(cid:47)(cid:56)(cid:51)(cid:44)(cid:49)(cid:3)(cid:40)(cid:59)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:22)
`(cid:47)(cid:88)(cid:83)(cid:76)(cid:81)(cid:3)(cid:89)(cid:17)(cid:3)(cid:76)(cid:38)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:68)
`(cid:56)(cid:54)(cid:3)(cid:51)(cid:68)(cid:87)(cid:72)(cid:81)(cid:87)(cid:3)(cid:49)(cid:82)(cid:17)(cid:3)(cid:27)(cid:15)(cid:28)(cid:28)(cid:28)(cid:15)(cid:22)(cid:27)(cid:26)
`
`Page 1
`
`

`
`1
`
`i25&699
`
`2
`Colours. flavours and aromatising agents may also be
`included in theformulations.
`
`Page 2
`Page 2
`
`The solid drug formulations may be in the form of 2
`simple mixture of the ingredients which can be filled
`into sachets that can be emptied into water. Preferably
`the solid drug formulations are in the fonn 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. must 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 flavours are used they may be added at
`any stage of the process.
`The invention is illustrated by the following Exam-
`pies.
`
`EXAMPLE 1
`
`Diclofenac free acid, lactose and an aliquot of sodium
`croscarrnellose 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.
`
`
`
`Quantity
`mg/tablet
`46.5
`DICLOFENAC
`l£Kl.D
`Microcrystalline Cellulose
`19.0.0
`Lactose HP
`21.0
`Sodium Croscanneilose
`1.82
`Hydroxypropylinethylcellulose 3 cps
`1.5
`Hydrogenated Castor Oil
`1.5
`Purified Talc
`0.045
`Sodium Lauryl Sulphate
`
`Total weight of Tablet 211365 mg
`
`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.
`
`
`
`Quantity
`mgftablet
`46.5
`DICLOFENAC
`203.0
`Calcium Hydrogen Phosphate
`18.0
`Sodium Crcscarniellose
`1.82
`llydroaypropylmethylcellulose 3 cps
`1.5
`Hydrogenated Castor Oil
`L5
`Ptuified Talc
`0.045
`Sodium Lauryl Sulphate
`
`Total weight of Tablet 269.365 mg
`
`EXAMPLE 3
`
`Diclofenac free acid is dry blended with micro-crys-
`talline cellulose, sodium crosscarmellose and colouring
`material. The mass is then wet granulated with water.
`
`DISPERSIBLE TABLET FORMULATION OF
`DICLOFENAC ACID FREE BASE
`
`'
`
`This application is a continuation of application Ser.
`No. 691,156, filed Apr. 24, 1991, now abandoned, which
`is a continuation. of application Ser. No. 421,578, filed
`Oct. 16, 1939, 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 alias, as enteric coated tablets
`and sustained release tablets containing diclofenac so-
`dium, and also as sugar coated tablets of dielofenac
`potassium.
`Some patients are unable or unwilling to swallow
`tablets. and for thfie 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 diclofensc 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 finely divided
`diclofenac as the free acid, from 5 to 25% by weight of
`a disintegrant and "a pharmaceutically acceptable dilu-
`ent.
`,
`The diclofenac may be in the form of a finely 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 croscarrnellose, crospovidone and
`sodium starch glycollate. In some instances it is advan-
`tages to use a combination of disintcgrants.
`is
`The amount of disintegrant, or mixture thereof.
`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. nomdispersible) for-
`mutation.
`The formulations of the invention also contain at least
`one diluent in order to give sufficient material to tablet
`and facilitate the compression process used to make
`tablets. Suitable diluents include rnicrocrystalline 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 flow. 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.
`-
`
`5
`
`l0
`
`l5
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`

`
`5,256,699
`
`4
`
`Page 3
`Page 3
`
`
`
`Quantity
`mg/tablet
`4-6.5
`DICLOFENAC
`100.2
`Mierocrystalline cellulose
`0.3
`F.D.l't C. Red No. 3
`1.3
`F.D.lt E. Red No. 3.2%] Lake
`30.0
`Blackcurrant Flavour
`2.5
`S-odium'IIct:ItIJ'i.It
`23.2
`Sodium croacarmellose
`6.0
`Magnesium Stearate
`
`Total weight or Tablet 190.0 mg
`
`We claim:
`1. A dispersible solid drug formulation in the form of
`a tablet comprising finely 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-
`disintcgrant selected from the group consisting of cros-
`carmellose, crospovidone. and sodium starch glycollatc
`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 I in which the
`diluent is selected from the group of rnicrocrystalline
`cellulose, calcium hydrogen phosphate,
`lactose, and
`mixtures thereof.
`4. A process for the preparation of a dispcrsible solid
`drug formulation in form of a tablet as defined in claim
`1, which comprises formulating by mixing finely di-
`vided diclofenac, in an amount as given in claim 1 or 4,
`a superdisintcgrant selected from the group consisting
`of croscarmellose, crospovidone. and sodium starch
`glycollate, and a pharmaceutically 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.
`B. A formulation according to claim 7 wherein said
`lubricant is present in an amount of up to 2% by weight
`of the formulation. C
`C
`I
`C
`I
`
`3
`The granules are then blended with the remainder of
`the excipients and compressed into tablets having the
`following composition.
`
`10
`
`15
`
`
`
`Quantity
`mg/tablet
`46.5
`DICLOFENAC
`158.5
`Microcrystalline cellulose
`0.3
`F.D.& (3. Red No. 3
`‘
`I.3
`F.D.& C. Red No. NA] Lake
`30.0
`Blackcurrant Flavour
`2.5
`Sodium saccharin HP
`14.5
`Sodium croscarmellose
`29.0
`Sodium starch glycollate
`1.5
`Hydrogenated Castor Oil
`L5
`Purified Talc
`4.4
`Colloidal silicon dioxide
`
`Total weight of Tablet 290 mg
`
`EXAMPLE 4
`
`Diclofenac free acid is blended with all the excipicnts
`other than the lubricant. The mixture is then blended
`
`25
`
`with the lubricant and compressed into tablets having
`the following composition.
`
`35
`
`45
`
`55
`
`65
`
`
`
`Quantity
`rngftablet
`46.5
`DICLOFENAC
`180.2
`Miemcrystalline cellulose
`0.3
`F.D.& C. Red No. 3
`1.3
`F.D.& C. Red No. 3.011 Lake
`30.0
`Blackcurrant Flavour
`2.5
`Sodium saecharin
`3.0
`Purified Talc
`3.0
`Hydrogenated Castor Oil
`13.2
`Sodium croscarrnellose
`Total weight of Tablet 290.0 mg
`
`
`
`EXAMPLE 5
`
`Example 4 is repeated to produce tablets having the
`following composition.
`
`

`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENTND.
`
`: 5«255«699
`
`npcrgn
`
`; October 26th, 1993
`
`It is certified that error appears in the abrwe-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`On the title page,
`
`['33] Assignee
`
`, delete "Geify" and
`
`insert --Geigy--
`
`Arrest:
`
`Signed and Sealed this
`
`Nineteenth Day of April, 1994
`
`fléfid YLIC»-M-\_
`
`BRUCE LEHMAN
`
`Commissioner of Pam-us and Trademarks
`Arresting Ofiicer
`
`
` Page 4
`
`Page 4