`A1 (“EP ‘001”)  
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`Exhibit 1022
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`European Patent Application No. 0 453 001
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`J
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`Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
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`© Publication number:
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`0 4 5 3 0 0 1 A 1
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`E U R O P E A N PATENT A P P L I C A T I O N
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`© Application number: 91200173.2
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`© int. CIA A61K 9/24, A61K 9/54
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`@ Date of filing: 29.01.91
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`® Priority: 17.04.90 IT 2005490
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`@ Date of publication of application:
`23.10.91 Bulletin 91/43
`
`© Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE
`
`© Applicant: GIULIANI S.p.A.
`Via P. Palagi, 2
`1-20129 Milano(IT)
`
`© Inventor: Calanchi, Massimo
`Via Calatafimi, 12
`I-20052 Monza(IT)
`
`Inventor: Zema, Marco
`Via Verga, 10
`1-22100 Como(IT)
`Inventor: Brunetti, Gabriele
`Viale dei Mi lie, 27
`1-20100 Milan(IT)
`Inventor: Giorgetti, Enzo
`Via Palmanova, 191
`1-20100 Milan(IT)
`
`© Representative: Appoloni, Romano et al
`Ing. Barzano & Zanardo S.p.A. Via
`Borgonuovo 10
`1-20121 Milano(IT)
`
`© Pharmaceutical composition for the targeted controlled release of an active principle within the
`intestine, and particularly within the colon.
`
`© The invention provides pharmaceutical compositions with the property of targeted controlled release of
`active principles which act pharmacologically within the intestine and in particular within the colon and the
`terminal portion of the ileum.
`To attain this object the active principle is prepared in multiparticle multidose form and is covered with at
`least two membranes, one of pH-dependent solubility and the other insoluble but permeable to the intestinal
`fluids.
`While the covered active principle remains in the stomach and in the initial intestinal portion, ie while the pH
`is less than 5.5, it is not released.
`Only when it reaches an environment of higher pH (small intestine or colon) does the pH-dependent
`membrane dissolve to commence release of the active principle.
`From this moment the second membrane, which is pH-independent but permeable to the intestinal fluids,
`acts to slow down and control the dissolution of the medicament within the small intestine-colon tract.
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`Rank Xerox (UK) Business Services
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`EP 0 453 001 A1
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`This invention relates to pharmaceutical compositions for obtaining targeted controlled release of active
`principles required to act pharmacologically within the intestine, and particularly within the terminal portion
`of the ileum and the colon.
`USA patent 4,503,030 relates to osmotic release tablets consisting of a core containing the medicament
`covered with a pH-dependent semipermeable membrane containing a hole connecting the core to the
`outside. The tablet remains integral in the stomach, release occurring through the hole in the membrane,
`whereas in the intestine the membrane disintegrates completely.
`USA patent 4,432,966 describes the preparation of tablets which disintegrate in the colon. This is
`obtained by covering the tablet core with two layers, the first consisting of a pH-independent polymer and
`10 microcrystalline cellulose, and the second a pH-dependent polymer.
`The microcrystalline cellulose together with the pH-independent polymer ensure disintegration of the
`tablet within the colon, as the microcrystalline cellulose is digested by specific enzymes and bacteria
`present in the colon.
`A problem relating to the use of such known compositions is the possible occurrence of mucosa
`irritation phenomena due to a high local medicament concentration.
`An object of the present invention is to solve this problem for determined classes of active principle.
`A requirement of the present invention is that the core or membrane of the pharmaceutical composition
`must not disintegrate within the colon, but instead the membrane must remain whole in order to slow down
`the dissolution of the medicament, and consequently prolong its action along the intestine, the colon and
`the terminal portion of the ileum, with a substantial improvement in the active principle absorption.
`The present invention is aimed at active principles which exhibit their activity within the intestine, and
`particularly in the colon. As is well known, certain diseases of the intestine, and particularly of the colon, are
`cured by active principles with topical action. It is therefore important for such active principles to be
`transported intact into the site in which their pharmacological action is to take effect.
`According to the present invention it is essential that the release of the active principle and its contact
`with the mucosa takes place along the entire colon. It is therefore necessary to slow down the release so
`that the effect is prolonged in time and acts on all parts subject to the disturbance and not only on the initial
`tract.
`The aforesaid objects are attained according to the present invention by a pharmaceutical composition
`for the targeted controlled release of an active principle within the intestine, and in particular within the
`terminal portion of the ileum and the colon, characterised in that said active principle is chosen from the
`following: antiinflammatory-antiphlogistic agents of local and general action, such as 5-aminosalicylic acid
`(or mesalazine) and analogous salicylic derivatives, peppermint oil, corticosteroids of the kind directed to
`the local treatment of chronic intestinal diseases of inflammatory and irritative type; said active principle
`35 being formulated in multiparticle multidose form, each particle thereof being covered with at least two
`membranes, one of which is soluble at a pH equal to or greater than 5.5 and the other of said membranes
`being insoluble at said pH but permeable to the intestinal fluids.
`The present invention is applicable to multiparticle multidose forms, ie to active principles prepared in
`particles in the form for example of crystals, granules, pellets or very small-dimension tablets (also known
`as minitablets), which are covered as described hereinafter. These covered active principles are then
`formulated as capsules, single-dose sachets, rapid disintegration tablets or other pharmaceutical forms
`suitable for oral administration.
`Thus according to the invention it has been found that by applying separately to the active principle
`particles a membrane of pH-dependent solubility and a membrane which is insoluble in but permeable to
`the intestinal fluids, the dissolution of the active principle is slowed down so that it is released slowly and
`can thus exercise its action along the entire colon. For example, if an active principle is covered with a
`membrane which dissolves at a pH greater than 6 there is very slow release in buffer solutions up to pH 6.2
`(first three hours). However, when the pH passes to 7.2 the composition rapidly dissolves.
`By applying over the first membrane another membrane which is insoluble in the intestinal fluids but
`so permeable to them, the release of the medicament is slowed down and the effect prolonged for a further 3
`hours. According to the invention the same result is obtained by applying firstly the delay membrane and
`then the pH-dependent membrane, whereas if the constituent substances of the two membranes are mixed
`together the delay effect is not obtained and instead the release is very similar to that obtained by applying
`only the pH-dependent polymer.
`The present invention therefore provides for applying in succession, in either order, a membrane
`soluble at a given pH and a membrane which is insoluble in but permeable to the intestinal fluids.
`In this manner the release of the active principle can be targeted towards a certain tract of the intestine
`(colon) and also be prolonged to thus make it effective along the entire remaining intestinal tract.
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`EP 0 453 001 A1
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`The dimensions of the individual units of the multidose forms, ie of the individual crystals, granules,
`pellets or minitablets, vary between 0.1 and 3.5 mm, it being in any event advisable not to exceed 5 mm. In
`this respect, the smaller the individual units the more widespread is their distribution within the gastrointes-
`tinal tract, and in addition whereas units exceeding 5 mm are retained in the full stomach, units of less than
`5 mm pass through the stomach more rapidly and in a manner similar to liquids. This phenomenon is
`described for example in the article by S.S. Davis entitled "The design and evaluation of the controlled
`release systems for the gastrointestinal tract" published in the "Journal of Controlled Release", 2 (1985) 27-
`38.
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`As the active principles are often in the form of fine powders, they are generally granulated using
`10 known wet or dry (compacting) methods, to obtain the desired particle size.
`It should be noted that in the following description, that which refers to active principles in granular form
`is also valid for the other multiparticle multidose forms, ie crystals, pellets, minitablets etc.
`The granulated active principle is placed in the container of a Glatt UNI fluidized bed provided with a
`Wurster insert and, by spraying with a suitable atomizer, is covered with a pH-dependent polymer dissolved
`in an organic solvent or in a mixture of organic solvents or in a mixture of organic solvent or solvents and
`water, or in an aqueous solution, dispersion or emulsion.
`It is also convenient to add plasticizers and adjuvants. Polymer types for forming the pH-dependent
`membrane include by way of non-limiting example: copolymers of methacrylic acid (Eudragit L, Eudragit S),
`cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, shellac,
`20 hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, cellulose acetate trimellitate,
`copolymers of maleic acid and phthalic acid derivatives.
`Plasticizers include by way of non-limiting example: polyethylene glycol, dibutyl phthalate, diethyl
`phthalate, citric acid esters. Other adjuvants include: talc, silicon dioxide, titanium dioxide, magnesium
`stearate.
`The covered granules are dried with hot air (about 50 C) for about 30 minutes.
`A second pH-independent membrane permeable to intestinal fluids is then applied to the granules
`covered with the pH-dependent membrane.
`Organic or aqueous solutions or aqueous dispersions/emulsions can again be used, and it is again
`convenient to add plasticizers and adjuvants of the aforesaid type.
`Polymer types for forming the pH-independent membrane include by way of non-limiting example:
`copolymers of methacrylic esters (Eudragit RS/RL/NE), ethylcellulose, polyethylene and polysiloxanes,
`either alone or mixed with each other or with other pH-independent polymers soluble in water, such as:
`hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcelluiose, polyvinylpyr-
`rolidone.
`The granules covered with the membranes are dried with hot air (about 50° C) for about 30 minutes.
`As already stated, the two membranes can be applied in the reverse order to that described.
`Some non-limiting examples of the practical implementation of the invention are described hereinafter.
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`EXAMPLE 1
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`800 g of 5-aminosalicylic acid granulated with hydroxypropylmethyl cellulose and having a particle size
`of between 710 and 1300 urn are placed in the container of a Glatt UNI fluidized bed provided with a
`Wurster insert.
`This granulate is covered with a first membrane of Eudragit S, by spraying with a suitable atomizer a
`suspension having the following composition: 468 g of methyiene chloride, 156 g of isopropyl alcohol, 55.6
`g of Eudragit S, 5.5 g of dibutylphthalate and 28 g of talc.
`The covered granules were dried with hot air (about 50° C) for 30 minutes and their release was then
`determined with the USP apparatus (bladed stirrer), using the following succession of artificial juices: 2
`hours in 0.1 N HCI; 1 hour in pH 6.2 buffer and the subsequent hours in pH 7.2 buffer.
`The following results were obtained:
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`time (hours)
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`release (%)
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`1
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`6
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`2
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`11
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`3
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`12
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`4
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`61
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`5
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`96
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`A second membrane of ethylcellulose was then applied to 700 g of these granules covered with Eudragit S,
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`EP 0 453 001 A1
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`by spraying the following solution: 199 g of methylene chloride, 44 g of ethyl alcohol, 4.3 g of ethyl
`cellulose, 8.6 g of hydroxypropylmethylcellulose and 1.5 g of diacetylated monoglycerides, and finally
`drying with air at 50° C for about 30 minutes.
`The granules covered with the two membranes were again tested in the aforedescribed manner,
`obtaining the following results:
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`time (hours)
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`release (%)
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`1
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`4
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`2
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`3
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`4
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`5
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`6
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`8
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`9
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`9
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`51
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`74
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`95
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`EXAMPLE 2
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`700 g of 5-aminosalicylic acid granulated with hydroxypropylmethyl cellulose and having a particle size
`of between 710 and 1300 urn are placed in the container of a Glatt UNI fluidized bed provided with a
`20 Wurster insert.
`This granulate is covered with a first membrane of ethylcellulose/hydroxypropylmethyicellulose, by
`spraying with a suitable atomizer a solution having the following composition: 200 g of methylene chloride,
`45 g of ethyl alcohol, 6.4 g of ethyicellulose, 6.4 g of hydroxypropylmethylcellulose and 1.4 g of
`diacetylated monoglycerides.
`The covered granules were dried with hot air (about 50° C) for 30 minutes and their release was then
`determined with the USP apparatus (bladed stirrer), using the following succession of artificial juices: 2
`hours in 0.1 N HCI, 1 hour in pH 6.2 buffer and the subsequent hours in pH 7.2 buffer.
`The following results were obtained:
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`time (hours)
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`r e l e a s e (%)
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`1
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`31
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`2
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`56
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`3
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`74
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`4
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`86
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`100
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`A second membrane of Eudragit S was then applied to these covered granules by spraying the following
`suspension^ 34 g of methylene chloride, 65 g of isopropyl alcohol, 23 g of Eudragit S, 2.3 g of dibutyl
`phthalate and 1 1.5 g of talc, and finally drying with air at 50° C for about 30 minutes.
`The granules covered with the two membranes were again tested in the aforedescribed manner,
`40 obtaining the following results:
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`time (hours)
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`release (%)
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`1
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`4
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`2
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`7
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`3
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`11
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`4
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`36
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`5
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`59
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`6
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`75
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`8
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`100
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`EXAMPLE 3 (comparison)
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`800 g of 5-aminosalicylic acid granulated with hydroxypropylmethyl cellulose and having a particle size
`of between 710 and 1300 um are placed in the container of a Glatt UNI fluidized bed provided with a
`Wurster insert.
`This granulate is covered with a membrane of ethylcellulose/hydroxypropylmethylcellulose/Eudragit S,
`55 by spraying with a suitable atomizer a suspension having the following composition: 836 g of methylene
`chloride, 418 g of isopropyl alcohol, 5.8 g of ethyicellulose, 11.8 g of hydroxypropylmethylcellulose, 58.7 g
`of Eudragit S, 3.7 g of dibutylphthalate and 29 g of talc.
`The covered granules were dried with hot air (about 45° C) for 30 minutes an their release was then
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`EP 0 453 001 A1
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`determined with the USP apparatus (bladed stirrer), using the following succession of artificial juices: 2
`hours in 0.1 N HCI, 1 hour in pH 6.2 buffer and the subsequent hours in pH 7.2 buffer.
`The following results were obtained:
`
`time (hours)
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`release (%)
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`1
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`3
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`2
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`5
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`3
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`6
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`4
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`54
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`5
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`89
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`6
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`100
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`w
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`75
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`20
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`A comparison of the results of the active principle release obtained with the pharmaceutical composi-
`tions of Examples 1 and 2 with the results obtained with the composition of the comparison Example 3
`demonstrates the advantages of the invention compared with the case in which a single membrane covering
`is provided. The applicant also conducted clinical tests with the pharmaceutical composition of Example 2,
`the methods used and the results obtained being described briefly below.
`A study was conducted on the release of the mesalazine contained in the composition of said Example
`2 within the terminal portion of the ileum and within the colon both of healthy volunteers and of patients
`suffering from ulcerative colitis and Crohn's disease, using radiological methods.
`To monitor the granule transit and dispersion within the intestinal tract each subject received one
`capsule of a test preparation containing 600 mg of iodamide granules, with a repeat test after 7 days.
`The location of the granules at the various levels and their dispersion were visually displayed by taking
`radiographs of the abdominal region, these being repeated every 2 hours until 10 hours from administration
`of the composition, and then after 12 or 24 hours if granules were still visible.
`The radiographs obtained were then examined in a blind test, the following parameters being consid-
`ered in radiographically evaluating the behaviour of the granules of said composition:
`1 ) homogeneous presence of granules in the jejunal ansa and ileal ansa;
`2) presence of granules in the distal ileum;
`3) presence of granules in the proximal colon;
`4) time for numerical reduction in the sense of an appreciable reduction in the granule quantity, to the
`extent of about 25% of the overall initial quantity;
`5) reduction in opacity in the sense of a significant attenuation in the radio-opacity of the granules;
`6) time for maximum numerical reduction in the sense of a considerable reduction in the granule
`quantity, of greater than 75%.
`The results obtained showed that the pharmaceutical composition of Example 2 of the present invention
`is able to release the active principle in accordance with the initially stated requirements, with radiologically
`determined dissolution taking place mainly in the proximal colon.
`
`Claims
`
`40 1. A pharmaceutical composition for the targeted controlled release of an active principle within the
`intestine, and in particular within the terminal portion of the ileum and the colon, characterised in that
`said active principle is chosen from the following: antiinflammatory-antiphlogistic agents of local and
`general action, such as 5-aminosalicylic acid (or mesalazine) and analogous salicylic derivatives,
`peppermint oil, corticosteroids of the kind directed to the local treatment of chronic intestinal diseases
`of inflammatory and irritative type; said active principle being formulated in multiparticle multidose form,
`each particle thereof being covered with at least two membranes, one of which is soluble at a pH equal
`to or greater than 5.5, the other of said membranes being insoluble at said pH but permeable to the
`intestinal fluids.
`
`45
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`50 2. A composition as claimed in claim 1 , characterised in that said active principle is covered with a first
`membrane soluble at said pH values, this first membrane being covered with a second membrane
`insoluble at said pH values but permeable to the intestinal fluids.
`
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`3. A composition as claimed in claim 1 , characterised in that the active principle is covered with a first
`membrane insoluble at said pH values but permeable, and being covered with a second membrane
`soluble at said pH values in natural or artificial fluids.
`
`4. A composition as claimed in claim 1, characterised in that said active principle in multiparticle
`
`

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`EP 0 453 001 A1
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`multidose form is in the form of crystals, granules, pellets or minitablets having a particle size
`distribution of between 0.1 and 3.5 mm.
`
`5
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`5. A composition as claimed in claim 1 , characterised in that said membrane soluble at a pH equal to or
`greater than 5.5 consists of one or more of the following polymers: copolymers of methacrylic acid
`(Eudragit L, Eudragit S), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl
`acetate phthalate, shellac, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose,
`cellulose acetate trimellitate, copolymers of maleic acid and phthalic acid derivatives.
`
`w 6. A composition as claimed in one or more of the preceding claims, characterised in that the membrane
`insoluble at said pH values but permeable to the intestinal fluids consists of copolymers of methacrylic
`esters (Eudragit RS/RL/NE), ethylcellulose, polyethylene and polysiloxanes, either alone or mixed with
`each other or with other pH-independent polymers soluble in water, such as hydroxypropylmethylcel-
`lulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone.
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`7. A composition as claimed in claim 5, characterised in that said membrane (pH-dependent) consists of
`Eudragit S.
`
`8. A composition as claimed in claim 6, characterised in that said membrane (pH-independent) is
`ethylcellulose, or ethylcellulose mixed with hydroxypropylmethylcellulose in a ratio varying from 1:3 to
`3:1.
`
`9. A composition as claimed in claim 1 , characterised in that said membranes comprise further compo-
`nents such as plasticizers, preferably consisting of polyethylene glycol, dibutyl phthalate, diethyl
`phthalate, or citric acid esters.
`
`10. A composition as claimed in claim 1, characterised in that said membranes also comprise adjuvants,
`preferably consisting of talc, silicon dioxide, titanium dioxide or magnesium stearate.
`
`30 11. A composition as claimed in claim 1, characterised in that said active principle is 5-aminosalicylic acid
`(or mesalazine).
`
`12. A composition as claimed in claim 1, characterised in that said active principle is peppermint oil.
`
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`

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`European
`Patent Office
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`J
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`EUROPEAN S E A R C H
`R E P O R T
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`D O C U M E N T S CONSIDERED TO BE R E L E V A N T
`Relevant
`Citation of document with indication, where appropriate,
`to claim
`of relevant passages
`
`Category
`
`X
`
`X
`
`X
`
`EP-A-0 239 361
`(KINAFORM TECHNOLOGY.INC.)
`* the whole document *
`
`(LEJUS MEDICAL AKTIEBOLAG)
`EP-A-0 1 48 81 1
`* the whole document *
`
`EP-A-0 212 745
`PANY)
`* the whole document *
`
`(THE PROCTER AND GAMBLE COM-
`
`WO-A-8 503 437 (A/S ALFRED BENZON)
`* the whole document *
`
`A,D
`
`GB-A-2 066 070
`(ROUSSEL-UCLAF)
`* the whole document & US-A-4432966 *
`
`GB-A-2 134 785
`LTD. A/S)
`* the whole document *
`
`(LEO PHARMACEUTICAL PRODUCTS
`
`1,3-6,
`8-11
`
`1 ,3-1 1
`
`1-2,4-7,
`9-11
`
`1 ,3-1 1
`
`1 ,3-1 1
`
`1-12
`
`Application Number
`
`EP 91 20 0 1 7 3
`
`CLASSIFICATION OF THE
`APPLICATION (Int. CI.5)
`
`A 61 K 9/24
`A 61 K 9/54
`
`TECHNICAL FIELDS
`SEARCHED (Int. C1.5)
`A 61 K
`
`The present search report has been drawn up for all claims
`Date of completion of search
`Place of search
`21 June 91
`Berlin
`CATEGORY OF CITED DOCUMENTS
`X : particularly relevant if taken alone
`Y : particularly relevant if combined with another
`document of the same catagory
`A: technological background
`O: non-written disclosure
`P : intermediate document
`T : theory or principle underlying the invention
`
`Examiner
`SIATOU E
`E : earlier patent document, but published on, or after
`the filing date
`D : document cited in the application
`L : document cited for other reasons
`& : member of the same patent family, corresponding
`document