Delayed Delivery System For Acid-Sensitive Benzimidazoles
FIELD OF THE INVENTION
The patent invention describes a new oral pharmaceutical formulation comprising acid labile proton pump inhibitors. The new formulation is stabilized due to the inhibition of interaction between the enteric membrane and proton pump inhibitors. This is accomplished by ionization of the carboxylic acid functionality of the polymethacrylate anion, which chemically defines the enteric membrane.
BACKGROUND OF THE INVENTION
The following proton pump inhibitors are considered suitable for this invention because of their commonality in terms of reactivity with acidic compounds:

There are seven patents assigned to Astra, US Patents Nos. 4,786,505, 4,853,230, 4,255,431, 4,636,499, 5,093,342, 5,599,794 and 5,629,305. These patents are directed to the compound Omeprazole, (US Patent No. 4,255,431), a sulphenamide rearrangement product formed from Omeprazole (US Patent No. 5,093,342), a synergistic composition comprising Omeprazole and clarithromycin, (US Patent No. 5,599,799), and a composition comprising a proton pump inhibitor and an acid degradable antibacterial compound (US Patent No. 5,629,305). Another patent 6,013,281 was assigned to Astra based on the formation of a separating layer by In situ reaction between enteric polymethacrylate anion and the alkaline core material. US Patents 4,853,230 and 4,786,505 describe an oral pharmaceutical preparation comprising a core region consisting of omeprazole plus an alkaline reacting compound, and inert subcoating of water soluble or rapidly disintegrating polymeric film forming compounds and finally outer layer comprising an enteric coating.
US Patent 6,013,281, appears to negate the need for a polymeric water soluble subcoating layer by proposing that an in situ water soluble salt between the alkaline reacting compound and enteric coating polymer is formed and that compound serves as the separation layer. In other words, the separation layer in US Patent '505' a discrete

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separation layer was not required, because a water soluble compound would be formed between the enteric polymer and the alkaline material by the outward migration of the alkaline material through the polymeric water soluble subcoating layer.
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SUMMARY OF THE INVENTION
The present invention provides a stable pharmaceutical preparation of
delayed release drug delivery system containing acid-sensitive
benzimidazoles.
The pellets are prepared by coating non-pareil (sugar) beads with a
first coating comprising an alkaline separation layer and a second
coating comprising benzimidazole layer. This is followed by a third
coating of alkaline separation layer and a fourth coating comprising
benzimidazole layer. The layering is repeated until there are four drug
layers and five alkaline separation layers. These concentrically layered
pellets are coated with an enteric layer of modified by neutralization of
polymethacrylate anion, a plasticizer such as triethyl citrate and an
antiadherant such as talc.
When the bead substrate comprising layers of benzimidazole
alternated with separation layers of magnesium trisilicate is coated with
modified enteric membrane, which is formed by a reaction between
enteric polymethacrylate weak anion and strong basic cation.
The alkaline core structure for the manufacture of enteric-coated
pellets can be prepared according to two main principles. Firstly, sugar
seeds can be suspension layered with the alkaline suspension layers or
the sugar seeds can be powder-layered with a spheronizing agent and
an alkaline powdered material.
The separation layers are deposited as physical barriers for stabilizing
acid sensitive benzimidazole, which adversely interact with the
carboxylic acid functionalities of the gastroresistant enteric
membranes.
Prior to suspension layering of the seeds with the first alkaline layer and
the second drug layer, the separation layer and the drug layer
dispersions are separately pressure-homogenized in order to obtain
narrow particle size distributions of these materials for applying uniform
layers or to prevent clogging of spray nozzles. The pressure for
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homogenization is most preferably maintained at 10000 psi.
A typical particle diameter in terms of cumulative percent undersize for
the active substance after microfluidization will be about 5 microns,
whereas for magnesium trisilicate it will be 50 microns. The coating
process parameters are adjusted to meet the requirements of the
coating equipment to obtain uniform build up of the membrane
weight gain without loss of processing time due to nozzle clogging.
Brief description of the figures:
Fig-1 : Dissolution profile of Omeprazole DR Capsules, 20 mg Lot #
ODRC-P06-I, ODRC-P07B and ODRC-P08B at 6.8 pH at 50 rpm. Fig-2 : A diagrammatic Cross-section of A Single Pellet.
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DESCRIPTION OF THE INVENTION
The pellets are prepared by coating non-pareil (sugar) beads with a first coating (separation layer) comprising magnesium trisilicate dispersion of water soluble binder such as hydroxypropyl methyl cellulose, other cellulose esters, water soluble polymers and the like and an antifoam agent such as simethicone which forms an alkaline core. The alkaline core coated beads are over coated with a drug layer comprising benzimidazole, preferably omeprazole dispersed in water soluble binders such as hydroxypropyl methyl cellulose and other cellulose esters such as hydroxypropyl cellulose and an antifoam agent such as simethicone. This is the first drug layer. This followed by a second basic separation layer comprising magnesium trisilicate in water-soluble polymer and an antifoam agent which followed by application of a second drug layer comprising omeprazole dispersed in water-soluble binders and an antifoam agent, The layering is repeated until there are four drug layers and five basic separation layers. The pellets with about four drug layers and about five separation layers are coated with a partially neutralized enteric polymethacrylate anion, plasticized with triethyl citrate and an antiadherant such as talc. The separation layers are deposited as physical barriers for stabilizing acid-sensitive drugs such as omeprazole which adversely interact with the carboxylic acid functionalities of gastroresistant, enteric membranes.
The alkaline compounds in the separation layers provide a pH of at least 9.0, preferably at least 9.5, more preferably at least 10.0 and most preferably at least 10.5 or at least 11.0 (up to 12, for example). The concentration of the alkaline material in the pellet would range from 0 to 20 percent, more preferably from 5 to 15 percent, and most preferably about 10 percent.
The enteric coating layers are applied to the pelletized core substrates by using a suitable aqueous coating technique generically known as the Wurster Coater (traded by Glatt Air Techniques, NJ or Vector /
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Freund Corporation, Iowa or Niro Aeromatic, Maryland).
An enteric coating material is selected from the enteric polymers like
methacrylic acid copolymers, cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate,
which is then applied by dispensing in aqueous vehicle.
The enteric coating layers may contain pharmaceutically acceptable
plasticizers to obtain desired mechanical properties, such as flexibility
and strength. The amount of plasticizers based on drug
polymethacrylate anion ranges from 10 to 30 percent, more preferably
15 to 25 percent, and most preferably about 20 percent.
The seeds which serve as core substrates for the first basic alkaline layer
can be sugars, non-pareils or microcrystalline cellulose (traded as
Celpheres). The size of the seeds may vary approximately from 0.1 to 2
mm.
Prior to suspension layering of the seeds with the first basic alkaline layer
and the second drug layer, the separation layer and the drug layer
dispersions are separately pressure homogenized into order to obtain
narrow particle size distributions of these materials for applying uniform
layers or to prevent the clogging of the nozzle during the Wurster
Coating process. The pressure for homogenization may preferably
range from 5000 to 15000 psi and most preferably be at 10000 psi.
The active substance (micronized) is mixed with pharmaceutically
acceptable additives such as a blend of hydroxypropyl
methylcellulose, hydroxypropyl cellulose and polyethylene glycol (PEG
or Macrogol). The alkaline component (unmicronized magnesium
trisilicate, for example) is mixed with pharmaceutically acceptable
additives such as hydroxypropyl methylcellulose, titanium dioxide,
polydextrose, triacetin and PEG.
A typical particle diameter in terms of cumulative 90 percent undersize
for the active substance after microfluidization will be about 5 microns,
whereas for magnesium trisilicate after microfluidization will be 50
microns.
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The prepared pelletized cores are spray coated with aqueous enteric coating polymer. The process parameters such as inlet air temperature, air flow, atomizer air flow and spraying rate are adjusted to meet the requirements of the coating equipment in order to obtain uniform build up of the membrane weight gain without loss of processing time due to nozzle clogging, etc.
The invention is described in more detail in the following examples, which do not limit the scope of the invention.
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EXAMPLE-1

NO. INGREDIENTS QTY./20 mg PERCENT
1. Magnesium trisilicate 29.45 12.61
2. Opadry white Y-22-7719 19.63 8.41
3. Opadry Y-5-7095 20.00 8.57
4. Omeprazole, USP (micronized) 20.00 8.57
5. Simethicone 30% emulsion 0.36 0.15
6. Eudragit L-30 D-55 42.18 18.07
7. Triethyl citrate 8.44 3.62
8. Sodium hydroxide 0.39 0.17
9. Talc 8.44 3.62
10. Opadry Y-1-7000 4.57 1.96
11. Nu-pareils sugar spheres 30/35 mesh 80.00 34.27
TOTAL 233.46 100.00
12. Empty hard gelatin capsules size 2 - -
The pellets are prepared by coating non-pareil (sugar) beads (2 kg) with a first coating comprising an alkaline separation layer (25% w/w solids comprised of 15% of magnesium trisilicate and 10% opadry Y-22-7719, in 700.0 g of dispersion) and a second coating comprising benzimidazole layer (20% of w/w solids comprised of 10% benzimidazole & 10% of opadry Y-5-7095, in 1250.0 g of dispersion). This is followed by a third coating of alkaline separation layer and a fourth coating comprising benzimidazole layer. The layering is repeated until there are four drug layers and five alkaline separation layers. The fifth alkaline layer is applied with 2100.0 g of dispersion.
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Pass 4.74 kg Eudragit L30D-55 through 60 mesh into a 10 L stainless steel (s.s.) container. Into a separate s.s. container equipped with impeller type mechanical stirrer, add 2,1 kg Distilled water. Add 0.285 kg Triethyl Citrate, NF to Distilled water. Mix for 10 minutes, Add 0,285 kg Talc, USP to dispersion and mix for 10 minutes, add 0,020 kg Simethicone 30% emulsion. Continue mixing until well dispersed.
Into a 10 L s.s. container equipped with an anchor type mechanical stirrer in place, containing Eudragit L30D-55, add a mixture of Triethyl Citrate/Talc/Distilled water. Mix until thoroughly dispersed. Adjust the pH of the dispersion to 5.2 with the help of 5% Sodium hydroxide. Mix the enteric coating dispersion at slow speed throughout the coating process. Filter the enteric coat dispersion through 60 mesh. These concentric layered pellets are coated with an enteric layer of partially neutralized polymethacrylate anion, a plasticizer such as Triethyl citrate and an antiadherant such as talc.
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EXAMPL.E-2

NO. INGREDIENTS QTY./20 mg PERCENT
1. Magnesium trisilicate 29.45 12.61
2. Opadry white Y-22-7719 19.63 8.41
3. Opadry Y-5-7095 • 20.00 8.57
4. Lansoprazole, USP (micronized) 20.00 8.57
5. Simethicone 30% emulsion 0.36 0.15
6. Hydroxypropyl methyl cellulose phthalate 42.18 18.07
7. Triethyl citrate 8.44 3.62
8. Sodium hydroxide 0.39 0.17
9. Talc 8.44 3.62
10. Opadry Y-l-7000 4.57 1.96
11. Nu-pareils sugar spheres 30/35 mesh 80.00 34.27
TOTAL 233.46 100.00
12. Empty hard gelatin capsules size 2 - -
The pellets are prepared by coating non-pareil (sugar) beads (2 kg) with a first coating comprising an alkaline separation layer (25% w/w solids comprised of 15% of magnesium trisilicate and 10% opadry Y-22-7719, in 700.0 g of dispersion) and a second coating comprising benzimidazole layer (20% of w/w solids comprised of 10% benzimidazole & 10% of opadry Y-5-7095, in 1250.0 g of dispersion). This is followed by a third coating of alkaline separation layer and a fourth coating comprising benzimidazole layer. The layering is repeated until there are four drug layers and five alkaline separation layers. The fifth alkaline layer is applied with 2100.0 g of dispersion.
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Pass 4.74 kg Hydroxypropyl methyl cellulose phthalate through 60 mesh into a 10 L stainless steel (s.s.) container. Into a separate s.s. container equipped with impeller type mechanical stirrer, add 2.1 kg Distilled water. Add 0.285 kg Triethyl Citrate, NF to Distilled water. Mix for 10 minutes. Add 0,285 kg Talc, USP to dispersion and mix for 10 minutes, add 0.020 kg Simethicone 30% emulsion. Continue mixing until well dispersed.
Into a 10 L s.s. container equipped with an anchor type mechanical stirrer in place, containing Eudragit L30D-55, add a mixture of Triethyl Citrate/Talc/Distilled water. Mix until thoroughly dispersed. Adjust the pH of the dispersion to 5.2 with the help of 5% Sodium hydroxide, Mix the enteric coating dispersion at slow speed throughout the coating process. Filter the enteric coat dispersion through 60 mesh. These concentric layered pellets are coated with an enteric layer, plasticizer such as triethyl citrate and an antiadherant such as talc.
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EXAMPLE-3

NO. INGREDIENTS QTY./20mg PERCENT
1. Magnesium trisilicate 29.45 12.61
2. Opadry white Y-22-7719 19.63 8.41
3. Opadry Y-5-7095 20.00 8.57
4. Pantoprazole USP micronized 20.00 8.57
5. Simethicone 30% emulsion 0.36 0.15
6. Cellulose acetate trimellitate 42.18 18.07
7. Triethyl citrate 8.44 3.62
8. Sodium hydroxide 0.39 0.17
9. Talc 8.44 3.62
10. Opadry Y-1-7000 4.57 1.96
11. Nu-pareils sugar spheres 30/35 mesh 80.00 34.27
TOTAL 233.46 100.00
12. Empty hard gelatin capsules size 2 - -
The pellets are prepared by coating non-pareil (sugar) beads (2 kg) with a first coating comprising an alkaline separation layer (25% w/w solids comprised of 15% of magnesium trisilicate and 10% opadry Y-22-7719, in 700.0 g of dispersion) and a second coating comprising benzimidazole layer (20% of w/w solids comprised of 10% benzimidazole & 10% of opadry Y-5-7095, in 1250.0 g of dispersion). This is followed by a third coating of alkaline separation layer and a fourth coating comprising benzimidazole layer. The layering is repeated until there are four drug layers and five alkaline separation layers. The fifth alkaline layer is applied with 2100.0 g of dispersion.
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Pass 4.74 kg Cellulose acetate trimellitate through 60 mesh into a 10 L stainless steel (s.s.) container. Into a separate s.s. container equipped with impeller type mechanical stirrer, add 2.1 kg Distilled water. Add 0.285 kg Triethyl Citrate, NF to Distilled water. Mix for 10 minutes. Add 0.285 kg Talc, USP to dispersion and mix for 10 minutes, add 0.020 kg Simethicone 30% emulsion. Continue mixing until well dispersed. Into a 10 L s.s. container equipped with an anchor type mechanical stirrer in place, containing Cellulose acetate trimellitate, add a mixture of Triethyl citrate/Talc/Distilled water. Mix until thoroughly dispersed, Adjust the pH of the dispersion to 5.2 with the help of 5% Sodium hydroxide. Mix the enteric coating dispersion at slow speed throughout the coating process. Filter the enteric coat dispersion through 60 mesh. These concentric layered pellets are coated with an enteric layer, a plasticizer such as triethyl citrate and an antiadherant such as talc.
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EXAMPLE-4

NO. INGREDIENTS QTY./20 mg PERCENT
1. Magnesium trisilicate 29.45 12.61
2. Opadry white Y-22-7719 19.63 8.41
3. Opadry Y-5-7095 20.00 8.57
4. Pariprazole, USP (micronized) 20.00 8.57
5. Simethicone 30% emulsion 0.36 0.15
6. Eudragit L-30 D-55 42.18 18.07
7. Triethyl citrate 8.44 3.62
8. Ammonium hydroxide 0.39 0.17
9. Talc 8.44 3.62
10. Opadry Y-l-7000 4.57 1.96
11. Nu-pareils sugar spheres 30/35 mesh 80.00 34.27
TOTAL 233.46 100.00
12. Empty hard gelatin capsules size 2 - -
The pellets are prepared by coating non-pareil (sugar) beads (2 kg) with a first coating comprising an alkaline separation layer (25% w/w solids comprised of 15% of magnesium trisilicate and 10% opadry Y-22-7719, in 700.0 g of dispersion) and a second coating comprising benzimidazole layer (20% of w/w solids comprised of .10% benzimidazole & 10% of opadry Y-5-7095, in 1250.0 g of dispersion). This is followed by a third coating of alkaline separation layer and a fourth coating comprising benzimidazole layer. The layering is repeated until there are four drug layers and five alkaline separation layers. The fifth alkaline layer is applied with 2100.0 g of dispersion.
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Pass 4.74 kg Eudragit L30D-55 through 60 mesh into a 10 L stainless steel (s.s.) container. Into a separate s.s. container equipped with impeller type mechanical stirrer, add 2.1 kg Distilled water. Add 0.285 kg Triethyl Citrate, NF to Distilled water. Mix for 10 minutes. Add 0.285 kg Talc, USP to dispersion and mix for 10 minutes, add 0.020 kg Simethicone 30% emulsion. Continue mixing until well dispersed.
Into a 10 L s.s. container equipped with an anchor type mechanical stirrer in place, containing Eudragit L30D-55, add a mixture of Triethyl Citrate/Talc/Distilled water. Mix until thoroughly dispersed. Adjust the pH of the dispersion to 5.2 with the help of 5% Ammonium hydroxide. Mix the enteric coating dispersion at slow speed throughout the coating process. Filter the enteric coat dispersion through 60 mesh. These concentrically layered pellets are coated with an enteric layer, modified by neutralization of polymethacrylate anion, a plasticizer such as triethyl citrate and an antiadherant such as talc.
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EXAMPLE-5

NO. INGREDIENTS QTY./20 mg PERCENT
1. Magnesium trisilicate 29.45 12.61
2. Opadry white Y-22-7719 19.63 8.41
3. Opadry Y-5-7095 20.00 8.57
4. Leminoprazole USP micronized 20.00 8.57
5. Simethicone 30% emulsion 0.36 0.15
6. Hydroxypropyl methylcellulose phthalate 42.18 18.07
7. Dibutyl sebacate 8.44 3.62
8. Sodium hydroxide 0.39 0.17
9. Talc 8.44 3.62
10. Opadry Y-l-7000 4.57 1.96
11. Nu-pareils sugar spheres 30/35 mesh 80.00 34.27
TOTAL 233.46 100.00
12. Empty hard gelatin capsules size 2 - -
The pellets are prepared by coating non-pareil (sugar) beads (2 kg) with a first coating comprising an alkaline separation layer (25% w/w solids comprised of 15% of magnesium trisilicate and 10% opadry Y-22-7719, in 700.0 g of dispersion) and a second coating comprising benzimidazole layer (20% of w/w solids comprised of 10% benzimidazole & 10% of opadry Y-5-7095, in 1250.0 g of dispersion). This is followed by a third coating of alkaline separation layer and a fourth coating comprising benzimidazole layer. The layering is repeated until there are four drug layers and five alkaline separation layers. The fifth alkaline layer is applied with 2100.0 g of dispersion,
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Pass 4.74 kg Hydroxypropyl methylcellulose phthalate through 60 mesh into a 10 L stainless steel (s.s.) container. Into a separate s.s, container equipped with impeller type mechanical stirrer, add 2.1 kg Distilled water. Add 0.285 kg Dibutyl sebacate to Distilled water. Mix for 10 minutes. Add 0.285 kg Talc, USP to dispersion and mix for 10 minutes, add 0.020 kg Simethicone 30% emulsion. Continue mixing until well dispersed.
Into a 10 L s.s. container equipped with an anchor type mechanical stirrer in place, containing Hydroxypropyl methylcellulose phthalate, add a mixture of Dibutyl sebacate/Talc/Distilled water. Mix until thoroughly dispersed. Adjust the pH of the dispersion to 5.2 with the help of 5% Sodium hydroxide. Mix the enteric coating dispersion at slow speed throughout the coating process. Filter the enteric coat dispersion through 60 mesh.
These concentrically layered pellets are coated with an enteric layer, a plasticizer such as triethyl citrate and an antiadherant such as talc.
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BIOEQUIVALENCE
In order to compare the bioavalibility of Omeprazole delayed release capsules 20 mg manufactured by Wockhardt Limited and Prilosec 20 mg manufactured by Astra Merck, an open label, randomized two way cross over study was conducted under fasted and fed conditions in adult male volunteers. The various Pharmacokinetic parameters in Fasting and Food conditions are tabulated below.
Fasting study:

Parameters Test Reference T/R Confidence Intervals
Cmax 590.22 516.49 1.14 96.23-132.31
AUC O-oo 98149.2 91669.16 1.07 91.72-122.41
Tmax 115.2 114.0 1.01 78.52-123.58
Food study:

Parameters Test Reference T/R Confidence Intervals
Cmax 604.86 619.17 0.97 83.07-112.30
AUC O-oo 7237 7543 0.96 74.55-117.31
Tmax 153.89 222.78 0.69 42.53-95.63
Beside the fact that the Omeprazole is highly variable drug, the Pharmaceutical preparation was found to be bioequivalent for Cmax and AUC on the limited number of subjects in the fasting and fed study. Further it is observed that the present invention do not show an appreciable change in Cmax and Tmax parameters during fasting and food effect as compared to the reference formulation.
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CLAIMS
We claim :
i- A stable, oral delayed release, prandial-independent pharmaceutical preparation comprising,
(a) a core of a alkaline material.
(b) multiple coatings of benzimidazole and alternating alkaline • material, surrounding said core of alkaline material
(c) a modified enteric membrane formed by an interaction between weak enteric anions and strong basic cations.
said system being characterized by having multiple layers of •
benzimidazole separated by alkaline separation layers and at least one modified enteric plastisized film former, said enteric membrane having a weight gain sufficient to permit release of not more than 10% benzimidazole after immersion in 0.1 N HCI followed by not less than 60% release of the said benzimidazole in 45 minutes at pH 6.8
2. The pharmaceutical preparation of claim 1 wherein said core comprises a sugar non-pareil on which are applied layers of alkaline material.
3. The pharmaceutical preparation of claim 2 wherein each of said pellets comprise an alkaline core structure and at least two distinct drug layers comprising benzimidazole, each of said drug layers being separated from other drug layers by separation layers comprising alkaline material.
4. The pharmaceutical preparation of claim 1 wherein an enteric layer formed by a mixture of enteric anion and a strong basic cation.
5. The pharmaceutical preparation of claim 1 wherein enteric layer comprising enteric film former plasticized with a water soluble / water insoluble plasticizer.
6. The pharmaceutical preparation of claim 1 wherein said enteric coating is acrylic resin or cellulose base polymer having apparent pka ranging from 3-7.
7. The pharmaceutical preparation of claim 1 wherein said plasticizer is triethyl citrate.
8. The pharmaceutical preparation of claim 1 wherein said plasticizer is dibutyl sebacate.
9. The pharmaceutical preparation of claim 1 wherein said benzimidazole is omeprazole.
10. The pharmaceutical preparation of claim 1 wherein said benzimidazole is lansoprazole.
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11. The pharmaceutical preparation of claim 1 wherein said benzimidazole is pantoprazole.
12. The pharmaceutical preparation of claim 1 wherein said benzimidazole is pariprazole.
13. The pharmaceutical preparation of claim 1 wherein said benzimidazole is leminoprazole.
14. The pharmaceutical preparation of claim 1 wherein said alkaline material is selected from the group consisting of salts of strong basic cations and weak acid anions (ratio of benzimidazole to alkaline material being from 1:1 to 1 : 5).
15. The drug release system of claim 1 where the enteric coating polymer is a copolymer of methacrylic acid or methylmethacrylate ester.
16. The drug release system of claim 1 where the enteric coating polymer is cellulose phthalic acid ester derivatives.
17. The drug release system of claim 1 where the enteric coating polymer is cellulose acetate trimellitate.
18. The drug release system of claim 1 where the in situ reactant for the enteric membrane is a hydroxide of an alkali metal.
19. The Pharmaceutical oral preparation of claim 1 which is prandial-independent.
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A new oral pharmaceutical dosage form comprising an alkaline core structure that is layered with a proton pump inhibitor which is interspersed between layers of alkaline material. An enteric coating layer is formed by in situ reaction between polymethacrylate weak anion and strong base cation and is applied on the drug-layered alkaline core structure. The invention also describes a dosage form independent of Food effect.
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