Exhibit 1012
`
`U.S. Patent No. 4,844,907 (“the ‘907 Patent”)
`
`

`
`United States Patent [19]
`Elger et al.
`
`Patent Number:
`[11]
`[45] Date of Patent:
`
`4,844,907
`Jul. 4, 1989
`
`[54] PHARMACEUTICAL COMPOSITION
`COMPRISING ANALGESIC AND
`ANTI-INFLAMMATORY AGENT
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`2,738,303 3/1956 Blythe ............................... .. 424/458
`3,950,508 4/1976 Mony et al.
`424/480 X
`
`3,558,768 1/1971 Klippel . . . . . . . .
`
`. . . .. 424/480
`
`[75] Inventors: Gordon A. Elger, Huntingdon;
`Stewart T. Leslie; Sandra T. A.
`Malkowska, both of Cambridge, all
`of United Kingdom; Ronald B.
`Miller, Basel, Switzerland; Philip J.
`Neale, Cambridge, United Kingdom
`[73] Assignee: Euroceltique, S.A., Luxembourg,
`Luxembourg
`
`[21] Appl. No_: 896,214
`
`[22] Filed:
`
`Aug. 14, 1986
`
`Foreign Application Priority Data
`[30]
`Aug. 28, 1985 [GB] United Kingdom ............... .. 8521350
`
`[51] Int. Cl.4 ....................... .. A61K 9/20; A6lK 9/24;
`A6lK 9/ 50
`[52] US. Cl. .................................. .. 424/465; 424/ 470;
`424/472; 424/475; 424/477; 424/479; 424/480;
`424/481; 424/482; 424/499; 424/500; 424/ 501;
`424/ 502
`[58]‘ Field of Search ............. .. 424/465, 470, 480, 472,
`424/475, 477, 479, 481, 482, 499, 500, 501, 502
`
`4,601,894 7/l986 Hanna et al. . . . . . . . .
`
`. . . . . . . .. 424/480
`
`4,606,909 8/1986 Bechgaard et al. .......... .. 424/480 X
`Primary Examiner—Thurman K. Page
`Attorney, Agent, or Firm—Steinberg & Raskin
`[5 7]
`ABSTRACT
`A pharmaceutical composition in the form of a multi
`phase (especially a bilayered, optionally coated) tablet.
`The tablet has a narcotic analgesic phase containing a
`therapeutically effective quantity of a narcotic analgesic
`or an analgesically effective salt thereof (e.g. codeine
`phosphate) and a non-steroidal anti-in?ammatory phase
`containing a therapeutically effective quantity of a non
`steroidal anti-in?ammatory carboxylic acid or an anti
`inflammatory salt or ester thereof (e.g. ibuprofen). The
`narcotic analgesic phase is free from a non-steroidal
`anti-in?ammatory carboxylic acid or salt or ester
`thereof, stearic acid and stearate salt, and the non-steroi
`dal anti-in?ammatory phase is free from a narcotic anal
`gesic or salt thereof, stearic acid and a stearate salt.
`Further, both the narcotic analgesic phase and the non
`steroidal anti-in?ammatory phase contain a self
`lubricating, compression aid, especially a self-lubricat
`ing, direct compression a'id, such as microcrystalline
`cellulose.
`
`13 Claims, N0 Drawings
`
`

`
`1
`PHARMACEUTICAL COMPOSITION
`COMPRISING ANALGESIC AND
`ANTI-INFLAMMATORY AGENT
`This invention relates to a pharmaceutical composi
`tion, in particular to a pharmaceutical composition for
`the relief of mild to severe pain and for the treatment of
`in?ammation in musculo- skeletal disorders.
`Narcotic analgesics, such as codeine and dihy
`drocodeine, have been used in the relief of pain, espe
`cially mild to severe pain. Severe pain, in particular,
`requires the use of large and increasing doses of a nar
`cotic analgesic.
`A major disadvantage of narcotic analgesics is that
`patients may develop a dependence and tolerance to
`their action. Further adverse reactions, such as respira
`tory and circulatory depression, are observed when
`large doses of narcotic analgesics are used.
`20
`Non-steroidal anti-inflammatory drugs, such as ibu
`profen, have been used in rheumatic and degenerative
`diseases of the joints, for reducing platelet adhesiveness
`and for dental pain.
`European Patent Application No. 68838A (Upjohn)
`describes the synergistic effect obtained for the manage
`ment of moderate to severe pain when a combination of
`narcotic analgesic and ibuprofen is administered.
`In the Examples of EP No. 68838A, tablets contain
`ing morphine, ibuprofen and magnesium stearate as
`lubricant, are disclosed. The applicant also states, at
`page 9, lines 22 to 26, that tablets containing ibuprofen
`and codeine may be prepared simply by replacing the
`morphine in the exempli?ed tablets with codeine.
`The present inventors have found that tablets con
`taining a narcotic analgesic, such as codeine, a non
`steroidal anti-in?ammatory carboxylic acid, such as
`ibuprofen, and magnesium stearate, as described in EP
`No. 68838A, exhibit serious incompatability, poor
`crushing strength and long disintegration times.
`It is therefore a primary object of the present inven
`tion to provide a tablet containing both a narcotic anal
`gesic and a non-steroidal anti-in?ammatory carboxylic
`acid which overcomes, to a substantial degree, the
`above problems.
`Other objects and advantages of the present invention
`will become apparent from the following detailed de
`scription thereof.
`According to the present invention there is provided
`a pharmaceutical composition in the form of a multi
`phase tablet comprising at least one narcotic analgesic
`phase containing a therapeutically effective quantity of
`a narcotic analgesic or an analgesically effective salt
`thereof and at least one non-steroidal anti-inflammatory
`phase containing a therapeutically effective quantity of
`a non-steroidal anti-inflammatory carboxylic acid or an
`anti-in?ammatory salt or ester thereof wherein the at
`least one narcotic analgesic phase is free from a non
`steroidal anti-in?ammatory carboxylic acid or salt or
`ester thereof, stearic acid and a stearate salt, and the at
`least one non-steroidal anti-inflammatory phase is free
`from a narcotic analgesic or salt thereof, stearic acid
`and a stearate salt, and further wherein, both the at least
`one narcotic analgesic phase and the at least one non
`steroidal anti-in?ammatory phase contain at least one
`self-lubricating, compression aid.
`Preferably the self-lubricating compression aid is a
`self-lubricating, direct compression aid.
`
`4, 844,907
`2
`Preferably the composition is in the form of a layered
`tablet, especially a bilayer tablet. Optionally the layered
`tablet may be ?lm coated.
`The narcotic analgesic may be naturally occurring,
`semi-synthetic or synthetic. Examples include pentazo~
`cine (HCl salt), pethidine (HCL salt) and phenazocine
`(HBr salt). Preferably, however, the narcotic analgesic
`is a morphinan-6-ol or a morphinan-6-one derivative,
`especially morphine (sulphate), ethylmorphine (HCl
`salt), hdyromorphone (HCl salt), hydrocodone (tar
`trate), dihydrocodeine (tartrate) and, which is particu
`larly preferred, codeine (phosphate).
`Analgesically effective salts of the narcotic analgesics
`of the present invention must be pharmaceutically ac
`ceptable.
`The non-steroidal anti-inflammatory carboxylic acid
`will generally be an aromatic or heterocyclic carboxylic
`acid. Examples include aspirin, fenbufen, flufenamic
`acid, indomethacin, meclofenamic acid (sodium salt),
`sulindac and tolmetin (sodium salt). Preferably, how
`ever, the non-steroidal anti-inflammatory carboxylic
`acid is a benzeneacetic acid, such as alclofenac, di
`clofenac (sodium salt) and fenclofenac, a Z-naphthylo
`propionic acid, such as naproxen (sodium salt), or,
`which is particularly preferred, a 2-phenylpr0pionic
`acid, such as fenoprofen (sodium or calcium salt), flurbi
`profen, indoprofen, ketoprofen and, especially, ibu
`profen.
`Anti-in?ammatory effective salts or esters of the non
`steroidal anti-inflammatory carboxylic acids of the pres
`ent invention must be pharmaceutically acceptable, e.g.
`alkali metal salt and C1-C6 alkyl esters.
`Therapeutically effective quantities of the present
`narcotic analgesics or salts thereof and non-steroidal
`anti- inflammatory carboxylic acids or salts or esters
`thereof will be suf?cient, in combination, either to re
`lieve mild to severe pain or to treat in?ammatory condi
`trons.
`Preferred therapeutically effective quantities of the
`preferred narcotic analgesics and the preferred non
`steroidal anti-inflammatory carboxylic acids of this in
`vention are listed in the Table.
`TABLE
`Therapeutically effective quantity
`Preferred
`Particularly Preferred
`Single Dose
`Single Dose
`w
`Codeine
`5-60 mg
`Dihydrocodeine
`l0-60 mg
`Ethylmorphine
`5-60 mg
`Hydrocodone
`. 5-20 mg
`Hydromorphone
`l-5 mg
`Morphine
`2-120 mg
`Pentazocine
`10-100 mg
`Pethidine
`20-150 mg
`Phenazocine
`2.5-20 mg
`Non Steroidal
`Anti-in?ammatory
`Carbox lic Acid
`Aspirin
`Alclofenac
`Diclofenac
`Fenbufen
`Fenclofenac
`Fenoprofen
`Flufenarnic acid
`Flurbiprofen
`Ibuprofen
`Indomethacin‘
`Indoprofen
`Ketoprofen
`
`60
`
`200-1000 mg
`400-1000 mg
`25-75 mg
`200-900 mg
`200-600 mg
`200-800 mg
`50-250 mg
`25-100 mg
`50-800 mg
`20-100 mg
`50-200 mg
`50-200 mg
`
`300-900 mg
`25-50 mg
`300-600 mg
`300-600 mg
`
`200-600 mg
`25-75 mg
`100-200 mg
`
`25
`
`45
`
`7.5-30 mg
`20-40 mg
`
`5-100 mg.
`
`55
`
`

`
`3
`TABLE-continued
`Therapeutically effective quantity
`Preferred
`Particularly Preferred
`Single Dose
`Single Dose
`50-200 mg
`250-1000 mg
`100-200 mg
`200-800 mg
`
`500-750 mg
`200-600 mg
`
`Meclofenamic acid-
`Naproxen
`Sulindac
`Tolmetin
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4,844,907
`4
`hydroxyethyl cellulose, starches, polyvinyl pyrrol
`idone, natural gums and gelatin,
`(b) Glidants, such as talc andfumed silica,
`(c) Anti-Adherents, such as talc, fumed silica and
`corn starch,
`(d) Disintegrants, such as starch and its derivatives,
`(e.g. sodium starch glycollate), microcrystalline
`celllose, croscamellose sodium (Ac-Di-Sol, Trade
`Mark), low substituted hydroxypropyl cellulose
`and cross-linked polyvinylpyrrolidone,
`(e) Colorants, Flavorants and Sweeteners.
`In addition to the above materials, in a further aspect
`of the present composition, the at least one non-steroi
`dal anti-in?ammatory and/or narcotic analgesic phases
`may also contain substances suitable for the formation
`of a controlled release formulation. In particular the
`phase or phases may contain a hydrated water soluble
`hydroxy alkyl cellulose, especially hydroxyethyl cellu
`lose, and a higher aliphatic alcohol, especially cetostea
`ryl alcohol, as described in British Pat. No. 1405088
`(equivalent to US Pat. No. 3,965,256 and U.S. Pat. No.
`4,235,870), the contents of which documents are herein
`incorporated by way of reference.
`Advantageously, the present multi-phase tablet may
`have, as one of its phases, a protective coating which
`may, for example, serve to mask the taste of both the
`non-steroidal anti-in?ammatory carboxylic acid or salt
`or ester thereof and the narcotic analgesic or salt
`thereof. Suitable coating materials, which must be com
`patible with both the anti-in?ammatory carboxylic acid
`or salt or ester thereof and the narcotic analgesic or salt
`thereof will be known to those skilled in this art. An
`example favoured by the present inventors uses hydrox
`ypropyl methyl cellulose as the ?lm former and propy
`lene glycol as the plasticiser.
`The precise amount of non-steroidal anti-in?amma
`tory carboxylic acid or salt or ester thereof and narcotic
`analgesic or salt thereof present in the present pharma
`ceutical composition will be determined by, amongst
`other factors,
`(a) the number of times per day the composition is to
`be administered,
`(b) whether the at least one non-steroidal anti-in?am
`matory and/or narcotic analgesic phases are a nor
`mal or controlled release formulation, and
`(c) the type of treatment required and stage of treat
`ment reached by the patient.
`For most of the therapeutic applications (e.g. treat
`ment of pain and inflammation) envisaged by the pres
`ent inventors, tablets of the present type will contain an
`amount of narcotic analgesic and non-steroidal anti-in
`?ammatory carboxylic acid as set out in the Table
`above. If a salt or ester is employed the dose will be
`adjusted accordingly to give the required amount of
`base or acid. Thus, tablets containing ibuprofen and
`codeine will preferably contain between 50 and 800 mg,
`especially between 200 and 600 mg, of ibuprofen and
`between 5 and 60 mg, especially between 7.5 and 30 mg,
`of codeine.
`The amount and/or ratio of self lubricating, compres
`sion aids, together with, as required, binders, glidants,
`anti-adherents, disintegrants, colorants, ?avor-ants,
`sweeteners, etc. contained in the present pharmaceuti
`cal composition is determined by, amongst other fac
`tors,
`(a) the amount of non-steroidal anti-in?ammatory
`carboxylic acid or salt or ester thereof and narcotic
`
`In a particularly preferred embodiment of the present
`composition the narcotic analgesic phase contains co
`deine (as its phosphate salt) and the non-steroidal anti
`inilammatory phase contains ibuprofen (as the free
`acid).
`As mentioned above, when the present inventors
`attempted to prepare narcotic analgesic/non-steroidal
`anti-in?ammatory
`carboxylic
`acid
`(especially
`codeine/ibuprofen) tablets as in EP No. 68838A they
`found that the tablets exhibited poor pharmaceutical
`qualities. This was surprisingly found to be caused pri
`marily by incompatability between the narcotic analge
`sic (codeine), the non-steroidal anti-in?ammatory car
`boxylic acid (ibuprofen) and the lubricant employed,
`magnesium stearate.
`Having made this observation, the present inventors
`then overcame these problems by an inventive combi
`nation of devices. These were
`(i) Separating the narcotic analgesic or salt thereof
`and the non-steroidal anti-in?ammatory carboxylic
`acid or salt or ester thereof in a multi-phase, prefer
`ably layered, tablet,
`(ii) Removing stearic acid and/or stearate salts (espe
`cially magnesium stearate) from the composition,
`and
`(iii) Adding at least one self lubricating, direct com
`pression aid, preferably a self lubricating, direct
`compression aid, to the mixtures used to form both
`the at least one narcotic analgesic and the at least
`one non-steroidal anti-in?ammatory phases of the
`tablet in order to provide the lubrication necessary
`in tablet formation.
`The self lubricating compression aids, preferably self
`lubricating, direct compression aids, employed in the
`present pharmaceutical composition combine at least
`two properties required of tablet vehicles. First they
`produce hard, stable tablets via compression, preferably
`via direct compression, and second they act as a lubri
`cant to facilitate tablet ejection after compression. Ex
`amples of such compression aids will be well known to
`those skilled in the tablet formulation art. Amongst the
`aids that are preferred in the present composition are
`Elcema G-250 (Trade Mark, Degussa, cellulose gran
`ules derived from powdered cellulose N.F.), Starch
`1500 (Trade Mark, Colorcon, a free flowing, directly
`compressible starch), and, which is particularly pre
`ferred, microcrystalline cellulose, especially Avicel
`(Trade Mark, FMC).
`In addition to self lubricating, compression aids, the
`60
`present composition may also contain, in one or more of
`its phases, other additives and components, provided
`they are compatible with the narcotic analgesic or salt
`thereof and the non-steroidal anti-in?ammatory carbox
`ylic acid or salt or ester thereof. Suitable materials in
`clude
`,
`(a) Binders, such as cellulose and its derivatives, e.g.
`ethyl cellulose hydroxypropylmethyl cellulose,
`
`45
`
`65
`
`

`
`4, 844,907
`.
`5
`analgesic or salt thereof present in the tablet’s pha
`ses,
`(b) the requirement of tablet integrity,
`(0) the time for tablet disintegration required,
`(d) the rate of tablet dissolution required,
`(e) the requirement of tablet content uniformity, and
`(f) the weight, thickness and size of the tablet.
`Given the number of variables involved in the formu
`lation of a pharmaceutical composition according to the
`present invention, it is difficult to give speci?c ranges
`for the concentrations of the above materials. In a pre
`ferred embodiment of the present pharmaceutical com
`position, however, especially wherein the at least one
`self lubricating compression aid comprises microcrys
`talline cellulose, the concentration of the compression
`aid in the at least one non-steroidal anti-in?ammatory
`phase is between 10% and 90%, especially between
`15% and 40%, by wt. (of the phase), whilst the concen
`tration of the compression aid in the at least one nar
`cotic analgesic phase is between 50% and 99%, espe
`cially between 70% and 95%, by wt. of the phase.
`The present pharmaceutical composition may be
`prepared by direct compression, but is preferably pre
`pared by wet granulation techniques. Thus, in a further
`aspect of the present invention, there is provided a wet
`granulation process for the preparation of a pharmaceu
`tical composition according to this invention compris
`mg
`(a) granulating a narcotic analgesic or an analgesi
`cally effective salt thereof with at least one self
`lubricating, compression aid to form narcotic anal
`gesic granules,
`(b) granulating a non-steroidal anti-in?ammatory
`carboxylic acid or an anti-in?ammatory salt or
`ester thereof with at least one self lubricating, com
`pression aid to form non-steroidal anti-inflamma
`tory granules, and
`(c) compressing the narcotic analgesic granules and
`the non-steroidal anti-in?ammatory granules to
`form a multi-phase tablet.
`In both steps (a) and (b) of the above process two
`methods of granulation may be used. In the first
`method, the drug, the compression aid and a binder are
`dry mixed. The mixed powders are then granulated by
`wetting with a solvent. In the second method, the drug
`and the compression aid are dry mixed and then granu
`lated by wetting with a solution of a binder.
`Suitablebinders for these methods are hydroxypro
`pylmethyl cellulose or polyvinylpyrrolidone.
`The present pharmaceutical composition, together
`with processes for its preparation, will now be de~
`scribed by way of example only.
`COMPARATIVE EXAMPLES
`A. Combination of Ibuprofen and Codeine within a
`Single Layer Tablet with Magnesium Stearate as
`Lubricant
`Single layer tablets were prepared from the following
`ingredients using a wet granulation process,
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`Ibuprofen
`Codeine Phosphate
`Microcrystalline Cellulose
`(Avicel PH 102)
`Croscarmellose Sodium
`(Ac-Di-Sol)
`
`mg/ tablet
`200.00
`12.50
`23.75
`5.00
`
`65
`
`-continued
`
`Hydroxypropylmethyl cellulose
`(6 cps)
`Magnesium Stearate
`
`mg/ tablet
`3.75
`2.45
`
`These tablets had poor disintegration times, poor
`crushing strengths and exhibited sticking problems on
`compression.
`B. Combination of Ibuprofen and Codeine within a
`Single Layer Tablet
`Single layer tablets were prepared from the following
`ingredients using a wet granulation process.
`
`15
`
`Ibuprofen
`Codeine Phosphate
`Microcrystalline cellulose
`(Avicel PHIOZ, Trade Mark)
`Sodium Starch Glycollate
`(Explotab, Trade Mark)
`I-Iydroxypropyl methyl cellulose
`(viscosity, 3 cps)
`
`mg/ tablet
`200.0
`12.5
`65.4
`45.0
`7.1
`
`When tablets prepared in this manner were com
`pressed to crushing strengths of 9-17 kp, they exhibited
`sticking and ejection problems. The tablets, when pre
`pared, had unacceptably long disintegration times.
`C. Bi-Layer Formulation with Magnesium Stearate
`Present as a Lubricant
`An ibuprofen layer having the following ingredients
`(in mg) was prepared by a wet granulation process.
`
`Ibuprofen
`Microcrystalline cellulose
`(Avicel PH102)
`Sodium Starch Glycollate
`(Explotab)
`I-Iydroxypropylmethyl cellulose
`(3 CPS)
`Sodium Lauryl Sulphate
`Erythrosine Aluminium Lake
`
`200.00
`70. 84
`45.00
`8.16
`1.00
`3.28
`
`A codeine layer having the following ingredients (in
`mg) was prepared by a wet granulation process.
`
`Codeine Phosphate
`Dicalcium Phosphate
`Hydroxypropylmethyl cellulose
`(3 cps)
`Sodium Starch Glycollate
`Magnesium Stearate
`
`12.5
`289.5
`8.7
`12.6
`1.7
`
`When the two layers were compressed together the
`codeine content decreased markedly after short term
`stability at room and elevated temperatures. Also a
`brown colour formed, especially at the interface be
`tween the two layers.
`D. Bi-Layer Formulation with Magnesium Stearate as
`Lubricant
`The ibuprofen layer was prepared as described in
`Example C. The codeine layer was prepared from the
`following ingredients (in mg) by a wet granulation pro~
`cess.
`
`

`
`7
`
`Codeine Phosphate
`Microcrystalline cellulose
`(Avicel Pl-Il02)
`Hydroxypropyl methyl cellulose
`(3 cps)
`Sodium Starch Glycollate
`(intragranular)
`Sodium Starch Glycollate
`(extragranular)
`Magnesium Stearate
`
`12.5
`267.0
`7.0
`3.0
`9.0
`1.5
`
`When the codeine layer was compressed it was found
`that crushing strengths above 6 kp were difficult to
`achieve even with increasing compression forces.
`EXAMPLES ACCORDING TO THE INVENTION
`EXAMPLE 1
`Ibuprofen Layer
`An ibuprofen layer having the following ingredients
`(in mg) was prepared by a wet granulation process.
`
`20
`
`200.0
`65.0
`20.0
`15.0
`
`Ibuprofen
`Microcrystalline cellulose
`(Avicel PI'I102)
`Sodium Starch Glycollate
`l-Iydroxypropylmethyl cellulose
`(3 CPS)
`The ibuprofen, microcrystalline cellulose, sodium
`starch glycollate and hydroxypropyl methyl cellulose
`were dry mixed. Water was then added to the dry pow
`der and the mixture was granulated to give pharmaceu
`tical ibuprofen containing granules.
`Codeine layer
`A codeine layer containing the following ingredients
`(in mg) was prepared by a wet granulation process.
`
`Codeine Phosphate
`Microcrystalline cellulose
`(Avicel Pl-I102)
`Starch 1500 (Trade Mark),
`Ingragranular
`Starch 1500, Extragranular
`
`12.50
`227.47
`20.00
`40.00
`
`25
`
`35
`
`40
`
`45
`
`Codeine Phosphate, microcrystalline cellulose and
`intragranular Starch 1500 were dry mixed. Water was
`then added and the mixture was granulated to form
`pharmaceutical, codeine containing granules. Starch
`1500 was then mixed with the granules. Finally the
`codeine and ibuprofen granules were compressed to
`give an ibuprofen-codeine bi-layer tablet with a crush
`ing strength of 11-12 kp.
`EXAMPLE 2
`The procedure of Example 1 was followed except
`that the ibuprofen layer had the following composition
`(111 mg),
`
`50
`
`55
`
`60
`
`4,844,907
`
`8
`EXAMPLE 3
`The procedure of Example 1 was followed except
`that the ibuprofen layer had the following composition
`(in mg).
`
`Ibuprofen
`Microcrystalline cellulose
`(Avicel PH102)
`Sodium Starch Glycollate
`l-Iydroxypropylmethyl cellulose
`(3 CPS)
`Sodium Lauryl Sulphate
`Erythrosine Aluminium Lake
`
`200.00
`70.84
`45.00
`8.16
`1.00
`3.28
`
`The sodium lauryl sulphate and the erythrosine alu
`minium lake were mixed in the dry powder prior to the
`addition of water. In this case-the resulting tablet was
`coated using hydroxypropylmethyl cellulose as film
`former, and PEG400 as plasticiser.
`EXAMPLE 4
`
`Ibuprofen Layer
`This was prepared as described in Example 3.
`Codeine Layer
`A codeine layer containing the following ingredients
`(in mg) was prepared by a wet granulation process.
`
`'
`
`12.50
`227.50
`40.00
`10.00
`40.00
`
`Codeine Phosphate
`Microcrystalline cellulose
`(Avicel PH 102)
`Starch 1500
`Polyvinylpyrrolidone
`(Kollidon K30, Trade Mark)
`Microcrystalline cellulose
`(Avicel PHlOl)
`Codeine Phosphate, microcrystalline cellulose (Avi
`cel PI-Il02) and Starch 1500 were dry mixed. An aque
`ous solution of polyvinylpyrrolidone was then added to
`the dry powder and the mixture was granulated to give
`codeine granules. Microcrystalline cellulose (Avicel
`PHlOl) was then mixed with the granules. Finally, the
`codeine and ibuprofen granules were compressed to
`give an ibuprofen-codeine bilayer tablet with a crushing
`strength of 11-12 kp.
`EXAMPLE 5
`The procedure of Example 4 was followed except
`that the ibuprofen (layer had the following composition
`(in mg),
`
`Ibuprofen
`Microcrystalline cellulose
`(Avicel PHIOZ)
`Sodium Starch Glycollate
`I-Iydroxypropylmethyl cellulose
`(3 CPS)
`Erythrosine Aluminium Lake
`
`200.00
`68.59
`45.00
`8.16
`3.25
`
`Ibuprofen
`Microcrystalline cellulose
`(Avicel Pl-1l02)
`Sodium Starch Glycollate
`l-lydtoxypropylmethyl cellulose
`(3 CPS)
`
`200.00
`50.00
`12.50
`12.50
`
`EXAMPLE 6
`The procedure of Example 5 was followed except
`that the amount of Starch 1500 in the codeine layer was
`reduced to 25.0 mg. In this case the resulting bilayer
`tablet was coated with hydroxypropylmethyl cellulose
`as ?lm former, and propylene glycol as plasticiser.
`
`

`
`4,844,907
`10
`Tablets prepared in accordance with Examples 1 to 6
`The tablets were ?lm coated with hydroxypropyl
`above exhibited pharmaceutically acceptable properties
`methyl cellulose as ?lm former and polyethylene glycol
`with regard to stability, disintegration times and dissolu
`as plasticiser.
`tion rates.
`
`EXAMPLE 7
`Ibuprofen Layer
`Ibuprofen (30 gm), microcrystalline cellulose (Avicel
`pH 102, 5.01 gm), lactose anhydrous (5.01 gm), hydrox
`yethyl cellulose (0.5 gm), hydroxypropylmethyl cellu
`lose (5cps, 0.95 gm) and trisodium 7-hydroxy-8-(4-sul
`phonato-l-napthylazo) naphthalene-1,3-di sulphonate
`(onceau 4R, Trade Mark, 0.43 gm) were dry blended.
`To the mixture was added suf?cient water to produce a
`granulated mass.
`The wet granules were then partially dried in a Fluid
`Bed dryer at 50° C. The partially dried mass was granu
`lated through a 12 mesh screen and then further dried.
`The dried granules were passed through a 16 mesh
`screen. Molten cetostearyl alcohol (1.0 gm) was then
`added, with mixing, to the granules. Finally, talc (0.4
`gm) was blended with the granules.
`Codeine Layer
`Codeine granules were prepared as described in Ex
`ample 4 above.
`Finally the codeine and the ibuprofen granules were
`compressed to give an ibuprofen-codeine bilayer tablet
`containing 300 mg ibuprofen/ 12.5 mg codeine phos
`phate and having a controlled release ibuprofen layer
`and a normal release codeine layer.
`Tablets prepared in accordance with Example 7 ex
`hibited pharmaceutically acceptable properties with
`regard to stability, disintegration times and dissolution
`rates.
`
`EXAMPLE 8
`The procedure of Example 7 was followed except
`that the codeine layer had the following composition (in
`mg).
`
`Codeine Phosphate
`Microcrystalline cellulose (Avicel PH 102)
`Starch 1500
`Polyvinylpyrrolidone
`Microcrystalline cellulose
`
`20.0
`364.0
`40.0
`16.0
`64.0
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Again, tablets prepared in accordance with Example
`8 exhibited pharrnaceutically acceptable properties with
`regard to stability, disintegration times and dissolution
`rates.
`
`50
`
`EXAMPLE 9
`The procedure of Example 8 was followed. The tab
`lets were then film coated with hydroxypropylmethyl
`cellulose as ?lm former and propylene glycol as plasti
`ciser.
`
`EXAMPLE 10
`The procedure of Example 4 was followed except
`that the codeine layer had the following composition (in
`mg).
`
`Codeine Phosphate
`Microcrystalline cellulose (Avicel PH 102)
`Starch 1500
`
`12.5
`227.5
`60.0
`
`55
`
`60
`
`65
`
`EXAMPLE 1 l
`Theiprocedure of Example 4 was followed except
`that dihydrocodeine tartrate replaced codeine phos
`phate and the dihydrocodeine layer had the following
`composition (in mg).
`
`Dihydrocodeine tartrate
`Microcrystalline cellulose (Avicel PH 102)
`Starch 1500
`Polyvinylpyrrolidone (PVP-K30)
`Microcrystalline cellulose (Avicel PH 101)
`
`30.0
`200.0
`40.0
`1010
`3010
`
`EXAMPLE 12
`The procedure of Example 4 was followed except,
`that naproxen replaced ibuprofen and the naproxen
`layer had the following composition (in mg).
`
`Naproxen
`Microcrystalline cellulose (Avicel PH 102)
`Starch 1500
`Sodium Starch Glycollate (Explotab)
`Hydroxypropylmethyl cellulose
`
`500.0
`150.0
`45.0
`100.0
`20.0
`
`EXAMPLE 13
`The procedure of Example 4 was followed except
`that flurbiprofen replaced ibuprofen and the flurbi
`profen layer had the following composition (in mg).
`
`Flurbiprofen
`Microcrystalline cellulose (Avicel PH 102)
`Sodium Starch Glycollate
`Hydroxypropylmethyl cellulose
`Erythrosine Aluminium Lake
`
`100.0
`35.0
`20.0
`5.0
`1.5
`
`What I claim is:
`1. A pharmaceutical composition in the form of a
`multiphase tablet comprising at least one narcotic anal
`gesic phase containing a therapeutically effective quan
`tity of a narcotic analgesic or an analgesically effective
`salt thereof and at least one non-steroidal anti-inflamma
`tory phase containing a therapeutically effective quan
`tity of a non-steroidal anti-in?ammatory carboxylic acid
`or an anti-in?ammatory salt or ester thereof wherein the
`at least one narcotic analgesic phase is free from a non
`steroidal anti-inflammatory carboxylic acid or salt or
`ester thereof, stearic acid and a stearate salt, and the at
`least one non-steroidal anti-in?ammatory phase is free
`from a narcotic analgesic or salt thereof, stearic acid
`and a stearate salt, and further wherein both the at least
`one narcotic analgesic phase and the at least one non
`steroidal anti-in?ammatory phase contain at least one
`self-lubricating, compression aid.
`2. A composition according to claim 1 wherein the
`narcotic analgesic comprises a morphinan-6-ol or a
`morphinan-6-one derivative, selected from morphine,
`ethylmorphine, hydromorphone, hydrocodone, dihy
`drocodeine and codeine.
`'
`3. A composition according to claim 1 wherein the
`analgesically effective salt of the narcotic analgesic
`comprises codeine phosphate.
`
`

`
`4,844,907
`11
`-
`12
`narcotic analgesic phase is between 50% and 99% (by
`4. A composition according to claim 1 wherein the
`wt).
`non-steroidal anti-inflammatory carboxylic acid com
`10. A composition according to claim 9 wherein the
`prises at least one of naproxen, a benzeneacetic acid,
`concentration is between 70% and 95% (by wt).
`selected from alclofenac, diclofenac and fenclofenac,
`11. A composition according to claim 1 in the form of
`and a Z-phenylpropionic acid, selected from fenoprofen,
`a layered tablet.
`?urbiprofen, indoprofen, ketoprofen and ibuprofen.
`12. A composition according to claim 11 in the form
`5. A composition according to claim 4 wherein the
`of a bilayered tablet.
`non-steroidal anti-inflammatory carboxylic acid com
`13. A wet granulation process for the preparation of
`prises ibuprofen.
`a pharmaceutical composition according to claim 1
`comprising
`6. A composition according to claim 1 wherein the at
`(a) granulating a narcotic analgesic or an analgesi
`least one self lubricating, compression aid comprises at
`cally effective salt thereof with at least one self
`least one self lubricating, direct compression aid, se
`lubricating, compression aid to form narcotic anal
`lected from microcrystalline cellulose and a free flow
`gesic granules,
`ing, directly compressible starch.
`(b) granulating a non-steroidal anti~inflammatoryi
`7. A composition according to claim 1 wherein the
`carboxylic acid or an anti-in?ammatory salt or
`concentration of the compression aid in the at least one
`ester thereof with at least one self lubricating, com
`non-steroidal anti-inflammatory phase is between 10%
`pression aid to form non-steroidal anti-in?amma
`and 90% (by wt).
`tory granules, and
`8. A composition according to claim 7 wherein the
`(c) compressing the narcotic analgesic granules and
`concentration is between 15% and 40% (by wt).
`the non-steroidal anti-in?ammatory granules to
`9. A composition according to claim 1 wherein the
`form a multiphase tablet.
`concentration of the compression aid in the at least one
`*
`* * * *
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65