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`PCT /DK98/00388
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`9
`
`the processing of the ingredients to obtain the first fraction (cf. Danish Patent
`
`Application filed on 10 September 1998 in the name of Nycomed Danmark). In those
`
`cases, where a coating is present on the units of the first fraction, the coating may of
`
`course also contribute to the control of the release of the active drug substance from
`
`5 the first fraction. In the second fraction, the release rate is primarily governed by the
`
`constitution and thickness of a controlled release membrane which are applied on pellet
`
`cores (also denoted "pellets").
`
`The delayed and extended fraction is based on the application of a release controlling
`
`1 0 membrane. The release is being controlled by the membrane which makes the
`
`formulation much more robust and easier to manipulate and manufacture. Ideally there is
`
`no release controlling effect from the uncoated units of the second fraction, i.e. the
`
`uncoated multiple-units of the second fraction do not significantly contribute to any
`
`control of the extended release of the active drug substance but the uncoated multiple-
`
`1 5 units merely release the active drug substance freely without any significant retardation.
`
`The modified release multiple-units dosage forms of the present invention achieve and
`
`maintain therapeutic levels and, at the same time, reduces the risks for any side effect,
`
`which are believed to be associated with high blood levels of NSAID substances.
`
`20 Furthermore, the delayed or extended release properties of the coating applied on the
`
`second fraction of the multiple-units dosage forms of the present invention are
`
`unaffected by the pH in the gastro-intestinal tract.
`
`The first fraction of the multiple-units dosage form of the invention may also be in the
`
`25 form of coated multiple-units provided that the release rate of such a fraction is so fast
`
`in the dissolution medium employed in dissolution method II described herein that at
`
`least 50% w/w of the total dose of the first fraction is released within the first 20 min.
`
`When a coating is present on the multiple-units of the first fraction then it could
`
`30 advantageous be of the same kind as an outer coating on the multiple-units of the
`
`second fraction. The employment of the same kind of coating for each fraction may be
`
`performed with substantially identical procedures and materials and the production cost
`
`can be kept at a low level.
`
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`wo 99/12524
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`PCT /DK98/00388
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`DETAILED DISCLOSURE OF THE INVENTION
`
`10
`
`Accordingly, the present invention relates to an oral pharmaceutical modified release
`
`multiple-units composition in unit dosage form for administration of a therapeutically
`
`5 and/or prophylactically effective amount of a non-steroid anti-inflammatory drug
`
`substance (an NSAID substance), a unit dosage form comprising two NSAJD-containing
`
`fractions,
`
`i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID
`
`10 substance, and
`
`ii) a second NSAID-containing fraction of multiple-units for extended release of the
`
`NSAID substance,
`
`1 5 the first fraction which - when subjected to dissolution method II as defined herein
`
`employing 0.07 N HCI as dissolution medium -releases at least 50% w/w of the NSAJD
`
`substance present in the fraction within the first 20 min of the test,
`
`the second fraction being in the form of coated delayed release multiple units for
`
`20 extended release of the NSAID substance.
`
`As discussed above it is very important to secure that the release pattern of the active
`
`drug substance contained in the composition is suitable for a composition for
`
`administration once or twice daily. The employment of at least two different fractions of
`
`25 multiple-units gives very flexible formulation parameters. Thus, it is possible to vary i)
`
`the percentage of the total dose of the NSAID substance contained in each fraction and
`
`ii) the weight ratio between the different fractions. The system (i.e. formulation
`
`concept) is therefore very suitable to not only one specific drug substance but can
`
`within certain limits be applied on a class or many classes of active drug substances
`
`30 once the target release profile has been determined. Of course, a change from one
`
`active drug substance to another active drug substance may give rise to certain
`
`adjustments of the constitution of the individual fractions to the specific substance. In
`
`the following is given a discussion of how to determine a target profile for an active
`
`drug substance and the release requirements generally applicable for the group of active
`
`35 drug substances belonging to the non-steroid anti-inflammatory drug substances.
`
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`PCT !OK98/00388
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`Dissolution requirements
`
`11
`
`As described in the following, a target release profile can be designed for any NSAID
`
`5 substance. In the following the target release profile for a selected NSAID substance is
`
`described, namely lornoxicam.
`
`Based on the knowledge of the pharmacokinetics of lornoxicam and a study performed
`
`by us employing a plain tablet and a solution (Hitzenberger G, Radhofer-Welte S, Takacs
`
`10 F, Rosenow D.: Pharmacokinetics of lornoxicam in man, Postgrad. Med. J. 1990, 66, pp
`
`S22-S26), a target in vivo profile for a once daily product has been estimated (Figure 1 ).
`
`The presumptions made in estimating this target profile were:
`
`15 i) a double peak and an effective concentration for 24 hours are desired from a
`
`therapeutic point of view {i.e. plasma lornoxicam concentrations at 24 hours should be
`
`similar to the plasma concentration obtained 8-1 2 hours after administration of half the
`
`dose in the form of a plain tablet),
`
`20 ii) that the first fraction of the composition should have an absorption rate similar to or
`
`faster than that of plain tablets
`
`iii) that the peak concentration should not be higher than the peak concentration
`
`observed after administration of half the dose in the form of a plain tablet, and
`
`25
`
`iv) that the second peak should appear about 5-6 hours after dosing.
`
`A person skilled in the art is capable of determining the actual values with respect to the
`
`above-mentioned provisions and based on such values perform any necessary correction
`
`30 to the estimated profile (target profile).
`
`The estimated target plasma profile as well as the profile from plain tablets have been
`
`deconvoluted with plasma concentrations from an oral solution to give an estimated in
`
`vivo dissolution profile (Figure 2). All data were normalised to a dose of 16 mg. In the
`
`35 deconvolution a time interval of 0.5 hours was employed {cf. Langenbucher F., and H.
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`12
`
`Meller: Correlation of in vitro drug release with in vivo response kinetics. Part 1:
`
`Mathematical treatment of time functions. Pharm. Ind. 1983, 45, pp 623-8 and
`
`Langenbucher F. and H. Meller: Correlation of in vitro drug release with in vivo response
`
`kinetics. Part II: Use of function parameters. Pharm. Ind. 1983, 45, pp 629-33).
`
`5
`
`The presumptions in making this deconvolution were that the daily dose of lornoxicam is
`
`the same irrespective of whether a once daily composition or a plain tablet or a solution
`
`were administered,
`
`1 0 The estimated in vivo dissolution profile for a once daily product can be used as the
`
`target in vitro profile for the combination of a fast or quick release fraction (i.e. the first
`
`fraction) and an extended or slow release fraction (i.e. the second fraction, coated
`
`pellets). The estimated in vivo dissolution profile for the once daily composition can be
`
`used as the target in vitro profile, when performing the dissolution tests in vitro with 1
`
`15 hour in 0.1 N HCI and then shift to phosphate buffer pH 7.3 or 7.4 (dissolution methods
`
`Ill or IV described herein). This knowledge has been utilized in order to arrive at the
`
`dissolution requirements described in the following.
`
`The presumptions made in using the estimated in vivo profile as target for in vitro profile
`
`20 were:
`
`i) that a plain tablet will remain in the stomach for about 1 hour before a passage into
`
`the intestine takes place {estimated from the difference in T max between the solution
`
`(0.5 hours) and the plain tablet (1.5 hour),
`
`25
`
`ii) that the correlation between the in vitro dissolution and the in vivo dissolution is a
`
`1:1 correlation, and
`
`iii) that lornoxicam is absorbed through the whole gastrointestinal tract (including colon)
`
`30 in order not to loose any amount of active drug substance ready for absorption into the
`
`circulatory system.
`
`Before going into detail with respect to the release requirement to the first fraction, the
`
`second fraction and the composition in its final form, in the following is given details
`
`

`
`wo 99/12524
`
`PCT IDK98/00388
`
`with respect to the target release profile for a once daily lornoxicam composition. The
`
`target profile has been estimated as described above.
`
`13
`
`Target release in vivo profile {corresponds to target release profile in vitro employing
`
`5
`
`dissolution methods Ill or IV as described herein):
`
`Time (hours)
`
`% w /w released lornoxicam
`
`0.5
`
`1
`
`10
`
`2
`
`3
`
`4
`
`5
`
`6
`
`15
`
`7
`
`8
`
`9
`
`10
`
`12
`
`20
`
`16
`
`20
`
`24
`
`21 {range: 1 0-25%)
`
`29 (range: 15-35%)
`
`37 (range: 25-45%)
`
`42 {range: 30-55%)
`
`52 (range: 40-65%)
`
`62 (range: 45-70%)
`
`69 (range: 50-75%)
`
`75 (range: 55-80%)
`
`79 {range: 60-85%)
`
`83 {range: 60-90%)
`
`86 {range: 60-95%)
`
`89 (range: 65-99%)
`
`94 (range: at least about 85%)
`
`97 (range: at least about 90%)
`
`100 (range: at least about 90%)
`
`As apparent from the above, the first fraction must release the active drug substance
`
`25 very quickly in 0.1 N HCI or in the dissolution medium employed in dissolution method II
`
`described herein, i.e. under conditions simulating the conditions in the stomach and
`
`under these conditions the second fraction does not release any significant amount of
`
`the active drug substance. In this connection it is important to note that even if the
`
`second fractions does not release any significant amount of the active substance within
`
`30 the first 20 min or 1 hours under acidic conditions, then the controlled release coating is
`
`not necessarily designed as an enteric coating, i.e. a coating which is insoluble at acidic
`
`pH and soluble at neutral/basic pH. The compositions according to the invention
`
`exemplified in the experimental section are examples on compositions wherein the
`
`controlled release coating of the second fractions is not an enteric coating. Furthermore,
`
`35 application of an enteric coating on e.g. pellets would not lead to an extended release of
`
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`PCT/DK98/00388
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`an active drug substance. The release will of course be delayed (no release under acidic
`
`conditions) but as the pH becomes neutral and alkaline, then the enteric coating
`
`dissolves, Leo there is no membrane left to control the release.
`
`14
`
`5 Notably, the release of the active drug substance from the first fraction is at least 55%
`
`w/w such as, e.g., at least about 60% w/w, at least about 65% w/w, at least about
`
`70% w/w, at least about 75% w/w or at least about 80% w/w of the total NSAID
`
`substance present in the first fraction within the first 20 min of the test, i.e. the
`
`dissolution method II (pH corresponding to 0.07 N HCI) as defined in the experimental
`
`10 section.
`
`In one embodiment the composition may comprise modified release multiple units
`
`wherein the in vitro dissolution characteristics of the first fraction of quick release
`
`multiple-units within 0.5 hour provides a release as defined by the dissolution methods II
`
`1 5 as described herein of at least about 50% w /w, at least about 60% w /w, at least about
`
`70% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w
`
`or at least about 95% w/w calculated on the total amount of active drug substance
`
`contained in the first fraction.
`
`20 In addition, the composition may comprise modified release multiple units wherein the in
`
`vitro dissolution characteristics of the first fraction of quick release multiple units within
`
`1 hour provides a release as defined by the dissolution methods II described herein of at
`
`least about 50% w/w, such as, e.g., at least about 60% w/w, at least about 70% w/w,
`
`at least about 80% w/w, at least about 85%, at least about 90% w/w or at least about
`
`25 95% w/w calculated on the total amount of active drug substance in the first fraction.
`
`As apparent from the discussion above, the overall release characteristics with respect
`
`to release of the active drug substance from the final composition are composed of the
`
`release characteristics of the first and the second fraction of multiple-units, respectively.
`
`30 With regard to compositions containing an NSAID substance intended for administration
`
`once or twice daily, the present inventors have found that the release characteristics of
`
`the second fractions most suitably should have the following order of magnitude
`
`provided that the release characteristics of the first fraction are as discussed above.
`
`

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`WO 99/12524
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`PCT/DK98/00388
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`15
`
`Accordingly, the in vitro dissolution characteristics of the second fraction of extended
`
`release multiple units may in one embodiment within 1 hour provide a release as defined
`
`by the dissolution method Ill described herein in the range of 0%- about 30% w/w, such
`
`as, e.g., in the range of 0%- about 20% w/w, in the range of 0%-about 1 O%w/w such
`
`5 as about 5% w/w calculated on the total amount of active drug substance in the second
`
`fraction.
`
`Furthermore, the in vitro dissolution characteristics of the second fraction of extended
`
`release multiple units may within 3 hours provide a release as defined by the dissolution
`
`10 method Ill described herein in the range of about 10%-70% w/w, such as, e.g., in the
`
`range of about 10%-60% w/w, in the range of about 12%-50% w/w, in the range of
`
`14%-45% w/w, in the range of about 15%-30% w/w, in the range of about 15%-20%
`
`w/w such as, e.g., about 17% w/w of the NSAID substance.
`
`15 Within 6 hours, the in vitro dissolution characteristics of the second fraction of extended
`
`release multiple units may provide a release as defined by the dissolution method Ill
`
`described herein in the range of about 35%-95% w/w, such as, e.g., in the range of
`
`about 50%-90% w/w, in the range of about 50%-80% w/w, in the range of 50%-75%
`
`w/w, in the range of about 50%-60% w/w, in the range of about 53%-59% w/w such
`
`20 as, e.g. about 56% w/w of the NSAID substance.
`
`In addition, within 9 hours the in vitro dissolution characteristics of the second fraction
`
`of extended release multiple units may provide a release as defined by the dissolution
`
`method Ill described herein in the range of about 50%-100% w/w, such as, e.g., in the
`
`25 range of about 60%-98% w/w, in the range of about 65%-95% w/w, in the range of
`
`about 70%-90% w/w, in the range of about 70%-80% w/w such as, e.g., about 76%
`
`w/w of the NSAID substance.
`
`To ensure that the final composition has a proper constitution with respect to the
`
`30 weight amount of first fraction relative to the amount of second fraction, the
`
`in vitro dissolution characteristics of the first and second fractions are in one
`
`embodiment adapted so that the first fraction is substantially released when the release
`
`from the second fraction is initiated, corresponding to at least 50% w/w release of the
`
`first fraction at the time at the most about 15% w/w such as, e.g., at the most about
`
`35 10% or at the most about 5% w/w of the second fraction is released, as measured by
`
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`16
`
`the dissolution method Ill described herein. in addition, the in vitro dissolution
`
`characteristics of the first and second fractions in the same or a second embodiment as
`
`mentioned above are adapted so that the first fraction is substantially released when the
`
`release from the second fraction is initiated, corresponding to at least 70% w/w release
`
`5 of the first fraction at the time at the most about 20% w/w such as, e.g., at the most
`
`15% w/w or at the most about 10% w/w of the second fraction is released, as
`
`measured by the dissolution method Ill described herein.
`
`Apart from the requirements to the individual fractions contained in the composition it is
`
`1 0 of course of utmost importance to ensure that the composition in its final form has in
`
`vitro dissolution characteristics which give evidence for a suitable in vivo behaviour, i.e.
`
`a fast onset of the effect together with an extended release of the active drug
`
`substance to ensure a therapeutic and/or prophylactic effect upon administration once
`
`or twice daily.
`
`15
`
`The two fractions of multiple units may be selected, with respect to the release from
`
`each fraction and the ratio between the two fractions, so that the in vitro dissolution
`
`characteristics of the composition within 1 hour provide a release of the NSAID
`
`substance in the first and second fractions in the range of from about 5% w/w to about
`
`20 50% w/w, such as, e.g., in the range of from about 5% w/w to about 45% w/w, in
`
`the range of from about 15% w/w to about 40% w/w, in the range of from about 20%
`
`w/w to about 35% w/w such as about 29% w/w, as defined by the dissolution method
`
`Ill described herein.
`
`25 In addition, the two fractions of multiple units may be selected, with respect to the
`
`release from each fraction and the ratio between the two fractions, so that the in vitro
`
`dissolution characteristics of the composition within 3 hours provide a release as
`
`defined by the dissolution method Ill described herein in the range of from about 20%
`
`w/w to about 80% w/w, such as, e.g., in the range of from about 25% w/w to about
`
`30 70% w/w, the range of from about 30% w/w to about 60% w/w, in the range of from
`
`35% w/w to about 55% w/w such as about 42% w/w.
`
`In an additional aspect, the two fractions of multiple units may be selected, with respect
`
`to the release from each fraction and the ratio between the two fractions, so that the in
`
`35 vitro dissolution characteristics of the composition within 6 hours provide a release as
`
`

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`PCT /DK98/00388
`
`17
`
`defined by the dissolution method Ill described herein in the range of from about 40%
`
`w/w to about 98% w/w, such as, e.g., in the range of from about 50% w/w to about
`
`95% w/w, in the range of from about 60% w/w to about 90% w/w, in the range of
`
`from about 60% w/w to about 85% w/w, in the range of from about 60% to about
`
`5 83% such as about 69-70% w/w.
`
`Furthermore, the two fractions of multiple units may be selected, with respect to the
`
`release from each fraction and the ratio between the two fractions, so that the in vitro
`
`dissolution characteristics of the composition within 9 hours provide a release as
`
`10 defined by the dissolution method Ill described herein in the range of from about 50%
`
`w/w to about 100% w/w, such as, e.g., in the range of from about 60% w/w to about
`
`99% w/w, in the range of from about 70% w/w to about 98% w/w, in the range of
`
`from about 70% w/w to about 97% w/w, in the range of from about 75% w/w to
`
`about 96% w/w, such as in the range of from about 80% w/w to about 96%, such as
`
`15 about 80-85% w/w.
`
`In a preferred embodiment, the composition fulfils the above criteria with respect to the
`
`dissolution characteristics of the composition in the full time span mentioned.
`
`20 The percentage of NSAID substance in the first fraction is in the range of about 5%-
`
`50% w/w such as, e.g., in the range of about 10%-45% w/w, in the range of about
`
`15%-45% w/w, in the range of about 20%-40% w/w, in the range of about 25%-40%
`
`w/w, in the range of about 25%-35% w/w such as, e.g., about 30% w/w, calculated
`
`on the total amount of NSAID substance in the composition.
`
`25
`
`The percentage of NSAID substance in the second fraction is in the range of about
`
`30%-99% w/w such as, e.g. in the range of about 40%-98% w/w, in the range of
`
`about 45%-95% w/w, in the range of about 50%-95% w/w, in the range of about
`
`55%-85% w/w, in the range of about 60%-80% w/w, in the range of about 60%-75%
`
`30 w/w, in the range of abut 65%-75% w/w such as, e.g., about 70% w/w, calculated on
`
`the total amount of NSAID substance in the composition.
`
`In a preferred embodiment, the multiple units of the second and, when appropriate, the
`
`first fraction are coated, cross-sectionally substantially homogeneous pellets.
`
`35
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`18
`
`It is preferred that the multiple units of the first fraction result in a peak plasma
`
`concentration of the NSAID substance which is substantially the same as the peak
`
`concentration resulting from the second fraction. As the peak plasma concentration of
`
`the second fraction is adapted so that plasma concentration has a prolonged character
`
`5 due to the dissolution characteristics of the fraction described herein, the peak of this
`
`second fraction should preferably substantially represent the upper level of the
`
`therapeutic plasma concentration. In a preferred embodiment, the plasma concentration
`
`level is of such a size that no NSAID substance is in excess.
`
`1 0 Since the total amount of NSAID substance contained in the first fraction is balanced
`
`compared to the total amount of NSAID substance in the composition, a peak plasma
`
`concentration of NSAID substance derived from the first fraction which is higher than
`
`the peak concentration resulting from the second fraction does not necessarily represent
`
`a substantial waste of the NSAID substance.
`
`15
`
`20
`
`25
`
`However, unless the patient suffers from heavy breakthrough symptoms wherein a
`
`higher plasma concentration than the plasma concentration for maintaining symptom
`
`alleviation often seems to be needed, the concentrations obtained from the first fraction
`
`should not exceed the peak from the second fraction.
`
`Even in the circumstances wherein the peak of the first fraction is preferably higher than
`
`the peak from the second fraction, unsuitable high plasma concentrations (within the
`
`toxic level) derived from the first fraction may easily be avoided by adjusting the amount
`
`of active drug substance contained in the first fraction.
`
`In another embodiment, e.g. in the circumstances wherein the patient is well treated by
`
`administration once or twice a day with a composition according to the invention, the
`
`first fraction may be adapted so that it results in a peak plasma concentration of the
`
`NSAID substance which is lower than the peak concentration resulting from the second
`
`30 fraction. This would not necessarily result in breakthrough symptoms as the NSAID
`
`substance remaining in the plasma from the previous dosage administered may
`
`contribute to maintaining the plasma concentration sufficiently high until the second
`
`fraction of the composition is released. In other cases, the daily dosage may be admini(cid:173)
`
`stered at a suitable time of the day when the patient has experienced less need for the
`
`35 NSAID, e.g. before bedtime.
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`19
`
`Accordingly, an important aspect of the invention is an embodiment wherein the first
`
`fraction results in a therapeutically active plasma concentration of the NSAID substance
`
`until the delayed release of an NSAID substance from the second fraction of modified
`
`5 release multiple units contributes to the maintenance of a therapeutically active plasma
`
`concentration of the NSAID substance.
`
`As discussed above, the multiple-units of the first fraction may be in the form of
`
`uncoated pellet cores, coated pellet cores, granules, a granulate or small plain tablets
`
`10 provided that the requirements with respect to release of active drug substance in 0.1 N
`
`HCI and under conditions as those described under dissolution method II herein are
`
`fulfilled. In those cases, where the first fraction is in the form of coated pellets,
`
`the time lag of the release from the second fraction relative to the first fraction may be
`
`obtained by a modified release coating of the second fraction which is present in a
`
`15 range of about 2%-80% such as, e.g., about 2%-70%, about 2-60%, about 3-50%,
`
`about 3-40%, about 4-30%, about 5-20% or about 2-5%, relative to the uncoated unit.
`
`It is also preferred that the modified release coating of the fraction(s) is substantially
`
`water-insoluble, but water-diffusible and substantially pH-independent which will
`
`20 facilitate an absorption independent of the presence of food in the stomach.
`
`Dosage
`
`In general, the dosage of the active drug substance present in a composition according
`
`25 to the invention depends inter alia on the specific drug substance, the age and condition
`
`of the patient and of the disease to be treated.
`
`Compositions according to the invention intended for once daily administration will
`
`generally contain a daily dose of the active drug substance whereas compositions
`
`30 according to the invention intended for twice daily administrations will generally contain
`
`half the daily dose of the active drug substance. However, the daily dose may be
`
`divided into several dosage forms.
`
`In the following is listed the recommended daily doses for selected NSAID substances.
`
`35
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`20
`
`Aceclofenac: 200 mg
`
`Diclofenac: 1 00 mg
`
`Etodolac: 400 mg
`
`Fenbufen: 900 mg
`
`5 Fenoprofen: 1.5 g
`
`Flurbiprofen: 200 mg
`
`Ibuprofen: 1.6 g
`
`lndometacin: 1 00 mg
`
`Ketoprofen: 200 mg
`
`10 Meloxicam: 1 5 mg
`
`Nabumeton: 1 g
`
`Naproxen: 750 mg
`
`Piroxicam: 20 mg
`
`Sulindac: 300 mg
`
`15 Tenoxicam: 20 mg
`
`Tiaprofenic acid: 600 mg
`
`Tolfenamic acid: 400 mg
`
`Tolmetin: 800 mg
`
`20 The amount of an NSAID substance of the modified release multiple-units composition
`
`according to the invention may be selected so that is corresponds to about 1 mg, 2 mg,
`
`3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 16 mg, 20 mg, 24 mg, 25 mg, 30 mg, 32
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`mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg,
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`800 mg, 900 mg, 1 g, 1 .1 g, 1.2 g, 1 .3 g or 1 .6 g of NSAID substance which are
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`25 dosages generally known in the art. However, the composition according to the
`
`invention preferably comprises an amount of an NSAID substance which is a daily
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`therapeutically effective amount of the NSAID substance.
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`Generally, with conventional dosage forms such as plain tablets comprising an NSAID
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`30 substance, it is not always possible to obtain identical release profiles when different
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`dosages are administered together as the load of active ingredient may differ depending
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`on the size of the tablet. The release profile for 1 00 mg given in a single dosage may
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`thus differ from 1 00 mg given as 5 dosages comprising 20 mg each. Not even with the
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`commercially available modified release dosage forms, a substantially identical release
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`35 profile within the different dosages is always observed.
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`With a composition according to the present invention, it is now possible to administer
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`different dosages with identical release profiles (ct. results reported in the experimental
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`section). For example, if each modified release multiple-units composition according to
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`5 the invention is prepared with the same type of multiple units of the first and second
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`fractions and in the same ratios, each of the dosage forms may be administered
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`together to obtain any desired total dosage without altering the overall release profile
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`from the total dosage. Accordingly, reliable and predictable plasma concentrations
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`during the complete time span between administration may be obtained independently
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`10 of the total dosage.
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`Therefore, a further advantage of the composition according to the invention is that the
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`composition may be produced in different series of dosage forms of e.g. 4 mg, 8 mg,
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`12 mg, 16 mg, 24 mg, 32 mg etc., each of the series having individual properties
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`1 5 resulting from the design of modified release of the first and second fractions as well as
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`from the ratio between the fractions. Any desired total dosage can then be selected
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`from the relevant dosage forms within each of the series.
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`The preferred dosage form according to the invention is in the form of a capsule, tablet,
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`20 sachet etc. The size of the dosage form is adapted to the amount of the NSAID
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`substance of the composition.
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`The above suggested dosage amounts should not be regarded as a limitation of the
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`scope of the invention as it is obvious for the skilled person that any desired amount of
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`25 the NSAID substance may be applied and is only limited by the size of the composition
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`and the type of the NSAID substance.
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`The overall goal of the present invention is to provide a composition in unit dosage form
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`for the administration of a therapeutically effective amount of an NSAID substance once
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`30 a day. However, as some patients may still need to, or prefer to, receive administration
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`twice a day, the invention should not be limited to a once-a-day composition as long as
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`each of the unit dosage forms fulfils the criteria with respect to the dissolution
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`mentioned above.
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`In a further aspect, the invention relates to a process for the preparation of an oral
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`pharmaceutical modified release composition, the process comprising incorporating into
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`the unit dosage at least two fractions as follows:
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`22
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`5 a first fraction of quick release multiple-units for relatively quick release in vivo of an
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`NSAID substance to obtain a therapeutically or prophylactically active plasma
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`concentration within a relatively short period of time, and a second fraction of coated
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`extended release multiple-units for extended release in vivo of an NSAID substance to
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`maintain a therapeutically active plasma concentration in order to enable dosing once or
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`1 0 twice daily,
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`the formulation of the first and the second fractions, with respect to release therefrom
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`and with respect to the ratio between the first and the second fraction in the unit
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`dosage, being adapted so as to obtain:
`
`15
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`a relative quick in vitro release of the NSAID substance from the first fraction of quick
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`release multiple-units, as measured by the dissolution method II defined herein,
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`an extended in vitro release of the NSAID substance from the second fraction of
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`20 extended release multiple-units relative to the in vitro release of the first fraction of the
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`NSAID substance, as measured by the dissolution method Ill as defined herein, the
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`quick release and the extended in vitro release being adapted so that the first fraction is
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`substantially released when the release from the second fraction is initiated
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`corresponding to at least about 50% w/w release of the NSAID substance contained in
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`25 the first fraction at the time when about 5% w/w of the NSAID substance contained in
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`the second fraction is released as measured by the dissolution method Ill as defined
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`herein.
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`Definitions of selected terms used herein
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`30
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`The term "modified release multiple-units composition" used in the present context is
`
`defined as the release of the drug differs from that of a traditional composition. The
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`release rate is in other words controlled and it is possible to manipulate the release rate
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`by means of e.g. changing the formulation parameters. The rate is often controlled in
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`35 such a manner that the plasma concentration levels are maintained for the longest
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`23
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`possible period above the therapeutic (the therapeutically active) level, but below the
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`toxic level. However, the term "modified" is not restricted to an extended or prolonged
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`effect, the term ~~modified" may as well cover the situation where the release rate is
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`manipulated in such a manner that a quicker release than normally expected is obtained.
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`5 Thus, in the present context the terms "quick" , "fast" and "enhanced" release as well
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`as "controlled", "delayed", "sustained", prolonged", "extended" and other synonyms
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`well known to a person skilled in the art are covered by the term "modified".
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`The term modified release in the present context refers to a composition which can be
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`1 0 coated or uncoated and prepared by using pharmaceutically acceptable excipients and/or
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`specific procedures which separately or together are designed to modify the rate or the
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`place at which the active ingredient or ingredients are released (Ph. Eur. 97).
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`The term "extended release" in the present context refers