CLIAMS:1. A process for the preparation of a pharmaceutical composition comprising NSAID, PPI or salts thereof, which process comprises steps of:
(a) preparing plurality of enteric coated components comprising NSAID or salts thereof coated with at least one enteric coating layer comprising one or more enteric polymers;
(b) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(c) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(d) formulating all the components in to a pharmaceutical composition.

2. The process of claim 1, wherein plurality of enteric coated components comprising NSAID or salts thereof are prepared by a process, which process comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture;
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof; and
(c) coating the immediate release components of NSAID or salts thereof with one or more enteric coating layer comprising one or more enteric polymers.

3. The process of claim 1, wherein plurality of immediate release components comprising NSAID or salts thereof are prepared by a process, which process comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof.

4. The process of claim 1, wherein plurality of immediate release components comprising PPI or salts thereof are prepared by a process, which process comprises steps of-
(a) belnding PPI or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of PPI or salts thereof.

5. The process of claim 1, wherein the release of the NSAID from its immediate release component begins before the release of PPI from the immediate release components PPI layer starts.

3. The process of claim 1, wherein the release of the NSAID and PPI from their respective immediate release components begins simultaneously.

4. The process of claim 1, wherein the components are in the form of pellets, granules, mini-tablets or their combinations.

5. The process of claim 1, wherein NSAID in the enteric coated components is not released until the pH of the surrounding medium is higher than 3.5.

7. The process of claim 1, wherein PPI and NSAID in immediate release components are released in the medium having pH 3.5 or less.

8. The process of claim 1, wherein the ratio of the amount of NSAID in the enteric coated components and to the amount of NSAID in the immediate release components ranges from about 1:0.4 to 1:0.01.
,TagSPECI:The present invention relates to a process of preparing pharmaceutical compositions of NSAID and PPI or salts thereof. In particular, the invention relates to a process of preparing pharmaceutical compositions of plurality of components of NSAID and PPI or salts thereof. The invention also includes method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID -associated gastric ulcers.

Non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAID or NSAIDs) are widely accepted as effective agents for controlling pain, however their administration can lead to the development of gastro-duodenal lesions, e.g., ulcers and erosions, in susceptible individuals. It appears that a major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients. Other major factors contributing to NSAID-associated gastropathy include a local toxic effect of NSAIDs and inhibition of protective prostaglandins, which may also make some patients more susceptible to the ulcerogenic effects of other noxious stimuli.

In general, more potent and longer lasting proton pump inhibitors (hereinafter referred as PPI or PPIs), are thought to be more protective during chronic administration of NSAIDs than shorter acting agents, e.g., histamine H2 receptor antagonists (H-2 blockers). The most likely explanation for this is that gastric pH fluctuates widely throughout the dosing interval with short acting acid inhibitors leaving the mucosa vulnerable for significant periods of time. In particular, the pH is at its lowest point, and hence the mucosa is most vulnerable, at the end of the dosing interval (least amount of acid inhibition) and for some time after the subsequent dose of PPI. In general, it appears that when a short acting acid inhibitors and an NSAID are administered simultaneously, NSAID-related mucosal damage occurs before the pH of the gastrointestinal tract can be raised and after the acid inhibiting effect of the short acting acid inhibitors dissipates.

Although longer lasting agents, such as proton pump inhibitors (PPIs), usually maintain a consistently higher gastroduodenal pH throughout the day, after several days dosing, their antisecretory effect may be delayed for several hours and may not take full effect for several days. Their effect may be diminished toward the end of the usual dosing interval. Intragastric pH rises particularly slowly with the first dose in a course of treatment since this class of drugs is enteric coated to avoid destruction by stomach acid. As a result, absorption is delayed for several hours. Even then, some patients fail to respond consistently to drugs of this type and suffer from "acid breakthrough" which again leaves them vulnerable to NSAID-associated gastroduodenaldamage.

Despite a significant reduction in gastro-duodenal lesions with the concomitant administration of a proton pump inhibitor during six months of NSAID therapy, up to 16% of patients still develop ulcers, indicating that there remains substantial room for improvement. Thus, the addition of a pH sensitive enteric coating to an NSAID could provide additional protection against gastroduodenal damage not provided by the H2 blocker or PPI alone.

Recognizing the potential benefits of PPIs for the prevention of NSAID-induced gastroduodenal damage, there are strategies disclosed in the art for combining the two types of active agents for therapeutic purposes, other than by concomitant administration.

U.S. Patent No. 6,365,184 discloses a means of delivery that would expose the gastrointestinal tract to complete dose of NSAIDs prior to onset of PPI activity.

U.S. Patent No. 6,926,907 and 8,206,741 discloses pharmaceutical formulations that provide coordinated release of an acid inhibitor and an NSAID. Particularly, NSAID is released when the pH of the surrounding medium is 3.3 or higher.

U.S. Patent Application Publication No. 2010/0305163 discloses a fixed dose composition of a NSAID and a proton pump inhibitor.

However, the prior art suggesting only overcoming NSAID induced gastric or duodenal erosions and ulcers, while it may not effectively control the pain. There still exists a need for alternative pharmaceutical formulation comprising NSAID and proton pump inhibitor that provides at least a portion of NSAID available for therapeutic effect and along side release the PPI that can reduce the intra-gastric acid levels to non-toxic level prior to the release of remaining substantial amount of NSAID for continuous and effective pain management.

The inventors of the present invention have surprisingly found that said objectives can be addressed by devising a formulation of NSAID and PPI in the form of a plurality of components comprising NSAID and PPI or salts thereof, such that one type of the components exhibit immediate release of NSAID.

In one general aspect, there is provided a pharmaceutical composition comprising:
(a) plurality of enteric coated components comprising NSAID or salts thereof and one or more pharmaceutical excipients;
(b) plurality of immediate release components comprising NSAID or salts thereof and one or more pharmaceutical excipients; and
(c) plurality of immediate release components comprising PPI or salts thereof and one or more pharmaceutical excipients,
wherein each type of component is distinct and physically separable from each other.

In another general aspect, the release of the NSAID from its immediate release component begins before the release of PPI from the immediate release components PPI layer starts.

In another general aspect, the release of the NSAID and PPI from their respective immediate release components begins simultaneously.

In another general aspect, there is provided a capsule comprising:
(a) plurality of enteric coated pellets comprising NSAID or salts thereof and one or more pharmaceutical excipients;
(b) plurality of immediate release pellets comprising NSAID or salts thereof and one or more pharmaceutical excipients; and
(c) plurality of immediate release pellets comprising PPI or salts thereof and one or more pharmaceutical excipients.

In another general aspect, NSAID in the enteric coated components of the pharmaceutical composition is not released until the pH of the surrounding medium is higher than 3.5.

In another general aspect, PPI and NSAID in immediate release components of the pharmaceutical composition are released in the medium having pH 3.5 or less.

In another general aspect, the ratio of the amount of NSAID in the enteric coated components and to the amount of NSAID in the immediate release components ranges from about 1:0.4 to 1:0.01.

In another general aspect, there is provided a process for preparation of a pharmaceutical composition comprising NSAID, PPI or salts thereof, which process comprises steps of:
(a) preparing plurality of enteric coated components comprising NSAID or salts thereof coated with at least one enteric coating layer comprising one or more enteric polymers;
(b) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(c) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(d) formulating all the components in to a pharmaceutical composition.

In another general aspect, the process for the preparation of plurality of enteric coated components comprising NSAID or salts thereof, which process comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture;
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof; and
(c) coating the immediate release components of NSAID or salts thereof with one or more enteric coating layer comprising one or more enteric polymers.

In another general aspect, the process for the preparation of plurality of immediate release components comprising NSAID or salts thereof, which process comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof.

In another general aspect, the process for the preparation of plurality of immediate release components comprising PPI or salts thereof, which process comprises steps of-
(a) belnding PPI or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of PPI or salts thereof.

In another general aspect, the enteric coating layers are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.

In another general aspect, the components of the pharmaceutical composition are prepared by coating the dispersions of NSAID, PPI or salts thereof in pharmaceutical excipients over inert cores (e.g. non-pareil sugar beads, microcrystalline cellulose beads).

In another general aspect, the pharmaceutical composition of NSAID, PPI or salts thereof retains at least 90% w/w of total potency of NSAID and PPI after storage at 40°C and 75% relative humidity for at least 3 months.

In another general aspect, there is provided a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID-associated gastric ulcers in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

The inventors of the present invention have surprisingly found that when the pharmaceutical composition of NSAID and PPI comprises at least a part of the NSAID exhibiting immediate release relative to the enteric coated part of the NSAID, the resulting composition may effectively control the pain as well as reduce the risk of gastrointestinal side effects of NSAID. The composition thus may improve the patient compliance.

The pharmaceutical composition of the present invention may exhibit excellent storage stability over the storage period.

In an embodiment, the pharmaceutical composition of the present invention comprises:
(a) plurality of enteric coated components comprising NSAID or salts thereof and one or more pharmaceutical excipients;
(b) plurality of immediate release components comprising NSAID or salts thereof and one or more pharmaceutical excipients; and
(c) plurality of immediate release components comprising PPI or salts thereof and one or more pharmaceutical excipients.
Each type of the component is distinct and physically separable from each other.

In a further embodiment, the release of the NSAID from its immediate release component begins before the release of PPI from the immediate release components PPI layer starts.

In a further embodiment, the release of the NSAID and PPI from their respective immediate release components begins simultaneously.

In another embodiment, the pharmaceutical composition of NSAID, PPI or salts thereof retains at least 90% w/w of the total potency of both NSAID and PPI after storage at 30°C and 60% relative humidity, at 40°C and 75% relative humidity, or at 25°C and 60% relative humidity for at least 3 months.

The term "NSAID" and “PPI” or “proton pump inhibitor” used throughout the specification refers to not only NSAID and PPI per se, but also various pharmaceutically acceptable salts, solvates, derivatives and hydrates thereof.

The term "component" used throughout the specification encompasses solid unit physical forms, which are distinct and physically separated from each other. The components may be in the form of granules, pellets, tablets and mini-tablets or mixtures thereof. The term “type of component” used throughout the specification means immediate release or delayed release components of NSAID and PPI.

NSAID suitable for use in the composition of the present invention may be selected from, but not limited to, aspirin, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, lornoxicam, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone and cycloxogenase-2 inhibitor.

PPI suitable for use in the composition of the present invention may be selected from, but not limited to, omeprazole, esomeprazole, lansoprazole, rabeprazole and Pantoprazole.

In an embodiment, the enteric coated components comprises NSAID or salt thereof in an amount ranging from about 5 to about 80% w/w of the composition.

In another embodiment, the ratio of the amount of NSAID in the enteric coated components and to the amount of NSAID in the immediate release components ranges from about 1:0.4 to 1:0.01.

In an embodiment, NSAID in the enteric coated components of the pharmaceutical composition is not released until the pH of the surrounding medium is higher than 3.5.

ENTERIC COATING

The enteric coatings work by presenting a surface that is not soluble in acidic aqueous medium while soluble in neutral or basic aqueous medium. Enteric coating agent is an excipient that allows releasing the active substance from the composition only under certain environmental condition and or by a certain release rate.

Enteric polymers are applied onto the NSAID components as solutions or dispersion in organic or aqueous solvents. The solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof. The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution.

Acid resistant or enteric polymers suitable for enteric coating layer may be selected from, but not limited to acrylic acid polymers, phthalate polymers, copolymers or mixtures thereof. An acrylic polymer such as polyacrylates or polymethacrylates is the preferred polymer for enteric coating layer applied over the cores.

Polyacrylates, the polymethacrylates and the copolymers of acrylic and methacrylic acid are commercially available under the name Eudragit® and are particularly suitable. Examples of Eudragit® products include Eudragit L30D, Eudragit® L30 and Eudragit® D-55 etc. Other suitable enteric polymers include, for example, cellulose derivates such as, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, etc.

Furthermore enteric coating polymers may be combined together in order to induce both time dependent and pH dependent control of the release of tamsulosin. The amount of enteric coating calculated on the uncoated component basis is more than 15%, preferably more than 18%, more preferably more than 20%.

The amount of acid resistant enteric polymer in the coating layer is more than 50% by weight of the coating, In an embodiment more than 70% by weight of coating. In a further embodiment more than 80% by weight relative to the total weight of the coating layer.

The amount of acid resistant polymer is preferably within the range of 20-85 mass %, more preferably 30 to 75%, and typically 50 to 75%, calculated on a dry basis of the coating layer.

The coating formulation for enteric coating contains at least one polymer and a coating solvent, which preferably is water, which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from, but not limited to pharmaceutically acceptable acid resistant acrylic polymers, water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred.

SEAL COATING:

The components of the pharmaceutical composition of the present invention may further comprise one or more seal coating layers. Preferably, the seal coating layers comprises one or more polymers.

In an embodiment, the enteric coated component of NSAID comprises cores comprising NSAID or salts thereof coated with one or more seal coating layer and our enteric coating layer, which further may be coated with another seal coating layer.

The coating formulation for seal coating layers contains at least one polymer and a coating solvent, which preferably is water, which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from, but not limited water-soluble polymer, water-insoluble polymer, or mixtures thereof. Particularly, water-soluble polymers are preferred.

Examples of polymers suitable for seal coating layers include, but not limited to cellulose base polymers such as hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose; methacrylic polymers. The coating layer may also optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; and an anti-adherent or glidant such as talc, fumed silica or magnesium stearate, opacifying agent such as titanium dioxide. The coating layer may also include iron oxide based colorants.

Examples of suitable coating solvents include, but not limited to water, ethanol, methanol, dichloro methane and isopropyl alcohol, with water being preferred.

PPI Component:

The immediate release PPI component of the composition of the invention comprises PPI or salts thereof, one or more pharmaceutical excipients and optionally, one or more polymers.

The amount of PPI, or salts thereof in the immediate release component is in the range from about 20 to about 80%, preferably from about 40 to about 80% w/w, based on the weight of the component.

The amount of polymer in the PPI component may range from about 1 to about 50%, preferably from about 5 to about 30% w/w of the component.

The immediate release PPI component may be present in an amount within the range from about 10 to about 40%, preferably from about 15 to about 25% w/w of the composition.

In an embodiment, PPI in the immediate release components of the composition is released in the medium having pH 3.5 or less.

NSAID IR Component

The plurality of immediate release NSAID components of the present invention comprises one or more pharmaceutical excipients.

The amount of NSAID, or salts thereof in the immediate release components is in the range from about 50 to about 99%, preferably from about 70 to about 90% w/w, based on the weight of the component.

In an embodiment, NSAID is present in the immediate release components in amount insufficient to cause gastric ulcerogenic effect.

The amount of polymer in the NSAID immediate release components may range from about 1 to about 30%, preferably from about 10 to about 20% w/w of the component.

The NSAID immediate release components may be present in an amount within the range from about 1 to about 25%, preferably from about 5 to about 15% w/w of the composition.

In an embodiment, NSAID in the immediate release components of the pharmaceutical composition is released in the medium having pH 3.5 or less.

Outer Coating:

The composition of the invention further may include one or more outer layers where the coating suspension is prepared as in the case of the other coating compositions but without active ingredient and acid resistant polymer. The coating suspension is then can be coated onto the previously coated composition to form a protective coating layer thereon. Preferably, the composition of the outer layer is same that of the seal coating layers.

The composition of the present invention further may comprise an outermost protective layer comprising one or more polymers and one or more pharmaceutical excipients.

The outermost coating layer where present will preferably be similar in composition to the outer protective coating layer and will include colorant as desired, such as within the range from about 0.5 to about 5.0% w/w, based on the total weight of the outermost coating layer.

The outer and outermost protective coating layer if present, may each be present in an amount within the range from about 1 to about 10%, preferably from about 1 to about 5% w/w of the composition.

EXCIPINETS:

The enteric coated or immediate release components further may comprise one or more pharmaceutical excipients selected from, but not limited to one or more of bulking agents or diluents, binders, plasticizers, surfactants, lubricants, colorants, pH adjusting agents.

The bulking agents or fillers may be present in the core in an amount within the range from about 1 to about 95% w/w and preferably from about 10 to about 85% w/w of the composition. Examples of bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressible sugars, and other known bulking agents or fillers, and/or mixtures thereof, preferably microcrystalline cellulose.

The binder may be present in the core in an amount within the range from about 0 to about 20% w/w, preferably from about 1 to about 10% w/w of the composition. Examples of binders suitable for use herein include, but are not limited to, hydroxypropyl cellulose, corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP) (molecular weight ranging from about 5,000 to about 1,000,000, preferably about 40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia, ethyl cellulose, cellulose acetate, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agent and/or mixtures thereof, preferably hydroxypropyl cellulose.

The disintegrant may be present in the core in an amount within the range from about 0 to about 20% w/w, preferably from about 0.25 to about 10% w/w of the composition. Examples of disintegrants suitable for use herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or other known disintegrant, preferably croscarmellose sodium.

The lubricant may be present in the core in an amount within the range from about 0.1 to about 5% w/w, preferably from about 0.2 to about 2% w/w of the composition. Examples of tableting lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate or hydrogenated vegetable oils and fats, or mixtures thereof, preferably magnesium stearate.

In another embodiment, the bulking agents are microcrystalline cellulose, the disintegrant is pregelatinized starch, and the lubricant/glidant is colloidal silica.

In an embodiment, the components preferably contain at least one bulking agent or filler; optionally at least one binder; optionally at least one disintegrant; and preferably but optionally at least one lubricant. The bulking agent or filler may present in an amount within the range from about 1 to about 95% w/w, preferably from about 10 to about 85% w/w of the composition. The binder may present in an amount within the range from about 0 to about 20% w/w, preferably from about 1 to about 10% w/w of the composition. The disintegrant may present in an amount within the range from about 0 to about 20% w/w, and preferably from about 0.25 to about 10% w/w of the composition. The lubricant may present in an amount within the range from about 0 to about 5% w/w, preferably from about 0.2 to about 2% w/w of the composition.

PROCESS:

The composition of the present invention may be prepared by various processes known to the person skilled in the art, including various processes of preparing the components of NSAID and PPI in accordance with the invention.

The components in the composition of the invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The components may be manufactured by wet granulation, dry granulation, direct blending or any other pharmaceutically acceptable process.

In an embodiment, the process of preparing the components includes the steps of blending the one or more excipients such as bulking agent, optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate core formation.

In another embodiment, the process of preparing the components includes the steps of coating the dispersion comprising NSAID or PPI and one or more pharmaceutical excipients over inert beads of sugar or microcrystalline cellulose.

In a further embodiment, the process for preparing the pharmaceutical composition comprises steps of:
(a) preparing plurality of enteric coated components comprising NSAID or salts thereof coated with at least one enteric coating layer comprising one or more enteric polymers;
(b) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(c) preparing plurality of immediate release components comprising NSAID or salts thereof; and
(d) formulating all the components in to a pharmaceutical composition.

In an embodiment, the process for the preparation of plurality of enteric coated components comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture;
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof; and
(c) coating the immediate release components of NSAID or salts thereof with one or more enteric coating layer comprising one or more enteric polymers.

In an embodiment, the process for the preparation of plurality of immediate release components of NSAID comprises steps of-
(a) belnding NSAID or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of NSAID or salts thereof.

In a further embodiment, the process for the preparation of plurality of immediate release components of PPI comprises steps of-
(a) belnding PPI or salts thereof with one or more pharmaceutical excipients to form a mixture; and
(b) granulating the mixture with granulating solvent to form immediate release components of PPI or salts thereof.

In a further embodiment, the seal coating or enteric coating layers of the components are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.

In a further embodiment, the coating layers are subjected to sufficient drying after application over the core, or before application of the subsequent coating layer.

The composition of the present invention may be formulated in suitable a dosage forms including, but not limited to, a tablet, caplet, pellets, granules, capsule filled with tablets, mini-tablets, pellets, granules or mini-tablets or combinations thereof.

The components of the composition of the present invention may be formulated in the form of, tablets, pellets, granules, mini-tablets or combinations thereof.

The present invention further provides a method of treating upper gastrointestinal injury associated with NSAID and for the secondary prevention of cardiovascular disease in patients at risk for NSAID -associated gastric ulcers in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Aspirin-Omeprazole Capsule

I. Formula for Seal coated Pellets of Aspirin:

Ingredient Quantity (mg/Capsule)
Formulation I (40/325) Formulation II (40/81)
Aspirin Pellets (Immediate Release)
Sugar Spheres (NPS # 40-60) 100.000 29.923
Aspirin 325.000 81.000
Hypromellose 6 cps 15.000 3.740
Isopropyl Alcohol (60 %) q. s. q. s.
Dichloro Methane (40 %) q. s. q. s.
Core Tablet Weight 440.000 109.662
Seal Coating I (3.0 % w/w of core)
Hypromellose 6 Cps (Methocel E 6 Premium LV) 10.560 2.791
Talc 2.640 0.698
Isopropyl Alcohol IPA:DCM (60:40) to make 4% w/w solution
Dichloromethane
Seal coated pellets weight 453.725 112.950

Immediate Release Aspirin pellets:
Note: 12.3 % w/w of seal coated pellets were kept uncoated and filled in capsule as immediate release portion
For 40/325 mg strength: 55.844 mg of Seal coated pellets equivalent to 40 mg Aspirin were filled in capsule as immediate release portion
For 40/81 mg strength: 13.50 mg of Seal coated pellets equivalent to 9.969 mg of Aspirin were filled in capsule as immediate release portion.

II. Formula for Enteric coated Aspirin Pellets:

Ingredient Quantity (mg/Capsule)
Formulation I (40/325) Formulation II (40/81)
Seal coated Pellets of Aspirin 397.882 96.164
Enteric Coating 20.0 % w/w
Methacrylic acid coploymer Type C (Eudragit L 100 55) 63.661 15.387
Talc 9.549 2.308
Triethyl citrate 6.366 1.539
Isopropyl Alcohol To make 10 % w/w dispersion
Enteric coated Pellets weight 477.458 115.399

Note:
For 40/325 mg strength: 393.110 mg of enteric coated pellets equivalent to 285 mg Aspirin were filled in capsule as delayed release portion
For 40/81 mg strength: 115.399 mg of enteric coated pellets equivalent to 71.031 mg of Aspirin were filled in capsule as delayed release portion

III. Formula for Immediate Release Omeprazole pellets:

Drug coated pellets
Ingredient Quantity (mg/Capsule)
Formulation I (40/325) Formulation II (40/81)
Sugar Spheres (NPS #40-60) 20.000 20.000
Omeprazole 40.000 40.000
Hypromellose 6 cps 8.000 8.000
Sodium Lauryl Sulfate 1.000 1.000
Disodium Hydrogen Phosphate 1.600 1.600
Purified Water q. s. q. s.
Omeprazole pellet weight 70.600 70.600

Capsule Filling:
Ingredient Quantity (mg/Capsule)
Formulation I (40/325) Formulation II (40/81)
Empty Hard Gelatin Capsule Shell Size “0 EL” 1 No. --
Empty Hard Gelatin Capsule Shell Size “2” -- 1 No.
Immediate release Aspirin:Seal coated pellets of Aspirin 55.844 13.500
Delayed Release Aspirin:Enteric coated pellets of Aspirin 477.458 115.399
Immediate Release Omeprazole pellets 70.600 70.600
Capsule fill weight 603.902 199.499

Procedure:

Stage 1: Seal Coated Pellets of Aspirin
Aspirin Drug layered Pellets:
Aspirin and Hypromellose 6 cps was dissolved in IPA:DCM mixture. Sugar spheres #40-60 were coated with aspirin drug layering solution in Fluidized bed processor. After completion of drug layering pellets were dried for 15-20 minute at 40°C.
Seal coating:
Hypromellose 6 cps was dissolved in IPA:DCM mixture (60:40) and talc was added to this dispersion to form coating dispersion. Tablets were coated in perforated coating pan to obtain desired weight gain of 3.0 ± 0.5 %.
Stage 2: Enteric coating of Aspirin Pellets
Enteric coating solution was formed by dissolving Eudragit L 100 55 in Isopropyl Alcohol followed by dispersing Talc and Triethyl citrate under stirring. Seal coated pellets were enteric coated using coating dispersion to target weight gain of 20.0 ± 1.0 %.
Stage 3: Omeprazole immediate release pellets
Disodium hydrogen phosphate was dissolved in purified water followed by addition of sodium lauryl sulfate to dissolve. Hypromellose was dissolved in above mixture under stirring. Omeprazole was dispersed in above solution to form fine dispersion. Sugar spheres #40-60 were coated with dispersion to form drug layered pellets of omeprazole.
Stage 4: Capsule filling
Immediate release aspirin, enteric coated aspirin and immediate release omeprazole pellets were filled in respective size of empty hard gelatin capsule shell to target fill weight.