycol, hydrogenated vegetable oils and
`talc. Silicon dioxide can also be added to impart better
`mold release properties.
`Additionally, further tablet-binding agents in tablet-
`30 binding amounts can be added. Materials suitable for
`- - - - - - - - - - - - - - - - - - - - - use as the optionally included additional binder agent
`include, for example, starch (starch paste), polyvinyl(cid:173)
`(~;;c:~~)
`pyrrolidone, hydroxypropylmethylcellulose, hydroxy-
`propylcellulose, gelatin, natural gums (e.g., gum acacia,
`35 gum tragacanth, etc.), lactose, sucrose, mannitol, ethyl-
`cellulose, microcrystalline cellulose, synthetic polymer
`binders commonly used in the industry, and compatible
`The granulation of this invention is preferably made
`mixtures of two or more such materials.
`by the method mentioned above, which includes the use
`Disintegrants, such as cross-linked polyvinylpyrroli(cid:173)
`of a fluid bed granulator-dryer. A suitable sized fluid
`done (crospovidone) or sodium starch glycolate, may
`bed granulator-dryer (FBGD) is charged with the ibu- 40
`also be added in disintegrating amounts. Additional
`profen and a portion of the binder. The amount of
`water may be added to facilitate compression.
`binder added from about 0.5 to about 8 percent by
`The amounts of the added excipients are preferably
`weight based on the total dry weight of the granulation.
`the minimum amounts necessary to accomplish their
`Preferably, about 4.5 percent on the above basis is
`purposes. The lubricant component is present in a lubri(cid:173)
`charged to the fluid bed. The materials are fluidized 45
`cating amount sufficient to impart mold release proper(cid:173)
`until thoroughly blended. The remaining binder, i.e.,
`ties to tablets formed from the formulation and prefera(cid:173)
`about 0.5 to about 7 percent, which was not added to
`bly insufficient to increase disintegration time and disso(cid:173)
`the fluid bed is dispersed with the PVP in water to yield
`lution time of such tablets, and preferably insufficient to
`a slurry of between about 5 and about 10 weight percent
`decrease the hardness obtainable for tablets formed
`solids, using a high shear mixer. Preferably, about 5 50
`from a formulation having no additional lubricant. A
`percent binder is dispersed. The dispersion is then
`preferred composition for tab letting, prepared using the
`sprayed onto the fluidized bed of ibuprofen/binder at a
`preferred embodiment of the granulation as stated
`rate sufficient to maintain the powder bed moisture
`above, is shown in Table I.
`between about-5 and about 20 weight percent, and pref-
`TABLE 1
`erably between about 7 and about 14 weight percent. 55
`After complete addition of the dispersion to the fluid - - - - - - - - - - - - - - - - - - - - -
`bed, the fluidization is continued until the bed moisture
`TABLET FORMULATION
`MATERIAL
`is reduced to less than 2.0 weight percent, and prefera-
`bly from about 0.8 to about 1.8 weight percent. The
`fluidization is then terminated.
`The fluid bed granulator-dryer is operated under the
`following conditions: a stream of heated air is intro-
`duced from the bottom of the fluid bed at a sufficient
`velocity to fluidize the powder bed and at a temperature
`sufficient to heat the powder bed at between about 20' 65
`C. to about 50' C. The optimum air velocity, inlet air
`temperature and the powder bed temperature are de(cid:173)
`pendent on the batch size, dew point of air, and spray
`
`79.3
`0.8
`2.4
`0.5
`~.0
`6.5
`6.5
`
`The granulation of the present invention is also par(cid:173)
`ticularly useful in producing combination pharmaceuti(cid:173)
`cals. The high ibuprofen content and limited number of
`
`Par Pharm., Inc.
`Exhibit 1010
`Page 003
`
`

`

`4,911,921
`
`6
`EXAMPLE2
`200 and 800 mg ibuprofen tablets
`Ninety percent ibuprofen granulation, prepared as in
`Example 1, was formulated as shown in Table 1, above,
`to produce a directly compressible formulation.
`Tablets having an average of 200 or 800 mg ibuprofen
`per unit were formed. They had the physical properties
`shown in Table 2.
`
`TEST
`
`800 MG.
`
`TABLE 2
`TABLET PROPERTIES
`200 MG.
`10.2
`0.206
`0.22
`6:30
`
`100
`
`Hardness (kp)
`Thickness (inch)
`Friability(%)
`Disintegration Time
`(minutes:seconds)
`Dissolution (by USP XXI,
`Method 2)
`(% in 3o minutes)
`_....;_ _ _ _ ......;......; _ _ _ _ _ _ _ _ _ _ _ _
`
`19.2
`0.339
`0.20
`6:30
`
`97.4
`
`5
`exc1p1ents make it amenable to blending with other
`active ingredients. Examples of such active ingredients
`are antihistimines, decongestants, antitussives, and other
`analgesics, muscle relaxants, and the like.
`Tablets prepared from the present granulation formu- 5
`lations can contain from 100 to 1200 mg ibuprofen. The
`formulations are particularly helpful in preparing tab(cid:173)
`lets containing high doses of ibuprofen such as 400 mg
`or more per tablet.
`As used herein the term "KP" means kilo ponds, as 10
`well known unit of force for expressing hardness or
`crushing strength of pharmaceutical tablets; when such
`hardness is determined on a Schleuniger Tablet Hard-
`ness Tester.
`The following examples and tables illustrate the in- 15
`vention. As used herein, the following terms have the
`meanings indicated:
`(a) "Disintegration time" means the time measured
`using the disintegration time test method set forth in 20
`U.S. Pharmacopeia (hereinafter "USP") XXI for un-
`coated tablets except that the disks are not employed;
`(b) "Dissolution time" means the time measured using
`the dissolution time test method set forth in USP XXI
`for ibuprofen tablets;
`(c) "Hardness" means the hardness measured on a
`Schleuniger Tablet Hardness Tester;
`(d) "Friability" means the friability measured on a
`Roche Friabulator for 40 tablets and 375 revolutions.
`Unless otherwise indicated, all tablet hardness values 30
`are averages for 10 tablets and all tablet weights are
`averages obtained by weighing 20 tablets as a whole and
`then dividing by 20. Further, unless otherwise indi(cid:173)
`cated, tablet disintegration times were measured for
`tablets having about 9 kp hardness.
`
`25
`
`35
`
`What is claimed is:
`1. A pharmaceutical, high drug content ibuprofen
`granulation composition, comprising
`(a) about 85 to about 99 percent ibuprofen on a dry
`weight basis;
`(b) about 0.9 to about 15.0 percent pharmaceutically
`acceptable binder on a dry weight basis;
`(c) about O.lto 5.0 percent polyvinylpyrrolidone on a
`dry weight basis; and
`(d) a moisture content of 0.1 to 2.0 percent of the total
`weight;
`said granulation being in the form of agglomerates of
`ibuprofen and binder held together by binder and poly(cid:173)
`vinylpyrrolidone.
`2. A composition according to claim 1, wherein said
`binder is selected from a group consisting of starches,
`celluloses, and sugars.
`3. A composition according to claim 2, wherein said
`binder is pregelatinized starch.
`4. A composition according to claim 2, wherein said
`binder is microcrystalline cellulose.
`5. A composition according to claim 1, wherein said
`polyvinylpyrrolidone has a molecular weight average
`Percent
`_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (;,d....:ry_w_t....:.l _ _ _ 45 greater than 600,000 Daltons (a K value of 90 or
`greater).
`Ibuprofen
`90.0
`Pregelatinized Starch NF
`9
`5
`6. A composition according to claim 1, wherein said
`·
`Plasdone @ K-90, PVP U.S.P.
`0
`5
`moisture is from about 0.8 to about 1.8 percent by total
`'
`weight.
`7. A composition according to claim 1, wherein said
`polyvinylpyrrolidone is about 0.5 percent on a dry
`weight basis.
`8. A composition according to claim 1, wherein said
`ibuprofen is present at about 90 percent on a dry weight
`basis; said binder is present at about 9.5 percent on a dry
`weight basis; and said polyvinylpyrrolidone is present at
`about 0.5 percent on a dry weight basis.
`* * * * *
`
`EXAMPLE 1
`Ninety percent ibuprofen granulation
`A granulation composition having the following dry
`weight composition was prepared in a fluid bed 40
`granulator-dryer (Aeromatic, Inc., Model STREA-1):
`
`The starch was split into two parts as described 50
`above. The first part, 4.4 percent of total solids, was
`fluidized with the ibuprofen in the granulator. The sec(cid:173)
`ond part, 5.1 percent of total solids, was dispersed in
`warm water with the PVP.
`The batch size exclusive of water was 1.0 kg. After 55
`spraying, the granulation was dried to a moisture level
`of less than 2.0 percent of the total weight of the granu(cid:173)
`lation.
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1010
`Page 004
`
`