NZ510231A

NZ510231A - Omeprazole formulation comprising an alkaline core and an enteric coating

Info

Publication number: NZ510231A
Application number: NZ510231A
Authority: NZ
Inventors: Chih-Ming Chen; Joseph Chou; Unchalee Kositprapa
Original assignee: Andrx Pharmaceuticals Inc
Priority date: 1998-08-28
Filing date: 1999-08-27
Publication date: 2003-11-28

Abstract

A stable pharmaceutical dosage formulation for oral administration consisting essentially of: (a) a core comprising 5-50 weight percent based on the total weight of the core of omeprazole, a surface active agent, a filler , a binder, 0.5-10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent, wherein the alkaline agent is selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent, 5-50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and enteric coating layer.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 510231 510231 WO 00/12064 PCT/US99/19847 OMEPRAZOLE FORMULATION BACKGROUND OF THE INVENTION The present invention relates to a stable formulation of omeprazole. It is well known that 5 omeprazole is sensitive to acidic conditions and after contact with an acid, omeprazole will degrade and will not function in its intended manner. Initially, alkaline materials were added to a core of omeprazole and later an enteric coating was applied over the core 10 to prevent the omeprazole from contacting the acidic pH conditions of the stomach. This approach is satisfactory if the product is administered within a short time after it is manufactured but if the product is stored under ambient conditions, the acidic residue 15 of the enteric coating appears to.degrade the omeprazole before it is administered to a patient. To solve this problem, the prior art has used a separate layer of a coating agent to coat a pellet core which contains omeprazole and an alkaline material which is 20 thereafter coated with the enteric coating. This technique is described in U.S. 4,786,505. In addition WO 96/24338 discloses the use of an in situ formed interlayer that is based on the reaction of an aqueous enteric coating material with an alkaline material in 25 the core. This dual layer coating technique requires the application of two separate functional coating operations which increases the length of the manufacturing process and the cost of the product. The 30 applicants have surprisingly discovered a coating system which avoids the need to use a coating layer to separate the omeprazole core from the enteric coating layer in an omeprazole dosage form. The separate coating system is based on the combined use of an 35 enteric coating agent which is applied to a pelletized core or a granular core of omeprazole as a suspension 1 SUBSTITUTE SHEET (RULE 26) PCT/US99/19847 in a suitable solvent. The applicants have also surprisingly discovered that arginine or lysine can be used as a pH stabilizing agent. SUMMARY OF THE INVENTION In one aspect the present invention broadly provides a stable pharmaceutical dosage formulation for oral administration comprising a plurality of enteric coated pellets, wherein each pellet comprises: (a) a core comprising 10-50 weight percent based on the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent, 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer, wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and the enteric coating layer. In another aspect, the present invention broadly provides a method for preparing a stable oral pharmaceutical dosage formulation which comprises: 2 (followed by page 2a) INTELLECTUAL P^OP£RTY OFFICE OF N.Z. \ 6 SEP 2003 (a) forming a pellet core comprising 10 to 50 weight percent based on the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) applying an enteric coating directly onto the core without a separating layer, wherein the enteric coating layer surrounds the core and comprises an enteric coating agent 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer. Accordingly, it is a primary object of this invention to provide a pharmaceutical dosage formulation of omeprazole which is stable upon prolonged storage, is stable when administered to a patient and is capable of providing the desired therapeutic effect. It is also an object of this invention to provide a pharmaceutical dosage form of omeprazole which is bioeguivalent to dosage forms of omeprazole which have an intermediate layer., of an inert coating material. It is also an object of this invention to provide INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED WO 00/12064 PCT/US99/19847 a stable dosage form of omeprazole which may be produced without the need to provide an intermediate coating layer that separates the omeprazole containing core from the enteric coating layer. It is to be understood that the above-mentioned objects are independently objects of preferred embodiments of the invention. These and other objects of the invention will become apparent from a review of the appended specification. DETAILED DESCRIPTION OF THE INVENTION The omeprazole formulation of the invention is preferably based on a core of omeprazole or pharmaceutically equivalent salt, a filler and an alkaline material selected from the group consisting of arginine or lysine; and a single layer of coating on said core which comprises a layer of an enteric coating agent applied from an organic solvent based system. The Omeprazole core can either be pelleted or tabletted as described herein. In the case of both the pelleted form and the tabletted form of the core a filler is used. A filler is used as a granulation substrate. Sugars such as lactose, dextrose, sucrose, maltose, or microcrystalline cellulose and the like may be used as fillers in either the pellet or the granulation composition. In the case of the pelleted form the filler may comprise from 20 to 90wt% and preferably 65-85wt% based on the total weight of the drug layer composition. In the case of the tabletted form the filler may comprise from 20 to 60wt% and preferably 20 to 40wt% based on the total weight of the granulation. In the case of the tabletted form of the invention a tablet disintegrant may be added which comprises corn starch, potato starch, croscarmelose sodium, crospovidone and sodium starch glycolate in an effective amount. An effective amount which may be INTELLECTUAL PROPERTY 3 OFFICE OF N.Z. 16 SEP 2003 WO 00/12064 PCT/US99/19847 from 3 to 10wt% based on the total weight of the granulation. In the case of both the tabletted form and the pelleted form of the core an alkaline agent that is 5 either lysine or arginine is used as a stabilizer. In the case of the tabletted form a level of from 20 to 60wt% and preferably 30 to 55wt% based on the weight of the granulation may be employed. In the case of the pelleted form a level of from 0.5 to 10wt% and 10 preferably 1 to 3wt% based on the weight of the pellet may be employed. In the case of both the pelleted form and the tabletted form of the invention an enteric coating agent is placed over the core. In both cases the 15 enteric coating may comprise an acid resisting material which resists acid up to a pH of above about 5.0 or higher which is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, 20 carboxymethylethylcellulose, Eudragit L (poly(methacrylic acid, methylmethacrylate), 1:1 ratio; MW (No. Av. 135,000 - USP Type A) or Eudragit S (poly(methacrylic acid, methylmethacrylate, 1:2 ratio MW (No. Av. 135,000 - USP Type B) and mixtures thereof. 25 The enteric coating agent may also include an inert processing aid in an amount in the case of the tabletted form from 15 to 55wt% and preferably 20 to 45wt% based on the total weight of the acid resisting component and the inert processing aid. In the case of 30 the pelleted form the inert processing aid is preferably in an amount from 5 to 50wt% and most preferably 10-20wt%. The inert processing aids include finely divided forms of talc, silicon dioxide, magnesium stearate etc. Typical solvents which may be 35 used to apply the acid resisting component-inert processing aid mixture include water, isopropyl alcohol, INTELLECTUAL PROPERTY OFFICE OF N.7. 1 6 SEP 2003 received WO 00/12064 PCT/US99/19847 acetone, methylene chloride and the like. Generally the acid resistant component-inert processing aid mixture will be applied from a 5 to 20wt% of acid resisting component-inert processing aid mixture based on the 5 . total weight of the solvent and the acid resistant component-inert processing aid. In the case of both the tabletted form and the pelleted form of the invention omeprazole or a pharmaceutically equivalent salt is used in the core. 10 In the tabletted formulation the omeprazole may comprise from 5 to 70wt% and preferably 10 to 30wt% of the granulation. In the pelleted form the Omeprazole may comprise from 10 to 50wt% and preferably 10 to 20wt% of the drug layer composition. 15 A surface active agent is used in both the tabletted and the pelleted form of the invention. The surface active agent may be any pharmaceutically acceptable, non-toxic surfactant. Suitable surface active agents include sodium lauryl sulfate, 20 polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the like. The surface active agent may be present at a level of from 0.1 to 5wt%. In the case of the tabletted form the surface active agent is preferably 0.20 to 2.0wt% based on the total weight of 25 the granulation. In the pelleted form the surface active agent is preferably 0.20 to 2.0wt% of the total weight of the drug layer composition. The binder is used in both the tabletted and the pelleted form of the invention. The binder may be any 30 pharmaceutically acceptable, non-toxic pharmaceutically acceptable binder. The binder is preferably a water soluble polymer of the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and 35 the like. A water soluble binder is preferred which is applied from an aqueous medium such as water at a level 5 WO 00/12064 PCT/US99/19847 of from 0.1 to 10wt% and preferably from 0.25 to 7.5wt% of binder based on the total weight of the granulation. In the case of the tabletted form of the invention a granulation is formed by contacting the alkaline 5 agent, the omeprazole, the surface active agent and the binder with a medium which may comprise any low viscosity solvent such as water, isopropyl alcohol, acetone, ethanol or the like. When fluids such as water are employed, this will usually require a weight of 10 fluid which is about three times the weight of the dry components of the coating composition. After the granulation is formed and dried, the granulation is tabletted and the tablets are directly coated with the enteric coating agent. A color 15 imparting agent may be added to the enteric coating agent mixture or a rapidly dissolving seal coat containing color may be coated over the enteric coating agent layer provided that the seal coat is compatible . with and does not affect the dissolution of the enteric 20 coating layer. The rapidly dissolving seal coat may comprise Opadry pink which comprises approximately 9lwt% hydroxypropyl methylcellulose (E-6), color and 9wt% polyethylene glycol which is applied as a 8-15%w/w solution in purified water. In addition the color may 25 be provided as Chromateric which is available from Crompton & Knowles. This product contains water, talc, Ti02, triethyl citrate, propylene glycol, synthetic red. iron oxide, potassium sorbate, xanthan gum, sodium citrate and synthetic yellow iron oxide. If desired, 30 conventional sugar based seal coats may be used which contain FDA certified dyes. In the case of a pelleted form the invention is preferably based on pellets having a core forming inert component which may comprise a starch or sugar sphere 35 such as non-pareil sugar seeds having an average size of 14 to 35 mesh, preferably about 18 to 20 mesh. The 6 WO 00/12064 PCT/US99/1M47 core forming inert component is coated with a formulation which comprises Omeprazole, a surface active agent, a filler, an alkaline material that is either lysine or arginine and a binder, which are 5 collectively referred to as the drug layer composition. The core forming inert component is employed at 1:1 to 5:1 and preferably from 2:1 to 3:1 weight ratio to the drug layer composition. The cores are formed by spraying the non-pareil 10 seeds with an aqueous or non-aqueous suspension which contains the alkaline agent, the omeprazole, the surface active agent and the binder. The suspension medium may comprise any low viscosity solvent such as water, isopropyl alcohol, acetone, ethanol or the like. 15 When fluids such as water are employed , this will usually require a weight of fluid which is about seven times the weight of the dry components of the coating composition. After the cores are dried, the cores are coated 20 with the enteric coating agent. A color imparting agent may be added to the enteric coating agent mixture or a rapidly dissolving seal coat over the enteric coating agent layer provided that the seal coat is compatible with and does no affect the dissolution of 25 the enteric coating layer. DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples 1 to 5 describe a tabletted form of the 30 invention and Example 6 describes a pelleted form of the invention. EXAMPLE 1 35 Granulation. A granulation containing omeprazole is formed in a fluid bed coater using a top spray granulation forming 7 WO 00/12064 PCT/US99/19847 suspension containing omeprazole, micronized to 95% less than 15 microns, 5%w/w of the total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl sulfate and purified water which is sprayed onto a 5 mixture of microcrystalline cellulose, 95%w/w of the total amount of L-arginine and sodium starch glycolate. The formulation for making the granulation has the following composition: 10 povidone, USP (Plasdone K90) 100.Og sodium starch glycolate 100.Og sodium lauryl sulfate, NF/USP 6.0g microcrystalline cellulose (AvicelPHlOl) 965.6g L-arginine, USP/FCC 1020.Og 15 omeprazole, USP (micronized) 340. Og purified water, USP 1100.Og Tabletting. The granulation is tabletted into tablets 20 containing 20mg of omeprazole by first mixing the omeprazole granules with glyceryl monostearate: omeprazole granules 118.Og glyceryl monostearate (Myvaplex) 6.0g 25 Tabletting tools: 0.2812" target weight : 124mg/tab target hardness : 7Kp LOD of granules : less than 3% 3 0 Enteric coating. . An enteric coating is applied to prepare enteric coated tablets as follows: omeprazole tablets 35 (prepared above) 124.0g hydroxypropyl methylcellulose phthalate 8 WO 00/12064 PCT/US99/19847 talc acetyl tributyl citrate acetone 14.7g 4. 2g 2. 9g 148.Og isopropyl alcohol 148.0g 10 The solid coating materials were dissolved in the acetone and isopropyl alcohol and this solution was coated onto the omeprazole tablets using a perforated pan Seal coat: 15 A seal coat was applied to the enteric coated tablets as follows: 20 Enteric coated tablet 146.0g Opadry II pink 4.5g Water 450.0g The seal coat was applied onto the enteric coated omeprazole tablets using a perforated pan coater. 25 EXAMPLE 2 Granulation. A granulation containing omeprazole is formed in fluid bed coater using a top spray granulation forming 30 suspension containing omeprazole, micronized to 95'% less than 15 microns, 2.68%w/w of the total amount of L-arginine, polyvinyl pyrrolidone, polysorbate 80 and purified water which is sprayed onto a mixture of microcrystalline cellulose and 95.0%w/w of the total 35 amount of L-arginine. The formulation for making the granulation has the following composition: mg/tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80 (Tween 80) 0.58 9 WO 00/12064 PCT/US99/19847 L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 20.0 microcrystalline cellulose (Avicel PH102) 25.54 purified water, USP n/a 5 Tabletting. The granulation is tabletted into tablets containing 20mg of omeprazole by first mixing the omeprazole granules with glyceryl monostearate: 10 omeprazole granules 112.Omg glyceryl monostearate (Myvaplex) 6.8mg crospovidone XL 16.2mg Tabletting tools: 0.2812" target weight : 135mg/tab 15 target hardness : 7Kp LOD of granules : less than 3%' Enteric coating. An enteric coating was applied to prepare enteric 20 coated tablets as follows: omeprazole tablets (prepared above) 135.Omg 25 Eudragit L30D-55 14.Omg color (Chromateric) 7.Omg 1M NaOH (to adjust pH to 5.0)qs na Purified water qs na The solid coating materials were dispersed in the water and this mixture was coated onto the omeprazole tablets using a perforated pan. 30 35 EXAMPLE 3 Granulation. A granulation containing omeprazole is formed in 10 WO 00/12064 PCT/US99/19847 fluid bed coater using a top spray granulation forming suspension containing omeprazole, micronized to 95% less than 15 microns, 5.0%w/w of the total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl 5 sulfate and purified water which is sprayed onto a mixture of microcrystalline cellulose and 95.0%w/w of the total amount of L-arginine. The formulation for making the granulation has the following composition: mg/tablet 10 povidone, USP (Plasdone K90) 5.0 sodium lauryl sulfate 0.3 L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 10.Og microcrystalline cellulose (AvicelPH102) 24.7 15 purified water, USP n/a Tabletting. The granulation is tabletted into tablets containing lOmg of omeprazole by first mixing the 20 omeprazole granules with glyceryl monostearate: omeprazole granules 100.Omg glyceryl monostearate (Myvaplex) 5.Omg sodium starch glycolate 5. Omg Tabletting tools: 0.2812" 25 target weight : 11Omg/tab target hardness : 7Kp LOD of granules : less than 3% -. Enteric coating. 30 The tablets were coated with the same enteric coating that was applied to the tablets in Example 2. EXAMPLE 4 35 Granulation. A granulation containing omeprazole is formed in 11 WO 00/12064 PCT/US99/19847 fluid bed Coater using a top spray granulation forming suspension containing omeprazole, micronized to 95% less than 15 microns, 5.0%w/w of the total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl 5 sulfate and purified water which is sprayed onto a mixture of microcrystalline cellulose and 95.0%w/w of the total amount of L-arginine. The formulation for making the granulation has the following composition: mg/tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80 0.60 L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 20.0 crospovidone XL 5.88 microcrystalline cellulose 25.54 purified water, USP n/a Tabletting. The granulation is tabletted into tablets 20 containing 20mg of omeprazole by first mixing the omeprazole granules with glyceryl monostearate: omeprazole granules 117.9mg glyceryl monostearate (Myvaplex) 6.1mg Tabletting tools: 0.2812" 25 target weight : 124mg/tab target hardness : 7Kp LOD of granules : less than 3% Enteric coating. 30 The tablets were coated with the same enteric coating that was applied to the tablets in Example 1. EXAMPLE 5 35 The granulation of Example 1 was prepared and tabletted into tablets containing 20.Omg of omeprazole. 12 WO 00/12064 PCT/US99/19847 These tablets were coated as follows: Enteric coating. An enteric coating was applied to prepare enteric coated tablets as follows: 5 omeprazole tablets (prepared above} Eudragit L30D-55 10 1M NaOH (to adjust pH to 5.0)qs acetyl tributyl citrate 15 talc polysorbate 80 Purified water qs 20 The solid coating materials were dispersed in the water and this mixture was coated onto the omeprazole tablets using a perforated pan. A seal coat was applied using the procedure of Example 1. 25 EXAMPLE 6 In the case of a pharmaceutical formulation with a pelleted omeprazole core, the core is comprised of omeprazole, a surface active agent, a filler, an 30 alkaline material and a binder. Omeprazole activated pellets (sodium free) are prepared as follows: 13.650 kg of Purified water is dispensed into a suitably sized stainless steel container. L-Arginine Base (0.210 kg), Lactose 35 Anhydrous, NF (1.75 kg) and Povidone (Plasdone ®K-90) (0.056 kg) is added to the purified water while homogenizing at full speed (about 5,000 rpm) . Homogenizing is continued until the materials are completely dissolved. Polysorbate 80, NF (0.044 kg) is 40 added to the solution while homogenizing at a lower speed (700 -3300 rpm) to avoid excess foaming. 126.OOmg 17. OOmg na 1.7 Omg 3.8 Omg 1.5Omg na 13 WO 00/12064 PCT/US99/19847 The material is homogenized until dissolved completely. Half of the solution (7.855 kg) is transferred into a 5-10 gallon stainless steel container. The original container is hereafter 5 referred to as "container A" and the new container is henceforth referred to as "container B." Micronized omeprazole 95% less than 15 microns (0.980 kg) is added to container A while homogenizing at a lower speed (700-3300 rpm) to avoid excess foaming. The Omeprazole 10 is allowed to disperse into the solution completely and then homogenized for another 10 minutes. The homogenizer is replaced with a mechanical stirrer and the suspension is continuously stirred throughout the coating process. When approximately three fourth of 15 the omeprazole suspension in container A is consumed, 0.980 kg of micronized omeprazole is added to container B while homogenizing at a lower speed (700-3300) to avoid excess foaming. The Omeprazole is allowed to disperse in the solution completely and homogenization 20 is continued for another 10 minutes. The homogenizer is replaced with a mechanical stirrer and the suspension is continuously stirred throughout the coating process. 9.98 kg of sugar spheres are added to a fluidized bed coater and preheated until the 25 product reaches 40-45°C. The drug suspension from containers A and B are sprayed onto the spheres. The atomization pressure is between 1.5 to 3.5 bar and the, pump rate is 2-100 ml/min. The spray rate does not exceed 20ml/min in the first two hours to avoid 30 agglomeration of the sugar spheres. The coating suspension is transferred to a smaller container to facilitate stirring when the surface of the coating suspension reaches the stirring blade. After the coating suspension has been consumed the pump is 35 stopped and the fluidization is continued in the fluidized bed coater with the heat off until the 14 WO 00/12064 PCT/US99/19847 product temperature drops below 32SC. The pellets are then transferred to a fluidized bed coater into a 50°C oven (45-55°C) . The pellets are dried until the moisture content of the pellets is not 5 more then 2.5%. The pellets are separated into different size fractions by using a SWECO Separator equipped with 14 and 24 mesh screens. The pellets are collected in doubled polyethylene lined plastic containers and stored with desiccant. 10 ENTERIC COATING PROCESS 10.844 kg of isopropyl alcohol, USP is dispensed into a suitably sized stainless steel container. 10.844 kg of acetone is added to the isopropyl alcohol. 1.683 kg of hydroxypropyl methylcellulose 15 phthalate (Hypromellose 55, Substitution type 200731) and cetyl alcohol, NF (0.084 kg) are added to the solution while homogenizing at full speed until all the materials are dissolved completely. The homegnizer is then removed and replaced with a 20 mechanical stirrer. Talc (1.683 kg) is added while stirring. The talc is mixed until fully dispersed in the solution and the mixing is continued throughout the entire coating process. A fluidized bed coater is preheated 25 to 32°C. The omeprazole active pellets (11.550 kg) are loaded into the fluidized bed coater and preheated until the temperature reaches 30°C. The coating suspension is sprayed on the pellets using a product temperature of 25-35°C, an atomization 30 pressure of 1.5 to 3.0 bar and a pump rate of 200-300 ml/min. The coating suspension is transferred to a smaller container to facilitate stirring when the surface of the coating suspension reaches the stirring blade. 35 After the coating suspension has been consumed the coated pellets are dried in a fluidized bed 15 WO 00/12064 PCT/US99/19847 coater for 20 minutes using the same coating conditions except lowering the atomization pressure to 2 bars or below. The coated pellets are discharged into double polyethylene bags. The 5 pellets are separated into different size fractions by using a SWECO separator equipped with 14 and 24 mesh screens. The pellets which are larger than 14 mesh and smaller than 24 mesh are rejected. The pellets that passed through the 14 mesh and retained 10 on the 24 mesh are retained in polyethylene bags. BLENDING Omeprazole enteric coated pellets (Sodium Free), blended are prepared as follows: 14.400 kg of omeprazole enteric coated pellets 15 (Sodium free) are charged into a blender. Talc, USP (0.225 kg) is sprinkled on top of the pellet bed and then blended at 28 rpm for 5 minutes. 0.2 to 0.5 grams of each sample is withdrawn into separate vials from the blender. The blended pellets are unloaded 20 into plastic containers lined with double polyethylene. The excess talc is screened off using a SWECO separator equipped with a 24 mesh screen. The pellets are collected in containers lined with double polyethylene bags and stored with desiccant. 25 ENCAPSULATION An encapsulation room is prepared in which the relative humidity is in the range of 35-65% and the temperature is in the range of 15-25°C. Omeprazole enteric coated pellets (Sodium Free) blended are 30 encapsulated using the following equipment and guidelines. A capsule machine model MACOFAR MT-20 is prepared for the procedure placing the machine setting at 4, using capsule machine size part 1, capsule magazine 1. The target-filled capsule weight 35 is 457.15 mg. If the total weight is not within 3% of the target weight, further adjustment must be 16 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/12064 PCT/US99/19847 performed. Capsule fill verification is performed at twenty minutes intervals on ten individual capsules. Acceptable capsules are collected in containers lined with double polyethylene bags and placed under 5 desiccant. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are 10 skilled in the art. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention. 15 17 WHAT WE CLAIM IS:

1. A stable pharmaceutical dosage formulation for oral administration comprising a plurality of enteric coated pellets, wherein each pellet consists of: (a) a core comprising 10-50 weight percent based on the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent; selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer, wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and die enteric coating layer.

2. The pharmaceutical dosage formulation as recited in claim 1, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of omeprazole.

3. The pharmaceutical dosage formulation as recited in claim 1, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of a pharmaceutically acceptable salt of omeprazole.

4. The pharmaceutical dosage formulation as recited in claim 1,2 or 3, wherein 18 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED the enteric coating layer comprises the plasticizer.

5. The pharmaceutical dosage formulation as recited in claim 1, 2, 3 or 4, wherein the enteric coating agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethyl cellulose, and co-polymerized methacrylic acid/ methacrylic acid methyl esters.

6. The pharmaceutical dosage formulation as recited in any one of claims 1 to 5, wherein the inert processing aid is selected from the group consisting of talc, silicon dioxide and magnesium stearate.

7. The pharmaceutical dosage formulation as recited in any one of claims 1,2 and 4 to 6, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of omeprazole, 0.20 to 2.0 weight percent based upon die total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total weight of the core of the pharmaceutically acceptable alkaline agent

8. The pharmaceutical dosage formulation as recited in any one of claims 1 and 3 to 6, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of the pharmaceutically acceptable salt of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total 19 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 received weight of the core of the pharmaceutically acceptable alkaline agent

9. A stable pharmaceutical dosage formulation for oral administration comprising a plurality of enteric coated pellets, wherein each pellet consists of: (a) a core consisting of: (a) an inert core and (b) a drug layer comprising 10-50 weight percent based on the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on die total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer, wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and die enteric coating layer.

10. The pharmaceutical dosage formulation as recited in claim 9, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of omeprazole.

11. The pharmaceutical dosage formulation as recited in claim 9, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of a pharmaceutically acceptable salt of omeprazole.

12. The pharmaceutical dosage formulation as recited in claim 9, 10 or 11, 20 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED wherein the enteric coating layer comprises the plasticizer.

13. The pharmaceutical dosage formulation as recited in claim 9,10,11 or 12, wherein the enteric coating agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethyl cellulose, and co-polymerized methacrylic acid/ methacrylic acid methyl esters.

14. The pharmaceutical dosage formulation as recited in any one of claims 9 to 13, wherein the inert processing aid is selected from the group consisting of talc, silicon dioxide and magnesium stearate.

15. The pharmaceutical dosage formulation as recited in any one of claims 9,10 and 12 to 14, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total weight of the core of the pharmaceutically acceptable alkaline agent

16. The pharmaceutical dosage formulation as recited in any one of claims 9 and 11 to 14, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of the pharmaceutically acceptable salt of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the 21 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED total weight of the core of the pharmaceutically acceptable alkaline agent.

17. A method for preparing a stable oral pharmaceutical dosage formulation which consists of: (a) forming a pellet core comprising 10 to 50 weight percent based on the total weight of die core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) applying an enteric coating directly onto the core without a separating layer, wherein the enteric coating layer surrounds the core and comprises an enteric coating agent, 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plastidzer.

18. The method as recited in claim 17, wherein the enteric coating layer is applied from an organic solvent based system.

19. The method as recited in claim 17, wherein the step of forming the core further comprises the step of applying the core ingredients onto an inert core.

20. A stable pharmaceutical dosage formulation for oral administration comprising a plurality of enteric coated pellets, wherein each pellet comprises: (a) a core comprising 10-50 weight percent based on the total weight of 22 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent, 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer, wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and the enteric coating layer.

21. The pharmaceutical dosage formulation as recited in claim 20, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of omeprazole.

22. The pharmaceutical dosage formulation as recited in claim 20, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of a pharmaceutically acceptable salt of omeprazole.

23. The pharmaceutical dosage formulation as recited in claim 20, 21 or 22, wherein the enteric coating layer comprises the plasticizer.

24. The pharmaceutical dosage formulation as recited in claim 20, 21, 22 or 23, wherein the enteric coating agent is selected from title group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, 23 INTELLECTUAL PROPERTY OFFICE OF N.Z. H SEP 2003 RECEIVED carboxymethylethyl cellulose, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

25. The pharmaceutical dosage formulation as recited in any one of claims 20 to 24, wherein the inert processing aid is selected from the group consisting of talc, silicon dioxide and magnesium stearate.

26. The pharmaceutical dosage formulation as recited in any one of claims 20, 21 and 23 to 25, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent; 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total weight of the core of the pharmaceutically acceptable alkaline agent

27. The pharmaceutical dosage formulation as recited in any one of claims 20 and 22 to 25, wherein the core comprises 10 to 50 weight percent based on the total weight of the core of the pharmaceutically acceptable salt of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total weight of the core of the pharmaceutically acceptable alkaline agent

28. A stable pharmaceutical dosage formulation for oral administration comprising a plurality of enteric coated pellets, wherein each pellet comprises: (a) a core comprising an inert core and a drug layer comprising 10-50 24 INTELLECTUAL PROPERTY OFFICF OF N.Z. 16 SEP 2003 RECEIVED weight percent based on the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent, 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer, wherein the enteric coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and the enteric coating layer.

29. The pharmaceutical dosage formulation as recited in claim 28, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of omeprazole.

30. The pharmaceutical dosage formulation as recited in claim 28, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of die core of a pharmaceutically acceptable salt of omeprazole.

31. The pharmaceutical dosage formulation as recited in claim 28, 29 or 30, wherein the enteric coating layer comprises the plasticizer.

32. The pharmaceutical dosage formulation as recited in claim 28,29,30 or 31, wherein the enteric coating agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 received carboxyxnethylethyl cellulose, and co-polymerized methacrylic acid/ methacrylic acid methyl esters.

33. The pharmaceutical dosage formulation as recited in any one of claims 28 to 32, wherein the inert processing aid is selected from the group consisting of talc, silicon dioxide and magnesium stearate.

34. The pharmaceutical dosage formulation as recited in any one of claims 28, 29 and 31 to 33, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the binder and 1 to 3 weight percent based on the total weight of die core of the pharmaceutically acceptable alkaline agent.

35. The pharmaceutical dosage formulation as recited in any one of claims 28 and 30 to 33, wherein the drug layer comprises 10 to 50 weight percent based on the total weight of the core of the pharmaceutically acceptable salt of omeprazole, 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent, 20 to 90 weight percent based on the total weight of the core of the filler, 0.1 to 10 weight percent based on the total weight of the core of the hinder and 1 to 3 weight percent based on the total weight of the core of the pharmaceutically acceptable alkaline agent.

36. A method for preparing a stable oral pharmaceutical dosage formulation which comprises: (a) forming a pellet core comprising 10 to 50 weight percent based on 26 INTELLECTUAL PROPERTY OFFICE OF N.Z. 13 SEP 2003 received the total weight of the core of omeprazole or a pharmaceutically acceptable salt thereof, a surface active agent, a filler, a binder and 0.5 to 10 weight percent based on the total weight of the core of a pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) applying an enteric coating directly onto the core without a separating layer, wherein the enteric coating layer surrounds the core and comprises an enteric coating agent, 5 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and optionally a plasticizer.

37. The method recited in claim 36, wherein the enteric coating layer is applied from an organic solvent based system.

38. The method recited in claim 36, wherein the step of forming the core further comprises the step of applying the core ingredients onto an inert core.

39. A stable pharmaceutical dosage formulation for oral administration comprising: (a) a tableted core comprising 5 to 70 weight percent based on the total weight of the core of omeprazole, 0.1 to 5 weight percent based on the total weight of the core of a surface active agent, 25 to 50 weight percent based on die total weight of the core of a filler, 0.1 to 10 weight percent based on the total weight of the core of a binder and 20 to 60 weight percent based on the total weight of the core of a 27 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 f ™ 203 received pharmaceutically acceptable alkaline agent selected from the group consisting of lysine and arginine; and (b) a coating layer surrounding the core that comprises an enteric coating agent, 10 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and 0 to 40 weight percent based on the total weight of the coating layer of a plasticizer, wherein die coating layer is applied directly to the omeprazole containing core without a separating layer between the omeprazole containing core and the coating layer.

40. The pharmaceutical dosage formulation as recited in claim 39, wherein the alkaline agent is arginine.

41. The pharmaceutical dosage formulation as recited in claim 39 or 40, wherein the enteric coating agent is selected from die group consisting of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

42. The pharmaceutical dosage formulation as recited in claim 39, 40 or 41, which includes sodium lauryl sulfate as the surface active agent.

43. The pharmaceutical dosage formulation as recited in claim 39, wherein the core comprises 10 to 30 weight percent based upon the total weight of the core of omeprazole; 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent; 0.25 to 7.5 weight percent based upon the total weight of the core 28 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 ?:? HD3 RECEIVED of the binder; 20 to 40 weight percent based upon the total weight of the core of the filler and 30-55 weight percent based upon the total weight of the core of the alkaline agent.

44. The pharmaceutical dosage formulation as recited in claim 39 or 43, wherein the coating layer comprises 20 to 40 weight percent based upon the total weight of the coating layer of the inert processing aid and 10 to 20 weight percent based upon the total weight of the coating layer of the plasticizer.

45. The pharmaceutical dosage formulation as recited in claim 39, wherein the core comprises 10 to 30 weight percent based upon the total weight of the core of omeprazole; 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent; 0.25 to 7.5 weight percent based upon the total weight of the core of the binder; 20 to 40 weight percent based upon the total weight of die core of the filler and 30-55 weight percent based upon the total weight of the core of the alkaline agent.

46. The pharmaceutical dosage formulation as recited in claim 39 or 45, wherein the coating layer comprises an enteric coating agent, 20 to 40 weight percent based upon the total weight of the coating layer of the inert processing aid and 10 to 20 weight percent based upon the total weight of the coating layer of the plasticizer.

47. A method for preparing a stable oral pharmaceutical dosage formulation which comprises: (a) forming a tablet core comprising 5 to 70 weight percent based on the total weight of the core of omeprazole, 0.1 to 10 weight percent based on die 29 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 received total weight of the core of a binder, 25 to 50 weight percent based on the total weight of the core of a filler, 0.1 to 5 weight percent based on the total weight percent of the core of a surface active agent and 20-60 weight percent based on the total weight of the core of an alkaline agent selected form the group consisting of lysine and arginine; and (b) applying a coating layer to the tablet core that surrounds the tablet core and comprises an enteric coating agent, 10 to 50 weight percent based on the total weight of the coating layer of an inert processing aid and 0 to 40 weight percent based on the total weight of the coating layer of a plasticizer, wherein the coating layer is applied directly to the omeprazole containing tablet core without a separating layer between the omeprazole containing tablet core and the coating layer.

48. The method as recited in claim 47, wherein the core comprises 10 to 30 weight percent based upon the total weight of the core of omeprazole; 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent; 0.25 to 7.5 weight percent based upon the total weight of the core of the binder; 20 to 40 weight percent based upon the total weight of the core of the filler and 30-55 weight percent based upon the total weight of the core of the alkaline agent.

49. The method as recited in claim 47 or 48, wherein the coating layer comprises 20 to 40 weight percent based upon the total weight of the coating layer of the inert processing aid and 10 to 20 weight percent based upon the total weight of the coating layer of the plasticizer. 30 INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 SEP 2003 RECEIVED

50. The method as recited in claim 47, wherein the core comprises 10 to 30 weight percent based upon the total weight of the core of omeprazole; 0.20 to 2.0 weight percent based upon the total weight of the core of the surface active agent; 0.25 to 7.5 weight percent based upon the total weight of the core of the binder; 20 to 40 weight percent based upon the total weight of the core of the filler and 30-55 weight percent based upon the total weight of the core of the alkaline agent.

51. The method as recited in claim 47 or 50, wherein the coating layer comprises an enteric coating agent of 20 to 40 weight percent based upon the total weight of the coating layer of the inert processing aid and 10 to 20 weight percent based upon the total weight of the coating layer of die plasticizer.

52. The method as recited in any one of claims 47 to 51, wherein die coating layer is applied from an organic solvent system.

53. The method as recited in any one of claims 17 to 19,36 to 38 and 47 to 52, substantially as herein described.

54 A stable pharmaceutical dosage formulation whenever prepared by a method as recited in any one of claims 17 to 19,36 to 38 and 47 to 53.

55. A stable pharmaceutical dosage formulation as recited in any one of claims 1 to 16,20 to 35 and 39 to 46, substantially as herein described. 31 INTELLECTUAL PROPERTY OFFICE OF N.Z. H SEP 2m </div>