United States Patent [19]
`Denton
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,837,031
`Jun. 6, 1989
`
`[54] COMPOSITIONS CONTAINING
`IBUPROFEN
`Larry -E. Denton, Collinsville, Ill.
`Inventor:
`[75]
`[73] Assignee:
`Mallinckrodt, Inc., St. Louis, Mo.
`· [21] Appl. No.:
`97,850
`[22] Filed:
`Sep. 17, 1987
`[51]
`Int. Cl.4 ................................................ A61K 9/14
`[52] U.S. Cl ..................................... 424/464; 424/465;
`424/490; 424/492; 424/494; 424/497
`[58] Field of Search ............... 424/464, 465, 490, 492,
`424/494, 497; 514/568
`References Cited
`U.S. PATENT DOCUMENTS
`4,036,948 7/1972 Kitamori et al. .................... 424/492
`4,439,453 3/1984 Vogel .................................. 424/494
`4,555,399 11!1985 Hsiao ................................... 424/497
`4,562,024 12/1985 Rogerson ............................ 514/562
`4,609,675 9/1986 Franz .................................. 514/568
`4,661,521 4/1987 Salpekar et al. .................... 514/613
`
`[56]
`
`Primary Examiner-William R. Dixon, Jr.
`Assistant Examiner-David M. Brunsman
`Attorney, Agent, or Firm-Rogers, Howell, Moore &
`Haferkamp
`
`ABSTRACT
`[57]
`A granular composition containing 2-(4-isobutyl(cid:173)
`phenyl)propionic acid (ibuprofen.) as an active anti-in(cid:173)
`flammatory pharmaceutical ingredient as a major com(cid:173)
`ponent, together with carboxymethylcellulose, a lubri(cid:173)
`cant and water as minor components, is disclosed. Parti(cid:173)
`cles of ibuprofen and carboxymethylcellulose are both
`fluidized and coated with an aqueous disperson of a
`starch binder. After being dried to a moisture level of
`about 1-5% and blended with a lubricant and additional
`carboxymethylcellulose, the resulting granules can be
`directly molded into a pharmaceutically acceptable
`tablet having high hardness, short disintegration time
`and fast dissolution rate.
`
`25 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 001
`
`

`

`1
`
`4,837,031
`
`COMPOSITIONS CONTAINING IBUPROFEN
`
`2
`weight percent may be included along with carboxy(cid:173)
`methylcellulose as binders and disintegrants. The
`amount of disintegrants is sufficient to impart excellent
`dissolution and disintegration characteristics to tablets
`5 made therefrom,
`the pharmaceutically acceptable
`(c) optionally,
`binder of povidone in an amount of about 0.1-3.0
`weight percent sufficient to impart suitable binding
`properties to tablets made from the composition,
`(d) a pharmaceutically acceptable lubricant in an
`effective amount of about 0.1-3.0 weight percent for
`imparting sufficient mold release properties to tablets
`made from the composition, and
`(e) water in an effective amount of about 1.0-5.0
`weight percent.
`The dosage of the ibuprofen active ingredient will
`normally range from about 100 to about 300 mg per
`tablet made from the composition of the present inven-
`tion.
`.
`It is important that the arrangement of the ingredients
`of the compositions of.the resulting granules be
`acheived by a fluid bed granulation-drying technique
`involving the steps of:
`(a) charging the ibuprofen and a portion of the cellu(cid:173)
`losic disintegrant to a fluid bed granulator-dryer,
`(b) fluidizing the ibuprofen and cellulose disintegrant
`until thoroughly blended,
`(c) dispersing pregelatinized starch and water with a
`high sheer mixer to form a dispersion having from about
`5 to about 15 weight percent solids,
`(d) spraying the starch dispersion onto the fluidized
`bed of active ingredient and cellulose disintegrant at a
`rate sufficient to maintain the fluidized bed moisture
`between 5 to about 20 percent by weight,
`(e) continuing drying after all the dispersion has been
`sprayed to reach a bed moisture of about 5 percent by
`weight or less,
`(f) stopping the fluidization,
`(g) transferring the dried product of the fluidization
`to a blender,
`(h) adding an lubricant to the blender, and
`(i) blending the lubricant onto the fluidized composi(cid:173)
`tion.
`
`BACKGROUND OF THE INVENTION.
`1. Field of the Invention
`The present invention relates to new and useful table(cid:173)
`table pharmaceutical compositions and methods of mak(cid:173)
`ing the same. More particularly, the present invention
`relates to new and useful granular compositions con(cid:173)
`taining ibuprofen which are eminently suitable for 10
`forming into tablets and methods for preparing such
`compositions using a fluidized bed apparatus.
`2. Description of Prior Art
`Ibuprofen, the generic name for 2-(4-isobutylphenyl)(cid:173)
`propionic acid, is a well known anti-inflammatory drug 15
`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 capsules.
`U.S. Pat. No. 4,609,675 discloses a method of preparing 20
`a pharmaceutical ibuprofen-containing grauulate com(cid:173)
`position suitable for preparing tablets of relatively high
`dosage. This is accomplished by dry mixing ibuprofen
`with croscarmellose sodium NF (cross-linked sodium
`carboxymethylcellulose) in certain relative amounts, 25
`passing the resulting mixture through a roller compac(cid:173)
`tor or slugging the composition and thereafter applying
`a size to the resulting compacted or slugged product.
`Acetaminophen, the generic name for N-acetyl-p(cid:173)
`aminophenol, is a wei, known analgesic drug and is 30
`disclosed in U.S. Pat. No. 2,998,450.
`U.S. Pat. No. 4,661,521 discloses a method of prepar(cid:173)
`ing a pharmaceutical acetaminophen-containing granu(cid:173)
`late composition suitable for shaping into tablets. This is
`accomplished by using a fluid bed granulator-dryer 35
`involving spraying an aqueous slurry of a portion of a
`pregelatinized starch onto a fluidized composition of
`acetaminophen and thereafter drying the same. A lubri(cid:173)
`cant may be added during or after drying.
`· Ibuprofen-containing granules having good com- 40
`pressibility properties to form tablets is a desideratum of
`long standing. Heretofore, when granules of ibuprofen
`are compressed to insure good crumbling resistance, the
`dissolution rate of the tablets is slower than desired.
`
`45
`
`SUMMARY OF THE INVENTION
`Briefly, the present invention provides a new free(cid:173)
`flowing pharmaceutical dry granules containing ibu(cid:173)
`profen. The granules are suitable for directly shaping
`into tablets having excellent compressibility properties 50
`such that tablets compressed from the granules have
`good resistance to crumbling without significant sacri(cid:173)
`fice of the dissolution rate of the tablet.
`The present invention also provides a method of
`preparing a free-flowing particulate composition capa- 55
`ble of being directly formed into a tablet having high
`hardness, short disintegration time, and fast dissolution
`rate without being unacceptably friable.
`The composition comprises as components thereof:
`(a) the pharmaceutically active ingredient of ibu- 60
`profen in an amount of about 50 to 85 weight percent
`based on the total weight of the final composition,
`(b) the pharmaceutically acceptable cellulosic disinte(cid:173)
`grant of an internally cross-linked alkalai (sodium) car(cid:173)
`boxymethylcellulose in an effective amount of about 65
`1-5 weight percent. Additionally, a pharmaceutically
`acceptable pregelatinized starch of about 10-25 weight
`percent and a microcrystalline cellulose of about 6-18
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The ibuprofen component is preferably provided in a
`powder or other finely divided form. The ibuprofen
`powder should be of high purity of greater than 99%.1t
`has been found that when more than 30% by weight of
`the ibuprofen powder is larger than 60 mesh (U.S. Stan(cid:173)
`dard Siev(e), then the compressibility of the granules is
`adversely affected. For use in the present invention
`preferably all of the ibuprofen powder should pass
`through a 60 m~sh screen, more preferably 95% will
`pass through an 100 mesh screen. The particle size of
`the ibuprofen powder is about 15-60 microns.
`The internally cross-linked alkalai carboxymethylcel(cid:173)
`lulose component of the directly tabletable composition
`of the present invention may be obtained from any well
`known manufacturer such as, for example, FMC Cor(cid:173)
`poration of Philadelphia, Pennsylvania. Sodium carbox(cid:173)
`ymethylcellulose is a cellulose ether produced by react(cid:173)
`ing alkali cellulose with sodium monochloroacetate
`under rigidly controlled conditions. This cellulosic ma(cid:173)
`terial in solid pharmaceutical compositions aids in the
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 002
`
`

`

`4,837,031
`
`4
`not more than 1.5, more preferably about 1.0 dry weight
`percent of the composition.
`A preferred embodiment or the present invention
`includes the following componenets in the amounts
`indicated.
`
`3
`dissolution rates and disintegration characteristics and
`must meet all of the NF requirements for such material.
`The pregelatinized starch may be obtained from any
`well known manufacturer such as, for example, the
`National Starch Corporation. Pregelatinized starches 5
`useful in the present invention should meet all the NF
`requirements for such starches.
`Povidone may be included as an optionally additional
`binder and is a polymer of vinylpyrrolidone and is pro(cid:173)
`duced commercially as a series of products having mean 10
`molecular weights ranging from about 10,000 to
`700,000. Povidone is also readily available from various
`manufacturers as a pharmaceutical excipient.
`The lubricant component may be any suitable phar(cid:173)
`maceutically acceptable lubricant, which may be, e.g., 15
`hydrophilic or hydrophobic. This component is present
`in a lubricating amount at least sufficient to impart mold
`release properties to tablets formed from the composi(cid:173)
`tions and preferably insufficient to increase disintegra(cid:173)
`tion and dissolution time of such tablets, and preferably 20
`insufficient to decrease the hardness of tablets formed
`from compositions of this invention containing lower
`lubricating amounts of the same lubricant.
`Suitable lubricants for use as the lubricating compo- 25
`nent include, for example, stearic acid, metal stearates,
`such as sodium, calcium, magnesium and zinc stearate
`etc., sodium lauryl sulfate, polyethylene glycol, hydro(cid:173)
`genafed vegetable oils, talc and compressible mixtures
`of two or more such materials. Stearic acid and calcium 30
`stearate, singly or in combination, are preferred.
`In general the lubricant may be present in an amount
`from about 0.1 to about 3.0 percent, more preferably
`from about 0.5 to 1.5 percent, and most preferably about
`1 percent, based on the total dry we;ght of the composi- 35
`tion.
`The composition also includes water in an amount
`effective for aid in direct tablet formation. Such an
`effective amount is generally found to be between about
`1.0 to 5.0 percent based on the total weight of the com- 40
`position, preferably from about 2.3 to 3.3 percent on the
`same basis.
`To increase the shelf life of the tablets, the composi(cid:173)
`tion may also contain an effective amount of a preserva(cid:173)
`tive. Suitable preservatives include methyl paraben 45
`which is the methyl ester of parahydroxybenzoic acid
`and propyl paraben which is the propyl ester of parahy(cid:173)
`droxybenzoic acid. Both of these esters are known sub(cid:173)
`stances for preventing microbial contamination. While
`the preservatives may be added during any stage in the so
`preferred that any preservative be added during the
`spraying step.
`Optionally, the composition may further include a
`pharmaceutically acceptable compressibility-promoting
`binder as an additional binding agent in the amount 55
`effective for increasing the obtainable hardness of tab(cid:173)
`lets formed from the composition. Materials suitable for
`use as the optionally included binding agents include,
`for example, starch paste, polyvinylpyrrolidone, hy(cid:173)
`droxypropylmethylcellulose, hydroxypropylcellulose, 60
`gelatin, microcrystalline cellulose, natural gums, e.g.,
`gum acacia, gum tragacanth, etc., sucrose, mannitol,
`ethylcellulose, synthetic polymer binders, used in the
`industry and compatible mixtures of two or more of the
`materials. Polyvinylpyrrolidone (PVP) is preferred 65
`(more preferably PVP @K-90). In general, such an
`effective amount of optional binder is from about 0.5 or
`less to about 2.5 or more dry weight percent, preferably
`
`TABLE 1
`
`Component
`
`Approximate Amount
`
`Active
`carboxymethylcellulose
`Additional binders/disintegrants
`Lubricant
`
`50-85
`1-5
`10-45
`0.1-3.0
`
`The amounts shown in Table 1 are in parts per 100
`parts on a dry bases of the granular composition.
`The best embodiment composition of the invention
`contemplated at the time of executing this patent appli(cid:173)
`cation is as follows, wherein the amount given are in
`parts per 100 parts by weight on a dry bases of the
`granular composition.
`TABLE2
`Approximate Amount
`
`Component
`
`Ibuprofen
`Na carboxymethyl(cid:173)
`cellulose
`Pregelatinized starch
`Microcrystalline
`cellulose
`Lubricant
`Povidone
`Preservative
`
`63.0
`3.0
`
`17.4
`15.0
`
`1.0
`0.5
`0.1
`
`In general, the just mentioned composition can be
`repeatedly formed into tablets having a hardness of 5 kp
`or more and having a disintegration rate of 5 minutes or
`less.
`In use, the granular compositions of the present in(cid:173)
`vention advantageously may be built to include other
`active ingredients and/or other excipients. The addi(cid:173)
`tional substances may be added either prior to compos(cid:173)
`iting the components to form the granular composition
`or after the composition is formed (e.g., by dry blending
`the built granules with such ingredients). Thereafter,
`the composition may be directly compressed into tablets
`having eminently suitable values of hardness and disin(cid:173)
`tegration rates for a variety of end use applications
`including the formation of tablets and capsules.
`The compositions of the present invention are prefer(cid:173)
`ably made by the method mentioned above, which in(cid:173)
`cludes the use of a fluidized bed granulator-dryer. A
`suitable sized fluidized bed granulator-dryer is charged
`with ibuprofen and a portion of the cellulosic disinte(cid:173)
`grant. The amount of cellulosic material added is from
`about 1 to about 5 percent by weight based on the total
`weight of the composition. Preferably, about 1.5 per(cid:173)
`cent of the cellulosic material is charged to the fluidized
`bed. The substances added to the granulator-dryer ini(cid:173)
`tially are fluidized until they are thoroughly blended. A
`second portion of the cellulosics is dispersed in water to
`yield a slurry of between about 5 and about 15 weight
`percent solids, using a high sheer mixer. Other compo(cid:173)
`nents, if desired, may be added either to the dry blend or
`to the slurry, as needed. The resulting dispersion is then
`sprayed onto the fluidized bed of ibuprofen and the
`cellulosic material at a rate sufficient to maintain a bed
`moisture between about 5 and 20 weight percent and
`preferably between about 10 and about 16 percent by
`weight. After complete addition of the dispersion to the
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 003
`
`

`

`4,837,031
`
`6
`1) from the following components given on a dry
`weight percent basis.
`
`components
`
`TABLE 3
`Approximate Amounts, %
`
`Ibuprofen
`Povido-ne K-90 USP
`Pregelatinized Starch USP
`Na carboxymethylcellulose
`Corn starch
`Calcium hydrogen phosphate
`Magnesium stearate
`
`55.5
`0.5
`3.5
`3.0
`18.0
`19.0
`0.5
`
`The batch size exclusive of added water was 1.0 kg.
`The composition was dried to a final moisture content
`of 2.4 percent.
`· The granular composition was directly formed into
`tablets of 9.5 mm diameter, which had the physical
`properties as set forth in Table 4 below.
`TABLE4
`
`Properties
`
`Tablet weight
`Tablet hardness
`Maximum hardness
`Tablet disintegration time
`Tablet ·dissolution time (T 80)
`Tablet friability
`
`Values
`
`361 mg
`12.8 kp
`18.3 kp
`2 min. 20 sec.
`<10 min
`0.4%
`
`EXAMPLE2
`Using the procedure described above, a directly ta(cid:173)
`bletable granular composition was prepared as in Exam(cid:173)
`ple 1 from the following components given on a dry
`weight percent basis.
`
`Components
`
`TABLE 5
`Approximate Amounts
`
`Ibuprofen
`Pregelatinized starch USP
`Calcium hydrogen phosphate
`Na carboxymethylcellulose
`Magnesium stearate
`Methyl paraben
`Propyl paraben
`
`55.5
`18.0
`24.0
`1.8
`0.5
`0.16
`0.04
`
`25
`
`5
`fluid bed, the fluidization is continued until the bed
`moisture has been reduced to about 2 to about 5 percent.
`The fluidization is then halted. After the fluidization is
`terminated, the material is sized to the desired propor(cid:173)
`tionate dimensions by using suitable equipment such as. 5
`a Glatt Quick Sieve TM or Stoke's Granulator TM . A
`lubricant is blended with the suitably sized granules
`using a suitable blending device, such as a double-cone
`blender which is preferred.
`The fluidized bed granulator-dryer may be operated 10
`under the following conditions: a stream of heated air is
`introduced from the bottom of the fluid bed at a suffi(cid:173)
`cient velocity and force to fluidize the powder bed of
`ibuprofen and cellulosic disintegrant and at a tempera(cid:173)
`ture sufficient to heat the powder bed to between about 15
`20• C. and about so• C. The air velocity, inlet air tem(cid:173)
`perature and the powder bed temperature are depen(cid:173)
`dent on the batch size, dew point of air, and spray rate
`of the binder solution during the granulatio phase and
`therefore are adjusted accordingly. The particle size of 20
`the bed material is influenced by the atomization pres(cid:173)
`sure used to spray the granulating dispersion, as well as
`by the moisture level of the fluid bed during the granu(cid:173)
`lation stage. By adjusting operating parameters, the
`desired particle size and size distribution of the granules
`can be obtained. If needed, further sizing of the dry
`granules to obtain a narrow particle size distribution
`may be achieved by using a Glatt Quick Sieve or other
`suitable sizing equipment. The built granules preferably 30
`will have a particle size of about 140-225 microns.
`The term "direct tableting" and terms of like import,
`as used herein, means that the composition can be
`formed into a tablet using conventional tablet-forming
`apparatus and processes without the need for addition 35
`of any adjuvant material to the composition. As used
`herein the term "kp" means kilo ponds, a well known
`unit of force for expressing hardness or crushing
`strength of pharmaceutical tablets, when such hardness
`is determined on a Schleuniger Tablet Hardness Tester. 40
`The following examples and tables illustrate the in(cid:173)
`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 45
`U.S. Pharmacoepia (hereinafter "USP") XXI for un(cid:173)
`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) "Maximum hardness" means the maximum hard(cid:173)
`ness in which the tablets are substantially free oflamina(cid:173)
`tion;
`(e) "Friability" means the friability measured on a
`Roche Friabulator for 20 tablets and 100 revolutions.
`Unless othewise indicated, all tablet hardness values
`are averages for 10 tablets and all tablet weights are
`averages obtained by weighing 20 tablets as a whole and 60
`then dividing by 20. Further, unless otherwise indi(cid:173)
`cated, tablet disintegration times were measured for
`tablets having about 9 kp hardness.
`EXAMPLE 1
`Using the procedure described above, a directly ta(cid:173)
`bletable granular composition was prepared in a fluid
`bed granulator-dryer (Aeromatic, Inc. Model STREA-
`
`The batch size exclusive of added water was 1.0 kg.
`The composition was dried to a final moisture content
`of 3.1 percent.
`The granular composition was directly formed into
`50 ablets of 9.5 mm diameter, which had the physical rop(cid:173)
`erties set forth in Table 6 below.
`TABLE 6
`
`55
`
`Properties
`
`Tablet weight
`Tablet hardness
`Maximum hardness
`Tablet disintegration time
`Tablet dissolution time (T 80)
`Tablet friability
`
`Values
`
`364 mg
`ll.8 kp
`16.3 kp
`2.8-3.2 min
`<10 min
`0.4%
`
`EXAMPLE 3
`Using the procedure described above, a directly ta-
`65 bletable granular composition was prepared in a fluid(cid:173)
`ized bed granulator-dryer (Glatt Air Technique, Inc.)
`from the following components given on a dry weight
`percent basis.
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 004
`
`

`

`7
`TABLE 7
`Charge to Fluid Bed
`
`Ibuprofen
`Pregelatinized starch NF
`Microcrystalline cellulose
`Na carboxymethylcellulose
`Dispersion
`
`4,837,031
`
`63
`13.88
`10
`1.5
`
`5
`
`Methyl paraben
`Propyl paraben
`Povidone (PVP K-90) USP
`Pregelatinized starch NF
`Charge to Blender
`0.5
`Stearic acid NF
`0.5
`Ca stearate NF
`1.5
`Na carboxymethylcellulose
`5.0
`Microcrystalline cellulose
`--------~------------------------rs
`
`0.1
`0.02
`0.5
`3.5
`
`10
`
`The batch size exclusive of added water was 452.1 kg.
`The composition was dried to a final moisture content
`of 2.8 percent and had a density of 0.51 glee. The gran(cid:173)
`ular composition was sized to the following particle size 20
`distribution using a Glatt Quick Sieve.
`TABLE 8
`Cum % Retained
`
`Mesh
`
`+20
`+60
`+100
`+200
`-200
`
`7
`49
`69
`89
`100
`
`25
`
`EXAMPLE4
`In this example the same ingredients in the same pro(cid:173)
`portions as used to form the tablets of Example 3 were 45
`physically mixed together without being subjected to
`the process of the present invention using the fluidized
`bed technique. It was found that the physical blend
`could not be tableted because of the poor flow charac-
`teristics.
`
`so
`
`8
`into a pharmaceutically acceptable tablet having high
`hardness, short disintegration time and fast dissolution
`rate comprising as components thereof:
`(a) from about 50 to about 85 percent, based on the
`dry weight of the composition, of ibuprofen;
`(b) from about 1 to about 5 percent based on the dry
`weight of the composition, of an internally cross(cid:173)
`linked alkali carboxymethylcellulose;
`(c) a pharmaceutically acceptable lubricant in an
`amount of at least sufficient to impart effective
`mold release properties to the tablet;
`(d) cellulose and starch binders and disintegrants; and
`(e) water,
`said composition having been prepared in a fluidized
`bed granulator-dryer by a process which comprises
`spraying an aqueous dispersion of a starch binder
`onto a fluidized powder comprising ibuprofen and
`a portion of the said carboxymethylcellulose, dry(cid:173)
`ing the resulting granules to a moisture level of
`from about 1 to about 5 percent based on the total
`weight of the composition; and thereafter blending
`a lubricant and the remaining portion of the said
`carboxymethylcellulose with the dry granules.
`2. A tablet shaped from the composition of claim 3.
`3. The composition of claim 3 wherein the blending is
`· carried out using a double-cone blender.
`4. The composition of claim 3 wherein the lubricant is
`calcium stearate and comprises about 0.1 to 3.0 percent
`based on the dry weight of the composition.
`The granular campo ,[tion was directly formed into 30
`5. The composition of claim 7 wherein the aqueous
`tablets of 10.3 mm diameter, which had the tablet physi(cid:173)
`spray contains a second pharmaceutically acceptable
`cal properties as setforth in Table 9 below.
`compressibility-promoting binder in an amount effec(cid:173)
`TABLE9
`tive for further increasing the obtainable hardness of
`_ _ _ P_ro~p-er_ti_es;..._ _ _ _ _ _ _ _ _ _ _ v....:a;;;lu:..:e;;;s _ _ _ 35 tablets formed from such composition.
`6. The composition of claim 8 wherein the second
`324 mg
`Tablet weight
`binder is povidone.
`Tablet hardness
`6.6 kp
`Maximum hardness
`6.6 kp
`7. The composition of claim 1 wherein the initially
`Tablet disintegration time
`2 min
`< 10 !nin
`fluidized powder contains a second pharmaceutically
`Tablet dissolution time (T 80)
`_ _ _ T_ab_l_et_f_ria....:b....:il;.;;ity:...._ _ _ _ _ _ _ _ _ .;.;o . .:..5'!'<....:o _ _ _ 40 acceptable compressiiility-promoting binder
`in an
`amount effective for further increasing the hardness of
`tablets formed from such composition.
`8. The composition of claim 10 wherein the second
`binder is pregelatinized starch.
`9. A method of building free-flowing particulate ibu(cid:173)
`profen-containing granules capable of being directly
`molded into a pharmaceutically acceptable tablet hav(cid:173)
`ing high hardness, short disintegration time, and fast
`dissolution rate comprising:
`(a) fluidizing a finely divided powder of ibuprofen
`and an internally cross-linked alkali carboxy(cid:173)
`methylcellulose, each component having a particle
`size of about 15 to about 60 microns;
`(b) during the fluidization, spraying the fluidized
`powder with an aqueous dispersion of a pharma(cid:173)
`ceutically acceptable compressiblilty-promoting
`binder in an amount effective for increasing the
`obtainable hardness of tablets made from the result(cid:173)
`ing composition;
`(c) ceasing the spraying;
`(d) continuing the fluidization until the thus-built
`granules have a moisture content of about 2.0 to 5.0
`weight percent water based on the total weight of
`the composition;
`(e) ceasing the fluidization; and
`(f) blending the dried granules with a pharmaceuti(cid:173)
`cally acceptable lubricant in an amount at least
`sufficient to impart effective mold release proper-
`
`EXAMPLE 5
`In this example the procedure described in Example
`IV of U.S. Patent 4,661,521 was followed except that
`instead of using acetaminophen as the active ingredient, 55
`ibuprofen was used. It was found that tablets made from
`the ibuprofen-containing granules had inferior dissolu(cid:173)
`tion and disintegration characteristics as compared to
`tablets made from the acetaminophen-containing gran(cid:173)
`ules. Furthermore, tablet lubrication is very poor with 60
`the ibuprofen granules.
`It is understood that the foregoing detailed descrip(cid:173)
`tion is given merely by way of illustration and that
`many modifications may be made therein without de(cid:173)
`parting from the spirit or scope of the present invention. 65
`What is claimed is:
`1. A free flowing particulate ibuprofen-containing
`granular composition capable of being directly molded
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 005
`
`

`

`4,837,031
`
`9
`ties to tablets made from the resulting granules and
`with additional carboxymethylcellulose, whereby
`free-flowing granules having a particle size of
`about 140-225 microns are produced and being
`capable of being directly formed into pharmaceuti- 5
`cally acceptable tablets.
`10. The process of claim 9 wherein the blending is
`carried out using a double-cone blender.
`11. The process of claim 9 wherein the lubricant is
`stearic acid and comprises about 0.1 to 3.0 percent based 10
`on the dry weight of the granules.
`12. The process of claim 9 wherein the lubricant is
`calcium stearate and comprises aboiut 0.1 to 3.0 percent
`based on the dry weight of the granules.
`13. The process of claim 1 the aqueous spray disper- 15
`sion contains a second pharmaceutically acceptable
`compressibility-promoting binder in an amount effec(cid:173)
`tive for further increasing the obtainable hardness of
`tablets formed from the granules.
`14. The process of claim 1 wherein the second binder 20
`is povidone.
`15. The process of claim 9 wherein both the initially
`fluidized powder contains a second pharmaceutically
`acceptable compressibility-promoting binder ·in an
`amount effective for increasing the hardness of tablets 25
`formed from the granules.
`16. The process of claim 13 wherein the second
`binder is pregelatinized starch.
`17. The process of claim 9 wherein a preservative is
`addded during the spra:, ing step in an amount sufficient 30
`to minimize microbial contamination of tablets made
`from the granules.
`18. The process of claim 17 wherein the preservative
`is a lower alkyl ester of parahydroxybenzoic acid.
`19. The process of claim 18 where in the alkyl moeity 35
`of the preservative is C1-Cs alkyl.
`20. A method of building a free-flowing particulate
`ibuprofen-containing granules capable of being directly
`molded into a pharmaceutially acceptable tablet having
`high hardness, short disintegration time, and fast disso- 40
`lution rate comprising:
`(a) fluidizing a dry finely divided powder of ibu(cid:173)
`profen together with a pharmaceutically accept(cid:173)
`able binder composed of a mixture on internally
`cross-linked sodium carboxymethylcellulose, pre- 45
`gelatinized starch and microcrystalline cellulose,
`each ingredient of which having a particle size of
`about 15 to about 60 microns.
`(b) during the fluidization; spraying the fluidized
`powder with an aqueous dispersion containing a SO
`pharmaceutically acceptable binder composed of a
`
`10
`mixture of pregelatinized starch and povidone and
`a lower alkyl ester of parahydroxybenzoic acid as a
`pharmaceutically acceptable preservative;
`(c) ceasing the spraying;
`(d) continuing the fluidization until the intermediate
`built granules have a moisture content of about 2.0
`to about 5.0 weight percent water based on the
`total weight of the composition;
`(e) ceasing the fluidization;
`(f) blending the intermediate built granules with a
`lubricant, additional internally cross-linked sodium
`carboxymethylcellulose and microcrystalline cellu(cid:173)
`lose as a mixture of binders;
`(g) the binders present in the intially fluidized powder
`and the aqueous dispersion and added during
`blending being present in an amount effective for
`increasing
`the obtainable hardness of tablets
`molded from the ultimate granules;
`(h) the lubricant being present in an amount sufficient
`to impart effective mold release properties to tab(cid:173)
`lets molded from the ultimate granules;
`(i) the preservative being present in an amount suffi(cid:173)
`cient to minimize microbial contamination of tab(cid:173)
`lets molded from the ultimate granules;
`whereby free-flowing granules having a particle size
`of about 140-225 microns are built and being capa(cid:173)
`ble of directly molded into pharmaceutically ac(cid:173)
`ceptable tablets with an ibuprofen dosage of about
`100 to about 300 mg.
`21. The process of claim 20 wherein the internally
`cross-linked sodium carboxymethylcellulose composes
`about 3 weigl).t percent of the ultimate granules and
`having been incorporated in the initially fluidized pow(cid:173)
`der and in the composition added during blending in
`approximately equal amounts.
`22. The process of claim 22, wherein the ultimate
`granules on a dry basis comprises about 63% ibuprofen,
`about 17% pregelatinized starch, about 15% microcrys(cid:173)
`talline cellulose, 3% internally corss-linked sodium car(cid:173)
`boxymethylcellulose, about 1% lubricant, about 0.5%
`povidone and about 0.1% lower alkyl ester of parahy(cid:173)
`droxybenzoic acid.
`23. The process of claim 22 wherein the ester of para(cid:173)
`hydroxybenzoic acid is a mixture of methyl and ethyl
`esters.
`24. The composition of claim 3 wherein the lubricant
`is stearic acid and comprises about 0.1 to 3.0 percent
`based on the dry weight of the composition.
`25. The composition of claim 3 wherein the lubricant
`is a mixture of stearic acid and calcium stearate.
`* * * * *
`
`55
`
`60
`
`65
`
`Par Pharm., Inc.
`Exhibit 1032
`Page 006
`
`