United States Patent
`
`[191
`
`5,690,960
`Nov. 25, 1997
`[45] Date of Patent:
`Bengtsson et al.
`
`Illllllllllllfllllllllllllfllllllllllfllllllllllllflflllllll
`
`USOU569U960A
`
`[:1] Patent Number:
`
`[54] PHARMACEUTICAL FORMULATION OF
`OMEPRAZOLE
`.
`
`,
`
`[56]
`A
`
`‘
`
`References Cited
`US. PA'I‘EN'I‘ DOCUMENTS
`
`[75]
`
`Inventors: Inga Siv Bengt.-sson, Goteborg; Kurt
`Ingmar Lavgren, Mfilnlycke, both of
`Sweden
`
`411938 Brandstrcml ........................ 5141338
`4,733,974
`1111938 Lovgren et al.
`........................ 424I468
`4,786,505
`FOREIGN PATENT DOCUMENTS
`
`[73] Assignee: Astr-aAktiebo]ag,>Soderta1je, Sweden
`
`[21] Appl. No.:
`
`313,036
`
`[22] PCI‘ Filed:
`
`Jul. 8, 1994
`
`[36] PCT No.:
`
`PCTSEQ4/00681
`
`§37l Date:
`
`Sep. 27, 1994
`
`§ 102(e) Date: Sep. 27, 1994
`
`[87] PCI‘ Pub. No.: W095.’01783
`
`PCI‘ Pub. Datc:Jan. 19, 1995
`
`Foreign Application Priority Data
`[30]
`Jul. 9, I993
`[SE]
`Sweden .................................. 9fl395
`
`Int. Cl.‘ ........................ A61K 9132; A61K 9136
`[S 1]
`[52] US. Cl. ...................._. 424/480; 424/474; 424/482;
`4-24I494; 4Z4I49’I
`424I480, 474,
`424/482, 494, 497
`
`[58] Field of Search
`
`-#1931
`0005129
`European Pat. OE. .
`1111984
`0124495
`European Pat. Ofi’.
`.
`034252 1111989
`European Pat. OE .
`0247983 I2fl99O European Pat. Off. .
`9501783 M1994 WIPO .
`01"HER PUBLICATIONS
`
`Pilbrant et—a1., “Development of an oral formulation of
`omepcrazole,” Scand J Gastroenterol 1985; vol. 20 (Suppl
`103): 113-120.
`
`Primary Emminer—-Thurman K. Page
`Assistant Examiner—James M. Spear
`Attome); Agent, or Firm—White & Case
`[57]
`ABSTRACT
`
`A new oral pharmaceutical formulation containing a novel
`physical form of a magnesium salt of omcprazole, a method
`for the manufacture of such a formulation, and the use of
`such a formulation in medicine.
`
`22 Claims, No Drawings
`
`PZV0000000059
`
`
`

`
`5,690,960
`
`1
`PHARMACEUTICAL FORMULATION OF
`OMEPRAZOLE
`
`This application is a 371 of Pcr/SE 9410068 1 filed Jul.
`8, 1994.
`
`5
`
`FIELD OF THE INVENTION
`
`The present invention is related to a new pharmaceutical
`formulation containing a novel physical form of a magne-
`sium salt of omeprazole, to a method for the manufacture of
`such a formulation, and to the use of such a formulation in
`medicine.
`
`BACKGROUND OF THE INVENTION
`
`The compound known under the . generic name
`omeprazole, 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-
`pyridinyl)m.ethyl)sulfiny1)-1H-benzimidazole,
`is described
`i.a. in EP-A D 005 129.
`
`2
`attractive in full scale production. Performing the process
`without crystallization of the magnesium omeprazole gives
`a product which is less suitable as a pharmaceutical sub-
`Sl'3.lZl.Cfl.
`
`In order to use the magnesium salt of omeprazole, in this
`specification denoted magnesium cmcprazole, in full manu-
`facturing scale in preparing pharmaceutical formulations
`primarily for oral administration, such as tablets,
`it is
`necessary that said magnesium orneprazcle possesses a
`combination of properties which makes such full scale
`manufacturing feasible.
`The combination of physical properties of the novel
`magnesium omeprazole product described in the present
`specification with respect to the degree of crystallinity,
`particle diameter, density, hygroscopicity, low water content
`and low content of other solvents is favorable and permits
`the manu.t’acture of magnesium omeprazole in a form which
`is useful for the manufacture of the new pharmaceutical
`formulation.
`
`The novel form of magnesium omeprazole can be formu-
`lated into diflierent dosage forms ft: oral and rectal admin-
`istration. Examples of such formulations are tablets,
`granules, pellets, capsules, suppositories and suspensions.
`SUMMARY OF THE INVENTION
`
`One object of the present invention is to provide a"
`pharmaceutical formulation of magnesium omeprazole.
`Another object of the present invention is to provide a
`process for full scale production of pharmaceutical formu-
`lations of omeprazolc, especially an emetic coated dosage
`form of omeprazole, which is resistant to dissolution in acid
`-media and which dissolves rapidly in neutral to alkaline
`media and has a good stability during long-term storage.
`Yet another object of the invention is to provide an
`‘environment friendly completely water-based process for
`t.he manufacture of pharmaceutical formulations of omep_ra-
`zole.
`
`The new dosage form is characterized in the following
`way. Core material in the form ofpellets, granules or tablets
`containing the novel form of a magnesium salt of
`omeprazole, optionally together with an alkaline reacting
`compound, and on said core material one or more subcoating
`layers optionally comprising tablet excipients which are
`soluble or insoluble but disintegrating in water, or
`polymcric, filrnforming compounds, optionally containing
`pH-butfering, alkaline compounds between the core ad an
`outer layer, which is an enteric coating. Thislthese inner
`layerllayers separates/separate the core material from the
`outa layer being an enteric coating.
`The process of forming the enteric coated dosage form is
`preferably water-based. Also the enteric coating process
`step, which usally is carried out using an organic solvent,
`can be carried out using a water-based process which is
`desirable both for the working environment inside the phar-
`maceutical plant and for global environmental reasons.
`It has been found that a magnesium omeprazole having a
`degree of crystallinity which is higher than 70% is useful in
`the manufacture of the pharmaceutical formulations of ome-
`prazole according to the present invention.
`DETAILED DESCRIPTION OF THE
`JNVENTION
`
`The new pharmaceutical formulation is defined in claims
`1-8, a process for the manufacture of the pharmaceutical
`formulation according to the present invention is defined in
`
`I0
`
`15
`
`20
`
`35
`
`50
`
`55
`
`65
`
`Omeptazole is useful for inhibiting gastric acid secretion
`and has gastric mucosa [xotective
`In a more general
`sense, orueprazole may be used for prevention and treatment
`of gastric acid related disorders in mammals and man,
`including e.g. gastroesofageal reflux disease, gastritis, gas-
`tric ulcer and duodenal ulcer. Omeprazole is susceptible to
`dcgradationftransfonnation in acid reacting and neutral
`media. The half-life of degradation of omeprazole in water
`‘ solutions at pH-values less than four is shorter than ten
`minutes. Also at neutral pH-values degradation proceeds -
`30
`rapidly, e.g. at pH=7 the half-life of omeprazole is about 14
`hcurs, while at higher pH-values the stability in solution is
`much better (Pilbtrant and Cederberg, Scand. I. Gastroenter-
`ology 1935; 20 (suppl. 108) p. 113-120). Omeprazole also
`in the solid state is susceptible to degradation and is stabi-
`lized in mixtures with alkaline reacting compounds. The‘
`stability of omeprazole is also affected by moisture, heat,
`organic solvents and to some degree by light.
`From what is said about the stability properties of
`omeprazole, it is obvious that an oral dosage form of
`omeprazole must be protected from contact with the acid
`reacting gastric juice and the active substance must be
`transferred in intact form to that part of the -gastrointestinal
`tract where pH is near neutral and where rapid absorption of
`omeprazolc can occur.
`A pharmaceutical oral solid dosage form of omeprazole
`must be protected from contact with acidic gastric juice by
`an enteric coating. In US. Pat. No. 4,786,505 is described an
`enteric coated omeprazole preparation containing a separat-
`ing subcoat between the core material and the enteric
`coating. Said preparation contains an alkaline core compris-
`ing omeprazole, a snbcoating and an enteric coating.
`Certain salts of omeprazole including alkaline reacting .
`salts of omeprazole are described in EP-A 0 124 495. In said
`patent specification the requirements and importance regard-
`ing storage stability of omeprazole for incorporation in
`pharmaceutical preparations are emphasized.
`There is however, a demand for the development of new
`enteric preparations of omeprazole with enhanced stability
`and for environmental aspects there is also a strong desire
`for the use of water based processes in production of
`pharmaceutical products.
`The isolation and purification in full manufacturing smle -
`of the magnesium omeprazole salts described in EP-A O 124
`495 presents one major problem in that the magnesium
`orneprazole salt particles are very fragile making pharma-
`ceutical manufacturing processes utilising this product less
`
`PZV0000000060
`
`
`

`
`5fi9Q960
`
`3
`claims 9-10 and the use of the formulation in medicine is
`defined in claims 11-17.
`
`Magnesium Omeprazole
`Magnesium orneprazole feasible for the manufacturing of
`the claimed formulation has the following properties:
`a) Crystalline form, with a degree of erystallinity of not
`less than 70%, preferably higher than 75% as deter-
`mined by X-ray powder diffraction
`It is desirable that the product also exhibits the following
`properties;
`b) ParI:icle size measured as mean mass diameter (MMD)
`less than 30 um, preferably less than 20 pm as deter-
`mined by laser diffraction technique.
`c) Density between 1.33 glcrna and 1.35 g,/crna as deter-
`mined by powder pycnometer.
`.
`d) Hygroscopicity not exceeding 2% increase of weight
`upon storage for one month up to 94% relative anno-
`spheric humidity as determined gravimenically.
`e) A content of water of between 5% and 10% by weight
`as determined by titration according to Karl Fischer.
`t) A content of methanol less than 0.1% preferably less
`than 0.05% by weight as determined by gas
`chromatography, in case methanol is used as solvent.
`The process for producing the novel form of magnesium
`omeprazole is characterized by the following consecutive
`steps
`1) treating omepramle or a salt thereof with magnesium
`alcoholate in a solution
`2) separating inorganic salts from the reaction mixture
`3) crystallizing magnesium omeprazole
`4) isolating the obtained crystalline magnesium omepra-
`zole and, optionally
`5) purifying and drying the crystalline magnesium ome-
`prazole using conventional methods.
`The process for manufacturing the novel magnesium
`orncprazole can be described in the following way:
`A lower alcohol, such as methanol, ethanol, n-propanol or
`iso-1:1-opanol, preferably methanol, is treated in a solution of
`polar solvents with a weighed amount of magnesium at
`temperatures between 0° C. and reflux temperature. The
`temperature should preferably be between 10° and 30° C.
`After addition of the magnesium to the solution the tem-
`perature can, in a second step be raised further to between
`0° C. and reflux temperature, preferably 20°-50° C. After
`termination of the reaction the temperature is reduced to
`0°-40° (3., preferably lO°—25" C. Omeprazole or a salt of
`omeprazole is then added to the solution and after termina-
`tion of the reaction the mixture is cooled to -10° C. to +20”
`C., preferably -5“ C. to +5” C. The solvent is then evapo-
`rated to 40-60% of the
`volume, which makes the
`inorganic salts precipitate. The precipitate is separated from
`the reaction solution for example by centrifugation or fil-
`tration and the solution is heated to 5“ C.
`to 30° C.
`whereafter the solution is seeded with magnesium omepra—
`zole crystals. An amount of water, which is approximately
`equal to the volume of the solution, is added to start the
`crystallization. The solution is cooled to —l0°to +20° C.,
`preferably 0"—10° C. to complete the crystallization. The
`crystals are then separated from the mother liquid for
`example by ccntrifugation or filtration and washed with
`polar solvents preferably an aqueous lower alcohol such as
`aqueous methanol. Finally, the tnystals are dried preferably
`under reduced pressure and heating.
`Pharmaceutical formulations containing the novel mag-
`nesium omeprazole described above are manufactured as
`described herein below.
`
`5
`
`20
`
`35
`
`40
`
`45
`
`50
`
`55
`
`4
`Core Material
`
`The novel magnesium salt of omeprazole, herein referred
`to as magnesium omcprazole, is mixed with inert, preferably
`water soluble, conventional pharmaceutical constituents to
`obtain the preferred concentration of omeprazole in the final
`mixture. Optionally the magnesium omepraaole may be
`mixed with an alkaline reacting, otherwise inert, pharma-
`ceutically acceptable substance (or substances). Such sub-
`stances can be chosen among, but are not resn-icted to
`substances such as the sodium, potassium, calcium, magne-
`sium and altuniniurn salts of phosphoric acid; carbonic acid,
`citric acid or other suitable weal: inorganic or organic acids;
`aluminium hydroxidefsodium bicarbonate coprecipitate;
`substances normally used in antacid preparations such as
`aluminium, calcium and magnesium hydroxides; magne-
`sium oxide or composite substances, such as
`AI,O3.6MgO.C02.12H,O, (MggAl2(0H),5C03.4H2()),
`MgO.A12O_-,.2Si02.n.H;.O or similar compounds; organic
`pH-buffering
`substances
`such
`as
`trihydroxymethylaminomethane, basic amino acids and
`their salts or other similar, pharmaceutically acceptable
`pH-buifering substances.
`, The powder mixture is then formulated into pellets,
`granules or tablets, by conventional pharmaceutical proce-
`dures. The pellets, granules or tablets are used as core
`material for further processing.
`Separating Layer—SubcoatEng
`The cores containing magnesium omeprazole and option-
`ally alkaline reacting substances are separated from the
`enteric coating polymer(s). The subcoating layer, in the
`following defined as the separating layer, serves as 3
`pH-buifuing zone in which hydrogen ions dittusing from
`the outside in towards the core can react with hydroxyl ions
`difiusing from the core towards flze surface of the coated
`particles. The pl-I-buffering properties of the separating Layer
`can be further strengthened by introducing in the layer
`substances chosen from a group of compounds usually used
`in antacid formulations such as, for instance, magnesium
`oxide, hydroxide or carbonate, aluminium or calcium
`hydroxide, carbonate or silicate; composite aluminium!
`magnesium compounds such as, for instance
`Al203.I5Mg0.CO2.12H,0, (Mg,,Al2(0H),5C03.4H,0),
`MgO.Al2O3.2Si0,.nH20, aluminium hydroxidelsodium
`bicarbonate coprecipitate or similar compounds; or other
`pharmaceutically acceptable pl-I-buffering compounds such
`as, for instance the sodium, potassium, calcium, magnesitnn
`and aluminium salts of phosphoric, carbonic, citric or other
`suitable, weak,
`inorganic or organic acids; or suitable
`organic bases, including basic amino acids or salts thereof.
`The separating layer may consist of one or more layers.
`The separating layer(s) can be applied to the core
`material—pellets, granules or tablets—by conventional
`coating procedures in a suitable coating pan, centrifugal
`fluidized coating-granulator, or in a fluidized bed apparanrs
`using water and/or conventional organic solvents for the
`coating solution. The material for the separating layer is
`chosen among pharmaceutically acceptable,
`inert com-
`pounds or polymers used for film-coating applications such
`as,
`for instance, sugar, polyethylene glycol,
`polyvinylpyrrolidonc, polyvinyl alcohol, hydroxypropyl
`cellulose, methylcellulose, ethylcellulosc, hydroxymethyl
`cellulose or hydroxypropyl methylcellulose. The separating
`layer, “subcoat.ing”, applied to the core material may con-
`stitute from approximately 0.5 to 25% by weight of the core
`weight," preferably 2.0-10.0%, and more preferably
`2.5—5.0%.
`
`PZVOOOOOOOO61
`
`
`

`
`5 ,690,960
`
`'
`
`5
`In the case of atablet formulation another method to apply
`the separating layer(s) can be performed by drycoating
`technique. First a tablet containing magnesium orneprazole
`is formulated as described above. Around this tablet one or
`more layers are compressed using a suitable tableting
`machine. The separating layer(s) consists of pharmaceuti-
`cally acceptable, soluble or insoluble but in water disinte-
`grating tablet excipients. The separating layer(s) has pref-
`erably a thiclmess of not less than approximately 1 mm.
`Ordinary plasticizers, colorants, pigments,
`titanium
`dioxide, talc and other additives may also be included into
`one or more of the separating layer(s).
`
`Enteric Coating Layer
`
`The enteric coating layer is applied in one or more layers
`onto the subcoated core material by conventional coating
`techniques such as, for instance, pan coating or fluidized bed
`coating using solutions of polymers in water, or by using
`latex suspensions of said polymers or optionally using
`polymer solutions in suitable organic solvents. As enteric
`coating polymers can be used one or more of the following,
`for example solutions or dispersions of acrylates
`(methacrylic acidfmethacrylic acid methylester copolyrner),
`cellulose acetate phthalate, hydroxypropyl methylcellulose
`phthalate, hydroxypropyl methylcellulose acetate succiuate,
`polyvinyl acetate phthalate, cellulose acetate trirnellitate,
`carboxymethylethylcellulose, shellac or other suitable
`cntefic coating polyIner(s). Preferably water-based polymer
`dispersions such as for example compounds known under
`the trade names Aquatcric® (FMC Corporation), Eudragit®
`(Riihrn Pharma), Aqoatm (Shin-Etsu Chemical), Opadrym
`(Colorcon) or sirnilar compounds are used to obtain enteric
`coatings. ‘The enteric coating layer can optionally contain a
`pharmaceutically acceptable plasticizer for example cetanol,
`triacetin, citric acid esters such as, those known under the
`trade name Cit:rollex® (Pfizer), phthaiic acid esters, dibutyl
`succinate, polyethylene glycol (PEG) or similar plasticizers.
`The amount of plasticizer is usually optimized for each
`enteric coating po1ymer(s) and is usually in the range of
`1—50% of the enteric coating polyrneris). Dispersants such
`as talc, colorants and pigments may also be included into the
`enteric coating layer or sprayed onto the enteric coated
`material as an overcoat.
`-
`
`The thickness of -the enteric coating may vary widely
`without influencing the in vitro release of omeprazole in test
`solutions which mimic in vivo conditions in man. To protect
`the acid susceptible orneprazole compound and to obtain an
`acceptable acid resistance, the enteric coating constitutes at
`least an amount of 1.0% by weight of the core weight,
`preferably at least 3.0% and especially at least 6.0%. The
`upper amount of the applied enteric coating is normally only
`limited by processing conditions. This possibility to vary the
`thickness of the enteric coating without deleterious influence
`on the release of omeprazole is especially desirable in large
`scale processes. The enteric coating layer(s) may be applied
`on the pre-processed formulation containing subcoating
`layer(s) without exactly controlling the thickness of the
`applied coating layer(s).
`Thus, the formulation according to the invention consists
`of core material containing magnesium omeprazole option-
`ally mixed with alkaline reacting compound(s). The addition
`of alkaline reacting material is not necessary, in any sense,
`but such a substance may further enhance the stability of
`omeprazole. The core material is coated wit.h an enteric
`coating rendering the dosage form insoluble in acid media,
`but disintegratingdissolving in neutral to alkaline media
`
`6
`such as, for instance the liquids present in the proximal part
`of the small intestine, the site where dissolution is wanted.
`The core material is further coated with an soluble or
`insoluble but in water disintegrating coating, optionally
`containing one or more pH-butfering substances, which
`separate the core material from the enteric coating.
`
`Final Dosage Form
`
`10
`
`25
`
`30
`
`35
`
`45
`
`50.
`
`55
`
`65
`
`The final dosage form is either an enteric coated tablet or
`capsule or in the case of enteric coated pellets or granules,
`these pellets or granules dispensed in hard gelatin capsules
`or sachets. The final dosage form may further be coated with
`an additional layer containing pigment(s) andlor colorant(s).
`It is essential for the long term stability during storage that
`the water content of the final dosage form containing mag-
`nesium omeprazole (enteric coated tablets, capsules, gran-
`ules or pellets) is kept low.
`Process
`
`Aprocess for the manufacture of a dosage form according
`to the present invention represents a further aspect of the
`invention. 'After the forming of the core material, said
`material is first coated with the separating layer-(s) and then
`with the enteric coating layer(s). The coating(s) are carried
`out as described above. Further another aspect of the inven-
`tion is that the pharmaceutical processes can be completely
`water-based.
`
`The preparation according to the invention is especially
`advantageous in ‘reducing gastric acid secretion. It is admin-
`istered one to several times a day. The typical daily dose of
`the active substance varies and will depend on various
`factors such as the individual requirements of the patients,
`the mode of administration and the disease. In general. the
`daily dose will be in the range of 1-400 mg of omeprazole.
`The invention is illustrated in detail by the following
`examples. Example 1 discloses the preparation of the novel
`magnesium orneprazole product, which product is suitable
`in manufacturing of the pharmaceutical formulations
`according to the present invention. Example 2 discloses
`compositions of different enteric coated tablets containing
`magnesium omeprazole and results from acid resistaucetest
`and in vilro dissolution test. Examples 3 discloses tablet
`formulations with ditferent thickness of the enteric coating,
`the obtained gastric acid resistance of said formulations and
`the in vitro release rate of omeprazole. Example 4 discloses
`an enteric coated pellet formulation.
`EXAMPLES
`
`The following detailed Example 1 will serve to illustrate
`a process for manufacturing the magnesium omeprazole,
`which will be used in the pharmaceutical preparations
`according to the present invention.
`
`Example 1
`A reactor was filled with 2026 liters of methanol. The
`stirrer was started and the temperature was adjusted to 20°
`C. 3,90 kg of magnesium was added to the vessel and
`immediately thereafter 1,0 liter of Cl-IZCI2. The reactor was
`heated to 40° C. and kept at this temperature for 60 min. It
`was then cooled to 15° C. before the addition of 99,9 kg of
`omeprazole. The reactor was loept at this temperature for 60
`min and then cooled to 0° C. The temperature was kept at
`this level for 30 minutes before 1000 L of methanol were
`evaporated under vacuum and the inorganic solid salt was
`separated from the liquid first by centrifugation and then by
`
`PZV0000000062
`
`
`

`
`5,690,960
`
`8
`
`Acid resistance
`Tablet Strength
`(95)
`(I112)
`95 (93-98)
`10
`100 (94-102)
`20
`
`40 100 (96-103)
`
`Investigation of In-Vin-o Dissolution
`
`After exposure to add enviromnent, pH 1.2, as'described
`above, the medium was switched to artificial intestinal fluid
`without enzymes. pH 6.8. The dissolved amount of ome-
`prazole was determined by HPLC.
`
`
`Tablet
`
`Dissolved amount of ggpmzole {E} after gminmes]
`
`Strength
`0
`1
`s
`10
`15
`20
`25
`30
`
`(ms)
`(%)
`(95)
`(95)
`(95)
`('5)
`(%)
`(95)
`10 ‘
`0
`2
`78
`92
`93
`94
`94
`no
`0
`0
`75
`93
`96
`96
`97
`40
`0
`9
`71
`as
`91
`91
`94
`
`7
`filtration. The liquid was heated to 10° C. and the liquid was
`seeded with magnesium omcprazole crystals whereafter the
`magnesium omeprazole salt was precipitated by addition of
`900 L of water. The mixture was then cooled to 5° C. After
`the crystallization had been completed the magnesium ome-
`prazole crystals were cenlrifuged off and then washed with
`a mixture of 50 L of methanol and 150 L of water. The
`produced magnesium omeprazole was dried under reduced
`pressure finally producing 92,5 kg of crystalline product
`colzresponding to a yield of 81,!-1%.
`The novel form of the magnesium salt of omeprazole
`according to Example 1 fulfills the properties defined above.
`
`10
`
`Example 2
`
`Tablet formulations containing magnesium omeprazole.
`
`10
`tmsltabl)
`
`20
`(msllabll
`
`40
`(mambo
`
`20
`
`Amolmt onnepsaaole
`Insrudscnx
`Tablet core
`
`Magnesium omeprazole
`Mannilol
`-
`Microciyslafline cellulose
`Sodium starch glycolate
`1-[ydmxypropyl Imthyleellulose
`Talc
`Sodium stearyl ftunamte
`‘Water purified
`Sub-coating layer
`
`Hydroxypmpyl methylcellulose
`Hydrogen peroxide 30%
`Water purified
`Enteric coating layer
`
`Methsczylic acid cupolyrner
`Polyethylene glycol
`Titanium dioxide
`Colour irul oxide. red-brown
`Colour iron oxide, yellow
`Water purified
`Polish
`
`11.2
`68.7
`25.0
`6.0
`6.0
`5.0
`25
`50.0
`
`3.7
`0.04
`34.0
`
`9.1
`1.0
`0.82
`0.04
`0.02
`45.0
`
`22.5
`57.4
`25.0
`6.0
`6.0
`5.0
`2.5
`50.0
`
`' 3.7
`0.04
`34.0
`
`9.1
`1.0
`1.1
`0.13
`—
`45.0
`
`45.0
`34.9
`25.0
`6.0
`6.0
`5.0
`25
`50.0
`
`3.?
`004
`340
`
`9.1
`1.0
`0.51
`0.43
`—
`45.0
`
`All values of dissolved amount of omeprazole are mean
`values of 12 tablets.
`
`Example 3
`
`35
`
`Tablet forrnnlations containing magnesium omeprazole
`with diiferent thickness of the enteric coating.
`The composition of the tablets is the same as in Example
`2 (20 mg omeprazole). The tablets (n=6) have been exposed
`in an artificial gastric juice (pH 1.2) during 2 hours and then
`analysed for remaining amount of omeprazole (acid
`resistance). The release of omeprazole was analysed on
`tablets (n=6) pro-exposed in gastric juice 2 hrs and thereafter
`exposed in a buifer solution (pH 6.8) during 30 min.
`
`
`Paraflinpawdcr
`
`0.05
`
`o.05
`
`'
`
`0.05
`
`The tablets with an amount of 20 mg omeprazoleftablet
`have been manufactured both in a pilot scale of about 300
`000 tablets and a large scale of about 2 million tablets.
`
`Description of Manufacturing
`
`Magnesium omeprazole, mannitol, hydroxypropyl
`methylcellulose, microcrystalline cellulose and sodium
`starch glycolate are dry-mixed, moistened with water and
`wet mixed. The wet mass is dried and milled and finally
`mixed with anti-adherent and lubricant substances. The
`milled granulate is compressed to tablets with a diameter of
`7 mm. The tablets are sub-coated with a polymer film based
`on hydroxypropyl methyloellulose and enteric coated with a
`mcthacrylic acid copolymer film. Water used in the manu-
`facture of the tablets is removed during subsequent process-
`mg.
`
`50
`
`55
`
`Investigation of Acid-Resistance
`
`Six individual tablets wae exposed to artificial gastric
`fluid without enzymes, pH l.2.'After six hours the tablets
`were removed, washed and analysed for omeprazole content
`using HPLC. The amount of omeprazole is taken as acid
`resistance.
`
`Release
`Acid resistance
`Enteric coating
`(Vfizweightper
`(%resicl11eafier
`(%afier30I:ui11:
`
`Experiment?“
`tabiet)
`2 I1; [:11 1.2)
`pH 6.8)
`A
`s
`101 (93-105)
`94 (93-96)
`B
`s
`100 (98-102)
`95 (s5—9s)
`C
`16
`98 (95—1(I))
`
`“A mamsfactured in large scale
`13 manufactured in pilot scale
`C rmnufactured in laboratory scale
`
`Example 4
`
`Enteric coated pellet forrnulation containing magnesium
`omeprazole.
`
`Pellet core
`
`Magnesium omeprazole
`Mannitol
`I-Iydroxypropyl cellulose
`Micnocrystalline cellulose
`Lactose anhydmus
`Sodium lauryl sulphate
`
`inM88833
`
`naoaueoaoem
`
`PZVOOOOOOOO63
`
`
`

`
`5,690,960 T
`
` -continued
`Disodium hydrogen phosphate
`8 g
`dihydrate
`Water purified
`Subcuating layer (1)
`
`550 g
`
`‘
`
`I-Iydronypropyl methylcellulose
`Water purified
`Enterit-acoating layer (11)
`
`Metliacrylic acid copolymer
`Polyethylene glycol
`Water purified
`Polish
`
`70 g
`1450 g
`
`430 g
`40 g
`1890 g
`
`
`
`Magnesium ste-arate S g
`
`The dry ingredients given above were mixed well in a
`mixer. Addition of granulation liquid was made and the
`mixture was kneaded and granulated to a proper consistency.
`The wet mass was pressed through an exlruder and the
`granules were converted to spherical form in a spheronizer.
`The pellets were dried and classified into suitable particle
`size ranges, e.g. 0.5-1.5 mm.
`The polymer solution (I) was sprayed on the uncoatcd
`pellets in a fluidized bed apparatus under conditions suitable
`for the equipment used.
`The polymer dispersion (II) was sprayed on the subcoated
`pellets in a fluidized bed apparatus. The enteric-coated
`pellets were classified, polishing material was adinixed and
`the pellets were filed into hard gelatin capsules in an amount
`corresponding to 20 mg of omeprazole, using a capsule
`filling machine.
`
`Biopharmaceutical Tests
`The entenic coated fon-nulations according to Example 2
`have been tested in humans with good results.
`We clailni
`1. A stable oral formulation comprising:
`a core containing a magnesilun salt of omeprazolc said
`salt having more than 70% crystallinity as determined
`by x—ray powder ditfracfion;
`a subcoating layer; and
`an enteric coating layer, whereby the thickness of the
`enteric coating layer does not effect the release of
`omeprazole into solution . at the" pH predominantly
`present in the small intestine.
`2. A formulation according to claim 1, wherein the
`fonznulation is a tablet formulation.
`3. A formulation according to claim 1, wherein the
`formulation is a pellet formulation.
`. 4. Aformulation according to claim 1, wherein the enteric
`coating comprising an enteric coating material, optionally
`containing one or more pharmaceutically acceptable
`plasticizers, dimersants, colorants and pigments.
`5. Aformulation according to claim 4, wherein the enteric
`coating comprises water-based polymer solutions or disper-
`sions of acrylates, hydroxypropyl methylcellulose acetate
`succinate, hydroxypropyl methylcellulose phthalate, poly-
`vinyl acetate phlhalate, cellulose acetate trimellitate andlor
`cellulose acetate phthalate.
`6. Aformulation according to claim 1, wherein the enteric
`coating constitutes from 1.0% by weight of the weight of the
`core material.
`
`'
`
`10
`
`20
`
`30
`
`35
`
`45
`
`55
`
`10
`7.Aformulation according to claim 6, wherein the enteric
`coating constitutes at least 3.0% by weight of the weight of
`the core material.
`8. A formulation according to claim 1 wherein the sub-
`ccating Iaycr(s) comprise polymeric, filmformiug com-
`pounds or tablet cxcipients which are soluble or insoluble
`but disintegrating in water, and optionally containing
`pl-I-bufiering, alkaline compounds.
`9. A formulation according to claim 1 wherein the pro-
`duced euteric coated formulation contains an overcoat,
`optionally comprising one or more pharmaoeutically accept-
`able plasticizers, dispersants, colorants and pigments.
`10. A process for the manufacture of a formulation of a
`pharmaceutical composition for the oral administration of
`magnesium omeprazole comprising the steps of:
`(a) forming a core material containing magnesium ome-
`prazole salt said salt having at least 70% crystallinity as
`determined by x-ray powder diffiaction;
`(b) applying in the presence of watt: at least one sub-
`coating layer onto the core;
`'
`(c) fmther applying in the pittance of water at least one
`entcric coating layer onto the subcoated core; and
`drying the prepared formulation.
`11. A process according to claim 10, wherein the sub-
`coating layer(s) is applied on the core material by a dry-
`coating process.
`12. The oral formulation according to claim 8 or 1
`wherein the core is coated with more than one subcoating
`la er.
`y13. The oral formulation according to any one ofthe claim
`1, 4-7 or 9 wherein the enteric coating comprises more than
`one layer.
`14. The oral formulation according to claim 1 wherein the
`crystalline magnesium omeprazolc has a mean mass particle
`size diameter of less than 30 |.u1:I.
`15. The oral formulation according to claim 1 wherein the
`crystalline magnesium omeprazole has a hygmscopicity of
`less than 2% by weight.
`16- The formulation according to claim 1, wherein the
`core material is in the form of pellets, granules or tablets.
`17. A method for inhibiting gastric acid secretion in
`mammals and man by administering to a host in need thereof
`a therapeutically effective dose of an enteric coated formu-
`lation according to any of claims 1 to 9.
`18. A method for the treatment of gastric acid related
`diseases in mammals and man by administering to a host in
`need thereof a therapeutically effective dose of an enteric
`coated formulation according to any of claims 1 to 9.
`19. The formulation according to claim 1, wherein the
`core further comprises an alkaline reacting compound
`20. The process according to claim 10, wherein the core
`material further comprises an alkaline reacting compound.
`21. A pharmaceutical composition produced in accor-
`dance with the process of claim 10.
`22. An improved oral pharmaceutical composition con-
`taining a core of omeprazole salt with a subcoating and an
`enteric coating wherein the improvement comprises mag-
`nesium omeprazole salt having more than 70% crystallinity
`as determined by x-ray powder diffraction.
`
`=l=$$‘**
`
`PZVOOOOOOOO64
`
`
`

`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`
`I
`;
`
`5 1 690 , 960
`November 25, 1997
`
`;NVENToR(3) :
`
`Bengtsson et al .
`
`It is certified that error appears in the above—indenIified patent and that said Letters Patent is hereby
`conemedasshownbebwz
`
`col. 9. line 43 (claim 1, line 7), change “effect” to
`--significantly affect-—;
`
`P
`col. 10, line 22, change "pittance" to —- resence--;
`
`col. 10,
`
`lines 31, change "claim" to ---claims-—.
`
`Am‘-'
`
`Signed and Sealed this
`
`Second Day of June, 1998
`
`@4144 W
`
`BRUCE LEHMAN
`
`Artesting Officer
`C'anImr