STABLE BENZIMIDAZOLE FORMULATION

Abstract

An omeprazole delayed release tablet comprises a core and an enteric coating over the core. The core consists essentially of omeprazole, lactose, sodium starch glycolate, sodium stearate, and sodium stearyl fumarate. The enteric coating over the core consists essentially of hydroxypropyl methyl cellulose (HPMC) acetate succinate, triethyl citrate, sodium lauryl sulfate, talc, monoethanol amine, and less than 500 ppm of residual ammonium hydroxide.

Claims

1. An omeprazole delayed release tablet comprising: a core consisting essentially of omeprazole, lactose, sodium starch glycolate, sodium stearate, and sodium stearyl fumarate; and an enteric coating over the core consisting essentially of hydroxypropyl methyl cellulose (HPMC) acetate succinate, triethyl citrate, sodium lauryl sulfate, talc, monoethanol amine, and less than 500 ppm of residual ammonium hydroxide.

2. An omeprazole delayed release tablet comprising: a core and an enteric coating over the core, wherein the core consists essentially of about: 20 mg omeprazole, 203 mg lactose monohydrate, 10 mg sodium starch glycolate, 10 mg sodium stearate, and 7 mg sodium stearyl fumarate, wherein the enteric coating consists essentially of about: 32 mg hydroxypropyl methyl cellulose (HPMC) acetate succinate, 4.5 mg triethyl citrate, 0.5 mg sodium lauryl sulfate, 8.1 mg talc, 1 mg monoethanol amine, and less than 500 ppm of residual ammonium hydroxide.

3. An omeprazole delayed release tablet comprising: a core and an enteric coating over the core, wherein the core consists essentially of about: 8 weight % omeprazole, 81.2 weight % lactose monohydrate, 4 weight % sodium starch glycolate, 4 weight % sodium stearate, and 2.8 weight % sodium stearyl fumarate by weight percent of the core, wherein the enteric coating consists essentially of about: 56.1 weight % hydroxypropyl methyl cellulose (HPMC) acetate succinate, 7.9 weight % triethyl citrate, 0.9 weight % sodium lauryl sulfate, 14.3 weight % talc, 1.8 weight % monoethanol amine, and less than 500 ppm of residual ammonium hydroxide by weight percent of the enteric coating.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0042] In the drawings:

[0043] FIGS. 1-6 relate to the suitability of test method for determination of residual monoethanolamine.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The formulation of the present invention contains a benzimidazole derivative, such as Omeprazole, and is able to maintain the stability of this active ingredient without a separating layer between the active compound and an enteric coating layer. Instead, the enteric coating layer is prepared as an aqueous dispersion or in organic solvent and neutralized with an alkalinizing agent, before being applied as a solution directly to the benzimidazole derivative substrate.

[0045] Preferably, the aqueous dispersion has a pH in the range of at least 6.5, and more preferably in the range of from about 7 to about 10.

[0046] After being applied to the substrate, the aqueous dispersion dries to form a coating layer, preferably having a pH in the range of from about 4.5 to about 6.5, and more preferably from about 5 to about 6, as measured in 30 ml of distilled water at 22° C.

[0047] The resulting formulation comprises less than about 500 parts per million of residual alkalizing agent relative to the total weight of the composition.

[0048] Preferably, the composition comprises less than about 1000 parts per million of residual organic solvent and more preferably less than about 500 ppm.

[0049] The resultant formulation maintains the stability of the benzimidazole derivative during storage and at the same time protects the product during passage through the acidic environment of the stomach. The problem of interaction between the enteric coat and the alkaline core is thus completely eliminated as the enteric coat at this stage does not release the free protons that are responsible for its acidic properties. At the same time, the formulation has low levels of residual alkalinizing agent and residual organic solvent in the final product.

[0050] The preparation of the benzimidazole-containing compositions of the present invention is described first with reference to the following general description and then with reference to the following non-limiting examples of the preparation and application of the compositions of the present invention.

[0051] The formulation of the present invention includes a substrate which features the benzimidazole derivative. A coating suspension, which has a pH value of at least 6.5 and more preferably of from about 7 to about 10, is prepared with the enteric coating material. Preferably, a pH value in the desired range is obtained by adding an alkalinizing agent to an enteric coating material

[0052] More preferably, the alkalinizing agent is selected from the group consisting of basic sodium, potassium, methanolamine or ammonium hydroxide, amino alcohols and alkylene diamines, arginine, and lysine. This enteric coating solution is then layered directly over the substrate to form the composition of the present invention.

[0053] The term “substrate” refers to substantially any structure which features the benzimidazole derivative, such as Omeprazole. For example, this structure could be an active core containing the benzimidazole derivative. The active core may comprise, for example, a pellet, a bead, or a tablet. This active core could be prepared in a number of different ways which are known in the art. For example, the active core could be formed by compressing the benzimidazole derivative with an alkaline substance. As another example, the active core could be prepared by mixing the benzimidazole derivative with an alkaline substance, spheronizing the mixture and then forming cores through pelletisation. As yet another example, the active core is optionally and preferably prepared by embedding the active ingredient in a poloxamer and compressing the embedded material into tablets. The active core is also optionally formed by granulating the active ingredient with an alkaline substance and compressing the granulation into tablets.

[0054] Alternatively and optionally, the structure could include a neutral core, such as a sugar bead which does not contain the benzimidazole derivative, over which the benzimidazole derivative is coated. The coating includes Omeprazole or other benzimidazole derivative with a suitable adhesive polymer. The pellet may optionally be prepared by spheronization and pelletization of the benzimidazole derivative and a suitable binding agent.

[0055] The benzimidazole derivative of the present invention may comprise, for example, Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, or Rabeprazole, or pharmaceutically acceptable salts thereof. Preferably, the benzimidazole derivative is omeprazole.

[0056] Optionally, the substrate may further comprise a filler. Examples of suitable fillers include microcrystalline cellulose, sodium carboxymethycellulose, ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or a mixture thereof.

[0057] Further optionally, the substrate may comprise a disintegrant, such as, for example, low-substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, and low substituted hydroxypropyl cellulose magnesium aluminum silicate, or a mixture thereof.

[0058] Also optionally, the substrate may further comprise a lubricant, such as, for example, sodium stearyl fumarate, polyethylene glycol, silica colloidal anhydrous and magnesium stearate, or a mixture thereof.

[0059] The substrate may optionally further comprise an alkalinizing agent, such as, for example, sodium stearate, meglumine, disodium phosphate, magnesium carbonate, and ammonia, or a mixture thereof.

[0060] Substantially any type of neutralized suitable enteric coating material could be used in order to coat the benzimidazole substrate, including but not limited to, cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate; cellulose acetate trimellitate; poly((methacrylic acid, methyl methacrylate)1:1) (Eudragit L100™), poly((methacrylic acid, ethyl acrylate)1:1) (Eudragit L30D-55) or Eudragit L100-55™, (poly(methacrylic acid, methyl methacrylate)1:2) Eudragit™, hypromellose acetate succinate (HPMCAS), sodium alginate, and alginic acid or mixtures thereof.

[0061] As used herein, the term “neutralized enteric coating material” refers to enteric coating material which has been at least partially neutralized by reaction with an alkalizing agent. Suitable alkalizing agents for neutralizing the enteric polymer include, but are not limited, to amino alcohols such as methanolamine, monoethanol amine, propanolamine and alkylene diamines such as methylene diamine, ethylene diamine, propylene diamine, and ammonia solution such as ammonium hydroxide, basic ammonium salts, arginine, lysine and any other pharmaceutically acceptable amino compound bases, or a combination thereof.

[0062] Preferably, the enteric coating material is at least about 60% neutralized, more preferably the enteric coating material is at least about 80% neutralized, and most preferably the enteric coating material is at least about 95% neutralized.

[0063] The enteric coating is optionally prepared in an organic solvent, such as, for example, acetone, ethanol or isopropanol, or a combination thereof; such as a mixture of ethanol and water (30/70 or 40/60); or a mixture of isopropyl alcohol and ethanol.

[0064] The enteric coating optionally contains at least one of a plasticizer (such, as for example, a citric acid ester or a phthalic acid ester), a surfactant (such as, for example, polysorbate 80 or sodium lauryl sulfate), a glidant (such as, for example, talc or titanium dioxide), a coloring agent and a polishing agent.

[0065] The method for applying the enteric coating material to the substrate can vary. Substantially any coating method can be used, such as pan coating or fluidized bed coating, with the solution of the enteric coat chosen.

[0066] A preferred embodiment of the formulation of the present invention is presented in Example 1 below. Residual akalinizing agent in the coating was analyzed as described in Examples 2 and 3, respectively.

[0067] The following specific examples illustrate various aspects of the compositions of the present invention, and are not intended to be limiting in any way. Specific reference is made to Omeprazole for the purposes of description only and without intending to be limiting.

EXAMPLES

Example 1: Delayed Release Tablets, 20 mg OTC Formulation

[0068]

TABLE-US-00001 Pharmaceutical Amount Percent/ Ingredients function mg/tablet tablet Active constituent Omeprazole USP Active 20.00 6.51 Core Lactose monohydrate NF Filler 203.00 66.12 Sodium starch glycolate NF disintegrant 10.00 3.25 Sodium stearate NF alkalinizing agent 10.00 3.25 Sodium stearyl fumarate NF lubricant 7.00 2.28 Coating Hypromellose acetate enteric coating 32.00 10.42 succinate NF polymer Triethyl citrate NF plasticizer 4.50 1.47 Sodium lauryl sulfate NF wetting agent 0.50 0.16 Talc USP Glidant 8.14 2.65 Strong ammonium solution NF alkalinizing agent NA* — Monoethanolamine NF alkalinizing agent 1.00 0.33 Sepisperse AP 3527 coloring agent 10.80 3.52 Carnauba wax NF polishing agent 0.06 0.02 Purified water Solvent NA* — Total weight 307.00 Ca 100 *strong ammonium solution is used as a volatile alkalizing agent which is evaporated during the coating process.

[0069] Preparation of the substrate: Omeprazole was thoroughly mixed with lactose, sodium starch glycolate, sodium stearate and sodium stearyl fumarate. The mixture was then compressed into tablets weighing 250 mg each. The tablets were then transferred into a conventional coating pan and coated with the enteric coating, prepared as described below.

Preparation of Enteric Coating

[0070] Coating A: triethyl citrate was dissolved in water, sodium lauryl sulfate was then added to this solution, HPMCAS and talc were dispersed in this solution, such that the concentration of HPMCAS was about 7% weight per volume. Monoethanolamine was added to this dispersion. Ammonia in a 25% solution was added to adjust the pH value in a range of from about 7 to about pH 9. The pigment was then added to the enteric coating dispersion.

[0071] Coating B: Triethyl citrate was dissolved in a mixture of isopropyl alcohol and alcohol, sodium lauryl sulfate was then added to this solution, HPMCAS and talc were dispersed in this solution, such that the concentration of HPMCAS was about 6% weight per volume. Ammonia in a 25% solution was added to adjust the pH value in a range of from about 7 to about pH 9. The pigment was then added to the enteric coating dispersion. The tablet cores were then transferred into a conventional coating pan and coated with the enteric coating layer.

[0072] Coating C: Triethyl citrate was dissolved in water to form an aqueous solution; sodium lauryl sulfate was then added to this aqueous solution. HPMCAS, colloidal silicon dioxide and talc were dispersed in this solution, such that the concentration of HPMCAS was about 7% weight per volume. Ammonia in a 25% solution was added to adjust the pH value of the coating dispersion in a range of from about 7 to about pH 9.

[0073] Coating D: Triethyl citrate was dissolved in water to form an aqueous solution; sodium lauryl sulfate was then added to this aqueous solution. HPMCAS, talc, and monoethanolamine were dispersed in this solution. Ammonia in a 25% solution was added to adjust the pH value of the coating dispersion in a range of from about 7 to about pH 9.

Example 2: Omeprazole Delayed Release Tablets 20 mg—Determination of Ammonia

[0074] Samples were stored at room temperature prior to analysis.

[0075] The samples were analyzed according to Standard Methods for Examination of Water and Waste Water, Ed. 19, 1995, Method 4500-NH.sub.3 F (phenate method). The samples were prepared in triplicate by adding 30 ml HPLC grade water to one tablet, shaking overnight on an inverting shaker, followed by centrifugation at 4000 rpm for 15 minutes. This solution was filtered through 2 layers of glass fiber cartridge (GFC) filters and analyzed according to the above mentioned method. Quantitation was performed using a calibration curve prepared from solutions of NH.sub.4Cl in water in the concentration range of 0.05 μg/mL to 1.0 μg/mL NH.sub.3. The uncoated tablets served as a control sample for the analysis of the coated tablets.

[0076] Results are presented in Table 1.

TABLE-US-00002 TABLE 1 Batch No. Lab (based on no. Example 1) NH.sub.3 mg/tablet 3789 BO415 (coated) 0.011; 0.07; 0.011 Mean 0.010 3980 BO425 (coated) 0.09; 0.010; 0.010 Mean 0.010 3981 BO515 (coated) 0.010; 0.012; 0.011 Mean 0.011

Example 3: Omeprazole Delayed Release Tablet 20 mg—Determination of Residual Monoethanolamine

[0077] Samples were stored at room temperature prior to analysis.

Materials

[0078]

TABLE-US-00003 Dansyl chloride Across 1158500 Sodium hydrogen carbonate Merck 106329 Acetone J.T. Baker 9002 Acetonitrile J.T. Baker 9017 Sodium hydroxide J.T. Baker 3722 Water HPLC grade Milli-Q in-house Monoethanolamine Analyst sample 5015 Hydrochloric acid Riedel de Haen 30721

Equipment

[0079]

TABLE-US-00004 Test tubes PP 50 ml Laboratory glassware Class A GFC filter paper 12.5 cm Whatman 1822-125 Shaker Heidolf Centrifuge capable of maintaining 4000 rpm
HPLC instrument and conditions

TABLE-US-00005 Apparatus: Agilent 1100 with variable wavelength detector and autosampler and Chemstation Rev A 10.01 software Column: Symmetry C 18 4.6 × 150 mm, 3.5μ Injection volume: 10 μL Flow rate: 1.0 mL/min Detection: 254 nm Column temperature: ambient Run time:   10 minutes Retention time of MEA derivative: −5.3 minutes

Solutions

[0080] Hydrochloric acid 4 N was prepared by mixing 83.3 mL of concentrated hydrochloric acid (specific gravity 1.19, 37%) with 200 mL water in a 250 mL volumetric flask. The volume was made up with water.

[0081] Dilute hydrochloric acid was prepared by adding 1.2 mL hydrochloric acid (specific gravity 1.19, 37%) to a 1 L volumetric flask containing about 500 mL water, diluting to volume with water and mixing well.

[0082] Mobile phase was prepared by mixing 600 mL of water with 400 mL acetonitrile, mixing well and sonicating to degas.

[0083] 0.2% dansyl chloride was prepared by weighing accurately about 100 mg dansyl chloride in a 50 mL volumetric flask and diluting with acetone.

[0084] 0.1 M sodium hydrogen carbonate was prepared by weighing about 840 mg of sodium hydrogen carbonate into a 100 mL volumetric flask, diluting with water to give a pH of 9.0.

[0085] Monoethanolamine standard stock solution (1000 μg/mL) was prepared in duplicate by weighing accurately about 100 mg of monoethanolamine into a 100 ml volumetric flask, dissolving and diluting with water.

[0086] Monoethanolamine intermediate standard stock solution (100 μg/mL) was prepared by adding 5.0 mL standard stock solution to a 50 mL volumetric flask with dilute hydrochloric acid.

[0087] Monoethanolamine working standard solution (10 μg/mL) was prepared from intermediate standard stock solution by adding 5.0 mL to a 50 mL volumetric flask with dilute hydrochloric acid.

Sample Preparation

[0088] Samples were prepared in duplicate. One tablet was placed per 50 mL conical test tube and 50 mL of water added. Test tubes were placed on an inverting shaker at speed 6 for 2-3 hours, until disintegration of the tablets, then acidified by adding 200 μL of 4 N HCl. Test tubes were centrifuged for 15 minutes at 4000 rpm and filtered through Whatman GFC.

Derivatization Reaction

[0089] The procedure was performed on water as control and on all standards and samples, directly in autosampler vials.

[0090] 100 μL of water, standard or sample solution was mixed with 200 μL 0.2% dansyl chloride solution. 400 μL 0.1 M sodium hydrogen carbonate and 400 μL acetone were added. The vials were closed, mixed and heated for 20 minutes in a water bath at 60° C. The contents of the vials were cooled to room temperature and injected into the HPLC system.

[0091] Results are presented in Table 2.

TABLE-US-00006 TABLE 2 Lab Sample no. name Monoethanolamine mg/tablet 3789 BO415 0.77 (% RSD = 6.0) 3980 BO425 0.730; 0.681 Mean 0.71 3981 BO515 0.822; 0.755 Mean 0.79 5273 BO615 0.908; 0.780 Mean 0.84

Example 4: Suitability of Test Method for Determination of Residual Monoethanolamine

[0092] In order to evaluate the suitability of the method as described above, the method was evaluated for specificity, linearity, precision (system and method) and recovery.

[0093] In order to demonstrate the specificity, the following samples and solutions were analyzed: a sample blank (water); a standard containing 10 μg/mL monoethanolamine that had undergone the derivatization procedure; omeprazole tablets, prepared without the use of monoethanolamine, prepared according to the test method; and water.

Specificity

[0094] As shown in FIGS. 1 to 6, no interfering peaks at the retention time of monoethanolamine were recorded in the chromatograms of the blank sample, water, or the tablet without monoethanolamine.

Linearity

[0095] The linearity of the method was demonstrated in the range of from 1 to 50 μg/mL, monoethanolamine, corresponding to 0.05 to 2.5 mg/tablet. Results are presented in Table 3.

TABLE-US-00007 TABLE 3 Concentration Peak area % (μg/mL) mAU*s difference 0/96 7.4978E±00 43.7 1.92 1.5817E±01 10.9 4.81 4.4112E±01 −2.5 9.62 9.2365E±01 −6.0 19.24 2.0443±02 −0.4 48.10 5.2640±02 0.3 correlation 0.99982 square correlation 0.99963 slope 1.1074E+01 intercept −7.8104E+00 −7.6

Precision

[0096] The precision of the method was evaluated by replicate injections of a standard containing a nominal 10 μg/mL monoethanolamine derivatized according to the test method (system precision) and by preparing a sample of omeprazole tablets in 6 independent replicates according to the test method (method precision).

[0097] The system precision results as presented in Table 4 show that good precision was obtained for the peak areas as well as for the retention times.

TABLE-US-00008 TABLE 4 Retention time Peak areas Replicate (mm) mAU*s 1 5.291 9.0628E+01 2 5.286 8.9055E+01 3 5.283 9.1252E+01 4 5.283 8.8879E+01 5 5.762 8.9296E+01 6 5.225 9.0930E+01 Mean 5.272 9.0007E+01 % RSD 0.5 1.2

[0098] Method precision was performed using 6 preparations of omeprazole tablets (analyst sample 3789). Results were calculated against a standard containing 9.62 μg/mL monothenaolamine with an average peak area of 9.5519E+01 mAU*s, using the following formula:

[00001]$m\text{g/t}\mathrm{ablet}=\frac{\mathrm{area}\mathrm{smp}\times \mathrm{Cst}\times 50}{\mathrm{area}\mathrm{st}\times 1000}$ [0099] area smp=monoethanolamine peak area in sample chromatogram [0100] area st=average peak area of standard “10 μg/mL” [0101] cst=standard concentration in μg/mL [0102] 50=sample extraction volume (mL) [0103] 1000=conversion factor of μg to mg

[0104] A representative chromatogram is presented in FIG. 5.

[0105] Method precision data and results are presented in Table 5.

TABLE-US-00009 TABLE 5 Concentration of MEA in Analyst MEA sample MEA in no. and Sample peak area solution tablets replicate name mAU*s (μg/mL) mg/tablet 3789-1 coated 1.4518E+0.2 14.6 0.731 3789-2 BO415 1.6711E+0.2 16.8 0.842 3789-3 1.4151E+0.2 14.3 0.713 3789-4 1.5385E+0.2 15.5 0.775 3789-5 1.5710E+0.2 15.8 0.791 3789-6 1.5804E+0.2 15.9 0.796 MEAN 0.774 % RSD 6.0

Recovery

[0106] The recovery of the method was demonstrated by spiking control (no monoethanolamine) and monoethanolamine-containing omeprazole tablets with three levels of monoethanolamine.

[0107] Omeprazole tablets containing monoethanolamine (sample 3789, batch B0415) were spiked at the 0.1% w/w level in triplicate. Omeprazole control tablets (no MEA) were spiked at three levels with 0.15, 0.3 and 0.9 mg/tablet, corresponding to 0.05, 0.1 and 0.3% w/w. The test was performed by transferring the tablets to 50 mL test tubes, adding suitable volumes of a solution of 1000 μg/mL MEA, followed by 50 ml of water and preparation according to the method described above.

[0108] Results as presented in Tables 6 and 7 show good recovery results, within generally accepted limits for residue analysis. Recovery results were calculated against a standard containing 9.62 μg/mL MEA with an average peak area of 9.5519E+01 mAU*s. The recovery results in the tablets containing MEA were calculated as follows:

[00002]$\%\mathrm{recovery}=\frac{m\text{g/t}\mathrm{ablet}\mathrm{found}\times 100}{\mathrm{average}m\text{g/t}\mathrm{ablet}\left(\mathrm{unspiked}\right)+m\text{g/t}\mathrm{ablet}\mathrm{added}}$

[0109] A representative chromatogram of omeprazole tablets (analyst sample 3789 Batch B0415) spiked with MEA is presented in FIG. 6.

TABLE-US-00010 TABLE 6 Concentration of MEA in MEA Spiking sample MEA Analyst No. Sample peak area level in solution in % and replicate name (mAu*s) mg/tablet (μg/mL) tablets recovery 5274-1 omeprazole 0.0000E+00 0.0 0.000 5274-2 20 mg 0.0000E+00 0.0 0.000 5274-3 uncoated 0.0000E+00 0.0 0.000 100605 Mean 0.000 5274-1 omeprazole 2.4417E+0.1 0.144 2.46 0.123 85.5 5274-2 20 mg 2.4339E+01 2.45 0.123 85.2 5274-3 uncoated 2.4966E+01 2.51 0.126 87.4 100605 Mean 0.124 86.0 % RSD 1.4 1.4 5274-1 + 0.1% omeprazole 4.9693E+01 0.289 5.00 0.252 87.2 5274-2 + 0.1% 20 mg 5.1115E+01 5.15 0.259 89.7 5274-3 + 0.1% uncoated 5.1356E+01 5.17 0.260 90.1 100605 Mean 0.257 89.0 % RSD 1.8 1.8 5274-1 + 0.3% Omeprazole 1.845E+02 0.962 18.59 0.948 98.5 5274-2 + 0.3% 20 mg 1.8919E+02 19.05 0.972 101.0 5274-3 + 0.3% uncoated 1.8982E+02 19.12 0.975 101.4 100605 Mean 0.965 100.3 % RSD 1.5 1.5

TABLE-US-00011 TABLE 7 Concentration of MEA in MEA Spiking sample MEA in Analyst No. Sample peak area level solution tablet % and replicate name mAU*s mg/tablet μg/mL mg/tablet recovery 3789-1 coated 1.4518E+02 14.6 0.731 3789-2 BO415 1.6711E+02 16.8 0.842 3789-3 1.4151E+02 14.3 0.713 Mean 0.762 % RSD 9.7 3789-1 + 0.1% coated 2.1507E+0.2 0.289 21.721.773.8 1.083 107.6 3789-2 + 0.1% B0415 2.1576E+0.2 1.086 107.9 3789-3 + 0.1% 2.3641E+0.2 1.1190 118.2 Mean 1.120 111.2 % RSD 5.5 5.5

Standard and Sample Solution Stability

[0110] During the method development, stock solution stability was demonstrated for 48 hours at room temperature. In addition, it was found that the MEA derivative is stable in autosampler vials at room temperature for at least 48 hours, because the response of the MEA derivative did not change upon reinjection.

Example 5: Omeprazole Delayed Release Tablets 20 mg—Determination of Final pH of Enteric Coating

[0111] Enteric coated omeprazole tablets were prepared according to the composition of Example 1 (Batch #B0425). The enteric coating was prepared in aqueous dispersion, and the pH value of the coating dispersion was adjusted to the range from about 7 to about pH 9 by a combination of monoethanolamine and concentrated ammonia solution. The ammonia solution evaporated during the coating process.

[0112] The pH of the coating layer following evaporation of the ammonia solution was measured in the following test solutions: [0113] 1. Purified water (pH 5.9 at 22° C.), obtained from MILI Q system; and [0114] 2. 1% buffer solution of Intestinal Fluid NF (pH 6.9 at 22° C.) using potassium dihydrogenphosphate (lot #B36148 purchased from Baker), and sodium hydroxide (lot #B452998549 from Merck), with no pancreatin added.

[0115] For each test solution, three coated tablets were split and the core was removed by washing using purified water. The resulting film coats were then transferred into a vial containing 30 ml test solution, and stirred for 2 hours with a magnetic stirrer at 1000 rpm. The pH of the medium was determined.

[0116] It was found that in purified water, the coating films partially disintegrated and partially dissolved. The pH value of the medium was found to be 5.4.

[0117] In intestinal fluid, the coating films were fully disintegrated and fully dissolved (except for talc and the coloring powder of Sepisperse). The pH value of the medium was found to be 5.3. Hence, it is shown that the polymer retains its acidic properties and thus provides an acidic reaction.

[0118] Since the pH of the coating solution was initially basic, it can be concluded that the change in pH occurs due to evaporation of ammonia solution, causing the polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS) to revert to its acid form, having enteric properties. The acidic form of HPMCAS can be soluble in water only through ionization of all free acidic groups in an aqueous medium with pH values above 5.5. This is in fact the reason that the polymer is characterized as an enteric polymer. While the native pH value of pure HPMCAS aqueous dispersion is about 4.5, the pH value of about 5.3 found using the composition of the present invention may be due to the presence of residual monoethanolamine, which is used a second alkalizing agent for neutralization of HPMCAS.

[0119] The present study shows that when the entering coating polymer is placed in purified water as test medium, a partial dissolution of the polymer first takes place, which continues for as long as the pH of the medium remains basic. Once the pH of the medium reaches an acidic value of about 5.4, dissolution of the polymer stops and the polymer disintegrates. In diluted neutral buffer solution-1% simulated intestinal fluid, on the other hand, an acidic pH was achieved only after full polymer dissolution.

[0120] The temporarily neutralized HPMCAS coating prepared using a high concentration of ammonia during the coating process provides an enteric film coat surrounding the omeprazole-containing cores which can withstand pH values of up to about 5. This can provide the active material with an appropriate protection while passim through the stomach even if the pH values of gastric fluid are elevated.

[0121] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0122] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.