(12) INTERNATIONAL APPLICATIO]
`(19) World Intellectual Property
`Organization
`International Bureau
`
`Doc Ref. FP22
`App]. No. 11/273,575
`
`1
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`1
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`JTENT COOPERATION TREATY (PCT)
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`llllllIllllillllIlllllllllllllllIlllllllllllIlllllllllllllllllllllllllllllllIllllflllllllllllll
`
`
`
`(43) International Publication Date
`WO 2005/079748 A2
`1 September 2005 (01.09.2005)
`
`
`(10) International Publication Number
`
`(51) International Patent Classification":
`
`A61K 9/00
`
`(21) International Application Number:
`PCT/EPZOO5/001154
`
`(22) International Filing Date: 4 February 2005 (04.02.2005)
`
`(25) Filing Language;
`(26) Publication Language:
`
`mg“
`English
`
`(30) Priority Data:
`ES
`13 February 2004 (13.02.2004)
`P 200400338
`(71) Applicant (for all designated States except US): LACER,
`S.A. [ES/ES]; Calle Sardenya 350, E-08025 Barcelona
`(E3).
`
`(72) Inventors; and
`JURADO
`only):
`(for US
`(75) Inventors/Applicants
`SANCHEZ, Francisco [ES/ES]; 4, calle Garcia Lorca1
`
`E-08860 Castelldefels (ES). DE PABLO SEDANO,
`Marta [ES/ES]; 628-630,
`calle Mallorca, E-08026
`Barcelona (ES). ARGILAGA CAMPANO, Monica
`[ES/ES]; 13, calle Can Farell, 12-08186 Llica de Munt
`(ES)-
`
`(74) Agent: SUGRANES-VERDONCES-FERREGIJELA;
`(Association No.
`121), 304, Calle Provenza, E-08008
`Barcelona (ES).
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AT, AU, AZ BA, 1313, BG’ BR, BW, BY, BZ, CA, CH, CN’
`CO, CR, CU, CZ, DE, DK, DM: D2, EC, EE: EG, ES, FL
`GB, GD: GE. GH, GM, HR, HU, ID, IL, IN, 15,313 KB.
`KG, KP, KR, KZ, 1c, LK, LR, LS, LT, LU, Lv, MA, MD,
`MG, MK, MN, Mw, Mx, Mz, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, 'I'l‘, TZ, UA, UG, US, UZ,VC,VN, YU,ZA, ZM,
`ZW.
`
`[Continued on next page]
`
`(54) Title: PHARMACEUTICAL PREPARATION FOR SUSTAINED RELEASE OF A PHARMACEUTICALLY ACTIVE IN-
`GREDIENT
`
`(57) Abstract: Pharmaceutical preparation for sustained release
`of a pharmaceutically active
`ingredient A pharmaceutical
`preparation for sustained release of a pharmaceutically active
`ingredient(s), which preparation comprises particles having an
`inner core (1) and a first coating (2) provided thereon, wherein
`said coating (2) contains a mixture of: (a) between 50% and 95%
`by weight of a copolymer of ethyl acrylate, methylmethacrylate
`and trimethylamminoethyl methacrylate chloride in a molar ratio
`of the three acrylates of 1
`: 1.8-2.2 : 0.08-0.12, preferably of
`12:01, (b) between 2% and 30% by weight of a copolymer of
`ethylacrylate and methacrylic acid in a molar ratio of l: 0.8-1.2,
`preferably of 1:1, and (c) between 1 % and 40% by weight of the
`pharmaceutically active ingredient.
`
`(3’ b
`
`[2) a, b, c
`
`(2“, a
`
`‘3’ b
`
`(2‘) c
`
`(2‘) a, b
`
`(31 b
`
`(2“) c. b
`
`
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`W02005/079748A2l||||||||||||||l||||l||||l||||||||||l|||||ll|l||l|l|l|||||||||||||||l|||||||||||||||||||||||||l
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`

`

`WO 2005/079748 A2
`
`IlllllIllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllflllllllllflll
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD. RU, TJ, TM).
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT. LT, LU, MC, NL, PL. PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`-— without international search repon and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations " appearing at the begin-
`ning ofeach regular issue of the PCT Gazette.
`
`

`

`WO 2005/079748
`
`PCT/EP2005/001154
`
`PHARMACEUTICAL PREPARATION FOR SUSTAINED RELEASE OF
`
`A PHARMACEUTICALLY ACTIVE INGREDIENT
`
`Field of the invention
`
`The present
`
`invention relates to a pharmaceutical preparation for
`
`sustained release of a pharmaceutically active ingredient.
`
`10
`
`Technical background
`
`For many applications it is desirable to use an oral preparation with
`
`modified release characteristics, to control the timing of release, the
`
`location of drug release in the gastro-intestinal tract or the temporal
`
`15
`
`release profile of a drug.
`
`One of the most common modified release preparations is such wherein
`
`the active ingredient or the pharmaceutical product is provided with a
`
`coating of enteric, i.e. gastric juice-resistant material, which is insoluble
`
`20
`
`in the acid environment of the stomach (ca. pH 1 to 3), but dissolves in
`
`the weakly acidic to weakly alkaline region of the duodenum (pH > 5.5).
`
`This type of preparation allows to control
`
`the location of release
`
`dependent on pH of the gastro-intestinal tract, and also results in a
`
`delayed release (i.e. delayed by the time spent in an acid environment).
`
`25
`
`Such particles are e.g. used to protect the gastric lining from certain
`
`compounds. or to protect acid-instable active ingredients from the harsh
`
`gastric environment. that would result in their immediate inactivation.
`
`This type of modified release preparation can further be developed to
`
`30
`
`exhibit an equivalent pH-optimum for release that corresponds to the pH
`
`normally encountered in particular sections of the intestinal tract. Thus, a
`
`more differentiated
`
`control of
`
`the
`
`location
`
`of
`
`release of
`
`the
`
`pharrnaceutically active ingredient can be achieved.
`
`35
`
`Many such modified release preparations comprise multi-layered
`particles, wherein the active ingredient is usually located close to the
`
`centre, optionally on or in a neutral particle, which then is coated with a
`
`

`

`WO 2005/079748
`
`PCT/EP2005/001154
`
`-2-
`
`material of desired solubility in a defined portion of the intestine. A further
`
`layer may consist of an enteric coating,
`
`i.e. gastric juice-resistant
`
`material. This type of preparation is exemplified in EP 0 720 473 that
`describes budesonide particles with a controlled release profile. which
`
`comprise from the inside to the outside: (a) a neutral particle. (b) an
`
`active substance layer comprising micronized budesonide and one or
`
`more water—soluble auxiliary agents, (c) a first lacquer layer comprising
`
`lacquers which are insoluble in gastric juice and soluble or insoluble in
`
`intestinal juice. and (d) a second lacquer layer consisting of lacquers
`
`10
`
`insoluble in gastric and intestinal juices.
`
`Other preparations primarily resuit in a temporally protracted liberation of
`
`the active ingredient from the galenic preparation, so-wlled sustained
`
`release preparations. This can be a necessity. for example, for active
`
`15
`
`ingredients that exhibit a short plasma half-life, but need to act over a
`
`prolonged time to achieve the pharmaceutical effect. Sustained release
`
`preparations can help to avoid repetitive dosing, which is prone to human
`
`error and uncomfortable for the patient.
`
`20
`
`Such sustained release preparations can comprise.
`
`for example. a
`
`sponge-like polymeric matrix in which the active
`
`compound is
`
`incorporated. Diffusion, mechanical and chemical erosion of the matrix in
`
`the course of gastro-intestinal passage results in the liberation of the
`
`active ingredient from the matrix over a prolonged period.
`
`25
`
`Alternatively,
`
`sustained release
`
`can be achieved by composite
`
`preparations that comprise particles (also called pellets, particles, grains,
`
`microtablets or granules) with different polymer coatings. The coatings
`on the different particles differ in their solubility. The solubility of the
`
`30
`
`coating layers can be adjusted to the local pH value of the digestive tract,
`
`as outlined above. Thus, in the finished medicament (for example, hard
`
`gelatine capsules) a mixture of laminated particle is present which
`
`releases the active ingredient in different portions of the digestive tract.
`
`Such a preparation results in the control of both the lomtion and timing
`
`35
`
`of release of the active ingredient.
`
`

`

`WO 2005/079748
`
`PCT/EP2005/001 154
`
`-3-
`
`Also. release characteristics can be modified by protecting the active
`
`ingredient by a coating layer of a certain thickness and a defined pH-
`
`dependent solubility. When the thick layer is slowly degraded in the
`
`intestinal environment, degradation is not even at the entire surface of
`
`the particle. Thus, at some places clefts or pores may form that allow
`
`initial
`
`liberation of active ingredient. As the coating layer is further
`
`degraded, an increasing amount of the active ingredient layer is exposed
`
`and can dissolve. ,
`
`In particular for highly active drugs, a slow and tightly controlled release .
`
`must be achieved, to prevent temporal “spikes" of plasma levels to occur.
`
`The sustained release preparations wherein the active ingredient layer is
`
`covered by a layer of a polymer of a certain solubility may not achieve
`
`the desired level of reproducibility and control of release.
`
`Obviously, for many active ingredients the control of both the location
`
`within the gastrointestinal tract and the timing of release is beneficial.
`
`Preparations
`
`exist
`
`that
`
`combine
`
`layers with
`
`delayed-release
`
`characteristics, e.g. by employing polymers with a pH-dependent
`
`solubility with layers that provide sustained-release characteristics e.g.
`
`by using water insoluble polymer matrixes with a defined permeability for
`
`the active ingredient.
`
`Frequently, different Eudragit® polymers are used for the different
`coating layers outlined above.
`Eudragit® L100 is a copolymer of
`
`methacrylic acid and methylmethacrylate combined in a certain ratio and
`
`is insoluble in an acidic environment, for example in the stomach, and
`
`therewith forms a largely impermeable protective layer well-know like the
`enteric coating. Eudra'git® L100-55 is a copolymer of methacrylic acid
`
`and ethylacrylate, whereby the ratio of the monomers is chosen in such a
`
`manner that it is insoluble at a pH inferior to 5.5, but is soluble at a pH
`
`above this.
`
`Another type of polymers widely used are exemplified by Eudragit®RS
`(low permeability) or Eudragit®RL (high permeability). These polymers
`
`are water—insoluble, and independently of pH form membranes of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`W0 2005/079748
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`PCT/EP2005/001154
`
`-4-
`
`differing permeability. The mixing ratio of RSIRL and the layer thickness
`
`defines the permeability characteristics of the resulting preparation.
`
`Furthennore, mixtures of polymers with pH dependent solubility, such as
`Eudragit®L and polymers that form water-insoluble diffusion barriers,
`such as Eudragit®RL or RS are known in the art.
`
`Preparations with coating layers comprising mixtures of
`
`insoluble
`
`polymers and such with pH dependent solubility are exemplified by EP 0
`
`10
`
`377 517.
`
`It describes a sustained release pharmaceutical preparation
`
`which comprises a core particle with a theophylline compound
`
`embedded therein and a coating thereon including (i) a polymeric matrix,
`
`which is substantially insoluble independent of pH, (ii) an enteric polymer
`
`whose solubility is pH dependent, and (iii) an at least partially water
`
`15
`
`soluble component.
`
`A different kind of mixed layer is disclosed in US 5,175,003. It describes
`
`a galenic preparation comprising particles with a mixed layer of a
`
`polymer with pH dependent
`
`solubility. an active pharmaceutical
`
`20
`
`ingredient and hydroxyethyl cellulose, or hydroxypropyl cellulose, or
`
`shellac, or mixtures thereof.
`
`25
`
`30
`
`35
`
`A mixture of the active ingredient with a certain kind of polymer is also
`
`known in the art. EP 1 060 743 discloses a dosage form of cisapride for
`
`sustained release. This dosage form comprises a layer wherein a single
`
`type of an enteric polymer with pH dependent solubility, such as eg.
`Eudragit®L and cisapride are mixed.
`
`The insoluble or partially soluble polymers used in the prior art are rather
`
`expensive and their thickness cannot be reduced beyond a certain limit
`
`to ensure a sustained release after passing the stomach. Furthermore,
`
`the degree of sustained release achievable by coating layers of a certain
`
`thickness is inadequate for some applications. Furthermore. the degree
`
`of pH-dependent solubility is inadequate for some applications.
`
`Thus, it is desirable to provide a galenic preparation that has well defined
`
`delayed- and sustained-release characteristics, an improved sustained-
`
`

`

`WO 2005/079748
`
`PCT/EP2005/001154
`
`-5-
`
`release profile (i.e. slower liberation of active ingredients), an improved
`
`pH-dependent solubility and at the same time a minimized use of
`expensive excipients such as the Eudragit® polymers.
`
`Summary of the invention
`
`The present
`
`invention provides a solution to these problems, by
`
`providing a pharmaceutical preparation for sustained release of a
`
`pharmaceutically active ingredient, which preparation comprises particles
`
`1O
`
`having an inner core (1) and a first coating (2) provided thereon, wherein
`
`said coating (2) contains a mixture of:
`
`(a)
`
`between 50% and 95% by weight of a copolymer, preferably 60 to
`
`80 percent by weight of ethyl acrylate, methylmethacrylate and
`
`15
`
`trimethylammonioethyl methacrylate chloride in a molar ratio of the three
`
`acrylates of 1
`
`: 1.8—2.2 : 0.08-0.12, preferably 1:2:O.1, (Eudragit ® RS)
`
`and
`
`(b)
`
`between 2% and 30% by weight. preferably 5 to 20 percent by
`
`20
`
`weight of a copolymer of ethyl acrylate and methacrylic acid in a molar
`
`ratio of 1: 0.8-1.2, preferably of 1:1, (Eudragit ® L 100-55) and
`
`(c)
`
`between 1% and 40% by weight, preferably 5 to 15 percent by
`
`weight of the pharmaceutically active ingredient; wherein the percent
`
`25
`
`values of components (a), (b) and (c) relate to coating (2) only;
`
`and optionally, a second coating (3) thereon, which comprises an enteric
`
`coating. Said second coating (3) is particularly preferable in cases where
`acid-sensitive active ingredients are used, or such that have the potential
`
`30
`
`to irritate the gastric mucosa. Furthermore, said second coating (3) is
`
`preferably employed to minimize in-vivo variability of drug delivery, as
`
`gastric delivery of the drug is avoided.
`
`Surprisingly, when using a pharmaceutical preparation according to the
`
`35
`
`invention, comprising a mixed layer of components (a), (b) and (c) on an
`
`inner core, a more prolonged release profile can be obtained as
`
`compared to prior art preparations.
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`

`

`W0 2005/079748
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`PCT/EP2005/001154
`
`Moreover, the present preparation shows a surprisingly high and reliable
`
`sensitivity to varying pH conditions. This means that the sustained
`
`release can be adjusted very accurately to broader pH ranges than it
`
`was possible for prior art preparations. Thus it is possible to precisely
`
`modify the delivery of the drug in accordance with pH conditions
`
`encountered in the gastrointestinal tract having a physiological pH-range
`
`of approximately 1.5 to 8.
`
`10
`
`15
`
`A particular advantage of the present invention resides in the surprising
`
`finding that a lower amount of insoluble or partially soluble polymers can
`
`be used compared to the sustained release preparations of the prior art
`
`which however still has a comparable sustained release profile as prior
`
`art preparations.
`
`An additional advantage of the present invention is the fact that the
`
`production process of the pharmaceutical preparation contains fewer
`
`steps, and thus is shorter. easier to perform, and therefore economically
`
`preferable. This advantage is due to the use of only one mixed active
`
`20
`
`ingredient / polymer layer where prior art uses two separate layers of
`
`active ingredient and polymer (irrespective of further layers that may be
`
`present).
`
`Brief description of the drawings
`
`25
`
`30
`
`Figure 1: a schematic cross section of particles according to the
`
`invention (A) and different prior art particles (B) and (C). The prior art
`
`particles are made of the same basic components in the same amounts
`as (A), namely insoluble ccpolymer (a) and ccpolymer (b) with pH
`
`dependent solubility (e.g. Eudragit ® RS and Eudragit ® L 100-55,
`
`respectively) and a pharmaceutically active ingredient (c). but comprising
`
`layers with different compositions of said components.
`
`Figure 2: Release profiles (% dissolution over time) of particles and
`
`35
`
`reference particles at pH=6. a) 0.4 mg Tamsulosin particles according to
`
`Example 1 and Reference Example 1, b) 0.4 mg Diltiazem particles
`
`according to Example 2 and Reference Example 2, c) 1 mg Diltiazem
`
`

`

`WO 2005/079748
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`PCT/EP2005/001154
`
`-7-
`
`particles of Example 3 and Reference Example 3. d) 0.6 mg Tamsulosin
`
`particles of Example 4 and Reference Example 4, and e) 0.6 mg
`
`Tamsulosin particles according to Example 5 and Reference Example 5.
`
`Figure 3: Release profiles
`
`(% dissolution over
`
`time) of 0.4 mg
`
`Tamsulosin particles according to Example 1 and Reference Example 1
`
`at two different ambient pH values (pH=6.0 and 6.8).
`
`Figure 4: Release profiles (% dissolution over time) of 0.4 mg Diltiazem
`
`1O
`
`particles according to (a) Example 2 and (b) Reference Example 6 at
`
`three different ambient pH values.
`
`Figure 5: Release profiles (% dissolution over time) of Tamsulosin
`
`particles according to Example 6 at four different ambient pH values
`
`15
`
`(pH=5.5, 6.0. 6.8, and 7.2).
`
`Figure 6: Release profiles (% dissolution over time) of three different
`
`batches A, B and C of particles according to Example 9 containing 0.4
`
`mg Tamsulosin and different amounts of copolymers (a) and (b) in layer
`
`2O
`
`(2) at ambient pH=6.8.
`
`Figure 7: Release profiles (% dissolution over time) of two different
`
`batches of Tamsulosin particles according to Example 6 and Example 10
`
`at two different ambient pH values ((a) pH= 6.0 and (b) pH =68).
`
`Figure 8: Release profiles (% dissolution over time) of Tamsulosin
`
`particles according to Example 6 at two different paddle stirring speeds.
`
`Detailed description of the invention
`
`25
`
`30
`
`“Sustained release” as used in the invention refers to any temporally
`
`protracted release of an active ingredient from a galenic preparation.
`
`This means that by physical or chemical measures related to the active
`
`ingredient and l or further excipients, fillers, coatings or other elements of
`
`35
`
`the galenic preparation. a more protracted release is achieved than in
`
`the absence of said physical or chemical measures.
`
`

`

`WO 2005/079748
`
`PCT/EP2005/001154
`
`-3-
`
`A “particle” as used in the invention refers to any kind of particles that
`
`can form part of or constitute a galenic preparation. Such particles
`
`comprise, but are not limited to pellets, granules, powder, grains, seed
`
`elements, tablets, wpsules. They can consist of a homogenous material,
`
`or comprise distinguishable layers or components. Particles may also be
`
`composite particles comprising smaller particles. Such composite
`
`particles may be tablets or capsules, but are not
`
`limited to such.
`
`Composite particles may comprise one or several
`
`types of smaller
`
`particles, wherein each type may consist of different
`
`layers and
`
`10
`
`substances. Composite particles may comprise smaller particles that
`
`comprise an enteric coating. Alternatively, an enteric coating may be
`
`applied to the whole composite particle, rather than to the smaller
`
`particles comprised therein.
`
`15'
`
`A “physiologically acceptable excipient” as used in the invention refers to
`
`any excipient used in pharmaceutical preparations for oral application
`
`generally known in the art. Such excipients are exemplified, but not
`
`limited to talcum. sucrose, corn starch, starch hydrolysates, sugar,
`
`lactose, micro crystalline cellulose. manitol, dextrose,
`
`triethyl citrate,
`
`20
`
`methacrylic acid polymers, cellulose derivatives, plasticizers, lubricants
`
`and/or release agents, and optionally coloured pigments and/or a
`
`silicone antifoam agents.
`
`A “Pharmaceutically active ingredient” as used in the invention relates to
`
`25
`
`any active ingredient that is suitable for oral administration, or can be
`
`made suitable for oral administration by providing a suitable galenic
`
`preparation. Such active ingredients comprise, but are not limited to
`
`Amlodipine, Budesonide, Candesartan, Cisapride, Diclofenac, Diltiazem,
`Donepezil, Fentanyl, Glimepiride, Mebeverine, Memantine, Nicardipine,
`
`30
`
`Olanzapine, Omeprazole, Ondansetron,
`
`Oxybitinin, Pramipexol,
`
`Ramipril, Risperidone, Rivastigmin, Tamsulosin, Theophylline, Tibolone,
`
`Tolterodine, Topiramate, or Trandolapril.
`
`Other active ingredients that can be administered orally include for
`
`35
`
`example, acidic compounds such as acetylsalicylic acid and Diclofenac
`
`(o—(2,6—dichloroanilino) phenyl) acetic acid). As these substances exhibit
`
`

`

`WO 2005/079748
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`PCT/EP2005/001154
`
`-9-
`
`side-effects which irritate or damage the mucosa of the stomach with
`
`longer use, they are often incorporated in modified-release preparations.
`
`Also, modified-release preparations are used to protect acid-instable
`
`active ingredients from the harsh gastric environment, that would result
`
`in their immediate inactivation. Among such acid-sensitive compounds
`
`are eg. the benzimidazole derivatives employed as a H+/K+-ATPase
`
`inhibitor for ulcer treatment, Omeprazole (5-methoxy-2(((4-methoxy-3,5—
`
`dimethyl-Z-pyridyl)methyl)—sulfinyl)-1H-benzimidazole), Lansoprazole (2-
`
`10
`
`(((3-methyI-4-(2,2,2-tn'fluoroethoxy)-2-pyridyl)methyl)-sultinyl)-1 H-
`
`benzimidazole) and Pantoprazole (5-difluoromethoxy—2—((3,4-dimethoxy-
`
`2-pyridyl)methyl)-sulfinyl)—1H-benzimidazole) which function as potent
`
`inhibitors in the secretion of gastric acid. Omeprazole has proven itself in
`
`the therapy of duodenal ulcer, gastric ulcer,
`
`reflux esophagitis and
`
`15
`
`Zollinger-Ellision syndrome. Parenteral and solid peroral medicaments
`
`are employed in this connection. Omeprazole. for example, has a half-
`life of less than ten minutes in aqueous solution at pH values under 4.
`
`Therefore,
`
`solid peroral medicines (tablets, pellets, granulates) of
`
`Omeprazole and derivatives must be completely protected against
`
`20
`
`gastric juice during passage through the stomach.
`
`Further typical active ingredients for modified release preparations, and
`
`in particular sustained release preparations, are such that have a short
`
`plasma half life. Then, sustained release preparations may reduce
`
`25
`
`dosing frequency.
`
`Particles according to the invention may comprise one or more active
`
`ingredient(s), wherein said active ingredients may be comprised in one
`
`or more of the particle layers
`
`30
`
`The present
`
`invention provides a pharmaceutical preparation for
`
`sustained release of a pharrnaceutically active ingredient, which
`
`comprises particles with layers made of different components. Such
`
`particles may contain an inner core, made of physiologically acceptable
`
`35
`
`excipients, preferred examples include, but are not limited to. sucrose,
`
`corn starch, hydrolysates of starch, sugar,
`
`lactose, micro crystalline
`
`cellulose, manitol, or dextrose. Such an inner core is also called inert
`
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`WO 2005/079748
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`PCT/EP2005/001154
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`-10-
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`core. Alternatively. the particles may contain an inner core comprising a
`
`pharmaceutically active ingredient. Such a core is also called active core.
`
`The size of the inner core is not limiting for the invention, as long as it is
`
`suitable for the desired pharmaceutical preparation. A person skilled in
`
`the art is familiar with the size and type of inner cores used for composite
`
`particles in pharmaceutiml preparations. The diameter of the inert core
`
`may vary from approximately 0.1 to 2 mm. In a preferred embodiment,
`
`the inner core has a diameter in the range of 0.4 to 0.8 mm, most
`
`10
`
`preferably of 0.5 mm. This core seed may be of such a diameter to
`
`provide a final particle having a diameter of approximately 0.3 to 2.5 mm.
`
`The core seeds may vary from approximately 5 to 95% by weight,
`
`preferably 50 to 90% by weight based on the total weight of the finished
`
`particles. For the purpose of reference, said core element in the following
`
`15
`
`is also referred to by the numerical (1).
`
`20
`
`25
`
`On the inner core (1) is applied a mixed layer formed by at least one
`
`active ingredient mixed with copolymers. and l or excipients and I or
`
`fillers (2) that according to the invention comprises:
`
`- 50% and 95% by weight of a copolymer of ethyl acrylate,
`
`methylmethacrylate and trimethylamminoethyl methacrylate chloride in a
`
`molar ratio of the three acrylates of 1 : 1.8—2.2 : 0.08-0.12, preferably of
`
`12220.1, also referred to as component (a) in the following,
`
`‘
`
`- between 2% and 30% by weight of a copolymer of ethylacrylate and
`
`methacrylic acid in a molar ratio of 1: 0.8-1.2, preferably of 1:1, also
`
`referred to as component(b) in the following, and
`
`30
`
`- between 1% and 40% by weight of the pharmaceutically active
`
`ingredient, also referred to as pharmaceutical ingredient(s) (c) in the
`
`following, and
`
`- plastifiers I lubricants l excipients, also referred to as component (d) in
`
`35
`
`the following.
`
`In a preferred embodiment, layer (2) comprises:
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`WO 2005/079748
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`PCT/EP2005/001154
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`-11-
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`-component (a)
`
`with 60 - 90% by weight of a copolymer of ethyl
`
`acrylate, methylmethacrylate and trimethylamminoethyl methacrylate
`
`chloride in a molar ratio of the three acrylates of 1 : 1.8—2.2 : 0.08-0.12,
`
`preferably of 12220.1,
`
`-component (b)
`
`with 5% - 20% by weight of a copolymer of
`
`ethylacrylate and methacrylic acid in a molar
`
`ratio of 1: 0.8-1.2,
`
`preferably of 1:1, and
`
`-pharmaceuticalingredient(s)(c)with 5% - 15% by weight of
`
`the
`
`pharmaceutically active ingredient(s), and
`
`- component (d) with plastifiers I lubricants l excipients.
`
`In an especially preferred embodiment of the invention the layer (2)
`
`consists of:
`
`10
`
`15
`
`-component (a)
`
`with 50 — 85% by weight of a copolymer of ethyl
`
`20
`
`acrylate, methylmethacrylate and trimethylamminoethyl methacrylate
`
`chloride in a molar ratio of the three acrylates of 1 : 1.8-2.2 : 0.08-0.12,
`
`preferably of 12:01,
`
`-component (b)
`
`with 10 - 30% by weight of a copolymer of
`
`25
`
`ethylacrylate and methacrylic acid in a molar
`
`ratio 'of 1: 0.8-1.2,
`
`preferably of 1:1,
`
`with 5 — 40% by weight of the
`— pharmaceutical ingredient(s) (c)
`pharmaceutically active ingredient(s),and
`
`30
`
`- component (d) with plastifiers I lubricants I excipients.
`
`In another preferred embodiment,
`
`further
`
`layers with or without
`
`pharrnaceuticaliy active compounds may be present.
`
`In a particularly
`
`35
`
`preferred embodiment. such further layer is an enteric coating. In another
`
`preferred embodiment, such further layer is a lacquer layer.
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`WO 2005/079748
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`PCT/EP2005/001 154
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`-12-
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`Pharmaceutical preparations comprising the components (a),
`
`(b) and
`
`pharmaceutical ingredient(s) (c) are well known in the art. However, it is
`
`not known to mix all three components in a single layer. The art teaches
`
`mixtures of components (a) and (b) as a separate layer applied on top of
`
`a layer comprising pharmaceutical ingredient(s) (c), or teaches a layer
`
`comprising a mixture of component (b) and pharmaceutical ingredient(s)
`
`(c), with a separate further layer comprising component (a).
`
`Surprisingly. the mixture of all three elements, components (a), (b) and
`
`10
`
`pharmaceutical ingredient(s) (c) results in improved characteristics of the
`
`pharmaceutical preparation with respect
`
`to sustained release, pH-
`
`sensitivity and amount of substances needed for a desired release
`profile.
`
`15
`
`When comparing release characteristics of particles according to the
`
`invention with prior art particles containing the same amounts of the
`
`individual components, but wherein pharmaceutical
`
`ingredient(s)
`
`(c)
`
`forms a separate layer that is coated by a layer comprising components
`
`(a) and (b), particles of the present invention exhibit improved release
`
`20
`
`characteristics. This means that the active compound is more slowly
`
`released, i.e. release is more sustained from particles according to the
`
`invention. This finding is unexpected, as in the prior art particles the
`
`mixed layer comprising components (a) and (b) covering the separate
`
`layer of the pharmaceutical ingredient(s) (c) must first be eroded at least
`
`25
`
`partially before pharmaceutical
`
`ingredient(s) (c) can be liberated.
`
`In
`
`contrast, one would assume, that in the present invention pharmaceutical
`
`ingredient(s) (c) can be liberated as soon as the mixed layer starts to
`
`erode or is exposed to the surrounding liquids. Unexpectedly this is not
`the case.
`'
`
`30
`
`35
`
`A further advantage of a pharmaceutical composition according to the
`
`invention is
`
`that where prior art uses two separate layers (e.g.
`
`pharmaceutical ingredient(s) (c) in one layer and components (a) and (b)
`
`in a separate layer, or pharmaceutical ingredient(s) (c), and component
`
`(b) in one layer and component (a) in a separate layer). the invention
`
`uses only one layer (components (a) and (b) and pharmaceutical
`
`ingredient(s) (c), all mixed in one single layer). In the fist case, each layer
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`W0 2005/079748
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`PCT/EP2005/001154
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`-13-
`
`is applied consecutively in the course of production. and is therefore
`
`associated with processing time and additional handling requirements.
`
`Thus, reduction of the absolute number of layers required to obtain a
`
`desired release profile results in shorter and less complex production
`
`processes which are associated with economic benefits.
`
`Furthermore, the composition according to the present invention exhibits
`
`a surprising effect regarding the pH-sensitivity of release of the active
`
`compound. This can be observed for particles containing all components
`
`10
`
`of the different layers in the same total amount in a pellet, but the
`
`composition of
`
`individual
`
`layers is different. Thus, where particles
`
`according to the invention have one mixed layer of all three elements
`
`(components (a), (b) and active ingredient (c)). state of the art pellets
`
`have two separate layers made of different mixtures of these three
`
`15
`
`elements (see also Figure 1A (particles of the invention), B and C
`
`(particles included in the state of the art».
`
`In particles included in the state of the art, the liberation of the active
`
`ingredient is sensible to small variations of ambient pH that result in
`
`different release profiles of the active ingredient over time. That means
`
`e.g. less active ingredient is released at an ambient pH=6 as at ambient
`
`pH=6.8. Such differences in the amount of active ingredient released can
`
`be observed at different time-points, thus resulting in different release
`
`profiles over time.
`
`20
`
`25
`
`Surprisingly,
`
`in particles according to the invention this sensitivity of
`
`active ingredient release to small pH changes was more pronounced as
`
`compared to prior art particles. That means. the active ingredient release
`was more strongly affected over a longer period of time as compared to
`
`30
`
`the prior art pellets. Thus, at
`
`time-points where prior art particles
`
`exhibited no difference in active ingredient
`
`liberation at different pH
`
`values (e.g. at 300 min after start of the dissolution at pH = 6 and pH=
`
`6.8). particles according to the invention still showed a different release
`
`of active ingredient at the same two pH values. Also, the degree to which
`
`35
`
`release was affected at such pH values was more pronounced for
`
`particles of the invention, as compared to prior art particles. This means,
`
`that the release profiles at different pH values were more different for the
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`

`WO 2005/079748
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`PCT/EP2005/001154
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`-14-
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`particles of the invention.
`
`In other words, e.g. the difference of active
`
`ingredient released at a certain pH value at a given time-point was bigger
`
`than the difference observed at the same pH values and time-point for
`
`state of the art particles.
`
`Moreover,
`
`the pH sensitivity of prior art particles is restricted to a
`
`narrower pH range. This means, pH-dependent differences in release
`
`profiles can e.g. only be observed for an ambient pH in the range of 6 to
`
`6.8, but not below or above that value. Thus, the release profiles at e.g.
`
`10
`
`pH=6.8 or 7.2 are indiscemible for the particles included in the prior art.
`
`in contrast. particles of the invention results in a different release profile
`
`over a wider range of pH values. In other words, the release profiles at
`
`an ambient pH of e.g. 7.2 is still different to one at e.g. pH=6.8.
`
`15
`
`Also, the pH sensitivity of the particles according to the invention is
`
`evenly graded over a wide pH range, e.g. from pH= 5.5 and pH= 7.2.
`
`This means, that the difference between release profiles at different
`
`ambient pH values like, e.g. 5.5 and 6.0 is similar to the difference in
`
`release profiles obtained to values of pH like, e.g. 6.8 and 7.2. In other
`
`20
`
`words, the differences in the amount of active ingredient released at any
`
`given time-point for differing ambient pH values are similar (e.g. between
`
`pH 5.5 and 6.0 or between pH 6.8 and 7.2).
`
`Such a reliable and predictable response to different pH values is a
`
`25
`
`prerequisite for precise control of the timing and the loca