`
`Exhibit 1014
`
`European Patent Application EP 1 020 182 A2
`(“EP182”)
`
`

`

`(19)
`
`(12)
`
`Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`(11)
`
`EP 1 020 182 A2
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`19.07.2000 Bulletin 2000/29
`
`(21) Application number: 00300305.0
`
`(22) Date of filing: 17.01.2000
`
`(51) Int. Cl.7: A61K 9/20, A61K 31/557
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE
`Designated Extension States:
`AL LT LV MK RO SI
`
`(30) Priority: 18.01.1999 CA 2259727
`
`(71) Applicant:
`SHERMAN, Bernard Charles
`Willowdale, Ontario M2L 2K1 (CA)
`
`(72) Inventor:
`SHERMAN, Bernard Charles
`Willowdale, Ontario M2L 2K1 (CA)
`
`(74) Representative:
`Votier, Sidney David
`CARPMAELS & RANSFORD
`43, Bloomsbury Square
`London WC1A 2RA (GB)
`
`(54)
`
`A two-layer pharmaceutical tablet comprising an nsaid and misoprostol
`
`(57)
`A pharmaceutical tablet comprising misopros-
`tol and an NSAID, said tablet comprising two layers
`wherein one of the misoprostol and NSAID is incorpo-
`rated into only one layer and the other of the misoprostol
`and NSAID either is incorporated into the other layer or
`is incorporated between the two layers.
`
`Printed by Xerox (UK) Business Services
`2.16.7 (HRS)/3.6
`
`EP 1 020 182 A2
`
`

`

`EP 1 020 182 A2
`
`Description
`
`BACKGROUND OF THE INVENTION
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`[0001]
`The invention herein is directed to a pharmaceutical tablet which comprises both an NSAID and misoprostol.
`[0002]
`Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a class of drugs which have long been recognized
`as having high therapeutic value especially for the treatment of inflammatory conditions such as exhibited in inflamma-
`tory diseases like osteoarthritis and rheumatoid arthritis. While the NSAIDs present a beneficial therapeutic value, they
`also exhibit undesirable side effects. An especially undesirable side effect of the administration of NSAIDs is the ulcer-
`ogenic effects generally associated with chronic use. NSAID induced ulcers in the stomach can be dangerous. Such
`ulcers generally exhibit few or no symptoms and may cause dangerous bleeding when undetected. In some instances,
`bleeding ulcers can prove fatal.
`[0003]
`Certain prostaglandins have been shown to prevent NSAID induced ulcers. Misoprostol is a prostaglandin
`which has been accepted for use in the treatment of NSAID induced ulcers in many countries, including the United
`States.
`[0004]
`It is desirable to provide a pharmaceutical composition which exhibits the beneficial properties of an NSAID
`and which also exhibits the beneficial properties of misoprostol for countering the ulcerogenic side effects attendent to
`NSAID administration.
`[0005]
`This can be achieved by combining an NSAID and misoprostol in a single pharmaceutical tablet. However
`this is not easy to do, because misoprostol is highly unstable, and it is thus desirable not to have the misoprostol and
`NSAID mixed together, so as to prevent any deleterious effect of the NSAID on the stability of the misoprostol.
`[0006]
`One solution to this problem, which is disclosed in US Patent 5601843, is to produce a tablet consisting of
`an inner core which comprises the NSAID and a mantle which surrounds the inner core and comprises the misoprostol.
`It is also disclosed that, in order to prevent contact between the misoprostol and the NSAID at the surface of the inner
`core, the inner core may be coated with an inert coating. Such coating may be an enteric coating, which also serves to
`reduce the likelihood of the NSAID dissolving in the stomach and thereby prevent exposing the stomach to the NSAID.
`[0007]
`While the invention of US Patent 5601843 accomplishes its objective of separating the NSAID from the mis-
`oprostol, it has certain disadvantages. One disadvantage is the need to have a coating on the inner core in order to
`completely prevent contact between the NSAID in the inner core and the misoprostol in the mantle.
`[0008]
`A second disadvantage is that the misoprostol is dispersed throughout the mantle, and is thus exposed to
`the environment at the surface of the tablet. This exposure increases the vulnerability of the misoprostol to degradation
`due to the effects of light or atmospheric oxygen and moisture.
`[0009]
`The object of the present invention is to enable a pharmaceutical tablet that incorporates both an NSAID and
`misoprostol in a different manner from that disclosed in U.S. patent 5601843.
`
`DESCRIPTION OF THE INVENTION
`
`[0010]
`The present invention is a pharmaceutical composition in the form of a tablet comprising two layers. Either
`the misoprostol or the NSAID is incorporated within a first layer, and the other of the misoprostol and NSAID is either
`incorporated in a second layer or is incorporated between the first layer and second layer.
`[0011]
`Pharmaceutical tablets are routinely made on a rotary tablet press. In the tabletting process, a mixture of
`materials in the form of a free flowing powder or granular mix is filled into dies as they pass under a feed frame. A punch
`protrudes into each die from beneath. After the die has passed under the feed frame, a second punch is then inserted
`into the die from above, and pressure is applied to the upper and lower punches to cause the powder or granular mix
`to be compressed into a tablet. The upper punch is then withdrawn, and the tablet is ejected from the die by raising the
`lower punch further into the die.
`[0012]
`To make a two-layer tablet, a rotary tablet press with two feed frames is used. The material of which the first
`or lower layer of the tablet is to be comprised is filled into the die as it passes under the first feed frame, and the material
`of which the upper layer is to be comprised is added as the die passes under the second feed frame.
`[0013]
`Compositions (i.e. tablets) of the present invention will be made on a rotary tablet press equipped as afore-
`said with at least two feed frames so as to make tablets comprising at least two layers. The tablet press may optionally
`also be adapted with feed devices to feed pellets or smaller tablets into the dies so as to incorporate such pellets or
`smaller tablets into either or both layers of the tablet or to insert them between the two layers of the tablet.
`[0014]
`Compositions of the present invention may be made in a number of variations, for example, as follows.
`[0015]
`The misoprostol may be incorporated into the first or lower layer of the tablet in any of the following ways:
`
`i) The misoprostol may be mixed with excipients (including a binder and a lubricant) and the resulting mixture fed
`into the die at the first feed frame so as to form the first or lower layer of the tablet. The misoprostol will then be
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`distributed uniformly throughout the first layer.
`
`EP 1 020 182 A2
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`ii) The misoprostol may be mixed with excipients and incorporated into small pellets in a separate operation done
`prior to the manufacture of the final two-layer tablet of the present invention. Those pellets may then be mixed with
`further excipients and the resulting mixture fed into the die at the first feed frame, so as to form the first or lower
`layer of the tablet. The misoprostol will then be located in pellets scattered in the first layer.
`
`iii) The misoprostol may be mixed with excipients and incorporated into a small tablet (i.e. substantially smaller than
`the intended final two-layer tablet of the present invention) or into small pellets in a separate tabletting or pelletizing
`operation, done prior to the manufacture of the final two-layer tablet of the present invention. Either one such small
`tablet or a number of such small pellets comprising the misoprostol may then be fed into the die on the two-layer
`tablet press when the die is empty, before it passes under the first feed frame for addition of the powder or granular
`mix of which the first layer is to be comprised. As the die passes under the first feed frame, the powder or granular
`mix will cover and surround the small tablet or pellets comprising the misoprostol, so that upon subsequent com-
`pression to form the final two-layer tablet, the small tablet or pellets comprising the misoprostol will be incorporated
`into the first or lower layer.
`
`[0016]
`Similarly, the NSAID may be incorporated into the second layer (or between the first and second layer) in
`any of the following ways:
`
`i) The NSAID may be mixed with excipients (including a binder and a lubricant) and the resulting mixture fed into
`the die at the second feed frame so as to form the second or upper layer of the tablet. The NSAID will then be dis-
`tributed uniformly throughout the second layer.
`ii) The NSAID may be mixed with excipients and incorporated into small pellets in a separate operation done prior
`to the manufacture of the final two-layer tablet of the present invention. Those pellets may then be mixed with fur-
`ther excipients and the resulting mixture fed into the die at the second feed frame, so as to form the second or upper
`layer of the tablet. The NSAID will then be located in pellets scattered in the second layer.
`iii) The NSAID may be mixed with excipients and incorporated into a small tablet (i.e. substantially smaller than the
`intended final two-layer tablet of the present invention) or into small pellets in a separate tabletting or pelletizing
`operation, done prior to the manufacture of the final two-layer tablet of the present invention. Either one such small
`tablet or a number of such small pellets comprising the NSAID may then be fed into the die on the two-layer tablet
`press after it passes under the first feed frame for addition of the powder or granular mix of which the first layer is
`to be comprised, but before it passes under the second feed frame. As the die passes under the second feed frame,
`the powder or granular mix will cover and surround the small tablet or pellets comprising the NSAID, so that upon
`subsequent compression to form the final two-layer tablet, the small tablet or pellets comprising the NSAID will be
`incorporated between the first and second layers.
`
`[0017]
`It will be understood that the order of addition of the misoprostol and NSAID may be reversed, in which case
`the NSAID will be incorporated in the first or lower layer and the misoprostol will be incorporated either into the second
`layer or between the two layers.
`[0018]
`The NSAID will preferably be piroxicam or diclofenac or a salt of diclofenac such as diclofenac sodium or
`diclofenac potassium. Most preferably, the NSAID will be diclofenac sodium.
`[0019]
`Where diclofenac or a salt thereof is used, the amount per final tablet will preferably be from 25 to 75 mg.
`Preferably, the diclofenac or salt thereof will be incorporated into a small tablet or pellets as aforesaid and said small
`tablet or pellets will be coated with an enteric film coating to prevent the diclofenac or salt thereof from dissolving until
`after it has passed through the stomach and entered the small intestine. The enteric coating can be formulated with any
`suitable enteric coating polymer, many of which are known to those skilled in the art. Where piroxicam is used as the
`NSAID, the amount per tablet will preferably be 10 to 20 mg. Again the tablet containing piroxicam will also comprise
`usual tablet excipients.
`[0020]
`The invention will be further understood from the following example, which is intended to be illustrative and
`not limiting of the scope of the invention.
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`EXAMPLE 1
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`[0021]
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`Small tablets comprising misoprostol are made with a mixture of ingredients as follows:
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`EP 1 020 182 A2
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`Misoprostol 1% dispersion in hydroxypropyl methylcellulose
`
`20.0 mg
`
`Amount per tablet
`
`Microcrystalline cellulose
`
`Magnesium stearate
`
`Croscarmellose sodium
`
`8.5 mg
`
`0.5 mg
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`1.0 mg
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`30.0 mg
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`EXAMPLE 2
`
`[0022]
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`Small tablets comprising diclofenac sodium are made with a mixture of ingredients as follows:
`
`Diclofenac sodium
`
`Microcrystalline cellulose
`
`Magnesium stearate
`
`Croscarmellose sodium
`
`Amount per tablet
`
`50.0 mg
`
`24.0 mg
`
`1.0 mg
`
`5.0 mg
`
`80.0 mg
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`[0023]
`These cores are then optionally enteric coated by spraying onto them a suspension or solution of an enteric
`coating polymer and a plasticizer.
`
`EXAMPLE 3
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`[0024]
`A powder mixture for producing both the first and second layers of the final tablet is prepared as a mixture
`of 99.5% by weight microcrystalline cellulose and 0.5% magnesium stearate.
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`EXAMPLE 4
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`[0025]
`The final composition is then made on a two-layer tablet press.
`[0026]
`The powder mixture from example 3 is loaded into the hoppers that supply both feed frames so that both lay-
`ers of the final composition will be comprised of this same mixture. However, just before each die passes under the first
`feed frame, a tablet of example 1 is inserted into each die; and similarly just before each die passes under the second
`feed frame a tablet of example 2 is inserted into each die.
`[0027]
`After the die passes out from under the second feed frame, an upper punch is inserted and pressure is
`applied between the upper and lower punches to compress the contents of the die into the final tablet of the invention.
`The upper punch is then withdrawn, and the lower punch is raised from below to eject the tablet.
`[0028]
`It will be understood that the small tablet comprising misoprostol is thereby incorporated into the lower layer
`of the tablet and the small tablet comprising the diclofenac sodium is incorporated between the two layers of the tablet
`or at the bottom of the upper layer.
`
`Claims
`
`1. A pharmaceutical composition in the form of a tablet comprising misoprostol and an NSAID and comprising two lay-
`ers, wherein one of the misoprostol and the NSAID is incorporated into only one of the two layers and the other of
`the misoprostol and NSAID either is incorporated into the other of the two layers or is incorporated between the two
`layers.
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`EP 1 020 182 A2
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`2. A composition of claim 1 wherein the misoprostol is incorporated into only one of the two layers and the NSAID
`either is incorporated into the other of the two layers or is incorporated between the two layers.
`
`3. A composition of claim 1 or 2 wherein the misoprostol is incorporated into a tablet that is substantially smaller than
`the composition and said tablet is incorporated into one of the two layers.
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`4. A composition of any of claims 1 to 3, wherein the NSAID is incorporated into a tablet that is substantially smaller
`than the composition and said tablet is incorporated into the one of the two layers or is incorporated between the
`two layers.
`
`5. A composition of claim 4 wherein the NSAID is incorporated into a tablet that is substantially smaller then the com-
`position and the said tablet is enteric coated.
`
`6. A composition of any of claims 1 to 5 wherein the NSAID is diclofenac or a salt thereof.
`
`7. A composition of claim 6 wherein the amount of diclofenac or salt thereof is from about 25 to about 75 mg.
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`8. A composition of claim 6 or 7 wherein the NSAID is diclofenac sodium.
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`9. A composition of any of claims 1 to 8 wherein the amount of misoprostol is about 200 micrograms.
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