CA2193681A1 - New oral pharmaceutical formulation containing magnesium salt of omeprazole - Google Patents
New oral pharmaceutical formulation containing magnesium salt of omeprazoleInfo
- Publication number
- CA2193681A1 CA2193681A1 CA002193681A CA2193681A CA2193681A1 CA 2193681 A1 CA2193681 A1 CA 2193681A1 CA 002193681 A CA002193681 A CA 002193681A CA 2193681 A CA2193681 A CA 2193681A CA 2193681 A1 CA2193681 A1 CA 2193681A1
- Authority
- CA
- Canada
- Prior art keywords
- formulation according
- enteric
- formulation
- enteric coating
- omeprazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
A new oral pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole coated with one or more enteric coating layers, a method for the manufacture of such a formulation, the use of such a formulation in medicine and a blister package containing the new formulation.
Description
2 1 93~8 1 ~ WO 96101622 ~ S
NEW ORAL PHARMACEUTICAL FORMULATION CONTAINING MAGNESIUM
SALT OF OMEPRAZOLE
Field of the invention.
5 The present invention is related to a new p~ ;nal r~ containing a no~el physical form of a 1 ~c.~ salt of .,.,.. ~ , to a method for the ur4l,h.,c: of such a fulululf ~iun~ and to the use of such a rulluul~Liull in medicine.
10 Back~round of thc invention.
The compound known under the generic name ....,. ~ . 5-methoxy-2(((~
methoxy-3,5-dimethyl-2-pyfidinyl)methyl)sulfinyl)-lH-f~ L~,f~lr, is described i.a. in EP-A 0 005 129.
Omeprazole is useful for inhibiting gastric acid secretion in mammals and man. In a more general sense. said substances may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux ,cophAci~ic, gastritis, duodenitis, gastric ulcer and duodenal ulcer. F~lh~ u~, ull~ Lolc may20 be used for treatment of other y~ uintu lil.al disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAlD therapy. in patients with l'lon Ulcer Dyspepsia, in patients with symptomatic gastro c.~ul ' ~ ' reflux disease, and in patients with g~c~Tinf mAc Omeprazole may also be used in patient~s in inten,sive care situations, in patients with acute upper y"~llu;..,~Li,.al bleeding, 25 pre- and pu .lu~ dlively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Further, n..,~ may be useful in the treatment of psoriasis as well as in the treatment of ll~lif Ot.lA' ~' ' infections and diseases related to these.
~l '3.~8~
WO g6/0162Z P~ ,6 Omeprazole is susceptible ~o .J- E,.r I ~ii.ll/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-vamesless than three is shorter than ten minutes. Omeprazole may be stabilized in mixtures with alkaline ~ nl~u~ k The stability of u~ dzule is also affected by 5 moisture, hea~, organic solvents and to some degree by light.
Prom what is said about the stability properties of ~ rf t~ 1, it is obvious that an oral dosage form of u~ ~ulc must be protected from contact with the acid gastric juice and the active substance must be transferred in intact form to that part 10 of the E;~l~ ' tract where pH is near neutral and where rapid absorption of o..._~!l~ùle can occur.
A uLa~ àcc~.~i~l oral dosage fonn of omeprazole may well be protectea from contact with acidic gastric juice by an enteric coating. In US-A 4,786,5ûS an 15 enteric coateci ~.n. ~ ".1~ preparation is described. Said, "r '- ~ICpdlaiiUII
contains an alhline core comprising omPp~ lP, a subcoating and an enteric coating.
The hard gelatine capsules containing an enteric coated pellet fonT~ irln of 20 n 1 ~ r marketed by the Applicant today, are not suitable for press-through blister packages. Thus, there has boen a demand for dc~lv~,...e.ll of new enteric coated ~ ~dLi~ . of o,n. ~ ; with good chemical stability as well as improved mechanical stability making it possible to produce well fi Li.~.~ing and patient-friendly packages.
~5 Certain salts of o..,. ~ including alkaline salts of .~ A~ /u1. are described in~P-A 0 124 495. In said patent ~ ll the ,cquilclr.~ and importance regarding storage stability of omeprazole for bl~.Vl~Ul~l~iUII in ph-~ t~t ~IC,~I..tiUlls are ~ c;, wo 96/0~622 2 I q 3 6 8 1 r ~ a~
There Is however. a demand for the d~v~ ,u~en~ of ne~ cnteric iul~iualatidns of omeprazole with enhanced ~stai ility and for environmental aspects there is also a strong desire for the use of v ater based processes in production of pll Lilua~ Lil al products.
The isolation and pllrifi' atiori in full manufacturing scale of the .
salt~s described in EP-A 0 124 495 presents one major problem in that the ~ ,olr sait particles are very fragile making tJLaullla~ dl f~ d~g processes utilising this product less attractive in full scale IU production. ~v'- ' g of mRgn~ Cil~m un.~ without a separate crystaPiisation step gives a product which is less suitable as a 1~1~ --.,. ~i. ~1 substance.
In order to use the ll ~c -: .. salt of l~ ul in this ~iJ~' irlcaLiùll denoted ~l; . in full I ' , scale in preparing r' - ~ - C ~
f,"." ~-l;,...~ prim~rily for orai ,..I...;n;~l,..l;n... such as tablets, it is necessary that said magn~cillm ....,~ 1...,ok possesses a cnmhinatinn of properties which makessuch full scale niallura~ .t, feasible.
20 The ~ ,-".1.;" ~~i,-" of physical properties of the novel m c- - ---- ~ ~ I,...ink product described in W09510197~ with respect to the degree of crystaliinity.
particle diameter, density, Lr~;lusuui i~ iiy, low water content and low content of other solvents is favorable and permits the Illall ra~Luic of , u,.,~i~,aLule in â fon-n which is dJv~i.,La~ous for the ll~a..urdo~u~;i of the new pl.- ,n~ c ~
~s rUIIllUiaLiUlls.
The novel form of ~,-~c....: -1 uul~.iJiaLulc can be formulated into different dosa.~e forms for oral and rectal administration. E~amples of such 11~ "c are tablets granules, pellets. capsules ~ uu~ /-i., and sllcrl-ncinnc WO 9C/01622 q 3 6 8 1 ~ ~ " j,.
Description of the in~ention One objec~ of the present invention is to pro~ide a ph~ ulical forrnulatic~n of Another object of the present invention is to provide a process for full scale production Of 1~ I fu~ ul~ lus of ..".. ~ , espccially an enteric coated dosage form of .. ,. ~ olc, which is resistane to dissolution in acid media and which dissolves rapidly in neutral to aLkaline media and which has a good In stability even agi~inst discoloration.
Yet another object of the invention is to provide an environmental friendly completely water-based process for the Illal~ur~ U~i of ~h~U---~.. iu~l r of .-,... ~..,.,. 1 A further object of the present invention is to provide a dosage form comprising.,.,.. I..~,.~l~ which is suitable for press-through blister packages and which also has an improved patient :~-cer~ c 20 The new dosage form is .'-~ ;,. .1 m the following way. Core material in the form of pellets, granules, beads or tablets containing the novel form of a ." g salt of ~ ,le and on said core material one or more enteric coating layers.
25 The process of forrning the enteric coated dosage form is pret'erably water-based.
Also the enteric coating process step ean be carried out using a water-based process which is desirable both for the working ellvi~u~u~ inside the pharmaceutical plant and for global environmental reasons.
WO96101622 ~ 3 6 8 I r~ ll~h'Slt 1~
It has been found that a m,qgnt chlm u~ "~;uk ha~,ing a degree of crystallinity which jc higher than 70';7r is advantageous in the manut:acture of p~ m~irellticql formulations of ~"".,~ ok accordin,g to the present in~ention.
Detailed descriPtion of the invention The new ,uh.-iillld.c...-ul'. ru~ ulalioli is defined in clairns 1-9. a process for the manufacture of the ~ c~ ru".. ~ .. according to the present invention is 10 defined in claims 10-11, the use of the fulluuh~liùn in medicine is defined in claims 12-18 and a press-through blister package is stated in clairn 19.
15 A ~ g~ ~h ~ r advui.L~c~,uu~ for the m~ rd~ g of the claimed formulation is described in WO95/01977 hereby iil~Ul~U- ' ' in a whole by reference. Said m ~ k has a degree of crystallinity of not less than 70~7c~ preferably higher than 75% as determined by X-ray powder diffraction 20 rl ~ ..- . irql fu~ rin.lc containing the ~ are u..~llurdul. c-~ as described herein below.
Core materia-2S The novel m~ivnecinrn salt ûf 0.1~ L-, herein referred to as mqgnecillm w~ llc, is m~L~ed with 1,l - ". ~"~;. ,.1 ~O..cli~ to obtain preferred handling and processing properties and a suitable cnm~. ntrqrir~n of the active substance in the ftna. mLYture. rl ~ . ., c..~ in ...~ such as fllers, binders, lubricants, ' ~, agents, surfactants and other pl..u.. ~ lly a-,ceptable additives, 30 can be used. The core may alsû contain ar. a-kaline "1 ",~ . irqlly acceptable wo 96101622 2 ~ q 3 ~ ~8 1 1~ h~ . 16 substance (or substances). The optionally added alkaiine substance(s) i5 IlOt essential tor the inventiorl. However, it may further improve lhe chemical stabilily of the formulations. Such ph~ u~i.dlly acceptable substances can be chosen among~ but are not restricted to substances such as the sodium~ potassiumt calcium, 5 '~L:~ ~ 'h~ and aluminium salt.s of phosphoric acid. carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium l.y~Lu~idc/.sodium biudliJo~l~tc ~Ui~lC~iiJi~dlC, substances normally used in antacid ylcl~diJull~ such QS
nnlm~ calcium and ,-...~ ., hydlu~dd~, 1l 0 oxide or composite substances, such as A12O3.6MgO.CO2.12H2O,~Mg6A12~OH)loCO3.4H2O), MgO.A12O3. 2~iO2.nH2O or similQr ~ r- ' . organic pH-buffering sub.stances such as l-;hydlu~y~ lly' ' , basic amino acids and their salts or othcr similar, I'l'~ ily acceptable pH-buffering substances.
The powder mixture is then formulated into peUes, granules, beads or tablets by 15 pl. _. ~"~ procedures. The pellets. granules, beads or tablets are used as corc material for further processing.
Enteric coatin1~ laver 20 The enteric coating layer is applied in one or more layers onto the formulated core material by coating procedures in suitable equipments such as pan coating~ coating granulator or fluidized bed appQratus using solutions of polyrners in water, or by using latex ,"y) ~ s of said polymers or optionally using polyrner solutions in suitable organic solYents. As enteric coating polymers can be used one or more of 25 the following, for example solutions or dispersions of acrylates (~ h~ylic acid/methacrylic acid Ill.LIIY1~t~. copolymer), cellulose acetate phthalate.
hydroxypropyl .I.~.ll.yl..llulose phthalate, hydroxypropyl methylcellulose acetate su~cinate, polyvinyl acetate phthalate. cellulose acetate trimellitate, ~"~1 u~y~u~.iLy~ lyl~cllulose~ shellac or other suitable enteric coating polymer(s:l.
30 Preferably water-based polymer dispersions such as for example ~UIIIIJU~..ld~ knOWII
WO 96/01622 2 1 ~ ~ 6 ~
under the trade names Aquateric~ (FMC Corporation) Eudragit6) (Rohm Pharma)~
AqoatTM ~Shin-Etsu Chemical), OpadryT~' (Colorcon) or similar ~,ulllr . ~c are used to obtain enteric coatings. The enteric coating layer can optionally contain a pharmq~ e~lt~ ly acceptable plasticizer for example cetanol, triacetin, citric acid es-5 ters such as. those known under the trade name Citrûflex(~ (Pfizer), phthalic acidesters, dibutyl succinate, poly~,.l.~lel.~, glycol (PEG:1 or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-50 % of the enteric coating polymer(s). Additives such as talc, colorants and pigments may also be included into the enteric coating layer 10 or sprayed onto the enteric coated material as an overcoat.
The thickness of the enteric coating may vary videly without influencing the release rate of o~ ."~ To protect the acid susceptible ~ )k 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 9ra andmore preferably more than 8.0 %. The upper amount of the applied enteric coatingis normally only limited by processing conditions. This possibility to increase the thickness of the enteric coating without deleterious influence on the release rate of ul~ oh is especially desirable in large scale processes. The enteric coating 20 layer(s) may be applied on the pre-processed f~ ' . without exactly controlling the thickness of the applied coating layer(s).
Thus, the r~ according to the invention consists of core material containing magnesium ...~ . The core material is coated with enteric~5 coating~s) rendering the dosage form insoluble in acid media, but t' ~ ; g,/dissolving in neutral to alkaline media such as, for instance the liquids present in the prûximal part of tne small intestine, the site where dissolution is wanted.
wog6~0l~22 21 ~3~J31 x Fhlal dosaYe form The fm.ll dosaye form is either an enteric coated tablet or capsule or in the case of enteric coated pellets. beads or granules, these pellets, beads or yranules are 5 dispensed in hard yelatin capsules or sachets. The final dosage form may further be coateo with an additional layer containing pigment(s) andlor colourant~s). It isessential for the long term stability during storage that thc wat,r content of the final dosage form containing magnesium omeprazole lenteric coated tablets.
capsules. granules, beads or pellets) is kept low.
Process A process for the ~ rh-~ of a dosage form according to the pre.sent invention 15 represents a further aspect of the invention. After the forming of the core material, said material is coated with enteric coating layer(s). The coating(.s) are carried out as desc~ribed above. Further ano~her aspect of the invention is that the ~,1.,...",,~ ~ .a;. ~I processes can be completely water-based.
20 The ~ Jala~ l according to the invention is especially ad~u.L,~vus in reducing yastric acid secretion. It is a.l-~ c.J 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 IC~IULIU~ S of the pa~ients, the mode of i~.l.,,..,;~n,.l;o.. and the disease. In ~eneral the daily dose will be in the rangc of 1-400 mg of ..".
The hl~ ention is illustrated in detail by the following examples. Examples 1-~disclose u.."~ h ~ of different enteric coated tablets containing magnesium OII~ L~U1C. Said examples also show the result of a gastric acid resistance te.st in vitro. Example 3 discloses an enteric coated pellet f~nlllulà~iun Said e~ample also 30 shows the result of a yastric acid resistance test in vitro.
~ 1 q368 1 WO 96/01622 . ~, I /a~ ~.'C 16 Exam~le I
Tablet formulation containing magnesium omepra~ole being produced as described in W095/01977.
Amount u~ ulc 10 Ingredient (mgJtabl) Tablet core U~ ,lc I I.2 Mannitol 68.7 Microcrystalline cellulose 25.0 Sodium starch glycolate 6.0 Hydroxypropyl methylcellulose 6.0 Talc 5.0 Sodium stearyl fumarate 2.5 Water pu~ified 50.0 Enteric coatin~ laYer Methacrylic acid copolymer 9.1 Polyethylene glycol 1.0 Titaniurn dioxide 0.82 Colour iron oxide, red-brown 0.04 Colour iron o~;ide, yellow 0.02 Water purified 45.0 Polish Paraffin powder 0.05 ~' 936~1 W0~6/~1622 .~11~1' . .
Tablet.s with the composition described above have been l~anurdulul~l in a laboratory scale of about 20 000 tablets.
Descri~tion oF manufacturin~
5 Magnesium omeprawle, mannitol, hydroxypropyl methylcellulose, microcrystallinecellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally rnixed with anti-adherent and lubricant substances. The milled granulate is w~ /.c~ l to tablets with a diameter of 7 mm. The tablets are enteric coated with a ".~,I..,~,.~I;c acid copolymer film.
10 Water used in the ~ lf~-~ul~ of the tablets is removed during subscquent processing.
Investi~ation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymcs, pH
15 1.2. After six hours the tablets were removed, washed and analysed for u-~ ~c~lc contcnt using HPLC. The amount of Ulll.~JI~UI~, is taken as acid resistance.
Tablet Acid resistance Stren~th (mg) (%) lOI (CJ8- 103) 25 Exam~le 2 Tablet fululul~licn containing " ..~ll. ,;"". ~lm~pr~7ole being produced as dcscribed in W095/0j977.
Amoullt l,~ 40 Ingredient (mg/tabl.) 7 1 ~3~ f WO ~6/01622 ~ 16 Table core Magnesium omeprazole 45.() Mannitol 34 9 5 Microcrystalline cellulose 25.0 Sodium st~rch glycolate 6.0 Hydroxypropyl methylcellulose 6.0 Talc 5 0 Sodium stearyl fumarate 2.5 Water purifed 50.0 Enteric coatin~ laver Metacrylic acid copolymer 9.1 rol~ yl~llc glycol 1.0 Titanium dioxide 0.51 Colour iron oxide red-brown 0.43 Water purifed 45.0 Polish Paraffin 0 05 Descrivtion of ~ d~
Mag..~siu,., 0111~ IGUIC~ mannitol, l~y~Lu~y~lu~yl methylcellulose, ~uulucly~L~lline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet 25 mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. The milled granulate is compres.sed to tablets ~hith a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.
Water used in the u~ ural~tul~ of the tablets is removed duling subsequent processing.
21 '1 ~'6~1 W096fO1622 11 I~,rld~ . IG
[nvestiyation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymes, pH
1.''. Atter six hours the tablets were removed, washed and analysed tcr omeprazole content using HPLC The amount of ~ ~O]C is taken as acid resist~nce.
s Tablet Acid re.sistance Strength (mg) (%) 95 (92-101) Exam~le 3 Enteric coated pellet forrnulation containing mqen~sinrn ....,. I.,.., ,lf being produced as described in WO95/01977.
Pellet Core Mqgm~ci m ~ lr 1.5 kg Non-pareil pellets 1.5 kg Hydroxypropyl methylcellulose 0.23 kg Water purified 4.0 kg Enteric-coatiny laver Uncoated pellets 500 g Methacrylic acid copolymer 300 g Triethyl citrate 90 g Mono- and di~lyc.lid~s (NF) 15 g Polysorbate 80 1.5 y Water purified 1290 g 21 ~3h,~'1 ~ w~ 96101622 ~ 5~ 16 Description of manufacturine.
Suspension layering was performed in a fluid bed apparatus. Magnesium u",~,~,,a~ulc was sprayed onto inert non-pareil cores from a water .suspension containing the dissolved binder. The prepared pellets were enteric-coated in a tluid 5 bed apparatus.
~ ,ull of acid resistance.
Pellets were added to gastric fluid USP (without enzyme), 37~C (paddle) 100 r/min. After 2 hours the actual amount of ~ ul~ remaining intact in the 1() ful~ /LIliu., was determined.
Acid resistance (n=6) Pellets ~7c 20 mg 94 ( 9:3 - 95 )
NEW ORAL PHARMACEUTICAL FORMULATION CONTAINING MAGNESIUM
SALT OF OMEPRAZOLE
Field of the invention.
5 The present invention is related to a new p~ ;nal r~ containing a no~el physical form of a 1 ~c.~ salt of .,.,.. ~ , to a method for the ur4l,h.,c: of such a fulululf ~iun~ and to the use of such a rulluul~Liull in medicine.
10 Back~round of thc invention.
The compound known under the generic name ....,. ~ . 5-methoxy-2(((~
methoxy-3,5-dimethyl-2-pyfidinyl)methyl)sulfinyl)-lH-f~ L~,f~lr, is described i.a. in EP-A 0 005 129.
Omeprazole is useful for inhibiting gastric acid secretion in mammals and man. In a more general sense. said substances may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux ,cophAci~ic, gastritis, duodenitis, gastric ulcer and duodenal ulcer. F~lh~ u~, ull~ Lolc may20 be used for treatment of other y~ uintu lil.al disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAlD therapy. in patients with l'lon Ulcer Dyspepsia, in patients with symptomatic gastro c.~ul ' ~ ' reflux disease, and in patients with g~c~Tinf mAc Omeprazole may also be used in patient~s in inten,sive care situations, in patients with acute upper y"~llu;..,~Li,.al bleeding, 25 pre- and pu .lu~ dlively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Further, n..,~ may be useful in the treatment of psoriasis as well as in the treatment of ll~lif Ot.lA' ~' ' infections and diseases related to these.
~l '3.~8~
WO g6/0162Z P~ ,6 Omeprazole is susceptible ~o .J- E,.r I ~ii.ll/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-vamesless than three is shorter than ten minutes. Omeprazole may be stabilized in mixtures with alkaline ~ nl~u~ k The stability of u~ dzule is also affected by 5 moisture, hea~, organic solvents and to some degree by light.
Prom what is said about the stability properties of ~ rf t~ 1, it is obvious that an oral dosage form of u~ ~ulc must be protected from contact with the acid gastric juice and the active substance must be transferred in intact form to that part 10 of the E;~l~ ' tract where pH is near neutral and where rapid absorption of o..._~!l~ùle can occur.
A uLa~ àcc~.~i~l oral dosage fonn of omeprazole may well be protectea from contact with acidic gastric juice by an enteric coating. In US-A 4,786,5ûS an 15 enteric coateci ~.n. ~ ".1~ preparation is described. Said, "r '- ~ICpdlaiiUII
contains an alhline core comprising omPp~ lP, a subcoating and an enteric coating.
The hard gelatine capsules containing an enteric coated pellet fonT~ irln of 20 n 1 ~ r marketed by the Applicant today, are not suitable for press-through blister packages. Thus, there has boen a demand for dc~lv~,...e.ll of new enteric coated ~ ~dLi~ . of o,n. ~ ; with good chemical stability as well as improved mechanical stability making it possible to produce well fi Li.~.~ing and patient-friendly packages.
~5 Certain salts of o..,. ~ including alkaline salts of .~ A~ /u1. are described in~P-A 0 124 495. In said patent ~ ll the ,cquilclr.~ and importance regarding storage stability of omeprazole for bl~.Vl~Ul~l~iUII in ph-~ t~t ~IC,~I..tiUlls are ~ c;, wo 96/0~622 2 I q 3 6 8 1 r ~ a~
There Is however. a demand for the d~v~ ,u~en~ of ne~ cnteric iul~iualatidns of omeprazole with enhanced ~stai ility and for environmental aspects there is also a strong desire for the use of v ater based processes in production of pll Lilua~ Lil al products.
The isolation and pllrifi' atiori in full manufacturing scale of the .
salt~s described in EP-A 0 124 495 presents one major problem in that the ~ ,olr sait particles are very fragile making tJLaullla~ dl f~ d~g processes utilising this product less attractive in full scale IU production. ~v'- ' g of mRgn~ Cil~m un.~ without a separate crystaPiisation step gives a product which is less suitable as a 1~1~ --.,. ~i. ~1 substance.
In order to use the ll ~c -: .. salt of l~ ul in this ~iJ~' irlcaLiùll denoted ~l; . in full I ' , scale in preparing r' - ~ - C ~
f,"." ~-l;,...~ prim~rily for orai ,..I...;n;~l,..l;n... such as tablets, it is necessary that said magn~cillm ....,~ 1...,ok possesses a cnmhinatinn of properties which makessuch full scale niallura~ .t, feasible.
20 The ~ ,-".1.;" ~~i,-" of physical properties of the novel m c- - ---- ~ ~ I,...ink product described in W09510197~ with respect to the degree of crystaliinity.
particle diameter, density, Lr~;lusuui i~ iiy, low water content and low content of other solvents is favorable and permits the Illall ra~Luic of , u,.,~i~,aLule in â fon-n which is dJv~i.,La~ous for the ll~a..urdo~u~;i of the new pl.- ,n~ c ~
~s rUIIllUiaLiUlls.
The novel form of ~,-~c....: -1 uul~.iJiaLulc can be formulated into different dosa.~e forms for oral and rectal administration. E~amples of such 11~ "c are tablets granules, pellets. capsules ~ uu~ /-i., and sllcrl-ncinnc WO 9C/01622 q 3 6 8 1 ~ ~ " j,.
Description of the in~ention One objec~ of the present invention is to pro~ide a ph~ ulical forrnulatic~n of Another object of the present invention is to provide a process for full scale production Of 1~ I fu~ ul~ lus of ..".. ~ , espccially an enteric coated dosage form of .. ,. ~ olc, which is resistane to dissolution in acid media and which dissolves rapidly in neutral to aLkaline media and which has a good In stability even agi~inst discoloration.
Yet another object of the invention is to provide an environmental friendly completely water-based process for the Illal~ur~ U~i of ~h~U---~.. iu~l r of .-,... ~..,.,. 1 A further object of the present invention is to provide a dosage form comprising.,.,.. I..~,.~l~ which is suitable for press-through blister packages and which also has an improved patient :~-cer~ c 20 The new dosage form is .'-~ ;,. .1 m the following way. Core material in the form of pellets, granules, beads or tablets containing the novel form of a ." g salt of ~ ,le and on said core material one or more enteric coating layers.
25 The process of forrning the enteric coated dosage form is pret'erably water-based.
Also the enteric coating process step ean be carried out using a water-based process which is desirable both for the working ellvi~u~u~ inside the pharmaceutical plant and for global environmental reasons.
WO96101622 ~ 3 6 8 I r~ ll~h'Slt 1~
It has been found that a m,qgnt chlm u~ "~;uk ha~,ing a degree of crystallinity which jc higher than 70';7r is advantageous in the manut:acture of p~ m~irellticql formulations of ~"".,~ ok accordin,g to the present in~ention.
Detailed descriPtion of the invention The new ,uh.-iillld.c...-ul'. ru~ ulalioli is defined in clairns 1-9. a process for the manufacture of the ~ c~ ru".. ~ .. according to the present invention is 10 defined in claims 10-11, the use of the fulluuh~liùn in medicine is defined in claims 12-18 and a press-through blister package is stated in clairn 19.
15 A ~ g~ ~h ~ r advui.L~c~,uu~ for the m~ rd~ g of the claimed formulation is described in WO95/01977 hereby iil~Ul~U- ' ' in a whole by reference. Said m ~ k has a degree of crystallinity of not less than 70~7c~ preferably higher than 75% as determined by X-ray powder diffraction 20 rl ~ ..- . irql fu~ rin.lc containing the ~ are u..~llurdul. c-~ as described herein below.
Core materia-2S The novel m~ivnecinrn salt ûf 0.1~ L-, herein referred to as mqgnecillm w~ llc, is m~L~ed with 1,l - ". ~"~;. ,.1 ~O..cli~ to obtain preferred handling and processing properties and a suitable cnm~. ntrqrir~n of the active substance in the ftna. mLYture. rl ~ . ., c..~ in ...~ such as fllers, binders, lubricants, ' ~, agents, surfactants and other pl..u.. ~ lly a-,ceptable additives, 30 can be used. The core may alsû contain ar. a-kaline "1 ",~ . irqlly acceptable wo 96101622 2 ~ q 3 ~ ~8 1 1~ h~ . 16 substance (or substances). The optionally added alkaiine substance(s) i5 IlOt essential tor the inventiorl. However, it may further improve lhe chemical stabilily of the formulations. Such ph~ u~i.dlly acceptable substances can be chosen among~ but are not restricted to substances such as the sodium~ potassiumt calcium, 5 '~L:~ ~ 'h~ and aluminium salt.s of phosphoric acid. carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium l.y~Lu~idc/.sodium biudliJo~l~tc ~Ui~lC~iiJi~dlC, substances normally used in antacid ylcl~diJull~ such QS
nnlm~ calcium and ,-...~ ., hydlu~dd~, 1l 0 oxide or composite substances, such as A12O3.6MgO.CO2.12H2O,~Mg6A12~OH)loCO3.4H2O), MgO.A12O3. 2~iO2.nH2O or similQr ~ r- ' . organic pH-buffering sub.stances such as l-;hydlu~y~ lly' ' , basic amino acids and their salts or othcr similar, I'l'~ ily acceptable pH-buffering substances.
The powder mixture is then formulated into peUes, granules, beads or tablets by 15 pl. _. ~"~ procedures. The pellets. granules, beads or tablets are used as corc material for further processing.
Enteric coatin1~ laver 20 The enteric coating layer is applied in one or more layers onto the formulated core material by coating procedures in suitable equipments such as pan coating~ coating granulator or fluidized bed appQratus using solutions of polyrners in water, or by using latex ,"y) ~ s of said polymers or optionally using polyrner solutions in suitable organic solYents. As enteric coating polymers can be used one or more of 25 the following, for example solutions or dispersions of acrylates (~ h~ylic acid/methacrylic acid Ill.LIIY1~t~. copolymer), cellulose acetate phthalate.
hydroxypropyl .I.~.ll.yl..llulose phthalate, hydroxypropyl methylcellulose acetate su~cinate, polyvinyl acetate phthalate. cellulose acetate trimellitate, ~"~1 u~y~u~.iLy~ lyl~cllulose~ shellac or other suitable enteric coating polymer(s:l.
30 Preferably water-based polymer dispersions such as for example ~UIIIIJU~..ld~ knOWII
WO 96/01622 2 1 ~ ~ 6 ~
under the trade names Aquateric~ (FMC Corporation) Eudragit6) (Rohm Pharma)~
AqoatTM ~Shin-Etsu Chemical), OpadryT~' (Colorcon) or similar ~,ulllr . ~c are used to obtain enteric coatings. The enteric coating layer can optionally contain a pharmq~ e~lt~ ly acceptable plasticizer for example cetanol, triacetin, citric acid es-5 ters such as. those known under the trade name Citrûflex(~ (Pfizer), phthalic acidesters, dibutyl succinate, poly~,.l.~lel.~, glycol (PEG:1 or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-50 % of the enteric coating polymer(s). Additives such as talc, colorants and pigments may also be included into the enteric coating layer 10 or sprayed onto the enteric coated material as an overcoat.
The thickness of the enteric coating may vary videly without influencing the release rate of o~ ."~ To protect the acid susceptible ~ )k 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 9ra andmore preferably more than 8.0 %. The upper amount of the applied enteric coatingis normally only limited by processing conditions. This possibility to increase the thickness of the enteric coating without deleterious influence on the release rate of ul~ oh is especially desirable in large scale processes. The enteric coating 20 layer(s) may be applied on the pre-processed f~ ' . without exactly controlling the thickness of the applied coating layer(s).
Thus, the r~ according to the invention consists of core material containing magnesium ...~ . The core material is coated with enteric~5 coating~s) rendering the dosage form insoluble in acid media, but t' ~ ; g,/dissolving in neutral to alkaline media such as, for instance the liquids present in the prûximal part of tne small intestine, the site where dissolution is wanted.
wog6~0l~22 21 ~3~J31 x Fhlal dosaYe form The fm.ll dosaye form is either an enteric coated tablet or capsule or in the case of enteric coated pellets. beads or granules, these pellets, beads or yranules are 5 dispensed in hard yelatin capsules or sachets. The final dosage form may further be coateo with an additional layer containing pigment(s) andlor colourant~s). It isessential for the long term stability during storage that thc wat,r content of the final dosage form containing magnesium omeprazole lenteric coated tablets.
capsules. granules, beads or pellets) is kept low.
Process A process for the ~ rh-~ of a dosage form according to the pre.sent invention 15 represents a further aspect of the invention. After the forming of the core material, said material is coated with enteric coating layer(s). The coating(.s) are carried out as desc~ribed above. Further ano~her aspect of the invention is that the ~,1.,...",,~ ~ .a;. ~I processes can be completely water-based.
20 The ~ Jala~ l according to the invention is especially ad~u.L,~vus in reducing yastric acid secretion. It is a.l-~ c.J 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 IC~IULIU~ S of the pa~ients, the mode of i~.l.,,..,;~n,.l;o.. and the disease. In ~eneral the daily dose will be in the rangc of 1-400 mg of ..".
The hl~ ention is illustrated in detail by the following examples. Examples 1-~disclose u.."~ h ~ of different enteric coated tablets containing magnesium OII~ L~U1C. Said examples also show the result of a gastric acid resistance te.st in vitro. Example 3 discloses an enteric coated pellet f~nlllulà~iun Said e~ample also 30 shows the result of a yastric acid resistance test in vitro.
~ 1 q368 1 WO 96/01622 . ~, I /a~ ~.'C 16 Exam~le I
Tablet formulation containing magnesium omepra~ole being produced as described in W095/01977.
Amount u~ ulc 10 Ingredient (mgJtabl) Tablet core U~ ,lc I I.2 Mannitol 68.7 Microcrystalline cellulose 25.0 Sodium starch glycolate 6.0 Hydroxypropyl methylcellulose 6.0 Talc 5.0 Sodium stearyl fumarate 2.5 Water pu~ified 50.0 Enteric coatin~ laYer Methacrylic acid copolymer 9.1 Polyethylene glycol 1.0 Titaniurn dioxide 0.82 Colour iron oxide, red-brown 0.04 Colour iron o~;ide, yellow 0.02 Water purified 45.0 Polish Paraffin powder 0.05 ~' 936~1 W0~6/~1622 .~11~1' . .
Tablet.s with the composition described above have been l~anurdulul~l in a laboratory scale of about 20 000 tablets.
Descri~tion oF manufacturin~
5 Magnesium omeprawle, mannitol, hydroxypropyl methylcellulose, microcrystallinecellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally rnixed with anti-adherent and lubricant substances. The milled granulate is w~ /.c~ l to tablets with a diameter of 7 mm. The tablets are enteric coated with a ".~,I..,~,.~I;c acid copolymer film.
10 Water used in the ~ lf~-~ul~ of the tablets is removed during subscquent processing.
Investi~ation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymcs, pH
15 1.2. After six hours the tablets were removed, washed and analysed for u-~ ~c~lc contcnt using HPLC. The amount of Ulll.~JI~UI~, is taken as acid resistance.
Tablet Acid resistance Stren~th (mg) (%) lOI (CJ8- 103) 25 Exam~le 2 Tablet fululul~licn containing " ..~ll. ,;"". ~lm~pr~7ole being produced as dcscribed in W095/0j977.
Amoullt l,~ 40 Ingredient (mg/tabl.) 7 1 ~3~ f WO ~6/01622 ~ 16 Table core Magnesium omeprazole 45.() Mannitol 34 9 5 Microcrystalline cellulose 25.0 Sodium st~rch glycolate 6.0 Hydroxypropyl methylcellulose 6.0 Talc 5 0 Sodium stearyl fumarate 2.5 Water purifed 50.0 Enteric coatin~ laver Metacrylic acid copolymer 9.1 rol~ yl~llc glycol 1.0 Titanium dioxide 0.51 Colour iron oxide red-brown 0.43 Water purifed 45.0 Polish Paraffin 0 05 Descrivtion of ~ d~
Mag..~siu,., 0111~ IGUIC~ mannitol, l~y~Lu~y~lu~yl methylcellulose, ~uulucly~L~lline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet 25 mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. The milled granulate is compres.sed to tablets ~hith a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.
Water used in the u~ ural~tul~ of the tablets is removed duling subsequent processing.
21 '1 ~'6~1 W096fO1622 11 I~,rld~ . IG
[nvestiyation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymes, pH
1.''. Atter six hours the tablets were removed, washed and analysed tcr omeprazole content using HPLC The amount of ~ ~O]C is taken as acid resist~nce.
s Tablet Acid re.sistance Strength (mg) (%) 95 (92-101) Exam~le 3 Enteric coated pellet forrnulation containing mqen~sinrn ....,. I.,.., ,lf being produced as described in WO95/01977.
Pellet Core Mqgm~ci m ~ lr 1.5 kg Non-pareil pellets 1.5 kg Hydroxypropyl methylcellulose 0.23 kg Water purified 4.0 kg Enteric-coatiny laver Uncoated pellets 500 g Methacrylic acid copolymer 300 g Triethyl citrate 90 g Mono- and di~lyc.lid~s (NF) 15 g Polysorbate 80 1.5 y Water purified 1290 g 21 ~3h,~'1 ~ w~ 96101622 ~ 5~ 16 Description of manufacturine.
Suspension layering was performed in a fluid bed apparatus. Magnesium u",~,~,,a~ulc was sprayed onto inert non-pareil cores from a water .suspension containing the dissolved binder. The prepared pellets were enteric-coated in a tluid 5 bed apparatus.
~ ,ull of acid resistance.
Pellets were added to gastric fluid USP (without enzyme), 37~C (paddle) 100 r/min. After 2 hours the actual amount of ~ ul~ remaining intact in the 1() ful~ /LIliu., was determined.
Acid resistance (n=6) Pellets ~7c 20 mg 94 ( 9:3 - 95 )
Claims (19)
1. An oral enteric coated formulation containing a core material of an active substance coated with one or more enteric coating layers characterized in that the core material as active substance contains a magnesium salt of omeprazole havinga degree of crystallinity which is higher than 70% as determined by X-ray powderdiffraction and on the core material enteric coating layer(s), whereby the thickness of the enteric coating does not essentially influence the release of omeprazole into aqueous solutions at pH values predominantly present in the small intestine.
2. A formulation according to claim 1, wherein the formulation is a tablet formulation.
3. A formulation according to claim 1, wherein the formulation is a pellet formulation.
4. A formulation according to claim 1, wherein the enteric coating comprising an enteric coating material, optionally containing one or more pharmaceutically acceptable plasticizers, dispersants colorants and pigments.
5. A formulation according to claim 4, wherein the enteric coating comprises water-based polymer solutions or dispersions of acrylates, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and/or cellulose acetate phthalate.
6. A formulation according to claim 1, wherein the enteric coating constitutes from 1.0% by weight of the weight of the core material.
7. A formulation 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 6, wherein the enteric coating constitutes at least 8.0% by weight of the weight of the core material.
9. A formulation according to claim 1, wherein one of the coating layers is an overcoat applied on the enteric coated formulation, which overcoat optionally comprises one or more pharmaceutically acceptable plasticizers, dispersants, colorants and pigments.
10. A process for the manufacture of a formulation according to claim 1 in whichcore material containing magnesium omeprazole is coated with one or more entericcoating layer(s), having a thickness which does not essentially influence the release rate of omeprazole into aqueous solutions at pH values predominantly present in the small intestinate.
11. A process according to claim 10 in which the enteric coated formulation is further coated with an overcoat.
12. An oral enteric coated formulation according to any of claims 1 to 9 for usein therapy.
13. An oral enteric coated formulation according to any of claims 1 to 9 for usein inhibiting gastric acid secretion in mammals and man.
14. An oral enteric coated formulation according to any of claims 1 to 9 for usein the treatment of gastric acid related diseases in mammals and man.
15. The use of an oral enteric coated formulation according to any of claims 1 to 9 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals and man.
16. The use of an oral enteric coated formulation according to any of claims 1 to 9 in the manufacture of a medicament for treatment of gastric acid related diseases in mammals and man.
17. A method for inhibiting gastric acid secretion in mammals and man by administring to a host in need thereof a therapeutically effective dose of an enteric coated formulation according to any of claims 1 to 9.
18. A method for the treatment of gastric acid related diseases in mammals and man by administring to a host in need thereof a therapeutically effective dose of an enteric coated formulation according to any of claims 1 to 9.
19. A press-through blister package comprising a formulation according to any ofclaims 1-9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| WOPCT/SE94/00679 | 1994-07-08 | ||
| SE9400679 | 1994-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2193681A1 true CA2193681A1 (en) | 1996-01-25 |
Family
ID=20393105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002193681A Abandoned CA2193681A1 (en) | 1994-07-08 | 1995-07-03 | New oral pharmaceutical formulation containing magnesium salt of omeprazole |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0768872A1 (en) |
| KR (1) | KR970704426A (en) |
| BR (1) | BR9508261A (en) |
| CA (1) | CA2193681A1 (en) |
| CZ (1) | CZ379596A3 (en) |
| EE (1) | EE03378B1 (en) |
| FI (1) | FI970058A0 (en) |
| HU (1) | HUT78132A (en) |
| IS (1) | IS4398A (en) |
| MX (1) | MX9700152A (en) |
| NO (1) | NO970036D0 (en) |
| NZ (1) | NZ289958A (en) |
| PL (1) | PL181265B1 (en) |
| SK (1) | SK166096A3 (en) |
| WO (1) | WO1996001622A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9500478D0 (en) * | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US5900258A (en) * | 1996-02-01 | 1999-05-04 | Zeolitics Inc. | Anti-bacterial compositions |
| SI9700186B (en) | 1997-07-14 | 2006-10-31 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Novel pharmaceutical preparation with controlled release of active healing substances |
| SE9704870D0 (en) * | 1997-12-22 | 1997-12-22 | Astra Ab | New pharmaceutical formulation I |
| SE9704869D0 (en) * | 1997-12-22 | 1997-12-22 | Astra Ab | New pharmaceutical formulaton II |
| SE9802973D0 (en) | 1998-09-03 | 1998-09-03 | Astra Ab | Immediate release tablet |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| EP1133987A1 (en) * | 2000-03-09 | 2001-09-19 | Ian Whitcroft | Treatment of inflammatory dermatoses with combinations of erythromycin or clarythromycin, metronidazole and a hydrogen pump inhibitor |
| CA2413923A1 (en) * | 2000-03-09 | 2001-09-13 | Andrew Ilchyshyn | Treatment of inflammatory dermatoses comprising erythromycin or clarythromycin metronidazole and a gastrointestinal hydrogen pump inhibitor |
| ES2534713T3 (en) | 2002-10-16 | 2015-04-27 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| EP1755566A2 (en) * | 2004-06-15 | 2007-02-28 | Teva Pharmaceutical Industries Ltd | Stable pharmaceutical formulations of benzimidazole compounds |
| CN105106168B (en) * | 2015-08-19 | 2018-03-06 | 德州德药制药有限公司 | A kind of esomeprazole magnesium intestines capsule and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2189698A (en) * | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
| JPH0768125B2 (en) * | 1988-05-18 | 1995-07-26 | エーザイ株式会社 | Oral formulation of acid labile compounds |
| SE9302396D0 (en) * | 1993-07-09 | 1993-07-09 | Ab Astra | A NOVEL COMPOUND FORM |
| SE9302395D0 (en) * | 1993-07-09 | 1993-07-09 | Ab Astra | NEW PHARMACEUTICAL FORMULATION |
-
1995
- 1995-07-03 HU HU9700039A patent/HUT78132A/en unknown
- 1995-07-03 EE EE9700014A patent/EE03378B1/en not_active IP Right Cessation
- 1995-07-03 MX MX9700152A patent/MX9700152A/en unknown
- 1995-07-03 BR BR9508261A patent/BR9508261A/en not_active Application Discontinuation
- 1995-07-03 WO PCT/SE1995/000816 patent/WO1996001622A1/en not_active Application Discontinuation
- 1995-07-03 CA CA002193681A patent/CA2193681A1/en not_active Abandoned
- 1995-07-05 SK SK1660-96A patent/SK166096A3/en unknown
- 1995-07-05 EP EP95926067A patent/EP0768872A1/en not_active Withdrawn
- 1995-07-05 KR KR1019970700059A patent/KR970704426A/en not_active Application Discontinuation
- 1995-07-05 PL PL95318464A patent/PL181265B1/en unknown
- 1995-07-05 CZ CZ963795A patent/CZ379596A3/en unknown
- 1995-07-05 NZ NZ289958A patent/NZ289958A/en unknown
-
1996
- 1996-12-17 IS IS4398A patent/IS4398A/en unknown
-
1997
- 1997-01-06 NO NO970036A patent/NO970036D0/en not_active Application Discontinuation
- 1997-01-07 FI FI970058A patent/FI970058A0/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6780435B2 (en) | 1997-11-14 | 2004-08-24 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6855336B2 (en) | 1998-08-28 | 2005-02-15 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| KR970704426A (en) | 1997-09-06 |
| PL181265B1 (en) | 2001-06-29 |
| AU695723B2 (en) | 1998-08-20 |
| EP0768872A1 (en) | 1997-04-23 |
| NO970036L (en) | 1997-01-06 |
| EE03378B1 (en) | 2001-04-16 |
| HU9700039D0 (en) | 1997-02-28 |
| BR9508261A (en) | 1997-12-23 |
| AU2994795A (en) | 1996-02-09 |
| WO1996001622A1 (en) | 1996-01-25 |
| MX9700152A (en) | 1997-04-30 |
| PL318464A1 (en) | 1997-06-09 |
| FI970058A (en) | 1997-01-07 |
| WO1996001622A8 (en) | 1999-12-23 |
| CZ379596A3 (en) | 1997-08-13 |
| NZ289958A (en) | 1998-09-24 |
| FI970058A0 (en) | 1997-01-07 |
| SK166096A3 (en) | 1997-09-10 |
| HUT78132A (en) | 2000-06-28 |
| NO970036D0 (en) | 1997-01-06 |
| EE9700014A (en) | 1997-06-16 |
| IS4398A (en) | 1996-12-17 |
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