Title of Invention

A COMPOSITION BEING AN ENTERIC COATED ORAL PHARMACEUTICAL FORM GIVING DISCONTINUOUS RELEASE OF A H+,K+-ATPASE INHIBITOR

Abstract A composition being an enteric coated oral pharmaceutical form giving a discontinuous release of a H+, K+-ATPase inhibitor, wherein the release of the H+K+-ATPase inhibitor is in the form of at least two consecutive pulses separated in time by from 0.5 and up to 12 hours, and at least one fraction of the said form has a pulsed delayed release and another fraction has instant release, in neutral form or in the form of an alkaline salt thereof, or one of its single enantiomers or an alkaline salt of the single enantiomer thereof and a process for its preparation.
Full Text Field of the invention
The present invention is related to new oral pharmaceutical dosage forms which comprise a proton pump inhibitor, i.e. a H ,K -ATPase inhibitor. The new dosage forms are enteric coated formulations which provide a discontinuous pattern of two or more discrete release pulses of the H ,K -ATPase inhibitor in the small and/or large intestines. The pulses are separated in time by from 0.5 and up to 12 hours, they are preferably separated by from 0.5 and up to 6 hours, and more preferably from 0.5 and up to 4 hours. Furthermore, the present invention refers to the manufacture of such pulsed delayed release pharmaceutical formulations, and their use in medicine.
Background of the invention and prior art
Acid labile H , K -ATPase inhibitors also named as gastric proton pump inhibitors are for
instance compounds known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are disclosed in EP-A1 -0005129, EP-A1-124495, WO 94/27988, EP-A1-174726, EP-A1-166287 and GB 2163747.
These pharmaceutical substances are useful for inhibiting gastric acid secretion in mammals including man by controlling gastric acid secretion at the final step of the acid secretory pathway and thus reduce basal and stimulated gastric acid secretion irrespective of stimulus. In a more general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrom. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, and in patients with symptomatic gastro-oesophageal reflux disease

and/or large intestines (but not in the stomach), releases the proton pump inhibitor in two or more discrete pulses separated in time by from 0.5 up to 12 hours, preferably separated in time by from 0.5 and up to 8 hours, and more preferably by from 0.5 and up to 4 hours.
According to another aspect of the invention a discontinuous release pattern of the proton pump inhibitor by once daily administration of a dosage form is provided wherein a part of the dosage form gives a pulsed delayed release, and other parts of the dosage form release the proton pump inhibitor instantly. The dosage form provides at least two consecutive pulses for release of substance, the pulses should be separated in time by from 0.5 and up to 12 hours, preferably by from 0.5 and up to 8 hours, and more preferably by from 0.5 and up to 4 hours interval.
The present pulsed release formulations show an improved patient compliance over an administration regimen comprising consecutive administration of two or more unit doses within specified time intervals
A composition being an enteric coated oral pharmaceutical form giving a discontinuous release of a H+, K+-ATPase inhibitor, wherein the release of the H+K+-ATPase inhibitor is in the form of at least two consecutive pulses separated in time by from 0.5 and up to 12 hours, and at least one fraction of the said form has a pulsed delayed release and another fraction has instant release, and the H+, K+-ATPase inhibitor is a compound chosen from

(Formula Removed)


(Formula Removed)
in neutral form or in the form of an alkaline salt thereof, or one of its single enantiomers or an alkaline salt of the single enantiomer thereof, said composition comprising;
(Formula Removed)
a) a core material comprising one portion of the H+, K+-ATPase inhibitor, a water swellable substance, and optionally pharmaceutically acceptable excipients,
b) the following sequence of layers, covering the core material
bl) a lag time controlling layer,
b2) at least an additional layer comprising the second portion of the H+, K+-ATPase inhibitor, and b3) an enteric coating layer, or
a) a core material comprising one portion of the H+, K+-ATPase inhibitor and optionally pharmaceutically acceptable excipients,
b) the following sequence of layers, covering the core material
bl) a swelling layer comprising a water swellable substance, b2) a lag time controlling layer,
b3) at least an additional layer comprising the second portion the H+, K+-ATPase inhibitor, and b4) an enteric coating layer;
wherein the lag time controlling layer constitutes from 0.5 to 25% counted on the weight of the core material including water swelling substances or swelling layer, and the lag time controlling layer is a disrupting semi-permeable membrane.
Detailed description of the invention Active substance.
Compounds of interest for the novel pharmaceutical formulations according to the present invention are compounds of the general formula I, an alkaline salt thereof, one of the single enantiomers thereof or an alkaline salt of one of the enantiomers

(Formula Removed)
wherein




Detailed description of the invention Active substance.
Compounds of interest for the novel pharmaceutical formulations according to the present invention are compounds of the general formula I, an alkaline salt thereof, one of the single enantiomers thereof or an alkaline salt of one of the enantiomers
wherein
Hetj is

Het2 is


wherein
N in the benzimidazole moiety means that one of the ring carbon atoms substituted by Rg-Rg optionally may be exchanged for a nitrogen atom without any substituents;
RI, R2 and R3 are the same or different and selected from hydrogen, alkyl, alkoxy
optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;
R4 and R5 are the same or different and selected from hydrogen, alkyl and arylalkyl;
Rg' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;
Rg-Rg are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, and trifluoroalkyl, or adjacent groups Rg-Rg form ring structures which may be further substituted;
RIO is hydrogen or forms an alkylene chain together with R3 and
R! i and R12 are the same or different and selected from hydrogen, halogen or alkyl. Examples of specifically interesting compounds according to formula I are

The compound suitable to be used in the pulsed release formulations according to the present invention may be used in neutral form or in the form of an alkaline salt, such as for
instance the Mg +, Ca , Na+ or K salts, preferably the Mg salts. The compounds may
also be used in the form of one of its single enantiomers or an alkaline salt of the single enantiomer.
Especially preferred compounds for the oral pharmaceutical preparation according to the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the (-)-enantiomer of omeprazole. Omeprazole and related substances as well as their preparations are described in EP 5129, EP 124 495, WO 95/01977, WO 94/27988 hereby incorporated in a whole by references.
The above compounds are susceptible to degradation/transformation in acidic and neutral media. Generally, the degradation is catalyzed by acidic reacting compounds and the active compounds are stabilized with alkaline reacting compounds. There are different enteric coating layered preparations comprising omeprazole as well as other proton pump
inhibitors described in the prior art, see for instance US-A 4,853,230, WO 95/ 01783, and WO 967 01623. Especially, the latter describes alternative manufacturing methods for the preparation of enteric coating layered pellets comprising omeprazole and similar compounds.
The dosage forms according to the invention provide at least a part of the dose with a pulsed delayed release of the drug and another part of the formulation with rapid or instant release. The instant and pulsed delayed release of the drug can be achieved according to different principles, such as
by single dose layered pellets or tablets,
by multiple dose layered pellets or tablets, or
by two or more different fractions of single or multiple dose layered pellets or tablets,
optionally in combination with pellets or tablets having instant release.
Multiple dose layered pellets, or two or more different populations of single or multiple dose layered pellets prepared according to any of the below described principles, are filled into a capsule or together with tablet excipients compressed into a multiple unit tablet. Alternatively, a multiple dose layered tablet may be prepared.
Single dose layered pellets or tablets.
According to one aspect of the invention, pellets or tablets giving one single delayed release pulse of the drug are prepared. The single dose layered pellets or tablets may be constructed as to comprise the following parts:
- a core material, optionally layered on a seed/sphere, the core material comprises the drug
together with a water swellable substance, and optionally pharmaceutically acceptable
excipients, and the core material is being free from acidic compounds, and thereupon the
following sequence of layers:
- a surrounding lag time controlling layer, and finally
- an enteric coating layer positioned to cover the lag time controlling layer.
According to an alternative aspect of the invention, it is also possible to construct the layered pellets or tablets as to comprise the following parts:
- a core material, optionally layered on a seed/sphere, the core material comprises the drug
optionally together with pharmaceutically acceptable excipients, and the core material is
being free from acidic compounds, and thereupon the following sequence of layers:
- a surrounding layer comprising a water swellable substance, and thereupon
- a surrounding lag time controlling layer, and finally
- an enteric coating layer positioned to cover the lag time controlling layer.
Multiple dose layered pellets or tablets.
According to another aspect of the invention, multiple dose layered pellets or tablets giving two or more delayed release pulses of the drug are prepared. These pellets or tablets may be constructed as to comprise the following parts:
- a core material (I), optionally layered on a seed/sphere, the core material comprises the
drug together with a water swellable substance, and optionally pharmaceutically acceptable
excipients, and the core material is being free from acidic compounds, and thereupon the
following sequence of layers:
- a surrounding lag time controlling layer (II), and
- a layer (III) comprising the drug optionally together with a water swellable substance,
and/or pharmaceutically acceptable excipients; the layer is being free from acidic
compounds, and
- optionally a separating layer (IV) which is water-soluble or in water rapidly
disintegrating,
wherein the layers II and III and the optional layer IV may appear in repeated sequences (in this order) and each set of layers (II + III) gives an additional single pulse of the drug. The dosage form is finally covered by an outer enteric coating layer (V).
Thus, a three-pulsed delayed release pellet or tablet could be constructed as having the following sequence of layers 1+ II + III + II + III + an optional layer IV, and the prescribed outer enteric coating layer (V).
According to an alternative aspect of the invention, the multiple dose layered pellets or tablets may also be constructed with the following parts:
- a core material (I), optionally layered on a seed/sphere, the core material comprises the
drug optionally together with pharmaceutically acceptable excipients, and the core material
is being free from acidic compounds, and thereupon the following sequence of layers:
- a surrounding layer (II) comprising a water swellable substance, followed by
- a surrounding lag time controlling layer (III) and
- a layer (IV) comprising the drug optionally together with pharmaceutically acceptable
excipients; the layer is being free from acidic compounds, and
- optionally a separating layer (V) which is water-soluble or in water rapidly disintegrating,
wherein the layers II, III, IV and the optional layer V may appear in repeated sequences (in this order) and each set of layers (II + III+ IV) gives an additional single pulse of the drug. The dosage form is covered by an outer enteric coating layer (VI).
Thus, a three-pulsed pellet or tablet could be constructed as having the following sequence of layers 1+ II + III + IV+ II + III + IV + an optional layer V, and the prescribed outer enteric coating layer (VI).
The core material comprising the active drug can be prepared either by coating layering the drug onto a seed, such as for instance sugar spheres, or by extrusion
/spheronization of a mixture comprising the drug and pharmaceutical acceptable excipients. It is also possible to prepare the core material by using tablet technology, i.e. compression of drug granules and optionally pharmaceutically acceptable excipients into a tablet core.
For pellets of the two types, i.e. single or multiple dose pellets, which have the drug deposited onto a seed/sphere by layering, it is also possible to have an optional layer comprising a water swellable substance beneath the drug containing layer in the core material.
The prepared core material is used for further processing. Different techniques to prepare the core material for pellets or tablets are described below.
Core material
The core material for the individual pellets or tablets can be constituted according to different principles. A seed/sphere layered with active substance, the active substance is optionally mixed with a water swellable substance and/or a pharmaceutically acceptable excipient, can be used as core material for the further processing. The core material is free from acidic compound except that the active substance as such might be slightly acidic.
The micro environment around the acid susceptible H K -ATPase inhibitor should
preferable be not less than pH=7, and more preferably not less than pH=8 when water is absorbed to the core material mixture or when water is added in small amount to the mixture.
The seeds/spheres can be water insoluble and comprise different oxides, celluloses, organic polymers and other materials, alone or in mixtures, or be water soluble and comprise different inorganic salts, sugars and other materials, alone or in mixtures. Further, the seeds/spheres may comprise active substance in the form of crystals, agglomerates, compacts etc. The size of the seeds may vary between approximately 0.1 and 2 mm. The
seeds layered with active substance are produced either by powder or solution/suspension layering using for instance granulating or spray coating/layering equipment.
Before the seeds are layered, the active substance may be mixed with further components to obtain preferred handling and processing properties and a suitable concentration of the active substance in the final mixture.
Such components can be binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures. The binders are for example celluloses such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, gelatine, sugars, starches and other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic surfactants, such as polysorbate 80, or ionic surfactants such as for instance sodium lauryl sulfate.
Optionally an osmotic agent is placed in the core material. Such an osmotic agent is water soluble and will provide an osmotic pressure in the tablet. Examples of osmotic agents are magnesium sulfate, sodium chloride, lithium chloride, potassium chloride, potassium sulfate, sodium carbonate, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium lactate, urea, magnesium succinate, sucrose or mixtures thereof.
Alternatively, the active substance optionally mixed with any of the components defined above can be formulated into a core material. Said core material may be produced by extrusion/spheronization, balling or compression utilizing different process equipments. For extrusion/spheronization processes incorpaoration of a microcrystalline cellulose and a low-substituted hydroxypropylcellulose in the core material is preferred. The size of the formulated core materials is approximately between 0.1 and 4 mm, preferably between 0.1 and 2 mm for a pellet preparation, and between 2 and 10 mm, preferably between 3 and 7 mm for a tablet preparation.
Suitable alkaline additives can be chosen among, but are not restricted to, substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or
composite substances, such as Al203.6MgO.C02.12H20, (Mg6Al2(OH)16C03.4H2O),
MgO.Al2O3. 2Si02.nH20 or similar compounds; organic pH-buffering substances such as
trihydroxymethylaminomethane, basic amino acids such as arginine, and their salts or other similar, pharmaceutically acceptable pH-buffering substances.
Alternatively, the aforementioned core material for a pellet preparation can be prepared by using spray drying or congealing techniques.
Swelling layer.
The applied swelling layer comprises one or more water swellable substances, a suitable binder, and optionally pharmaceutically acceptable excipient(s). Suitable swellable substances, binders, as well as pharmaceutically acceptable excipients are described below. The swelling layer expands when exposed for an aqueous solution such as intestinal fluid.
Alternatively, one of the additional drug containing layers applied onto the core material may be a combined drug swelling layer.
Water swellable substances.
Water swellable substances suitable for the dosage forms according to the present invention are compound which are able to expand when they are exposed to an aqueous solution, such as intestinal fluid.
One or more water swellable substances may be present in the core material together with the active substance and optionally pharmaceutically acceptable excipient(s). Alternatively, one or more water swellable substances are included in-a Swelling layer applied onto the core material. As a further alternative, swellable substances(s) they may also be present in an optional swelling layer situated beneath the drug containing layer, if a layered seed or sphere is used as the core material.
The amount and art of water swellable substance(s) in the swelling layer or in the core material is chosen in such a way that the core material or the swelling layer in contact with an aqueous solution, such as intestinal fluid, will expand to such a degree that the surrounding lag-time controlling membrane ruptures. A water swellable substance may also be included in the drug comprising layer of the multiple layered pellets or tablets to increase dissolution rate of the drug fraction.
Suitable substances which can be used as water swellable substances are for instance, low-substituted hydroxypropyl cellulose, e.g. L-HPC; cross-linked polyvinyl pyrrolidone (PVP-
TM TM
XL), e.g. Kollidon CL and Polyplasdone XL; cross-linked sodium
TM TM
carboxymethylcellulose, e.g. Ac-di-sol , Primellose ; sodium starch glycolate, e.g.
TM TM
Primojel ; sodium carboxymethylcellulose, e.g. Nymcel ZSB 10 ; sodium
TM TM TM
carboxymethyl starch, e.g. Explotab ; ion-exchange resins, e.g. Dowex or Amberlite ;
TM
microcrystalline cellulose, e.g. Avicel ; starches and pregelatinized starch, e.g. Starch
TM TM TM
1500 , Sepistab ST200 ; and formalin-casein, e.g. Plas-Vita . One of these substances can be used or any combinations or mixtures thereof, taking into consideration that the use of any acidic compound not is suitable.
Lag time controlling layer.
The lag time controlling layer is a semipermeable membrane comprising a water resistant polymer that is semipermeable for an aqueous solution, such as intestinal fluid. Suitable polymers are cellulose acetate, ethylcellulose, polyvinyl acetate, cellulose acetate butyrate,
T.M
cellulose acetate propionate, acrylic acid copolymers, such as Eudragit RS or RL. The
polymer may optionally comprise pore forming agents, such as a water soluble substance, eg. sucrose, salt; or a water soluble polymer eg. polyethylene glycol. Also pharmaceutically acceptable excipients such as fillers and membrane strength influencing agents such as talc, aerosil, or sodium aluminium silicate may be included.
There is at least one lag time controlling layer present in the dosage forms according to the invention. The lag time controlling layer positioned nearest the inner core material is constructed in the form of a semipermeable membrane that will disrupt after a desired time after ingestion.
A desired lag time may be adjusted by the composition and thickness of the layer. The amount of substances forming such a disrupting semipermeable membrane, i.e. a lag time controlling layer, is usually in the range from 0.5 to 25 % counted on the weight of the core material including swelling substances or a swelling layer. Preferably the amount of such a lag time controlling layer, i.e. a disrupting semipermeable membrane , is between 2 to 20 % by weight.
A preferred disrupting semipermeable membrane, i.e. lag time controlling layer, is composed of a mixture of ethylcellulose and talc. The mixture contains most preferably 10 to80%w/woftalc.
Optionally, any additional lag time controlling layer may be constructed as a disrupting semipermeable membrane.
Enteric coating layer(s) and separating layer(s).

Before applying an enteric coating layer onto the layered pellets or tablets, they may optionally be covered with one or more separating layers comprising pharmaceutical excipients optionally including alkaline compounds such as for instance pH-buffering compounds. This separating layer separates the composition of the layered pellets or tablets from the outer enteric coating layer.
The separating layer as well as the other type of layers, such as the swelling and lag time controlling layers, can be applied by coating or layering procedures in suitable equipments such as coating pan, coating granulator, centrifugal granulator or in a fluidized bed apparatus (including Wurster type) using water and/or organic solvents for the coating process. As an alternative the layer(s) can be applied by using powder coating or press-coating techniques.
Suitable materials for the optional separating layer are pharmaceutically acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc, pH-buffering substances and other additives may also be included into the separating layer.
When the optional separating layer is applied to the layered pellets or tablets it may constitute a variable thickness. The maximum thickness of the optional separating layer is normally only limited by processing conditions. The separating layer may serve as a diffusion barrier and may act as a pH-buffering zone. The optional separating layer may improve the chemical stability of the active substance and/or the physical properties of the dosage form.
Finally the layered pellets or tablets are covered by one or more enteric coating layers by using a suitable coating technique. The enteric coating layer material may be dispersed or

dissolved in either water or in suitable organic solvents. As enteric coating layer polymers one or more, separately or in combination, of the following can be used; e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating layer polymer(s).
Additives such as dispersants, colorants, pigments, additional polymers e.g. poly(ethylacrylat, methylmethacrylat), anti-tacking and anti-foaming agents may also be included into the enteric coating layer. Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible material. The enteric coating layer(s) constitutes a thickness of approximately at least 10 urn, preferably more than 20 jam. The maximum thickness of the applied enteric coating layer(s) is normally only limited by processing conditions.
Any of the applied polymer containing layers, and specially the enteric coating layers may also contain pharmaceutically acceptable plasticizers to obtain desired mechanical properties. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, glycerol monoesters, polysorbates or other plasticizers. The amount of plasticizer is preferably optimized for each formula, in relation to the selected polymer(s), selected plasticizer(s) and the applied amount of said polymer(s).
Final dosage form
The prepared layered pellets, optionally mixed with tablet excipients are filled into a capsule, or compressed into a multiple unit tableted dosage form. Alternatively, the dosage form is a multiple layered-tablet. Prepared tablets are optionally covered with filmforming agent(s) to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport. Such a tablet coating layer may further comprise

additives like anti-tacking agents, colorants and pigments or other additives to obtain a tablet of good appearance.
The dosage forms according to the invention are suitable for oral administration. The dose will depend on the nature and severity of the disease to be treated. The dose may also vary according to the age, body weight, and response of the individual patient. Children and patients with liver diseases as well as patients under long term treatment will generally benefit from doses that are somewhat lower than the average. In the treatment of other conditions higher doses than average will be used.
Preferably, a dosage form of the proton pump inhibitor, for instance 1 - 500 mg is administered once a day. Suitable doses comprise for instance about 5-100 mg of the substance, and more preferably 10-80 mg. The dosage form may be administered together with other suitable drugs, such as antibacterial compound(s), NSAID(s), motility stimulating agents, and/or antacida.
Examples
The following examples describe the invention more in detail without restricting it. Example 1.
Pulsed single dose delayed release layered pellets comprising magnesium salt of S-omeprazole (pellet strength approx. 44 mg/g).
Preparation of core material (spheres layered with drug).
A drug containing suspension was made according to the composition below;
S-omeprazole Mg-salt lOOg
HPMC, 6 cps 15 g

Polysorbate 80 2 g
Purified water 323 g
HPMC was dissolved in water during stirring with subsequent addition of Polysorbate 80 and the drug. The suspension was sprayed onto 290 g of sugar spheres (Non-pareil) in a fluidized bed. The weight of the obtained product was 395 g.
Application of a swelling layer
A (water free) suspension containing in water swellable substances was prepared according
to the following composition;
Low-substituted hydroxypropylcellulose (L-HPC) 162 g
Hydroxypropylcellulose LF (HPC-LF) 74 g
Talc 354 g
EtOH(99.5%) 3100g
HPC-LF was dissolved in ethanol during stirring, then talc and swelling agent L-HPC was added. The suspension was sprayed onto 175 g of the core material from above in a Wurster equipped fluidized bed. The weight of the obtained product was 711 g.
Application of lag time controlling layer (semipermeable membrane). A coating suspension was made according to the following formula;
Ethylcellulose, lOcps 10 g
Talc 23 g
EtOH(99.5%) lOOOg
The ethylcellulose was dissolved in the ethanol during stirring, then talc was added. Spraying of the suspension onto 150 g of swelling layered pellets from above (0.61- 0.71

mm obtained by sieving) was done in a Wurster equipped fluidized bed. The weight of the obtained pellets was 176 g.
Pellets (corresponding to approx. 10 mg active substance) were analyzed using USP dissolution apparatus No. 2 (paddle), and operated at 100 rpm, 37°C and with a phosphate buffer pH 6.8. The dissolution of active substance was followed by registration of the absorbance at 292 run in a buffer solution, using a 0.5 cm flow-through compact cell. The dissolution profile measured at 292 nm is shown in Figure 1.
Example 2.
Pulsed single dose delayed release layered pellets comprising magnesium salt of S-omeprazole (pellet strength approx. 43 mg/g).
Preparation of core material (spheres layered with drug)
A drug containing suspension was made according to the composition below;
S-omeprazole Mg-salt lOOg
HPMC,6cps 15 g
Polysorbate 80 2 g
Purified water 323 g
HPMC was dissolved in water during stirring with subsequent addition of Polysorbate 80 and the substance. The suspension was sprayed onto 290 g of sugar spheres (Non-pareil) in a fluidized bed. After coating the weight of the obtained product was 395 g.
Application of swelling layer
A water free suspension containing in water swellable substances was prepared according
to the following composition;
Low-substituted hydroxypropylcellulose (L-HPC) 162 g
Hydroxypropylcellulose LF (HPC-LF) 74 g
Talc 354 g
EtOH(99.5%) 3100g
HPC-LF was dissolved in ethanol during stirring, then talc and swelling agent L-HPC was added. The suspension was sprayed onto 175 g pellets from above in a Wurster equipped fluidized bed. The weight of the obtained product was 711 g.
Application of lag time controlling layer (semipermeable membrane).
100 g of the swelling layered pellets obtained above were coated to obtain a lag-time
controlling layer with the suspension below;
Ethylcellulose, 10 cps 8 g
Talc 9 g
Mg-Stearate 2 g
EtOH (99.5%) 620 g
The suspension was prepared by dissolving the ethylcellulose in the ethanol during stirring, then the other compounds were added. Spraying of the suspension onto the pellets was done in a Wurster equipped fluidized bed. The weight of the obtained pellets was 116 g.
The pellets were analyzed as is described in Example 1. The dissolution profile is shown in Figure 2.
Example 3.
Single dose layered pellets, i.e. enteric coated pulsed single dose delayed release pellets comprising magnesium salt of S-omeprazole (pellet strength approx. 37 mg/g).
Application of enteric coating layer.
Pellets from Example 1 were enteric coated in a fluidized bed with a coating dispersion
according to below;
Eudragit L30 D-55 (30% w/w dispersion) 73.3g
Triethylcitrate (TEC) 6.6 g
Glycerole monostearate (CMS) 0.3 g
Polysorbate 80 0.03 g
Purified water 40.4 g
A homogenous coating dispersion was prepared by dispersing polysorbate 80 and glycerol monostearate in water. Triethylcitrate was dissolved in the Eudragit dispersion and thereafter the two dispersions were mixed to obtain the coating dispersion.
The coating dispersion was applied onto 120 g pellets from Example 1, using a Wurster equipped fluidized bed. The weight of the layered pellets was 140 g.
Pellets (corresponding to approx. 10 mg active substance) were analyzed using USP dissolution apparatus No. 2 (paddle) and operated at 100 rpm and 37°C. First the pellets were immersed n 0.1M HC1 for 2 hours (pH 1.2), thereafter phosphate buffer components were added to obtain pH 6.8. The dissolution profile was registered as described in example 1, and is shown in Figure 3. The pellets were examined with respect to acid resistance. After exposure to 0.1 M HC1 during two hours, 96 % of the active substance remained intact.
Example 4.
Single dose layered pellets, i.e. enteric coated pulsed single dose delayed release pellets comprising magnesium salt of omeprazole (pellet strength approx. 35 mg/g.).
Preparation of core material (spheres layered with drug).
A drug containing suspension was made according to the composition below;
Omeprazole Mg-salt lOOg
HPMC, 6cps 15 g
Polysorbate 80 2 g
Purified water 323 g
HPMC was dissolved in the water during stirring with subsequent addition of Polysorbate 80 and the drug. The suspension was sprayed onto 290 g of sugar spheres (Non-pareil) in a fluidized bed. After the coating the weight of the obtained product was 395 g.
Application of swelling layer
A (water free) suspension containing in water swellable substances was prepared
according to the following composition;
Low-substituted hydroxypropylcellulose (L-HPC) 162 g
Hydroxypropylcellulose LF(HPC-LF) 74 g
Talc 354 g
EtOH(99.5%) 3100g
HPC-LF was dissolved in ethanol during stirring, then the talc and the swelling agent L-HPC was added. The suspension was sprayed onto 175 g of core material from above in a Wurster equipped fluidized bed. The weight of the obtained product was 711 g.
Application of lag time controlling layer (semipermeable membrane).
120 grams of the swelling layered pellets (the fraction 0.61 mm - 0.71 mm obtained by
sieving) obtained above were coated with the suspension below;
Ethylcellulose, 10 cps 8 g
Talc 18 g
EtOH(99.5%) 810g
The suspension was prepared by dissolving ethylcellulose in ethanol during stirring, then talc was added. The suspension was sprayed onto the pellets in a Wurster equipped fluidized bed. The weight of the obtained product was 137 g.
Application of enteric coating layer .
120 grams of the pellets from the previous step above were coated with an enteric coating
solution according to below;
HPMCP (HP-55) 33 g
Cetanol 2.4 g
Acetone 353 g
EtOH(99.5%) 151 g
The coating solution was prepared by dissolving HPMCP and cetanol in a mixture of the solvents during stirring. The coating solution was applied in a Wurster equipped fluidized bed. The weight of the layered pellets was 149 g.
The layered pellets were examined with respect to acid resistance in 0.1 M HC1. The acid resistance was 97 %.
Example 5.
Single dose layered tablets, i.e. enteric coated pulsed single dose delayed release tablets comprising magnesium salt of S-omeprazole (Tablet strength approx. 16 mg).
Granules
Granules for homogeonous tablet cores were made according to the following composition;
S-omeprazole Mg-salt 229 g
Microcrystalline cellulose, AvicelpH 101 151 g
Microcrystalline cellulose, Avicel PH 102 sp. coarse grade 400 g
L-HPC 256 g
PVP-XL 302 g
Sodium laurylsulphate (SLS) 30 g
Water purified 1060 g
A granulating solution was prepared by dissolving the SLS in 460 g of purified water.
The powders above were mixed in a mixer after which the solution was added in an even stream. Thereafter approx. 600 g water was added during continued mixing, to give satisfactory consistency to the mass.
The mass was dried in a drying oven at 50°C over night.
Preparation of tablet cores
After milling through a 1.0 mm screen the obtained granules were mixed with tablet lubricant, sodium chloride, and an additional amount of swellable substance, according to the following composition;
Granules for tablet core 400 g
Sodium chloride (passing 0.3mm) 80 g
Sodium stearyl rumarate (Pruv®) 8 g
Polyvinyl pyrrolidone cross-linked (PVP-XL) 20 g
The mixing was performed to homogeneity in a Kenwood mixer.
The mixture was compressed to 6 mm in diameter tablets having an average weight of 126 mg, on a single punch tableting machine (Diaf).
Application of lag time controlling layer (semipermeable membrane).
The tablets from previous step were coated in a Wurster equipped fluidized bed coating
apparatus with a coating suspension of the following composition;
EtOH 99.5% (w/v) 291 parts by weight
Ethyl cellulose N-10 11 parts by weight
Talc, micronized 7 parts by weight
Sum: 309 parts.
200 grams of tablets were processed and the coating was continued until the average tablet weight was 134 mg.
Application of enteric coating layer
The tablets obtained in the previous step were coated with an enteric coating layer in the
same equipment as for the preceding coating step. The coating solution had the following
composition;
Hydroxypropyl methylcellulose phtalate (HP-55®) 16 parts by weight
Cetanol 1
Acetone 151 -"-
Ethanol (95% w/v) 65
Sum: 233 parts
100 grams of the tablets were processed and the coating was continued until the average tablet weight was 148 mg.
Individual tablets were analyzed using USP dissolution apparatus No. 2 (paddle) equipped with stationary baskets and operated at 100 rpm and 37°C. First the tablets were pre-
exposed for 0.1 M HC1 for two hours (pH 1.2), whereafter the dissolution medium was changed to phosphate buffer pH 6.8.
The dissolution profile obtained was registered as described in example 1, and can be seen in Figure 4.
Example 6.
Multiple dose layered tablets, i.e. enteric coated dual pulsed multiple release tablets, (tablet strength approx. 2x15 mg).
Granules
Granules for tablet cores were made according to the following composition;
S-omeprazole Mg-salt 229 g
Microcrystalline cellulose, AvicelPH 101 151 g
Microcrystalline cellulose, Avicel PH 102 sp. Coarse grade 400 g
L-HPC 256 g
PVP-XL 302 g
Sodium laurylsulphate (SLS) 30 g
Water purified 1060 g
A granulating solution was prepared by dissolving the SLS in 460 g of purified water.
The powders above were mixed in a mixer after which the solution was added in an even stream. Thereafter approx. 600 g water was added during continued mixing, to give satisfactory consistency to the mass.
The mass was dried in a drying oven at 50°C over night.
Preparation of tablet cores
After milling through a 1.0 mm screen the obtained granules were mixed with tablet lubricant, sodium chloride, and an additional amount of swellable substance, according to the following composition;
Granules for homogenous tablet core 400
Sodium chloride (passing 0.3mm) 80
Sodium stearyl fumarate (Pruv®) 8
Polyvinyl pyrrolidone cross-linked (PVP-XL) 20
The mixing was performed to homogeneity in a Kenwood mixer.
The mixture was compressed to 6 mm in diameter tablets having an average weight of 126 mg, on a single punch tableting machine (Diaf).
Application of lag time controlling layer (semipermeable membrane).
The tablets from previous step were coated in a Wurster equipped fluidized bed coating
apparatus with a coating suspension of the following composition;
EtOH 99.5% (w/v) 291 parts by weight
Ethyl cellulose N-10 11 parts by weight
Talc, micronized 7 parts by weight
Sum: 309 parts.
200 grams of tablets were processed and the coating was continued until average tablet weight was 134 mg.
Application of a drug comprising layer
The tablets obtained in previous step were coated in the same equipment as above with a
coating suspension of the following composition;
S-omeprazole Mg-salt 20 parts by weight
Hydroxypropyl methylcellulose 6 cps 13 parts by weight
Ethanol99% 128 parts by weight
Water purified 128 parts by weight
Sum: 289 parts.
99 grams of tablets were processed and the coating was continued until the average tablet weight was 162 mg.
Application of enteric coating layer
The tablets obtained in previous step were coated with an enteric coating layer in the same
equipment as for the preceding coating step. The coating solution had the following
composition;
Hydroxypropyl methylcellulose phtalate (HP-55) 16 parts by weight
Cetanol 1
Acetone 153 -"-
Ethanol (95% w/v) 65
Sum: 235 parts
119 grams of the tablets were processed and the coating was continued until the average tablet weight was 173 mg.
Individual tablets were analyzed using USP dissolution apparatus No. 2 (paddle) equipped with stationary baskets and operated at 100 rpm and 37°C. First the tablets were pre-exposed for 0.1 M HC1 for two hours, whereafter the dissolution medium was changed to phosphate buffer pH 6.8.
The dissolution profile obtained was registered as described in example 1, and can be seen in Figure 5. The acid resistance of the tablets were examined and the result was 98 %.
Example 7
Multiple dose capsule formulation comprising (2 x 20) mg of omeprazole in the form of
enteric coated pellets, mixed with an enteric coated tablet with delayed release.
Suspension layering
Magnesium omeprazole 5 kg
Sugar spheres cores (0.25-0.355 mm diam.) 10 kg
Hydroxypropyl methylcellulose 0.8 kg
Water purified 20 kg
Separating layer
Drug containing cores (ace. to above) 14.6 kg
Hydroxypropyl cellulose 1.5 kg
Talc 2.5 kg
Magnesium Stearate 0.2 kg
Water purified 29 kg
Enteric coating
Pellets (ace. to above) 9 kg
Methacrylic acid copolymer (30% suspension) 15 kg
Triethyl citrate 1.4 kg
Mono- and diglycerides (NF) 0.2 kg
Polysorbate 80 0.02 kg
Water purified 9 kg
Over-coating
Enteric coated pellets 9 kg
Hydroxypropyl methylcellulose 0.2 kg
Mg-Stearate 0.005 kg
Water purified 3.6 kg
Suspension layering was performed in a fluid bed apparatus. Magnesium omeprazole was sprayed onto inert sugar sphere cores from a water suspension containing the dissolved binder.
The prepared core material was sub-coated in a fluid bed apparatus with a hydroxypropyl cellulose solution containing talc and magnesium stearate.
The enteric coating consisting of methacrylic acid copolymer, mono- and diglycerides, triethylcitrate and polysorbate was sprayed onto the sub-coated pellets in a fluid bed apparatus. In the same type of apparatus the enteric coated pellets were coated with hydroxypropyl methylcellulose/Mg-Stearate suspension. The over-coated pellets were classified by sieving, to pass 0.71 mm.
The product was analyzed and found to contain 209 mg/g Mg-omeprazole.
Single dose layered tablets, i.e. enteric coated delayed release tablets comprising magnesium salt of omeprazole. (Tablet strength approx. 16 mg.)
Granules
Granules for tablet cores were made according to the following composition (parts by
weight);
Omeprazole Mg-salt 229 g
Microcrystalline cellulose, AvicelPH 101 145 g
Microcrystalline cellulose, Avicel PH 102 sp. coarse grade 400 g
L-HPC 251 g
PVP-XL 302 g
Hydroxy methylcellulose 6 cps 11 g
Sodium laurylsulphate (SLS) 30 g
Water purified 960 g
A granulating solution was prepared by dissolving the SLS in 460 g of purified water.
The powders above were mixed in a mixer after which the solution was added in an even stream. Thereafter approx. 500 g water was added during continued mixing, to give satisfactory consistency to the mass.
The mass was dried in a drying oven at 50°C over night.
Preparation of tablet cores
After milling through a 1.0 mm screen the obtained granules were mixed with tablet lubricant, sodium chloride and an additional amount of swellable substance, according to the following composition;
Granules for tablet core 400 g
Sodium chloride (passing 0.3mm) 80 g
Sodium stearyl fumarate (Pruv®) 8 g
Polyvinyl pyrrolidone cross-linked (PVP-XL) 20 g
The mixing was performed to homogeneity in a Kenwood mixer.
The mixture was compressed to 6 mm in diameter tablets having an average weight of 126 mg, on a single punch tableting machine (Diaf).
Application of lag time regulating layer (semipermeable membrane).
The tablets from previous step were coated in a Wurster equipped fluidized bed coating
apparatus with a coating suspension of the following composition;
EtOH 99.5% (w/v) 291 parts by weight
Ethyl cellulose N-10 11 parts by weight
Talc, micronized 7 parts by weight
Sum: 309 parts.
200 grams of tablets were processed and the coating was continued until the average tablet weight was 134mg.
Application of enteric coating layer
The tablets obtained in previous step were coated with an enteric coating layer in the same
equipment as for the preceding coating step. The coating solution had the following
composition;
Hydroxypropyl methylcellulose phtalate (HP-55®) 16 parts by weight
Cetanol 1
Acetone 151 -"-
Ethanol (95% w/v) 65
Sum: 233 parts
100 grams of the tablets were processed and the coating was continued until the average tablet weight was 148 mg.
Filling of capsule
0.10 g of the pellets prepared above and one of the layered tablets obtained above were filled in a hard gelatine capsule size 1.
The best mode to practice the invention is according to the description given in Example 6.

WE CLAIM:
1. A composition being an enteric coated oral pharmaceutical form giving a discontinuous release of a H+, K+-ATPase inhibitor, wherein the release of the H+K+-ATPase inhibitor is in the form of at least two consecutive pulses separated in time by from 0.5 and up to 12 hours, and at least one fraction of the said form has a pulsed delayed release and another fraction has instant release, and the H+, K+-ATPase inhibitor is a compound chosen from
(Formula Removed)


in neutral form or in the form of an alkaline salt thereof, or one of its single enantiomers or an alkaline salt of the single enantiomer thereof, said composition comprising;
a) a core material comprising one portion of the H+, K+-ATPase inhibitor, a water swellable substance, and optionally pharmaceutically acceptable excipients,
b) the following sequence of layers, covering the core material
bl) a lag time controlling layer,
b2) at least an additional layer comprising the second portion of the
H+, K+-ATPase inhibitor, and b3) an enteric coating layer, and optionally a separating layer beneath
the enteric coating layer or
a) a core material comprising one portion of the H+, K+-ATPase inhibitor and optionally pharmaceutically acceptable excipients,
b) the following sequence of layers, covering the core material
bl) a swelling layer comprising a water swellable substance, b2) a lag time controlling layer,

b3) at least an additional layer comprising the second portion the H+,
K+-ATPase inhibitor, and b4) an enteric coating layer; and optionally a separating layer beneath
the enteric coating layer
wherein the lag time controlling layer constitutes from 0.5 to 25% counted on the weight of the core material including water swelling substances or swelling layer, and the lag time controlling layer is a disrupting semi-permeable membrane.
2. A composition as claimed in claim 1, wherein the H+, K+-ATPase inhibitor is omeprazole, an alkaline salt of omeprazole, the (-) enantiomer of omeprazole or an alkaline salt of the (-)-enantiomer of omeprazole.
3. A composition as claimed in claim 2, wherein the alkaline salt is a magnesium salt.
4. A composition as claimed in any of claims 1-3, wherein the H+K+-ATPase inhibitor optionally comprises an admixture of an alkaline additive.
5. A composition as claimed in any of claims 1-4 wherein the water-swellable substance is selected from the group of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium starch glycolate.
6. A composition as claimed in any one of claims 1-5, wherein the disrupting semi-permeable membrane is composed of a mixture of ethylcellulose and talc.
7. A composition as claimed in claim 6, wherein the mixture contains 10-80% w/w of talc.

8. A process for the preparation of a composition being an enteric coated form comprising a H+,K+-ATPase inhibitor as defined in claim 1, wherein the inhibitor compound is present in at least two portions giving a release of the H+, K+-ATPase inhibitor in at least two separate pulses, which process comprises the following steps:
a) a core material is shaped comprising one portion of the H+,K+-ATPase inhibitor, a water swellable substance, and optionally pharmaceutically acceptable excipients,
b) the core material is layered with the following layers:
bl) a lag time controlling layer,
b2) a layer comprising the second portion of the H+, K+-ATPase inhibitor,
and b3) the enteric coating layer;
or
a) a core material is shaped comprising one portion of the H+,K+-ATPase inhibitor optionally mixed with pharmaceutically acceptable excipients,
b) the core material is layered with the following layers:
bl) a swelling layer comprising a water swellable substance,
b2) a lag time controlling layer,
b3) a layer comprising the second portion of the H+, K+-ATPase inhibitor,
and b4) the enteric coating layer;

wherein the lag time controlling layer constitutes from 0.5 to 25% counted on the weight of the core material including water swelling substances or swelling layer, and the lag time controlling layer is a disrupting semi-permeable membrane.
9. A composition being an enteric coated oral pharmaceutical form
substantially as hereinbefore described with reference to the foregoing
examples.

Documents:

3769-DEL-1998-Abstract-(25-09-2008).pdf

3769-del-1998-abstract.pdf

3769-DEL-1998-Claims-(16-04-2009).pdf

3769-DEL-1998-Claims-(25-09-2008).pdf

3769-del-1998-claims.pdf

3769-DEL-1998-Correspondence-Others-(25-09-2008).pdf

3769-del-1998-correspondence-others.pdf

3769-DEL-1998-Description (Complete)-(25-09-2008).pdf

3769-del-1998-description (complete).pdf

3769-DEL-1998-Drawings-(25-09-2008).pdf

3769-del-1998-drawings.pdf

3769-DEL-1998-Form-1-(25-09-2008).pdf

3769-del-1998-form-1.pdf

3769-del-1998-form-18.pdf

3769-DEL-1998-Form-2-(25-09-2008).pdf

3769-del-1998-form-2.pdf

3769-DEL-1998-Form-3-(25-09-2008).pdf

3769-del-1998-form-4.pdf

3769-del-1998-form-6.pdf

3769-DEL-1998-GPA-(25-09-2008).pdf

3769-del-1998-gpa.pdf

3769-DEL-1998-Petition-137-(25-09-2008).pdf

3769-DEL-1998-Petition-138-(25-09-2008).pdf


Patent Number 235635
Indian Patent Application Number 3769/DEL/1998
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 09-Jul-2009
Date of Filing 16-Dec-1998
Name of Patentee ASTRA AKTIEBOLAG
Applicant Address S-151 85 SODERTALJE, SWEDEN
Inventors:
# Inventor's Name Inventor's Address
1 PER JOHAN LUNDBERG ASTRA HASSLE AB, S-431 83 MOLNDAL, SWEDEN
2 BRITA SJOBLOM ASTRA HASSLE AB, S-431 83 MOLNDAL, SWEDEN
PCT International Classification Number A61K9/28
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9704870.6 1997-12-22 Sweden