(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`28 December 2000 (28.12.2000)
`
` ll|||l|||||l|||||||||l|ll||IIIIIIHIIIIIIII|||||||l||I|l|||I|lllllllllllllllllll
`
`PCT
`
`(10) International Publication Number
`W0 00/78293 A1
`
`(51) International Patent Classification7:
`A61P 1/04
`
`A61K 9/36,
`
`(21) International Application Number:
`
`PCT/SE00/01310
`
`(22) International Filing Date:
`
`20 June 2000 (20.06.2000)
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, M2,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM,
`TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`9902386-3
`
`English
`_
`Enghsh
`
`22 June 1999 (22.06.1999)
`
`SE
`
`(71) Applicant (for all designated States except US): AS-
`TRAZENECA AB [SE/SE]; S-151 85 Sodertalje (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): LUNDBERG, Per,
`Johan [SE/SE]; AstraZeneca R & D Molndal, 8-431 83
`Molndal (SE). SJOBLOM, Brita [SE/SEJ; AstraZeneca R
`& D Mfihldal, S—431 83 Molndal (SE).
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG,
`CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments.
`
`(74) Agent: ASTRAZENECA AB; Global Intellectual Prop-
`erty, Patents, S—151 85 Sodertalje (SE).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations ” appearing at the begin—
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: NEW FORMULATION
`
`Semipermeable membrane
`
`Separate swelling layer
`
`'1
`
`Active ingredient containing part
`
`= core material
`
`Starter seed (e.g. Non Pareil)
`
`||||l|||||||||||||||||llllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`
`
`
`00/78293A1
`
`(57) Abstract: An oral dosage form comprising a core material coated with a semipermeable membrane wherein the core material
`0 comprises an active ingredient selected from the group of omeprazole, an alkaline salt thereof, S-omeprazole and an alkaline salt
`thereof, in admixture with one or more alkaline additives, one or more swelling agents, and optionally phannaceutically acceptable
`excipients, and the dosage form is not entetic coated.
`
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`

`

`WO 00/78293
`
`PCT/SE00/01310
`
`NEW‘FORMULATION
`
`Field of the invention
`
`The present invention relates to new oral pharmaceutical dosage forms comprising as
`
`active ingredient omeprazole, an alkaline salt of omeprazole, S—omeprazole or an alkaline
`
`salt of S-omeprazole. The dosage form comprises a core material of the active ingredient,
`
`one or more alkaline additives, and one or more swelling agents, wherein the core material
`
`is covered with a semipermeable membrane and without an enten'c coating. Furthermore,
`
`the invention refers to the manufacture of such dosage forms and their use in medicine.
`
`Background of the invention and prior art.
`
`The acid labile H+, K+-ATPase inhibitor known under the generic name omeprazole is
`
`disclosed in EP-0005129. Certain salts of omeprazole are described in EP-124495, a
`
`magnesium salt of omeprazole is described in WO 95/01977, and the single enantiomers of
`
`omeprazole and certain salts thereof are described in WO 94/27988.
`
`Omeprazole is useful for inhibiting gastric acid secretion in mammals including man by
`
`controlling gastric acid secretion at the final step of the acid secretory pathway and thus
`
`reduce basal and stimulated gastric acid secretion irrespective of stimulus.
`
`In a more
`
`general sense, omeprazole may be used for prevention and treatment of gastric-acid related
`
`diseases in mammals and man, including e. g. reflux oesophagitis, gastritis, duodenitis,
`
`gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. Furthermore, it may be used
`
`for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is
`
`desirable e. g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, and in
`
`patients with symptomatic gastro—oesophageal reflux disease (GORD). Omeprazole may
`
`also be used in patients in intensive care situations, in patients with acute upper
`
`gastrointestinal bleeding, pre—and post-operatively to prevent aspiration of gastric acid and
`
`to prevent and treat stress ulceration. Further, it may be useful in the treatment of psoriasis
`
`10
`
`15
`
`25
`
`30
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`WO 00/78293
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`PCT/SE00/01310
`
`as well as in the treatment of Helicobacter infections and diseases related to these where
`
`therapeutic control of gastric acid secretion is fundamental in the treatment.
`
`Omeprazole is, however, susceptible to degradation or transformation in acidic and neutral
`
`media. The stability of omeprazole isalso affected by moisture, heat, organic solvents and
`to some degree by light. With respect to the stability properties of omeprazole, it is
`
`established that an oral solid dosage form must be protected from contact with the acidic
`
`gastric juice and that omeprazole must be transferred in intact form to that part of the
`
`gastrointestinal tract where pH is near neutral and where rapid absorption can occur.
`
`5
`
`l0
`
`A pharmaceutical dosage form of omeprazole is best protected from contact with acidic
`
`gastric juice by an enteric coating layer. For instance, US 4,786,505 describes such enteric
`
`coated formulations. These formulations have a core comprising an alkaline salt of the
`
`drug or a core comprising the drug together with an alkaline reacting compound, the core is
`
`15
`
`coated with a water soluble or in water rapidly disintegrating separating layer and further
`
`with an enteric coating layer. There are numerous published patent applications from
`
`different companies describing enteric coated formulations comprising omeprazole or
`
`other proton pump inhibitor compounds.
`
`20 WO 96/01623 describes tableted dosage forms of omeprazole, wherein enteric coating
`
`layered pellets are compressed into a multiple unit tableted dosage form. It is essential in
`
`these tableted formulations that the enteric coating layer can withstand the compression
`
`forces.
`
`[9 (.1
`
`There are different technologies and pharmaceutical formulations described in the prior art
`
`which provide a delayed release of an administered drug. Such formulations are for
`
`instance based on osmotic differences, slow-eroding/dissolving layers, diffusion through a
`
`membrane, time controlled explosion systems or any combinations thereof. In the
`
`following some of these principles are exemplified. For instance, US 4 871 549 describes a
`
`30
`
`time controlled explosion system. Conte et a1 (Drug Development and Industrial
`
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`WO 00/78293
`
`PCT/SE00/01310
`
`Pharmacy, 1989, vol. 15, pp. 2583 —96) describes a three-layer tablet giving a double
`
`pulsed system suitable for ibuprofen. US 5 5 67 441 describes a dosage form for diltiazem
`
`comprising a mixture of one fraction of slow release pellets and another fraction of delayed
`
`pulse release membrane coated pellets. WOW/02020 describes a dosage form of
`
`m
`
`pantoprazole in combination with antibacterial substances wherein one part of the
`
`pantoprazole dose is in slow release form with a continuously release during time. US 5
`
`178 867 describes a dosage form with an exit port or hole that connects the interior of the
`
`dosage form with the exterior.
`
`l0
`
`Summary of the invention
`
`The present invention provides — in contrast to earlier presented oral dosage forms for
`
`proton pump inhibitor compounds - a dosage form without an enteric coating layer.
`
`15
`
`The dosage form according to the present invention comprises a core material coated with
`
`a semipermeable membrane. The core material contains an active ingredient selected from
`
`omeprazole, an alkaline salt thereof, S—omeprazole or an alkaline salt thereof, one or more
`
`alkaline additives, and one or more swelling agents. The semipermeable membrane is able
`
`to disrupt or may change its permeability after a pre-determinated time. One or more
`
`20
`
`swelling agents are placed in the core material to effectuate a disruption or an increased
`
`permeability of the semipermeable membrane after such a suitable time. Optionally
`
`pharmaceutically acceptable excipients such as an osmotic agent may also be included in
`
`the core material.
`
`25
`
`Surprisingly, the formulation according to the present invention is prepared without an
`
`enteric coating, which previously have been almost an axiom for dosage forms containing
`
`omeprazole or any other proton pump inhibitor compounds. The present invention also
`
`provides the possibility to avoid the separating layer needed under an enteric coating layer
`
`to separate omeprazole from the enteric coating polymer. Omeprazole should preferably
`
`30
`
`not be in contact with the enteric coating due to discoloration and degradation of
`
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`

`WO 00/78293
`
`PCT/SE00/01310
`
`omeprazole. Thus, the present invention provides a simplified process than previous
`
`manufacture processes requesting double coating layers on the core material. See for
`
`instance, EP 247 983.
`
`U!
`
`According to a further aspect of the present invention, the dosage form may preferably be
`
`in the form of a multiple unit pellet system. The prepared core material, in the form of
`
`small pellets coated with a semipermeable membrane and without an enteric coating may
`
`be filled into a capsule or compressed into a multiple unit tablet.
`
`10
`
`The core material comprises an alkalizing agent, that is sufficiently alkaline and is present
`
`in a sufficiently high amount. The core material also comprises a swelling agent that upon
`
`contact with moisture starts to swell. When the coated pellets pass the stomach small
`
`amounts of gastric fluid will be absorbed through the semipermeable membrane. The
`
`alkalizing agent in the core material will neutralize the absorbed acidic fluid and protect
`
`15
`
`the active ingredient against degradation. At the same time the swelling agent, will be
`
`exposed to the penetrating fluid or moisture, and it will start to expand. After a pre-
`
`determined time interval this expansion leads to disruption of the superimposed
`
`semipermeable membrane by the built—up pressure or to a swelling that will increase the
`
`permeability of the membrane. The time interval is to be determined so that the pellets
`
`20
`
`have had time to pass the stomach at that very moment, and have reached the small
`
`intestines. The entire dose of the active ingredient will then start to be released into the
`
`small intestine where absorption can occur.
`
`Detailed description of the drawings
`
`25
`
`Figures 1 — 4 illustrate principles for construction of dosage forms according to the present
`
`invention. The invention comprises a core material layered with a semipermeable
`
`membrane. The core material can be prepared according to at least four different principles
`
`as shown in the Figures. The drawings are not intended to illustrate the size or relative
`
`30
`
`sizes of the dosage form or its different parts.
`
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`WO 00/78293
`
`PCT/SE00/01310
`
`Detailed description of the invention
`
`The present invention provides a core material in the form of pellets or small tablets coated
`
`u.
`
`with a semipermeable membrane. The composition of the core material protect the active
`
`ingredient against the gastric fluid, that permeates through the semi permeable coating
`
`during the pellet’s passage through the stomach. Such pellet formulations are generally
`
`emptied from the stomach within 2-4 hours. When the pellets have left the stomach, the
`
`semipermeable membrane covering the individual pellets disrupts‘and/or starts to release
`
`10
`
`the active ingredient in the small intestine.
`
`The pellets coated with the semipermeable membrane may be filled into capsules prepared
`
`from gelatine or hydroxypropyl methylcellulose (HPMC), be filled into sachets or be
`
`mixed with tablet excipients and compressed to a fast disintegrating tablet or to an
`
`15
`
`effervescent tablet.
`
`Core material
`
`The core material may be produced with starter seeds, for instance sugar spheres like Non-
`pareilsm, by layering the active ingredient on the seeds by conventional technique or by
`
`the use of a centrifugal granulator/ roto granulator. Alternatively, the core material has a
`
`homogenous distribution of the active agent and excipients, and is prepared e. g. by
`
`extrusion and spheronization, or by compression. Other conventional techniques known in
`
`the art are also suitable in preparing the core material.
`
`20
`
`25
`
`The core material is in the form of pellets, spheroids or small tablets. The size of the
`
`formulath core materials is approximately between 0.1 and 4 mm, and preferably the core
`
`material has a diameter of 0.2 to 2.5 mm.
`
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`WO 00/78293
`
`PCT/SE00/01310
`
`The core material comprises the active ingredient, an alkalizing agent, a swelling agent and
`
`optionally binders, osmotic agents and other pharrnaceutically acceptable excipients.
`
`The active ingredient is selected from the group consisting of omeprazole, an alkaline salt
`
`thereof, S—omeprazole or an alkaline salt thereof. Suitable alkaline salts are for instance the
`Mg2+, Ca2+, Na+, K+ salts, preferably the Mg2+salts in a highly crystalline form. A
`
`preferred magnesium salt of omeprazole having a crystallinity of more than 70%
`
`determined by X-ray powder diffration is described in WO95/01977, hereby incorporated
`
`by references.
`
`5
`
`10
`
`Before the seeds are layered, the active ingredient may be mixed with further components
`
`to obtain preferred handling and processing properties and a suitable concentration of the
`
`active ingredient in the final mixture.
`
`15
`
`Such further components can be binders, surfactants, fillers or other pharmaceutically
`
`acceptable ingredients, alone or in mixtures. The binders are for example cellulose
`
`derivatives such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl
`
`cellulose and carboxymethyl-cellulose sodium, and others such as polyvinyl pyrrolidone.
`
`gelatine, sugars, starches or other pharrnaceutically acceptable substances with cohesive
`
`20
`
`properties. Suitable surfactants are found in the groups of pharmaceutically acceptable
`
`non—ionic surfactants, such as polysorbate 80, or ionic surfactants such as for instance
`
`sodium lauryl sulphate.
`
`An alkalizing agent is incorporated in the core material together with the active ingredient
`
`25
`
`and/or the swelling agent, preferably together with the active ingredient. The alkalizing
`
`agent is present in an amount of approximately 5 to 35 % w/w in the core material,
`
`preferably 10 to 35 % w/w, or most preferably 15 to 35 % by weight calculated on the
`
`weight of the core material excluding the weight of the optional starter seed.
`
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`WO 00/78293
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`PCT/SE00/01310
`
`The alkalizing agent is selected from compounds like disodium hydrogen phosphate,
`
`trisodium phosphate, arginine or talc etc, provided that they give a pH of not less than 8.5
`
`when measured in a 2% w/w water solution/dispersion with a pH—measuring electrode. At
`
`least one alkalizing agent has to be incorporated in the core material, but also any
`
`combinations of alkalizing agents can be used.
`
`The swelling agent is selected among pharrnaceutically acceptable disintegrants, preferably
`
`among crosslinked polyvinyl pyrrolidone, crosslinked sodium carboxymethylcellulose,
`
`sodium starch glycolate or low-substituted hydroxypropyl cellulose (L—HPC), alone or in
`
`10
`
`any combinations. The amount of swelling agent is pre-determined to effectuate the start of
`
`dissolution of the core material at a proper time. Preferably, the core material comprises
`
`approximately 20 to 60 °/o by weight of the swelling agent calculated on the weight of the
`
`core material excluding any optional starting seed. More preferably a concentration of 25
`
`to 55 % by weight, or especially 30 to 50 % by weight ofthe swelling agent calculated in
`
`15
`
`the same manner.
`
`Alternatively, the swelling agent or a portion of the swelling agent may optionally be
`
`prepared and incorporated in a separate layer. Such a separate layer will cover the core
`
`material and also comprise binders and optionally an alkalizing agent and/or
`
`20
`
`pharmacetically acceptable excipients.
`
`Optionally, an osmotic agent is incorporated in the core material. Such an osmotic agent is
`
`watersoluble and will provide an osmotic pressure in the tablet. Examples of osmotic
`
`agents are magnesium sulphate, sodium chloride, lithium chloride, potassium chloride,
`
`potassium sulphate, sodium carbonate, lithium sulphate, calcium bicarbonate, sodium
`
`sulphate, calcium lactate, urea, magnesium succinate, sucrose or mixtures thereof.
`
`Alternatively, the active ingredient, optionally mixed with any of the components defined
`
`above, can be formulated into a core material. Said core material may be produced by
`
`30
`
`extrusion/spheronization, balling or compression utilizing different process equipments.
`
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`W0 (JO/78293
`
`PCT/SE00/01310
`
`For extrusion/spheronization processes incorporation of a microcrystalline cellulose and a
`
`low—substituted hydroxypropylcellulose in the core material is preferred.
`
`Semip ermeable membrane.
`
`The membrane comprises a water insoluble polymer and a modifying additive and
`
`optionally pharmaceutically acceptable excipients like fillers, colorants etc. The excipients
`
`should be insoluble or hardly soluble in acidic solutions, or present in such amounts that
`
`they do not influence the solubility properties of the membrane.
`
`10
`
`15
`
`Preferably, water insoluble polymer may be selected among semipermeable water
`
`insoluble polymers like ethylcellulose, cellulose acetate, polyvinyl acetate, and ammonio
`
`methacrylate copolymer type A and type B (Eudragit RL, Eudragit RS) etc.
`
`The modifying agent in the semipermeable membrane may be a talc or fumed silica (e.g.
`
`Aerosil or Cab-O-Sil.). Preferably an alkaline reacting modifying agent such as talc is
`
`used.
`
`Preferred composition of the semipermeable membrane comprises an amount of modifying
`
`agent to water insoluble polymer on a weight to weight ratio of from 90:10 up to 50:50.
`
`Preferably the amount of modifying agent to water insoluble polymer on a weight to
`
`weight ratio is from 80:20 up to 60:40 in the membrane.
`
`The core material will be layered with a sufficient amount of the semipermeable membrane
`
`composition to cover the core material. Preferably, the amount of semipermeable
`
`membrane applied is approximately 3-30% by weight of the weight of the core material.
`
`The amount of semipermeable membrane for a desired dosage form is adjusted to obtain a
`
`desired lagtime and an adequate dissolution.
`
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`PCT/SE00/01310
`
`Final dosage form
`
`Ur
`
`l0
`
`15
`
`20
`
`The prepared core material coated with the semipermeable membrane is filled into a
`
`capsule (gelatine or HPMC capsule), or optionally mixed with tablet excipients and
`
`compressed into a multiple unit tableted dosage form. In the expression “tablet cxcipients"
`
`is also effervescent tablet excipients included when referring to multiple unit tablets.
`
`Prepared tablets are optionally covered with filmforming agent(s) to obtain a smooth
`
`surface of the tablet and/or to further enhance the stability of the tablet during packaging
`
`and transport. Such a tablet coating layer may fiirther comprise additives like anti-tacking
`
`agents, colorants and pigments or other additives to obtain a tablet 'of good appearance.
`
`The claimed dosage forms are suitable for oral administration. The dose will depend on the
`
`nature and severity of the disease to be treated. The dose may also vary according to the
`
`age, body weight, and response of the individual patient. Children and patients with liver
`
`diseases as well as patients under long term treatment will generally benefit from doses
`
`that are somewhat lower than the average. In the treatment of severe conditions higher
`
`doses than average may be used.
`
`Preferably, a dosage form comprising for instance 1 - 100 mg of omeprazole or S-
`
`omeprazole will be administered once a day. Suitable doses comprise preferably 10 — 80
`
`mg. The dosage form may be administered together with other suitable drugs, such as
`
`antibacterial compound(s), NSAID(s), motility stimulating agents, and/or antacids.
`
`Examples
`
`The following examples describe the invention more in detail without restricting the scope
`
`of the invention.
`
`Example 1
`
`30
`
`Core materials in the form of pellets made by extrusion and spheronization.
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`WO 00/78293
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`
`10
`
`The following compositions were used to prepare core materials;
`
`_ Pellets A
`
`Pellets B
`
`Pellets C
`
`Comound
`
`
`Amount
`Amount
`Amount
`
`
`_®-®--- 40o
`
`
`Low-substituted
`
`Hydroxypropyl cellulose
`
`82.0
`
`20.6
`
`(g)
`
`84.0
`
`
`
`
`————.L.
`0/0 Ofdl'V
`
`pellets
`
`21 ‘O
`
`-
`
`
`
`Polyvinyl pyrrolidone
`
`crosslinked micronized
`
`Microcrystalline
`
`cellulose PH 101
`Mannitol powder
`
`Sodium chloride (<0.20
`
`mm)
`
`.
`
`.
`
`.
`136.0
`
`.
`1
`1 15.0 _-
`
`rnsodiumphosphaw _----
`
`Disodium hydrogen
`
`phosphate*
`20.0
`5 0
`_---- -
`Sodiumlauryl sulphate --M-fl-
`Waterpunfied -----
`
`Total weight of dry subst.
`
`418
`
`* In this example the amounts for all phosphates are indicated as free of crystal water.
`
`The powders were mixed and then wetted with the granulating solution. When needed
`
`extra water was added afterwards, until total amount added water corresponded to the
`
`value given in the table above. The wet mass was subjected for extrusion through a screen
`
`having 1.0 mm in diameter apertures. The strings obtained were shaped to pellets in a
`
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`
`11
`
`spheronizer operated at 350 rpm. The pellets were dried in a fluid bed apparatus with inlet
`
`air temperature set to 50 degrees Celsius.
`
`Granulating liquid used for composition A was 2.72 g of the trisodium phosphate and all
`
`5
`
`the sodium lauryl sulphate dissolved in 50 grams of the water.
`
`Granulating liquid used for composition B was 10.0 g of the arginine and all the sodium
`
`lauryl sulphate dissolved in 100 grams of the water.
`
`to
`
`Granulating liquid used for composition C was 8.06 g of the disodium hydrogen phosphate
`
`and all the sodium lauryl sulphate dissolved in 100 grams of the water.
`
`Remark: Only parts of composition B were possible to get through the extruder, however
`
`material for further experimentation was obtained.
`
`15
`
`20
`
`Example 2
`
`Core material in the form of pellets prepared by layering technique.
`
`A drug containing suspension was made according to the composition below;
`
`Compound
`
`Omeprazole
`
`HPMC, 6 cps
`
`
`Arnount
`
`219 g
`
`39.8 g
`
`Disodiumhydrogen phosphate
`
`42.9 g
`
`Polysorbate 80
`
`Purified water
`
`4.8 g
`
`919 g
`
`First the polysorbate 80 was dissolved in the water. Then the phosphate was dissolved
`
`during stirring. Then the HPMC was dissolved whereafter the drug was suspended in the -
`
`obtained solution. The suspension was sprayed onto 150 g of sugar spheres (Non-pareil) in
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`WO 00/78293
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`PCT/SE00/01310
`
`12
`
`a fluidized bed. The weight of the obtained product was 355 g and the omeprazole content
`
`was 456 mg/g.
`
`A suspension containing swellable substance was prepared according to the following
`
`5
`
`composition;
`
`%
`
`Cross-linked polyvinyl pyrrolidone micronized (Kollidon CL-M)
`
`187.8 g
`
`41*
`
`Hydroxypropylcellulose L (HPC-L from Nisso)
`
`Talc
`
`EtOH (99.5%)
`
`* % w/w of core material not including starter seed.
`
`46.9 g
`
`'
`
`140.8 g
`
`1500
`
`g
`
`HPC—L was dissolved in ethanol during stirring, then the tale and swelling agent Kollidon
`
`CL-M was added. The suspension was sprayed onto 130 g of the drug-layered spheres as
`
`10
`
`prepared above in a Wurster equipped fluidized bed until the omeprazole content of the
`
`obtained core material was 130 mg/g. The weight of the obtained product was 455 g.
`
`Example 3
`
`Membrane coated pellets.
`
`15
`
`The core material from Example 2 was coated in a fluid bed apparatus with an ethyl
`
`cellulose solution having talc suspended therein. The composition of the suspension used
`
`was:
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`WO 00/78293
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`PCT/SE00/01310
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`Substance
`
`13
`
`
`Amount
`
`%ofdr_‘y
`
`membrane
`
`
`
`
`
`___
`
`
`
`
`
`
`
`
`
`5
`
`10
`
`80 grams of core material from example 2 was coated with this suspension until the
`
`omeprazole content was 107 mg/g.
`
`Example 4
`
`Test of the prepared membrane coated pellets.
`
`The prepared membrane coated core material was tested for gastric acid resistance and
`
`dissolution as described below.
`
`Test for gastric acid resistance
`
`The pellets were tested for gastric acid resistance by immersing them in 0.1 M HCl for 2
`
`hrs and the determining the remaining drug fraction. The fluid phase (the HCl) had an
`
`addition of 0.1 g/liter of sodium lauryl sulphate as wetting agent. The remaining drug
`
`15
`
`fraction was 96%.
`
`Test for dissolution
`
`Dissolution of active substance was tested accordingly, first pellets were immersed in the
`
`test-fluid described above for 2 hrs, then buffer components (phosphate salts) were added
`
`20
`
`to change the pH to 6.8.
`
`Samples of the dissolution medium were withdrawn and analyzed with HPLC at the given
`
`time intervals. Results;
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`WO 00/78293
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`14
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`Time , Hrs
`
`% Dissolved
`
`in acid medium)
`
`(after 2hrs of pre-exposure
`
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`W0 (JO/78293
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`PCT/SE00/01310
`
`15
`
`Claims
`
`1. An oral dosage form comprising a core material coated with a semipermeable
`
`membrane wherein the core material comprises an active ingredient selected from the
`
`5
`
`group of omeprazole, an alkaline salt thereof, S—omeprazole and an alkaline salt thereof, in
`
`admixture with one or more alkaline additives, one or more swelling agents, and optionally
`
`pharmaceutically acceptable excipients, and the dosage form is not enteric coated
`
`2. A dosage form according to claim 1 wherein the semipermeable membrane is able to
`
`10
`
`disrupt.
`
`3. A dosage form according to claim 1 wherein the active ingredient is omeprazole.
`
`4. A dosage form according to claim 1 wherein the active ingredient is a magnesium salt
`
`15
`
`of omeprazole having a crystallinity of more than 70% determined by X-ray powder
`
`diffration.
`
`5. A dosage form according to claim 1 wherein the active ingredient is magnesium salt of
`
`S—omeprazole.
`
`6. A dosage form according to claim 1 wherein the core material comprises a sugar
`
`sphere layered with a suspension or solution of the active ingredient, one or more alkaline
`
`additives, one or more swelling agents and optionally pharmaceutically acceptable
`
`excipients.
`
`7. A dosage form according to claim 1 wherein the dosage form comprises individual
`
`pellets of the core material coated with the semipermeable membrane.
`
`8. A dosage form according to claim 1 wherein the core material comprises a further
`
`30
`
`component in the form of an osmotic agent.
`
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`WO 00/78293
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`PCT/SE00/01310
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`16
`
`9. A dosage form according to claim 1 wherein the alkaline additive is an agent selected
`
`from the group of compounds that give a pH of not less than 8.5 when measured in a 2%
`
`w/w water solution/dispersion with a pH-measuring electrode.
`
`10. A dosage form according to claim 9 wherein the alkaline additive is an agent selected
`
`from the group of disodium hydrogen phoshate, trisodium phosphate, arginine and talc.
`
`11. A dosage form according to claim 1 wherein the alkaline additive is present in an
`
`amount of approximately 5 to 35 % by weight of the core material excluding the weight of
`
`an optional sugar sphere.
`
`12. A dosage form according to claim 1 wherein the alkaline additive is present in an
`
`amount of 15 to 35 % by weight of the core material excluding the weight of an optional
`
`sugar sphere.
`
`13. A dosage form according to claim 1 wherein the swelling agent is selected from the
`
`group of crossliked polyvinyl pyrrolidone, crosslinked sodium carboxymethylcellulose,
`
`sodium starch glycolate and low-substituted hydroxypropyl cellulose (L-HPC).
`
`14. A dosage form according to claim 1 wherein the swelling agent is present in an
`
`amount of approximately 20 to 60 °/o by weight of the core material excluding the weight
`
`of an optional sugar Sphere.
`
`15. A dosage form according to claim 1 wherein the swelling agent is present in an
`
`amount of 30 to 50 % by weight of the core material excluding the weight of an optional
`
`sugar sphere.
`
`16. A dosage form according to claim 1 wherein the semipermeable membrane comprises
`
`a water insoluble polymer and a modifying agent such as talc or fumed silica.
`
`IO
`
`15
`
`20
`
`25
`
`30
`
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`WO 00/78293
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`PCT/SE00/01310
`
`17
`
`17. A dosage form according to claim 1 wherein the water insoluble polymer is selected
`
`from the group of ethylcellulose, cellulose acetate, polyvinyl acetate, and ammonio
`
`methacrylate copolymer type A and type B.
`
`5
`
`18. A dosage form according to claim 1 wherein the water insoluble polymer is present in
`
`an amount of approximately 3-30% by weight of the core material.
`
`19. A dosage form according to claim 1 wherein the semipermeable membrane comprises
`
`a modifying agent and a water insoluble polymer in a ratio ofbetween 90: 10 and 50:50.
`
`10
`
`20. A process for the manufacture of a dosage form as defined in claim 1, wherein a core
`
`material is formed comprises an active ingredient selected from the group of omeprazole,
`
`an alkaline salt thereof, S—omeprazole and an alkaline salt thereof, in admixture with one or
`
`more alkaline additives, one or more swelling agents, and optionally pharmaceutically
`
`15
`
`acceptable excipients, the core material is coated with a semipermeable membrane and has
`
`no enteric coating.
`
`21. Use of an oral pharmaceutical dosage form as defined in any of claims 1 - 19 in the
`
`manufacture of a medicament with improved inhibition of gastric acid secretion.
`
`20
`
`22. Use of an oral pharmaceutical dosage form as defined in any of claims 1 — 19 in the
`
`manufacture of a medicament with improved therapeutic effect in the treatment of
`
`gastrointestinal disorders associated with excess acid secretion.
`
`25
`
`23. A method for improving inhibition of gastric acid secretion which comprises
`
`administering to a patient in need thereof, an oral pharmaceutical dosage form as defined
`
`in any of claims 1 - 19.
`
`24. A method for improving the therapeutic effect in the treatment of gastrointestinal
`
`30
`
`disorders associated with excess acid secretion which comprises administering to a patient
`
`in need thereof, an oral pharmaceutical dosage form as defined in any of claims 1 - 19.
`
`Page 18
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`WO 00/78293
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`PCT/SE00/01310
`
`l/l
`
`Semipermeable membrane
`
`Active ingredient containing part}- = core material
`
`Semipermeable membrane
`
`Active ingredient containing part
`
`Starter seed (e.g. Non Pareil)
`
`= core material
`
`v 0.
`
`Semiperrneable membrane
`
`Separate swelling layer
`
`Active ingredient containing part
`
`= core material
`
`F%Q_ é
`
`
`
`
`Semipermeable membrane
`
`Separate swelling layer
`
`Active ingredient containing part
`
`= core material
`
`Starter seed (e.g. Non Pareil)
`
`Page 19
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`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/SE 00/01310
`
`A. CLASSIFICATION OF SUBJECF MATTER
`
`IPC7: A61K 9/36, A61P 1/04
`According to International Patent Classification (IPC) or to both national classification and IPC
`B FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`IPC7: A61K
`Documentation searched other than minimum documentation to the extent that such docume