Note: Descriptions are shown in the official language in which they were submitted.
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
EXAM1PLES
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 )
