_
`
`UIlltEd States Patent [19]
`Murphy et al.
`
`lllllllllllllllll "III 11111 I111 1111 I111 I111 I111 I111 I111 Illlllllllll ,
`[11] Patent Number:
`5,256,699
`[45] Date of Patent:
`Oct. 26, 1993
`
`US005256699A
`
`[54] DISPERSIBLE TABLET FORMULATION 0F
`DICLOFENAC ACID FREE BASE
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`.
`[75] Invenmrs’ mm‘ M- Mmhy; Gm R
`Matthews, both of Horsham,
`England
`
`[73] Assignee: Ciba-Geify Corporation, Ardsley,
`NY.
`
`[21] Appl. No.: 869,087
`
`[22] Filed:
`
`Apr. (12, 1992
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 691,156, Apr. 24, 1991, aban
`doned, which is a continuation of Ser. No. 421,578,
`Oct. 16, 1989, abandoned.
`
`Foreign Application Priority Data
`[30]
`Oct. 18, 1988 [GB] United Kingdom ............... .. 8824392
`
`- [51] Int. Cl.5 .................... .. A61K 31/135; A61K 9/20
`[52] US. Cl. .................................. .. 514/658; 514/960;
`514/961; 424/464; 424/465
`[58] Field of Search ............. .. 514/557, 658, 534, 535,
`514/960, 961; 424/464, 465
`
`3,558,690 1/1971 Sallrnann et a1. ................... .. 550/47
`4,209,513 ' 6/1980 Towde et a1. . . . . .
`. . . . .. 424/223
`4,234,601 11/1980 Gardocki ..................... .. 424/319
`4,567,178 1/1986 Eberlein et a1. .............. .. 514/215
`4,609,675 9/1986 Franz ................................ .. 514/568
`4,711,777 12/1987 Tan ......... ..
`424/79
`4,774,083 9/1988 Tan et a1. .... ..
`424/79
`4,867,985 9/ 1989 Hea?eld et a1. ................... .. 424/461
`
`FOREIGN PATENT DOCUMENTS
`0255002 2/1988 European Pat. Off. .
`0324981 7/1989 European Pat. Off. .
`
`OTHER PUBLICATIONS
`Pharmaceutical Technology vol. 15, N0. 3, pp. 49-56
`(1991).
`-
`Primary Examiner-Frederick E. Waddell
`Assistant Examiner-T. J. Criares
`Attorney, Agent, or Firm-Irving M. Fishrnan; Karen G.
`Kaiser
`ABs'rRAcr
`[57]
`The invention provides a dispersible solid drug formula
`tion comprising ?nely divided diclofenac as the free
`acid, from 5 to 25% by weight of a disintegrant and a
`pharmaceutically acceptable diluent.
`
`8 Claims, No Drawings
`
`Page 1
`
`LUPIN EX. 1013
`Lupin v. iCeutica
`US Patent No. 9,017,721
`
`

`
`1
`
`DISPERSIBLE TABLET FORMULATION OF
`DICLOFENAC ACID FREE BASE
`
`5,256,699
`2
`Colours, ?avours and aromatising agents may also be
`included in the'formulations.
`The solid drug formulations may be in the form of a
`simple mixture of the ingredients which can be ?lled
`into sachets that can be emptied into water. Preferably
`the solid drug formulations are in the form of tablets.
`Tablets can be manufactured in several known differ
`ent ways. In the so-called direct compression process a
`suitable diluent, for example microcrystalline cellulose,
`selected grades of calcium hydrogen phosphate, or
`lactose, is chosen to allow the components to be mixed
`and tabletted.
`In the so-called wet granulation process, most of the
`components of the formulation, including the di
`clofenac, diluent and all or part of the disintegrant are
`formed into granules by the addition of a liquid, usually
`water, and optionally a binding agent. The remaining
`components such as the remainder of the disintegrant
`and lubricants are then added and the blend tabletted. If
`colour and/or ?avours are used they may be added at
`any stage of the process.
`The invention is illustrated by the following Exam
`ples.
`
`15
`
`20
`
`This application is a continuation of application Ser.
`No. 691,156, ?led Apr. 24, 1991, now abandoned, which
`is a continuation, of application Ser. No. 421,578, ?led
`Oct. 16, 1989, now abandoned.
`The present invention relates to a dispersable solid
`dry formulation containing diclofenac.
`Diclofenac is an effective analgesic and antiarthritic
`agent. It is available, inter alia, as enteric coated tablets
`and sustained release tablets containing dielofenac so
`dium, and also as sugar coated tablets of diclofenac
`potassium.
`Some patients are unable or unwilling to swallow
`tablets, and for these patients, and others, a tablet which
`disperses in water or other suitable liquid is advanta
`geous because it is more acceptable. Being swallowed in
`dispersed or dissolved form, the drug is rapidly effec~
`tive.
`If diclofenac sodium is incorporated in a dispersible
`tablet it dissolves when the tablet is dispersed in water
`or other suitable liquid producing a liquid with an unde
`sirable bitter taste. Diclofenac potassium also produces
`a liquid with a bitter taste.
`We have found that this difficulty is overcome if
`diclofenac is dispersed as the free acid rather than as a
`salt. This has a low solubility and is virtually tasteless.
`Accordingly the present invention provides a dispers
`- ible solid drug formulation comprising ?nely divided
`diclofenac as the free acid, from 5 to 25% by weight of
`a disintegrant and-a pharmaceutically acceptable dilu
`
`25
`
`30
`
`EXAMPLE 1
`Diclofenac free acid, lactose and an aliquot of sodium
`croscarmellose are granulated with an aqueous solution
`of hydroxypropyl methylcellulose 3 cps and sodium
`lauryl sulphate in a fluid bed granulator. The granules
`are dried and then blended with the remaining excipi
`ents and compressed into tablets having the following
`composition.
`
`DICLOFENAC
`Microcrystalline Cellulose
`Lactose B?
`Sodium Croscarmellose
`Hydroxypropylmethylcellulose 3 cps
`Hydrogenated Castor Oil
`Puri?ed Talc
`Sodium Lauryl Sulphate
`Total weight of Tablet
`
`Quantity
`mg/tablet
`46.5
`100.0
`100.0
`21.0
`1.82
`1.5
`1.5
`0.045
`272.365 mg
`
`ent.
`
`_
`
`35
`
`45
`
`The diclofenac may be in the form of a ?nely divided
`powder having a particle size diameter of about 4 to 100
`pm.
`As disintegrant there may be used compounds such as
`micro. crystalline cellulose, starches and starch deriva
`tives. Preferably a compound known as a superdisinte
`grant is used, such as croscarmellose, crospovidone and
`sodium starch glycollate. In some instances it is advan
`tages to use a combination of disintegrants.
`The amount of disintegrant, or mixture thereof, is
`from 5 to 25%, preferably from 5 to 15%. We prefer to
`use higher concentrations of disintegrant than is nor
`mally used in a conventional (i.e. non-dispersible) for
`mulation.
`The formulations of the invention also contain at least
`one diluent in order to give suf?cient material to tablet
`and facilitate the compression process used to make
`tablets. Suitable diluents include microcrystalline cellu
`lose, calcium hydrogen phosphate, and lactose. The
`function of the diluent may be performed by other com
`ponents, especially. disintegrants.
`The formulation of the invention may also contain
`wetting agents to improve the disintegration and/or
`dispersion. Suitable wetting agents include dioctyl sodi
`umsulpho. succinate, polysorbates or sodium lauryl
`sulphate. The amount of wetting agent is usually not
`more than 0.1% by weight of the formulation.
`The formulation of the invention may also include
`lubricants, including agents to improve ?ow. Suitable
`compounds include fatty acids such as stearic acid,
`metal stearates such as magnesium stearate, hydroge
`nated castor oil, talc, and colloidal silicon dioxide. Lu
`bricants may be used in amounts of up to 2% by weight
`of the formulation.
`-
`
`55
`
`EXAMPLE 2
`Tablets are made by the method of Example 1 except
`that calcium hydrogen phosphate is used in place of the
`microcrystalline cellulose and lactose. The tablets have
`the following composition.
`
`DICLOFENAC
`Calcium Hydrogen Phosphate
`Sodium Croscarmellose
`Hydroxypropylmethylcellulose 3 cps
`Hydrogenated Castor Oil
`Puri?ed Talc
`Sodium Lauryl Sulphate
`Total weight of Tablet
`
`Quantity
`mg/tablet
`46.5
`200.0
`18.0
`1.82
`1.5
`1.5
`0.045
`269.365 mg
`
`EXAMPLE 3
`Diclofenac free acid is dry blended with microcrys
`talline cellulose, sodium crosscarmellose and colouring
`material. The mass is then wet granulated with water.
`
`Page 2
`
`

`
`4
`
`DICLOFENAC
`Microcrystalline cellulose
`F.D.& C. Red No. 3
`F.D.& C. Red No. 3/Al Lake
`Blackcurrant Flavour
`Sodium‘ saccharin
`Sodium croscarmellose
`Magnesium Stearate
`Total weight of Tablet
`
`Quantity
`mg/tablet
`46.5
`180.2
`0.3
`l.3
`30.0
`2.5
`23.2
`6.0
`290.0 mg
`
`We claim:
`1. A dispersible solid drug formulation in the form of
`a tablet comprising ?nely divided diclofenac in the free
`acid form having a particle size diameter of from about
`4 to about 100 pm, from 5 to 25% by weight of a super
`disintegrant selected from the group consisting of cros
`carmellose, crospovidone, and sodium starch glycollate
`and a pharmaceutically acceptable diluent.
`2. A formulation as claimed in claim 1 in which the
`amount of superdisintegrant is from 5 to 15% by
`weight.
`3. A formulation as claimed in claim 1 in which the
`diluent is selected from the group of microcrystalline
`cellulose, calcium hydrogen phosphate, lactose, and
`mixtures thereof.
`4. A process for the preparation of a dispersible solid
`drug formulation in form of a tablet as de?ned in claim
`1, which comprises formulating by mixing ?nely di
`vided diclofenac, in an amount as given in claim 1 or 4,
`a superdisintegrant selected from the group consisting
`of croscarmellose, crospovidone, and sodium starch
`glycollate, and a pharrnaceutically acceptable diluent
`and compressing to tablets.
`5. A formulation according to claim 1 further com
`prising a wetting agent.
`6. A formulation according to claim 5 wherein said
`wetting agent is present in an amount of up to 0.1% by
`weight of the formulation.
`7. A formulation according to claim 1 further com
`prising a lubricant.
`8. A formulation according to claim 7 wherein said
`lubricant is present in an amount of up to 2% by weight
`of the formulation.
`
`1 i i ' ‘
`
`3
`The granules are then blended with the remainder of
`the excipients and compressed into tablets having the
`following composition.
`
`5,256,699
`
`DICLOFENAC
`Microcrystalline cellulose
`F.D.& C. Red No. 3
`F.D.& C. Red No. 3/Al Lake
`Blackcurrant Flavour
`Sodium saccharin B?
`Sodium croscarmellose
`Sodium starch glycollate
`Hydrogenated Castor Oil
`Puri?ed Talc _
`Colloidal silicon dioxide
`Total weight of Tablet
`
`Quantity
`mg/tablet
`46.5
`l58.5
`0.3
`1.3
`30.0
`2.5
`14.5
`29.0
`1.5
`1.5
`4.4
`290 mg
`
`EXAMPLE 4
`Diclofenac free acid is blended with all the excipients
`other than the lubricant. The mixture is then blended
`with the lubricant and compressed into tablets having
`the following composition.
`
`DlCLOFENAC
`Microcrystalline cellulose
`F.D.& C. Red No. 3
`F.D.& C. Red No. 3/Al Lake
`Blackcurrant Flavour
`Sodium saccharin
`Puri?ed Talc
`Hydrogenated Castor Oil
`Sodium croscarmellose
`Total weight of Tablet
`
`Quantity
`mg/tablet
`46.5
`180.2
`0.3
`1.3
`30.0
`2.5
`3.0
`3.0
`23.2
`290.0 mg
`
`EXAMPLE 5
`Example 4 is repeated to produce tablets having the
`following composition.
`
`10
`
`20
`
`35
`
`50
`
`55
`
`65
`
`Page 3
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`PATENTNO. 1 5,256,699
`DATED
`; October 26th, 1993
`
`INVENTOR(S): Murphy et al
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`On the title page, [73] Assignee
`insert -—Geigy—
`
`, delete “Geify" and
`
`Signed and Sealed this
`Nineteenth Day of April, 1994
`
`Men:
`
`?end W
`
`Arresting O?icer
`
`Commissioner of Patents and Trademarks
`
`BRUCE LEHMAN
`
`Page 4